On Monday, April 13, 2020 at 10:36:19 AM UTC-7, Mostowski Collapse wrote:
> Ross the Floss was thinking hard:
> "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.
> 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".)
> 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?
> "Antiviral effects of silymarin against Hepatitis C: the Jury Is Still Out"
> "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."
> "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."
> "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."
> "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
> 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.
> On Monday, April 13, 2020 at 5:41:03 PM UTC+2, Ross A. Finlayson wrote:
"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."
"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."
"Cyclophosphamide induces beneficial immunomodulatory effects in adaptive immunotherapy. Suggested mechanisms include:
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."
"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."
"... 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."
"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
"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)."
" 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."
"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."
"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
"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
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.)