Re: Whats the best vaccine against COVID-19?

[Ross A. Finlayson]

On Monday, April 13, 2020 at 10:36:19 AM UTC-7, Mostowski Collapse wrote:
> Ross the Floss was thinking hard:
>
> https://en.wikipedia.org/wiki/Sialic_acid
>
> "All influenza A virus strains need sialic acid to connect with cells.
> There are different forms of sialic acids which have different affinity
> with influenza A virus variety. This diversity is an important fact
> that determines which species can be infected.[22]
> When a certain influenza A virus is recognized by a sialic acid receptor
> the cell tends to endocytose the virus so the cell becomes infected."
>
> Tagging the corona proteins for rejection at the sialic acid receptor,
> here is for the various and what of the incomplete sialylization of
> the glycoprotein leaves intact under the structure of the protein,
> what is its carrier in assembly, and for making also that the immune
> system gets a true antibody for the receptor, too (eg not some released
> "false negative").
>
> That though seems it would suppress the immune system generally.
>
> Reversing the effects of the structural proteins,
> is for a soothing environment for helping the body
> break the condition. (And inhibiting the antagonist
> of the immune response, while not inhibiting the
> wrong machinery, instead the right machinery, of
> not flagging the system with having phages as
> brushed with both inhibitors and activators,
> the wrong ones or "switched".)
>
> https://en.wikipedia.org/wiki/Orthomyxoviridae
>
> If the flu virus fits in the other parts of the coronavirus
> it's very dangerous indeed.
>
> "The viruses bind to a cell
> through interactions between its hemagglutinin glycoprotein
> and sialic acid sugars on the surfaces of epithelial cells
> in the lung and throat."
>
> Definitely seems to be for a way to achieve cell senescence to
> replication if coronavirus is actively a DNA virus, while the
> inluenza is an RNA virus.
>
> "Since RNA proofreading enzymes are absent,
> the RNA-dependent RNA transcriptase
> makes a single nucleotide insertion error
> roughly every 10 thousand nucleotides,
> which is the approximate length of the influenza vRNA."
>
> And, for the cell to emit the antibody marker for the
> protein, that seems the point to make a free RNA
> protein, as what kicks out to the bacteriophage
> the antibody with the hate tag, for that then to
> turn sides on the what must be the way that the
> then is off of the introduction of the various host
> immunosuppression, one wonders how the body
> does this, as that it is, and here for whether milk thistle
> is a food.
>
> Is milk thistle right for all COVIDS patients?
>
>
> https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.22235
> "Antiviral effects of silymarin against Hepatitis C: the Jury Is Still Out"
>
>
> https://www.pnas.org/content/94/5/1822
> "Hepatitis B virus (HBV) envelope glycoproteins
> vary drastically in their sensitivity to glycan processing:
> Evidence that alteration of a single N-linked glycosylation site
> can regulate HBV secretion."
>
> "This highlights the potential role
> of the M protein oligosaccharide
> as a therapeutic target."
>
>
> https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-lipid-bound-sialic-acid-lsa-in-S1665268119315637
> "There are evidences that the changes
> in glycosylation and sialylation of proteins
> and lipids play an important role in the
> pathogenesis and progression of various liver diseases."
>
>
> https://www.elsevier.com/__data/assets/pdf_file/0009/976302/Coronaviruses_Perlman-and-McIntosh_155.pdf
>
> "While [the open reading frames'] coding functions are not clear,
> many of them are probably involved in immune evasion."
>
> "The strategy of replication of CoVs is similar to that of
> other nidoviruses, in that all messenger RNAs form a nested set
> with common polyadenylated 3′ ends, with only the unique portion
> of the 5′ end being translated. As in other RNA viruses, mutations
> are common in nature, although the mutation rate is much lower,
> approximately 2 × 10−6 per site per replication cycle."
>
> Looking to ruin the COVID mutation rate, let it fail.
>
> "Unlike other RNA viruses, CoVs encode a 3′→5′ exonuclease
> that has proofreading activities, playing a critical role
> in maintaining replication fidelity in cell cultures and
> in animals."
>
> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693484/
>
>
>
> https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=20&cad=rja&uact=8&ved=2ahUKEwjuhYrqyOToAhXB7Z4KHWalDPMQFjATegQIFxAB&url=https%3A%2F%2Fwwwnc.cdc.gov%2Feid%2Farticle%2F11%2F7%2Fpdfs%2F05-0219.pdf&usg=AOvVaw2_jLgKxCNztK5o75Wo7XY-
> "Vaccination of ferrets with MVA-based SARS vaccine
> expressing full-length S protein caused liver damage after
> animals were challenged with SARS-CoV (34). These
> findings raised concerns about the efficacy and safety of
> the vaccines containing or expressing full-length S protein."
>
> "About 15 years ago, during the in-depth bioinformatics
> analysis of the genome and proteome of the severe acute
> respiratory syndrome coronavirus (SARS-CoV), Alexander
> Gorbalenya and co-workers identified a 3′-5′ exoribonuclease
> (ExoN) signature sequence in a domain embedded in the
> replicase polyprotein of CoVs and other nidoviruses with
> a similarly large RNA genome, and speculated about its role
> as a proofreading enzyme in the evolution of such large nidovirus
> genomes (Snijder et al., 2003). Shortly after this ground-breaking
> discovery, ExoN activity was demonstrated biochemically for
> SARS-CoV (Minskaia et al., 2006) and – following its inactivation
> by reverse genetics – was indeed implicated in enhancing CoV
> replication fidelity (Eckerle et al., 2007)."
>
> "At the same time, quite different observations were made
> for multiple other CoVs, highlighting the need for a more
> extensive experimental characterization of the importance
> and function of the unique ExoN domain, both within the
> CoV family and in other nidovirus subgroups."
>
> "An ideal SARS vaccine should 1) elicit highly potent
> neutralizing antibody responses against a broad spectrum
> of viral strains; 2) induce protection against infection and
> transmission; and 3) be safe by not inducing any infection-
> enhancing antibodies or harmful immune or inflammatory
> responses."
>
> Alpha anti-trypsin's an anti-elastase.
> Neutrophils without anti-elastase tend to necrotize instead of apoptize.
> Necrotizing neutrophils cause the pulmonary edema.
>
> Panicking the neutrophils and breaking the AAT regulation
> could be bad and cause symptoms that looks like ARDS.
>
> I.e., maybe that's what SARS-Cov-2 does.
>
> Source:
> On Monday, April 13, 2020 at 5:41:03 PM UTC+2, Ross A. Finlayson wrote:
> https://groups.google.com/d/msg/sci.math/QoAapoenFxw/SBmTshQXCwAJ



"At this time, the precise location and function
of these proteins in the virion are unclear and
under investigation. Additionally, many host
cellular proteins were identified in the virion,
including many ribosomal, nuclear, endoplasmic
reticulum (ER), Golgi apparatus, and plasma membrane
proteins. The reason for the disparity among these three
studies is unknown but may represent differences
in the stringency of virion preparation or may be due to
differences in the culturing conditions. One complication
is that SARS-CoV produces noninfectious particles as well
as fully functional virions, potentially confounding interpretations
of data from mass spectrophoretic versus immunoelectron
microscopy studies. Continued work using antibodies to each
identified protein in virions will be necessary to determine
viral and cellular proteome participation in virion assembly,
maturation, and infectivity. The role of this plethora of host
proteins in coronavirus virion formation, function, infection,
and pathogenesis remains unknown but might help virions
escape immune recognition."

"When expressed in a chimeric vaccinia virus, the MHV N protein
was also shown to inhibit the activation of PKR,
a strongly antiviral protein, in the cytoplasm ."

"PKR activation normally leads to a block in protein synthesis
by phosphorylating the alpha subunit of the translation factor
eIF2. While N does not itself prevent PKR activation, it alters
PKR's function such that it no longer signals properly.
The N proteins between these two group 2 coronaviruses
are quite conserved, so it will be interesting to determine
if they both encode overlapping functions during infection
or whether there really are distinct inhibitory mechanisms."

"Of note, the various domains of coronavirus nucleocapsid
may affect many pathways similar to that of influenza virus NS1."


https://link.springer.com/chapter/10.1007/978-1-4684-1280-2_60

"Resistance to MHV-3 is dependent upon suitable numbers
of both T cells and macrophages and immunosuppression
with methylpredniso-lone, antilymphocyte globulin and
cyclophosphamide results in conversion of resistance to susceptibility."

https://en.wikipedia.org/wiki/Cyclophosphamide
"Cyclophosphamide induces beneficial immunomodulatory effects in adaptive immunotherapy. Suggested mechanisms include:[51]

Elimination of T regulatory cells (CD4+CD25+ T cells) in naive and tumor-bearing hosts
Induction of T cell growth factors, such as type I IFNs, and/or
Enhanced grafting of adoptively transferred, tumor-reactive effector T cells by the creation of an immunologic space niche."

https://en.wikipedia.org/wiki/Anti-lymphocyte_globulin


https://en.wikipedia.org/wiki/B_cell

"B cells, unlike the other two classes of lymphocytes,
T cells and natural killer cells, express B cell receptors (BCRs)
on their cell membrane. BCRs allow the B cell to bind to
a specific antigen, against which it will initiate an antibody response."

https://www.bethyl.com/content/b-is-for-bursa


"... in the present study, we screened and identified specific
B cell epitopes of SARS-CoV using phage-displayed peptide library,
Fab fragments from anti-SARS-CoV immunoglobulin G (IgG)
and normal human IgG as targets, and an improved biopanning
procedure. The immune responses induced by the four epitope-based
peptides were also evaluated with animal experiments."
-- https://www.sciencedirect.com/science/article/pii/S0042682206006696

"The structure of epitopes recognized and bound by B cell receptor (BCR)
was shown to be linear or spatial by the classical experiments of Michael Sela
30 years ago (Sela, 1969). Phage-displayed peptide libraries are generated by
shotgun cloning of random oligonucleotides into the 5′ ends of either the
pIII or pVIII genes of filamentous phage. The peptides encoded by inserted
nucleotides are displayed on the phage surface and have independent spatial
structure (Cwirla et al., 1990, Felici et al., 1993, Luzzago et al., 1993). So the
non-homologous peptide sequence might reflect the presence of a
discontinuous epitope of SARS-CoV. In addition, SARS-CoV is antigenically
cross-reactive with other viruses, so the non-homologous peptide sequence
might be also an epitope of a different virus. Certainly, this finding must be
studied further."

"The M proteins of other coronaviruses are immunogenic (Enjuanes et al., 1995).
The virion structure of SARS-CoV, B cell epitope characteristics, and our B cell
epitope results suggest that M protein of SARS-CoV also plays an important role
in inducing antibody production."


"Remarkably, some CoVs, among them two alphacoronaviruses
[transmissible gastroenteritis virus (TGEV) and feline enteric CoV (FeCV)],
use both protein- and sialoglycan-based receptor determinants,
with binding to aminopeptidase N (APN) required for entry
and cell surface sialic acids (Sias) serving as attachment factors (27⇓⇓–30).
Although this phenomenon of dual-receptor binding as yet
has received only modest attention in CoV research,
it may be highly relevant to host and organ tropism and pathogenesis.
Indeed, in the case of TGEV, binding to Sia is essential for enteropathogenicity (31)."
-- https://www.pnas.org/content/114/40/E8508

" This approach revealed a hitherto unknown, and potentially important,
interaction of the MERS-CoV spike protein domain S1A with sialoglycoconjugates
that may well contribute to the host and tissue tropism and transmission
of this zoonotic pathogen."

"Pretreatment of human mucin with sialidase completely inhibited binding
by MERS-CoV S1A and IAV HA, demonstrating the Sia-dependent nature
of the observed interactions."

"The receptor use of MERS-CoV resembles that of the
Alphacoronavirus TGEV and Betacoronavirus MHV,
for which binding to cell surface-sialylated glycans
was not required for infection of cultured cells but
contributes to the efficiency of binding."

"High-affinity binding to proteinaceous receptors
by MERS-CoV, TGEV, and MHV appears sufficient
for entry in cultured cells, and primary attachment
to sialylated proteins or lipids on the cell surface
may aid the virus to get into contact with its
protein receptor. This is in sharp contrast to other
Sia-binding CoVs such as BCoV and IBV, for which
no protein receptor has been identified and which
critically depend on (O-acetylated) Sias during cell entry."

https://elifesciences.org/articles/51230
"The human coronavirus HCoV-229E
S-protein structure and receptor binding"

"Four coronaviruses, HCoV-229E, HCoV-NL63,
HCoV-OC43 and HCoV-HKU1, circulate in the
human population where they are responsible
for approximately one-third of the common cold
(Gaunt et al., 2010; Lim et al., 2016). "

"The ability [of an S-protein to achieve a fusable conformation]
likely stems from the fact that the interfaces between monomers
in this region are hydrophilic, a property which we now show
is shared by all the coronavirus S-proteins whose structures
have been determined. These hydrophilic interfaces likely play
a role in the conversion of the coronavirus S-protein from its
pre-fusion to its post-fusion conformation during the process
of membrane fusion."

"The 229E S-protein contains as many as
30 predicted N-glycosylation sites on each monomer."

"The high degree of glycosylation shown by the coronaviruses
is thought to be important in shielding them from immune recognition
(Walls et al., 2016a). Protecting the pre-fusion HR2 triple helical
coiled-coil from immune recognition is another possible explanation
for the high degree of glycosylation observed in this region."



https://www.pnas.org/content/114/21/E4251

"Here we report that coronavirus nonstructural protein 15 (nsp15),
an endoribonuclease, is required for evasion of dsRNA sensors."

"Infection of macrophages with N15m1,
which expresses an unstable nsp15, or N15m3,
which expresses a catalysis-deficient nsp15,
activated MDA5, PKR, and the OAS/RNase L system,
resulting in an early, robust induction
of type I IFN, PKR-mediated apoptosis, and RNA degradation."

"Taken together, our findings demonstrate that
coronavirus nsp15 is critical for evasion of host dsRNA
sensors in macrophages and reveal that modulating nsp15
stability and activity is a strategy for generating
live-attenuated vaccines."

"Here we report that nsp15 is not required
for viral RNA synthesis per se, but acts to
mediate evasion of host dsRNA sensors. "

"We show that nsp15 mutant viruses
can elicit a protective immune response
against subsequent challenge with WT virus."

"These data suggest that infection of BMDMs by nsp15 mutant viruses
activates apoptotic cell death rather than RIPK1/RIPK3-dependent
necroptosis or caspase-1–mediated pyroptosis (30, 31).
However, we note that zVAD—a cysteine protease inhibitor—
may also affect viral replication (32); therefore, we investigated
other hallmarks of apoptotic cell death, including the activation
of caspase-3/7. We observed enhanced caspase-3/7 activity in
nsp15 mutant virus-infected BMDMs."


[Looks to be restoring the caspase 3/7 cascades.]

"It is now well established that certain caspases
(caspase-8, caspase-9, and caspase-10 in humans)
play upstream “initiator” roles in apoptosis by coupling
cell death stimuli to the downstream “effector” caspases
(caspase-3, caspase-6, and caspase-7). The initiator caspases
appear to be highly specific proteases that cleave few
proteins other than their own precursors and the downstream
effector caspases (3, 4). Thus, the bulk of the proteolysis
that takes place during apoptosis is carried out by the
effector caspases. However, the relative contributions
made by the effector caspases to the demolition phase
of apoptosis are still largely unknown."

"Caspases are activated in response to diverse cell death
stimuli and ultimately dismantle the cell through restricted
proteolysis of numerous cellular proteins that latest estimates
suggest number over 400 ."



Word is the S-protein inactivated might still be viral,
besides side products downstream, this is for actually
finding the markers and working those instead of the
antigen bodies and the S-protein.

I.e. for a nose vaccine, might want a nasal spray
as what is topical as the virus is, for pinata
anti-viruses besides then for proper infection of
the vaccine.

Then there are probably lines of what would be cold virus
products, here the point is figuring out the three or
four proteins to make anti-viruses and vaccines,
then growing those in egg shells and cell lines
making for temporary antibodies besides
making it so the immune system confronts the later infection.

The simplest way perhaps is a "de-sialinated" suspension
but that's just a wash. Figuring the nanoparticles are
many, is for nasal vaccines and injected vaccines, and
also for example boosters.




Figuring out a "hey, this cell wasn't infected by virus,
and now it is", maybe is for making components that work
like the components of the virus, that have it evade
detection, that _their_ purpose, when activated, disrupts
the other mechanism.

I.e., having similar viruses to "go along" may,
or may not, have building virus defense usually besides
a cold virus vaccine. For example the immune system might
discover regulating a shock it gave itself - this
might or might not be under better or worse circumstances.

In old times it was well known "there's no cold vaccine".

Everybody's immune system is what vaccine they've already made.

(I.e., the response.)

[Ross A. Finlayson]

Besides the COVID-19 coronavirus, the pandemic,
are a bunch of kinds of virus that look like the coronavirus
on the outside and in the genome, the scientists decoded
them and made 3-D molecules with the activation sites on
the proteins, detailing the reproductive machinery and
the biological machinery of the moving parts of the virus parts,
or the biologically effective parts.

Then, for example, there's still innocuous cold viruses,
often usually from people who don't suffer colds,
here these are kinds of coronavirus, some worse.

The idea of nose vaccines and injections is so
that it can't be infectious. This way then, for
worse kinds of coronavirus, the first vaccine is
so the body will reject it. Making somebody start
puking if they get the coronavirus doesn't seem
a good idea. Mostly though it makes a runny nose then
that the sialic activator is washed out, which also
happens to be how most virus are found to effectively spread.


Everyone has a runny nose, and that it runs,
and also stops running, is a key virus defense.

Viruses that cause runny nose affect all ages.
Often or for many people, being 3 or 4 years old
involves having a runny nose for a year.

Copious volumes of production in initial virus response,
can help the body reject the machinery, but where the
reaction is under immediate and direct bodily response
to the virus outbreak with the runny nose, might see the
need for specific antibodies after the exoribonucleases
as a supplement, for not allowing its chain reaction
viruses effects in some cases, either.

Still, innocuous infection is probably most important
in developing virus defenses. I.e., first time getting a cold:
don't want it to be the coronavirus.


Crowd and herd immunities here are a well-explored problem,
here the various after-effects of coronavirus variants,
make for crowd and herd treatment muchly with
innocuants: light colds that spread and crowd out other colds.

(Here "King Cold".)

[Mostowski Collapse]

Ross the Floss was thinking hard:

> <grope in the dark>

Please see here:

5. How similar is SARS-CoV-2
to the common cold and flu viruses?
===================================
SARS-CoV-2 is a beta-coronavirus whose genome is
a single ​≈​30 kb strand of RNA. The flu is caused by
an entirely different family of RNA viruses called
influenza viruses. Flu viruses have smaller genomes
(​≈​14 kb) encoded in 8 distinct strands of RNA, and
they infect human cells in a different manner than
coronaviruses. The “common cold” is caused by a
variety of viruses, including some coronaviruses and
rhinoviruses. Cold-causing coronaviruses (e.g. OC43
and 229E strains) are quite similar to SARS-CoV-2 in
genome length (within 10%) and gene content, but
different from SARS-CoV-2 in sequence (​≈​50% nucleotide
identity) and infection severity.

Source:
http://book.bionumbers.org/wp-content/uploads/2020/04/SARS-CoV-2_BTN_0401.pdf

[Ross A. Finlayson]

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188333

"A universal mammalian vaccine cell line substrate"?

In this paper the authors' idea seems to be that there
is a target surface for most any virus action, of viruses
transmitted in the wild and here the air, or RNA viruses.
[Here they mostly address other viruses than coronavirus.]

[Here the point of the vaccine cell line is to test with
the various gene combinations in the cell lines that
model virus and immune activity in the vaccine cell line,
looking for what particular expressions cause what
outcomes. I.e. it is investigative.]

"it is possible to knock-down (KD)
host genes affecting virus replication
allowing one to determine
pro- and anti-viral genes."

That's not so much the news, knocking out what
maybe the cell uses of what the genes are the central
dogma's.

"Specifically, there were several host genes
which enhanced virus replication
when CNTD2, COQ9, GCGR, NDUFA9, NEU2,
PYCR1, SEC16G, SVOPL, ZFYVE9, and ZNF205
genes were KD in Vero cells."

Supplementing action of those genes, where
there is knock-down but not knock-up genes,
or genetic engineering with the gene therapy,
sometimes can result from particulars, as what
knowing the proteome the gene encodes and
all the function of the gene, is for offering treatments
for people with different genetics.

Here probably looking for the most energetic
reactions (chemical reactions) of the virus action,
also the least energetic reactions of the virus action,
where anything in the middle is also directly the body's
natural action.

I.e. the virus is basically metabolized.

'The SVOPL gene is poorly annotated
and thought to function as a substrate-specific
transmembrane transporter."

"KD of COQ9, GCGR, and SVOPL
substantially increased virus replication in HEp-2 cells."


It seems for defining a systemic body response
that the non-infectious bits of the original virus,
if they break down to "small biologics" or "nano-
particles", the idea being not destroying the virus
and releasing from it harmful enzymes that end up
triggering interference with other highly (or, loosely)
regulated usual bodily systems of respiration and metabolism,
in their usual operations besides immune defense and immune response.

I.e., a good cure for coronavirus should cure everything else, too.

Or, a good cure for coronavirus should cure coronavirus infections.

Here the coronavirus with the "bat virus" or "rat virus",
for bovine and and avian and feline and monkey virus,
then there's porcine and canine, camels, horses,
the virus is probably most well-known in the laboratory animals.

(The other kinds of animal's viruses, are ones we usually _don't_ get.)

Be quite sure someone with the resources of a government could _cause_ a virus outbreak.

Treatment of the coronavirus (and, virus), in the human and mouse,
here some of the point of virus is that it "mutates", to:
having all the viruses.

Then the idea that most all the population could get SARS before
somebody gets SARS with Ebola-like hemhoragic bleed-out death,
that the body's reaction to the fever products offers a notation of
here capturing SARS, replacing it with its most innocuous version,
or the one with the preparedness in diet and some rational explanation
of why it is better to get SARS-Lite than SARS-Death, letting it go that people
then would still see SARS infection run its course, because people have
noses and there is SARS in the world (coronavirus, here novel coronavirus).

Otherwise it seems the novel coronavirus is clever, that it has simply
some factors like nano-particles as what it evades detection. There's
no idea to "add nano-particles" for a vaccine or cure, instead clean them
up. Maybe these "nano-particles" in solution could make for example
sticky phlegm as for the body to excrete from the nasal products and
the waste by-products of the coronaviruses' mad escapade and caper
through the immune system.

The danger of making SARS-Lite or "SARS, in a nasal spray, with some
solution in a saline mist, that you spray in your nose and it immediately
gives your nose SARS, that you have a cold for a week, during which
time the nose runs, making the recipient contagious with SARS-Lite",
is that the situation would demand everybody get an immunity to a
SARS or more or less a resistance. I.e., "to provide a safe cold" as a
vaccine, is unusual and for example anyone could get "vaccinated"
then would be "vaccinating" (infecting) all the people around them.
If there was also actively SARS going around, then it would be
indistinguishable which was which, except the people who
gave themself SARS.

I.e., making a vaccine for mass production as "inactive" and "safe"
then is for whether it should also be the "cure".

Personal medicine is internal medicine.

Everybody gets the same arm sling, nobody has the same DNA.

If someone get SARS, and just starting making some transmissible
DNA or RNA component, as some human virus, is for the idea of
finding novel immune defense for novel diseases, and figuring
out what chance led to their success, but that that's the result
of their DNA and the mutations.

Then for simply as making supplements for what genes people
don't have, as what more or less make up for the missing genes,
sometimes that's possible and otherwise it would involve gene therapy.

I.e., so far SARS doesn't look like an "Instant Death for Everybody" disease.

Then one point of not giving everyone SARS-Lite is that they
don't result and make from their immune response "SARS-Death".

But, it seems moot if SARS' transmission is effectively
perfectly compatible with natural aspiration in open air.
(And spread from nose droplets and saliva.)

Making a "SARS-Lite" involves reverse-"engineering" the
novel coronavirus, and manufacturing an initial sample
then from some correct volunteer giving them SARS-Lite
to infect everybody.

Man: mouse.



Here then if the "novel" part of the exoribonuclease is what
makes SARS "virions" work (evade or trick the immune system),
as what the payload of the virus has body viruses, then the point
of the SAR-Lite would be to proactively innoculate from that
mechanism of the infection, only. (Figuring that there's "no"
natural reason the biological pathway exists.)

Generating a universal vaccine for all sorts of viral infections,
have natural pathways of usual RNA and messenger signalling,
so it mostly must be quite particular, code of life in the DNA.



Last week, 4/7/2020:

https://www.sciencedaily.com/releases/2020/04/200407072712.htm
"Engineered virus might be able to block coronavirus infections,
mouse study shows"

"All the mice immunized with the modified PIV5 virus
survived MERS virus infection. In contrast, all the mice
immunized with the PIV5 without S died from the infection.
The intramuscular vaccine of inactivated MERS virus
only protected 25% of the mice from a lethal infection.
The mice that received inactivated MERS virus showed
above-average levels of eosinophils, white blood cells
that indicate infection or inflammation. This connection
raises a safety concern for inactivated MERS virus as a
potential vaccine, said He. The study demonstrates that
an intranasal, PIV5-based vaccine is effective against
MERS in mice, said He, and should be investigated for
its potential against other dangerous coronaviruses,
including SARS-CoV-2."

Here their approach was the S-protein, but there's
some problems with it as about what this and other
active components of the virus should result in
trying to keep the S-protein out, and here with a
pretty systematic understanding of effect.

The simplest model for mass production of this
virus, and a vaccine for it, is the virus itself.

"Finding an effective vaccine against the coronavirus
that causes COVID-19 is a race against time, McCray said.
"One hundred percent of the population is not going to
be exposed to the virus the first time around, which
means there will be more people to infect when it
comes again," he said. "We don't know yet if people
get lasting immunity from the SARS-CoV-2 infection,
so it's important to think about ways to protect
the population.""

[Mostowski Collapse]

Looks like we see the first vaccine bubble ever.
There was an internet bubble in the past that
burst late 1990s, but now rumors about vaccine

seem to help returning to business as usual a
nd possibly create some new bubbles:

Der Mythos vom bald kommenden Impfstoff!
https://www.youtube.com/watch?v=FBwuGsHthV0

[Ross A. Finlayson]

Clearly when immediately infected with any virus
the first response is the immediate nerve response.

Putting a responder on (the means of) the nerve response,
is usually associated _only_ with a nervous response,
setting up for antibody generation has that the nervous response
is the general response, for not activating anti-virus machinery
until detecting the virus action, conditioned by the nervous response.

The "modern theory of nano-machines" and "catalog of human metabolism",
here they don't help together that the theory is "modern theory of nano-machines"
and "catalog of human metabolism", simply categorizing metabolism as falling
under "natural nano-machines". Here conditioning a chemical response from
a nervous response, is that the immune defenses under bodily defenses have
that infection is an event, directly in the nervous system.

How the chemical infection becomes a nervous system event,
is in the electrochemical as drives from sensory neurons.

At the sites there are effectively collectors of static charge -
an environment of static effects in solution - here for making
activators of pathogen sensitivity among neurons (or ganglia).

Wow, look at this: "Reactome".

https://reactome.org/PathwayBrowser/

"snRNP Assembly"

"Small nuclear ribonucleoproteins (snRNPs)
are crucial for pre-mRNA processing to mRNAs.
Each snRNP contains a small nuclear RNA (snRNA)
and an extremely stable core of seven Sm proteins.
The U6 snRNA differs from the other snRNAs; it binds
seven Sm-like proteins and its assembly does not involve
a cytoplasmic phase. The snRNP biogenesis pathway for
all of the other snRNAs is complex, involving nuclear export
of snRNA, Sm-core assembly in the cytoplasm and re-import
of the mature snRNP. The assembly of the snRNA:Sm-core is
carried out by the survival of motor neurons (SMN) complex.
The SMN complex stringently scrutinizes RNAs for specific
features that define them as snRNAs and binds the RNA-binding
Sm proteins."

"tRNA processing in the nucleus"

"Genes encoding transfer RNAs are transcribed in the nucleus
by RNA polymerase III. (Distinct processes of transcription and
processing also occur in mitochondria.) The initial transcripts,
pre-tRNAs, contain extra nucleotides at the 5' end and 3' end.
6.3% (32 of 509) of human tRNAs also contain introns, which
are located in the anticodon loop, 3' to the anticodon. The
additional nucleotides are removed and a non-templated
CCA sequence is added to the resulting 3' terminus by
processing reactions in the nucleus and cytosol
(reviewed in Nakanishi and Nureki 2005, Phizicky and Hopper 2010).
The order of processing and nucleotide modification events
may be different for different tRNAs and its analysis is
complicated by a retrograde transport mechanism that
can import tRNAs from the cytosol back to the nucleus
(retrograde movement, Shaheen and Hopper 2005, reviewed in Phizicky 2005).
Generally, the 5' leader of the pre-tRNA is removed first by
endonucleolytic cleavage by the RNase P ribonucleoprotein complex,
which contains a catalytic RNA (RNA H1 in humans)
and at least 10 protein subunits (reviewed in Jarrous 2002,
Xiao et al. 2002, Jarrous and Gopalan 2010).
The 3' trailer is then removed by RNase Z activity,
a single protein in humans (reviewed in Maraia and Lamichhane 2011).
ELAC2 is a RNase Z found in both nucleus and mitochondria.
ELAC1 is found in the cytosol and may also act as an RNase Z.
Human tRNA genes do not encode the universal acceptor 3' terminus CCA,
instead it is added post-transcriptionally by TRNT1, an unusual polymerase
that requires no nucleic acid template (reviewed in Xiong and Steitz 2006,
Hou 2010, Tomita and Yamashita 2014).
In humans introns are spliced from intron-containing tRNAs in the nucleus
by a two step mechanism that is distinct from mRNA splicing (reviewed in
Popow et al. 2012, Lopes et al. 2015). The TSEN complex first cleaves 5' and 3'
to the intron, generating a 2'3' cyclic phosphate on the 5' exon and a 5' hydroxyl group
on the 3' exon. These two ends are ligated by a complex containing at least 6 proteins
in a single reaction that both hydrolyzes the 2' phosphate bond
and joins the 3' phosphate to the 5' hydroxyl.
(In yeast the ligation and the hydrolysis of the 2' phosphate
are separate reactions. The splicing reactions in yeast occur
in the cytosol at the mitochondrial outer membrane.)
Mature transfer RNAs contain a large number of modified nucleotide
residues that are produced by post-transcriptional modification reactions
(reviewed in Li and Mason 2014). Depending on the specific tRNA
these reactions may occur before or after splicing and before or after export
from the nucleus to the cytosol."


I studied a year's course at university in molecular biology.

Here the course is the virus into and (its many copies)
back out of the cellular replication machinery, for
regulating general mechanisms of virus replication.

DNA editing and mismatch repair?

https://pdfs.semanticscholar.org/6685/da2c0d005d81b8bc7fb29f64dc8ec027b3b1.pdf

"Minireview: Mismatch Repair in Mammalian Cells", Modrich, ..., Radman

"Since the re-paired DNA strand is recovered from nuclear extracts
largely as a full-length, covalently continuous species (7),
the last step of the reaction presumably involves ligase closure
of the strand break that remains after repair synthesis."

"Recombinant MSH2 has also been reported to bind
to mis-matched base pairs (17), but the heteroduplex affinity
of this pro-tein is considerably less than that of MutSa or MutSb(11, 14 –16).
Inasmuch as free MSH2 has not been detected during fractionation
of human nuclear extracts and since epistasis analysis suggests that
Saccharomyces cerevisiae MSH2 functions in mitotic genetic stability
only in conjunction with MSH3 or MSH6 (18, 19), the biological function
of free MSH2 must be regarded as uncertain."

"... consistent with function of both activities at an early step in [DNA] repair."

"The role of PCNA as a DNA polymerase processivity factor might
suggest that this protein is required during the repair synthesis
stage of mismatch correction."

[... or making post-proofreader work.]

"Nowell (34) and Loeb et al.(35)
proposed 20 years ago
that genetic destabilization
would predispose a cell
to tumor development.
Dramatic support for this idea
has appeared during the past several
years with the identification of a class
of tumor cells [...].

The body's mechanics of tumorization,
and, de-tumorization, is for DNA storage
in lines under machinery, here products
in-line of the code and re-expressed coding results.

As what the RNA virus of the coronavirus gets
to the nucleus besides cytosolic assembly,
here is for nuclear vesicles and cellular vesicles.

"Vesicular nucleo-cytoplasmic transport is
becoming recognized as a general cellular mechanism
for translocation of large cargoes across the nuclear envelope."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701712/
"Structural Basis of Vesicle Formation at the Inner Nuclear Membrane"


"Intracytoplasmic transport between compartments
is primarily mediated by vesicles (Schekman and Orci, 1996).
These vesicles are shaped by specific coat proteins
that are recruited to the site of assembly and
function to deform the membrane (McMahon and Gallop, 2005).

In contrast, movement into and out of the nucleus is
effected by “gated transport” via the nuclear pore complexes (NPCs).
NPCs allow free diffusion of small molecules and can mediate
active transport of cargo [...]."

"Recently, vesicular trafficking was reported to mediate
nucleo-cytoplasmic transport of ribonucleoprotein particles[...]."

https://www.pnas.org/content/112/29/9010
"Structure of a herpesvirus nuclear egress complex subunit
reveals an interaction groove that is essential for viral replication"

"A possible antiviral drug target is a two-subunit complex
that orchestrates nuclear egress, an essential, unusual mechanism
by which nucleocapsids move from the nucleus to the cytoplasm
during viral replication."

See: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0020380

"Components of Coated Vesicles and Nuclear Pore Complexes Share A Common Molecular Architecture"

"In modern eukaryotes, these systems have become elaborate internal membranes,
such as the Golgi apparatus, the endoplasmic reticulum (ER), and the nuclear envelope (NE)."







https://www.ncbi.nlm.nih.gov/pubmed/26861183
"The Role of the Reactive Oxygen Species Scavenger Agent,
Astaxanthin, in the Protection of Cisplatin-Treated Patients
Against Hearing Loss."

"Astaxanthin, a xanthophyll carotenoid,
has powerful anti-oxidant, anti-inflammatory,
and anti-apoptotic properties based on its unique
cell membrane function, diverse biological activities,
and ability to permeate the blood-brain barrier.
In this review, we summarize the role of ROS in CIHL
and the effect of astaxanthin on inhibiting ROS production.
We focus on investigating the mechanism of action
of astaxanthin in suppressing excessive production of ROS."




"Astaxanthin is a powerful antioxidant, [...]".


https://www.tandfonline.com/doi/full/10.1080/14756366.2019.1690480

"Since the autocleavage process is essential for viral propagation,
3CLpro is a good drug target for anti-coronaviral infection."

"Intriguingly, the three inhibitory compounds
obviously reduced the fluorescence intensity
of the catalytic domain compared with others (Figure 3).
The decreased emission intensity confirmed
the complex formation between the catalytic domain
and inhibitory compounds."

[Mostowski Collapse]

Ross the Floss halucinated:

On Tuesday, April 14, 2020 at 6:10:48 PM UTC+2, Ross A. Finlayson wrote:
> Clearly when immediately infected with any virus
> the first response is the immediate nerve response.

Not necessarely for a virus that modulates the innate
immune system, like SARS-Cov-1, if you mean by nerve
response a response by the innate immune system.

Maybe as well not for SARS-Cov-2. Also antibody
production is a matter of the humoral immune system.
In SARS-Cov-2 it seems to take 10-20 days,

so antibodies appear when the patient is already dead?

LoL

Source:
http://book.bionumbers.org/wp-content/uploads/2020/04/SARS-CoV-2_BTN_0401.pdf

[Mostowski Collapse]

Dead like Ross the Floss is brain dead,
because of his blistering herpes?

LMAO!

[Mostowski Collapse]

See also:

"The modulation of these pathways is critical
for virus survival, as evidenced by the many
viruses that express proteins that block
various key effector proteins in these pathways
and from the increased disease severity noted
in many gene knockout animals.
...
One way that viruses have evolved to combat the
innate immune system is to encode protein functions
that block various aspects of the host response
to viral infection.
...
Significant amounts of data support the hypothesis
that coronaviruses encode one or more IFN antagonist
genes. The virus may also be able to evade detection
by replicating in privileged sites that are
compartmentalized from the sensing and signaling
machinery."
...
Mechanisms of Severe Acute Respiratory Syndrome
Pathogenesis and Innate Immunomodulation
Microbiol Mol Biol Rev. 2008 Dec; 72(4): 672–685.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2593566/

[Ross A. Finlayson]

https://newatlas.com/medical/regenerate-heart-cells-gene-therapy/

"Cancer study stumbles onto potential way to regenerate heart cells"

"... the researchers ramped up expression
of the Ccnt1 and Myc genes,
which kickstarted cell replication
and increased the number of heart muscle cells."

"Initially, they set out to find ways to shut off the Myc gene,
which is overactive in most cancer types."

"A normal step in medical research like this
involves testing the opposite of the target –
so, for instance, if the goal of the study is
to investigate what happens when you turn off a gene,
the team also ramps it up in one group of test animals.
That ensures that this gene is responsible
for the negative effects you’re trying to treat."

https://medicalxpress.com/news/2020-04-key-cancer-gene-curative-treatment.html

""We want to use short-term, switchable technologies
to turn on Myc and Cyclin T1 in the heart. That way
we won't leave any genetic footprint
that might inadvertently lead to cancer formation,"
said [ Dr. Catherine Wilson, a researcher in the
University of Cambridge's Department of Pharmacology,
who led the study]."

Reading the news....

https://phys.org/news/2020-04-unpredictable-byproducts-genetic-modification.html

https://pink.pharmaintelligence.informa.com/PS141991/Gene-Therapies-Trivial-Changes-Will-Not-Be-Rewarded-With-Orphan-Drug-Designation-And-Exclusivity

https://pink.pharmaintelligence.informa.com/PS142032/US-FDA-Coronavirus-Response-Features-ThreeStep-Triage-Process-For-Inquiries

https://www.fda.gov/drugs/emergency-preparedness-drugs/coronavirus-covid-19-drugs

https://www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap

"FDA has created a special emergency program
for possible therapies, the Coronavirus Treatment
Acceleration Program (CTAP). It uses every available
method to move new treatments to patients as
quickly as possible, while at the same time finding
out whether they are helpful or harmful. We continue
to support clinical trials that are testing new treatments
for COVID so that we gain valuable knowledge
about their safety and effectiveness."

[Ross A. Finlayson]

https://journals.plos.org/plosbiology/article/figure?id=10.1371/journal.pbio.0020380.g005

"We investigated the functions of the largest of the accessory proteins,
the ORF 3a protein, using a 3a-deficient strain of SARS-CoV.
Cell death of Vero cells after infection with SARS-CoV
was reduced upon deletion of ORF 3a. Electron microscopy
of infected cells revealed a role for ORF 3a in SARS-CoV induced
vesicle formation, a prominent feature of cells from SARS patients.
In addition, we report that ORF 3a is both necessary and sufficient
for SARS-CoV-induced Golgi fragmentation and that the 3a protein
accumulates and localizes to vesicles containing markers for late endosomes."


"... overexpression of ADP-ribosylation factor 1 (Arf1),
a small GTPase essential for the maintenance of the Golgi apparatus,
restored Golgi morphology during infection. These results establish
an important role for ORF 3a in SARS-CoV-induced cell death,
Golgi fragmentation, and the accumulation of intracellular vesicles."
-- https://jvi.asm.org/content/84/2/1097

"... vesicles containing markers for late endosomes", ....



"There are three different types of endosomes:
early endosomes, late endosomes, and recycling endosomes."
-- https://en.wikipedia.org/wiki/Endosome#Types

"ORF 3a (previously also known as U274) is an accessory protein of 274 amino acids ..."
-- https://hub.hku.hk/bitstream/10722/52859/6/FullText.pdf?accept=1

"ORF-3a (also known as U274, SARS X1, or ORF-3), [...]".
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115782/

"A SARS-CoV protein, ORF-6, induces
caspase-3 mediated, [Endoplasmic Reticulum] stress and JNK-dependent apoptosis"

"Under ER stress, unfolded proteins accumulate
in the lumen of the ER, which eventually induces
conflicting cellular activities; survival and apoptosis."


"When misfolded proteins accumulate in the ER,
cells activate a self-protective mechanism,
termed the ER-stress response, to survive ER-stress conditions."

"The ER-stress response is initiated
by three types of ER membrane receptors,
ATF6, IRE1 and PERK."

"Three accessory proteins of SARS-CoV
have been shown to induce apoptosis,
ORF-3a (also known as U274, SARS X1,
or ORF-3), ORF-3b (also known as ORF-4)
and ORF-7a (also known as U122, SARS X4, or ORF-8)."


(The proteins expressed as the gene contents of the
contents of the open reading frames of the sequence
of the RNA transported under the coating into vesicles
of the cells, and for example connecting or about fusion
of the interconnecting interstices the membranes: both
interfere with normal operation and signal improper operation.)

Here it is key that the body's anti-viral and anti-tumor responses
involve the cells and their normal operation, and duplication or
replication after differentiation, and the cells' normal lifetime
of the apoptosis with planned and unplanned cell death, there
are rising concerns of damage to genetic machinery.

The body effectively reclaims and recyles the cells for their roles
in the course of homeostasis/haemostasis, that there's some
inter-cellular operation, of the cells, is otherwise about the
usual very precise (and even specific) targeting of a cell by the
immune system, and the neighboring cells as getting messages
from the central cell under the immune system response.

I.e., here the remarkable effectiveness of a virus strain with
complicating factors under the body's usual detection and elimination
of genetic damage or viral replication, is for what must be a
holistic approach: here looking for possible supplement (or,
drug) regimens, can help the immune system effectively act
anti-virally, among the range of anti-bacterial and anti-tumor
and other effective response, of the immune system, here under
genetic machinery and inter- and intra-cellular transport, and
also inter cellular transport membrane-membrane.


Here for example something like the caspase cascades:
it could be that _inhibition_ is good, but it might be
that _not suppression_ the other way is (eventually) correct.

Eg if caspase 3 and 7 reciprocate in cascades, regulating one
or the other might remove its input from a higher-level receptor,
that instead itself is involved in the process with signalling.

It is so with difficulties in understanding the mechanism of
metabolism, under specific concerns.

"Results in Fig. 2B showed that both ORF-6 and ORF-7a induced Caspase-3 activation, [...]".

"Results in Fig. 2B showed that both ORF-6 and ORF-7a induced [...] activation, [...]".

"Previous studies have shown that JNK is phosphorylated in SARS-CoV-infected Vero E6 cells ...".

"... and JNK inhibitor (SP600125) can block SARS-CoV-infected Vero E6 cells-induced apoptosis."

Here the _blocking_ of the apoptosis when its correction or "confirmation" actually
would occur as part of the metabolism, itself rings out as a _cause itself_, about the
confusion of underlying cause, and effective resolution (of conflicts in cause).

Then where the cells have genetic damage is (or, isn't) another problem.

https://pdfs.semanticscholar.org/2c1e/40e189a0ce158aa00422de5cf39b64c79500.pdf

"Furthermore while virus replication is normally inhibited by brefeldin A,
a resistant form of GBF1 containing a single amino acid substitution
is sufficient to support viral replication in the presence of the drug (21).
Thus, the 3A-mediated regulation of GBF1 is an important step
for blocking protein secretion during coxsackievirus and poliovirus infection." <-- not (necessarily) SARS

"... by regulating various Arf effectors
different enterovirus proteins can
direct alterations in the infected cell
that are essential for replication."


Cell-trafficking membrane/membrane:

https://en.wikipedia.org/wiki/Membrane_vesicle_trafficking

Here the consideration is something like "hidden messages",
in the intercellular (as, intracellular), as affecting other usual
immune concerns, the phages and cellular signals and receptors.


Eg, phagocytosis itself is unusual under the intercellular,
https://en.wikipedia.org/wiki/Phagocytosis (as, intra-cellular).

"Following apoptosis, the dying cells need to be taken up
into the surrounding tissues by macrophages in a process
called efferocytosis. One of the features of an apoptotic
cell is the presentation of a variety of intracellular molecules
on the cell surface, such as calreticulin, phosphatidylserine
(from the inner layer of the plasma membrane), annexin A1,
oxidised LDL and altered glycans.[12] These molecules are
recognised by receptors on the cell surface of the macrophage
such as the phosphatidylserine receptor or by soluble (free-floating)
receptors such as thrombospondin 1, GAS6, and MFGE8, which
themselves then bind to other receptors on the macrophage
such as CD36 and alpha-v beta-3 integrin. Defects in apoptotic cell
clearance is usually associated with impaired phagocytosis of
macrophages. Accumulation of apoptotic cell remnants often
causes autoimmune disorders; thus pharmacological potentiation
of phagocytosis has a medical potential in treatment of certain
forms of autoimmune disorders."


https://en.wikipedia.org/wiki/Pinocytosis
https://en.wikipedia.org/wiki/Receptor-mediated_endocytosis

"Viropexis":
"Viropexis is the process by which different classes of viruses—
particularly picornaviruses and papovaviruses—enter the host cell
in which they will be able to replicate. The hydrophobic structures
of the capsid proteins may be exposed after viral binding to the cell
(see viral attachment protein). These structures help the virion or
the viral genome slip through the membrane. It can be juxtaposed
with viral endocytosis, which is receptor mediated, and doesn't involve
direct penetration of the virion."

"Entry of SARS Coronavirus into Vero E6 Cells by Membrane Fusion."

http://www.life.illinois.edu/mcb/150/private/faq/index.php?action=artikel&cat=22&id=1311&artlang=en



"Hantaan virus (HTNV)-infected Vero E6 cells undergo
cell fusion with both infected and uninfected cells
under low-pH conditions. Flow cytometry and fluorescence
microscopy of HTNV-infected Vero E6 cells showed that
envelope glycoproteins (GPs) were located both on the
cell surface and in the cytoplasm. Neutralizing monoclonal
antibodies (MAbs) against the G1 and G2 envelope GPs
inhibited cell fusion, whereas nonneutralizing MAbs against
G1 or G2 and MAbs against the nucleocapsid protein (NP) did not.
Transfected Vero E6 cells that expressed GPs but not those
that expressed NP fused and formed syncytia. These results
indicate that HTNV GPs act as fusogens at the cell surface.
No fusion activity was observed either in infected Vero cells
that were passaged more than 150 times or in BHK-21 cells,
although GPs appeared to localize to the cell surface. This
variability in fusion induction suggests the involvement of
host cell factors in the process of cell membrane fusion."
-- https://www.ncbi.nlm.nih.gov/pubmed/15367644

https://en.wikipedia.org/wiki/Syncytium


https://jvi.asm.org/content/84/24/12658

"... the lysosome-tropic reagents failed to inhibit
[large syncytia induced by SARS-CoV infection]
whereas the heptad repeat peptide efficiently
inhibited viral entry into cells, suggesting that
TMPRSS2 affects the S protein at the cell surface
and induces virus-plasma membrane fusion.
On the other hand, production of virus in
TMPRSS2-expressing cells did not result in S-protein
cleavage or increased infectivity of the resulting virus.
Thus, TMPRSS2 affects the entry of virus but not other
phases of virus replication. We hypothesized that the
spatial orientation of TMPRSS2 vis-a-vis S protein is a
key mechanism underling [sic] this phenomenon."

"Results indicate that TMPRSS2 needs to be expressed
in the opposing (target) cell membrane to activate S protein
rather than in the producer cell, as found for influenza A virus
and metapneumoviruses. This is the first report of TMPRSS2
being required in the target cell for activation of a viral fusion
protein but not for the S protein synthesized in and transported
to the surface of cells. "

[Ross A. Finlayson]

"The results support a role for CoV-induced macropinocytosis
in cell fusion and virus cell-to-cell spreading, representing
novel exploitation of macropinocytosis machinery for virus use."
-- https://mbio.asm.org/content/5/4/e01340-14

"MHV-induced macropinocytosis is dependent
on the classical macropinocytosis pathway."

"Inhibition of macropinocytosis impairs MHV replication."

"... these results indicate that EIPA does not affect
intracellular virus replication, assembly, or maturation
but alters the overall peak titer of the infectious virus
in the supernatant, consistent with an effect on late stages
of virus release or cell-to-cell spreading."

"The presence of fusogenic spike protein at the plasma membrane
is required to induce macropinocytosis."


"Thus, released infectious MHV-2 does not have a fusogenic
spike protein, and cells infected with MHV-2 do not express
a fusogenic spike protein on the cell surface or generate
syncytia in culture."


This points to a requirement for a 1) nose vaccine
and 2) liver vaccine, and for breaking down SARS S-protein
generally, in a careful way as that the energetic metabolism
of the components doesn't release unusual triggers.

"MHV-induced macropinocytosis is associated with,
but independent of, syncytium formation."


[Here there's that syncytium formation is an auto-immune component,
causing the most well-known symptom of fatal ARDS, the respiratory failure.]

"CoVs have been shown previously to modify
cytoplasmic membranes to form viral replication complexes (7).
Here, we report that CoVs also have the capacity to modify
the plasma membrane through activation of the macropinocytosis
pathway. Prior to this study, the only role demonstrated for
virus-induced macropinocytosis was in virus entry. MHV-associated
macropinocytosis, in contrast, is initiated relatively late during
infection and is continuous once activated."

"MHV 2S does not stimulate cell-cell fusion or macropinocytosis
in infected cells but still causes disease in vivo, suggesting that
macropinocytosis may not be required for the fitness or pathogenesis
of all strains of MHV or for all CoVs. "

"The conservation of macropinocytosis during MHV and SARS CoV
infections, however, suggests that macropinocytosis induction
could be an important determinant of pathogenesis for viruses
capable of maintaining cleaved spike protein on the surface of
infected cells."

"Our results also show that expression of cleaved, fusogenic
spike protein on the cell surface is necessary to induce
macropinocytosis, whether by furin-mediated cleavage
in the cell or by exogenous cleavage by trypsin on the cell surface. "

"The results of our studies define novel roles
for the CoV spike protein and for macropinocytosis
during CoV infection and raise the possibility that
other RNA viruses may usurp macropinocytosis
machinery for purposes other than virus entry."

Citation: Freeman MC, Peek CT, Becker MM, Smith EC, Denison MR. 2014.
Coronaviruses induce entry-independent, continuous macropinocytosis.
mBio 5(4):e01340-14. doi:10.1128/mBio.01340-14.

[Ross A. Finlayson]

https://www.researchgate.net/publication/8334141_Cellular_entry_of_the_SARS_coronavirus

Article on Ebola: https://www.mdpi.com/1999-4915/11/3/274/htm

Coffee is an antioxidant.
Beer, not so much.

"Chronic Granulomatous Disease"

https://www.jimmunol.org/content/185/7/4030

"Chronic granulomatous disease (CGD)
is traditionally characterized by immunodeficiency
due to the lack of a functioning NADPH oxidase."

"Previous reports have demonstrated that
IFN-γ stimulation frequently results in de novo
synthesis of iNOS and increased NO production."

"Furthermore, NO production itself has been associated
with enhanced phagocytosis by LPS-stimulated Mϕs."

"... a requirement for NO at the time of engulfment
was demonstrated in that addition of an iNOS inhibitor, L-NIL,
for 15 min prior to uptake assays abrogated enhancement
due to IFN-γ priming, while having no effect on the constitutive
ability of either cell type to ingest apoptotic cells."

"On the contrary, in the absence of NO production,
IFN-γ priming of these cells resulted in diminished
uptake of apoptotic cells."

"Finally, concurrent neutralization of TNF-α
was effective in inhibiting Rac activation following IFN-γ priming,
but not after provision of NO by SNAP,
demonstrating that TNF-α acts upstream of NO production
leading to Rac activation, just as in apoptotic cell uptake."

"Because [... of] CGD and WT resident peritoneal Mϕs
as shown in Fig. 1D, we investigated the in vitro mechanism
as elucidated above for its role following in vivo IFN-γ treatment."

"... greater accumulations of apoptotic neutrophils
and reduced phagocytic indices for Mϕs
were observed in harvests from CGD
compared with WT mice (Fig. 8C).
These data are in accordance with a recent report
by Rajakariar et al. (56), and they were consistent
with defective clearance. In contrast to PBS treatment,
treatment with IFN-γ resulted in significantly fewer
neutrophils present in both CGD and WT mice,
with near resolution of neutrophilia noted in the latter mice. "

"Importantly, the clearance of cells by CGD Mϕs
was nearly normalized to levels observed for WT Mϕs (Fig. 8C)."

@article {Fernandez-Boyanapalli4030,
author = {Fernandez-Boyanapalli, Ruby and McPhillips, Kathleen A. and Frasch, S. Courtney and Janssen, William J. and Dinauer, Mary C. and Riches, David W. H. and Henson, Peter M. and Byrne, Aideen and Bratton, Donna L.},
title = {Impaired Phagocytosis of Apoptotic Cells by Macrophages in Chronic Granulomatous Disease Is Reversed by IFN-γ in a Nitric Oxide-Dependent Manner},
volume = {185},
number = {7},
pages = {4030--4041},
year = {2010},
doi = {10.4049/jimmunol.1001778},
publisher = {American Association of Immunologists},
abstract = {Immunodeficiency in chronic granulomatous disease (CGD) is well characterized. Less understood are exaggerated sterile inflammation and autoimmunity associated with CGD. Impaired recognition and clearance of apoptotic cells resulting in their disintegration may contribute to CGD inflammation. We hypothesized that priming of macrophages (Mϕs) with IFN-γ would enhance impaired engulfment of apoptotic cells in CGD. Diverse Mϕ populations from CGD (gp91phox-/-) and wild-type mice, as well as human Mϕs differentiated from monocytes and promyelocytic leukemia PLB-985 cells (with and without mutation of the gp91phox), demonstrated enhanced engulfment of apoptotic cells in response to IFN-γ priming. Priming with IFN-γ was also associated with increased uptake of Ig-opsonized targets, latex beads, and fluid phase markers, and it was accompanied by activation of the Rho GTPase Rac. Enhanced Rac activation and phagocytosis following IFN-γ priming were dependent on NO production via inducible NO synthase and activation of protein kinase G. Notably, endogenous production of TNF-α in response to IFN-γ priming was critically required for inducible NO synthase upregulation, NO production, Rac activation, and enhanced phagocytosis. Treatment of CGD mice with IFN-γ also enhanced uptake of apoptotic cells by Mϕ in vivo via the signaling pathway. Importantly, during acute sterile peritonitis, IFN-γ treatment reduced excess accumulation of apoptotic neutrophils and enhanced phagocytosis by CGD Mϕs. These data support the hypothesis that in addition to correcting immunodeficiency in CGD, IFN-γ priming of Mϕs restores clearance of apoptotic cells and may thereby contribute to resolution of exaggerated CGD inflammation.},
issn = {0022-1767},
URL = {https://www.jimmunol.org/content/185/7/4030},
eprint = {https://www.jimmunol.org/content/185/7/4030.full.pdf},
journal = {The Journal of Immunology}
}


"G. bethesdensis causes necrotizing lymphadenitis in CGD, which may recur or relapse."
-- https://wwwnc.cdc.gov/eid/article/16/9/09-1800_article

"... necrotizing lymphadenitis ...".

https://ashpublications.org/blood/article/132/Supplement%201/4949/262094/Histiocytic-Necrotizing-Lymphadenitis-a-Benign

https://onlinelibrary.wiley.com/doi/abs/10.1002/9781118818824

" ... respiratory syncytial virus involves macropinocytosis followed by proteolytic...".

https://www.ncbi.nlm.nih.gov/pubmed/23593008


"Studies have also highlighted that bats present long associations
with numerous viral families and genera (e.g., Paramyxoviridae,
Filoviridae, Lyssavirus, Henipavirus), with viruses detected in bats
usually being older than those found in humans or other animals."
-- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695591/

https://www.umassmed.edu/rare-disease-research/research-diseases-and-conditions/chronic-granulomatous/


[Excuse me, wouldn't want to improperly associate
chronic granulomatous disease and SARS, or, Murine
hepatitus virus MHV, macropinocytosis disorder,
the "respiratory syncytial virus".]



https://pubs.acs.org/doi/abs/10.1021/bi061686w

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112261/

"Structural insights into coronavirus entry"

"The sialoside-binding site identified in HCoV-OC43 S
is not conserved among CoVs which are also known
to interact with sialoglycans to initiate host cell infection
but are outside of the lineage A of β-CoVs, such as
MERS-CoV (β-CoV, lineage C) or infectious bronchitis virus (IBV, δ-CoV)."

"These findings suggest that CoVs have evolved
a fine-tuned mechanism to balance masking
of the receptor-binding motifs, putatively to avoid
neutralization by the host humoral immune response,
and their necessary exposure to enable receptor recognition
and infection of host cells."

"Upon host recognition, CoVs are internalized
via receptor-mediated clathrin-dependent,
caveolin-dependent or other uptake pathways."


"The anti-SARS-CoV S230 antibody, however,
functionally mimicked the receptor by
promoting S fusogenic conformational rearrangements
through a molecular ratcheting mechanism."

"These observations suggested that upon receptor recognition,
bound B domains are locked in the open state,
thereby releasing the constraints imposed on the HR1-central helix hairpin,
allowing refolding of the S2 fusion machinery and membrane fusion to occur."

"Proteolytic activation is likely required to ensure that S glycoproteins
will work in synergy, with proper spatial and temporal coordination,
to drive fusion of the viral and host membranes."

"A deep knowledge of the organization and chemical composition
of carbohydrates obstructing the surface of CoV S glycoproteins
is key for understanding accessibility to neutralizing antibodies
and for guiding the rational development of subunit vaccines
and therapeutics. "

1) nose vaccine
entry subunits
propagation subunits
2) liver vaccine
entry subunits
propagation subunits

"This observation suggested that
all CoVs face similar immune pressure
in their respective hosts, and that the
areas that are masked by the conserved glycans
might be key to the function of S."

Tortorici MA, Veesler D. Structural insights into coronavirus entry. Adv Virus Res. 2019;105:93–116. doi:10.1016/bs.aivir.2019.08.002

https://www.ijbs.com/v16p1724.htm

"Targeting the Endocytic Pathway and Autophagy Process as a Novel Therapeutic Strategy in COVID-19"

"... clathrin-dependent endocytosis and cathepsin- mediated S protein cleavage
are two critical steps for the viral entry and infection."

"Our results indicate that entry of MHV
depends on proteolytic processing
of its fusion protein S by lysosomal proteases."
-- https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004502

"Fusion of MHV was severely inhibited
by a pan-lysosomal protease inhibitor,
while trafficking of MHV to lysosomes
and processing by lysosomal proteases
was no longer required when a furin cleavage site
was introduced in the S protein immediately upstream
of the fusion peptide."

"In contrast, MERS-CoV, which contains a minimal
furin cleavage site just upstream of the fusion peptide,
was negatively affected by inhibition of furin, but not
of lysosomal proteases. We conclude that a proteolytic
cleavage site in the CoV S protein directly upstream of
the fusion peptide is an essential determinant of the
intracellular site of fusion."

"Collectively, these results indicate an important role
for clathrin-mediated uptake and for endosome- and
endosome-to-lysosome maturation for MHV infection."

"Fusion of MHV was not affected by the solvents or CHX,
[cycloheximide] the latter confirming that this assay is
independent of RNA replication and protein synthesis.
MHV fusion was barely affected by replication inhibitor
BrefA, whereas MG132 had a clear negative effect, in
agreement with the conclusion drawn previously that
MG132 inhibits entry of MHV as well as RNA synthesis."

"Considering that MHV was much less affected
by perturbation of the endosomal pH than IAV and VSV
while it requires trafficking to lysosomes for efficient entry,
we hypothesized that entry might depend on
cleavage of a viral protein by lysosomal proteases."

"... indicating that efficient entry requires the activity of lysosomal proteases."



[Lysosomal proteases are cellular virus defense destruction enzymes.]

"Introduction of the FCS resulted in the recombinant virus
being no longer sensitive to inhibition by lysosomal proteases
(Figure 7B), probably because the S protein is now
cleaved by furin in an endocytic compartment."

https://doi.org/10.1371/journal.ppat.1004502.g007

"In analogy with the results obtained with FCS-mutant MHV,
we predicted that FIPV and MERS-CoV would differ
in their protease inhibitor sensitivity and lysosomal trafficking requirements."

"The results of this study provide an explanation
for several, apparently conflicting results from
earlier studies with respect to the process of
MHV cell entry, particularly also regarding
the necessity of proteolytic cleavage of the CoV S protein."

"Based on the use of inhibitors, it was earlier concluded
that MHV entry depends on cholesterol and lipid-rafts,
which may be indicative of caveolae-mediated endocytosis."

"Interestingly, fusion of MHV was severely inhibited by EIPA,
an inhibitor of the Na+/H+ exchanger NHE1, which is regarded
as a hallmark inhibitor of macropinocytosis."

"... depletion of host proteins associated with late endosome
and late endosome-to-lysosome maturation (RAB7A, RAB7B,
and the HOPS complex subunits VPS11, VPS33A, VPS39 and VPS41)
or addition of U18666A, which blocks late endosome-to-lysosome
trafficking, were shown to inhibit both infection and virus-cell fusion."

"Also, the inhibition of MHV entry by MG132 may be explained
by the known ability of the proteasome inhibitor
to negatively affect lysosomal proteases [93]–[95],
although we cannot exclude that MG132 affects entry
by its interference with lysosomal trafficking."

"Our results indicate that cleavage of the S protein
immediately upstream of the FP
is essential for CoV entry and determines
the intracellular site of fusion.
Although we did not demonstrate cleavage of MHV S
at the FP proximal position directly, a recent study
found a cleaved form of the MHV S2 subunit to
correspond with the fusion-active form."


I really appreciate these scientists and this science
helping explain the mechanism of virus disease (and defense).


This can really help illustrate the importance of
(the investment in) government research
in the primary science.

"The concept of lysosomotropism was first introduced by De Duve et al. in 1974 17 . The term
was originally proposed for all substances taken up by lysosomes, regardless of their chemical
structure or mechanism of action. Interestingly, the importance of the potential antiviral
properties of lysosomotropic agents was emphasized even in the original publication 17 ."

"Homolak, J.; Kodvanj, I. Widely Available Lysosome Targeting Agents Should Be Considered as a Potential Therapy for COVID-19.

Interfering with cellular machinery is very strong.

"In general, most of the substances with weakly basic
and lipophilic properties are believed to demonstrate
lysosomotropism to some extent."

"Moreover, lysosomotropic agents inhibit endosomal maturation,
and disrupt endolysosomal trafficking,and these effects are of
particular interest in the context of viral infection as described above."


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112261/citedby/



"Another recent research suggested [23] that the mutation
in NSP2 and NSP3 play a role in infectious capability and
differentiation mechanism of SARS-CoV-2. This provokes
people to explore the difference of the host tropism and
transmission between SARS-CoV-2 and SARS-CoV or conduct
further investigations on the potential therapeutic targets."
-- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068984/


J Med Virol. 2020 Feb 21. doi: 10.1002/jmv.25719. [Epub ahead of print]
COVID-2019: The role of the nsp2 and nsp3 in its pathogenesis.
Angeletti S1, Benvenuto D2, Bianchi M3, Giovanetti M4, Pascarella S3, Ciccozzi M2.
-- https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25719


https://academic.oup.com/ajcp/article/153/4/420/5735509
"Three Emerging Coronaviruses in Two Decades"

https://wwwnc.cdc.gov/eid/
"Emerging Infectious Diseases Journal"


"Validated SARS-CoV-2 serologic assays are urgently needed
for contact tracing, epidemiologic and vaccine evaluation studies."
-- https://wwwnc.cdc.gov/eid/article/26/7/20-0841_article



https://wwwnc.cdc.gov/eid/article/26/5/et-2605_article

[Mostowski Collapse]

From the same article:

"although species highly tolerant to environmental
disturbances, such as insectivorous bats, tend to
persist in large urban environments"

Please note arthropoda are also virus reservoirs.
Dont blame the bat, maybe blame their diet.
Also arthopodas provide a special infection

route, which allows to classify viri as
arboviri = Arthropod borne viri. See also:

E. Jawetz et al., Medizinische Mikrobiologie ©
Springer-Verlag Berlin Heidelberg 1968
https://link.springer.com/content/pdf/10.1007/978-3-662-00155-4_29.pdf

[Ross A. Finlayson]

Data suggests transmission is an airborne cold,
of course no-one knows a person's viriome, but
there are at least modern ways to discover all sorts
of things about living, genetic expression, and disease.

The virome of viruses is their genetic material,
viruses here involve active genetic material,
according to the central dogma of molecular
biology, where genetic function is the proper
idea that everything follows from genetic material,
of course that active genetic material is also "included",
in the central dogma of molecular biology, as what
is the "proper" function of genetic machinery and as
usually that DNA before differentiation is particular
distinguished central domain, for the dogma.

It seems like the best vaccine for SARS delivered viruses
is a "SARS-Lite" that infects the population with an
innocuous disease, to prevent infection of other
SARS delivered viruses that are not innocuous.

Modern science can make this in the laboratory.

The Biological Safety Level or BSL is an indicator of
the controls necessary to make weapons-of-mass-destruction
like biological agents, active genetic material in virus delivery
form, or here universal vaccines (active genetic material).
It used to be they went up to 3, now it has 4, it says.

Of course that's complete control of the sequenced and
expressed genome of the viral material, and for example
also its cultivation in cell lines, modern science in the
institutional laboratories along Biological Safety here is
more or less whether to make "SARS-Lite", or to work up
other of the any number of ways conventional inactivated
viruses as vaccines, or particularly the cultivated introduction
of some "proper" immune system defenses in what must be
tailored for the diverse populace.

The genome and proteome and bacteriome and the usual
entire diverse vast catalog of sequencing results, and the
reconstitution in the models, modern science is totally
amazing in what it's discovered in fifty years.

As above there are very particular and promising results
mostly from SARS and MERS research to identity the
"mechanisms of virus disease", in the biological pathways
or metabolism, of this SARS-CoV-2 and Murine Hepatitis Virus,
and MERS and SARS, and other diseases, and understanding
of their corresponding diseases, for many approaches.


The viriome of people (or, under active genetic material)
is very vast and deeply researched, the viruses themselves
or their active agent is very well studied microscopically and
to the genetic sequencing of the viruses and the understanding
as genetic material that they express proteins, under genetic
machinery.

Then, usual agents like drosophila and melanogaster, viral
agents, these are also studied in terms of mostly knowing all
their genome. (I.e. the genomes have been sequenced.)

https://www.microbiologyresearch.org/content/journal/jgv/10.1099/0022-1317-28-1-165

(A primer.)

https://en.wikipedia.org/w/index.php?title=Virus_disease&redirect=no


From antioxidants to strong biologics, and many degrees between,
treatments for symptoms of SARS-CoV-2 are seeing lots of relief.

https://en.wikipedia.org/wiki/Virus_latency

("Virus latency", a link from "viral disease".)


A key component of the central dogma is that virus defenses are
latent or activated or acquired - basically with a modern dogma
that genetic material is latent or active.

This is well represented in differentiation (and, re-differentiation).

[Ross A. Finlayson]

"Mike Ryan, the WHO’s top emergencies expert, told a briefing on Friday. [...]"
“The expectation that ... the majority in society may have developed antibodies,
the general evidence is pointing against that, so it may not solve the problem of governments.”

"Coronavirus antibody testing finds Bay Area infections
may be 85 times higher than reported: researchers"

"According to Korea Centers for Disease Control and Prevention
data on Friday, the age and regional distribution of relapse cases
are largely in line with that of the total infections."


"Top KCDC officials said in recent briefings that the most likely
possibility is reactivation of remaining viruses in patients' systems.
If a patient had not developed sufficient immunity against the virus
or if a patient's immune system weakens after recovery, the previously
undetectable level of virus concentration could rebound. Or the novel
coronavirus may be capable of staying dormant before reactivating."



The biological system-on-chip test array is a kind of a device that is
getting a sample of biological material and establishing information
about its contents.

"Flash-bulb spectroscopy" is an idea for in-situ employment of the
spectroscopy, for molecular composition, of prepared, of some
system-on-chip biological detector, for example a sputum of
scratch test. Here the idea is to more or less be catalogin under
proteins, which is the problem of implementing system-on-chip,
of separated and preparing the sample then for what are basically
systolic lines, what can be inferred from usual, cultured, or accumulated
sample of the biological product, cellular and intercellular material.

Biological pathways and enzymatic reaction testing pathways, is the
idea of as for collecting for the metabolic pathways, that all quite
usual expected reactions hold true and under expected conditions.
This as well is for in-situ (microscopic) sources of for example free
chlorine or oxygen.

The Burse asked about the relevance of the liver in this virus disease,
and one note of import was the massive wide hepatocyte array and
what the body might make of it as a test-bed or sampling facility,
in terms of a usual location for mass reproduction of various results
as what define for the body a successful antigen.

It seems this Murine Hepatitis Virus that is part of some CoV payloads,
might be making for faulty transcription machinery and over-running
the hepatoctye function, and confusing the memory of the process as
what would otherwise "solve" itself.

(The mitochondria include their own post-transcription factors and
are as ancient as anything else outside the nucleus.)

https://www.pnas.org/content/108/10/3906
"Core promoter recognition complex changes
accompany liver development"

https://www.researchgate.net/profile/Iannis_Talianidis/publication/12538291_Transcriptional_activation_by_hepatocyte_nuclear_factor-1_requires_synergism_between_multiple_coactivator_proteins/links/56d668e408aebabdb4005c0a.pdf
"Transcriptional Activation by Hepatocyte Nuclear Factor-1 Requires
Synergism between Multiple Coactivator Proteins"

https://www.biorxiv.org/content/10.1101/2020.03.15.992438v1.full.pdf
"Computational analysis of microRNA-mediated interactions in
SARS-CoV-2 infection"

"It has been estimated that miRNAs might influence
around 60% of mammalian genes and their main effect
is on regulatory pathways including cancer, apoptosis,
metabolism and development."

"The major concerns regarding miRNAs of RNA viruses
are based on:

-the fact that RNA viruses that replicate in cytoplasm,
do not have access to nuclear miRNA machinery

-since RNA is the genetic material, miRNA production
would interfere with viral replication"

"... through targeting specific human genes by viral miRNAs,
it is possible to form an environment suitable for survival
and replication of the virus. Furthermore, for viral miRNAs
it is likely to escape host defensesystem since host itself
generates miRNAs in the same manner. "

"Since viruses would need to use at least some members
of host miRNA biogenesis pathway elements, viral miRNAs
should be similar to host miRNAs to a certain degree.
Therefore, a classification scheme trained with known human
miRNAs was applied on SARS-CoV-2 hairpins. Only 29 hairpins
out of 950 passed the 0.900 prediction score threshold and
used for further analysis. From these hairpins, 30mature
miRNA candidates were extracted and their possible targets
for human and SARS-CoV-2genes were investigated."


Here I'm thinking that a genetic mutation in the hepatocyte marshalling,
is making the gestalt of excess exercise of the mutation detection,
and having the liver hepatocytes run abnormally. Here I think that
normally the liver would work this out already, but that a dangerous
tonic of a usual gut trash reaction, is essentially leaving the cells bereft
of cleanup machinery and memory that the hepatocytes are functioning,
incorrectly.


( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1287583/
"The greatest reduction in virus growth was noted following ORF3a deletion."
"Deletion of one or more of the group-specific ORFs
in MHV, FIPV, and TGEV results in marked reductions in virulence." )


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1287583/figure/f8/

https://doi.org/10.1101/2020.03.15.992438
"... chart for the protein classes of human genes
that could be targeted by viral miRNAs. "

"... molecular elucidation of the roles of miRNAs
in host-virus interaction might provide
a deeper understanding for viral pathogenesis
and the development of an effective antiviral therapy
as shown in several viruses including
Herpesvirus, Enterovirus and Hepatitis C."

"However, there are several reports showing
the presence of non-canonical (due to the lack
of classical stem-loop structure in miRNAs),
small miRNA-like small RNAs produced during
viral infections as shown in
H5N1 Influenza 34, Ebola virus 35and HIV-1."


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100099/
"MicroRNA Function in the Profibrogenic Interplay upon
Chronic Liver Disease"

"Interestingly, miR-214 upregulated in activated HSC
was shown to be controlled by the master transcription factor,
Twist-1, [66]. miR-214 has to be considered as a main therapeutic
target, because genetically or therapeutically silencing resulted
in highly efficient inhibition of renal fibrosis."

"Lakner et al. identified 55 miRNAs that are divergently expressed
in quiescent versus activated HSCs [hepatic stellate cells] by microarray analyses."

"In addition to its role in ECM repression, miR-29 regulates
the growth factor profile of HSC by targeting profibrogenic
mediators, such as IGF-I and PDGF-C [71]. Moreover, Sekyia
et al. collected evidence that also the PDGF-β receptor is
targeted by miR-29 regulation [65]. This is of special interest,
because miR-29 itself is downregulated in HSC after PDGF-BB
stimulation [65]."

"However, whereas drug delivery to liver parenchyma
is highly efficient, organ and cell-type specific miRNA
targeting has to be achieved in liver fibrosis. Thus, in
order to avoid cell unspecific side effects of antifibrotic
therapies, that target miRNAs involved in liver fibrosis,
an HSC- or myofibroblast specific approach of drug delivery is needed."


"Role of microRNAs in non-alcoholic steatohepatitis"
- https://www.ncbi.nlm.nih.gov/pubmed/20370674
"The pathogenesis of non-alcoholic fatty liver disease (NAFLD)
is not entirely understood. Recently, the role of microRNA
in this liver disease entity and its implication in disease pathogenesis
and therapeutic potential has advanced rapidly over the year.
While the regulation of miRNA function and its mechanism
of actions on translational control of target mRNA expression
remain unknown, advances in miRNA research allow identification
and biochemical characterization of events that limit protein expression,
which is crucial in various forms of human diseases and their subsequent
development. It is hoped that further understanding of the role of microRNA
in NAFLD will advance potential therapeutics and preventive measures
to modify and alter this disease process."



"Adelmidrol | NF-κB Inhibitor | MedChemExpress"


"Non-Alcoholic Steatohepatitis"
https://www.pfizer.com/health-wellness/disease-conditions/non-alcoholic-steatohepatitis-nash :
"We know that the liver can regenerate. It is the only organ that
has this ability and if we are successul, we can treat NASH and
ultimately prevent is consequences."


https://www.researchgate.net/profile/Muhammad_Arshad100/publication/317801646_Crosstalk_of_liver_immune_cells_and_cell_death_mechanisms_in_different_murine_models_of_liver_injury_and_its_clinical_relevance/links/59d5a8420f7e9b7a7e46771a/Crosstalk-of-liver-immune-cells-and-cell-death-mechanisms-in-different-murine-models-of-liver-injury-and-its-clinical-relevance.pdf
"Crosstalk of liver immune cells and cell death mechanisms
in different murine models of liver injury and its clinical
relevance"

"The liver is regarded as special immunological organ
due to its enriched resident immune cell population
like natural killer (NK) cells, NKT cells (formally called pit cells),
Kupffer cells (KCs, resident macrophages of liver), dendritic cells (DCs),
hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSEC),
innate lymphoid cells (ILCs), B cells, T cells and cells of myeloid lineage.[1]
The ILCs are distinctly classified as ILC1s, ILC2s and ILC3s depending upon
cytokine production and transcription factors involved in their
development and function."

"The liver encounters many circulating antigens and toxins of gut origin. "

" The “dual edge” functions are regulated and controlled
by the resident immune cells of the liver by secreting
chemical mediators such as chemokines (for chemotaxis,
recruitment of immune cells) and cytokines (pro-inflammatory
and anti-inflammatory functions) collectively called as
“microenvironment”. "

"The coronaviruses, including MHV are large, enveloped,
positive-strand RNA viruses, with genome ranging in size
from 27-32 kb. The hepatotropic MHV3 serotype induced
severe fulminant hepatitis in mice with lethality depending
upon virus strain, route of infection, age, genetic background
and immune status of the mice.[86] Several strains of MHV
induce acute encephalitis and acute and chronic demyelinating
disease in mice.[86, 87] The MHV-induced hepatitis is an
excellent model for studying the immunological disorders
associated with viral hepatitis and it has mimicry with human
HBV infection."

"The MHV3 (pathogenic strain L2-MHV3) can replicate
in the hepatocytes, LSEC and KCs, leading to virus
induced necrotic cell death."

"... the strain ... a cloned sub-strain ... another strain ...".

MHV3
L2-MHV3 ("pathogenic")
MHV-A59 ("also ... pathogenic")
YAC-MHV3 ("... non-pathogenic" [?])




"VSIG4 inhibits proinflammatory macrophage activation by reprogramming mitochondrial pyruvate metabolism"
-- https://www.nature.com/articles/s41467-017-01327-4

"VSIG4 activates the PI3K/Akt–STAT3 pathway, leading to pyruvate
dehydrogenase kinase-2 (PDK2) upregulation and subsequent
phosphorylation of pyruvate dehydrogenase, which results in
reduction in pyruvate/acetyl-CoA conversion, mitochondrial
reactive oxygen species secretion, and macrophage inhibition.
Conversely, interruption of Vsig4 or Pdk2 promotes inflammation.
Forced expression of Vsig4 in mice ameliorates MHV-3-induced
viral fulminant hepatitis. These data show that VSIG4 negatively
regulates macrophage activation by reprogramming mitochondrial
pyruvate metabolism."


"V-set immunoglobulin-domain-containing 4 (VSIG4) is
a membrane protein belonging to complement receptor
of the immunoglobulin superfamily (CRIg)."


"Flow cytometric data also confirmed at protein levels
that inflammatory cytokines like pro-IL1-β, TNF, and IL-6,
were dramatically increased in virus-infected Vsig4 −/− PEMs
(Fig. 2f), suggesting Vsig4 deficiency promotes macrophage-derived
inflammation in vivo. Consistent with this, Vsig4 deficiency
in liver Kupffer cells also resulted in higher levels of these factors
deposited in the infected liver tissues, as detected by qRT-PCR (Fig. 2e),
western blot (Fig. 2g), and immunohistochemistry (Supplementary Fig. 4). "

"To avoid the cellular heterogeneity of conventional PEMs,
we next chose a macrophage line, RAW264.7 cells, as a
homogeneous model to examine the functional specificity
of VSIG4. RAW264.7 cells are lack of Vsig4 transcription,
but they with lentiviral-mediated restoration of Vsig4
expression (Len-Vsig4) exhibited a reduction in LPS-induced
M1 gene (Il1b, Il6, and Tnf) transcripts compared to the
control counterparts (Fig. 3e)."


Dot dot dot: "lentiviral-mediated restoration of Vsig4 expression
...".

"..., lentivirus-mediated overexpression of VSIG4 in RAW264.7
cells resulted in higher p-Akt [ser473] expression compared
to mock-infected controls (Fig. 6b), suggesting that VSIG4
transfers a feedback signal, licensing macrophages for Akt activation."


..., https://www.nature.com/articles/s41467-017-01327-4 ,
"VSIG4 inhibits proinflammatory macrophage activation ...".



"Mouse hepatitis virus is probably the most important
pathogen of laboratory mice. Although the infection
generally causes no overt clinical signs, it can cause
profound changes in the immune system, affecting the
interpretation of a wide variety of experimental results.
It is a ssRNA virus of the family Coronaviridae. Approximately
25 strains or isolates of MHV have been described."
-- https://research.illinois.edu/files/upload/mhv.pdf



https://pubs.acs.org/doi/10.1021/acscentsci.0c00272
"Research and Development on Therapeutic Agents and
Vaccines for COVID-19 and Related Human Coronavirus Disease"


"The patent analysis of coronavirus-related biologics includes
therapeutic antibodies, cytokines, and nucleic acid-based
therapies targeting virus gene expression as well as various
types of vaccines. More than 500 patents disclose methodologies
of these four biologics with the potential for treating and preventing
coronavirus infections, which may be applicable to COVID-19."


That's (not) funny, patents on metabolism, all I have here is prior art.
Maybe there could be a global pandemic patent escrow,
for preserving intellectual property rights and for remuneration.

"To date, there are no SARS-CoV-2-specific antiviral agents. "


Seems like, the proteases and lysome, are basically getting "crafted"
inputs the usual byproducts of which aren't being inert, instead active
("micro-" RNAs). It is only, though, a part of the puzzle.

"Because of their ability to interfere with viral replication,
interferons and interferon fusion proteins have been utilized
as therapeutic agents for treatment of viral infections
for the past 20 years. A few patents disclosing these proteins
and their use for treating SARS are described below."

Most of these patents have eventually public origin.

"RNA interference (RNAi) is a biological process wherein
small complementary RNA duplexes target and neutralize
specific mRNA molecules, resulting in inhibition of gene
expression [VSIG4?, ..., ed.]or genetic translation. Interfering
RNAs include microRNAs and small interfering RNAs (siRNAs)
that are generally about 21–25 nucleotides in length. "

"Since the discovery of RNAi in the late 1990s, it has become
a well-known method for silencing/suppressing target genes
associated with virulence and pathogenesis. "

"This report provides an overview of published information
on global research and development of coronavirus-related
therapeutic agents and preventive vaccines based on the
extensive CAS content collection, with a focus on patents.
It includes an overview of coronavirus morphology, biology,
and pathogenesis with a particular focus on antiviral strategies
involving small molecule drugs, as well as biologics targeting
complex molecular interactions involved in coronavirus infection
and replication. The drug-repurposing effort summarized in this
report is focused primarily on agents currently known to be
effective against other RNA viruses including SARS-CoV, MERS-CoV,
influenza, HCV, and Ebola as well as anti-inflammatory drugs.
The potential impact of biologics for treatment of coronavirus
infections is promising and includes a wide variety of options
including bioengineered and vectored antibodies, cytokines,
and nucleic acid-based therapies targeting virus gene expression
as well as various types of vaccines."

"Because of limited space, this report devotes minimal attention
to current efforts involved in advancing more efficient and
accurate COVID-19 diagnosis methods and products."


"Long-term drug development goals for the pharmaceutical
industry include identification of inhibitors aimed at the
replication or infection processes associated with SARS-CoV-2
or other related coronaviruses, as well as the symptomatic results
of their infections leading to severe disease and/or death."

[Mostowski Collapse]

LoL Ross the Floss, the new Pentcho Valev
of Covid-19. Pentcho Valevs motto "Not
happy with relativity and thermodynamics"

Ross the Floss motton "Not happy with
novelty and epidemology". LMAO!

[Ross A. Finlayson]

Well, Burse, that just seems wrong -
it comes across as frivolous nonsense.
That seems childish if not churlish.
Well, I hope Burse grows out of that,
but it's pretty much his usual demeanor.


https://en.wikipedia.org/wiki/V-set_and_immunoglobulin_domain_containing_4

"Alternate splicing results in multiple transcript variants."



I'm not a virologist or molecular biologist,
but, being able to read and having a scientific
vocabulary, and more or less a fundamental and
comprehensive exposure to modern science and
the central dogma and animal life as a gene machine,
I expect science (collectively) to have more-or-less
answers to the questions of what's going on and
answers to the questions of what's gone wrong and
answers to the questions of what to right.

Don't forget daily vitamins, an important
part of a well-balanced diet.

Science really hasn't answered yet "what is COVID-19"
versus "what are all these others strains of disease".

That there are various diseases all using the same
infection mechanism (or, vaying slightly as do SARS,
MERS, and SARS-CoV-2) and later having their own models
of disease internally, there's hope that the insight
to solving these diseases will also solve what were
other common and rare diseases.

("About writing measure theory in that", is another
point, but that's in mathematics.)

The notion that "the liver's the only organ that
regenerates itself", it's interesting to note the
article above as what is talking about what are
essentially "immune" responses in regeneration of
the smooth tissue of the heart, it's interesting news
and helps advise learnings past the standard dogma.

The notion of destruction after apoptosis and,
re-construction, or re-differentiation, is an
interesting theoretical note without much that
I know of academic support.

[Mostowski Collapse]

Blood also regenerates itself, Skin also
regenerates itself. Whats wrong with you?

[Ross A. Finlayson]

This isn't just shedding skin it's
recycling cells.


Burse asks his usual question:
"What's wrong with you?". Burse,
obviously if I stated something to
that extent, if you didn't have any
misunderestimation, of where I was
coming from, or that somebody else
doesn't, should be: "what's wrong with me?".






One thing I enjoy about Burse
is always pretty much being able
to forget what he says.

Or, at least next time when it's the same,
then I know it's either stupid or lame.

I "find" what I say.

So, it's easy enough to forget that, too,
because the simple theory sees me left
with all of that.

I can walk away from this with all of "Burse's"
and "Finlayson's" theories, which from my
perspective are not his and all mine.

Also, "all theirs".







For a crowd testing approach, idea is to say
"my entire immune system ran through a bunch
of cycles, probably because of an ubiquitous
coronavirus among a bunch of them".


Then, everybody in the crowd had all the symptoms,
immunologically, here is for "and this saved us".


I'd aver that the coronavirus outbreak of 2019
is reasonably enough to say quite dangerous, in
terms of viruses and basically its adapted
mechanism of virus disease, all the various
mechanisms of virus disease that are mechanisms
of respiration and metabolism, for well-being and
science to triumph through knowledge over tragedy.

The most very contagious and infectious mechanism
of the S-protein's role in nasal infection, here
is what must be an opportunity to immunologically
immunize not just that, but the entire approach,
to virological immunization.

[Mostowski Collapse]

In your case its not a nasal infection,
rather a basal infection. Shit for brains.

[Ross A. Finlayson]

There's even more bad news that the SARS-Cov-2 is
quite systemic a body infection, not just the nose,
not just the lungs, not just the liver, also the
gastrointestinal or gut.

This then is for a nose vaccine to prevent transmission
nasally, and here what that means for a liver vaccine,
as that then the liver gets right and pumps vaccine
to the rest of the tract.

Also there are worrisome reports of brain infections
besides quite various musculature feelings and here
about the "mild" symptoms throughout.

The immune reaction and in clotting is also
affecting people (both ways).

Symptoms are "mild", or, "under control", ...,
deactivating the coronavirus itself and its virions,
and, unblocking for them what should be the genetic
output if the virion got into the hepatocyte DNA,
or for the mitochondrian, DNA, might need be for
some people to find a way to provide the nutrient
as for the liver vaccine and biologic, and others
to restore the knock-out gene as it were, or as
otherwise that the mechanisms of virus disease,
is for the S-protein's more or less novel and
"unique", mechanisms, in the ecosystem as for
not letting the lysosome break the S-proteins
that expose their active conformation, instead
breaking them weak, or, anticipating and
fulfilling the furanoside that the lysosome
neatly destroys the S-protein and for that
the resulting material, is not itself secondary,
in the S-protein and infection of the coronavirus
(novel coronavirus).

One idea is to recruit a neutrophil with a virus,
and have it compete, that the neutrophil is
engineered to compete with the message bubbles
that the active infection provides to the
surrounding S-protein sites all over what
they are saying these days are the ACE2 receptors.

I.e. the various kinds of SARS various basically
have two different S-proteins, the SARS and MERS,
and that CoV-2 also has in the virus payload or
what results rapidly in infection, the confusing
messenger agents as what hide or _misdirect_,
with the point of preventing those, from having
the body's antibodies of course working away on
the S-protein in the cellular matrix.

Then there are the CoV-2's replication machinery
proof-readers, or error detection and correction
(or, suppression), besides the entry camouflage/sabotage,
improving the replication correctness several
orders of magnitude, about deactivating that,
without just making it thus spew mutations that
the body could interpret as dangerous to genetic
machinery (eg tumorigenic).

1) entry subunits
2) propagation subunits

For reducing the virus to minimal levels what for
that S-virus replication machinery is disrupted,
without causing cancer or other harm, it seems
for an approach to CoV-2, and an approach to
SARS and MERS and other coronaviruses with the
SARS S-protein, with some approach of sufficiency
that the body effectively has defense against SARS.

I.e. it would seem very difficult to develop a
natural defense to the SARS-CoV-2, without at
least some input from a systemic response, with
food, regimen, diet, study, ..., drugs, on paper
the relevant parts of the immune system are an open book.

Then this seems for "SARS-Lite" that the government's
genetic engineering and epidemiology arm honestly
talks about the fact that modern science with the
resources of a government basically holds "keys to
the kingdom" to make a "SARS" and call it "SARS-Lite".

A lot of different anti-viral approaches could be
very effective in reducing viral load in SARS.
But, there are many counterindications, many of
which were compounding the injury of SARS, confounding
protocol, that within months protocol has greatly
adapted to a usual setting of ubiquitous disease.

Then, there is hope for diet regimen, without side
effects for usual people, managing viral load
(to zero) in the case of MHV, SARS, MERS, ....
But, that's mostly a placebo.


Garlic, oregano, ..., many foods have non-nutritional
effect in immunological support. There are probably
also some things (foods) to avoid, I don't know them.

Daily vitamins (or, minerals) seem important in immune support.

My apologies, no news here.

[Mostowski Collapse]

Hey man. Did you just crawl out from under
your rock. This was already known in January.
In January it was stated that it is a virus,
and that the virus can procreate in organs,

among which we find the lung. If I remember
well in Janury it was communicated that
most organs failure is lung or kidney.
Sympthoms are somehow already known

from SARS-Cov-1:

Acute renal impairment in coronavirus-associated
severe acute respiratory syndrome
https://www.ncbi.nlm.nih.gov/pubmed/15673319

About gastrointestinal I don't know.
Maybe not that much.

[Mostowski Collapse]

But the paper concludes that the kidney
failure is indirect:

"The acute renal impairment is likely to be
related to multi-organ failure rather
than the kidney tropism of the virus."

Oki Doki.

[Ross A. Finlayson]

Big Cancer and King Cold - both these days
have so much more knowledge about their
biological pathways of the proteome, since,
say, the 1970's, or the last fifty years, that
these days in the laboratories already, the
entire genome sequence of the virus virogens,
much of the action of their function, the
particulars of SARS and CoV-2 and MERS and
their S-proteins, these are on display.

Then, the danger of the coronavirus that it
can deliver some 30 kilodaltons of genetic material
as into the machinery, then is for the RNA machinery
that could be genetically active, besides the S-protein
and related actions under the insertion, that also happen
to spew RNA material with the concomitant misrecognition
by the usual courses of the biological pathways in the
respiration and metabolism.

Then it seems like that the very pervasiveness of CoV-2,
is for taking from it its strength, and making a "SARS-Lite",
that preempts and takes advantage of the mechanism,
for the person instead of the virus.

Then it seems a matter of public interest that the tracking
of coronavirus strains and making publicy available the
coronavirus strain(s) that basically ward off the infection
of the "pathological" coronavirus strains, is something
both within the resources of a government's arm,
and what offers the possibility of solving the pandemic problem
(by replacing it with a pan-vaccine).

Not acknowledging that the government (and industry)
has this capability of a particular approach to the pandemic
by providing to the public a champion SARS, is as innocent
as not knowing that modern laboratories have the ability
to manufacture specified viruses, or that modern science
knows so much about the biological pathways that the
mechanisms of virus disease about this vector, COVID-19,
and others, have already seen institutional study (and
after review).

https://www.ncbi.nlm.nih.gov/pubmed/8116187

"Most research has focused on the S protein
as a candidate antigen for CV vaccines since
it induces virus neutralizing (VN) antibodies.
However the HE protein stimulates the production
of VN and HE inhibiting antibodies and the M protein
induces antibodies that neutralize virus in the presence
of complement. Attempts to correlate in vitro VN antibody
activity with in vivo protection have shown that the passive
transfer of VN mAb to the S or HE protein conferred passive
protection against CV challenge in some studies, but not others.
Additional research has implicated a possible role
for other CV proteins in immunity." (1993)

[Mostowski Collapse]

Here is Corona Test for Dummies:

Knock on your forehead. If your face
hurts somewhere, then its not Corona,
only a sinusitis.

Hint: Dont knock too hard.

[Ross A. Finlayson]

Expert systems is a talking philosopher.

Neural nets is a million clock cats,
all following the dot.

Then usually pushing the lever....


"Please remember that – across all our journals –
we protect primary research studies from being
considered “scooped” by closely related, parallel
studies recently published in other journals. So,
there is no need to rush your research, or revisions,
for the sake of being selected for novelty!"
-- https://blogs.plos.org/plos/2020/03/a-message-to-our-community-regarding-covid-19/

https://wellcome.ac.uk/coronavirus-covid-19/open-data

"These journals/publishers have also agreed
to make all of their COVID-19 and coronavirus-
related publications, and the available data
supporting them, immediately accessible in
PubMed Central (PMC) and license it in ways
that facilitate reuse."

[Mostowski Collapse]

If you want to avoid sinusitis try this:

"Some cases may be prevented by hand
washing, avoiding smoking, and immunization."
https://en.wikipedia.org/wiki/Sinusitis

But I was wrong. You should not knock
on the forehead, rather on the back of
your head with a flat hand.

"Zur Lokalisierung kann sich der Patient
mit der flachen Hand auf den Hinterkopf
schlagen, der Impuls verursacht einen
dumpfen, stechenden Schmerz in den
flüssigkeitsgefüllten Nebenhöhlen."
https://de.wikipedia.org/wiki/Sinusitis

Here you see how to do the head slap:

NCIS-Gibbs slaps Dinozzo for the first time
https://www.youtube.com/watch?v=IRq-CJW2_IY

[Mostowski Collapse]

On t=1.06 you see a self slap:

[NCIS] - Headslap Compilation
https://www.youtube.com/watch?v=NRM2OENl2jk

[Ross A. Finlayson]

Figuring the granulitis and the iron-mediated and
all that is working under the oxygen-mediated, and
what is the expression under the reactive oxygen species,
about what minerals to boost or make deficient, about
what the body is making granulitis after auto-immune
reponse, and also combined with the detritus of the
body's breaking down and only partially metabolizing,
the result that the granulitis is not metabolized fully
or readily.

https://www.researchgate.net/figure/Effects-of-angiotensin-II-and-the-iron-chelator-deferoxamine-DFO-on-ferritin_fig7_11561708

The kidneys' not being infected, here might have that
they're still downstream from all the metabolism, that
what then reactive oxygen species and in the kidney products,
is for working up what would make the active clotting factors
in the granulocyte and how and why the body is always
metabolizing about the clotting factors and why it is not.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970951/


Scabbing under oxygen usually, again is looking for the
oxidizing species, here for the ferrite interactions and
the clotting factors and their metabolism.

"Artificial lipid membranes were disturbed more by
CA-adsorbed CoFe2O4 nanoparticle suspensions
than by bare CoFe2O4 nanoparticle suspensions."
-- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970951/

https://www.ncbi.nlm.nih.gov/books/NBK6341/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046589/


Iron and Zinc:

"This apparent paradox is due to the fact
that in contact with oxygen iron forms oxides,
which are highly insoluble, and thus is not
readily available for uptake by organisms."

"The body requires iron for the synthesis of
its oxygen transport proteins, in particular
hemoglobin and myoglobin, and for the formation
of heme enzymes and other iron-containing enzymes
involved in electron transfer and oxidation-reductions."

"Internalized iron is transported to mitochondria
for the synthesis of heme or iron-sulfur clusters,
which are integral parts of several metalloproteins,
and excess iron is stored and detoxified in cytosolic ferritin."


Sulfates considered bad for health....

Sulfites considered bad for health....

https://www.jbc.org/content/119/1/9.full.pdf

"Many sulfites in suitable concentration will
precipitate proteins."

"... the precipitating power of the sulfites for
the protein of human serum or plasma is limited
largely by the solubility of the particular salt employed."


https://en.wikipedia.org/wiki/Coagulation

"The coagulation cascade of secondary hemostasis
has two initial pathways which lead to fibrin formation.
These are the contact activation pathway (also known
as the intrinsic pathway), and the tissue factor pathway
(also known as the extrinsic pathway), which both lead
to the same fundamental reactions that produce fibrin."

Calcium and Vitamin K: restrict?

"Many acute-phase proteins of inflammation
are involved in the coagulation system."


https://en.wikipedia.org/wiki/Agglutination_(biology)


http://josorge.com/publications/Citations/IJL/008.pdf

https://pubs.acs.org/doi/10.1021/ic061677b#


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136164/

"TACE, a metalloprotease, is required for the membrane-associated
cytokine pro-TNF-α to be processed to the soluble form found in serum."

[ "... Tumor necrosis factor-alpha converting enzyme ..." ,
-- https://www.ncbi.nlm.nih.gov/pubmed/10849774 ,
"Their proteolytic activity is regulated by tissue inhibitors
of metalloproteinases (TIMPs)."
https://en.wikipedia.org/wiki/ADAM17
A peptidase, TACE/ADAM17 ... "Radiotherapy can induce a
dose-dependent increase of furin-mediated cleavage of
the ADAM17 proform to active ADAM17,...",
"[...] has a role in the shedding of L-selectin, a cellular adhesion molecule." ]

[_Proinflammatory cytokines regular tissue inhibitors of
metalloproteinases and disintegrin metalloproteinase
in cardiac cells._ https://academic.oup.com/cardiovascres/article/42/1/162/324432 .
"The hypothesis is further supported by the fact that
the TIMPs function as an important regulatory control
on the activity of metalloproteinases by stabilizing the
proenzymes and by inhibiting the active enzymes.
Downregulation of TIMPs alters the extracellular
matrix equilibrium towards matrix degradation and
leads to an increase in tissue turnover and accelerated
remodeling. Therefore, agents that restore the TIMP–metalloproteinase
equilibrium in cardiac tissues might have clinical relevance." ]


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136164/:

"... rhesus θ-defensin 1 (RTD-1) is an 18-residue, macrocyclic, tri-disulfide
antibiotic peptide first found in the granules of neutrophils and monocytes
of rhesus macaque leukocytes."

"All BALB/c mice treated intranasally with RTD-1 at 5 mg/kg 15 min
prior to exposure to a mouse-adapted strain of SARS-CoV (MA15)
survived the infection with minimal weight loss. SARS-CoV-infected
mice had altered lung tissue cytokine patterns at days 2 and 4 post-virus
exposure compared with those of untreated animals, including a robust
IL-6 response in RTD-1-treated mice, which was significantly greater than
the IL-6 response in infected, untreated mice at day 2 post-virus exposure
(p < 0.05). RTD-1 did not significantly inhibit virus replication in the lungs,
nor did the treatment seem to affect the observable lung pathology
in a profound way. Thus, RTD-1 probably has immune modulatory properties,
or its antiviral activity may be to delay or limit viral replication to a level or
rate below a critical threshold beyond which the host is unable to adequately
control the virus infection."

"... , the data show that the ability to nonspecifically enhance
immune protection against a respiratory virus, most notably
in the absence of significant pulmonary inflammation,
is a feasible way of preventing SARS infections."

"One issue that that makes it more difficult to treat infections
with recombinant interferons is the short serum half-life.
Thus, a number of things have been done to interferons
to stabilize them, including PEGylating the interferon."

"Inhibiting virus attachment by binding to the virus
may be another way of preventing a SARS infection in vivo.
Stinging nettle lectin, UDA, is an N-acetyl glucosamine-specific
lectin that was reported to be a potent and selective inhibitor
of the SARS-CoV strain Frankfurt-1 ."

"Plant lectins like UDA probably target viral attachment
and fusion, and exocytosis or egress of the virus from the cell."

[Ross A. Finlayson]

"...there was a large demand worldwide for full-length
sequenced clones of the various SARS coronavirus genes."

"... individuals convalescing from SARS are known
to develop high titres of neutralizing antibodies."

"The appearance of these neutralizing antibodies
coincided with the onset of resolution of SARS pneumonia."


https://www.nature.com/articles/nrmicro930


http://edelweisspublications.com/articles/48/640/virucidal-activities-zinc-finger-antiviral-proteins-zinc-binding-domains

"Virucidal Activities of Zinc-Finger Antiviral Proteins
and Zinc-Binding Domains for Virus Entry, DNA/RNA
Replication and Spread", 2020

"Zinc homeostasis is rebalanced during resolution
of the inflammatory response that intracellularly
increased zinc can intoxicate engulfed pathogens
and acts cytoprotective by promotion of neutralizing
Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS)"


"The influence of zinc on apoptosis is very complex
that variables in this complex network are tissue
and cell type, zinc concentration, expression of zinc
transporters and zinc-binding proteins, oxidative or
nitrosative stress and the improvement of molecular
opposing functions."

"Replication of SARS-CoV requires proteolytic processing
of the replicase polyprotein by two viral cystein proteases,
a chymotrypsin-like protease (3CLpro) and a
Papain-Like Protease (PLpro). "

"The MERS-CoV PLpro Blocking Loop 2 (BL2) structure
differs from that of SARS-CoV PLpro, ...".

"The papain-like protease 1 (PL1pro) domain
is present in nonstructural protein 3 (nsp3)
of alphacoronaviruses and subgroup 2a beta
coronaviruses and the papain-like protease 2
(PL2pro) is present in SARS-CoV. "

"Zn2+ ions are capable of inhibiting PLpro activity
and the zinc conjugates to inhibit SARS-CoV
PLpro activity that targeting PLpro with antiviral
drug may have an advantage in not only inhibiting
viral replication but also inhibiting the dysregulation
of signaling cascades infected cells, leading to cell
death [33]. Zn2+ inhibits coronavirus and arterivirus
RNA polymelase activity and zinc ionophores block
the virus replication that the combination of Zn2+
and pyrithione at low concentrations inhibits the
replication of SARS-CoV and arterivirus RNA [34]. "

"High zinc ion concentration and the addition of
compounds that stimulate cellular import of zinc
ions were found to inhibit the replication of various
RNA virus, influenza viruses, respiratory syncytial virus
and coronaviruses [34]. Further, zinc conjugated
complexes as SARS-CoV 3C-like protease inhibitors
play important role for this Zn2+-centered coordination
pattern that the zinc-coordinating inhibitor is
tetrahedrally coordinated to the His40-Cys147
catalytic dyad of CVB3 3Cpro [35,36]."

"ZAP-70 kinase regulates HIV cell-to-cell spread
that HIV usurps components of the immunological
synapse machinery to ensure its own spread
through cell-to-cell contacts."

"An understanding of viral cell-to-cell transmission
spreading will enhance our ability to intervene in
the efficient spreading of viral infection."


"... Junin virus ZBD displays a novel fold containing
two zinc ions, in which the structural basis for
retention of the unique SSP submit [?, ed.] suggests
a mechanism whereby SSP is positioned in the
GPC complex to modulate pH-dependent membrane fusion."

"A complex zinc finger ZBD [zinc binding domain] modulates
the enzymatic activities of coronaviridae-Nidovirus helicases,
leading that the ZBD is critically involved in nidovirus replication
and transcription."


Zinc supplement recommended for all? Zinc and copper?


https://www.ncbi.nlm.nih.gov/pubmed/15140896
"Furin inhibition by compounds of copper and zinc"

https://www.sciencedaily.com/releases/2015/06/150619085536.htm

Article notes zinc supplement might interfere with
copper uptake:

"These findings underline the lack of awareness of
zinc induced copper deficiency,' write the researchers,
who caution: 'zinc is an essential trace element, and
so clinicians may consider it a safe nutrient rather
than a drug carrying potential risk."

https://www.greatplainslaboratory.com/copper-test-1

"According to one cell-based study, ionic copper may
weakly block papain-like protease-2, a protein that
SARS-CoV requires to multiply. Ionic zinc can also
block this protein, but at much lower levels than copper."
-- https://selfhacked.com/blog/copper-coronavirus/

https://research.arizona.edu/stories/could-copper-disable-virus-behind-covid-19

"We are using a virus that mimics the SARS-CoV-2 virus,
but that will not cause disease."

[Ross A. Finlayson]

"Cytokine storm" -> ??? metalloproteinase matrix -> "thrombin burst".

It is ..., kind of like chicken-pox, the clotting. [Varicella zoster.]

When I was an infant I was hospitalized for a pneumonia.

I had chicken pox at about 6 or 7. It came and went.

For a year or two in high school I was always coughing
my lungs out. Many bronchial infections, but it didn't
seem to catch to others.

Pertussis toxins? Enterovirus D-68? Don't forget pertussis?

("PT clearly plays a central role in the pathogenesis of
pertussis although this was discovered only in the early 1980s."
-- https://en.wikipedia.org/wiki/Pertussis_toxin
"PT can cause severe neurological complications; however,
recently it has been found that the medicinal usage of
Pertussis toxin can promote the development of regulatory
T cells and prevent central nervous system autoimmune
disease, such as multiple sclerosis." ]

[https://en.wikipedia.org/wiki/Pertussis_toxin#Metabolism
PT is known to dissociate into two parts in the endoplasmic reticulum (ER):
the enzymatically active A subunit (S1) and the cell-binding B subunit.
The two subunits are separated by proteolic cleavage. The B subunit
will undergo ubiquitin-dependent degradation by the 26S proteasome.
However, the A subunit lacks lysine residues, which are essential for
ubiquitin-dependent degradation. Therefore, PT subunit A will not be
metabolized like most other proteins.]




"... raising concerns of incipient varicella encephalitis ...".
-- https://www.sciencedirect.com/science/article/pii/S120197120900099X

["Varicella-Associated Purpura Fulminans: Chicken Pox is
Not Always Benign", https://www.karger.com/article/pdf/92188
"Conclusion: This case report shows that [Purpura Fulminans] can
occur as a post-infection syndrome after primary varicella. Early and
aggressive treatment of post-chicken pox PF might reduce the mortality
and morbidity associated with this condition."]

["It has been discovered that purpura fulminans is almost always
associated with disseminated intravascular coagulation and can
occur in subjects with inherited or acquired deficiencies of the
protein C anticoagulant pathway. Patients with liver compromise
may also be potential candidates for coagulopathies secondary
to hepatic dysfunction and impaired protein synthesis."
-- https://www.ncbi.nlm.nih.gov/pubmed/8215490 ]

[ https://en.wikipedia.org/wiki/Purpura_fulminans ]



"Microthrombotic complications of varicella zoster are not unusual...".

https://www.sciencedirect.com/topics/medicine-and-dentistry/protein-s

Protein S, the co-factor: not the S-protein, the corona-spike-form.

"Acquired protein S deficiency can be due to decreased synthesis,
increased consumption, loss, or shift of free protein S to the bound
form. Decreased synthesis can occur in patients with severe liver
disease, in those given l-asparaginase, and in patients given
vitamin K antagonists."

"The pathophysiologic consequences of this phenomenon
are uncertain. An association between antiphospholipid
antibodies and acquired protein S deficiency has been
reported in patients with severe forms of varicella zoster
virus infection complicated by purpura fulminans."

"Protein S deficiency is found in <5% of patients with
hypercoagulable states and has an incidence of
1 in 2500 in the general population."

"C4BP functions as an important regulator in the
protein C–protein S inhibitor pathway."

"It now appears that many cases previously ascribed
to protein S deficiency may actually have been due
to the APC resistance defect resulting from factor V Leiden."

"Type I deficiency is associated with a decrease
in both total and free protein S antigen. Type II
deficiency is characterized by normal free protein
S antigen, but low protein S activity (APC cofactor
activity). Type III is associated with a selective decrease
in free protein S. The protein S gene and a homologous
pseudogene are both located on human chromosome 3.
Although a number of specific mutations leading to
protein S deficiency have been identified, DNA testing
is still limited to the research setting."

"A study of a large cohort of well-established protein
S-deficient patients and first degree relatives demonstrated
that low free protein S level is the most reliable screening
test for protein S deficiency. Patients carrying a protein S
deficiency mutation showed a fivefold increased risk of thrombosis."


https://en.wikipedia.org/wiki/Protein_S_deficiency
"... Protein S is made in liver cells and the Endothelium."

"Viral coagulopathy", "Review: Viral Infections and
Mechanisms of Thrombosis and Bleeding",
http://williams.medicine.wisc.edu/viral_coagulopathy_2012.pdf

"A better understanding of the pathophysiology
behind the association of viral infections and coagulation
disorders is crucial for developing therapeutic strategies."

"It is not yet clear why some viruses cause hemorrhaging
(e.g., Ebola),others are associated with thrombosis (e.g.,
cytomegalovirus) and yet others show both complications
(e.g.,varicella zoster virus)."

"Coagulation results from a series of linked coagulation
pro-tease–zymogen reactions, ultimately ensuing in the
formation of fibrin."

"Thrombin generation is induced by the assembly of
the tissue factor–factor VIIa complex. Thrombin is able
to convert fibrinogen into (insoluble) fibrin."

"Coagulation is regulated by different inhibitory mechanisms.
A first mechanism is made up of the circulating inhibitors of
blood coagulation: antithrombin and heparin cofactor II
(both inhibitors of thrombin), and tissue factor pathway
inhibitor. Two other circulating inhibitors of blood coagulation
are protein C and protein S (the latter of which is a cofactor
for the proper functioning of activated protein C). A second
inhibitory mechanism consists of the endothelium-bound
modulators heparin sulfate and thrombomodulin, which
facilitate the inhibitory activity of antithrombin and the
activation of protein C, respectively. The third element,
the fibrinolytic system, is necessary to degrade the formed
fibrin strands."


"These activators initiate the conversion of plasminogen
to plasmin,which hydrolyses polymerized fibrin strands
into soluble fibrin degradation products, thus degrading
the fibrin clot."

"A relatively recent outbreak of SARS [circa 2012], a novel coronavirus,
showed significant morbidity and mortality. The clinical picture
pertaining to coagulation consisted of vascular endothelial damage
in both small- and mid-sized pulmonary vessels, disseminated intravascular
coagulation, deep venous thrombosis and pulmonary thromboemboli
resulting in pulmonary infarction [Lee et al., 2003; Chong et al., 2004;Hwang et al., 2005]."

"Thrombocytopenia caused by autoantibodies has been
described in SARS, influenza, chronic parvovirus B19,
herpes virus, CMV, VZV, Epstein Barr virus, HIV, and
hepatitis A virus and hepatitis C virus infections."

"An increase in binding sites for inflammatory cells,
such as granulocytes and platelets, can lead to a
further shift of the endothelial cell surface from
thromboresistance to a prothrombotic condition.
These inflammatory cells produce procoagulant
cytokines, which further induce the expression
of prothrombotic endothelial cell protein."

"The tissue factor expression on endothelial cell
surfaces after infection, which leads to a reduced
clotting time, may be a direct virus effect but it
may also be triggered by cytokines, such as IL-6."

"Increased numbers of intravascular thrombi
and fibrin deposition in lungs were found in
cases of influenza, avian influenza, and SARS
infection, and these may well be the result of
disseminated intravascular coagulation and
microthrombosis ."

"Several viral infections lead to deficiencies in
the natural anticoagulants protein C,protein S,
antithrombin, and heparin cofactor II. It is well known
that these deficiencies are associated with an
increased risk of thrombosis."

"Probable deficiency mechanisms include autoantibodies
against protein C, protein S and antithrombin, as described
in VZV infections."

Macropinocytosis disorder -> ??? -> microthrombosis.

"... increased levels of plasminogen activator inhibitor-1
have been found in influenza, SARS, VZV, CMV, dengue,
and HIV infections."

"In HIV infection, elevated plasminogen activator
inhibitor-1 levels have been shown to be related
to the metabolic syndrome and the use of protease
inhibitors as part of the antiretroviral therapy."

"In addition to this, increased plasma concentrations
of tissue-plasminogen activator and soluble thrombomodulin
were found in SARS infections [Liuet al., 2005]. However assays
quantifying tissue-plasminogen activator and plasminogen
activator inhibitor-1 used to measure both the circulating
proteins as the protein complexes. Which makes it hard to
identify actual plasma levels."

"The decreased thrombin-activatable fibrinolysis inhibitor
activity may have been due to liver dysfunction during the infection."

Wow, the "Review: Viral infections and mechanisms of thrombosis
and bleeding" has really helped to illustrate the panoply of actions
of viral infections under coagulation and haemostasis.

( https://www.stoptheclot.org/health-professionals/ )

Figuring why the "macropinocytosis disorder" and cell-cell signaling
of the SARS leads to microthrombosis, I'm wondering about how it
has to do with metalloproteinase and active, pathogenic products
that result from the body's defense metabolizing (and deactivating)
the SARS viruses, as what the byproduct detritus is as well having
the active sites as "micro-RNA" or just proteins and enzymes.

https://www.hematology.org/covid-19/covid-19-and-coagulopathy

"Elevated D-dimer at admission and markedly increasing D-dimer levels
(3- to 4-fold) over time were associated with high mortality, likely
reflecting coagulation activation from infection/sepsis, cytokine storm
and impending organ failure."


"Individual patient assessment, however, is required
to balance risks of thrombosis and bleeding."


Euh...

Should COVID patients eat aspirin?
Maybe not while they're infected, no.
Maybe after the infection's beat down.
But, that might be a long time.

https://covid19-druginteractions.org/


"While [...] aims to provide a forum for the exchange of information
that is helpful, accurate and up-to-date, the relevant health information
and data concerning the disease, as well as the various governmental
actions and responses to the disease, are changing constantly, and
[...] makes no representation, warranty, or guaranty whatsoever as
to any information that may be exchanged through this webpage."



"Because the control of breathing is largely automatic
and the regulation of breathing is intimately associated
with autonomic functions, the respiratory control system
is often confused as part of the autonomic nervous system.
However, ventilatory control is in many respects more similar
to systems controlling somatic motor functions, such as walking."
-- https://www.sciencedirect.com/topics/medicine-and-dentistry/control-of-breathing

"During exercise, the use of oxygen and the production of carbon dioxide
increase. Yet the control of respiration is such that alveolar ventilation
is correspondingly increased and the blood gas levels remain within
normal limits, except during the most strenuous exercise. The central
chemoreceptors are certainly involved in this control, as are peripheral
reflexes from muscles and joints, but the whole picture is not clear;
perhaps other chemoreceptors (as yet undefined) in the lungs or the
pulmonary vasculature are involved."


[Much obliged to the sources of these extended quotes, and
hopefully they're correct and relevant and contextually appropriate,
i.e. any mistakes are my own, and disclaimed as above.

I.e.: one's at one's own _risk_ .]



Bonne chance!

[Ross A. Finlayson]

https://onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2141.2003.04608.x

https://www.ncbi.nlm.nih.gov/pubmed/12682352?dopt=Abstract

https://www.atsjournals.org/doi/full/10.1164/ajrccm.182.3.436

https://www.merckmanuals.com/professional/hematology-and-oncology/thrombotic-disorders/antiphospholipid-antibody-syndrome-aps

"Results of in vitro clotting tests may paradoxically be prolonged
because the autoantibodies to phospholipid-bound proteins interfere
with coagulation factor assembly and activation on the phospholipid
components added to plasma to initiate the tests. The lupus anticoagulant
is an autoantibody that binds to phospholipid-bound protein complexes.
It was initially recognized in patients with systemic lupus erythematosus (SLE),
but these patients now account for only a minority of people with the
autoantibody."

["Lupus, the auto-immune disease...."]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092895/
"Indeed, the generation of auto-antibodies against a
phospholipid protein complex (Lupus anticoagulants) [30]
and a glycan moiety of human serum glycoprotein asialo-orosomucoid [31]
in SARS-CoV infection has been suggested."

"A marked increase in proinflammatory cytokine IL-1β
has been observed in children suffering from SARS [38].
Recently, Mizutani et al. [39] have demonstrated that
phosphorylation of STAT 3 is suppressed in SARS-CoV-infected
Vero E6 cells. In the present study, we document the anti-N
antibody might cross-react with IL-11. These results suggest
a possibility that SARS-CoV infection results in modulating
cytokine responses. Hence, a detailed analysis of SARS patients’
sera on anti-cytokine activities, in particular of those samples
that derived from severely ill or deceased patients, might help
us to have a better understanding of the pathogenesis of the
SARS syndrome."

https://journals.lww.com/jclinrheum/Abstract/2010/03000/Osteonecrosis_in_Patients_After_Severe_Acute.2.aspx

"Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19"
https://www.nejm.org/doi/full/10.1056/NEJMc2007575

"Lupus ["weak"] anticoagulant was not detected in any of the patients,
although testing was performed while the patients were acutely ill."

"Antiphospholipid antibodies abnormally target phospholipid proteins,
and the presence of these antibodies is central to the diagnosis of the
antiphospholipid syndrome. However, these antibodies can also arise
transiently in patients with critical illness and various infections."

https://www.ncbi.nlm.nih.gov/pubmed/16701900?dopt=Abstract
"Various mechanisms may explain the role of [cytomegalovirus] in
thrombosis: this virus can damage endothelial cells, activate coagulation
factors, and induce production of antiphospholipid (aPL) antibodies."


http://www.ant-tnsjournal.com/Mag_Files/14-3/14-3_p113.pdf

"... hemagglutinating encephalomyelitis virus [ in SARS, ...]".

"The proposed mechanisms for such a hypercoagulable state
included: presence of antiphospholipid-anticardiolipin antibodies,
decreased activities of natural anticoagulants (especially protein S),
and enhancement of thrombin formation and platelet activation(40,41,45).
However, the actual mechanisms for SARS-related cerebral infarction
are not clear."


https://rebelem.com/covid-19-thrombosis-and-hemoglobin/

"Endothelial tumefaction (swelling) and large numbers of
pulmonary megakaryocytes in pulmonary capillaries
(Indicate activation of coagulation cascade)"

"
Hemoglobin (This section is theoretical at this point and it’s
clinical relevance is unknown):
[...]
3.COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism. ChemRxiv Preprint 2020. [Epub Ahead of Print]
[https://chemrxiv.org/articles/COVID-19_Disease_ORF8_and_Surface_Glycoprotein_Inhibit_Heme_Metabolism_by_Binding_to_Porphyrin/11938173 ]
[...]
12. Read RJ et al. Flawed Methods in “COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism” ChemRxiv Prepring 2020 [Epub Ahead of Print]
[https://chemrxiv.org/articles/Flawed_methods_in_COVID-19_Attacks_the_1-Beta_Chain_of_Hemoglobin_and_Captures_the_Porphyrin_to_Inhibit_Human_Heme_Metabolism_/12120912/1 ]
"

[Euh, ... "post-transcriptional glycosylation"? http://www.paper.edu.cn/scholar/showpdf/MUz2ANwIMTD0YxeQh ?
" ... the spike is localized along the
typical
secretion pathway from endoplasmic reticulum to plasma membrane."
(Here there are some "a-typical" pathways cell-cell, re, "macropinocytosis disorder".)
[ https://www.ncbi.nlm.nih.gov/pubmed/14633616 ... ,
https://www.ncbi.nlm.nih.gov/pubmed/30870427 ]
Cf. https://www.futuremedicine.com/doi/full/10.2217/fvl-2018-0008
"Accumulating evidence suggests that coronavirus proteins are modified
by various kinds of PTMs, which remarkably affect viral replication and
pathogenesis. In this review, we summarize the current knowledge on
PTMs of coronavirus proteins, including structural, nonstructural and
accessory proteins, with an emphasis on their roles and function in
coronavirus biology and host–virus interaction. The ability of some CoV
proteins to interfere with PTMs of host proteins will also be discussed."
]



https://scholar.google.com/scholar?cites=10260855021187735668

https://www.sciencedirect.com/science/article/pii/S2173580820300523

Euh, ..., "SARS: the brain disease".

"On 31 December 2019, the World Health Organization reported a novel
CoV (SARS-CoV-2) in patients with pneumonia in the city of Wuhan, in the
Chinese province of Hubei; it subsequently spread rapidly through China
and the rest of the world. The novel virus is classified as a βCoV and bears
considerable similarity to SARS-CoV. SARS-CoV-2 infection has been
declared a pandemic; it is associated with high mortality and has caused
significant societal impact. The virus is expected to infect a large proportion
of the world’s population. "


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138655/
"Overall, despite the indications that SARS-CoV-2 infection
might have an influence on normal hepatic functions and the
fact that drugs are used for the treatment of COVID-19 that
have proven hepatotoxic properties (whether or not due to
overdosing), more mechanistic studies regarding SARS-CoV-2
entry and replication in liver cells and the potential consequences
of medication for vital organs, including the liver, are warranted."

http://disq.us/p/289seyf
"Main findings and limitations : Using bioinformatics approaches
of RNASeq analysis, this study reveals that ACE2 dominates in
[bile duct] cholangiocytes and is present at very low levels in
[liver] hepatocytes. The study does not provide mechanistic
insights into how SARS-CoV-2 can infect and replicate in cholangiocytes
and the types of intrinsic anti-viral responses induced by cholangiocytes
when infected. In addition, because the study relies on the assumption
that SARS-CoV-2 infects cells only through ACE2, it cannot discount
the possibility that the virus can infect hepatocytes through mechanisms
other than ACE2-mediated entry. Furthermore, because the scRNA-seq
analysis were performed on healthy liver samples, one cannot draw
any definitive conclusions about gene expression states (including ACE2
expression in liver cell types) in system-wide inflammatory contexts."

[As from above: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC416513/ ,
https://www.ncbi.nlm.nih.gov/pubmed/14767982 .]

https://www.biorxiv.org/content/10.1101/2020.02.03.931766v1.full
"Based on the scRNA-seq data of two independent cohorts,
we have identified cholangiocyte-specific expression of ACE2
in healthy human livers and normal liver samples from colorectal
cancer patients. Since ACE2 is capable in mediating 2019-nCoV
and SARS infections, its expression pattern reveals possibility
for direct infection of cholangiocytes by 2019-nCoV and SARS.
However, our findings suggest that hepatocytes might not be
targeted by these viruses, or at least not through ACE2. Therefore,
we speculate that liver damages in patients infected by 2019n-CoV
might not be caused directly by viral infection of hepatocytes.
Cholangiocytes are multifunctional and play critical roles in liver
regeneration and immune responses [15]. Thus, the potential
damage of cholangiocytes by 2019-nCoV may lead to profound
consequences in the liver."

https://www.bmj.com/content/368/bmj.m1252/rr-3
"Subject to testing, the model suggests that advice to patients
should include avoiding alcohol, other liver-damaging substances,
and prescribed drugs that are metabolized in the liver."

https://twitter.com/lfoquet/status/1247222100605063169
-> https://onlinelibrary.wiley.com/doi/full/10.1002/path.1560

https://www.biorxiv.org/content/10.1101/2020.03.14.988345v1

"Chen et al., 2005, confirmed that SARS-CoV spike protein could not
bind to CD147 but they found that the N protein could only bind and
speculated that N protein is relocated to the surface from the core
during maturation of the virus."
-- http://disq.us/p/27yiost
(cf. https://www.ncbi.nlm.nih.gov/pubmed/15688292 ,
https://pdfs.semanticscholar.org/aa59/37b165338beef983f713efc60ba5a4f8580c.pdf :
"CD147 [which is not ACE2] plays a functional role in
facilitating invasion of host cells by SARS-CoV." )

( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167302/ ,
"In addition to ACE2, Wang and co-worker [8] recently demonstrated
that SARS-CoV-2 SP also binds to CD147." )

https://academic.oup.com/jid/article/191/5/755/1238824

https://www.jimmunol.org/content/jimmunol/181/9/6337.full.pdf

"In contrast, our current data suggest that N protein-immunized mice
exhibit activation of both Th1 and Th2 responses after SARS-CoV infection.
In agreement with our data, Jin et al. (54) have demonstrated that prior
immunization with N protein generates stronger Ag-specific Th1 and Th2
responses than immunization with M or E protein. In addition, we
demonstrate the suppression of anti-inflammatory cytokine responses
in N protein-immunized mice. Interestingly, Shi et al. (55) demonstrated
that coinjection of M protein with N protein not only enhanced the
production of Th1 cytokines (IFN-gamma and IL-2), but also reduced
the rates of mortality and pathologic change in SARS-CoV-infected voles.
These results suggest that further studies, including epitope analysis,
are required to reveal the precise mechanism underlying the severe
pulmonary inflammation that results from SARS-CoV infection of
BALB/c mice immunized with the N protein of SARS-CoV."

(Antigenic cross-reactivity.)

"In summary, we demonstrate that the immunization of BALB/c mice
with the N protein of SARS-CoV causes severe pulmonary inflammation
upon subsequent SARS-CoV infection, probably via the imbalance
created between T cell activation and suppression,as well as by massive
proinflammatory cytokine production. These results provide new insights
into the mechanisms involved in the pathogenesis of SARS and help in
the development of safe vaccines."

(The "antibodies" or "monoclonal rabbit antibodies", to SARS proteins,
can be ordered today on-line and in bulk, problem is getting them
introduced right.)

1) S-protein nose vaccine (pretty clear)
2) M/N-protein liver vaccine (not sure...)

(Antigenic cross-reactivity: Which one first?)

SARS: two (or, ... more) viruses in one.

https://www.biorxiv.org/content/10.1101/2020.03.15.993097v1

[Mostowski Collapse]

LoL, brainless copy pasta spaghetti napoli?

Am Freitag, 24. April 2020 10:52:41 UTC+2 schrieb Ross A. Finlayson:
> https://www.

[Ross A. Finlayson]

...

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167302/ :
"CD147 as a Target for COVID-19 Treatment: Suggested
Effects of Azithromycin and Stem Cell Engagement"

[Mostowski Collapse]

Does it hurt to be that stupid?

[Mostowski Collapse]

Its not that your posts have any redacted
or journalistic value. Its just unfiltered
citations, nobody knows their importance,

except the little man in Ross the Flosses
brain. Ever heard about approaches to
communicating science to the public?

[Ross A. Finlayson]

"Azithromycin added to hydroxychloroquine was
significantly more efficient for virus elimination."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102549/

The workers wrote:
"Such results are promising and open the possibility
of an international strategy to decision-makers to
fight this emerging viral infection in real-time even
if other strategies and research including vaccine development
could be also effective, but only in the future. We therefore
recommend that COVID-19 patients be treated with hydroxychloroquine
and azithromycin to cure their infection and to limit the
transmission of the virus to other people in order to curb
the spread of COVID-19 in the world."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102549/table/tbl0003/?report=objectonly


If azithromycin plus hydroxychloroquine is an effective anti-viral,
those are also generic and already mass-manufactured.

(Or doxycycline, or other halides. "At subantimicrobial doses,
doxycycline is an inhibitor of matrix metalloproteases, and has
been used in various experimental systems for this purpose, such
as for recalcitrant recurrent corneal erosions.")

(Of course the sample size in that study is totally small,
but 100% remission is promising.)


Finding a vaccine has that the CD147 (and not just ACE2, Burse)
infections and neutralizing them is one thing, there's another
notion that cultivating an immune response (a vaccine) has
a tripwire. Otherwise it would be quite simple to introduce
antibodies for the immune system to pick up, i.e., it's "novel".

This is (not good) news to the community that would be printing
out vaccines of known common viruses, pretty much readily.

Plenty other of this conventional wisdom of this "novel
coronavirus" like "it's pneumonia not a catastrophic syncytia"
or "it's always accompanied with fever mm k maybe not all the time",
that conventional wisdom has been upended.

More conventional wisdom, Burse?


See above for collected reports as represent detail on
answering more the question words of COVID-19.


If azithromycin plus hydroxycholoroquine stops viral replication
within a few weeks and with few side effects, coronavirus patients
have a recommendation from that study's authors that it's the way.

For some people that won't work, but from at least one controlled
experiment, i.e. doing science, it will.

"P Gautret - ‎2020 - ‎Cited by 340"

A treatment course and vaccine will necessarily have to be
very economical to treat all the peoples.

Or, market forces shall make it so.

It's very good news that there's a cheap and at least
partially confirmed in a controlled experiment anti-viral,
that stops the progression of SARS syndrome,
then getting a vaccine right and simply releasing it into
the wild for everybody to get, is more than less economical.


The article above: "CD147 ...", Burse, has some more
technical detail as to the workings of structurally,
these things. One can well expect there will be
more of them, and soon.


Much thanks to those authors, I hope it comes out OK.






"This in turn explains the common sense knowledge problem. [...]
In each of these areas and many more, calculative rationality,
which is sought for good reasons, means a loss of expertise.
But in facing the complex issues before us we need all the
wisdom we can find. Therefore, society must clearly distinguish
its members who have intuitive expertise from those who have
only calculative rationality. It must encourage its children to cultivate
their intuitive capacities in order that they may achieve expertise,
not encourage them to reason calculatively and thereby become
human logic machines. In general, to preserve expertise we must
foster intuition all levels of decision making, otherwise wisdom
will become an endangered species of knowledge."
-- http://www2.psych.utoronto.ca/users/reingold/courses/ai/cache/Socrates.html

"Deliberative rationality is detached, reasoned observation of one's
intuitive, practice-based behavior with an eye to challenging, and
perhaps improving, intuition without replacing it by the purely
theory-based action of the novice, advanced beginner or competent performer."


"Searle emphasizes the fact that this kind of symbol manipulation
is syntactic (borrowing a term from the study of grammar). The
computer manipulates the symbols using a form of syntax rules,
without any knowledge of the symbol's semantics (that is, their meaning)."
-- https://en.wikipedia.org/wiki/Chinese_room

[Mostowski Collapse]

I nowhere mentioned ACE2 ever in one of my posts.
Thats the little man in your head which is aroused.

What does it mean, a new route for invading host
cells? That SARS-CoV-2 is even more dangerous?

LoL

[Mostowski Collapse]

On comp.lang.prolog I mentioned:

The novel coronavirus 2019 (2019-nCoV) uses the SARS-
coronavirus receptor ACE2 and the cellular protease TMPRSS2
for entry into target cells
https://www.biorxiv.org/content/10.1101/2020.01.31.929042v1

[Mostowski Collapse]

CD147 is involved in tropical malaria. But
concerning SARS-Cov-2:

Eric Billy - hypothesis of CD147 if super-poor.
it is based on a pre-print based on study of
interaction of purified proteins. the cellular
infection assay is weird, as it scores only
infection, but they claim replication
blocking -> I am not

https://www.biorxiv.org/content/10.1101/2020.03.14.988345v1

[Ross A. Finlayson]

It's about the liver, Burse, but I already shewed you
that much earlier in the thread. It's just an example
of something Burse thought was so, and it wasn't, and
I put together how it is, so, then he (or, it, one of
Burse's bots) giggles and puts it off with some baby-talk
diminutives, yeah, that was to make you look bad, Burse.
(Don't worry, Burse, if being a douche is sanitary you're
way ahead.)



https://www.journals.elsevier.com/international-journal-of-antimicrobial-agents/news/joint-isac-and-elsevier-statement-on-gautret-et-al-paper

"The WHO has included chloroquine/hydroxychloroquine as
one of four drugs to be evaluated in the SOLIDARITY mega-trial."

https://www.ncbi.nlm.nih.gov/pubmed/32229706
"As Azithromycin and Doxycycline are both commonly used
antibiotics that inhibit viral replication and IL-6 production,
we may want to consider this general class of antibiotics
that functionally inhibits cellular protein synthesis as a side-effect,
for the treatment and prevention of COVID-19 disease."

[The "senolytics" is a bit new-agey yet it's still the
same point.]

Now, we're here familiar with "probability theory"
and "statistical tests of statistical hypotheses", here
an article analyzes Gautret et alia from the issue of
non-randomization of the controls and small sample size.

https://www.medrxiv.org/content/10.1101/2020.03.31.20048777v1

https://clinicaltrials.gov/ct2/results?cond=SARS-CoV+2&term=azithromycin&cntry=&state=&city=&dist=

There's about 40 or more clinical trials (of zithromax and hydroxychloroquine),
getting going.

Official Title: Efficacy of Novel Agents for Treatment of SARS-CoV-2 Infection Among High-Risk Outpatient Adults: An Adaptive Randomized Platform Trial
Actual Study Start Date : April 16, 2020
Estimated Primary Completion Date : July 2020

Now, when Trump said "hydroxychloroquine is promising", and
we looked it up and it's an anti-malarial and scoffed because
Trump is often wrong, when later "results were mixed", lots of
people the rest-of-the-way round-filed the idea. Studying these
mechanisms of virus disease and SARS, MERS, COVID-19, and
why one of the actions of HCQ and AZ together is anti-viral,
and particularly anti-SARS and anti-COVID, I'm willing to overlook
that Trump had a good tip, in the interests of public health.
If Trump is actually eating HCQ and AZ on the advice of his doctor
as a prophylaxis against COVID, that's what he should say.
(It's anecdotal that tons of people are.)

Doctors can prescribe hydroxychloroquine and azithromycin
(or for example erythromycin) off-label.

(Of course one might note erythromycin might not mix with
statins, but we already heard ARBs are bad for ARDS, and there's
"no clinical evidence", but some ancedotes, that any of a variety
of usual maintenance drugs increase risk from SARS. Some people
can eat erythromycin just fine. Over here statins are totally
prescribed to most people over 50 instead of resins. Speaking
of cholesterol medications, ..., most people with "pre-existing
conditions" are on "pre-existing drugs".)

"Many people may be surprised to know
that the FDA regulates drug approval,
not drug prescribing, and ... doctors are
free to prescribe a drug for any [reason
they think is medically appropriate]." -- https://www.webmd.com/a-to-z-guides/features/off-label-drug-use-what-you-need-to-know#1


(Of course their lawyers would have to care if "off-label malpractice",
but here for the sake of simplicity we assume that doctors
are never guilty of malpractice.)


In Soviet China, everybody's prescribed it.


"FDA issued an Emergency Use Authorization (EUA) to authorize
use of chloroquine and hydroxychloroquine from the Strategic
National Stockpile for treatment of hospitalized adults and
adolescents (weight ≥50 kg) with COVID-19 for whom a clinical
trial is not available or participation is not feasible. The prescribing
health care provider is responsible for submitting patient outcomes
reports as described in the Emergency Use Authorization, and all
serious adverse events and medication errors should be reported
to FDA’s medical product safety reporting program MedWatch."

See https://www.fda.gov/media/136784/download.

https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-therapeutics-tracker

https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/

"The panel agreed that the overall certainty of evidence
was very low due to concerns with risk of bias, inconsistency,
indirectness, imprecision, and publication bias."

The approach of "here's a huge clinical trial, that the
controlled blind gets the emergency room or ICU placebo,
or sits it out in quiet desperation, because the infection rate
is so high we're quite sure so many people got it, let's see
how many survive, then test those left", seems a bit off-putting.

[Instead, some of the public expects "our germ warfare unit
made a SARS-Lite that should be pretty free of complications".]


Treatment today as "sit it out", or, "wash your hands,
and sit it out", ..., doesn't sit well. (Don't get me wrong -
closures has slowed the spread of coronavirus pandemic.
The campfire bonhomie though has about got boring.)
"Wash your hands of it, hide your face of it, and sit it out",
does not sit well.


https://www.nydailynews.com/coronavirus/ny-coronavirus-cuomo-20200423-alxgtumui5hk3odbusu2yr6kxq-story.html
"Statewide, 13.9% of New Yorkers tested positive
for the antibodies that are produced when people
fight off the virus."
"New Yorkers have died in the past two months
a rate much higher than previous years, suggesting
that coronavirus is killing far more people than the
official figures say."

They surveyed people in line for groceries, so, assuming
the rest of New York ever leaves their house, and any
grocer survives, everybody gets it. (Lions sleep or eat.)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195546/

(Looking at zinc and an alkalizing diet as helping.)


(P.s. it's "normalcy" here, not "normality".
And it's pretty normal, too. )


Many vaccine preparations are underway. Just today an
article from Rancho Cordova suggests at least one such
product will be available within some few months.

https://www.sacbee.com/news/coronavirus/article242173766.html


“We are so advanced at this because we leveraged our
unique global resources,” Xu said. “When this epidemic
started to surface in Asia, we have several top universities
in China where we collaborate and developed the science behind
this and did the screening. So now we are probably at least
four to six months ahead of any other comparable research
institution here (in the US).”

Read more here: https://www.sacbee.com/news/coronavirus/article242173766.html#storylink=cpy

Aww..., the magic of technology transfer, incubating private enterprise.

But, there might be better results for others with
different preparations.


Good luck all!

[Mostowski Collapse]

Also the market for liver organs was going
down, similar like oil market. Only des-
infectant markets are high right now.

I guess you wont get much for your liver now.

[Mostowski Collapse]

Anyway, who needs a liver if you have desinfectants?

[Ross A. Finlayson]

Here the theory is that the lysozome breaks
the S-protein, which reconnects itself with
other broken proteins, for making the forward
response, making the S-protein endpoint connectors,
as that the macrocytes naturally haul them away.

A "cell mower" lysosome motile for under furanosides
at the cellular interface, here is for cleaning up the
residues spewing out of the infection units, on the cells,
about the primary role of the S-protein itself and its
production, in serum and in the cells, here for the
S-protein cloud, energized by breaking and reconnecting,
that the active site on the S-protein, is reactive with
active sites and their lysosome induced deformation,
of other components after bodily infection, here for
immune clearance and deactivation of the S-protein
as of its free expression in the cellular matrix.

Activating motile macrophages about the cell, and
for that under the S-protein itself it's a natural state
of macrophage action, here is for the deactivation
of the S-protein, on the cell, or while it is in the cell,
then what for to do the broken parts of the primary
active component of the mechanism of the action of
the S-protein, that the lysosome of the cell wall induces.

Immunizing the B cells from the liver for S-proteins
from the corona virus (and other proteins), here is
for making the concomitant usual effects, that under
recognition factors for the cells, that the B-cell's have
a right conditioned response, when the cellular machinery
responds to usual genetic action.

Getting the B cells from the liver and resident action under
neutrophils, is for investing the liver with an antibody
presentation, as what it has under bad catalog, wrong response
on cell activation and deference.

Here the the catalog of immune response, is for what as
conditioning the response, makes for first virus response,
as what the B-cells are left conditioned to of course still just
activation under recognizers, that their "slow action" response,
induces a protein of another B-cell the B-cell resident
"antibodies".

The liver quite invests itself in working under all the
products of the usual lysome destruction of the protein,
cataloging under effect "bad hits" just under the algorithm,
expecting to break the protein "randomly" but that the
instead the S-protein's fragment leaves the liver with
not finding S-protein matches under protein, populating
the B-cell's with the antibody catalog content.

Liver algorithm of S-protein destruction fragments under B-cells

"SEPPA 3.0 - enhanced spatial epitope prediction
enabling glycoprotein antigens"
https://academic.oup.com/nar/article/47/W1/W388/5494762

"B-cell epitope information is critical to immune therapy
and vaccine design. Protein epitopes can be significantly
affected by glycosylation, while no methods have considered
this till now. Based on previous versions of Spatial Epitope
Prediction of Protein Antigens (SEPPA), we here present
an enhanced tool SEPPA 3.0, enabling glycoprotein antigens."


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2708941/

"Autoantibodies target nuclear antigens
(antinuclear antibodies, ANA),
smooth muscle antigens (SMA),
liver-kidney microsomes (LKM-1) and/or
soluble liver antigen/liver-pancreas antigen (SLA/LP)."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949635/
"B cells perform various immunological functions
that include
production of antibody,
presentation of antigens,
secretion of multiple cytokines and
regulation of immune responses
mainly via their secretion of interleukin (IL)-10."

"These findings suggest that hepatic B cells
have the potential to initiate
rather than regulate
inflammatory responses."

"As a major lymphoid organ that extracts nutrients
from the portal venous blood, the liver is under
constant immunological challenge by gut-derived
dietary and microbial commensal products,[....]"

"In this study we demonstrate that,
unlike splenic B cells, hepatic B cells
lack B10 cells and comprise significantly
smaller proportions of B1a and
marginal zone (MZ)-like B cells."


https://www.pnas.org/content/107/19/8766

Figuring out how to recruit a proper B-cell response from
the various sources of B-cells, and their organization, here
is for figuring out what is the combined virus mechanism
as besides what the B-cells are already organized, they would
be disorganized by the immunological, and, viral load on the
liver, about what and why it's possible that hepatic B-cell's
in disorder are strongly associated with attacks in immune
response.


https://www.nature.com/articles/cmi20163 :
"The human liver is usually perceived as a non-immunological
organ engaged primarily in metabolic, nutrient storage and
detoxification activities. However, we now know that the
healthy liver is also a site of complex immunological activity
mediated by a diverse immune cell repertoire as well as
non-hematopoietic cell populations. "

"In this complex microenvironment, the hepatic immune system
tolerates harmless molecules while at the same time remaining
alert to possible infectious agents, malignant cells or tissue damage."

"Hepatic inflammatory mechanisms therefore have a spectrum
of roles in the healthy adult liver; they are essential to maintain
tissue and organ homeostasis and, when dysregulated, are key
drivers of the liver pathology associated with chronic infection,
autoimmunity and malignancy."

"In healthy individuals, the liver is constantly bombarded
by a stream of dietary and commensal bacterial products
with inflammatory potential. These gut-derived molecules
must be tolerated by the hepatic immune system, which,
at the same time, is poised to respond to danger. In the
healthy liver, constantly changing metabolic and tissue
remodeling activity, combined with regular exposure to
microbial products, results in persistent, regulated inflammation. "

"These inflammatory processes act in a tightly controlled
fashion and are stimulated to additional activity only
when the liver is required to rid itself of hepatotropic
pathogens, malignant cells or toxic products of metabolic
activity. Failure to clear such dangerous stimuli and resolve
inflammation, leads to chronic infection, autoimmunity
or tumor growth."


https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep4.1200

"These findings suggest immune cells migrating
from the gut to the liver drive hepatic inflammation
and antigens shared between both tissue compartments
may trigger the activation of adaptive immunity [...]".

"... findings of bile duct irregularities on cholangiography."

https://www.ncbi.nlm.nih.gov/books/NBK493190/
"Percutaneous transhepatic cholangiogram ...".


"This extrahepatic anatomic configuration, on the one hand,
is almost invariable.

The configuration of the ducts within the liver,
on the other hand, is variable (see diagram
"bile duct anatomy"). The most common configuration,
seen in about 50% of people, is a single duct draining
the left lobe and a single duct formed by the union
of an anterior and posterior duct draining the right lobe.
The most common variant of this configuration is a
right anterior segmental branch that drains directly
into the CBD and a right posterior segmental branch
that drains elsewhere. The right anterior duct
(draining segments V and VIII) usually courses
in a somewhat craniocaudal orientation, while
the right posterior duct (draining segments VI and VII)
usually courses more lateromedially."

https://rupress.org/jem/article/187/8/1325/7611/B-1-Cell-Development-Evidence-for-an-Uncommitted

"At least two B cell subsets, B-1 and B-2, are present
in the mouse periphery (1–4). One of the most intriguing
aspects of these subsets is that they exhibit different
repertoires (5), presumably reflecting different functions
in the immune system."

"B-2 cells appear to be responsible for T cell-dependent
responses to exogenous antigens and for generating
memory B cells (4). In contrast, the B-1 subset harbors
a high frequency of cells with specificities to self-antigens
such as phosphatidyl choline (PtC),1 immunoglobulin
(rheumatoid factor), DNA, as well as specificities to
common bacterial carbohydrate antigens like
phosphorylcholine (6–10), and may be involved in
T cell-independent responses to common environmental antigens."

"Critical to understanding how B-1 and B-2 repertoires arise
is the relationship between the cells of these subsets.
The more commonly held view (the lineage hypothesis)
is that B-1 and B-2 cells derive from stem cells committed
to one or the other subset before Ig gene rearrangement,
thereby constituting two separate lineages (13–15). An
alternative hypothesis (the induced differentiation hypothesis)
is that they derive from a single lineage, and that an uncommitted
B cell is induced to differentiate to a B-1 cell after Ig gene
rearrangement by interaction with antigen, probably
T cell-independent antigens in the absence of T cell help (16, 17).
Since by this hypothesis the majority of splenic B cells
are uncommitted, they are referred to as B-0 cells. Thus,
the B-2 cells of the lineage hypothesis and the B-0 cells
of the induced differentiation hypothesis are equivalent
and referred to here as B-0. Each hypothesis predicts a
different means of arriving at distinct B-1 and B-0 repertoires."


"This mechanism is consistent with the induced differentiation
hypothesis in which commitment to the B-1 lineage occurs
after Ig gene rearrangement, is dependent on the specificity
of the B cell, and follows antigen stimulation. It is incompatible
with the two-lineage model of B cell development, which
requires commitment to one cell lineage or the other before
Ig gene rearrangement, and which does not accommodate
movement of cells from one subset to the other. Thus,
these data argue for a single B cell lineage that can give rise
to B-1 cells upon activation. An implication of this conclusion
is that the B-1 repertoire includes only antigen-selected B cells,
and that at no time is it equivalent to the B-0 repertoire."

https://www.nature.com/articles/s41467-019-12824-z
"B-1a cells are long-lived, self-renewing innate-like B cells
that predominantly inhabit the peritoneal and pleural cavities.
In contrast to conventional B-2 cells, B-1a cells have a receptor
repertoire that is biased towards bacterial and self-antigens,
promoting a rapid response to infection and clearing of apoptotic cells. "

https://www.nature.com/articles/s41467-019-12824-z
"This ‘alternate pathway’ of development enables
the production of B cells with self-reactive,
skewed specificity receptors that are peculiar
to the B-1a compartment. Together our findings
connect seemingly opposing lineage and selection
models of B-1a cell development and explain how
these cells acquire their unique properties."

"The lineage switch is rapid, induces a proliferative burst,
and cells migrate to their normal environments within
the pleural and peritoneal cavities."

"In the fetus, B-cell development takes place in the liver
and moves to the bone marrow after birth."


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789244/

"Signaling by vitamin A through its active metabolite
retinoic acid (RA) is critical for the normal development
and functions of the hematopoietic and immune systems."



Tranquilizing the B cell, briefly, would be for toxins.

[Mostowski Collapse]

The liver is only one of trash bin of the immune system.
The main work is done by the lymphatic system. Like 15%
of the blood goes through the lymphatic system. Lymph is
moved through the system by muscle contractions.

The lymphatic system collects waste and debris, and
returns it into the blood stream. Maybe the blood
stream has more trash bins than only the liver, since
since more organs transform blood into other things.

Further candidates are sweating and urine.

See also:

How does the body eliminate nanoparticles?
https://www.nanopartikel.info/en/nanoinfo/body-barriers/2103-how-does-the-body-dispose-of-nanoparticles

[Mostowski Collapse]

In as far the first responder is possible the
lymphatic system and not the liver. Also the
liver is not consider a lymphoid organ.

The lymphoid organs are listed here:

https://en.wikipedia.org/wiki/Lymphatic_system#Primary_lymphoid_organs

https://en.wikipedia.org/wiki/Lymphatic_system#Secondary_lymphoid_organs

Lymbphs are also found in the intestinal villi.
They absorbe some nutrients and deliver them
to other organs.

In general I have the impression that the
immmunesystem tries to recycle waste and debris
where possible.

[Mostowski Collapse]

New McDonalds drive in after corona:

**New**
Virus patty, rich on nutrients.
**New**

See also:

Enveloped viruses acquire lipid membranes as their outer coat
Viruses and Lipids
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3187601/

[Ross A. Finlayson]

Lymph: the T-cell highway.



"Conclusions: Without special surface alteration
more than 90 % of the nanoparticles
are recognised by the RES, taken up by these cells,
and then disposed and eliminated from the body.
For these reasons, particles for therapeutic purposes
have to be especially designed for instance
to achieve an enhanced tumour concentration."

I.e., it's a requirement but not good.

"The reticulohistocytic system...", "... also named
reticuloendithelial system (RES)
or mononuclear phagocyte system (MPS)
is a network of cells and tissues ...".

nanopartikel.info ....

Here the "nano-particle" action is "getting rid of
the lysosome-mediated virus shakings and disassembly",
getting the body to tear-down and clear up [in] the cytosome.

[Ross A. Finlayson]

Initiating the T-cell is for, at the matrix where the
S-protein is as the interface to the cell wall, that
it guides in usual vesicles and with their splitting
action engages the endoplasmic reticulum, is for
making that as a bacterio- or phagic, not to initiate
all the anti-bacterial as microcidal, still though that
the initiated response is under disruption, what is
that the S-protein activation site, about half-way up
for SARS-2 and one up for MERS, or down, that the
exposure reaction under the various cleavage activation
sites, would be for tagging the payload or walking up
the monomer, along the lines of rotating or making
a polymer reaction, here would be for lipids attaching
to the payload capsids, so that some "usual" S-protein
activation in intercellular activity under its action in
the macrocytic intracellular activity, that its not the
mechanism or the S-protein itself, but what how the
body is otherwise working the free monomers and
polymers in the solution that the SARS, MERS, and SARS-2,
and here MERS and SARS-2, has the particular lever of
the action of the cell association to the macropinocytic,
that the surrounding media of the intercellular matrix is
all ingested through the cell wall in cellular pressure.

I.e., this suggests that the body's reaction to infection of
the SARS, is employed by the virus, to shake up the virion
and break off its parts that float up to the cell wall where
they are brought about with the other vesicle activity,
this is the exoribosome effect, that for example otherwise
the exoribosome would be maintaining the cell wall
between cytosis and integrity the cell wall and by the
lysosome. The cytome as lysome then is as usual enough
for cytome and transport.


"Maturation of the virus" here must be its evolved viral
defense mechanism as some otherwise totally obvious
anti-viral response, for example in chain reaction. Here
one could for example imagine conformations of crossings,
in statically aligned charged particle in solution.

I.e. I have a microphysics view of basically the virion, then
the point being that it's all about the site, for all the "virion"
of the biome of the site, here that the body must have a catalog
for all the other evolved mechanism of the mechanism, of how
the virus is organized, as the body as so organized (and in dysregulation).

Then the point that B-cell proliferation is systemic, and the catalog,
for memory of immune response, and that T-cell's, with their various
actions, or otherwise B-cell responses are read out from catalog,
T-cell's in B-cell organized responses, make for usual programs of
tissue segmentation.

With the idea that T-cell initiation is "orchestration", of response,
lies under generally signals and what would be the nervous,
"orchestration of immune response", that that anti-microbial
and anti-viral immune response, are basically separate, also
both combined.

[Mostowski Collapse]

Hey Ross the Floss, Doctor Coronaris.
What about an estrogen therapy?

Scientists trial female sex hormone for Covid-19 patients
https://edition.cnn.com/videos/world/2020/04/28/estrogen-coronavirus-covid-19-pandemic-study-female-sex-hormone-curnow-intv-intl-ldn-vpx.cnn/video/playlists/coronavirus-intl/

[Ross A. Finlayson]

"Hormones", Burse, those are "hormones".

Everybody has estrogen.

Progesterone: the hormone.

Biomimetic cream?

Besides growth hormones under precursor hormones,
serum hormones run under secretion.

Xenohormones are kind of unavoidable in the
environment, not eating them.

Licorice or the glycorhizzal, it's a phytoestrogen.

No, it's not so much about the overall immune response,
having hormones in the lymph and so on from the glands.

Adrenalin: the hormone.

[Ross A. Finlayson]

On Tuesday, April 28, 2020 at 9:12:18 AM UTC-7, Ross A. Finlayson wrote:
> On Monday, April 27, 2020 at 3:03:47 AM UTC-7, Mostowski Collapse wrote:
> > The liver is only one of trash bin of the immune system.
> > The main work is done by the lymphatic system. Like 15%
> > of the blood goes through the lymphatic system. Lymph is
> > moved through the system by muscle contractions.
> >
> > The lymphatic system collects waste and debris, and
> > returns it into the blood stream. Maybe the blood
> > stream has more trash bins than only the liver, since
> > since more organs transform blood into other things.
> >
> > Further candidates are sweating and urine.
> >

"... protein S deficiency mutation ..."

Here that's the blood protein, protein S,
deficiency in protein S is rare in people,
and here for example illustrates five times
risk. It's associated with the liver function
that the overload of processing, it seems,
under the liver, for blood protein synthesis,
that it's the residual effect then letting out
the disease, under anticoagulation as usual
effective cytosis like hydration.

I.e., it seems, that's what is getting let out,
for the usual liver metabolism, as above in
the thread's material, there is a connection
to an association and about the various parts
of virus, that the variable concern then is for
understanding what would be the rare cytosis,
when testing is otherwise under the usual numbers
(and under checkups).

[
Then, the "protein S" or fibrin-S, as what is involved
in fibrolysis and anti-clotting in the natural amounts
involved, sees as for its deficiency (or consumption,
plainly), as for under what must be the "innocuous"
conditions, as what wouldn't be under recombinant
knockout, the protein's miscalculation or dysregulation
in the liver, as what is otherwise keeping its usual state.
]

Protein S deficiency mutation!

How to check and test for protein S deficiency mutations,
in the liver, is that the liver makes work for itself and distress
running backwards its protein machines in a general humoral
rejection. The protein S deficiency mutations, would probably
be causing some "beneficial" or "elevated" response, in other
condition, at the same time, in tremoral heartrate, or otherwise,
as what under some usual palliative condition, inspired by the virus,
here is for finding the metalloprotease under usual cases of good ease.

Find a particular type of food rejection as helping establish the
presence of the condition, then, establishing the particulars that
the protein S deficiency "mutation" (i.e., not the rare disease) is
actually something that can be reversed, is given the body's own
immune response, but that is a state.

"Protein S" is not the "S-protein".

https://www.mlo-online.com/home/article/13004628/siemens-releases-new-assay-for-specific-and-stable-free-protein-s-antigen-testing

"Protein S, a plasma protein manufactured in the liver,
is an anticoagulant that functions as a cofactor
for protein C-mediated inhibition of
activated factors V and VIII.
People with protein S deficiency, congenital or acquired,
are at greater risk for venous thrombosis.
Therefore, testing for protein S plays an important role
in thrombophilia screening."

I imagine the virus plays a role in longevity under replication,
or the purpose of one of the proteins, why it affects
young people less, as they don't already have lifetime
genetic damage.

https://radiopaedia.org/articles/covid-19-3?lang=us

"The definitive test for SARS-CoV-2 is the real-time
reverse transcriptase-polymerase chain reaction (RT-PCR) test.
It is believed to be highly specific, but with sensitivity reported
as low as 60-70% ... and as high as 95-97% .... Meta-analysis ... has
reported the pooled sensitivity of RT-PCR to be 89%. Thus,
false negatives are a real clinical problem, and several
negative tests might be required in a single case
to be confident about excluding the disease."


"The most common ancillary laboratory findings
in a study of 138 hospitalized patients were the following ...,...:

lymphopenia
increased prothrombin time (PT)
increased lactate dehydrogenase

Mild elevations of inflammatory markers (CRP 89 and ESR)
and D-dimer are also seen."


Making a simple test for "raging liver infection"
could help identify seeming imbalances in condition.

Fire in the belly?

Might just be burning fat.

Virulence in SARS, is very high because SARS is
very contagious, it is a contagion. SARS gets hauled
along in the nuclear components the initial reaction,
to the matchers, that the cold virus is metabolized
with its reaction products. Also dripping in cold response,
makes for components of SARS as airborne coronavirus.
Besides the S-protein then the related co-proteins that
make for SARS transmission, is among then setting conditions
on the liver for liver function, not fully expressing so generating
garbage machinery, for the liver to clean up. (Which it does.)

The liver usual resolves everything it gets and among machines
and the other organs of metabolism, is for understanding the
states of the liver, as a usual systolic cholesterol machine.

Quoting:

"These results suggest that further studies,
including epitope analysis,
are required to reveal the precise mechanism
underlying the severe pulmonary inflammation
that results from SARS-CoV infection of
BALB/c mice immunized with the N protein of SARS-CoV."

Using an N-protein as the immunizer, here is for unlocking
and resetting for example after exposure, then also that
the usual reactive products, are under the stimulus, and
associated with the condition, for an "immune reset" in
the liver to activate thusly a conditioned vaccine.

It seems this makes for besides the usual vaccine, to get
the first shot, wait for some hours, then get the second shot,
the actual vaccine, making way to clear out the liver infection,
for taking the vaccine and under N capsids.

"In summary, we demonstrate that the
immunization of BALB/c mice
with the N protein of SARS-CoV
causes severe pulmonary inflammation
upon subsequent SARS-CoV infection,
probably via the imbalance created
between T cell activation and suppression,
as well as by massive
proinflammatory cytokine production."

Here then one wonders the SARS strongly programs
its own response, more or less as a successful algorithm,
that when its infects where the antibody profile was
installed in the mice, the "auto-antibodies", here "anti-
anti-bodies", strongly react with immune system response,
as being so decentralized, as when the gut gets liver
components out of phlegm and from the lymph and
the digestive. Meeting together later in a time release
in the liver, it overreacts then must be terrified with
some "successful" regulation mechanism, symbolically,
why the associated syndromes are so reactive in immune
system machinery, there isn't though moderated the
auto-immune response, disease.

Time-of-day and diurnal associations or anecdotes,
disease progression, figuring out effective tests for
things, here is for figuring out the minimally invasive,
in the tests, and for example for activating colorants.


I'm under the impression that COVID N-protein metabolism
in the liver symbolically mimics protein S deficiency, and that,
the body's response to N-capsids is very strong, about what
must be restoring autophagy of infectious and disease material,
including conditioning autophagy to not rush the N-capsid
payload to the dumpster (where it thrives).

Interrupting N-capsid replication upstream seems where to
prevent the disease associated with N-capsid and other virus
payloads, as what the immune response to detecting extra-genetic
material is to metabolize and dispose, to condition the serum,
that the body handles the tear-down of S-protein and doesn't
suffer the secondaries that the virus maturation of the N-protein
is replaced in function by natural analogs (regulated).

Finding a vaccine involves peptides or epitopes for the antibodies,
for autophagy, then also conditions about what immune response
happens to break the particular parts of the virus that make it
successful (in infection or otherwise as dys-regulating).

I.e., programming the immune response where there is "antigen
cross-reaction" is problematic because the body would interpret
usual reverses as inputs, that for example could be systemic.
Programming the immune response with antibodies is definitely
part of healing from viral infection, here as what resonant or
sympathetic responses are confounded by the particulars of all
the virus mechanism components on the payload of the genetic
machinery, and how the body generally involves update and
maintenance of genetic machinery, that the right antibodies
includes discriminating among virus strains and actual results
of infection.

Then, a key part of diagnosis and application, is for tests in
hypothesis, that establish here negative (or, likely "beneficial"),
states as would suggest intervention or observation.

Some of the virus mechanism's material would be metabolized internally,
about what would be reasonable tests to detect internal infection,
given that any internal test is invasive. Here the idea would be to make
for some particular conditioning nutrient, as what for example
"protein S deficiency symptoms" could then be detected from urine.
(Or in the inorganic.)


"...the data show that the ability to nonspecifically enhance

immune protection against a respiratory virus, most notably
in the absence of significant pulmonary inflammation,
is a feasible way of preventing SARS infections."

[Mostowski Collapse]

So you are reposting your own stuff. LoL
The first paragraph was already copy paste
in a previous post of yours?

I guess your AI robot needs some oil.
Its broken.

[Ross A. Finlayson]

https://phys.org/news/2020-04-covid-genome-signature.html

"Hill believes the tool, which is able to classify
any newly discovered virus sequence COVID-19
or otherwise, will be an essential component
in the toolkit for vaccine and drug developers,
front-line health-care workers, researchers and
scientists during this global pandemic and beyond. "

"The machine-learning method achieves 100 percent
accurate classification of the COVID-19 sequences
and more importantly, discovers the most relevant
relationships among more than 5,000 viral genomes
again within minutes."

""All we needed was the COVID-19 DNA sequence
to discover its own intrinsic sequence pattern.
We used that signature pattern and a logical approach
to match that pattern as close as possible to other
viruses and achieved a fine level of classification in
minutes—not days, not hours but minutes," Hill said."

Getting genetic samples and implementing sequencers,
here is for making some hand-held approximation of an
instant DNA test for viral DNA.

https://phys.org/news/2020-04-coronavirus-genetic-material.html

""We were surprised to find that the structure
of the coronavirus polymerase is special—it
differs from other structures that we have
been investigating so far," explains Hauke Hillen."

"The path to the three-dimensional structure
of the corona polymerase was rocky. "First,
we had to reconstitute the polymerase from
three purified proteins. After some optimization,
it was finally functional in the test tube," explains
Goran Kokic. "Only then we were able to study how
it works.""



https://jvi.asm.org/content/92/14/e01031-17

"If you have any of the following symptoms
please self-treat at home and do not come into the office.

Cough
Fever
Sore Throat
Body ache
Ear pain
Congestion
Shortness of Breath"

[Ross A. Finlayson]

On Thursday, April 30, 2020 at 10:40:06 AM UTC-7, Ross A. Finlayson wrote:
> On Wednesday, April 29, 2020 at 12:59:01 PM UTC-7, Mostowski Collapse wrote:
> > So you are reposting your own stuff. LoL
> > The first paragraph was already copy paste
> > in a previous post of yours?
> >
> > I guess your AI robot needs some oil.
> > Its broken.

More copy-paste from some articles about the various
actions of virus replication and disease, in the SARS-CoV-2,
as what describe many approaches to targetting the virus.




https://www.nature.com/articles/s41467-019-10280-3

"Structure of the SARS-CoV nsp12 polymerase
bound to nsp7 and nsp8 co-factors" :

"The multi-subunit CoV RNA synthesis machinery
is a complex of non-structural proteins (nsp)
produced as cleavage products of the ORF1a
and ORF1ab viral polyproteins."

[This seems for conditioning the plasma that the
cleavage products lose their ability.]

"Though additional viral nsp subunits are likely
necessary to carry out the full repertoire of
replication and transcription activities, the
nsp12-nsp7-nsp8 complex so far represents
the minimal complex required for nucleotide
polymerization [of the virus]."

"In addition, many other CoV nsps possess
enzyme activities related to RNA modification."

"One notable gap in our structural knowledge
of the CoV RNA synthesis complex was a structure
of the nsp12 RNA polymerase. This structural gap
included information regarding the unique N-terminal
extension of nidovirus polymerases, which has been
proposed to contain a nucleotidyltransferase activity
(nidovirus RdRp-associated nucleotidyltransferase (NiRAN))."


"This 160 kDa complex [nsp12 bound to the nsp7 and nsp8 co-factors]
defines the largest portion of the viral RNA synthesis
complex yet to be structurally characterized at high resolution.
In addition to a structurally conserved polymerase domain,
this complex provides the first views of a nidovirus-unique
nsp12 N-terminal extension that possesses a kinase-like fold
and demonstrates an unexpected binding stoichiometry
of nsp7 and nsp8 co-factors."


[Here there's an idea that nsp7 and nsp8 could be deactivated
with some usual innocuous and low-level mineral or enzymatic
content in the cytoplasm, or, rather a hope.]

"Both SARS-CoV and dengue virus polymerase proteins
contain N-terminal extensions...".

"Although not previously predicted, the SARS-CoV nsp12
contains two metal-binding sites to which we have assigned
zinc atoms. The first is in the nidovirus-unique extension and
is coordinated by His295, Cys301, Cys306, and Cys310. The
second is in the fingers domain and is coordinated by Cys487,
His642, Cys645, and Cys646. All eight of these metal-coordinating
a.a. are highly conserved across the CoV family ."

"Both of these metal-binding sites are distal to known
active sites as well as protein–protein and protein–RNA
interactions. Thus these ions are expected to be structural
components of the folded protein rather than directly involved
in enzymatic activity. The presence of structural zinc ions
in nsp12 is reminiscent of bound zinc atoms in coronavirus
nsp3, nsp10, nsp13, and nsp14 and points to an extensive
utilization of zinc ions for folding proteins of the viral
replication complex."

"The nucleoside analog GS-5734 is capable of impairing
CoV RNA synthesis by targeting the viral RNA synthesis machinery."

"The CoV RNA synthesis complex is governed
by a large number of protein–protein interactions.
Both nsp7 and nsp8 have essential roles in the
formation and activity of the RNA synthesis machinery."

"The large number of interactions between nsp8 and nsp12
with the other viral nsps suggests that these two proteins
form a hub for protein–protein interactions within the viral
replication complex."

"Although nsp7 and nsp8 are known to form a 1:1 complex
and were provided in a 1:1 ratio, model building of the
nsp12-nsp7-nsp8 complex revealed unexpected density
for a second subunit of nsp8 (a.a. 77–191) without a bound nsp7.
This second subunit of nsp8 interacts with the nsp12 interface
domain proximal to the fingers domain and the RNA template-
binding channel."

"This hypothesis is consistent with the observation that,
while nsp12, nsp7, and nsp8 all individually recognize RNA
with no or poor affinity, the complex of nsp12-nsp7-nsp8
is significantly more capable of binding RNA."

"Although the SARS-CoV polymerase has been found to be
capable of carrying out de novo RNA initiation, the CoV
polymerase structure lacks a clear indication for how
this initiation occurs. "

"Viral co-factors nsp7 and nsp8 have been established
as being essential for a highly active nsp12 polymerase
complex. While the majority of nsp7 could be resolved
in this structure, the N-terminal regions of both nsp8
subunits are disordered in agreement with previous
observations and predictions. Given the large number
of other viral nsps and RNA that have been assigned
to contact nsp8, we speculate that these disordered
N-terminal regions may act as molecular handles for
recruiting additional viral factors and organizing the
viral replication complex."

"This model of nsp12 bound to nsp7 and nsp8 is the
first step toward unraveling the assembly and activity
of this viral macromolecular complex with key implications
for future studies of CoV antiviral design."


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118644/

"... remdesivir [GS-5734] is a prodrug of the parent adenosine
analog, GS-441524 (Fig. 1b), both of which are metabolized
into an active nucleoside triphosphate (NTP) by the host."

"The parent nucleoside, GS-441524, has displayed antiviral
activity against SARS-CoV, Marburg virus, and feline infectious
peritonitis virus, among others."

"After the host metabolizes remdesivir into active NTP,
the metabolite competes with adenosine triphosphate
(ATP; the natural nucleotide normally used in this process)
for incorporation into the nascent RNA strand."


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682535/

"The reverse transcriptase (RT) of human immunodeficiency
virus type 1 (HIV-1) is an RNA- and DNA-dependent DNA
polymerase that remains a prime target for antiretroviral
intervention. The two approved classes of RT inhibitors
are nucleoside analog (NRTI) and non-nucleoside analog
(NNRTI) RT inhibitors. "

"Binding of NNRTIs to a hydrophobic pocket near the
polymerase active site results in inhibition of nucleotide
incorporation without directly competing with the substrate."

"These findings represent strong evidence to show that
despite distinct structures, INDOPY-1 may share some
common properties with NRTIs."

https://www.futuremedicine.com/doi/full/10.2217/fvl.11.36

"... while the complete genome sequence for several viruses
was solved more than 20 years ago, despite this knowledge,
the majority of useful antiviral compounds have been
discovered by screening chemical libraries for activity
against whole-virus replication in cell culture or particular
virus-induced products in vitro and, to date, only a small
number have come from rational design programs."

"There are now six distinct classes of HIV inhibitor in
clinical use. Historically, nucleoside reverse transcriptase
inhibitors (NRTIs) were the first to be discovered. The
article by Scarth et al. reveals that, while there has been
much progress in our understanding of the mechanisms
of action of NRTIs, there is still much to be discovered about
this classical target. As well as reviewing current usage of NRTIs
and non-nucleoside reverse transcriptase inhibitors, the authors
discuss progress with new molecular targets including induction
of lethal mutagenesis, inhibition of RNase and the so-called
nucleotide-competing RT inhibitors (e.g., INDOPY-1). Success
with the latter compound provides proof-of-principle for a
new class of small-molecule RT inhibitor. It is apparent that
aiming at two different targets on RT raises the genetic barrier
to resistance development. The discovery of INDOPY-1-like
compounds suggests that combinations containing three
rather than two different classes of RT inhibitor are a realistic
possibility in the near future."

"The molecular targets [of SARS] identified encompass several
proteases, including a papain-like protease and an RNA-dependent
RNA polymerase."


https://pubs.acs.org/doi/10.1021/bi0504761

"We demonstrate that SARS-CoV PLP2 by itself differentially
cleaves between the amino acids Gly180 and Ala181, Gly818 and
Ala819, and Gly2740 and Lys2741 of the viral polypeptide pp1a,
as determined by reversed-phase high-performance liquid
chromatography analysis coupled with mass spectrometry.
This protease is especially selective for the P1, P4, and P6 sites
of the substrate. The study demonstrates, for the first time
among coronaviral PLPs, that the reaction mechanism of
SARS-CoV PLP2 is characteristic of papain and compatible
with the involvement of the catalytic dyad (Cys)-S-/(His)-Im+H
ion pair. With a fluorogenic inhibitor-screening platform,
we show that zinc ion and its conjugates potently inhibit
the enzymatic activity of SARS-CoV PLP2."


https://www.sciencedirect.com/science/article/pii/S2211383520302999

"Analysis of therapeutic targets for SARS-Cov-2 and discovery of
potential drugs by computational methods."

"Structure and screening results of important targets
such as 3-chymotrypsin-like protease (3CLpro), Spike,
RNA-dependent RNA polymerase (RdRp), and papain like
protease (PLpro) were discussed in detail."

"This study predicts a variety of compounds that may
inhibit novel coronaviruses and provides scientists
with information on compounds that may be effective."

"By aligning with the amino acid sequence of SARS PP1ab
and analyzing the characteristics of restriction cleavage
sites recognized by 3CLpro and PLpro, we speculated 14
specific proteolytic sites of 3CLpro and PLpro in SARS-CoV-2 PP1ab."

"Interestingly, as shown in Fig. 3A, important anti-virus
drug target protein like 3CLpro, PLpro, and RdRp are
highly conserved between those two human coronaviruses,
especially in functional region. As shown in Table S1, all
these potential drug target proteins have been homologously
modeled, and all generated protein models were provided
as the PDB files in Supporting Information."

"The therapies that act on the coronavirus can be divided
into several categories based on the specific pathways:
(1) some acting on enzymes or functional proteins that
are critical to virus, preventing the virus RNA synthesis
and replication; (2) some acting on structural proteins
of virus, blocking virus from binding to human cell receptors,
or inhibiting the virus's self-assembly process; (3) some
producing virulence factor to restore host's innate immunity;
(4) some acting on host's specific receptors or enzymes,
preventing virus from entering into host's cells. The related
target proteins include Nsp1, Nsp3 (Nsp3b, Nsp3c, PLpro,
and Nsp3e), Nsp7_Nsp8 complex, Nsp9–Nsp10, and Nsp14–Nsp16,
3CLpro, E-channel (E protein), ORF7a, Spike, ACE2,
C-terminal RNA binding domain (CRBD),
N-terminal RNA binding domain (NRBD),
helicase, RdRp, and TMPRSSS2."

"As an indispensable enzyme in the process of coronavirus
replication and infection of the host, PLpro has been a
popular target for coronavirus inhibitors. It is very valuable
for targeting PLpro to treat coronavirus infections, but no
inhibitor has been approved by the FDA for marketing."

"... catechin compounds ... exhibited high binding affinity
to PLpro protein, suggesting the potential utility of these
compounds in the treatment of SARS-CoV-2."


"Nsp12, a conserved protein in coronavirus, is an RNA-dependent
RNA polymerase (RdRp) and the vital enzyme of coronavirus
replication/transcription complex."

"Nsp8 can de novo synthesize up to six nucleotides in length,
which can be used as a primer for Nsp12-RdRp RNA synthesis.
Further, the Nsp7_Nsp8 complex increases the binding of Nsp12
to RNA and enhances the RdRps enzyme activity of Nsp12. In
the research of SARS-CoV and MERS-CoV inhibitors, Nsp12-RdRp
has been used as a very important drug target. In principle,
targeted inhibition of Nsp12-RdRp could not cause significant
toxicity and side effects on host cells, but no specific inhibitors
have been found until now."


"The natural products, such as many flavanoids from different sources
... showed high binding affinity to this target [Helicase(Nsp13)]."

"Except for Spike protein, E protein (E-channel) possesses important
biological functions for the structural integrity of coronavirus and
host virulence. NRBD and CRBD of coronavirus N protein are needed
for N proteins in host cells to bind with coronavirus RNA efficiently.
Therefore, E protein or N protein (NRBD and CRBD domains) can be
used as targets for the discovery of anti-viral drugs. Through virtual
screening, many anti-bacterial, anti-viral, anti-tumor, anti-asthmatic,
and anti-inflammatory drugs, etc. from ZINC database and our in-house
natural products/derivatives database were found to display relatively
good affinity to these targets."

"The results of the entire article are based on computer virtual
screening. We have not conduct further in vivo and in vitro anti-viral
experiments yet, because we want to share our results with scientists
in anti-SARS-CoV-2 research as soon as possible. Our subsequent
research will try to solve the three-dimensional structures of all
24 proteins of SARS-CoV-2 and their drug complexes, providing
more target information for drug intervention and long-term
drug design, perform in vivo and in vitro evaluations for candidate
drugs obtained in this study, and prepare for clinical trial applications."

[Ross A. Finlayson]

Also today, "A SARS-Cov-2 protein interaction map
reveals targets for drug repurposing" ,

https://www.nature.com/articles/s41586-020-2286-9
https://www.mercurynews.com/2020/04/30/coronavirus-repurposing-drugs-to-protect-human-cells/

Hmm, they don't refer to the article from Acta Ph. Sinica B,
maybe they didn't see ""Analysis of therapeutic targets

for SARS-Cov-2 and discovery of potential drugs by

computational methods", it's a similar approach.

"... the last pieces of data— revealing which host proteins
interacted with viral proteins— came in just as the lab shut
down to comply with the state’s shelter-in-place orders."


One item of note is the suggestion that "the usual
cough syrup ingredient dextromethorphan" is bad,
it's something that describes what _not_ to do in the
treatment of symptoms associated with COVID-19.
It's bad enough that COVID has a "papain-like protein" and
the poor papaya gets looked-at askance in the produce,
here it could be helpful to understand other things that
either basically promote viral replication or after infection
cause load on the over-loaded liver, like gut bombs or
fast food, as what to avoid, besides what to seek.

The other item of note is that hydroxychloroquine causes
heart damage, and that looking for other targets than
the ACE2 receptors would probably be better.

[Ross A. Finlayson]

"High degree glycosylation of S-proteins,
and detection and cure of S-protein infection"

"Protecting the pre-fusion HR2 triple helical
coiled-coil from immune recognition is another
possible explanation for the high degree of
glycosylation observed in this region."

Popping the corona S-proteins off the cell wall,
via immune recognition (and, rejection), here
seems for the cell wall, and the lipid membrane,
is about the surface layer and the [undefined]
endogens as for the exoribo nuclease and
disrupting the S-protein (and its infection).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351563/
https://www.frontiersin.org/articles/10.3389/fmicb.2019.01813/full

"Evidence strongly supporting the “proofreading exoribonuclease”
hypothesis has now accumulated, in particular for SARS-CoV and
murine hepatitis CoV (MHV)."

"Over the past 25 years, CoV replicase proteins have been
characterized using a combination of bioinformatics,
biochemistry, structural biology, and (reverse) genetics."

[Mostowski Collapse]

Pitty for Tesla elon musk you cannot offer a
car as a vaccine. Microsoft bill gates has
more talk in tow.

There are over 100 different coronavirus
vaccine candidates in the works. These
candidates take a variety of approaches to
protecting the body against COVID-19
https://www.gatesnotes.com/Health/What-you-need-to-know-about-the-COVID-19-vaccine

Warning mikey mouse voice:
https://www.youtube.com/watch?v=u1AQ5EXcJYc

[Mostowski Collapse]

Hey Ross the Floss, Doctor Coronavirus,
some new characterization of cytokine
release syndrome during COVID-19:

"Although, severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) is sufficiently
cleared by the early acute phase anti-viral
response in most individuals, some progress
to a hyperinflammatory condition, often with
life-threatening pulmonary involvement.
This systemic hyperinflammation results in
inflammatory lymphocytic and monocytic
infiltration of the lung and the heart,
causing ARDS and cardiac failure. Patients
with fulminant COVID-19 and ARDS have
classical serum biomarkers of CRS including
elevated CRP, LDH, IL-6, and ferritin."
https://www.sciencedirect.com/science/article/pii/S0924857920301047

[Ross A. Finlayson]

If you've never had a heart attack before, well,
if you're more than 20 years old you've may well
had a heart attack before, it's not so much that
the infiltration of the fibrosis was necessarily
long and conditioned, for the immune system to be
working down clearance.

The heart as "one big cell" or macrocellular,
here is that the fibrosis is in the tissue,
that the monocytes need make for clearance in
the cytoplasm, in the phases of the regimes of
the heart tissue.

So, its not so much a heart attack like constriction,
or heart failure, but the fibrosis makes for heartache.

The extracellular components that are the S-protein fragments
and with the other things among the extra-cellular matrix
used for investing antibodies, has for making clearance of
the extracellular pieces of the S-protein, that the tissue
has the markers against, all through the course of the reset
of effectively the free cellular expression.

The heart and lung have different monocytes, here
the lungs have monocytes while the heart is mostly muscle.
The heart's monocytes and pinocytosis here, in cytosis,
here as about the macropinocytotic machinery and contents,
the cases in suspension media are for clearance and cytosis.

The lung attack is partly the monocytes achieving a gel
suspension, that is locking, then for what you want to
actively breathe but a combination of lung fluids and
otherwise then the pressures, are that basically the
monocytes and alveoli and bronchi are one tissue, about
the tissue getting "infective" to itself thus irritating,
that the monocytes or matrix are defined as the contents
making the spasm of a lung attack.

The actual "moment", when for example a retinoic cascade
makes for clearance over the heart with reforming the
cellular matrix, that "retinoic" is just reflecting that
it's a reaction that is detected under nervous response,
or "flushing", is for figuring out, for example, prostaglandin
expression, after cytokines, that transport as part of flushing,
making clearance of system effects here, is that as well,
whether or not the actual infection is in effect, that
is so fully marked, is treat it like a hiccup.

Or, hiccough.

The hiccup, a spasm, or attack, is considered by itself
"mild", among attacks, but it is considered strong.

I suppose the most attacks before I've had have been
muscle attacks, or, the "Charlie horse".

Here lungs and heart rehabilitate differently, too,
for example whether the heart or lungs or both are
under more effective load, in terms of each other.
These maintain the pressures of the suspension medias
of the gases in the acqueous solution, or respiration.
The lung monocytes are in the interface, the heart
monocytes are in the tissue strata.

Building up cytokines and clearance, there are caspases,
there is free expression in the cellular matrix,
there's the free availability of the humoral response,
reducing free potassium probably helps turn off a
response to too much potassium.

(That though's under the theory for the retinoic
acid as the chain reaction initiator, or flush,
that the metabolic flush isn't for example from
prostaglandins expressed or otherwise that there
are more than one regime of cytosome clearance
and cytosis and intake and flush, in the intercellular,
and macrocellular, here for macrocellular flush.)


Interrupting response though is always where the
immune response is overall directing that.


It's probably important not to confuse usual attacks
of exertion, to attacks of immune system reset, or
humoral response, that are "temporary" in the sense
of their reset and clearance, while the attacks of
exertion are "acute". Here the issue is more a
"temporary" fibrosis, for the immune system to
effect a clearance, that the fibrosis here is
following the infection, the immune response following
the antibodies picked up from the S-protein and
their effective (or, ..., in-effective, but still
apparent) interference of the usual function,
by byproducts of the lysosome and exosome
demolishing the S-protein infection.

Please see above about M-phi neutrophil clearance.

Also, there are various considerations whether
considering an immunological approach, or for
some practical approach, that there's a big
difference between an exercise regimen and
a heart syringe.

Letting the body achieve fibrosis clearance here
seems the result overcoming fibrosis induced by
immune response after infection. See above as
about the heart expression. (The gene expression.)






Here's an article on hyperkalemia, high potassium.

https://link.springer.com/article/10.1007/s11897-019-00425-2

[Ross A. Finlayson]

https://www.sciencedirect.com/science/article/pii/S0092867420302622?via%3Dihub

"Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies
potently inhibited SARS-CoV-2 S mediated entry into cells, indicating
that cross-neutralizing antibodies targeting conserved S epitopes
can be elicited upon vaccination."

Here, for SARS-CoV-2, is for figuring for the body to make a humoral
response, on the CoV-2 before the SARS itself, as what otherwise they
have the same antigenic profile, that among coronavirus virions, that
antibody-restricting the SARS: doesn't antibody-restrict the CoV-2 so
much, as that the CoV-2 thus competes and wins, for the restricted
substrate all covered for example with dead coronavirus virions.

I.e., for the adaptive mechanism of the CoV-2, is for making that
its internal structure the N-proteins, then for about detecting and
making for cytosis, that the CoV-2 antibody profile is in front,
besides that the body then is also to make the SARS antibody profile.
(That CoV-2 and MERS share.)

"Based on these observations, we hypothesized that exposure
to one of the two viruses could elicit cross-reactive and potentially
neutralizing Abs against the other virus. We therefore investigated
the ability of plasma from four mice immunized with a stabilized
SARS-CoV S to inhibit SARS-CoV-2 S- and SARS-CoV S-mediated entry
into target cells. All sera tested completely inhibited transduction
of SARS-CoV S-MLV and reduced SARS-CoV-2 S-MLV transduction
to ∼10% of control in VeroE6 cells (Figure 5C). The elicitation of
a heterotypic response blocking SARS-CoV-2 S-mediated entry
into host cells concurs with the sequence and structural conservation
of SARS-CoV-2 S and SARS-CoV S along with their comparable
glycans shields and suggests that immunity against one virus
of the sarbecovirus subgenus can potentially provide protection
against related viruses."

"Collectively, these data underscore that S glycoprotein trimers
found in highly pathogenic human coronaviruses appear to exist
in partially opened states, while they remain largely closed in
human coronaviruses associated with common colds."

"The trimeric fusion glycoprotein (GP) is the sole target
for neutralizing antibodies and is the major focus of
vaccine development. "

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118701/

"Structure-Based Design of
Prefusion-Stabilized
Filovirus Glycoprotein Trimers"

https://www.rndsystems.com/research-area/scavenger-receptors

"The scavenger receptor (SR) family is a group of membrane receptors
that share the common ability to bind and internalize modified forms
of low-density lipoproteins (mLDL), a process which is centrally important
for the removal of foreign substances and waste materials.
SR-A is a type II, trimeric transmembrane glycoprotein."

"... and Class C receptors are separated based on their
extracellular N-terminal domain."

[Ross A. Finlayson]

"Alveolar macrophages are the first line cellular defense
patrolling alveolar spaces. They display an array of non-specific
receptors that grab pathogens and deliver these to intracellular
digestive vesicles called lysosomes without eliciting an inordinate
amount of inflammatory mediators but transmit sufficient signal
to alert the adaptive immune system to entry of new pathogens.
These include scavenger receptors, lectin receptors, toll-like receptors
on the macrophage surface, and intracellular recognition systems
that detect the presence of proteins and genetic material of viral
proteins. This critical property occurs in conjunction with surfactant
proteins that maintain alveolar macrophages in an anti-inflammatory
but immune vigilant state to respond quickly to external threats.
Alveolar macrophages emit signals that activate other innate
immune cells to secrete antiviral substances and work together
to elicit activation of the adaptive immune system."

https://hellenicnews.com/an-in-depth-look-at-covid-19s-pathogenesis-through-the-eyes-of-dr-zissis-chroneos/

"Protective immunity can wane over-time depending on the
antigenic repertoire processed for different pathogens at
the early stages of infection. The cellular branch of the
adaptive immune system includes T and B lymphocytes.
T lymphocytes process antigen, kill infected cells, secrete
interferons that suppress viral proliferation, and differentiate
to memory T cells, and help B cells to secrete antibodies
among many other functions. B lymphocytes process both
non-protein and protein antigen and maintain the humoral
immune system though life-long secretion of antibodies.
Antibodies bind pathogens mediating clearance by macrophages
and activate the classical complement cascade to kill pathogens."

"It has been found that some patients with COVID19 develop
pathogenic antibodies that amplify inflammatory responses
by delivering infection in immune cells in which degradation
of the virus is incomplete. Viral fragments can trigger excessive
inflammation by the innate immune system or alternatively,
allow some virus to escape, proliferate, and deplete immune
cells. It takes additional time for those who develop partial
inflammatory immunity to produce additional antibodies or
cell-mediated responses to eradicate the virus. The levels of
antiviral immunity and its impact on individuals who develop
critical COVID-19 illness is not yet known."


"SARS-CoV-2 has a prolonged incubation period lasting for
up to three weeks after infection that allows unsuspecting
individuals to spread the infection in the community. The
reasons for this are not yet understood. One possibility is
that partial pre-existing immunity to related Coronavirus
strains sustains a tolerable level of transmissible virus that
may delay the development of specific immunity to this
particular strain."


"The prospect for antiviral and host targeted drugs to
ameliorate inflammatory symptoms may come into play
in less than a year and we need to have multiple to treat
the heterogeneous disease of COVID-19. One of the
antivirals Remdesivir in current use for compassionate
care has shown some efficacy and may be in wider use
soon. Hydroxychloroquine and Zithromax have an
interesting mechanism of action rationale but at
this point in time, there is no agreement as to whether
they are helpful without data from randomized control
trials. Hydroxychloroquine is counter-indicated for individuals
with G6PD deficiency and other more rare blood disorders,
which is common in individuals with Mediterranean and
Asian heritage. They will likely be helpful to some patients
for the treatment of associated co-morbidities. There are
new drugs that have shown promise in preclinical trials
that have not gone through approval for clinical use yet."



https://www.fiercebiotech.com/research/a-map-liver-cells-provides-insights-into-nash
"A map of liver cells provides insights
that could boost search for NASH drugs."

A lot of knowledge of hepatic function
is provided in new models.

"Hepatic", this was a word that once, I didn't
really know, the liver basically feels like an inert,
uniform organ, so it wasn't until I started learning
about cholesterol that it entered the vocabulary.

Now it means "related to the liver".



"The major complications reported in fatal cases
are hyperkalemia with associated ventricular tachycardia,
disseminated intravascular coagulation,
pericarditis, and multiorgan failure."


"These arrhythmias can be further complicated
by another common adverse event: hypokalemia.
Since this hypokalemia is really a shift of potassium,
and not truly a depletion, cautious supplementation
is necessary to avoid hyperkalemia."
https://empharmd.com/2020/03/15/hydroxychloroquine-for-sars-cov-2/

"Bradykinin is rapidly inactivated in the circulating blood,
and it disappears completely in a single pass through the
pulmonary circulation. Angiotensin I also disappears in the
pulmonary circulation because of its conversion to angiotensin II.
Furthermore, angiotensin II passes through the lungs without
any loss. The inactivation of bradykinin and the conversion of
angiotensin I to angiotensin II in the lungs was thought to be
caused by the same enzyme."


https://cmr.asm.org/content/cmr/28/2/465.full.pdf


"The characteristic replication structures of CoVs,
including double-membrane vesicles and convoluted membranes,
are formed by the attachment of the hydrophobic domains
of the MERS-CoV replication machinery to the limiting membrane
of autophagosomes (58). These structures can be observed at the
perinuclear region of the infected cells under electron microscopy (58).
The viral papain-like protease and 3C-like protease cotranslationally cleave
the large replicase polyproteins pp1a and pp1ab encoded by ORF1a/b
into nsp1 to nsp16 (16,59,60). These nsps form the replication-transcription
complex,where transcription of the full-length positive genomic RNA
yields a full-length negative-strand template for synthesis of new genomic
RNAs as well as a series of overlapping subgenomic negative-strand
templates for synthesis of subgenomic 3' coterminal mRNAs that will
be translated to make viral structural and accessory proteins (58).
The relative abundance of the subgenomic mRNAs of MERS-CoV
is similar to those of other CoVs, with the smallest mRNA, which
encodes the N protein, being the most abundant (58). After adequate
viral genomic RNA and structural proteins have been cumulated, the
N protein assembles with the genomic RNA in the cytoplasm to form
the helical nucleocapsid.The nucleocapsid then acquires its envelope
by budding through intracellular membranes between the endoplasmic
reticulum and Golgi apparatus. The S, E, and M proteins are transported
to the budding compartment,..."


This seems for detecting the negative strand template for the
CoV's replication machinery, after clearance of the positive RNA,
for clearance of the negative RNA, resulting in clearance of infection.

Chan et al.'s, "Middle East Respiratory Syndrome Coronavirus:
Another Zoonotic Betacoronavirus causing SARS-Like Disease",
helps _a lot_ in explaining mechanisms of virus disease like
MERS and SARS-CoV-2. See Figure 3: "Candidate antiviral agents
for MERS-CoV in relation to the viral replication...".

["Factors"..., was "histones"] on the endoplasmic reticulum and Golgi,
on the way out from the nucleus as expressed as cellular egress from
after folding, is for changing the histones, from having the mRNA to
the S, E, and M proteins, ..., is for getting the right nuclear proteins
from the endoplasmic reticulum on the nucleolus, that when the
capsid or products as out through the Golgi make egress from the
cell, is here for tagging those with the functional factor as for how
the cell can selectively still release the assembled virions, but that
they would be both inert and also autophagic so that the right
scavengers pick them up and off the cell, then also for the conditions
of the extra-cellular for getting clearance of the result, both out of
the cell and correctly through pathways out of neighboring cells,
making for a "pro-active" immune response.

[ "Secretory proteins are transported from the endoplasmic reticulum
to the Golgi apparatus via COPII-coated intermediates."
https://www.ncbi.nlm.nih.gov/pubmed/17520482
"Major proteins corresponded to established and putative cargo receptors
and components mediating protein maturation and membrane traffic. "
https://www.ncbi.nlm.nih.gov/pubmed/15308636
"Proteomics of ERGIC Membranes: ... The identified proteins can
essentially be grouped into four classes: cargo receptors,
proteins involved in membrane traffic, chaperones involved
in protein maturation, and uncharacterized proteins." "The overall
composition of the ERGIC fraction confirms its high purity, because
it is devoid of marker membrane proteins for other organelles."
"We conclude that ERGIC-32 has two transmembrane domains
and that the greater part of the protein is luminally exposed,
whereas the NH2 and COOH termini are cytoplasmic. Consistent
with this topology, the (used) consensus sequence for N-glycosylation
is located between the two transmembrane domains. "
"[Yif1p]'s presence in ERGIC membranes together with Rab1
(the mammalian homolog of Yipt1p) may suggest that Yif1p
controls vesicle fusion at the ERGIC and/or Golgi. Further studies
are required to uncover the functions of Surf-4 and Yif1p. "
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579394/ :
"Enriched endoplasmic reticulum (ER) and Golgi membranes
subjected to mass spectrometry have uncovered over a thousand
different proteins assigned to the ER and Golgi apparatus of rat liver."
"Most biosynthetic proteins destined for the plasma membrane
and secretion, as well as resident proteins of endosomes, lysosomes,
the endoplasmic reticulum (ER), and the Golgi apparatus originate
with cotranslational translocation into the ER. This is followed by
carefully controlled folding and quality control. The ER is also a
major site for sensing cellular stress and for cholesterol and
phospholipid biosynthesis and constitutes a vast continuous
endomembrane system that often pervades the entire cytoplasm.
The ER commences as the nuclear envelope extends to rough
(ribosome-studded) membranes, and ends with tripartite-like
structures of tubular smooth (ribosome-free) ER."
"Biosynthetic cargo here [in the Golgi appartus], undergo extensive
posttranslational modifications including the maturation of N-linked
oligosaccharides, and the addition of O-linked oligosaccharides."]



Making clearance of the accessory proteins - and avoiding side effects
of their clearance that there is affected signaling on the immunatory channels -
is for a separate consideration of the accessory proteins than usual
clearance and proper signal in reponse of demolished S-protein fragments
and as with the N-protein structurally, is making for clearance of virions,
protein fragments, and accessory proteins, each according to how they're
cleared from the cytosome. Conditioning the clearance mechanisms in
effect, is for reducing scavenger confusion and gently making for primary
clearance, then introducing and cultivating antibodies will hopefully support
the immune mechanism of most people, and about that the very specificity
of Betacoronavirus like MERS and SARS-CoV-2, is cataloged in the immune
system then for resistance.




Looking to knock the N-protein out of reverse-trascriptase, with the
idea of making it so that the infection for an RNA anti-viral is making
broken N-proteins then that make assembly of coronaviruses that
would then fail when they went to infect the next cell. (And this
invoking an immune response to the S-protein, and then for also
investing the immune response for the N-protein, also.)

https://link.springer.com/article/10.1007%2Fs13238-013-3096-8
"The structural and accessory proteins M, ORF 4a, ORF 4b, and ORF 5
of Middle East respiratory syndrome coronavirus (MERS-CoV) are
potent interferon antagonists"

[Mostowski Collapse]

There is also genetic reshuffling, not only
cross over in sexual reproduction. But it
can also happen in other cell division.

With impact on pathogenes:

V(D)J recombination in organisms with an
adaptive immune system is a type of site-specific
genetic recombination that helps immune cells
rapidly diversify to recognize and adapt to new pathogens.

https://en.wikipedia.org/wiki/Genetic_recombination

V(D)J recombination is the unique mechanism of
genetic recombination that occurs only in developing
lymphocytes during the early stages of T and B cell
maturation. It involves somatic recombination, and
results in the highly diverse repertoire of antibodies/
immunoglobulins and T cell receptors (TCRs) found in
B cells and T cells, respectively. The process is a
defining feature of the adaptive immune system.
https://en.wikipedia.org/wiki/V%28D%29J_recombination

[Mostowski Collapse]

Antibodies might differ from species to species.

Coronavirus: Llamas offer hope in fight against the outbreak
Camelids produce antibodies that have been found to neutralise Covid-19

"Humans produce only one kind of antibody, made of
two types of protein chains — heavy and light — that
together form a Y shape. Heavy-chain proteins span
the entire Y, while light-chain proteins touch only
the Y’s arms. Llamas, on the other hand, produce
two types of antibodies."
https://www.independent.co.uk/news/science/coronavirus-llamas-antibody-prevent-winter-belgium-a9503411.html

LoL

[Ross A. Finlayson]

Finding the antibodies with the most particularly
selective binding to the particular structure of
the virus offers mostly the idea that it would be
least intrusive to other mechanisms.

I.e. one team had found an approach that bridges over
a gap in the S-protein, basically making a jig that
particularly fits it.

The LY6E protein is a target.


"Our study strongly supports a Jab1-mediated pathway
leading to tumor suppressor downregulation
initiated by the truncated LHBs mutant."

Antibody receptors and highly selective binding
An RNA machinery what catalogs highly selective RNA inputs




Here the point seems for poking the S-protein
into the exoribosome _before_ fusion, or after
fusion and before the protein works up to it as
a vesicle, what to give the S-protein, particularly,
a rejection among such proteins from the cell wall,
or the cell wall model of the S-protein: this way,
the exoribosome would be breaking them up anyways,
particularly before conformance or as broken down from
the fluid content after fusion on cytosis, that mediates
the S-protein entry.

Then for other Coronavirus S-protein like proteins,
mediating cytosis after trimer fusion, is among the
apparatus and the larger Coronavirus.

But, making the spike itself "more infectious", would
be for seeming that the actual cytosis was for programmed
rejection of the virus, under constituent assembly.

Engaging the scavengers correctly seems key, there's much
to make for the apparatus as what the traffic, has that there
is a microenvironment of bodily mechanisms that use the
same mechanisms as the virus, then for detection.

The Coronavirus under COVID-19 has a very particular and
active infection profile, establishing in a simple "smaller"
domain of the wild virus, needs for the effective exercise
of the immune system.

Waste and scavengers in immune rejection, cell waste from
the body fighting Coronavirus for example being exposed
and metabolizing it, makes for the importance of clearance,
waste-fighting immune response under dignified waste
immune response.

Looking to conserve wild-type immune support, acquired,
because of consequences, is about what to look for from
the effect of strong drugs like remdesivir, inside the cell
in the RNA machine, and leaving it in for Coronavirus and
leaving it out for the usual machine.

Already inside, there might be a cell disorder with drugs
for cell wall entry, as what would make less effective the
primary response, the S-protein response, then for reducing
propagation, to stop the otherwise active RNA machine,
which would reset, then.

Then, there's an idea to get something that does interfere
with the RNA machine, but that way gets immediately kicked
out, instead of happens to neatly stay resident, kicking it up
outside the RNA machine into detection, making for a graceful
operation of the RNA machine.

That way the particular uptakes, with strong binding to the
RNA machine (the reverse sense strand), would work at the
level of the protein arrays in gene machines, basically working
a wrench into the gene machine, that pops out, though, not
breaking the machine, but hitting the switch (then getting flushed).


CD147 seems it has a promoter then makes for ACE2, that
the S-protein facilitates cytosome fusion with the cell,
under the fat squirt that is the point gradient at the
wall/spike interface. Basically this is as the cells "breathe"
in cytosis, it's through pores besides vesicles, that the
lipid solution of the tissue of the cell, is for lipids under solution.
Lipids as gels in solution have internal pressure here for
the "breathing" cell. I.e. "the gel" stays the same, but the
liquid pressure, and solute, vents through it.

"Vaccination of ferrets with MVA-based SARS vaccine
expressing full-length S protein caused liver damage after
animals were challenged with SARS-CoV (34). These
findings raised concerns about the efficacy and safety of
the vaccines containing or expressing full-length S protein."


About the fibrosis, it seems recruited neutrohils, for making
for their clearance and rehabilitating the cells after making
for that the receptors, that the receptors are un-blocked of
the cell wall protein receptors, making for a "cell scrub".
(And clearance and secondary clearance.)


The virus uses the machinery of the cell, it's important not
to disrupt the machinery when knocking down and knocking out
the virus, toward a course of rehabilitating cells.

Sorry, no news here.

Making for the scavenger receptors' support of clearance by
unmasking the pre-fusion site, is for targetting the
accessory proteins, then for what vitamins and electrolytes
basically recommend a course of supplement.

It's sad that many people's response to hydroxychloroquine
is worse than the effect of a virus it was stockpiled for.


Infection might be gross, or insidious, simple models of
exposure to virions in the tiny quantities, that result in
infection, and thus bodily response to infection. This is
where open air models help explain why getting a sneeze
full of 10,000 times more virions ins't 10,000 times infectious,
but it is more and much more infectious, than 1 virion.
The body might respond right away to the larger infection,
that the 1 virion is insidious then gets attached.

The point then after infection is what results is the
properly "programmed" immune response: here for
the particulars of this virus disease and the mechanism
of biological pathways and the mechanim of virus disease.

Making for seriously reducing the reinfection, after whether
the cell is disinfected, is for the humoral response, ....

Naturally transmissible vaccine must be some component
of usual mass infection. I.e., at least some component of
a disease that is acquired socially, is that immunity is
acquired socially. Rather: the social biota, has for example
all the usual biota, and the microbiome.

Here also these days there was introduced in foods the
"genetically-modifying probiotics" then for about whether
food should be supplements or prebiotics not necessarily
the live organisms for what there are already, or, the colonies
with particular mutations that aren't wild (thus social).

Here this "acquired social immunity" can be as simple as
usual wellness, learning things and here for example that
a laboratory can make a "SARS-Lite" or "SARS-Block" and it
would effectively be an acquired immunity, as much as
infection.

Usual daily multivitamins, zinc supplement, thistle, and tea?

Not sure about zinc supplement....

Sorry, no news here.

[Ross A. Finlayson]

"In the circulation, about 60% of total protein S is
bound to C4b-binding protein, an acute phase
complement component. Because only 40% of the
protein S that is free is functionally active, only
patients with low free protein S levels are prone to
venous thrombosis. Therefore the diagnosis of
protein S deficiency requires measurement of both
free and bound forms of protein S."
-- https://www.sciencedirect.com/topics/neuroscience/protein-s

Looking into C4B binding protein and why when
there is too much then platelet protein S isn't free,
reading into an article about lectin complement.

https://www.medrxiv.org/content/10.1101/2020.03.29.20041962v1.full.pdf
"One Sentence Summary: The lectin pathway of complement activation
is a promising target for the treatment of highly pathogenic coronavirus
induced pneumonia. "

Wondering if CoV-2 proteins are "Vitamin K dependent". (And about Calcium.)

https://www.preprints.org/manuscript/202004.0457/v1

Starve it or feed it? Control plane / data plane?

Looking to support the lectin pathways.

[Ross A. Finlayson]

"As a “dual-edged sword”, complement is critical
for innate immunity against pathogens."

"... finding that the coronavirus N protein potentiating
complement activation provides a new insight into
the causation of pneumonia induced by SARS-CoV,
MERS-CoV and SARS-CoV-2 infection. Additionally,
we also noticed that the pre-infection of Ad-SARS N
or Ad-MERS N evidently increased the fatality of
LPS-induced pneumonia (Fig. 3), underlining the
potential role of N protein in the inflammatory injury
of tissue caused by the massive LPS released from
secondary bacterial infections."

"... it will make sense that complement cascade-targeted
immunomodulation may be effective for inflammation-control
in highly pathogenic coronavirus-related diseases. In this
pathway, C5a is the most potent complement protein
triggering inflammation. Blockage of C5a signaling has
also been reported to improve treatment of acute lung
injury (ALI) induced by highly pathogenic viruses (39).
Based on our scientific finding and the good safety record
in phase II trial for other disease by Staidson and inflaRx
GmbH (whom produce the anti-C5a antibody in the same
cell line), the recombinant anti-C5a antibody produced
by Staidson Biopharmaceutics was approved by NMDA
for the clinical trial for treatment of severe and critical
COVID-19 patients. At least in the first two patients, both
are in the disease deterioration, the anti-C5a antibody
showed rapid and promising effect exceeding the expect
of clinical physicians. Although the final efficacy will be
released until the clinical trial is finished, it is worth to
expect that anti-C5a antibody would provide a new approach
for the treatment of COVID-19. " [rote]

https://www.medrxiv.org/content/10.1101/2020.03.29.20041962v1.full.pdf

[Ross A. Finlayson]

On Saturday, May 9, 2020 at 2:52:23 PM UTC-7, Ross A. Finlayson wrote:

> "... it will make sense that complement cascade-targeted
> immunomodulation may be effective for inflammation-control
> in highly pathogenic coronavirus-related diseases. In this
> pathway, C5a is the most potent complement protein
> triggering inflammation. Blockage of C5a signaling has
> also been reported to improve treatment of acute lung
> injury (ALI) induced by highly pathogenic viruses (39).
> Based on our scientific finding and the good safety record
> in phase II trial for other disease by Staidson and inflaRx
> GmbH (whom produce the anti-C5a antibody in the same
> cell line), the recombinant anti-C5a antibody produced
> by Staidson Biopharmaceutics was approved by NMDA
> for the clinical trial for treatment of severe and critical
> COVID-19 patients. At least in the first two patients, both
> are in the disease deterioration, the anti-C5a antibody
> showed rapid and promising effect exceeding the expect
> of clinical physicians. Although the final efficacy will be
> released until the clinical trial is finished, it is worth to
> expect that anti-C5a antibody would provide a new approach
> for the treatment of COVID-19. " [rote]
>
> https://www.medrxiv.org/content/10.1101/2020.03.29.20041962v1.full.pdf

The nsp7 and nsp8 and helicase, here might be for introdcing
the gradient to the helicase, that for the weights of the protein
arms, and zipper, there is some way to swing the arm out, for
example with proteins that are slightly different than nsp7 and
nsp8.

"In addition, complexes of nsp7-nsp8, nsp10-nsp14 and nsp10-nsp16
were also determined."
-- https://www.nature.com/articles/s41467-019-10280-3

"Here we used cryo-electron microscopy (cryo-EM) to
determine the 3.1 Å resolution structure of SARS-CoV
nsp12 bound to the nsp7 and nsp8 co-factors. This 160 kDa
complex defines the largest portion of the viral RNA synthesis

complex yet to be structurally characterized at high resolution."

Here it looks the virus payload unpacked a bit from the
16 (or, under duplex) base pairs in the viral RNA, that here
as what results is for example the various structural proteins
about the N protein and the S protein, this is defined under
assembly.

I.e., under usual protein recipes, there's a lot to be said
for deprival, making that for whatever recipes the virus uses,
they are dependent under deprival.

"In addition to a structurally conserved polymerase domain,
this complex provides the first views of a nidovirus-unique
nsp12 N-terminal extension that possesses a kinase-like fold
and demonstrates an unexpected binding stoichiometry of
nsp7 and nsp8 co-factors."

Here it looks like the nsp12 uses the N proteins downstream
in synthesis, making for the clearance of the proteins in
solution and the size, filtration, clearance, and proteins in
cytosis for changing transport of here the actual structural
virus components, as actual structural bodily components.

"Both of these metal-binding sites are distal
to known active sites
as well as protein–protein and protein–RNA interactions.
Thus these ions are expected to be structural components
of the folded protein rather than directly involved in
enzymatic activity. The presence of structural zinc ions
in nsp12 is reminiscent of bound zinc atoms in coronavirus
nsp3, nsp10, nsp13, and nsp14 and points to
an extensive utilization of zinc ions for folding proteins
of the viral replication complex."

Here I would have that if the zinc is structural the assembly,
it's not "ionic" zinc that is solution, while they are still the
ions in the assembly under charge.

"One complication is that SARS-CoV produces
noninfectious particles as well as fully functional virions,
potentially confounding interpretations of data
from mass spectrophoretic versus immunoelectron
microscopy studies."

https://pdsa.org/treatments/complementary/vitamins-and-supplements.html

"Supplements can interact with other medications.
For example, people who are taking blood thinners
are advised to avoid vitamin K."


I've seen two people today who's what if they were
SARS symptoms I wouldn't call "mild". One it seems
had the fever, the other the cough.

I wanted to help them but not get anywhere nearer them.

[That's about it, though, everybody else on the street
didn't seem sick.]

https://arupconsult.com/content/thrombocytopenic-disorders

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112012/

https://loinc.org/

"Special Use codes are developed in response to an urgent
or emergent situation. These codes are based on the most
up to date information available at the time of their creation.
They have undergone the normal QA terminology process.
LOINC supports their use in the unique situation that resulted
in their rapid creation. However, be aware that downstream
users may not be ready to handle prerelease codes until they
are published in an official release."

https://www.cartercenter.org/resources/pdfs/health/ephti/library/lecture_notes/med_lab_tech_students/ln_hematology_mlt_final.pdf

Here for the nasal test, if for people to carry a nasal specimen
container with them, then when they get the nasal condition,
to test themself.

Or, handing out specimen containers.

https://www.h3abionet.org/images/DataAndStandards/DataStandards/StrokeResearch_REDCap.xml

https://ashpublications.org/blood/issue/134/Supplement_1


Should cough syrup be taken off the shelves during Coronavirus?

https://www.kqed.org/science/1963298/common-ingredient-in-common-cough-medicine-might-promote-coronavirus-study-finds

If the S-protein active sites are binding over disulfide bonds,
there's an idea for competing with it with solute.

Then, perhaps for some depressed condition could result
basically an infusion of metabolites as what more than less
disfavor the virus operation otherwise.

Here the idea is that the E protein, does the dance with the
S protein, under the (weak) disulfide bonds, then where under
usual separation of the S protein, the E protein gets pulled out
instead, working out in stoichiometry a switch.

"We identified a segment (NH2-_L-Cys-A-Y-Cys-Cys-N_-COOH) in
the carboxyl-terminal region of the E protein that appears to
form three disulfide bonds with another segment of corresponding
cysteines in the carboxyl-terminus of the S (spike) protein. These bonds
point to a possible structural association between the E and S proteins."

Here it looks the cysteines are shield or wrapped what with the role
into and out of the cell with unwrapped cysteines, these are angular
so turbofluidic when they get brought into macrocytosis.

"As a small structural protein, the E (envelope) protein is so-named
because it has generally been regarded as the main component of
the viral envelope since its first identification in RNA viruses."

https://jvi.asm.org/content/83/1/241
"Role of Thiol/Disulfide Exchange in Newcastle Disease Virus Entry"

https://academic.oup.com/jb/article/167/2/173/5650410?rss=1
"Pathological consequences of the unfolded protein response and
downstream protein disulphide isomerases in pulmonary viral
infection and disease"

"Protein folding within the endoplasmic reticulum (ER)
exists in a delicate balance; perturbations of this balance
can overload the folding capacity of the ER and disruptions
of ER homoeostasis is implicated in numerous diseases."

"Properly folded proteins are essential for the normal
function of the cell, and potentially misfolded proteins
are rapidly degraded by the ER-associated degradation (ERAD)."

"Generally, the PERK pathway limits protein synthesis,
the IRE1 pathway increases mRNA and protein degradation
and the size of the ER, while the ATF6 pathway up-regulates
chaperone proteins and protein degradation."

"The CXXC motif allows for the oxidoreductase activity of PDIs
by alternating between an oxidized form, where both cysteines
are linked through a disulphide bond, and a reduced form
containing two free sulphydryl groups. This effectively transfers
a disulphide to the client protein."

"This shift in pKa changes the C terminal Cys from a thiol to
a thiolate anion, which acts to resolve the mixed disulphide
through a subsequent nucleophilic attack."

https://academic.oup.com/view-large/197075131

https://www.biorxiv.org/content/10.1101/830026v1.full
"The Mammalian Cytosolic Thioredoxin Reductase Pathway
Acts via a Membrane Protein to Reduce ER-localised Proteins"

"These results provide compelling evidence for the critical
role of the cytosol in regulating ER redox homeostasis to
ensure correct protein folding and to facilitate the degradation
of misfolded ER proteins."

"We recently showed that the regeneration of NADPH within
the cytosol is required to ensure correct disulfide formation
in the ER lumen (Poet, Oka et al., 2017) raising the possibility
that the cytosolic reductive pathways are responsible for
ensuring correct disulfide formation in the ER lumen."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315136/
"Citrate as Cost-Efficient NADPH Regenerating Agent" :
"β-Nicotinamide adenine dinucleotide phosphate (NADPH)
is an obligatory frequent cofactor for oxidoreductases,
an important enzyme class in a manifold of academically
and industrially relevant reactions."

https://onlinelibrary.wiley.com/doi/pdf/10.1002/eji.201242849
"Immunoregulation through membrane proteins modified by
reducing conditions induced by immune reactions":
"Labile disulfide bonds are also important in platelet activation,
cytokine signalling and ina variety of diseases including cancer
and arthritis. In this review we will concentrate on recent advances
in understanding the conditions that lead to disulfide bond reduction
in membrane proteins and their effects in regulating immune function."

"Redox changes, such as secretion of thioredoxin, occur to balance
ROS [Reactive Oxygen Species] production. For example, the induction
of IL-1β processing in monocytes involves firstly an ROS response and
then an anti-oxidant response but studies with inhibitors show that
both are necessary for production of IL-1β[44]. As the effects of ROS
on the immune system have recently been reviewed [45], this shall not
be discussed further here."

https://www.ncbi.nlm.nih.gov/pubmed/22938635
"Redox regulation of T-cell function: from molecular mechanisms
to significance in human health and disease":
"The effects of reactive oxygen species (ROS) and reactive nitrogen
species (RNS) on immune cells and their roles in promoting or
controlling acute and chronic diseases have gained increasing
scientific prominence. "
"In an adaptive immune response, T cells recruit and activate B cells,
CD8+ T cells, macrophages, mast cells, neutrophils, eosinophils, and
basophils."

"While a direct crosstalk between p53 signaling and ROS production
is not clearly understood, it has been shown that T cells require low
concentrations of ROS for proper activation and signaling. However,
accumulating ROS may lead to activation of p53 and p53-inducible
genes, leading to apoptosis (225). Additionally, high levels of ROS
may result in the phosphorylation and stabilization of p53 and
subsequent activation of apoptotic signals as seen in other biological
systems and diseases (283)."

"GSH [Glutathione], a nonprotein thiol, acts as an antioxidant and
prevents cellular damage from ROS. The synthesis of GSH in cells
may be disrupted during aging and under pathologic conditions
such as diabetes mellitus (251) and cystic fibrosis (37)."

[Not sure if excess free glutathione is good or bad or
promotes equilibrium or hysteresis, and whether it should
be supplemented or restricted to reduce the action of SARS.]

https://jvi.asm.org/content/83/1/241 :
"We have previously reported that isomerase inhibitors
block virus infection (18). Thus, failure to detect free thiols
in virion-associated F protein suggested that free thiols
may be produced in virion-associated F protein only after
binding to target cells."
"These results suggested that particles must bind to cell
membranes to be exposed to the cell surface host cell
isomerases and only then are F protein disulfide bonds reduced."

"Comparisons of the positions of the cysteine residues in the
proposed pre- and postfusion structures of paramyxovirus F
proteins suggest that the disulfide bond linkages in the two
forms are identical. That is, there is no evidence for a reshuffling
of disulfide bonds upon the change from the prefusion to postfusion
forms of the protein. Thus, it may only be the transient disruption of
the bonds that facilitates the refolding of the F protein. Disruption
of some bonds may decrease the activation energy required or may
facilitate the refolding of the molecule. Another possible mechanism
may be a necessary transient covalent disulfide bond between the fusion
protein and a host cell protein. Actual reshuffling of disulfide bonds
has been demonstrated in the murine leukemia virus Env protein. It
is not clear whether reshuffling of disulfide bonds occurs in the avian
leukosis virus Env, the HIV Env, the alphavirus envelope protein, or
the hepatitis delta virus envelope protein."


https://www.atcc.org/en/Services/Biorepository_Management_Services.aspx

Making for a serum panel:

lipids, phospholipids
lipoproteins
"mycoplasma detection kit"

polymerase chain reaction and gel electrophoresis,
this was the lab in the molecular biology class we had.

Setting up labs, and experiments, then for making the
labor component, to be running the medical tests, if
for lots to figure out of a standard assembly, then what
is for some in-situ gel reclamation, or otherwise storing
all the tests, is for a solid state test, besides what here
for PCR and gel electrophoresis.

"Flow cytometry...".

"First generation devices are called Rapid Diagnostic Tests (RDT);
these are very cheap devices -up to a dollar per test- and most of
them meet the ASSURED criteria. Second generation devices
enable professionals to perform nucleic acid amplification tests
(NAAT) in order to detect the genetic material of the virus or
infecting organism."
-- https://www.bbvaopenmind.com/en/technology/innovation/low-cost-devices-for-diagnosing-diseases-in-poor-countries/

https://www.ajmc.com/journals/evidence-based-oncology/2014/may-2014/cheap-and-easy-to-use-diagnostic-tests-to-detect-disease-biomarkers-including-cancer

"Urinalysis assays using mPADs proved that
the platform was ideal for ASSURED diagnostics."


http://news.mit.edu/2020/covid-19-diagnostic-test-prevention-0312

"Another advantage of this approach is that
the paper tests can be easily and inexpensively
manufactured in large quantities, he adds."

There are still all the other diseases, mostly
not so much usually about SARS-CoV-2,
but the body's not a disease, so, there's lots
about having a nutrient environment, and diet,
making for living with disease, virus, fungus,
cancer, parasite, bacteriome, pollution,
and starvation.

[Mostowski Collapse]

The greatest fear of murica is that dark skin
gets better away with corona than light skin.

So USA will become south africa colony through corona
selection. Trump will be the last white president.

COVID-19 and vitamin D—Is there a link and an opportunity for intervention
Hrvoje Jakovac 16 Apr 2020
https://journals.physiology.org/doi/full/10.1152/ajpendo.00138.2020

The evolution of light skin color: Role of vitamin D disputed
Ashley H. Robins First published: 07 May 2009
https://onlinelibrary.wiley.com/doi/abs/10.1002/ajpa.21077

[Mostowski Collapse]

There are white bats!

Ectophylla alba
https://www.youtube.com/watch?v=eodkF5PRI_g

How cute!

[Mostowski Collapse]

What are the bunker boyz dreaming of?

East Indian Company
https://www.youtube.com/watch?v=lNRjt4rCymM

[Mostowski Collapse]

An the winner for the most stupid tweet of the day:

Buck Sexton
Molotov cocktails are lethal force, and from their
very origins, a “weapon of war” (thanks Finland!)
https://twitter.com/BuckSexton/status/1268038738686414848

LoL

Oh sorry Finland had to use improvised weapons
to fight the Soviets. How dare they?

[Mostowski Collapse]

No wonder Mark Zuckerberg seems to support
free speech. Not having this right would
deplete us of a lot of cringe. Now we can

estimate the overall IQ of the bunker
boyz, i.e. trump entourage. Possible doesn't
sum up to more than 20 points.

[Mostowski Collapse]

Even AP brain farto and John Gabbermonkey
now look more intelligent. I am

definitively Antidumbo. But I guess
this will be banned soon as well?

[Mostowski Collapse]

Oh, how the tables have turned. Trump is competing
for attention against Obama for the first time.

Their topic is education!

Trump, HBCUs and Progress
https://twitter.com/realDonaldTrump/status/1268258145656324098

Obama's Virtual Commencement Speech
https://www.youtube.com/watch?v=ta5anRPf8rQ

[Mostowski Collapse]

Just remember Trumps slurry has a large amount
of discrediting Obama, and Trump is even not
able to make complete sentences.

Nice song BTW:

Now I've got love in my heart
It gives me the strength
To make it through the day
Oh, love pride is have respect for yourself
And that's why I'm not looking for
Hand outs, charity
Welfare, don't need
Stealing, dealing
Not my feeling
No back stabbing
Greedy grabbing
Lying cheating
'Cause I've got a deeper love
A deeper love
A deeper love inside

Clivilles & Cole - A Deeper Love (Club Mix)
https://www.youtube.com/watch?v=XzOMFzJAc9o

[Mostowski Collapse]

*** Breaking News ***
Kayleigh McEnany lost one of her false eyelashes.
*** Breaking News ***

Oh, how the tables have turned II:

"WASHINGTON — Snap said on Wednesday that it
had stopped promoting the Snapchat account of
President Trump after determining that his
public comments off the site could incite
violence, in another hardened stance by a
social media company against the president."
https://www.nytimes.com/2020/06/03/technology/snapchat-trump.html

[Mostowski Collapse]

Lets look at the dreams of bunker boyz.
Currently the bunker boyz are not only
racist. They also try to find some islam

in Obama. So they are also against freedom
of religion. The meaning of Trumps "greatness"
is simple: white and christian.

Am Mittwoch, 3. Juni 2020 14:21:15 UTC+2 schrieb Mostowski Collapse:

[Mostowski Collapse]

BTW: Hitlers plan was not roman christian,
he needed some „old Germans“ idol. Maybe not
quite like Trumps "greatness" against "lowlifes".

"Runen, Okkultismus und deutsch-völkisches
Christentum. Odin oder Wotan: Oftmals wird
der Hauptgott der nordischen Mythologie als
der Hauptgott des rassistisch-mythologischen
Weltbilds der Nazis genannt."
https://religion.orf.at/radio/stories/2949845/

[Mostowski Collapse]

Maybe Trump will be able to utilize military
in the next days. But they might then sock
pupet him, as soon as they are in his house?

Possibly no more slurry tweets. So there is a
certain risk for Trump. I guess he is
currently calculating the risk.

Who knows?

"After Donald Trump threatens to send in the army
to crush protests, the head of the US military
reminds those in uniform that their oath is not
to protect Trump but the Constitution. It speaks
volumes that he issued such a statement"
https://twitter.com/Freedland/status/1268451642434871296

[Ross A. Finlayson]

Coronavirus immunogens -> coronavirus vaccine / RNA therapy


https://www.ncbi.nlm.nih.gov/pubmed/8116187

"Most research has focused on the S protein
as a candidate antigen for CV vaccines since
it induces virus neutralizing (VN) antibodies.
However the HE protein stimulates the production
of VN and HE inhibiting antibodies and the M protein
induces antibodies that neutralize virus in the presence
of complement. Attempts to correlate in vitro VN antibody
activity with in vivo protection have shown that the passive
transfer of VN mAb to the S or HE protein conferred passive
protection against CV challenge in some studies, but not others.
Additional research has implicated a possible role
for other CV proteins in immunity." (1993)

"[Cell Mediated Immunity] may play an important role in protection
of cats against FIPV, since induction of circulating antibodies to the
S protein of FIPV contributes to disease pathogenesis by the induction
of immune complexes and antibody dependent enhancement of the
infectivity of FIPV for macrophages."

"An increased understanding of antibody and [Cell Mediated Immunity]
responses following natural [Corona Virus] infections in animals is
needed to identify the the antigens and epitopes that induce
protective immune responses."

"The expression of [Corona Virus] structural protein genes in various
vectors will provide the recombinant proteins needed for future
immunogenicity studies in the host species. Furthermore, live rDNA
vectors that replicate in the gut and express coronavirus genes may
provide a new generation of coronavirus vaccines."

[Ross A. Finlayson]

Well this seems quite the rather accurate if unfortunate -
making for modern therapeutics advising traditional medicine.

It seems the tests if you want it would be several and more
dollars or usually urine tests daily for what all sorts of
metabolites, as could be made to react as with detection.

Not being quite sure the catalog of those items,
there are lots of approaches to make the virus disease
fail, but, each of those for that very reason, of the
success, of the 32 -> double 64 kDa resulting from the
Coronavirus or Sars-Cov-2, among SARS and derivatives,
there should be some good conditioners for skin treatments
as what would help inhibit infection, or, help un-infect,
what that besides the Coronavirus replication is the
interaction throughout, with all the intercellular machinery,
as what the bodies usual actors start about that size and
are as larger, in intercellular machinery of the body.

I.e., some treatments would be sterilizing or cauterizing,
here as what's worse the disease or cure.

A positive mental attitude, of overcoming adversity,
allows that some people survive by suffering while
some people survive by not suffering. Either way,
it's important to personally maintain for oneself
the "attitude" of health.

Sorry, no news here.

Basically would look to interfere the replication
machinery, under the error detection of the RNA
that happens to have juiced up the spike as it were,
but, the very danger of it is in of course all the
RNA machinery floating all around the cell, because
then the body might find that oncogenic, making cancer,
because how it reacts to cancer is killing the cells
or putting them down, the immune system. This is that
the apoptotic cycle, of cells, isn't just immediate lysis,
but all the teardown machinery as of recycling and where
these examples in systems of immune responses, there is
that curing it with genetic therapy must consider that
the body's own curing itself "might" (with as low probability)
be successful, over the otherwise pernicious, terminal,
progressive, permanent infections.

[That the body must make innocuous as that's what it does.]

So, that approach would be dangerous, where it seems the
approach is to replicate for the spike protein mostly,
yet that as well has the uses or importance of spike-like
proteins in the body already, again, like the intercellular
machinery mentioned above, or > 64 kDa.

The supply-and-demand of genetic replication and here
this particular self-contained little ecosystem, makes
for what a starvation or diet regime, combined with a
supplement, as lets the virus make itself wrong thus
fail, here would be for the very specific for example
perhaps in heavy waters, that the supplement, would
basically favor the virus the consumption of the supplement
for its use so much, as how to influence the construction
of the virus, as would be in the cytosis already.

I.e. for an immune response to flush, and then having the
metabolite or for example an electrolyte, contribute to
flush and also supply itself over the readily available
construction material it uses already, makes for that
un-natural amino acids are wrong, and just because the
body leaves over some uue codons that are close to what
the coronivirus would find, here the point is to give the
viruses, in their assembly, a fault and as to the cellular
machinery then to detect them and reject them instead of
in the resulting packaging dropping them back out the cell,
the virions or here the RNA assembly, also is for crowding
out the infecting S-protein N-protein unit, for the cell
to flush and cycle itself down, if not already infected
with many units on the cell.

These though being what would be their result in mechanisms
then the catalog, provides that, modern material science
makes the statement that "any material thing" can be built,
according to a cost schedule. Here modern material science
can make for example parallel micro-assemblies, the capillary.

Then, for people to make kits as basically try experiments,
in the molecular scale, here probably is for identifying in
the pharmacopaiea what is already helping people already,
to figure out what factories to build.

The factory setting of mass production of proteins
is usually out the vats. The factory setting is usually
an animal setting here. Here there is basically that
yeast vats, genetically-engineered, to produce biomimetic
human protein, it is an advanced field with much exploration
today.

Recombinant techniques, of building virus vaccines, should be
able to provide, for the downstream structural proteins, the
actual particular virus vaccine, but, I couldn't imagine it
wouldn't cause a reaction, i.e. as for introducing the vaccine
in a metered or dosed way, as what could be afforded for delivery,
that for the liver subunit as the primary dose itself, that the
development of the vaccine has a sound and direct approach after
the description of the liver unit structural proteins.

Figuring that when the liver stopped breaking it down that the
rest of the body would figure itself out, still has for that
under infections (and, reinfections), the surface for the connection
of the virus' successful action is ubiquitous under the bodies
own intercelullar machinery itself as so for genetic expression
it works that way (as besides under for example influence and
messaging of genetic expression, and bubbles, a modern descriptive
action of the intercellular machinery of genetic expression).



There's plenty to read here above pretty much as explains what
I could find there in the months into the Coronavirus Pandemic -
it's an epidemic, there could be worse ones but that doesn't
make it good - these days it's not "have you heard of coronavirus?"
it's "how's your coronavirus?".

For each of the coronaviruses' 17 or 18 natural things that
make it what it is, that otherwise the body would reject,
and even that it does: each of those approaches has many
industry initiatives basically designed to focus on it.
(And directly target it independently.)

Then, the goal isn't the strongest hammer or longest lever,
what that might save a life, because it would be too much -
each of those lines has about a right hammer, making
toolboxes for doctors, for example people practicing
medicine on themselves and their families.


I.e., anything that's not how the body's already is needs
its own exit strategy, itself. (Or coping with it.)


Can't imagine but what clean living must be good for you,
can't be bad.


Quite a few vaccines are on the way, what's best is
generally not to be infected with Coronavirus,
enough's enough and the Coronavirus is too much.

But, eventually, everyone has to see the grocer,
and people who don't have replication defenses,
if there's not a vaccine then the defenses, more
or less, have to be exercised and accumulated.


Let's not forget that modern medicine offers
quite a few other medical miracles, too.

But, the medicine of the coronavirus, is
the grocer, the chicken factory, and
the birds, too. (And we eat them.)


Fresh air, clean living.


Maybe COVID-19 "is" SARS-Lite.

Figuring out basically a rinse, a non-toxic, simple
disinfectant, as what makes for some low-level UV light
to complete, each strong enough to together disinfect,
and masks, for public hygiene, basically has that the only
concession to public hygiene is wearing masks, here in the
US, then besides of course that the role of sanitation
and hygiene has become very direct and clear, the reducing
transmission helps, about whether Coronavirus is continually
produced post-infection, basically has that at least working
that to zero stops re-infection, for giving the liver the
chance to work it out.


The importance of regular exercise to flushing the body
can not be understated.

Here it's a polyanna approach to "it's gonna work out".

[Mostowski Collapse]

Did you buy toilet paper?

[Mostowski Collapse]

BTW an interesting genetic antibiotic is fluoro-
quinolones, like ciprofloxacin. The fluor replacement
makes it 100x more potent.

Quinolones exert their antibacterial effect
by preventing bacterial DNA from unwinding
and duplicating. Specifically, they inhibit
the ligase activity of the type II topoisomerases,
gyrase, and topoisomerase IV, which cut DNA to
introduce supercoiling and with their ligase
activity disrupted, release DNA with single-
and double-strand breaks that lead to cell death.
https://en.wikipedia.org/wiki/Quinolone_antibiotic#Mechanism_of_action

This is making it a versatile bactericidal. Some
side effect is phototoxicity. But there is also
high veterinary use of such drugs,

with some danger that resistent bacteria strands
might evolve in humans and animals. The equivalent
against Sars-Cov-2 has not yet been discovered,

and is probably harder, since bacteria are
prokaryote whereas the Sars-Cov-2 virus replicates
with the help of an eukaryote cells.

But its nevertheless facinating that an antibiotic
can especially target prokaryotes inside an eukaryotic
organism, by takling one specific enzym, DNA gyrase.

[Mostowski Collapse]

Not the food market? Some Jan/Feb 2020 screening:

"Combining viral genomics with epidemiological
evidence of how people might have picked up
the infection, Zhang et al. show that the
viral genomes from six people with established
links to the Wuhan market cluster in clade I
on the SARS-CoV-2 family tree, whereas the viral
genomes of three cases without known links to the
market cluster in clade II. These data support
the idea that the market might not have been
the origin of the pandemic. Instead, they suggest
that clades I and II originated from a common
viral ancestor and spread independently at the
same time: clade I through the market
and clade II outside it."

A race to determine what drives COVID-19 severity
Nature - 29 June 2020
https://www.nature.com/articles/d41586-020-01915-3

Also some pharma:

The possibility that high cytokine levels cause
lymphocytopenia is consistent with the observation
that people with COVID-19 who were treated with
the drug tocilizumab, which blocks IL-6-mediated
signalling, had their bloodstream levels of lymphocytes
restored to nearer normal. However, further
experimental and mechanistic studies are needed
to establish whether a causal connection underlies
the correlation between these cytokine
levels and lymphocytopenia.

[Mostowski Collapse]

Copper surfaces might be safer:

Coronavirus on Different Surfaces
"Coronavirus can last for long durations on
different metal surfaces, ranging from hours
to days. Recent studies show that the coronavirus
can last about three days on a plastic surface
as well as on stainless steel surface, it can
also sustain for a period of whole one day on
cardboard, while it can only sustain only for
about four hours on a copper surface."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201236/

Common Touch Surface Materials
"In this new study, human coronavirus 229E was
rapidly inactivated on a range of copper alloys
(within a few minutes for simulated fingertip
contamination) and Cu/Zn brasses were very
effective at lower copper concentration. Exposure
to copper destroyed the viral genomes and
irreversibly affected virus morphology, including
disintegration of envelope and dispersal of surface spikes."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659470/

[Mostowski Collapse]

Trump the stump high as fuck as usual:

*** Breaking News ***
vaccines and therapeutics will soon...
...be on the way
https://twitter.com/realDonaldTrump/status/1283566319405797378
https://twitter.com/realDonaldTrump/status/1283566320802553857
*** Breaking News ***

Maybe, who knows? The tested drug is a genetically engineered,
and uses a Lipid-Based Nanoparticle shell:

About mRNA-1273, Moderna's Potential Vaccine Against COVID-19
https://www.youtube.com/watch?v=qJlP91xjvsQ

A Nanobiologist's Holy Grail
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885142/

[Mostowski Collapse]

Seems to have been successful in some liver problems:

"In 2018, these developments culminated in the approval of
Onpattro® (patisiran), the first RNAi drug, for treating hereditary
amyloidogenic transthyretin (ATTRv) amyloidosis"

From this article:

Lipid nanoparticle technology for therapeutic
gene regulation in the liver - online 2 July 2020
https://www.sciencedirect.com/science/article/pii/S0169409X20300727

[Luke Abbate]

you finally woke up, you stupid lemming fuck. But you have to organize,
waking not enough. They made sure you can't organize. They can. Drills,
simulations, models, meetings, plans etc etc. Open your fucḱing eyes.

[Mostowski Collapse]

4 letters, this can only be micro penis nymshifter.

Am Donnerstag, 16. Juli 2020 13:09:09 UTC+2 schrieb Luke Abbate:
> <gibberish>

[Mostowski Collapse]

Yeah, just the same mongo again, some non existing
email lu...@nntftpi.bu. You should use:

mi...@penis.zt

[Luke Abbate]

it's about the issue, not the messenger, you retard stupid. Who the hell
is this mostoski, and how can it be he is so stupid?

[Mostowski Collapse]

The messenger has some issues, micro penis.

[Mostowski Collapse]

LoL, Luke Abbate was rejected from the sperm bank:

https://ilikecomix.com/porncomix/a-small-deposit-devin-dickie-qos-comix/

[Dwight W. Hilburn]

Mostowski Collapse wrote:

> The messenger has some issues, micro penis.
>

>> Mostowski Collapse wrote:
>> > You should use:
>> > mi...@penis.zt

you are seemingly distinctly obsessed with "micro penis" you stinking
kike pedophile.

[Michael Moroney]

ooh, looks like you got the micropenised nymshifter really mad this time with
this latest nymshift..

What's the Serbian word for "micropenis"?

[Mostowski Collapse]

Not that I know. But you're an anti-semite?

The word kike (/ˈkaɪk/) is an ethnic slur for a Jew.

LoL