A long time reader asked ” I am curious what you keep in your database, what you use it for, etc. And why Mathematica?”
Here is the sort of thing kept in the database. It is card # 16094 of 16182 text cards in the database. This is the raw data it contains with some metadata getting it ready to move to Mathematica.
It contains my latest notes on what I’ve read about the pandemic and the virus responsible — they’re written for me and contain what I didn’t already know in the article — along with my comments to myself. Lots of typos, and comments.
The most recent things I’ve read is at the top. There are 6 older cards equally full just like it.
More about why move this stuff and why Mathematica another time.
Total Number of Cards = 1 Begin card “X4134989” card id 4134989 Wuhan virus — newest stuff at top — Negative strand RNA virus 29,903 nucleotides – 7 7 “Fluoroquinolones” 565705 “Glossary” “OlderStuff” 4383208 Xref “Fe-S clusters ” 766918 “Glossary” “NewerStuff ” 4139680 Xref “Frameshifting ” 1574232 Xref “PF4” 1171125 “Glossary” “Pseudoknot” 1235453 “Glossary” 1 Aspirin: prostaglandins: platelets: endothelium 182 [ Science vol. 373 pp. 1428 – 1429 ’21 ] Starting 1 August Israel gave a third short to 3 million people (mostly those over 40), yet they are still getting 900 – 1000 new cases (defined how) per day. This is a higher infection rate than the USA. Most transmission is occurring among the unVaccinated (no figure given for ‘most’ ). Presently 64% of Israelis have received 2 shots. It’s being blamed on Rosh Hashonna and Yom Kipur in September. 75% of Iraeli’s over 60 have received boosters. Another reason is increased testing. In midAugust 59% of severe cases were fully vaccinated (about the precentage of vaccinated people in the population)
[ Science 24 Sep ’21 ] Only 15% of India’s population has been vaccinated and daily new cases (defined how?) has fallen from 400,000 to 30,000. [ Nature vol. 597 p. 453 ’21 ] 1.1 million Israelis over 60 who had their first doses at least 5 months ago. 12 days after receiving the booster, participants were 19.5 times less likely to have severe COVID-19 than people who didn’t. [ Nature vol. 597 p. 453 ’21 ] 1.1 million Israelis over 60 who had their first doses at least 5 months ago. 12 days after receiving the booster, participants were 19.5 times less likely to have severe COVID-19 than people who didn’t.
[ Proc. Natl. Acad. Sci. vol. 118 e2114054118, 22109229118 ’21 ] The dark matter of the pandemic is asymptomatic infection. There have been 390 studies on the subject. It is more common in kids than adults. They talk about the danger of classifying presymptomatic individuals as asymptomatic (I don’t think this is big). Everyone was tested in the Diamond Princess outbreak 2/20 and asymptomatic infection occurred in 19% of an older population. Systematic testing in Israeli schools placed the frequency of asympomatic infection in kids at 51 – 70% They say that respiratory viral loads in asymptomatic people don’t differ from viral loads in sympaomtic infections < eLife vol. 10 10 ’21 >.
[ Nature vol. 597 p. 309 ’21 ] Masks cut symptomatic cases by 9% in a large study of 350,000 people in Bangladesh — face masks (not cloth) distribution increased mask usage from 13% to 42% in villages receiving them. This reduced symptomatic COVID19 cases by a measly 9%. Later experiments found that 3 layered cloth masks reduced transmission of small particles capable of airbone transmission by 37%, while surgical masks reduced it by 73% (even after 10 washing).
[ Science vol. 373 pp. 1180 -1181, ’21 ] A survey of 50,000 kids between 11 and 17 in the UK (not clear how many were actually infected clinically) showed that 14% of those previously infected with SARS-CoV-2 had 3 or more symptoms 15 weeks after infection — tiredness, headaches, shortness of breath. Of those vaccinated with breakthrough infections (how many?) only 5% still had symptoms after 4 weeks (vs. 11% of the unvaccinated infected). Unfortunately this is from the Lancet Infectious Diseases. By late August 2021 Delta accounted for 99.1% of USA cases, starting from 7.5% in late May Mu accounted for 69% of cases in Colombia in early July. In July it was 9% of 101 sequenced cases in Florida. Mu contains the E484K which helps the virus blunt vaccine and infection induced immunity. However, Delta has outcompeted Mu even in Columbia
[ Nature vol. 597 p. 162 ’21 ] 10% of people with severe COVID19 have autoantibodies against type I interferons, somthing seen in .18% of 35,000 healthy people between 18 and 69, 1.1% 70 – 79, and 3.4% > 80. This may explain the prevalence of severe COVID19 in the elderly. [ Science vol. 373 pp. 1066 – 1067 ’21 ] A large Israeli study showed that people who had SARS-CoV-2 infection were more protected against the Delta variant than those those who had 2 doses of the Pfizer vaccine. Giving the vaccine to the previously infected were more highly protected against reinfection. The risk of symptomatic COVID19 was 27 times higher in the previously vaccinated than in the unvaccinated but previously infected (determined by antibody levels) and the risk of hospitalization was 8 times higher. This is based on very small numbers — 8 hospitalizations in the vaccinated group in the 32,000 person analysis vs. 1 in the previously infected group. No one in the study who got a new SARS-CoV-2 infection died. Don’t have an infection party. Vaccinating the previously infected cut the reinfection rate in half (how big are these numbers?). The study was voluntary, so previously infected people developing mild symptoms were less likely to get tested than vaccinated people.
[ Science vol. 373 pp. 1072 – 1077 ’21 ] The (formerly vaunted) US intelligence review of the lab leak hypothesis submitted 24 August 21 reached no firm conclusion, but ‘leaned toward’ the theory that the virus had a natural origin. China has clamped down (implying that they have something to hide). The article is mostly about various experts say about the possibility. The closest similarity yet found (96.2%) to SARS-CoV-2 is with RatG13 a bat virus found in a mine in Yunnan where 6 miners fell ill with 3 dying. Could the virus have arisen from a Gain Of Function study (GOF study), which creates pathogens more virulent or more transmissible to humans. “More than 1,100 nucleotides separate the genomes of the two viruses” and the differences are scattered in a way that doesn’t suggest deliberate engineering — how many lumps do they occur in. The furin cleavage site is found in other coronaviruses casting doubt that it was engineered in. Could the pandemic virus have arisen by repeaed passage allowing mutations to accrue. Bat coronaviruses have been found in > 12 CHinese provinces, but only the ones from Yunnan could attach to ACE2. Coronavirus sequences in a database of the Wuhan Institute of Virology (WIV) were removed from the internet 9/19 ! ! claiming that the site had been hacked.
[ Proc. Natl. Acad. Sci. vol. 118 e210460118 ’21 ] Based on a model, workers from Brazil estimate that delaying the second dose of a vaccine (with first dose efficacy of 70%) by 12 weeks would reduce ICU admissions by 400/million people over 200 days. [ Science vol. 373 pp. 949 – 950 ’21 ] > 60% of Israeli’s have had 2 doses of Pfizer, but on 30 July a third dose is offered to any over 60, and on 20 August it said everyone over 40 SHOULD get one. The paper at last says that protection against hospitalization is close to 95% even though efficacy dropped to 91.7 to 80%. In Israel protection against severe disease is still 85% for those against (this wihout boosters).
[ Nature vol. 596 pp. 479 – 481 ’21 ] Vaccine induced Immune Thrombotic Thrombocytopenia (VITT) occurs in 1/50,000 who receive Oxford AstraZeneca vaccination. It is similar to Heparin Induced Thrombocytopenia (HIT) which is due to heparin binding to platelet factor 4 (PF4). In some cases antibodies develop to the complex which then binds and activates platelets causing clumping and clotting. VITT people produce antibodies against their own PF4. VITT only occurs in vaccines using adenovirus (but no cases of VITT have been reported in people getting Sputnik V which also uses adenoviruses). Mortality of VITT is high 49/220. VITT is more frequent in young people, so AZ is only given to people over 40. Thailand has given 1.7 million doses with no cases of VITT. VITT itself seems to be declining. [ Nature vol. 596 pp. 565 – 569 ’21 ] Using alanine screening mutagenesis, antibodies to PF4 in VITT patients use 8 amino acids on the PF4 surface, all of which are in the heparin binding site, which inhibits antibody binding. So VITT antibodies mimik heparin allowing PF4 tetramers to cluster and form immune complexes, which causes FcgammaRIIa < CD32a > platelet activation. In heparin induced thrombocytopenia (HIT) the antibodies bind to two different sites on PF4. VITT antibodies bind more strongly than HIT antibodies.
[ Nature vol. 596 pp. 472 – 473 ’21 ] The P681R mutation of the spike protein of the Delta virus is near?at? the furin cleavage site. A similar mutation was associated with infectivity in influenza and other viruses. It basically produces such a site, meaning the spike protein can be cleaved as the virus leaves a cell rather than when it enters. To enter cells the spike protein must be cut twice by host proteins. The Alpha variant has a P681 mutation (to what?) as well. The spike protein is cut much more efficiently in Delta than Alpha. Spike proteins with P681R fuse with the plasma membrane of uninfected cells 3 times faster than spike proteins without it.
[ Science vol. 373 pp. 931 – 936 ’21 ] Some 1,900 clinically safe drugs were screened for activity against OC43, a human cold virus. 20 drugs significantly inhibited replication of OC43 && SARS-CoV-2, 8 of them inhibited the SARS-CoV-2 main proteases (3CLpro). The most potent drug was masitinib, an orally available tyrosine kinase inhibitor, which inhibited 3CLPro. It worked against all tested variants of concern.
[ Cell vol. 184 pp. 4392 – 4400 ’21 ] Selective sweeps cause a reduction in the level of sequence variability at nearby genomic sites — this is how they are found. This work looked at 182,000 SARS-CoV-2 genomes and found that selective sweeps occurred in Spike and other regions. They found A1114G protucing T372A in the spike protein receptor binding domain. This is predicted to remove glycosylation at asparagine 370 and increase binding to human ACE2. The change is present in all human SARS-CoV-2 sequences but NOT in closely related viruses from bats and pangolins. T372A binds human ACE2 with higher affinity in experimental binding assays. THey made a revertant mutant A272T (presumably an ancestral virus) and show that it replciates 60x less efficiently in human lung epithelial cells..
[ Science vol. 373 pp. 844 – 849 ’21 (Kupferschmidt) ] THere is now enough immunity ij the human population to ratchet up an evolutionary competition, pressuring the virus to adapt further. At the same time, much of the world is still overwhelmed with infections giving the virus plenty of changes to replicate and throw up new mutations. The D614G mutations made it slightly more infectious. Almost ALL current viruses are descended from it. Delta is 40 – 60% more transmissible than the first virus found (alpha). Alpha binds more strongly to ACE2 (than what)( because of a muation called N501Y. The delta virus has the P681R mutation which makes cleavage by the human enzyme furin mnore efficient. Delta leads to virus levels in patient samples are 1,000 times higher (than previous variants). There is evidence of mutation making the ’18 more deadly — the second wave was 6x deadlier. Presently > 2 million viral genomes have been sequenced and published. It is possible to have a measure distance between genomes (by how many mutations are required to change one intothe other. Interestingly the beta variant is the farthest from the original Wuhan strain, with the Delat being closer than all but one (alpha). Measles is still 3x more transmissible than what we have now with Delta. Other work (based on tinkering with the virus) shows that 20 changes are needed for the spike protein to escape curent antibodies.
[ Science vol. 373 pp. 835 – 836 ’21 ] 78% of people over 12 are vaccinated in Israel (most with Pfizer). However there are 700 new cases/10^6 day of which half are fully vaccinated. What is meant by a ‘case’. The population of Israel is 9.3 million. Hospitalizations and ICU admissions ‘are beginning to follow’. 525 Israelis were hospitalized j with severe or critical COVID19 of whom 60% were fully vaccinated. Of the vaccinated, 87% were 60 or over. Israel began booster shots 30 July for those 60 and older.
[ Nature vol. 596 pp. 327 – 328 ’21 ] Already vaccinated people who become infected with the Delta variant (breakthrough infections) carry as much virus in their nose as do unvaccinated people. Is this true for some or all infected vaccinated. In the 469 Provincetown cases 3/4 were vaccinated, and vaccinated and unvaccinated cases had the same viral loads. Note that there were 5 hospitalizations. In texas 17% of cases ‘in the hospital system’ — is this the same as in the hospital ? — had been vaccinated. How were these ‘cases’ found — symptomatic, routine testing, testing as a requirement?
[ Nature vol. 596 pp. 175 – 176 ’21 ] New cases in the UK dropped in half from17 July to 2 August. Jody may be right. Presently 70% of the UK population is vaccinated. I all depends on how many people are taking the tsst. Hospital admissions also dropped 836 25 July to 645 1 August.m [ Nature vol. 596 p. 169 ’21 1/3 of the white-tailed deer in the northeastern USA have antibodies against SARS-CoV-2. 385 deer blood samples between 1/21 and 3/21 from Michigan, Pennsylvania, Illinois and NY.
[ Science vol. 373 p. 602 ’21 ] The Provincetown outbreak (Barnstable County). 3/4 of the 469 people infected in July were fully vaccinated, with the Delta variant present in 89% of 133 sequenced cases. Only 5 people were hospitalized, of which 4 had been fully vaccinated. Viral titers in the nose and throat of the fully vaccinated were as high as the unvaccinated. No deaths.
[ Science vol. 373 pp. 491 – 493 ’21 ] About 1/3 of people with symptomatic COVID-19 still have symptoms 3 months after onset. Long Covid has been defined by patients using social media platforms. The most prominent symptom of long COVID is fatigue (e.g. chronic fatigue syndrome). Then comes cognitive dysfunction. 6 month followup of discharged COVID19 patients in Wuhan showed 76% were still symptomatic. They at least mention chronic fatigue. People with long COVID have incresed cytokine levels 8 months after infection.
[ Science vol. 373 p. 472 ’21 ] 151/18,215 vaccinated transplant patients in the USA experienced breakthrough infections. 87/151 were hospitalized and 15/18.215 died.
[ Nature vol. 589 pp. 125 – 130 ’21 ] Using ribosome profiling techniques, a high resolution map of coding regions in the SARS-CoV genome is presented. This allows determination of the amount of expression of viral open reading frames and the identification of 23 unannotated viral ORFs (hadn’t anyone looked before?). These include iin frame internal ORFs within existing ORFs, resulting in amino terminally truncated products, as well as internal out of frame ORFs which generate novel proteins. Viral mRNAs are not translated more efficiently than host mRNAs; instead they dominate host translation because of high levels of viral transcripts. We know that two overlapping ORFs (ORF1a and ORF1b) are translated from the positive strand of genomic RNA. They are cleaved into polypeptides which eventual give a total of 16 nonStructural proteins. The translation of ORF1b is mediated by a -1 frameshift allowing translation to continue beyond the stop codon of ORF1a. Negative strand RNA intermediates are produced from the viral genome and serve as templates for the synthesis of positive strand genome RNA and subgenomic RNAs. The subgenomic RNAs contain a common 5′ leader fused to different segments from the 3′ end of the viral genome, a 5′ cap structure and a 3′ polyAdenine tail. The subgenomic RNAs code for 4 conserved structural proteins — spike, envelope, membrane and nucleocapsid (S, E, M, N) and several accessory proteins. Of the novel ORFs found, 14 are short (under 21 codons), or located in the 5′ UTR of genomic RNA — so they are probably regulatory. 3 of the novel ORFs are extensions or truncations of canonical ORFs. Some nonCanonical ORFs in SARS-CoV-2 have higher expression levels than the canonical viral ORFs.
[ Cell vol. 184 pp. 3962 – 3980 ’21 ] The present work describes the HLA-I immunopeptidome in two SARS-CoV-2 infected human cell lines. Some peptides from out of frame ORFs produce T cell responses in people with COVID-19 exceeding responses to canonical peptides (including some of the strongest epitopes reported to date). Previously people were looking a viral structural proteins, but some of the nonstructural proteins (nsps) are immunogenic. Peptides derived from out of frame ORFs produce T cell responses in immunized mice. They also find that SARS-CoV-2 interferes with the cellular proteasomal pathway, which might result in lower viral peptide presentation. ORF9b (out of frame of the N protein) has only 97 amino acids but it produced 16% of the total detected peptides.
[ Nature vol. 595 pp. 484 – 485 ’21 ] THe virus ‘has difficulty’ getting past the BBB, and doesn’t ‘necessarily’ attack neurons in any significant way. The virus can infect astrocytes (in brain organoids). The virus can infect ‘pericyte-like cells’ in brain organoids. There is some evidence that antiVIral antibodies could attack the brain, acting as autoAntibodies.
[ Nature vol. 595 pp. 359 – 360, 421 – 425, 426 – 431 ’21 ] Memory B and T cells have epigenetic changes which allow them to react rapidly to subsequent signs of infection. The presence in marrow of long lived antibody secreting memory plasma cells is ‘probably’ the best predictor of long lasting immune protection. Such cells secreting antibodies to the spike protein were found in 15/19 seven months after infection. At 11 months post infection, the cells were still present in 14/19. Antibody levels decline to 20% of the acute phase but remain stable after that. They were present at 11 months after mild COVID-19 in 77/77 patients Immunity can be boosted further in convalescent people by vaccinating them again. The second paper concerns 63 people who recovered from COVID-19 studied at 1.3, 6.2 and 12 months. 41% had also received mRNA vaccines. In those with no vaccine antibody levels against the receptor binding domain of the virus were stable between 6 and 12 post infection. Vaccination increased all antibody levels, and to higher levels than those recovering from the original Wuhan staran. B cell clones expressing broad and potent antibodies were selectively retained, and expanded markedly after vaccination. They were protective against the new variants as well.
[ Nature vol. 595 pp. 346 – 348 ’21 ] THe COVID-19 Host Genetics Initiative (HGI) is an amalgamation of 46 separate studies 50,000 with COVID-19 (defined how), tried to find risk factors. Some 12 variants increase the risk of severe COVID-19. One variant is near a family of antiviral genes called OAS (OligoAdenylate Synthase). The genes activate enzymes (apparently the genes are the enzymes themselves) which chew up viral RNA. A variant with lower circulating OAS 1 results in increasd risk of infection, hospitalization and critical illnes (how much of an increase. Typical of GWAS (head scratching result), the strongest association between any gene variant and sever COVID-19 lies in a poorly studied region of chromosome #3 which has genes involved in immune signaling and lung biology. People with the variant have double the risk of hospitalization with COVID-19.
[ Science vol. 373 pp. 236 – 241 ’21 ] Another way to atack the virus. NonStructural Protein 12 (NSP12) is the catalytic of SARS-CoV-2 RNA dependent RNA polymerases (RdRp). It binds two Fe-S cofactors essential for its activity. TEMPOL (4 hydroxy 2,2,6,6, tetr4amethylpiperidin-1-oxy) a stable nitroxide oxidizes the clusters, causing their disassembly, and inactivation of RdRp. A picture of the polymerase is given. It contains NSPs 6, 7, 8, 9, 10, 12, 13, 14, 16. NSP9 is a single strand binding protein, NSP10 is an exonuclease, NSP16 is 2′ O methyl transferase, NSP13 is a helicase. [ Nature vol. 595 pp. 17 – 18 ’21 ] Indian virus (Delta, B.1.617.2) it is 60% more transmissible than the alpha variant (B.1.1.7). Delta is twice as likely as alpha to put people in hospital. Fulluy vaccinate people at 94% less likely to be hospitalized with Delta than unvaccinated.
[ Cell vol. 184 pp. 3474 – 3485 ’21 ] SARS-CoV-2 has 16 nonStructural proteins (nsps), the mRNAs of which are capped, which is done by nsps. The viral Co-transcriptional Capping Complex (CCC) is made of nsps 9, 10, 12 and 14. NiRAN standfs for Nidovirus RdRp Associated Nucleotidyltransferase. It is a domain in nsp12. Nasp14 is a bifunctional enzyme containing an amino terminal exonuclease and a carboxy terminal N7 methylTransferase (for the cap). Nsp14 has 527 amino acids, nsp12 has 932 (it contains the RNA dependn RNA polymerase and niRAN. The complexes form a dimer, thought to be important in proofreading. The work is out of Beijing. Coronaviruses have the largest genomes of all RNA viruses, probably because they have proofreading ability.
[ Cell vol. 184 pp. 3426 – 3437 ’21 ] They claim that SARS-CoV-2 has a slow mutation rate relative to other RNA viruses (.8 x 10^-3 substitutions/site * year). D614G mutations have predominant since 6/20. This work concerns a California variant L452R in the spike protein, picked up 1/21. They call its two variants B.1.425/B.1.429. It increased from 0 in 9/20 to 50% of sequenced viruses in California in 1/21. There is increased viral shedding and increased L452R pseudovirus infections of cell culture and lung organids. There was 2 – 7 fold decrease in neutralizing antibody titers against the virus in convalescents and vaccine recipients. So the variant is more transmissible. The virus has two more spike protein mutations (S13Isoleucine, W152C). Infected patients shw an increased median viral load. The L452R mutation is thought to stabilize the interaction between the spike protein and the ACE2 recepor. The L452 amino acid doesn’t directly contact ACE2, (unlike the N501Y mutation in B.1.1.7, B.1.351 and P.1)
[ Science vol. 372 pp. 1392 – 1393, 1413 – 141x, 1418 – 14xx ’21 ’21 ] People with previous SARS-CoV-2 infection mount unusually potent immune responses to COVID-19 vaccines. Memory to previous infection is seen in B cells, CD4 cells, CD8 cells and antibodies — with a ‘relatively gradual’ decline which ‘partially’ stabilizes within a year. This is called natural immunity (because it was produced ‘naturally’?). Natural immunity against symptomatic infection < reinfection ? > (which is what you are really worried about?) is between 93 and 100% in large studies. Neutralizing antibody activity against most Variants Of Concern (VOCs) is reduced both for natural immunity and for vaccine generated immunity. AstaZenica vaccine efficacy against symptomatic acases dropped from 75% to 11% abainst B.1.351 (Beta variant), while Pfizer efficacy against symptomatic cases of Beta dropped from 95% to 75%, while efficacy against severe disease remained at 97%. Hybrid immunity occurs when previously infected people are then vaccinated — it is larger than expected. There are both B and T cell comonents. There is 100x more neutralizing antibody against Delta in hybrid immunity than infection alone, and 25x more than in vaccination alone. This was unanticipated. It might be due to B cells trying to ‘guess’ what viral variants might emerge in the future. Memory B cells are increased 5 – 10 X in hybrid immunity compared with natural infection or vaccination. Virus specific CD4+ and T_FH cells are the driver of the SARS-CoV-2 memory B cells. Most vaccines contain a single antigen, but the virus has 25 different proteins. Repeat vaccination is known to goad the immune system into committing more cells to a particular immune responses. So this plays a role in hybrid immunity. The magnitude of the hybrid response doesn’t depend on how severe the COVID19 actually was.
[ Science vol. 372 pp. 1375 – 1376 ’21 ] Delta variant (Indian variant from Mahararashtra) 12/20. It now (6/20) makes up 90% of all infections in England. Prevalence here in the USA is 14%. Delta has 9 mutations in the Spike protein. The P681R is close to the furin cleavage site, which makes it easier. Furin cleavage is essential for viral entry. There is deletion of amino acids at positions #156 and #157 along with an R158G mutation. There are also mutations in the nucleocapsid protein.
[ Science vol. 372 pp. 1306 – 1313 ’21 ] Frameshifting by -1 is important in SARS-CoV-2 (and all coronaviruses). The reading frame of translation is changed at the junction between open reading frames ORFs 1a and 1b. It is necessary for the synthesis of Nsp12 (nonstructural protein 12, the viral RNA dependent RNA polymerase) and other downstream proteins. This work shows that the viral RNA adopts a pseudoknot structure that lodges at the entry to the ribosomal mRNA channel, generating tension in the mRNA and ribosomal pausing. The nascent viral polyProtein forms distinct interactions with the ribosomal tunnel. Inhibiting this frameshifting hurts the virus — so it’s another target for therapy.
[ Proc. Natl. Acad. Sci. vol. 118 e2023051118 ’21 ] Using a high throughput compound screen they found that a fluoroquinolone, merafloxacin innhibits the -1 programmed ribosomal frameshift. Merafloxacin impedes SARS-CoV-2 replication in Vero E6 cells. [ Proc. Natl. Acad. Sci. vol. 118 e2101161118 ’21 ] NonStructural Protein 14 (NSP14) shuts down host protein synthesis. This is true for all human coronaviruses. NSP14 is required for viral replication due to its exoribonuclease activity (ExoN) and its N7 methyltransferase (N7MTase) activities. Binding to nsp10 enhances both actiities. It remains to be determined how SARS-CoV-2 overcomes the translation shutdown induced by the NSPs for the production of its own viral proteins. End card “X4134989”
Chemiotics II 