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Rxivist combines biology preprints from bioRxiv and medRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 161,368 papers from 673,916 authors.

Most tweeted biology preprints, last 24 hours

*There are gaps in historical Twitter data, most notably in spring 2020. This may result in some preprints appearing with less tweets than they should.

284 results found. For more information, click each entry to expand.

1: Fatal breakthrough infection after anti-BCMA CAR-T therapy highlights suboptimal immune response to SARS-CoV-2 vaccination in myeloma patients
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Posted 15 May 2021

Fatal breakthrough infection after anti-BCMA CAR-T therapy highlights suboptimal immune response to SARS-CoV-2 vaccination in myeloma patients
351 tweets medRxiv hematology

Adolfo Aleman, Oliver Van Oekelen, Bhaskar Upadhyaya, Sarita Agte, Katerina Kappes, Katherine Beach, Komal Srivastava, Charles R Gleason, PVI study group, Bo Wang, Tarek H Mouhieddine, Kevin Tuballes, Daniel Geanon, Zenab Khan, Ana S. Gonzalez-Reiche, Harm van Bakel, Konstantinos Mouskas, Nicole W. Simons, Alexander W Charney, Seunghee Kim-Schulze, Adeeb H Rahman, Emilia M. Sordillo, Florian M Krammer, Carlos Cordon-Cardo, Nina Bhardwaj, Sacha Gnjatic, Miriam Merad, Brian D. Brown, Larysa Sanchez, Ajai Chari, Sundar Jagannath, Viviana Simon, Ania Wajnberg, Samir Parekh

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly effective in healthy individuals. Patients with multiple myeloma (MM) are immunocompromised due to defects in humoral and cellular immunity as well as immunosuppressive therapies. The efficacy after two doses of SARS-CoV-2 mRNA vaccination in MM patients is currently unknown. Here, we report the case of a MM patient who developed a fatal SARS-CoV-2 infection after full vaccination while in remission after B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T treatment. We show that the patient failed to generate antibodies or SARS-CoV-2-specific B and T cell responses, highlighting the continued risk of severe coronavirus disease 2019 (COVID-19) in vaccine non-responders. In the largest cohort of vaccinated MM patients to date, we demonstrate that 15.9% lack SARS-CoV-2 spike antibody response more than 10 days after the second mRNA vaccine dose. The patients actively receiving MM treatment, especially on regimens containing anti-CD38 and anti-BCMA, have lower antibody responses compared to healthy controls. Thus, it is of critical importance to monitor this patient population for serological responses. Non-responders may benefit from ongoing public health measures and from urgent study of prophylactic treatments to prevent SARS-CoV-2 infection.

2: Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity: reinfections versus breakthrough infections
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Posted 25 Aug 2021

Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity: reinfections versus breakthrough infections
109 tweets medRxiv infectious diseases

Sivan Gazit, Roei Shlezinger, Galit Perez, Roni Lotan, Asaf Peretz, Amir Ben-Tov, Dani Cohen, Khitam Muhsen, Gabriel Chodick, Tal Patalon

Background: Reports of waning vaccine-induced immunity against COVID-19 have begun to surface. With that, the comparable long-term protection conferred by previous infection with SARS-CoV-2 remains unclear. Methods: We conducted a retrospective observational study comparing three groups: (1)SARS-CoV-2-naive individuals who received a two-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 vaccine, (2)previously infected individuals who have not been vaccinated, and (3)previously infected and single dose vaccinated individuals. Three multivariate logistic regression models were applied. In all models we evaluated four outcomes: SARS-CoV-2 infection, symptomatic disease, COVID-19-related hospitalization and death. The follow-up period of June 1 to August 14, 2021, when the Delta variant was dominant in Israel. Results: SARS-CoV-2-naive vaccinees had a 13.06-fold (95% CI, 8.08 to 21.11) increased risk for breakthrough infection with the Delta variant compared to those previously infected, when the first event (infection or vaccination) occurred during January and February of 2021. The increased risk was significant (P<0.001) for symptomatic disease as well. When allowing the infection to occur at any time before vaccination (from March 2020 to February 2021), evidence of waning natural immunity was demonstrated, though SARS-CoV-2 naive vaccinees had a 5.96-fold (95% CI, 4.85 to 7.33) increased risk for breakthrough infection and a 7.13-fold (95% CI, 5.51 to 9.21) increased risk for symptomatic disease. SARS-CoV-2-naive vaccinees were also at a greater risk for COVID-19-related-hospitalizations compared to those that were previously infected. Conclusions: This study demonstrated that natural immunity confers longer lasting and stronger protection against infection, symptomatic disease and hospitalization caused by the Delta variant of SARS-CoV-2, compared to the BNT162b2 two-dose vaccine-induced immunity. Individuals who were both previously infected with SARS-CoV-2 and given a single dose of the vaccine gained additional protection against the Delta variant.

3: The BNT162b2 mRNA vaccine against SARS-CoV-2 reprograms both adaptive and innate immune responses
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Posted 06 May 2021

The BNT162b2 mRNA vaccine against SARS-CoV-2 reprograms both adaptive and innate immune responses
74 tweets medRxiv infectious diseases

F. Konstantin Föhse, Büsranur Geckin, Gijs J. Overheul, Josephine van de Maat, Gizem Kilic, Ozlem Bulut, Helga Dijkstra, Heidi Lemmers, S. Andrei Sarlea, Maartje Reijnders, Jacobien Hoogerwerf, Jaap ten Oever, Elles Simonetti, Frank L van de Veerdonk, Leo A.B. Joosten, Bart L. Haagmans, Reinout van Crevel, Yang Li, Ronald P. van Rij, Corine H Geurts van Kessel, Marien I. de Jonge, Jorge Domínguez-Andrés, Mihai G. Netea

The mRNA-based BNT162b2 vaccine from Pfizer/BioNTech was the first registered COVID-19 vaccine and has been shown to be up to 95% effective in preventing SARS-CoV-2 infections. Little is known about the broad effects of the new class of mRNA vaccines, especially whether they have combined effects on innate and adaptive immune responses. Here we confirmed that BNT162b2 vaccination of healthy individuals induced effective humoral and cellular immunity against several SARS-CoV-2 variants. Interestingly, however, the BNT162b2 vaccine also modulated the production of inflammatory cytokines by innate immune cells upon stimulation with both specific (SARS-CoV-2) and non-specific (viral, fungal and bacterial) stimuli. The response of innate immune cells to TLR4 and TLR7/8 ligands was lower after BNT162b2 vaccination, while fungi-induced cytokine responses were stronger. In conclusion, the mRNA BNT162b2 vaccine induces complex functional reprogramming of innate immune responses, which should be considered in the development and use of this new class of vaccines.

4: The impact of SARS-CoV-2 vaccination on Alpha and Delta variant transmission
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Posted 29 Sep 2021

The impact of SARS-CoV-2 vaccination on Alpha and Delta variant transmission
70 tweets medRxiv infectious diseases

David W Eyre, Donald Taylor, Mark Purver, David Chapman, Tom Fowler, Koen Pouwels, Ann Sarah Walker, Tim EA Peto

Background Pre-Delta, vaccination reduced SARS-CoV-2 transmission from individuals infected despite vaccination, potentially via reducing viral loads. While vaccination still lowers the risk of infection, similar viral loads in vaccinated and unvaccinated individuals infected with Delta question how much vaccination prevents transmission. Methods We performed a retrospective observational cohort study of adult contacts of SARS-CoV-2-infected adult index cases using English contact testing data. We used multivariable Poisson regression to investigate associations between transmission and index case and contact vaccination, and how these vary with Alpha and Delta variants (classified using S-gene detection/calendar trends) and time since second vaccination. Results 54,667/146,243(37.4%) PCR-tested contacts of 108,498 index cases were PCR-positive. Two doses of BNT162b2 or ChAdOx1 vaccines in Alpha index cases were independently associated with reduced PCR-positivity in contacts (aRR, adjusted rate ratio vs. unvaccinated=0.32[95%CI 0.21-0.48] and 0.48[0.30-0.78] respectively). The Delta variant attenuated vaccine-associated reductions in transmission: two BNT162b2 doses reduced Delta transmission (aRR=0.50[0.39-0.65]), more than ChAdOx1 (aRR=0.76[0.70-0.82]). Variation in Ct values (indicative of viral load) explained 7-23% of vaccine-associated transmission reductions. Transmission reductions declined over time post-second vaccination, for Delta reaching similar levels to unvaccinated individuals by 12 weeks for ChAdOx1 and attenuating substantially for BNT162b2. Protection in contacts also declined in the 3 months post-second vaccination. Conclusions Vaccination reduces transmission of Delta, but by less than the Alpha variant. The impact of vaccination decreased over time. Factors other than PCR Ct values at diagnosis are important in understanding vaccine-associated transmission reductions. Booster vaccinations may help control transmission together with preventing infections.

5: No Significant Difference in Viral Load Between Vaccinated and Unvaccinated, Asymptomatic and Symptomatic Groups Infected with SARS-CoV-2 Delta Variant
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Posted 29 Sep 2021

No Significant Difference in Viral Load Between Vaccinated and Unvaccinated, Asymptomatic and Symptomatic Groups Infected with SARS-CoV-2 Delta Variant
57 tweets medRxiv infectious diseases

Charlotte B. Acharya, John Schrom, Anthea M Mitchell, David A Coil, Carina Marquez, Susana Rojas, Chung Yu Wang, Jamin Liu, Genay Pilarowski, Leslie Solis, Elizabeth Georgian, Maya Petersen, Joseph DeRisi, Richard Michelmore, Diane Havlir

We found no significant difference in cycle threshold values between vaccinated and unvaccinated, asymptomatic and symptomatic groups infected with SARS-CoV-2 Delta. Given the substantial proportion of asymptomatic vaccine breakthrough cases with high viral levels, interventions, including masking and testing, should be considered for all in settings with elevated COVID-19 transmission.

6: Open Science Discovery of Oral Non-Covalent SARS-CoV-2 Main Protease Inhibitor Therapeutics
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Posted 30 Oct 2020

Open Science Discovery of Oral Non-Covalent SARS-CoV-2 Main Protease Inhibitor Therapeutics
55 tweets bioRxiv biochemistry

The COVID Moonshot Consortium, Hagit Achdout, Anthony Aimon, Elad Bar-David, Haim Barr, Amir Ben-Shmuel, James Bennett, Melissa L. Boby, Bruce Borden, Gregory R. Bowman, Juliane Brun, Sarma BVNBS, Mark Calmiano, Anna Carbery, Emma Cattermole, Eugene Chernyshenko, John D. Chodera, Austin Clyde, Joseph E. Coffland, Galit Cohen, Jason Cole, Alessandro Contini, Lisa Cox, Milan Cvitkovic, Alex Dias, Kim Donckers, David L. Dotson, Alice Douangamath, Shirly Duberstein, Tim Dudgeon, Louise Dunnett, Peter K. Eastman, Noam Erez, Charles J. Eyermann, Mike Fairhead, Gwen Fate, Daren Fearon, Oleg Fedorov, Matteo Ferla, Rafaela S. Fernandes, Lori Ferrins, Richard Foster, Holly Foster, Ronen Gabizon, Adolfo Garcia-Sastre, Victor O Gawriljuk, Paul Gehrtz, Carina Gileadi, Charline Giroud, William G. Glass, Robert Glen, Itai Glinert, Andre S Godoy, Marian Gorichko, Tyler Gorrie-Stone, Ed J. Griffen, Storm Hassell Hart, Jag Heer, Michael Henry, Michelle Hill, Sam Horrell, Matthew F.D. Hurley, Tomer Israely, Andrew Jajack, Eric Jnoff, Dirk Jochmans, Tobias John, Steven De Jonghe, Anastassia L. Kantsadi, Peter W. Kenny, J. L. Kiappes, Lizbe Koekemoer, Boris Kovar, Tobias Krojer, Alpha A. Lee, Bruce A. Lefker, Haim Levy, Nir London, Petra Lukacik, Hannah Bruce Macdonald, Beth MacLean, Tika R. Malla, Tatiana Matviiuk, Willam McCorkindale, Briana L. McGovern, Sharon Melamed, Oleg Michurin, Halina Mikolajek, Bruce F. Milne, Aaron Morris, Garrett M. Morris, Melody Jane Morwitzer, Demetri Moustakas, Aline M. Nakamura, Jose Brandao Neto, Johan Neyts, Luong Nguyen, Gabriela D. Noske, Vladas Oleinikovas, Glaucius Oliva, Gijs J. Overheul, David Owen, Vladimir Psenak, Ruby Pai, Jin Pan, Nir Paran, Benjamin Perry, Maneesh Pingle, Jakir Pinjari, Boaz Politi, Ailsa Powell, Reut Puni, Victor L. Rangel, Rambabu N. Reddi, St Patrick Reid, Efrat Resnick, Emily Grace Ripka, Matthew C Robinson, Ralph P. Robinson, Jaime Rodriguez-Guerra, Romel Rosales, Dominic Rufa, Chris Schofield, Mikhail Shafeev, Aarif Shaikh, Jiye Shi, Khriesto Shurrush, Sukrit Singh, Assa Sittner, Rachael Skyner, Adam Smalley, Mihaela D. Smilova, Leonardo J. Solmesky, John Spencer, Claire Strain-Damerell, Vishwanath Swamy, Hadas Tamir, Rachael Tennant, Warren Thompson, Andrew Thompson, Susana Tomasio, Anthony Tumber, Ioannis Vakonakis, Ronald P. van Rij, Laura Vangeel, Finny S. Varghese, Mariana Vaschetto, Einat. B. Vitner, Vincent Voelz, Andrea Volkamer, Frank von Delft, Annette von Delft, Martin Walsh, Walter Ward, Charlie Weatherall, Shay Weiss, Kris M. White, Conor Francis Wild, Matthew Wittmann, Nathan Wright, Yfat Yahalom-Ronen, Daniel Zaidmann, Hadeer Zidane, Nicole Zitzmann

The COVID-19 pandemic is a stark reminder that a barren global antiviral pipeline has grave humanitarian consequences. Future pandemics could be prevented by accessible, easily deployable broad-spectrum oral antivirals and open knowledge bases that derisk and accelerate novel antiviral discovery and development. Here, we report the results of the COVID Moonshot, a fully open-science structure-enabled drug discovery campaign targeting the SARS-CoV-2 main protease. We discovered a novel chemical scaffold that is differentiated to current clinical candidates in terms of toxicity and pharmacokinetics liabilities, and developed it into orally-bioavailable inhibitors with clinical potential. Our approach leverages crowdsourcing, high throughput structural biology, machine learning, and exascale molecular simulations. In the process, we generated a detailed map of the structural plasticity of the main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. In a first for a structure-based drug discovery campaign, all compound designs (>18,000 designs), crystallographic data (>500 ligand-bound X-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2,400 compounds) for this campaign were shared rapidly and openly, creating a rich open and IP-free knowledgebase for future anti-coronavirus drug discovery.

7: SARS-CoV-2 causes brain inflammation and induces Lewy body formation in macaques
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Posted 23 Feb 2021

SARS-CoV-2 causes brain inflammation and induces Lewy body formation in macaques
37 tweets bioRxiv neuroscience

Ingrid H.C.H.M. Philippens, Kinga P. Boszormenyi, Jacqueline A. Wubben, Zahra C Fagrouch, Nikki van Driel, Amber Q. Mayenburg, Diana Lozovagia, Eva Roos, Bernadette Schurink, Marianna Bugiani, Ronald E Bontrop, Jinte Middeldorp, Willy M Bogers, Lioe-Fee de Geus-Oei, Jan A.M. Langermans, Marieke A Stammes, Babs E Verstrepen, Ernst J Verschoor

SARS-CoV-2 may cause acute respiratory disease, but the infection can also initiate neurological symptoms. Here we show that SARS-CoV-2 infection causes brain inflammation in the macaque model. An increased metabolic activity in the pituitary gland of two macaques was observed by longitudinal positron emission tomography-computed tomography (PET-CT). Post-mortem analysis demonstrated infiltration of T-cells and activated microglia in the brain, and viral RNA was detected in brain tissues from one animal. We observed Lewy bodies in brains of all rhesus macaques. These data emphasize the virus' capability to induce neuropathology in this nonhuman primate model for SARS-CoV-2 infection. As in humans, Lewy body formation is an indication for the development of Parkinson's disease, this data represents a warning for potential long-term neurological effects after SARS-CoV-2 infection.

8: Shedding of Infectious SARS-CoV-2 Despite Vaccination
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Posted 31 Jul 2021

Shedding of Infectious SARS-CoV-2 Despite Vaccination
36 tweets medRxiv infectious diseases

Kasen K Riemersma, Brittany E Grogan, Amanda Kita-Yarbro, Peter Halfmann, Anna Kocharian, Kelsey R Florek, Ryan Westergaard, Allen Bateman, Gunnar E Jeppson, Yoshihiro Kawaoka, David H O'Connor, Thomas C Friedrich, Katarina M Grande

The SARS-CoV-2 Delta variant is highly transmissible and contains mutations that confer partial immune escape. We compared RT-PCR cycle threshold (Ct) data from 699 test-positive anterior nasal swab specimens from fully vaccinated (n = 310) or unvaccinated (n=389) individuals. We observed low Ct values (<25) in 212 of 310 fully vaccinated (68%) and 246 of 389 (63%) unvaccinated individuals. Testing a subset of these low-Ct samples revealed infectious SARS-CoV-2 in 15 of 17 specimens (88%) from unvaccinated individuals and 37 of 39 (95%) from vaccinated people. To determine whether infectious virus titers differed in vaccinated and unvaccinated persons, we performed plaque assays on an additional set of 48 samples with Ct <25, finding no difference in infectious virus titer between groups.

9: Virological characteristics of SARS-CoV-2 vaccine breakthrough infections in health care workers
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Posted 21 Aug 2021

Virological characteristics of SARS-CoV-2 vaccine breakthrough infections in health care workers
26 tweets medRxiv infectious diseases

Marc Conrad Shamier, Alma Tostmann, Susanne Bogers, Janet De Wilde, Jeroen IJpelaar, Willemijn Van Der Kleij, Herbert De Jager, Bart Haagmans, Richard Molenkamp, Bas Oude Munnink, Carsten van Rossum, Janette Rahamat-Langendoen, Nannet Van Der Geest, Chantal Bleeker-Rovers, Heiman Wertheim, Marion Koopmans, Corine H Geurts van Kessel

SARS-CoV-2 vaccines are highly effective at preventing COVID-19-related morbidity and mortality. As no vaccine is 100% effective, breakthrough infections are expected to occur. We analyzed the virological characteristics of 161 vaccine breakthrough infections in a population of 24,706 vaccinated healthcare workers (HCWs), using RT-PCR and virus culture. The delta variant (B.1.617.2) was identified in the majority of cases. Despite similar Ct-values, we demonstrate lower probability of infectious virus detection in respiratory samples of vaccinated HCWs with breakthrough infections compared to unvaccinated HCWs with primary SARS-CoV-2 infections. Nevertheless, infectious virus was found in 68.6% of breakthrough infections and Ct-values decreased throughout the first 3 days of illness. We conclude that rare vaccine breakthrough infections occur, but infectious virus shedding is reduced in these cases.

10: Infection fatality rate of COVID-19 in community-dwelling populations with emphasis on the elderly: An overview
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Posted 13 Jul 2021

Infection fatality rate of COVID-19 in community-dwelling populations with emphasis on the elderly: An overview
25 tweets medRxiv epidemiology

Cathrine Axfors, John Ioannidis

Background: The infection fatality rate (IFR) of Coronavirus Disease 2019 (COVID-19) varies widely according to age and residence status. Purpose: Estimate the IFR of COVID-19 in community-dwelling elderly populations and other age groups from seroprevalence studies. Study protocol: https://osf.io/47cgb. Data Sources: Seroprevalence studies done in 2020 and identified by any of four existing systematic reviews. Study Selection: SARS-CoV-2 seroprevalence studies with [&ge;]1000 participants aged [&ge;]70 years that presented seroprevalence in elderly people; aimed to generate samples reflecting the general population; and whose location had available data on cumulative COVID-19 deaths in elderly (primary cutoff [&ge;]70 years; [&ge;]65 or [&ge;]60 also eligible). Data Extraction: We extracted the most fully adjusted (if unavailable, unadjusted) seroprevalence estimates and sampling procedure details. We also extracted age- and residence-stratified cumulative COVID-19 deaths (until 1 week after the seroprevalence sampling midpoint) from official reports, and population statistics, to calculate IFRs corrected for unmeasured antibody types. Sample size-weighted IFRs were estimated for countries with multiple estimates. Secondary analyses examined data on younger age strata from the same studies. Data Synthesis: Twenty-three seroprevalence surveys representing 14 countries were included. Across all countries, the median IFR in community-dwelling elderly and elderly overall was 2.4% (range 0.3%-7.2%) and 5.5% (range 0.3%-12.1%). IFR was higher with larger proportions of people >85 years. Younger age strata had low IFR values (median 0.0027%, 0.014%, 0.031%, 0.082%, 0.27%, and 0.59%, at 0-19, 20-29, 30-39, 40-49, 50-59, and 60-69 years). Limitations: Biases in seroprevalence and mortality data. Conclusions: The IFR of COVID-19 in community-dwelling elderly people is lower than previously reported. Very low IFRs were confirmed in the youngest populations.

11: Environmentally dependent and independent control of cell shape determination by Rho GTPase regulators in melanoma
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Posted 13 Oct 2021

Environmentally dependent and independent control of cell shape determination by Rho GTPase regulators in melanoma
23 tweets bioRxiv cell biology

Lucas G Dent, Nathan Curry, Hugh Sparks, Vicky Bousgouni, Vincent Maioli, Sunil Kumar, Ian Munro, Chris Dunsby, Chris Bakal

In order to invade 3D tissues, cancer cells dynamically change cell morphology in response to geometric and mechanical cues in the environment. But how cells determine their shape in 3D versus 2D environments is poorly understood. Studying 2D versus 3D single cell shape determination has historically been technically difficult due to the lack of methodologies to directly compare the two environments. We developed an approach to study cell shape in 2D versus 3D by measuring cell shape at different depths in collagen using stage-scanning oblique plane microscopy (ssOPM). We find characteristic shape changes occur in melanoma cells depending on whether a cell is attached to a 2D surface or 3D environment, and that these changes can be modulated by Rho GTPase regulatory proteins. Our data suggest that regulation of cell protrusivity undergoes a switch of control between different Rho GTPase regulators depending on the physical microenvironment.

12: A data compendium of Mycobacterium tuberculosis antibiotic resistance
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Posted 15 Sep 2021

A data compendium of Mycobacterium tuberculosis antibiotic resistance
21 tweets bioRxiv microbiology

Alice Brankin, Kerri M Malone, The CRyPTIC Consortium

The Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC) presents here a global collection of 15,211 Mycobacterium tuberculosis clinical isolates, all of which have undergone whole genome sequencing and have had their minimum inhibitory concentrations to 13 antitubercular drugs measured. The isolates represent five major M. tuberculosis lineages originating from 23 countries across four continents. 6,814 isolates were found resistant to at least one drug, including 2,129 samples fully satisfy the clinical definitions of RR/MDR, pre-XDR or XDR. Resistance status to eight antitubercular drugs can be accurately predicted using a genetic mutation catalogue for over 90% of the isolates. Furthermore, we show the presence of suspected resistance conferring mutations for isolates resistant to the newly introduced drugs bedaquiline, clofazimine, delamanid and linezolid. Finally, a case study of rifampicin mono-resistance is presented to showcase how this compendium could be used to advance our genetic understanding of rare resistance phenotypes and evaluate the likely performance of a widely used molecular diagnostic tool. It is hoped that this compendium, the largest M. tuberculosis matched phenotypic and genotypic dataset to date, will facilitate and inspire new research projects for years to come.

13: SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome
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Posted 13 Dec 2020

SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome
19 tweets bioRxiv genomics

Liguo Zhang, Alexsia Richards, Andrew Khalil, Emile Wogram, Haiting Ma, Richard A. Young, Rudolf Jaenisch

Prolonged SARS-CoV-2 RNA shedding and recurrence of PCR-positive tests have been widely reported in patients after recovery, yet these patients most commonly are non-infectious. Here we investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the human genome and that transcription of the integrated sequences might account for PCR-positive tests. In support of this hypothesis, we found chimeric transcripts consisting of viral fused to cellular sequences in published data sets of SARS-CoV-2 infected cultured cells and primary cells of patients, consistent with the transcription of viral sequences integrated into the genome. To experimentally corroborate the possibility of viral retro-integration, we describe evidence that SARS-CoV-2 RNAs can be reverse transcribed in human cells by reverse transcriptase (RT) from LINE-1 elements or by HIV-1 RT, and that these DNA sequences can be integrated into the cell genome and subsequently be transcribed. Human endogenous LINE-1 expression was induced upon SARS-CoV-2 infection or by cytokine exposure in cultured cells, suggesting a molecular mechanism for SARS-CoV-2 retro-integration in patients. This novel feature of SARS-CoV-2 infection may explain why patients can continue to produce viral RNA after recovery and suggests a new aspect of RNA virus replication.

14: Binding of SARS-CoV-2 spike protein to ACE2 is disabled by thiol-based drugs; evidence from in vitro SARS-CoV-2 infection studies.
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Posted 08 Dec 2020

Binding of SARS-CoV-2 spike protein to ACE2 is disabled by thiol-based drugs; evidence from in vitro SARS-CoV-2 infection studies.
18 tweets bioRxiv microbiology

Kritika Khanna, Wilfred Raymond, Annabelle R Charbit, Jing Jin, Irina Gitlin, Monica Tang, Hannah S. Sperber, Sergej Franz, Satish Pillai, Graham Simmons, John V Fahy

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the SARS-CoV-2 spike protein is an envelope glycoprotein that binds angiotensin converting enzyme 2 as an entry receptor. The capacity of enveloped viruses to infect host cells depends on a precise thiol/disulfide balance in their surface glycoprotein complexes. To determine if cystines in the SARS-CoV-2 spike protein maintain a native binding interface that can be disrupted by drugs that cleave cystines, we tested if thiol-based drugs have efficacy in receptor binding and cell infection assays. We found that thiol-based drugs, cysteamine and WR-1065 (the active metabolite of amifostine) in particular, decrease binding of SARS-CoV-2 spike protein to its receptor, decrease the entry efficiency of SARS-CoV-2 spike pseudotyped virus, and inhibit SARS-CoV-2 live virus infection. Our findings uncover a vulnerability of SARS-CoV-2 to thiol-based drugs and provide rationale to test thiol-based drugs, especially cysteamine and amifostine, as novel treatments for COVID-19.

15: Transcriptional Regulation of Synthetic Polymer Networks
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Posted 17 Oct 2021

Transcriptional Regulation of Synthetic Polymer Networks
18 tweets bioRxiv synthetic biology

Austin J Graham, Christopher M Dundas, Gina Partipilo, Ismar E Miniel Mahfoud, Thomas FitzSimons, Rebecca Rinehart, Darian Chiu, Avery E Tyndall, Adrianne M Rosales, Benjamin K Keitz

Individual cells direct non-equilibrium processes through coordinated signal transduction and gene expression, allowing for dynamic control over multicellular, system-wide behavior. This behavior extends to remodeling the extracellular polymer matrix that encases biofilms and tissues, where constituent cells dictate spatiotemporal network properties including stiffness, pattern formation, and transport properties. The majority of synthetic polymer networks cannot recreate these phenomena due to their lack of autonomous centralized actuators (i.e., cells). In addition, non-living polymer networks that perform computation are generally restricted to a few inputs (e.g., light, pH, enzymes), limiting the logical complexity available to a single network chemistry. Toward synergizing the advantages of living and synthetic systems, engineered living materials leverage genetic and metabolic programming to establish control over material-wide properties. Here we demonstrate that a bacterial metal respiration mechanism, extracellular electron transfer (EET), can control metal-catalyzed radical cross-linking of polymer networks. Linking metabolic electron flux to a synthetic redox catalyst allows dynamic, tunable, and predictable control over material formation and bulk polymer network mechanics using genetic circuits. By programming key EET genes with transcriptional Boolean logic, we rationally design computational networks that sense-and-respond to multiple inputs in biological contexts. Finally, we capitalize on the wide reactivity of EET and redox catalyses to predictably control another class of living synthetic materials using copper(I) alkyne-azide cycloaddition click chemistry. Our results demonstrate the utility of EET as a bridge for controlling abiotic materials and how the design rules of synthetic biology can be applied to emulate physiological behavior in polymer networks.

16: Predominance of antibody-resistant SARS-CoV-2 variants in vaccine breakthrough cases from the San Francisco Bay Area, California
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Posted 25 Aug 2021

Predominance of antibody-resistant SARS-CoV-2 variants in vaccine breakthrough cases from the San Francisco Bay Area, California
17 tweets medRxiv infectious diseases

Venice Servellita, Alicia Sotomayor-Gonzalez, Amelia Gliwa, Erika Torres, Noah Brazer, Alicia Zhou, Katherine Hernandez, Madeline Sankaran, Baolin Wang, Daniel Wong, Candace Wang, Yueyuan Zhang, Kevin Reyes, Dustin Glasner, Wayne Deng, Jessica Streithorst, Steve Miller, Edwin Frias, John Hackett, Susan Philip, Scott Topper, Darpun Sachdev, Charles Y Chiu

Associations between vaccine breakthrough cases and infection by SARS coronavirus 2 (SARS-CoV-2) variants have remained largely unexplored. Here we analyzed SARS-CoV-2 whole-genome sequences and viral loads from 1,373 persons with COVID-19 from the San Francisco Bay Area from February 1 to June 30, 2021, of which 125 (9.1%) were vaccine breakthrough infections. Fully vaccinated were more likely than unvaccinated persons to be infected by variants carrying mutations associated with decreased antibody neutralization (L452R, L452Q, E484K, and/or F490S) (78% versus 48%, p = 1.96e-08), but not by those associated with increased infectivity (L452R and/or N501Y) (85% versus 77%, p = 0.092). Differences in viral loads were non-significant between unvaccinated and fully vaccinated persons overall (p = 0.99) and according to lineage (p = 0.09 - 0.78). Viral loads were significantly higher in symptomatic as compared to asymptomatic vaccine breakthrough cases (p < 0.0001), and symptomatic vaccine breakthrough infections had similar viral loads to unvaccinated infections (p = 0.64). In 5 cases with available longitudinal samples for serologic analyses, vaccine breakthrough infections were found to be associated with low or undetectable neutralizing antibody levels attributable to immunocompromised state or infection by an antibody-resistant lineage. These findings suggest that vaccine breakthrough cases are preferentially caused by circulating antibody-resistant SARS-CoV-2 variants, and that symptomatic breakthrough infections may potentially transmit COVID-19 as efficiently as unvaccinated infections, regardless of the infecting lineage.

17: SARS-CoV-2 mRNA Vaccination-Associated Myocarditis in Children Ages 12-17: A Stratified National Database Analysis
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Posted 08 Sep 2021

SARS-CoV-2 mRNA Vaccination-Associated Myocarditis in Children Ages 12-17: A Stratified National Database Analysis
15 tweets medRxiv epidemiology

Tracy Beth Hoeg, Allison Krug, Josh Stevenson, John Mandrola

Objectives: Establishing the rate of post-vaccination cardiac myocarditis in the 12-15 and 16-17-year-old population in the context of their COVID-19 hospitalization risk is critical for developing a vaccination recommendation framework that balances harms with benefits for this patient demographic. Design, Setting and Participants: Using the Vaccine Adverse Event Reporting System (VAERS), this retrospective epidemiological assessment reviewed reports filed between January 1, 2021, and June 18, 2021, among adolescents ages 12-17 who received mRNA vaccination against COVID-19. Symptom search criteria included the words myocarditis, pericarditis, and myopericarditis to identify children with evidence of cardiac injury. The word troponin was a required element in the laboratory findings. Inclusion criteria were aligned with the CDC working case definition for probable myocarditis. Stratified cardiac adverse event (CAE) rates were reported for age, sex and vaccination dose number. A harm-benefit analysis was conducted using existing literature on COVID-19-related hospitalization risks in this demographic. Main outcome measures: 1) Stratified rates of mRNA vaccine-related myocarditis in adolescents age 12-15 and 16-17; and 2) harm-benefit analysis of vaccine-related CAEs in relation to COVID-19 hospitalization risk. Results: A total of 257 CAEs were identified. Rates per million following dose 2 among males were 162.2 (ages 12-15) and 94.0 (ages 16-17); among females, rates were 13.0 and 13.4 per million, respectively. For boys 12-15 without medical comorbidities receiving their second mRNA vaccination dose, the rate of CAE is 3.7-6.1 times higher than their 120-day COVID-19 hospitalization risk as of August 21, 2021 (7-day hospitalizations 1.5/100k population) and 2.6-4.3-fold higher at times of high weekly hospitalization risk (2.1/100k), such as during January 2021. For boys 16-17 without medical comorbidities, the rate of CAE is currently 2.1-3.5 times higher than their 120-day COVID-19 hospitalization risk, and 1.5-2.5 times higher at times of high weekly COVID-19 hospitalization. Conclusions: Post-vaccination CAE rate was highest in young boys aged 12-15 following dose two. For boys 12-17 without medical comorbidities, the likelihood of post vaccination dose two CAE is 162.2 and 94.0/million respectively. This incidence exceeds their expected 120-day COVID-19 hospitalization rate at both moderate (August 21, 2021 rates) and high COVID-19 hospitalization incidence. Further research into the severity and long-term sequelae of post-vaccination CAE is warranted. Quantification of the benefits of the second vaccination dose and vaccination in addition to natural immunity in this demographic may be indicated to minimize harm.

18: Effectiveness of Ivermectin-Based Multidrug Therapy in Severe Hypoxic Ambulatory COVID-19 Patients
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Posted 07 Jul 2021

Effectiveness of Ivermectin-Based Multidrug Therapy in Severe Hypoxic Ambulatory COVID-19 Patients
14 tweets medRxiv infectious diseases

Sabine Hazan, Sonya Dave, Anoja W. Gunaratne, Sibasish Dolai, Peter A McCullough, Robert Clancy, Thomas J Borody

Ivermectin is a safe, inexpensive and effective early COVID-19 treatment validated in 20+ RCTs. Having developed combination therapies for Helicobacter pylori, we tested various COVID-19 combinations and describe the most effective. In 24 consecutive COVID-19 subjects with high risk features, hypoxia and untreated moderate-severe symptoms averaging 9 days, we trialed this novel combination comprising ivermectin, doxycycline, zinc, and Vitamins D and C. It was highly effective. All subjects resolved symptoms in 11 days on average, and oxygen saturation improved in 24hrs (87.4% to 93.1%, p=0.001). Hospitalizations and deaths were significantly fewer (p<0.002 or 0.05, respectively) than in background-matched controls from the CDC database. Triple combination therapy is safe and effective even in moderate-severe patients with hypoxia treated in the outpatient setting.

19: Six Month Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine
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Posted 28 Jul 2021

Six Month Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine
13 tweets medRxiv infectious diseases

Stephen J. Thomas, Edson D Moreira, Nicholas Kitchin, Judith Absalon, Alejandra Gurtman, Stephen Lockhart, John L Perez, Gonzalo Pérez Marc, Fernando P. Polack, Cristiano Zerbini, Ruth Bailey, Kena A. Swanson, Xia Xu, Satrajit Roychoudhury, Kenneth Koury, Salim Bouguermouh, Warren V. Kalina, David Cooper, Robert W Frenck, Laura L. Hammitt, Özlem Türeci, Haylene Nell, Axel Schaefer, Serhat Ünal, Qi Yang, Paul Liberator, Dina B Tresnan, Susan Mather, Philip R. Dormitzer, Uğur Şahin, William C. Gruber, Kathrin U. Jansen, C4591001 Clinical Trial Group

Background: BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine encoding a prefusion-stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. BNT162b2 is highly efficacious against COVID-19 and is currently authorized for emergency use or conditional approval worldwide. At the time of authorization, data beyond 2 months post-vaccination were unavailable. Methods: In an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy study, 44,165 [&ge;]16-year-old participants and 2,264 12-15-year-old participants were randomized to receive 2 doses, 21 days apart, of 30 g BNT162b2 or placebo. Study endpoints reported here are vaccine efficacy (VE) against laboratory-confirmed COVID-19 and safety data, both up to 6 months post-vaccination. Results: BNT162b2 continued to be safe and well tolerated. Few participants had adverse events leading to study withdrawal. VE against COVID-19 was 91% (95% CI 89.0-93.2) through up to 6 months of follow-up, among evaluable participants and irrespective of previous SARS-CoV-2 infection. VE of 86%-100% was seen across countries and in populations with diverse characteristics of age, sex, race/ethnicity, and COVID-19 risk factors in participants without evidence of previous SARS-CoV-2 infection. VE against severe disease was 97% % (95% CI 80.3-99.9). In South Africa, where the SARS-CoV-2 variant of concern, B.1.351 (beta), was predominant, 100% (95% CI 53.5, 100.0) VE was observed. Conclusion: With up to 6 months of follow-up and despite a gradually declining trend in vaccine efficacy, BNT162b2 had a favorable safety profile and was highly efficacious in preventing COVID-19. (ClinicalTrials.gov number, NCT04368728)

20: Evidence for treatment with estradiol for women with SARS-CoV-2 infection
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Posted 24 Aug 2020

Evidence for treatment with estradiol for women with SARS-CoV-2 infection
13 tweets medRxiv epidemiology

Ute Seeland, Flaminia Coluzzi, Maurizio Simmaco, Cameron Mura, Philip E. Bourne, Max Heiland, Robert Preissner, Saskia Preissner

BACKGROUND Given that an individual's age and gender are strongly predictive of COVID-19 outcomes, do such factors imply anything about preferable therapeutic options? METHODS An analysis of electronic health records for a large (68,466-case), international COVID-19 cohort, in five-year age strata, revealed age-dependent sex differences. In particular, we surveyed the effects of systemic hormone administration in women. The primary outcome for estradiol therapy was death. Odds Ratios (ORs) and Kaplan-Meier survival curves were analyzed for 37,086 COVID-19 women in two age groups: pre- (15-49 years) and post-menopausal (>50 years). RESULTS The incidence of SARS-CoV-2 infection is higher in women than men (about +15%) and, in contrast, the fatality rate is higher in men (about +50%). Interestingly, the relationships between these quantities are also linked to age. Pre-adolescent girls had the same risk of infection and fatality rate as boys. Adult premenopausal women had a significantly higher risk of infection than men in the same five-year age stratum (about 16,000 vs. 12,000 cases). This ratio changed again in postmenopausal women, with infection susceptibility converging with men. While fatality rates increased continuously with age for both sexes, at 50 years there was a steeper increase for men. Thus far, these types of intricacies have been largely neglected. Because the hormone 17{beta}-estradiol has a positive effect on expression of the human ACE2 protein--which plays an essential role for SARS-CoV-2 cellular entry--propensity score matching was performed for the women's sub-cohort, comparing users versus non-users of estradiol. This retrospective study of hormone therapy in female COVID-19 patients shows that the fatality risk for women >50 yrs receiving estradiol therapy (user group) is reduced by more than 50%; the OR was 0.33, 95 % CI [0.18, 0.62] and the Hazard Ratio was 0.29, 95% CI [0.11,0.76]. For younger, pre-menopausal women (15-49 yrs), the risk of COVID-19 fatality is the same irrespective of estradiol treatment, probably because of higher endogenous estradiol levels. CONCLUSIONS As of this writing, still no effective drug treatment is available for COVID-19; since estradiol shows such a strong improvement regarding fatality in COVID-19, we suggest prospective studies on the potentially more broadly protective roles of this naturally occurring hormone.

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