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Most downloaded bioRxiv papers, since beginning of last month

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21: Seeding of outbreaks of COVID-19 by contaminated fresh and frozen food
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Posted to bioRxiv 18 Aug 2020

Seeding of outbreaks of COVID-19 by contaminated fresh and frozen food
2,962 downloads microbiology

Dale Fisher, Alan Reilly, Adrian Kang Eng Zheng, Alex R Cook, Danielle Anderson

An explanation is required for the re-emergence of COVID-19 outbreaks in regions with apparent local eradication. Recent outbreaks have emerged in Vietnam, New Zealand and parts of China where there had been no cases for some months. Importation of contaminated food and food packaging is a feasible source for such outbreaks and a source of clusters within existing outbreaks. Such events can be prevented if the risk is better appreciated. ### Competing Interest Statement The authors have declared no competing interest.

22: Saliva-Based Molecular Testing for SARS-CoV-2 that Bypasses RNA Extraction
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Posted to bioRxiv 18 Jun 2020

Saliva-Based Molecular Testing for SARS-CoV-2 that Bypasses RNA Extraction
2,961 downloads microbiology

Diana Rose E. Ranoa, Robin L. Holland, Fadi G Alnaji, Kelsie J. Green, Leyi Wang, Christopher B Brooke, Martin D. Burke, Timothy M. Fan, Paul J. Hergenrother

Convenient, repeatable, large-scale molecular testing for SARS-CoV-2 would be a key weapon to help control the COVID-19 pandemic. Unfortunately, standard SARS-CoV-2 testing protocols are invasive and rely on numerous items that can be subject to supply chain bottlenecks, and as such are not suitable for frequent repeat testing. Specifically, personal protective equipment (PPE), nasopharyngeal (NP) swabs, the associated viral transport media (VTM), and kits for RNA isolation and purification have all been in short supply at various times during the COVID-19 pandemic. Moreover, SARS-CoV-2 is spread through droplets and aerosols transmitted through person-to-person contact, and thus saliva may be a relevant medium for diagnosing SARS-CoV-2 infection status. Here we describe a saliva-based testing method that bypasses the need for RNA isolation/purification. In experiments with inactivated SARS-CoV-2 virus spiked into saliva, this method has a limit of detection of 500-1000 viral particles per mL, rivalling the standard NP swab method, and initial studies also show excellent performance with 100 clinical samples. This saliva-based process is operationally simple, utilizes readily available materials, and can be easily implemented by existing testing sites, thus allowing for high-throughput, rapid, and repeat testing of large populations. ### Competing Interest Statement The authors have declared no competing interest.

23: A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing
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Posted to bioRxiv 22 Mar 2020

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing
2,952 downloads systems biology

David E Gordon, Gwendolyn M. Jang, Mehdi Bouhaddou, Jiewei Xu, Kirsten Obernier, Matthew J. O’Meara, Jeffrey Z. Guo, Danielle L. Swaney, Tia A Tummino, Ruth Huettenhain, Robyn M. Kaake, Alicia L. Richards, Beril Tutuncuoglu, Helene Foussard, Jyoti Batra, Kelsey Haas, Maya Modak, Minkyu Kim, Paige Haas, Benjamin J. Polacco, Hannes Braberg, Jacqueline M. Fabius, Manon Eckhardt, Margaret Soucheray, Melanie J. Bennett, Merve Cakir, Michael J. McGregor, Qiongyu Li, Zun Zar Chi Naing, Yuan Zhou, Shiming Peng, Ilsa T. Kirby, James E. Melnyk, John S. Chorba, Kevin Lou, Shizhong A. Dai, Wenqi Shen, Ying Shi, Ziyang Zhang, Inigo Barrio-Hernandez, Danish Memon, Claudia Hernandez-Armenta, Christopher J.P. Mathy, Tina Perica, Kala B. Pilla, Sai J. Ganesan, Daniel J. Saltzberg, Rakesh Ramachandran, Xi Liu, Sara B. Rosenthal, Lorenzo Calviello, Srivats Venkataramanan, Jose Liboy-Lugo, Yizhu Lin, Stephanie A. Wankowicz, Markus Bohn, Phillip P. Sharp, Raphael Trenker, Janet M. Young, Devin A. Cavero, Joseph Hiatt, Theodore Roth, Ujjwal Rathore, Advait Subramanian, Julia Noack, Mathieu Hubert, Ferdinand Roesch, Thomas Vallet, Björn Meyer, Kris M. White, Lisa Miorin, Oren S. Rosenberg, Kliment A Verba, David A. Agard, Melanie Ott, Michael Emerman, Davide Ruggero, Adolfo García-Sastre, Natalia Jura, Mark von Zastrow, Jack Taunton, Alan Ashworth, Olivier Schwartz, Marco Vignuzzi, Christophe d’Enfert, Shaeri Mukherjee, Matt Jacobson, Harmit S. Malik, Danica Galonić Fujimori, Trey Ideker, Charles S. Craik, Stephen N. Floor, James S. Fraser, John D. Gross, Andrej Sali, Tanja Kortemme, Pedro Beltrao, Kevan M. Shokat, Brian K. Shoichet, Nevan J. Krogan

An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption[1][1],[2][2]. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 67 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains. * HC-PPIs : High confidence protein-protein interactions PPIs : protein-protein interaction AP-MS : affinity purification-mass spectrometry COVID-19 : Coronavirus Disease-2019 ACE2 : angiotensin converting enzyme 2 Orf : open reading frame Nsp3 : papain-like protease Nsp5 : main protease Nsp : nonstructural protein TPM : transcripts per million [1]: #ref-1 [2]: #ref-2

24: Report of Partial findings from the National Toxicology Program Carcinogenesis Studies of Cell Phone Radiofrequency Radiation in Hsd: Sprague Dawley® SD rats (Whole Body Exposure)
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Posted to bioRxiv 26 May 2016

Report of Partial findings from the National Toxicology Program Carcinogenesis Studies of Cell Phone Radiofrequency Radiation in Hsd: Sprague Dawley® SD rats (Whole Body Exposure)
2,906 downloads cancer biology

Michael Wyde, Mark Cesta, Chad Blystone, Susan Elmore, Paul Foster, Michelle Hooth, Grace Kissling, David Malarkey, Robert Sills, Matthew Stout, Nigel Walker, Kristine Witt, Mary Wolfe, John Bucher

The U.S. National Toxicology Program (NTP) has carried out extensive rodent toxicology and carcinogenesis studies of radiofrequency radiation (RFR) at frequencies and modulations used in the U.S. telecommunications industry. This report presents partial findings from these studies. The occurrences of two tumor types in male Harlan Sprague Dawley rats exposed to RFR, malignant gliomas in the brain and schwannomas of the heart, were considered of particular interest and are the subject of this report. The findings in this report were reviewed by expert peer reviewers selected by the NTP and National Institutes of Health (NIH). These reviews and responses to comments are included as appendices to this report, and revisions to the current document have incorporated and addressed these comments. When the studies are completed, they will undergo additional peer review before publication in full as part of the NTP's Toxicology and Carcinogenesis Technical Reports Series. No portion of this work has been submitted for publication in a scientific journal. Supplemental information in the form of four additional manuscripts has or will soon be submitted for publication. These manuscripts describe in detail the designs and performance of the RFR exposure system, the dosimetry of RFR exposures in rats and mice, the results to a series of pilot studies establishing the ability of the animals to thermoregulate during RFR exposures, and studies of DNA damage. (1) Capstick M, Kuster N, Kuhn S, Berdinas-Torres V, Wilson P, Ladbury J, Koepke G, McCormick D, Gauger J, and Melnick R. A radio frequency radiation reverberation chamber exposure system for rodents; (2) Yijian G, Capstick M, McCormick D, Gauger J, Horn T, Wilson P, Melnick RL, and Kuster N. Life time dosimetric assessment for mice and rats exposed to cell phone radiation; (3) Wyde ME, Horn TL, Capstick M, Ladbury J, Koepke G, Wilson P, Stout MD, Kuster N, Melnick R, Bucher JR, and McCormick D. Pilot studies of the National Toxicology Program's cell phone radiofrequency radiation reverberation chamber exposure system; (4) Smith-Roe SL, Wyde ME, Stout MD, Winters J, Hobbs CA, Shepard KG, Green A, Kissling GE, Tice RR, Bucher JR, and Witt KL. Evaluation of the genotoxicity of cell phone radiofrequency radiation in male and female rats and mice following subchronic exposure.

25: Head-to-head comparison of four antigen-based rapid detection tests for the diagnosis of SARS-CoV-2 in respiratory samples
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Posted to bioRxiv 30 May 2020

Head-to-head comparison of four antigen-based rapid detection tests for the diagnosis of SARS-CoV-2 in respiratory samples
2,883 downloads microbiology

Thomas Weitzel, Paulette Legarraga, Mirentxu Iruretagoyena, Gabriel Pizarro, Valeska Vollrath, Rafael Araos, José M. Munita, Lorena Porte

In the context of the Covid-19 pandemic, the development and validation of rapid and easy-to-perform diagnostic methods are of high priority. We compared the performance of four rapid antigen detection tests for SARS-CoV-2 in respiratory samples. Immunochromatographic SARS-CoV-2 assays from RapiGEN, Liming bio, Savant, and Bioeasy were evaluated using universal transport medium containing naso-oropharyngeal swabs from suspected Covid-19 cases. The diagnostic accuracy was determined in comparison to SARS-CoV-2 RT-PCR. A total of 111 samples were included; 80 were RT-PCR positive. Median patients' age was 40 years, 55% were female, and 88% presented within the first week after symptom onset. The evaluation of the Liming bio assay was discontinued due to insufficient performance. The overall sensitivity values of RapiGEN, Liming bio, and Bioeasy tests were 62.0% (CI95% 51.0–71.9), 16.7% (CI95% 10.0–26.5), and 85.0% (CI95% 75.6–91.2), respectively, with specificities of 100%. Sensitivity was significantly higher in samples with high viral loads (RapiGEN, 84.9%; Bioeasy, 100%). The study highlighted the significant heterogeneity of test performance among evaluated assays, which might have been influenced by the use of a non-validated sample material. The high sensitivity of some tests demonstrated that rapid antigen detection has the potential to serve as an alternative diagnostic method, especially in patients presenting with high viral loads in early phases of infection. This is particularly important in situations with limited access to RT-PCR or prolonged turnaround time. Further comparative evaluations are necessary to select products with high performance among the growing market of diagnostic tests for SARS-CoV-2.

26: Topography, spike dynamics and nanomechanics of individual native SARS-CoV-2 virions
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Posted to bioRxiv 17 Sep 2020

Topography, spike dynamics and nanomechanics of individual native SARS-CoV-2 virions
2,791 downloads biophysics

Bálint Kiss, Zoltán Kis, Bernadett Pályi, Miklós S.Z. Kellermayer

SARS-CoV-2, the virus responsible for the current COVID-19 pandemic, displays a corona-shaped layer of spikes which play fundamental role in the infection process. Recent structural data suggest that the spikes possess orientational freedom and the ribonucleoproteins segregate into basketlike structures. How these structural features regulate the dynamic and mechanical behavior of the native virion, however, remain unknown. By imaging and mechanically manipulating individual, native SARS-CoV-2 virions with atomic force microscopy, here we show that their surface displays a dynamic brush owing to the flexibility and rapid motion of the spikes. The virions are highly compliant and able to recover from drastic mechanical perturbations. Their global structure is remarkably temperature resistant, but the virion surface becomes progressively denuded of spikes upon thermal exposure. Thus, both the infectivity and thermal sensitivity of SARS-CoV-2 rely on the dynamics and the mechanics of the virus. One sentence summary The native coronavirus 2 displays a dynamic surface layer of spikes, a large mechanical compliance and unique self-healing capacity. ### Competing Interest Statement The authors have declared no competing interest.

27: SARS-CoV-2 is well adapted for humans. What does this mean for re-emergence?
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Posted to bioRxiv 02 May 2020

SARS-CoV-2 is well adapted for humans. What does this mean for re-emergence?
2,724 downloads evolutionary biology

Shing Hei Zhan, Benjamin E. Deverman, Yujia Alina Chan

In a side-by-side comparison of evolutionary dynamics between the 2019/2020 SARS-CoV-2 and the 2003 SARS-CoV, we were surprised to find that SARS-CoV-2 resembles SARS-CoV in the late phase of the 2003 epidemic after SARS-CoV had developed several advantageous adaptations for human transmission. Our observations suggest that by the time SARS-CoV-2 was first detected in late 2019, it was already pre-adapted to human transmission to an extent similar to late epidemic SARS-CoV. However, no precursors or parallel branches of evolution stemming from a less human-adapted SARS-CoV-2-like virus have been detected. The sudden appearance of a highly infectious SARS-CoV-2 presents a major cause for concern that should motivate stronger international efforts to identify the source and prevent near future re-emergence. Any existing pools of SARS-CoV-2 progenitors would be particularly dangerous if similarly well adapted for human transmission. To look for clues regarding intermediate hosts, we analyze recent key findings relating to how SARS-CoV-2 could have evolved and adapted for human transmission, and examine the environmental samples from the Wuhan Huanan seafood market. Importantly, the market samples are genetically identical to human SARS-CoV-2 isolates and were therefore most likely from human sources. We conclude by describing and advocating for measured and effective approaches implemented in the 2002-2004 SARS outbreaks to identify lingering population(s) of progenitor virus. ### Competing Interest Statement Shing Hei Zhan is a Co-founder and lead bioinformatics scientist at Fusion Genomics Corporation, which develops molecular diagnostic assays for infectious diseases.

28: An association between sexes of successive siblings in the data from Demographic and Health Survey program
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Posted to bioRxiv 12 Nov 2015

An association between sexes of successive siblings in the data from Demographic and Health Survey program
2,531 downloads physiology

Mikhail Monakhov

The prediction of future child's sex is a question of keen public interest. The probability of having a child of either sex is close to 50%, although multiple factors may slightly change this value. Some demographic studies suggested that sex determination can be influenced by previous pregnancies, although this hypothesis was not commonly accepted. This paper explores the correlations between siblings' sexes using data from the Demographic and Health Survey program. In the sample of about 2,214,601 women (7,985,855 children), the frequencies of sibships with multiple siblings of the same sex were significantly higher than can be expected by chance. A formal modelling demonstrated that sexes of the children were dependent on three kinds of sex ratio variation: a variation between families (Lexian), a variation within a family (Poisson) and a variation contingent upon the sex of preceding sibling (Markovian). There was a positive correlation between the sexes of successive siblings (coefficient = 0.067, p < 0.001), i.e. a child was more likely to be of the same sex as its preceding sibling. This correlation could be caused by secondary sex ratio adjustment in utero since the effect was decreasing with the length of birth-to-birth interval, and the birth-to-birth interval was longer for siblings with unlike sex.

29: FLASH irradiation enhances the therapeutic index of abdominal radiotherapy for the treatment of ovarian cancer
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Posted to bioRxiv 12 Dec 2019

FLASH irradiation enhances the therapeutic index of abdominal radiotherapy for the treatment of ovarian cancer
2,513 downloads cancer biology

Karen Levy, Suchitra Natarajan, Jinghui Wang, Stephanie Chow, Joshua T. Eggold, Phoebe Loo, Rakesh Manjappa, Frederick M. Lartey, Emil Schüler, Lawrie Skinner, Marjan Rafat, Ryan Ko, Anna Kim, Duaa Al Rawi, Rie von Eyben, Oliver Dorigo, Kerriann M. Casey, Edward E Graves, Karl Bush, Amy S. Yu, Albert C Koong, Peter G. Maxim, Billy W Loo, Erinn B Rankin

Peritoneal metastases are the leading cause of morbidity and mortality in ovarian cancer. Despite current surgery, chemotherapy and targeted therapies, the majority of patients diagnosed with advanced epithelial ovarian cancer develop recurrent disease and overall survival rates remain poor. It is known that ovarian cancer is a radiosensitive tumor. Historically, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of chemotherapy sensitive and resistant ovarian cancer. However, TAI fell out of favor due to high toxicity, particularly of the gastrointestinal tract. We have developed a preclinical irradiation platform that allows for total abdominal ultrahigh dose rate FLASH irradiation. We demonstrate that TAI-FLASH reduces radiation-induced intestinal injury in both healthy and tumor-bearing mice compared to conventional dose rate (CONV) irradiation. Single high dose TAI-FLASH reduced mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and decreased cell death in crypt base columnar cells. Importantly, FLASH and CONV irradiation had similar efficacy in the reduction of ovarian cancer peritoneal metastases. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of radiotherapy for the treatment of metastatic ovarian cancer in women.

30: Discovery of a Novel Inhibitor of Coronavirus 3CL Protease as a Clinical Candidate for the Potential Treatment of COVID-19
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Posted to bioRxiv 13 Sep 2020

Discovery of a Novel Inhibitor of Coronavirus 3CL Protease as a Clinical Candidate for the Potential Treatment of COVID-19
2,485 downloads pharmacology and toxicology

Britton Boras, Rhys M. Jones, Brandon J. Anson, Dan Arenson, Lisa Aschenbrenner, Malina A. Bakowski, Nathan Beutler, Joseph Binder, Emily Chen, Heather Eng, Jennifer Hammond, Robert Hoffman, Eugene P. Kadar, Rob Kania, Emi Kimoto, Melanie G. Kirkpatrick, Lorraine Lanyon, Emma K. Lendy, Jonathan R. Lillis, Suman A. Luthra, Chunlong Ma, Stephen Noell, R. Scott Obach, Matthew N. O’ Brien, Rebecca O’Connor, Kevin Ogilvie, Dafydd Owen, Martin Pettersson, Matthew R Reese, Thomas F Rogers, Michelle I. Rossulek, Jean G. Sathish, Claire Steppan, Martyn Ticehurst, Lawrence W. Updyke, Yuao Zhu, Jun Wang, Arnab K. Chatterjee, Andrew D. Mesecar, Annaliesa S. Anderson, Charlotte Allerton

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential to the viral life cycle across a broad spectrum of coronaviruses with no close human analogs. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, and in vitro antiviral activity data to warrant clinical evaluation. One Sentence Summary The phosphate prodrug PF-07304814 is disclosed as an investigational novel intravenous small molecule 3CL protease inhibitor for COVID-19. ### Competing Interest Statement A.D.M has a sponsored program contract with Pfizer to test compounds for inhibition of coronavirus proteases. JW has a sponsored research agreement with Pfizer to test compounds for inhibition of coronavirus proteases.

31: Ferrets not infected by SARS-CoV-2 in a high-exposure domestic setting
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Posted to bioRxiv 22 Aug 2020

Ferrets not infected by SARS-CoV-2 in a high-exposure domestic setting
2,465 downloads molecular biology

Kaitlin Sawatzki, Nichola Hill, Wendy Puryear, Alexa Foss, Jonathon Stone, Jonathan Runstadler

Ferrets ( Mustela putorius furo ) are mustelids of special relevance to laboratory studies of respiratory viruses and have been shown to be susceptible to SARS-CoV-2 infection and onward transmission. Here, we report the results of a natural experiment where 29 ferrets in one home had prolonged, direct contact and constant environmental exposure to two humans with symptomatic COVID-19. We observed no evidence of SARS-CoV-2 transmission from humans to ferrets based on RT-PCR and ELISA. To better understand this discrepancy in experimental and natural infection in ferrets, we compared SARS-CoV-2 sequences from natural and experimental mustelid infections and identified two surface glycoprotein (Spike) mutations associated with mustelids. While we found evidence that ACE2 provides a weak host barrier, one mutation only seen in ferrets is located in the novel S1/S2 cleavage site and is computationally predicted to decrease furin activity. These data support that host factors interacting with the novel S1/S2 cleavage site may be a barrier in ferret SARS-CoV-2 susceptibility and that domestic ferrets are at low risk of natural infection from currently circulating SARS-CoV-2. This may be overcome in laboratory settings using concentrated viral inoculum, but the effects of ferret host-adaptations require additional investigation. ### Competing Interest Statement The authors have declared no competing interest.

32: Limited evidence of tumour mutational burden as a biomarker of response to immunotherapy
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Posted to bioRxiv 04 Sep 2020

Limited evidence of tumour mutational burden as a biomarker of response to immunotherapy
2,403 downloads genomics

Carino Gurjao, Dina Tsukrov, Maxim Imakaev, Lovelace J. Luquette, Leonid A. Mirny

Cancer immunotherapy by immune checkpoint blockade (ICB) is effective for several cancer types [1][1], however, its clinical use is encumbered by a high variability in patient response. Several studies have suggested that Tumor Mutational Burden (TMB) correlates with patient response to ICB treatments [2][2]–[6][3], likely due to immunogenic neoantigens generated by novel mutations accumulated during cancer progression [7][4]. Association of TMB and response to checkpoint inhibitors has become widespread in the oncoimmunology field, within and across cancer types [7][4]–[11][5], and has led to the development of commercial TMB-based biomarker platforms. As a result, patient prioritization for ICB based on individual TMB level was recently approved by the FDA [12][6]. Here we revisit the association of mutational burden with response to checkpoint inhibitors by aggregating pan-cancer data of ICB-treated patients with whole-exome sequencing and clinical annotation. Surprisingly, we find little evidence that TMB is predictive of patient response to immunotherapy. Our analysis suggests that previously reported associations arise from a combination of confounding disease subtypes and incorrect statistical testing. We show that using a TMB threshold for clinical decisions regarding immunotherapy could deprive potentially responding patients of receiving efficacious and life-extending treatment. Finally, we present a simple mathematical model that extends the neoantigen theory, is consistent with the lack of association between TMB and response to ICB and highlights the role of immunodominance. Our analysis calls for caution in the use of TMB as a biomarker and emphasizes the necessity of continuing the search for other genetic and non-genetic determinants of response to immunotherapy. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-2 [3]: #ref-6 [4]: #ref-7 [5]: #ref-11 [6]: #ref-12

33: Scalable, multimodal profiling of chromatin accessibility and protein levels in single cells
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Posted to bioRxiv 08 Sep 2020

Scalable, multimodal profiling of chromatin accessibility and protein levels in single cells
2,401 downloads genomics

Eleni P. Mimitou, Caleb A. Lareau, Kelvin Y. Chen, Andre L. Zorzetto-Fernandes, Yusuke Takeshima, Wendy Luo, Tse-Shun Huang, Bertrand Yeung, Pratiksha I. Thakore, James Badger Wing, Kristopher L. Nazor, Shimon Sakaguchi, Leif S. Ludwig, Vijay G. Sankaran, Aviv Regev, Peter Smibert

Recent technological advances have enabled massively parallel chromatin profiling with single-cell Assay for Transposase Accessible Chromatin by sequencing (scATAC-seq) in thousands of individual cells. Here, we extend these approaches and present ATAC with Select Antigen Profiling by sequencing, ASAP-seq, a tool to simultaneously profile accessible chromatin and protein levels in thousands of single cells. Our approach pairs sparse scATAC-seq data with robust detection of hundreds of cell surface and intracellular protein markers and optional capture of mitochondrial DNA (mtDNA) for clonal tracking, thus concomitantly capturing three distinct modalities in single cells. Importantly, ASAP-seq uses a novel bridging approach that repurposes antibody:oligo conjugates designed for existing technologies that pair protein measurements with single cell RNA-seq. We demonstrate the utility of ASAP-seq by revealing coordinated and distinct changes in chromatin, RNA, and surface proteins during native hematopoietic differentiation, peripheral blood mononuclear cell stimulation, and as a combinatorial decoder and reporter of multiplexed perturbations in primary T cells. ### Competing Interest Statement COMPETING INTERESTS PS is listed as co-inventor on a patent related to this work (US provisional patent application 62/515-180). CAL, LSL, VGS, and AR are listed as co-inventors on a patent related to mtscATAC-seq (US provisional patent application 62/683,502). A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics and until August 31, 2020 was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov and ThermoFisher Scientific. From August 1, 2020, A.R. is an employee of Genentech.

34: SARS-CoV-2 and Malayan pangolin coronavirus infect human endoderm, ectoderm and induced lung progenitor cells
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Posted to bioRxiv 25 Sep 2020

SARS-CoV-2 and Malayan pangolin coronavirus infect human endoderm, ectoderm and induced lung progenitor cells
2,261 downloads microbiology

Bixia Hong, Xinyuan Lai, Yangzhen Chen, Tianming Luo, Xiaoping An, Lihua Song, Hui Zhuang, Huahao Fan, Tong Li, Kuanhui Xiang, Yigang Tong

Since the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in several somatic cells, little is known about the infection of SASRS-CoV-2 and its related pangolin coronavirus (GX\_P2V). Here we present for the first time that SARS-CoV-2 pseudovirus and GX\_P2V could infect lung progenitor and even anterior foregut endoderm cells causing these cells death, which differentiated from human embryonic stem cells (hESCs). The infection and replication of SARS-CoV-2 and GX\_P2V were inhibited when treated with whey protein of breastmilk and Remdesivir, confirming that these two viruses could infect lung progenitor and even anterior foregut endoderm. Moreover, we found that SARS-CoV-2 pseudovirus could infect endoderm and ectoderm. We found that whey protein blocked SARS-CoV-2 infecting these cells. In line with the SARS-CoV-2 results, GX\_P2V could also infected endoderm and ectoderm, and also was inhibited by Remdesivir treatment. Although expressing coronavirus related receptor such as ACE2 and TMPRSS2, mesoderm cells are not permissive for SARS-CoV-2 and GX\_P2V infection, which needed further to study the mechanisms. Interestingly, we also found that hESCs, which also express ACE2 and TMPRSS2 markers, are permissive for GX\_P2V but not SARS-CoV-2 pseudovirus infection and replication, indicating the widespread cell types for GX\_P2V infection. Heparin treatment blocked efficiently viral infection. These results provided insight that these stem cells maybe provided a stable repository of coronavirus function or genome. The potential consequence of SARS-CoV-2 and animal coronavirus such as GX\_P2V infection in hESCs, germ layer and induced progenitors should be closely monitored. ### Competing Interest Statement The authors have declared no competing interest.

35: Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system
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Posted to bioRxiv 07 Jun 2020

Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system
2,236 downloads microbiology

Ludovico Cantuti-Castelvetri, Ravi Ojha, Liliana D. Pedro, Minou Djannatian, Jonas Franz, Suvi Kuivanen, Katri Kallio, Tuğberk Kaya, Maria Anastasina, Teemu Smura, Lev Levanov, L Szirovicza, Allan Tobi, Hannimari Kallio-Kokko, Pamela Österlund, Merja Joensuu, Frédéric A. Meunier, Sarah Butcher, Martin Sebastian Winkler, Brit Mollenhauer, Ari Helenius, Ozgun Gokce, Tambet Teesalu, J Hepojoki, Olli Vapalahti, Christine Stadelmann, Giuseppe Balistreri, Mikael Simons

The causative agent of the current pandemic and coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)[1][1]. Understanding how SARS-CoV-2 enters and spreads within human organs is crucial for developing strategies to prevent viral dissemination. For many viruses, tissue tropism is determined by the availability of virus receptors on the surface of host cells[2][2]. Both SARS-CoV and SARS-CoV-2 use angiotensin-converting enzyme 2 (ACE2) as a host receptor, yet, their tropisms differ[3][3]-[5][4]. Here, we found that the cellular receptor neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, which was inhibited by a monoclonal blocking antibody against the extracellular b1b2 domain of NRP1. NRP1 is abundantly expressed in the respiratory and olfactory epithelium, with highest expression in endothelial cells and in the epithelial cells facing the nasal cavity. Neuropathological analysis of human COVID-19 autopsies revealed SARS-CoV-2 infected NRP1-positive cells in the olfactory epithelium and bulb. In the olfactory bulb infection was detected particularly within NRP1-positive endothelial cells of small capillaries and medium-sized vessels. Studies in mice demonstrated, after intranasal application, NRP1-mediated transport of virus-sized particles into the central nervous system. Thus, NRP1 could explain the enhanced tropism and spreading of SARS-CoV-2. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-5

36: Different pattern of pre-existing SARS-COV-2 specific T cell immunity in SARS-recovered and uninfected individuals
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Posted to bioRxiv 27 May 2020

Different pattern of pre-existing SARS-COV-2 specific T cell immunity in SARS-recovered and uninfected individuals
2,215 downloads immunology

Nina Le Bert, Anthony T Tan, Kamini Kunasegaran, Christine Y. L. Tham, Morteza Hafezi, Adeline Chia, Melissa Chng, Meiyin Lin, Nicole Tan, Martin Linster, Wan Ni Chia, Mark I-Cheng Chen, Lin-Fa Wang, Eng Eong Ooi, Shirin Kalimuddin, Paul Anantharajal Tambyah, Jenny Guek-Hong Low, Yee-Joo Tan, Antonio Bertoletti

Memory T cells induced by previous infections can influence the course of new viral infections. Little is known about the pattern of SARS-CoV-2 specific pre-existing memory T cells in human. Here, we first studied T cell responses to structural (nucleocapsid protein, NP) and non-structural (NSP-7 and NSP13 of ORF1) regions of SARS-CoV-2 in convalescent from COVID-19 (n=24). In all of them we demonstrated the presence of CD4 and CD8 T cells recognizing multiple regions of the NP protein. We then show that SARS-recovered patients (n=23), 17 years after the 2003 outbreak, still possess long-lasting memory T cells reactive to SARS-NP, which displayed robust cross-reactivity to SARS-CoV-2 NP. Surprisingly, we observed a differential pattern of SARS-CoV-2 specific T cell immunodominance in individuals with no history of SARS, COVID-19 or contact with SARS/COVID-19 patients (n=18). Half of them (9/18) possess T cells targeting the ORF-1 coded proteins NSP7 and 13, which were rarely detected in COVID-19- and SARS-recovered patients. Epitope characterization of NSP7-specific T cells showed recognition of protein fragments with low homology to "common cold" human coronaviruses but conserved among animal betacoranaviruses. Thus, infection with betacoronaviruses induces strong and long-lasting T cell immunity to the structural protein NP. Understanding how pre-existing ORF-1-specific T cells present in the general population impact susceptibility and pathogenesis of SARS-CoV-2 infection is of paramount importance for the management of the current COVID-19 pandemic. ### Competing Interest Statement A.B. is a cofounder of Lion TCR, a biotech company developing T cell receptors for treatment of virus-related diseases and cancers. None of the other authors has any competing interest related to the study.

37: Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition
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Posted to bioRxiv 10 Sep 2020

Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition
2,192 downloads microbiology

Allison J. Greaney, Tyler N. Starr, Pavlo Gilchuk, Seth J. Zost, Elad Binshtein, Andrea N. Loes, Sarah K Hilton, John Huddleston, Rachel Eguia, Katharine H. D. Crawford, Adam S Dingens, Rachel S Nargi, Rachel E Sutton, Naveenchandra Suryadevara, Paul W. Rothlauf, Zhuoming Liu, Sean P.J. Whelan, Robert H. Carnahan, James E. Crowe, Jesse D Bloom

Antibodies targeting the SARS-CoV-2 spike receptor-binding domain (RBD) are being developed as therapeutics and make a major contribution to the neutralizing antibody response elicited by infection. Here, we describe a deep mutational scanning method to map how all amino-acid mutations in the RBD affect antibody binding, and apply this method to 10 human monoclonal antibodies. The escape mutations cluster on several surfaces of the RBD that broadly correspond to structurally defined antibody epitopes. However, even antibodies targeting the same RBD surface often have distinct escape mutations. The complete escape maps predict which mutations are selected during viral growth in the presence of single antibodies, and enable us to design escape-resistant antibody cocktails–including cocktails of antibodies that compete for binding to the same surface of the RBD but have different escape mutations. Therefore, complete escape-mutation maps enable rational design of antibody therapeutics and assessment of the antigenic consequences of viral evolution. ### Competing Interest Statement J.E.C. has served as a consultant for Sanofi; is on the Scientific Advisory Boards of CompuVax and Meissa Vaccines; is a recipient of previous unrelated research grants from Moderna and Sanofi; and is a founder of IDBiologics. Vanderbilt University has applied for patents concerning SARS-CoV-2 antibodies analyzed in this work. S.P.J.W. and P.W.R. have filed a disclosure with Washington University for the recombinant VSV. The other authors declare no competing interests.

38: Iota carrageenan and xylitol inhibit SARS-CoV-2 in Vero cell culture
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Posted to bioRxiv 21 Aug 2020

Iota carrageenan and xylitol inhibit SARS-CoV-2 in Vero cell culture
2,188 downloads pharmacology and toxicology

Julio Cesar Vega, Shruti Bansal, Colleen B Jonsson, Shannon L. Taylor, Juan M Figueroa, Andrea V. Dugour, Carlos Palacios

COVID-19 (coronavirus disease 2019) is a pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome-coronavirus 2) infection affecting millions of persons around the world. There is an urgent unmet need to provide an easy-to-produce, affordable medicine to prevent transmission and provide early treatment for this disease. The nasal cavity and the rhinopharynx are the sites of initial replication of SARS-CoV-2. Therefore, a nasal spray may be a suitable dosage form for this purpose. The main objective of our study was to test the antiviral action of three candidate nasal spray formulations against SARS-CoV-2. We have found that iota-carrageenan in concentrations as low as 6 mcg/ mL inhibits SARS-CoV-2 infection in Vero cell cultures. The concentrations found to be active in vitro against SARS-CoV-2 may be easily achieved by the application of nasal sprays already marketed in several countries. Xylitol at a concentration of 5 % m/V has proved to be viricidal on its own and the association with iota-carrageenan may be beneficial, as well. ### Competing Interest Statement The study has been funded by Amcyte Pharma Inc. (US) Juan Manuel Figueroa, Andrea Dugour and Carlos Palacios receive funding from Fundacion Pablo Cassara (Argentina) Julio Cesar Vega receives salary from Laboratorio Pablo Cassara and is inventor of a US patent application related to this manuscript.

39: Single-cell profiling of histone modifications in the mouse brain
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Posted to bioRxiv 03 Sep 2020

Single-cell profiling of histone modifications in the mouse brain
2,063 downloads neuroscience

Marek Bartosovic, Mukund Kabbe, Gonçalo Castelo-Branco

The development of the mouse central nervous system (CNS) involves coordinated execution of transcriptional and epigenetic programs. These programs have been extensively studied through single-cell technologies in a pursuit to characterize the underlying cell heterogeneity. However, histone modifications pose additional layers of both positive and negative regulation that defines cellular identity. Here we show that the Cut&Tag technology can be coupled with a droplet-based single cell library preparation platform to produce high quality chromatin modifications data at a single cell resolution in tens of thousands of cells. We apply single-cell Cut&Tag (scC&T) to probe histone modifications characteristic of active promoters (H3K4me3), active promoters and enhancers (H3K27ac), active gene bodies (H3K36me3) and inactive regions (H3K27me3) and generate scC&T profiles for almost 50,000 cells. scC&T profiles of each of these histone modifications were sufficient to determine cell identity and deconvolute at single cell level regulatory principles such as promoter bivalency, spreading of H3K4me3 and promoter-enhancer connectivity. Moreover, we used scC&T to investigate the single-cell chromatin occupancy of transcription factor Olig2 and the cohesin complex component Rad21. Our results indicate that analysis of histone modifications and transcription factor occupancy at a single cell resolution can provide unique insights of epigenomic landscapes in the CNS. We also provide an online resource that can be used to interactively explore the data at <https://castelobranco.shinyapps.io/BrainCutAndTag2020/>. ### Competing Interest Statement The authors have declared no competing interest.

40: Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice
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Posted to bioRxiv 04 Oct 2019

Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice
1,991 downloads cell biology

Azar Asadi Shahmirzadi, Daniel Edgar, Chen-Yu Liao, Yueh-Mei Hsu, Mark Lucanic, Arash Asadi Shahmirzadi, Christopher Wiley, Rebeccah Riley, Brian Kaplowitz, Garbo Gan, Chisaka Kuehnemann, Dipa Bhaumik, Judith Campisi, Brian K Kennedy, Gordon J. Lithgow

The decline in early life mortality since the 1950s has resulted in dramatic demographic shift towards aged population. Aging manifests as a decline in health, multiple organ dysfunction and increased vulnerability to diseases, which degrades quality of life. A verity of genetic and pharmacological interventions, mostly from non-vertebrate models, have been identified that can enhance lifespan. Whether these interventions extend healthspan, the disease free and functional period of life, has only sometimes been tested and is often a matter of debate. Human aging indices have been developed to assess elements of functional decline with aging (e.g. sarcopenia, cognitive function). However, corresponding comprehensive indices in mice are seldom applied to aging studies. To probe the relationship between healthspan and lifespan extension in mammals, we performed a series of longitudinal, clinically-relevant healthspan measurements. Metabolism and aging are tightly connected and specific perturbations of nutrient-sensing pathways can enhance longevity in laboratory animals. Here we show that alpha-ketoglutarate (delivered in the form of a Calcium salt, CaAKG), a key metabolite in tricarboxylic (TCA) cycle that is reported to extend lifespan in worms , can significantly extend lifespan and healthspan in mice. AKG is involved in various fundamental processes including collagen synthesis and epigenetic changes. Due to its broad roles in multiple biological processes, AKG has been a subject of interest for researchers in various fields. AKG also influences several age-related processes, including stem cell proliferation and osteoporosis. To determine its role in mammalian aging, we administered CaAKG in 18 months old mice and determined its effect on the onset of frailty and survival, discovering that the metabolite promotes longer, healthier life associated with a decrease in levels of inflammatory factors. Interestingly the reduction in frailty was more dramatic than the increase in lifespan, leading us to propose that CaAKG compresses morbidity.

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