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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 93,041 bioRxiv papers from 397,262 authors.

Most downloaded bioRxiv papers, since beginning of last month

91,042 results found. For more information, click each entry to expand.

41: Targeted Genome Editing of Bacteria Within Microbial Communities
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Posted to bioRxiv 17 Jul 2020

Targeted Genome Editing of Bacteria Within Microbial Communities
1,769 downloads microbiology

Benjamin E. Rubin, Spencer Diamond, Brady F. Cress, Alexander Crits-Christoph, Christine He, Michael Xu, Zeyi Zhou, Dylan C Smock, Kimberly Tang, Trenton K Owens, Netravathi Krishnappa, Rohan Sachdeva, Adam M. Deutschbauer, Jillian F. Banfield, Jennifer Doudna

Knowledge of microbial gene functions comes from manipulating the DNA of individual species in isolation from their natural communities. While this approach to microbial genetics has been foundational, its requirement for culturable microorganisms has left the majority of microbes and their interactions genetically unexplored. Here we describe a generalizable methodology for editing the genomes of specific organisms within a complex microbial community. First, we identified genetically tractable bacteria within a community using a new approach, Environmental Transformation Sequencing (ET-Seq), in which non-targeted transposon integrations were mapped and quantified following community delivery. ET-Seq was repeated with multiple delivery strategies for both a nine-member synthetic bacterial community and a ~200-member microbial bioremediation community. We achieved insertions in 10 species not previously isolated and identified natural competence for foreign DNA integration that depends on the presence of the community. Second, we developed and used DNA-editing All-in-one RNA-guided CRISPR-Cas Transposase (DART) systems for targeted DNA insertion into organisms identified as tractable by ET-Seq, enabling organism- and locus-specific genetic manipulation within the community context. These results demonstrate a strategy for targeted genome editing of specific organisms within microbial communities, establishing a new paradigm for microbial manipulation relevant to research and applications in human, environmental, and industrial microbiomes. ### Competing Interest Statement The Regents of the University of California have patents pending related to this work on which B.E.R., S.D., B.F.C., A.M.D., J.F.B., and J.A.D. are inventors. J.A.D. is a co-founder of Caribou Biosciences, Editas Medicine, Intellia Therapeutics, Scribe Therapeutics and Mammoth Biosciences, a scientific advisory board member of Caribou Biosciences, Intellia Therapeutics, eFFECTOR Therapeutics, Scribe Therapeutics, Synthego, Mammoth Biosciences and Inari, and is a Director at Johnson & Johnson and has sponsored research projects by Biogen, Roche and Pfizer. J.F.B. is a founder of Metagenomi.

42: High-performance brain-to-text communication via imagined handwriting
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Posted to bioRxiv 02 Jul 2020

High-performance brain-to-text communication via imagined handwriting
1,751 downloads neuroscience

Francis R. Willett, Donald T. Avansino, Leigh R. Hochberg, Jaimie M. Henderson, Krishna V. Shenoy

Brain-computer interfaces (BCIs) can restore communication to people who have lost the ability to move or speak. To date, a major focus of BCI research has been on restoring gross motor skills, such as reaching and grasping or point-and-click typing with a 2D computer cursor. However, rapid sequences of highly dexterous behaviors, such as handwriting or touch typing, might enable faster communication rates. Here, we demonstrate an intracortical BCI that can decode imagined handwriting movements from neural activity in motor cortex and translate it to text in real-time, using a novel recurrent neural network decoding approach. With this BCI, our study participant (whose hand was paralyzed) achieved typing speeds that exceed those of any other BCI yet reported: 90 characters per minute at >99% accuracy with a general-purpose autocorrect. These speeds are comparable to able-bodied smartphone typing speeds in our participant's age group (115 characters per minute) and significantly close the gap between BCI-enabled typing and able-bodied typing rates. Finally, new theoretical considerations explain why temporally complex movements, such as handwriting, may be fundamentally easier to decode than point-to-point movements. Our results open a new approach for BCIs and demonstrate the feasibility of accurately decoding rapid, dexterous movements years after paralysis. ### Competing Interest Statement The MGH Translational Research Center has a clinical research support agreement with Neuralink, Paradromics, and Synchron, for which L.R.H. provides consultative input. JMH is a consultant for Neuralink Corp and Proteus Biomedical, and serves on the Medical Advisory Board of Enspire DBS. KVS consults for Neuralink Corp. and CTRL-Labs Inc. (part of Facebook Reality Labs) and is on the scientific advisory boards of MIND-X Inc., Inscopix Inc., and Heal Inc. All other authors have no competing interests.

43: Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2
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Posted to bioRxiv 14 Mar 2020

Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2
1,728 downloads microbiology

Linlin Bao, Wei Deng, Hong Gao, Chong Xiao, Jiayi Liu, Jing Xue, Qi Lv, Jiangning Liu, Pin Yu, Yanfeng Xu, Feifei Qi, Yajin Qu, Fengdi Li, Zhiguang Xiang, Haisheng Yu, Shuran Gong, Mingya Liu, Guanpeng Wang, Shunyi Wang, Zhiqi Song, Ying Liu, Wenjie Zhao, Yunlin Han, Linna Zhao, Xing Liu, Qiang Wei, Chuan Qin

A global pandemic of Corona Virus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is ongoing spread. It remains unclear whether the convalescing patients have a risk of reinfection. Rhesus macaques were rechallenged with SARS-CoV-2 during an early recovery phase from initial infection characterized by weight loss, interstitial pneumonia and systemic viral dissemination mainly in respiratory and gastrointestinal tracts. The monkeys rechallenged with the identical SARS-CoV-2 strain have failed to produce detectable viral dissemination, clinical manifestations and histopathological changes. A notably enhanced neutralizing antibody response might contribute the protection of rhesus macaques from the reinfection by SARS-CoV-2. Our results indicated that primary SARS-CoV-2 infection protects from subsequent reinfection. ### Competing Interest Statement The authors have declared no competing interest.

44: Genome-wide Spatial Expression Profiling in FFPE Tissues
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Posted to bioRxiv 25 Jul 2020

Genome-wide Spatial Expression Profiling in FFPE Tissues
1,727 downloads genetics

Eva Gracia Villacampa, Ludvig Larsson, Linda Kvastad, Alma Andersson, Joseph Carlson, Joakim Lundeberg

Formalin-fixed paraffin embedding (FFPE) is the most widespread long-term tissue preservation approach. Here we present a procedure to perform genome-wide spatial analysis of mRNA in FFPE tissue sections. The procedure takes advantage of well-established, commercially available methods for imaging and spatial barcoding using slides spotted with barcoded oligo(dT) probes to capture the 3' end of mRNA molecules in tissue sections. First, we conducted expression profiling and cell type mapping in coronal sections from the mouse brain to demonstrate the method's capability to delineate anatomical regions from a molecular perspective. Second, we explored the spatial composition of transcriptomic signatures in ovarian carcinosarcoma samples using data driven analysis methods, exemplifying the method's potential to elucidate molecular mechanisms in heterogeneous clinical samples. ### Competing Interest Statement JL, EVG, LL, LK, AA are scientific advisors to 10x Genomics Inc, which holds IP rights to the ST technology.

45: Genetic ancestry changes in Stone to Bronze Age transition in the East European plain
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Posted to bioRxiv 03 Jul 2020

Genetic ancestry changes in Stone to Bronze Age transition in the East European plain
1,706 downloads evolutionary biology

Lehti Saag, Sergey V. Vasilyev, Liivi Varul, Natalia V. Kosorukova, Dmitri V. Gerasimov, Svetlana V. Oshibkina, Samuel J. Griffith, Anu Solnik, Lauri Saag, Eugenia D’Atanasio, Ene Metspalu, Maere Reidla, Siiri Rootsi, Toomas Kivisild, Christiana Lyn Scheib, Kristiina Tambets, Aivar Kriiska, Mait Metspalu

Transition from the Stone to the Bronze Age in Central and Western Europe was a period of major population movements originating from the Ponto-Caspian Steppe. Here, we report new genome-wide sequence data from 28 individuals from the territory north of this source area - from the under-studied Western part of present-day Russia, including Stone Age hunter-gatherers (10,800-4,250 cal BC) and Bronze Age farmers from the Corded Ware complex called Fatyanovo Culture (2,900-2,050 cal BC). We show that Eastern hunter-gatherer ancestry was present in Northwestern Russia already from around 10,000 BC. Furthermore, we see a clear change in ancestry with the arrival of farming - the Fatyanovo Culture individuals were genetically similar to other Corded Ware cultures, carrying a mixture of Steppe and European early farmer ancestry and thus likely originating from a fast migration towards the northeast from somewhere in the vicinity of modern-day Ukraine, which is the closest area where these ancestries coexisted from around 3,000 BC. ### Competing Interest Statement The authors have declared no competing interest.

46: 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
1,701 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.

47: The Argo: A 65,536 channel recording system for high density neural recording in vivo
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Posted to bioRxiv 17 Jul 2020

The Argo: A 65,536 channel recording system for high density neural recording in vivo
1,698 downloads neuroscience

Kunal Sahasrabuddhe, Aamir A Khan, Aditya P Singh, Tyler M Stern, Yeena Ng, Aleksandar Tadić, Peter Orel, Chris LaReau, Daniel Pouzzner, Kurtis Nishimura, Kevin M. Boergens, Sashank Shivakumar, Matthew S Hopper, Bryan Kerr, Mina-Elraheb S. Hanna, Robert J Edgington, Ingrid McNamara, Devin Fell, Peng Gao, Amir Babaie-Fishani, Sampsa Veijalainen, Alexander V Klekachev, Alison M Stuckey, Bert Luyssaert, Takashi DY Kozai, Chong Xie, Vikash Gilja, Bart Dierickx, Yifan Kong, Malgorzata Straka, Harbaljit S Sohal, Matthew R Angle

Here we demonstrate the Argo System, a massively parallel neural recording system based on platinum-iridium microwire electrode arrays bonded to a CMOS voltage amplifier array. The Argo system is the highest channel count in vivo neural recording system built to date, supporting simultaneous recording from 65,536 channels, sampled at over 32 kHz and 12-bit resolution. This system is designed for cortical recordings, compatible with both penetrating and surface microelectrodes. We have validated this system by recording spiking activity from 791 neurons in rats and cortical surface Local Field Potential (LFP) activity from over 30,000 channels in sheep. While currently adapted for head-fixed recording, the microwire-CMOS architecture is well suited for clinical translation. Thus, this demonstration helps pave the way for a future high data rate intracortical implant. ### Competing Interest Statement K.S., A.A.K., A.P.S., T.M.S, Y.N., A.T., P.O., C.L., D.P., K.N., K.M.B., S.S., M.S.H., B.K., M-E.S.H., R.J.E., I.M., D.F., A.M.S., V.G., Y.K., M.S., H.S.S., M.R.A. are current or former compensated employees or consultants of Paradromics, Inc., a brain-computer interface company. P.G., A.B-F, S.V., A.V.K, B.L., B.D. are compensated employees or consultants of Caeleste, CVBA, a circuit design company.

48: 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)
1,677 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.

49: A single-dose live-attenuated YF17D-vectored SARS-CoV2 vaccine candidate
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Posted to bioRxiv 09 Jul 2020

A single-dose live-attenuated YF17D-vectored SARS-CoV2 vaccine candidate
1,671 downloads microbiology

Lorena Sanchez Felipe, Thomas Vercruysse, Sapna Sharma, Ji Ma, Viktor Lemmens, Dominique van Looveren, Mahadesh Prasad Arkalagud Javarappa, Robbert Boudewijns, Bert Malengier-Devlies, Suzanne F. Kaptein, Laurens Liesenborghs, Carolien De Keyzer, Lindsey Bervoets, Madina Rasulova, Laura Seldeslachts, Sander Jansen, Michael Bright Yakass, Osbourne Quaye, Li-Hsin Li, Xin Zhang, Sebastiaan ter Horst, Niraj Mishra, Lotte Coelmont, Christopher Cawthorne, Koen Van Laere, Ghislain Opdenakker, Greetje Van de Velde, Birgit Weynand, Dirk E. Teuwen, Patrick Matthys, Johan Neyts, Hendrik Jan Thibaut, Kai Dallmeier

The explosively expanding COVID-19 pandemic urges the development of safe, efficacious and fast-acting vaccines to quench the unrestrained spread of SARS-CoV-2. Several promising vaccine platforms, developed in recent years, are leveraged for a rapid emergency response to COVID-19. We employed the live-attenuated yellow fever 17D (YF17D) vaccine as a vector to express the prefusion form of the SARS-CoV-2 Spike antigen. In mice, the vaccine candidate, tentatively named YF-S0, induces high levels of SARS-CoV-2 neutralizing antibodies and a favorable Th1 cell-mediated immune response. In a stringent hamster SARS-CoV-2 challenge model, vaccine candidate YF-S0 prevents infection with SARS-CoV-2. Moreover, a single dose confers protection from lung disease in most vaccinated animals even within 10 days. These results warrant further development of YF-S0 as a potent SARS-CoV-2 vaccine candidate. ### Competing Interest Statement The authors have declared no competing interest.

50: Shotgun Transcriptome and Isothermal Profiling of SARS-CoV-2 Infection Reveals Unique Host Responses, Viral Diversification, and Drug Interactions
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Posted to bioRxiv 20 Apr 2020

Shotgun Transcriptome and Isothermal Profiling of SARS-CoV-2 Infection Reveals Unique Host Responses, Viral Diversification, and Drug Interactions
1,670 downloads molecular biology

Daniel J Butler, Christopher Mozsary, Cem Meydan, David Danko, Jonathan Foox, Joel Rosiene, Alon Shaiber, Ebrahim Afshinnekoo, Matthew MacKay, Fritz J. Sedlazeck, Nikolay A Ivanov, Maria Sierra, Diana Pohle, Michael Zietz, Undina Gisladottir, Vijendra Ramlall, Craig D Westover, Krista Ryon, Benjamin Young, Chandrima Bhattacharya, Phyllis Ruggiero, Bradley W. Langhorst, Nathan Tanner, Justyna Gawrys, Dmitry Meleshko, Dong Xu, Peter A D Steel, Amos J Shemesh, Jenny Xiang, Jean Thierry-Mieg, Danielle Thierry-Mieg, Robert E. Schwartz, Angelika Iftner, Daniela Bezdan, John Sipley, Lin Cong, Arryn Craney, Priya Velu, Ari M. Melnick, Iman Hajirasouliha, Stacy M. Horner, Thomas Iftner, Mirella Salvatore, Massimo Loda, Lars F Westblade, Melissa Cushing, Shawn Levy, Shixiu Wu, Nicholas P. Tatonetti, Marcin Imielinski, Hanna Rennert, Christopher E. Mason

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused thousands of deaths worldwide, including >18,000 in New York City (NYC) alone. The sudden emergence of this pandemic has highlighted a pressing clinical need for rapid, scalable diagnostics that can detect infection, interrogate strain evolution, and identify novel patient biomarkers. To address these challenges, we designed a fast (30-minute) colorimetric test (LAMP) for SARS-CoV-2 infection from naso/oropharyngeal swabs, plus a large-scale shotgun metatranscriptomics platform (total-RNA-seq) for host, bacterial, and viral profiling. We applied both technologies across 857 SARS-CoV-2 clinical specimens and 86 NYC subway samples, providing a broad molecular portrait of the COVID-19 NYC outbreak. Our results define new features of SARS-CoV-2 evolution, nominate a novel, NYC-enriched viral subclade, reveal specific host responses in ACE, interferon, hematological, and olfaction pathways, and examine risks associated with use of ACE inhibitors and angiotensin receptor blockers. Together, these findings have immediate applications to SARS-CoV-2 diagnostics, public health monitoring, and new therapeutic targets. ### Competing Interest Statement N.T. and B.L. are employees at New England Biolabs.

51: Integrated sample inactivation, amplification, and Cas13-based detection of SARS-CoV-2
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Posted to bioRxiv 28 May 2020

Integrated sample inactivation, amplification, and Cas13-based detection of SARS-CoV-2
1,638 downloads bioengineering

Jon Arizti-Sanz, Catherine A. Freije, Alexandra C. Stanton, Chloe K. Boehm, Brittany A. Petros, Sameed Siddiqui, Bennett M. Shaw, Gordon Adams, Tinna-Solveig F Kosoko-Thoroddsen, Molly E. Kemball, Robin Gross, Loni Wronka, Katie Caviness, Lisa E Hensley, Nicholas H. Bergman, Bronwyn L MacInnis, Jacob E. Lemieux, Pardis C Sabeti, Cameron Myhrvold

The COVID-19 pandemic has highlighted that new diagnostic technologies are essential for controlling disease transmission. Here, we develop SHINE (SHERLOCK and HUDSON Integration to Navigate Epidemics), a sensitive and specific integrated diagnostic tool that can detect SARS-CoV-2 RNA from unextracted samples. We combine the steps of SHERLOCK into a single-step reaction and optimize HUDSON to accelerate viral inactivation in nasopharyngeal swabs and saliva. SHINE's results can be visualized with an in-tube fluorescent readout - reducing contamination risk as amplification reaction tubes remain sealed - and interpreted by a companion smartphone application. We validate SHINE on 50 nasopharyngeal patient samples, demonstrating 90% sensitivity and 100% specificity compared to RT-PCR with a sample-to-answer time of 50 minutes. SHINE has the potential to be used outside of hospitals and clinical laboratories, greatly enhancing diagnostic capabilities. ### Competing Interest Statement C.A.F., P.C.S., and C.M. are inventors on patent filings related to this work. J.E.L. consults for Sherlock Biosciences, Inc. P.C.S. is a co-founder of, shareholder in, and advisor to Sherlock Biosciences, Inc, as well as a Board member of and shareholder in Danaher Corporation.

52: A Strategy to Treat COVID-19 Disease with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Non-clinical Pharmacokinetic Study
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Posted to bioRxiv 10 Jul 2020

A Strategy to Treat COVID-19 Disease with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Non-clinical Pharmacokinetic Study
1,629 downloads pharmacology and toxicology

Tien-Tzu Tai, Tzung-Ju Wu, Huey-Dong Wu, Yi-Chen Tsai, Hui-Ting Wang, An-Min Wang, Sheue-Fang Shih, Yee-Chun Chen

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing coronavirus disease 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infection in vitro and tested in clinical studies. However, lung concentration (6.7 μg/mL) to predict the in vivo antiviral efficacy might not be achievable with the currently proposed oral dosing regimen. Further, a high cumulative doses of HCQ may raise concerns of systemic toxicity, including cardiotoxicity. Here, we described a non-clinical study to investigate the pharmacokinetics of a novel formulation of liposomal HCQ administrated by intratracheal (IT) instillation in Sprague-Dawley (SD) rats which achieved 129.4 μg/g (Cmax) in the lung. Compared to unformulated HCQ administered intravenous (IV), liposomal HCQ with normalized dose showed higher (~30-fold) lung exposure, longer (~2.5-fold) half-life in lung, but lower blood exposure with ~20% of Cmax and 74% of AUC and lower heart exposure with 24% of Cmax and 58% of AUC. In conclusion, the pharmacokinetics results in an animal model demonstrate the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.

53: A direct RNA-protein interaction atlas of the SARS-CoV-2 RNA in infected human cells
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Posted to bioRxiv 15 Jul 2020

A direct RNA-protein interaction atlas of the SARS-CoV-2 RNA in infected human cells
1,535 downloads microbiology

Nora Schmidt, Caleb A. Lareau, Hasmik Keshishian, Randy Melanson, Matthias Zimmer, Luisa Kirschner, Jens Ade, Simone Werner, Neva Caliskan, Eric S Lander, Jörg Vogel, Steven A. Carr, Jochen Bodem, Mathias Munschauer

SARS-CoV-2 infections pose a global threat to human health and an unprecedented research challenge. Among the most urgent tasks is obtaining a detailed understanding of the molecular interactions that facilitate viral replication or contribute to host defense mechanisms in infected cells. While SARS-CoV-2 co-opts cellular factors for viral translation and genome replication, a comprehensive map of the host cell proteome in direct contact with viral RNA has not been elucidated. Here, we use RNA antisense purification and mass spectrometry (RAP-MS) to obtain an unbiased and quantitative picture of the human proteome that directly binds the SARS-CoV-2 RNA in infected human cells. We discover known host factors required for coronavirus replication, regulators of RNA metabolism and host defense pathways, along with dozens of potential drug targets among direct SARS-CoV-2 binders. We further integrate the SARS-CoV-2 RNA interactome with proteome dynamics induced by viral infection, linking interactome proteins to the emerging biology of SARS-CoV-2 infections. Validating RAP-MS, we show that CNBP, a regulator of proinflammatory cytokines, directly engages the SARS-CoV-2 RNA. Supporting the functional relevance of identified interactors, we show that the interferon-induced protein RYDEN suppresses SARS-CoV-2 ribosomal frameshifting and demonstrate that inhibition of SARS-CoV-2-bound proteins is sufficient to manipulate viral replication. The SARS-CoV-2 RNA interactome provides an unprecedented molecular perspective on SARS-CoV-2 infections and enables the systematic dissection of host dependency factors and host defense strategies, a crucial prerequisite for designing novel therapeutic strategies. ### Competing Interest Statement The authors have declared no competing interest.

54: Neuroinvasive potential of SARS-CoV-2 revealed in a human brain organoid model
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Posted to bioRxiv 26 Jun 2020

Neuroinvasive potential of SARS-CoV-2 revealed in a human brain organoid model
1,506 downloads microbiology

Eric Song, Ce Zhang, Benjamin Israelow, Peiwen Lu, Orr-El Weizman, Feimei Liu, Yile Dai, Klara Szigeti-Buck, Yuki Yasumoto, Guilin Wang, Christopher Castaldi, Jaime Heltke, Evelyn Ng, John Wheeler, Mia Madel Alfajaro, Benjamin Fontes, Neal G. Ravindra, David Van Dijk, Shrikant Mane, Murat Gunel, Aaron Ring, Craig B Wilen, Tamas L Horvath, Angeliki Louvi, Shelli F. Farhadian, Kaya Bilguvar, Akiko Iwasaki

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Reports indicate that 30-60% of patients with COVID-19 suffer from CNS symptoms. Yet, there is no consensus whether the virus can infect the brain, or what the consequences of infection are. Following SARS-CoV-2 infection of human brain organoids, clear evidence of infection was observed, with accompanying metabolic changes in the infected and neighboring neurons. Further, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Finally, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV2. ### Competing Interest Statement The authors have declared no competing interest.

55: SARS-CoV-2 RNA shedding in recovered COVID-19 cases and the presence of antibodies against SARS-CoV-2 in recovered COVID-19 cases and close contacts
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Posted to bioRxiv 17 Jul 2020

SARS-CoV-2 RNA shedding in recovered COVID-19 cases and the presence of antibodies against SARS-CoV-2 in recovered COVID-19 cases and close contacts
1,496 downloads immunology

Chintana Chirathaworn, Manit Sripramote, Piti Chalongviriyalert, Supunee Jirajariyavej, Phatharaporn Kiatpanabhikul, Jatuporn Saiyarin, Chulikorn Soudon, Orawan Thienfaidee, Thitisan Palakawong Na Ayuthaya, Chantapat Brukesawan, Dootchai Chaiwanichsiri, Duangnapa Intharasongkroh, Nasamon Wanlapakorn, Jira Chansaenroj, Jiratchaya Puenpa, Ritthideach Yorsaeng, Arunee Thitithanyanont, Rungrueng Kitphati, Anek Mungaomklang, Pijaya Nagavajara, Yong Poovorawan

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 emerged in December 2019 and has spread globally. Although Thailand has been effective at controlling the spread of COVID-19, disease surveillance and information on antibody responses in infected cases and close contacts are needed because there is still no specific treatment or vaccine available. We investigated 217 recovered COVID-19 cases to monitor their viral RNA shedding and production of antibodies against SARS-CoV-2. The presence of antibodies in blood samples from 308 close contacts of COVID-19 cases was also determined. Viral RNA was still detectable in 6.6 % of recovered COVID-19 cases. The most prolonged duration of viral RNA shedding detected in this study was 105 days. IgM, IgG, and IgA antibodies against SARS-CoV-2 were detected in 13.82, 88.48, and 83.41 % of the recovered cases 4–12 weeks after disease onset, respectively. Although the patients had recovered from their illness, the levels of antibodies detected showed association with their symptoms during their stay in hospital. Fifteen of the 308 contacts (4.87 %) of COVID-19 cases tested positive for IgG antibodies. The presence of antibodies against SARS-CoV-2 suggested that there was viral exposure among close contacts. Viral clearance and the pattern of antibody responses in infected individuals are both crucial for effectively combatting SARS-CoV-2. Our study provides additional information on the natural history of this newly emerging disease related to both natural host defenses and a strategy for vaccine development.

56: Complementary roles of dimensionality and population structure in neural computations
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Posted to bioRxiv 04 Jul 2020

Complementary roles of dimensionality and population structure in neural computations
1,479 downloads neuroscience

Alexis Dubreuil, Adrian Valente, Manuel Beiran, Francesca Mastrogiuseppe, Srdjan Ostojic

Neural computations are currently investigated using two competing approaches: sorting neurons into functional classes, or examining the low-dimensional dynamics of collective activity. Whether and how these two aspects interact to shape computations is currently unclear. Using a novel approach to extract computational mechanisms from networks trained with machine-learning tools on neuroscience tasks, here we show that the dimensionality of the dynamics and cell-class structure play fundamentally complementary roles. While various tasks can be implemented by increasing the dimensionality in networks consisting of a single global population, flexible input-output mappings instead required networks to be organized into several sub-populations. Our analyses revealed that the subpopulation structure enabled flexible computations through a mechanism based on gain-controlled modulations that flexibly shape the dynamical landscape of collective dynamics. Our results lead to task-specific predictions for the structure of neural selectivity and inactivation experiments. ### Competing Interest Statement The authors have declared no competing interest.

57: No evidence for increased transmissibility from recurrent mutations in SARS-CoV-2
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Posted to bioRxiv 21 May 2020

No evidence for increased transmissibility from recurrent mutations in SARS-CoV-2
1,453 downloads genomics

Lucy van Dorp, Damien Richard, Cedric C.S. Tan, Liam P. Shaw, Mislav Acman, François Balloux

The COVID-19 pandemic is caused by the coronavirus SARS-CoV-2, which jumped into the human population in late 2019 from a currently uncharacterised reservoir. Due to this extremely recent association with humans, SARS-CoV-2 may not yet be fully adapted to its human host. This has led to speculations that some lineages of SARS-CoV-2 may be evolving towards higher transmissibility. The most plausible candidate mutations under putative natural selection are those which have emerged repeatedly and independently (homoplasies). Here, we formally test whether any of the recurrent mutations that have been observed in SARS-CoV-2 to date are significantly associated with increased viral transmission. To do so, we developed a phylogenetic index to quantify the relative number of descendants in sister clades with and without a specific allele. We apply this index to a carefully curated set of recurrent mutations identified within a dataset of over 23,000 SARS-CoV-2 genomes isolated from patients worldwide. We do not identify a single recurrent mutation in this set convincingly associated with increased viral transmission. Instead, recurrent SARS-CoV-2 mutations currently in circulation appear to be evolutionary neutral. Recurrent mutations also seem primarily induced by the human immune system via host RNA editing, rather than being signatures of adaption to the novel human host. We find no evidence at this stage for the emergence of more transmissible lineages of SARS-CoV-2 due to recurrent mutations. ### Competing Interest Statement The authors have declared no competing interest.

58: Isolation, sequence, infectivity and replication kinetics of SARS-CoV-2
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Posted to bioRxiv 12 Apr 2020

Isolation, sequence, infectivity and replication kinetics of SARS-CoV-2
1,449 downloads microbiology

Arinjay Banerjee, Jalees A. Nasir, Patrick Budylowski, Lily Yip, Patryk Aftanas, Natasha Christie, Ayoob Ghalami, Kaushal Baid, Amogelang R. Raphenya, Jeremy A. Hirota, Matthew S Miller, Allison J McGeer, Mario Ostrowski, Robert A. Kozak, Andrew G McArthur, Karen Mossman, Samira Mubareka

SARS-CoV-2 emerged in December 2019 in Wuhan, China and has since infected over 1.5 million people, of which over 107,000 have died. As SARS-CoV-2 spreads across the planet, speculations remain about the range of human cells that can be infected by SARS-CoV-2. In this study, we report the isolation of SARS-CoV-2 from two cases of COVID-19 in Toronto, Canada. We determined the genomic sequences of the two isolates and identified single nucleotide changes in representative populations of our virus stocks. More importantly, we tested a wide range of human immune cells for productive infection with SARS-CoV-2. Here we confirm that human primary peripheral blood mononuclear cells (PBMCs) are not permissive for SARS-CoV-2. As SARS-CoV-2 continues to spread globally, it is essential to monitor single nucleotide polymorphisms in the virus and to continue to isolate circulating viruses to determine viral genotype and phenotype using in vitro and in vivo infection models. ### Competing Interest Statement The authors have declared no competing interest.

59: Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
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Posted to bioRxiv 27 Mar 2020

Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
1,444 downloads neuroscience

David H. Brann, Tatsuya Tsukahara, Caleb Weinreb, Marcela Lipovsek, Koen Van den Berge, Boying Gong, Rebecca Chance, Iain C Macaulay, Hsin-jung Chou, Russell Fletcher, Diya Das, Kelly Street, Hector Roux de Bézieux, Yoon-Gi Choi, Davide Risso, Sandrine Dudoit, Elizabeth Purdom, Jonathan S Mill, Ralph Abi Hachem, Hiroaki Matsunami, Darren W. Logan, Bradley J. Goldstein, Matthew S Grubb, John Ngai, Sandeep Robert Datta

Altered olfactory function is a common symptom of COVID-19, but its etiology is unknown. A key question is whether SARS-CoV-2 (CoV-2) - the causal agent in COVID-19 - affects olfaction directly by infecting olfactory sensory neurons or their targets in the olfactory bulb, or indirectly, through perturbation of supporting cells. Here we identify cell types in the olfactory epithelium and olfactory bulb that express SARS-CoV-2 cell entry molecules. Bulk sequencing revealed that mouse, non-human primate and human olfactory mucosa expresses two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. However, single cell sequencing and immunostaining demonstrated ACE2 expression in support cells, stem cells, and perivascular cells; in contrast, neurons in both the olfactory epithelium and bulb did not express ACE2 message or protein. These findings suggest that CoV-2 infection of non-neuronal cell types leads to anosmia and related disturbances in odor perception in COVID-19 patients. ### Competing Interest Statement DL is an employee of Mars, Inc. None of the other authors have competing interests to declare.

60: Genome-wide CRISPR screen reveals host genes that regulate SARS-CoV-2 infection
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Posted to bioRxiv 17 Jun 2020

Genome-wide CRISPR screen reveals host genes that regulate SARS-CoV-2 infection
1,421 downloads genetics

Jin Wei, Mia Madel Alfajaro, Ruth E Hanna, Peter C DeWeirdt, Madison S. Strine, William J. Lu-Culligan, Shang-Min Zhang, Vincent R. Graziano, Cameron O. Schmitz, Jennifer S. Chen, Madeleine C. Mankowski, Renata B. Filler, Victor Gasque, Fernando de Miguel, Huacui Chen, Kasopefoluwa Oguntuyo, Laura Abriola, Yulia V Surovtseva, Robert C. Orchard, Benhur Lee, Brett Lindenbach, Katerina Politi, David van Dijk, Matthew D. Simon, Qin Yan, John G. Doench, Craig B Wilen

Identification of host genes essential for SARS-CoV-2 infection may reveal novel therapeutic targets and inform our understanding of COVID-19 pathogenesis. Here we performed a genome-wide CRISPR screen with SARS-CoV-2 and identified known SARS-CoV-2 host factors including the receptor ACE2 and protease Cathepsin L. We additionally discovered novel pro-viral genes and pathways including the SWI/SNF chromatin remodeling complex and key components of the TGF-β signaling pathway. Small molecule inhibitors of these pathways prevented SARS-CoV-2-induced cell death. We also revealed that the alarmin HMGB1 is critical for SARS-CoV-2 replication. In contrast, loss of the histone H3.3 chaperone complex sensitized cells to virus-induced death. Together this study reveals potential therapeutic targets for SARS-CoV-2 and highlights host genes that may regulate COVID-19 pathogenesis. ### Competing Interest Statement Yale University (CBW) has a patent pending related to this work entitled: 'Compounds and Compositions for Treating, Ameliorating, and/or Preventing SARS-CoV-2 Infection and/or Complications Thereof.' Yale University has committed to rapidly executable non-exclusive royalty-free licenses to intellectual property rights for the purpose of making and distributing products to prevent, diagnose and treat COVID-19 infection during the pandemic and for a short period thereafter. JGD consults for Foghorn Therapeutics, Maze Therapeutics, Merck, Agios, and Pfizer; JGD consults for and has equity in Tango Therapeutics.

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