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.