bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selecting Student-Authored Questions for Summative Assessments
Authors: Huang Alice , Hancock Dale , Clemson Matthew , Yeo Giselle , Harney Dylan J , Denny Paul , Denyer Gareth 
Published: July 2020

AbstractProduction of high-quality multiple-choice questions (MCQs) for both formative and summative assessment is a time-consuming task requiring great skill, creativity, and insight. The transition to online examinations, with the concomitant exposure of previously tried-and-tested MCQs, exacerbates the challenges of question production, and highlights the need for innovative solutions.Several groups have shown that it is practical to leverage the student cohort to produce a very large number of syllabus-aligned MCQs for study banks. Although student-generated questions are well suited for formative feedback and practice activities, they are generally not thought to be suitable for high-stakes assessments. In this study, we aimed to demonstrate that training can be provided to students in a scalable fashion to generate questions of similar quality to those produced by experts, and that identification of suitable questions can be achieved with minimal academic review and editing.Biochemistry and Molecular Biology students were assigned a series of activities designed to coach them in the art of writing and critiquing MCQs. This training resulted in the production of over one thousand MCQs that were then gauged for potential by either expert academic judgement, or via a data-driven approach in which the questions were trialled objectively in a low-stakes test. Questions selected by either method were then deployed in a high-stakes in-semester assessment alongside questions from two academically authored sources: textbook-derived MCQs, and past paper questions.A total of 120 MCQs from these four sources were deployed in assessments attempted by over 600 students. Each question was subjected to rigorous performance analysis, including the calculation of standard metrics from classical test theory and more sophisticated Item Response Theory (IRT) measures. The results showed that MCQs authored by students and selected at low cost performed as well as questions authored by academics, illustrating the potential of this strategy for the efficient creation of large numbers of high quality MCQs for summative assessment.
Rapid detection of SARS-CoV-2 by pulse-controlled amplification (PCA)
Authors: Katrin Zwirglmaier , Maria Weyh , Christian Krüger , Rosina Ehmann , Katharina Müller , Roman Wölfel , Kilian Stoecker 
Published: July 2020

AbstractIn the current pandemic of SARS-CoV-2, rapid identification of infected individuals is crucial for management and control of the outbreak. However, transport of samples, sample processing and RT-qPCR analysis in laboratories are time-consuming. Here we present a nucleic acid-based test format – pulse controlled amplification – that allows detection of SARS-CoV-2 directly from up to eight swab samples simultaneously without the need for RNA extraction within 20 min in a point-of-care setting.
A blueprint for academic labs to produce SARS-CoV-2 RT-qPCR test kits
Authors: Mascuch Samantha J. , Fakhretaha-Aval Sara , Bowman Jessica C. , Ma Minh Thu H. , Thomas Gwendell , Bommarius Bettina , Ito Chieri , Zhao Liangjun , Newnam Gary P. , Matange Kavita R. , Thapa Hem R. , Barlow Brett , Donegan Rebecca K. , Nguyen Nguyet A. , Saccuzzo Emily G. , Obianyor Chiamaka T. , Karunakaran Suneesh C. , Pollet Pamela , Rothschild-Mancinelli Brooke , Mestre-Fos Santi , Guth-Metzler Rebecca , Bryksin Anton V. , Petrov Anton S. , Hazell Mallory , Ibberson Carolyn B. , Penev Petar I. , Mannino Robert G. , Lam Wilbur A. , Garcia Andrés J. , Kubanek Julia M. , Agarwal Vinayak , Hud Nicholas V. , Glass Jennifer B. , Williams Loren Dean , Lieberman Raquel L. 
Published: July 2020

AbstractWidespread testing for the presence of the novel coronavirus SARS-CoV-2 in individuals remains vital for controlling the COVID-19 pandemic prior to the advent of an effective treatment. Challenges in testing can be traced to an initial shortage of supplies, expertise and/or instrumentation necessary to detect the virus by quantitative reverse transcription polymerase chain reaction (RT-qPCR), the most robust, sensitive, and specific assay currently available. Here we show that academic biochemistry and molecular biology laboratories equipped with appropriate expertise and infrastructure can replicate commercially available SARS-CoV-2 RT-qPCR test kits and backfill pipeline shortages. The Georgia Tech COVID-19 Test Kit Support Group, composed of faculty, staff, and trainees across the biotechnology quad at Georgia Institute of Technology, synthesized multiplexed primers and probes and formulated a master mix composed of enzymes and proteins produced in-house. Our in-house kit compares favorably to a commercial product used for diagnostic testing. We also developed an environmental testing protocol to readily monitor surfaces across various campus laboratories for the presence of SARS-CoV-2. Our blueprint should be readily reproducible by research teams at other institutions, and our protocols may be modified and adapted to enable SARS-CoV-2 detection in more resource-limited settings.
Tocilizumab shortens time on mechanical ventilation and length of hospital stay in patients with severe COVID-19: a retrospective cohort study
Authors: Eimer Johannes , Vesterbacka Jan , Svensson Anna-Karin , Stojanovic Bertil , Wagrell Charlotta , Sönnerborg Anders , Nowak Piotr 
Published: July 2020

BackgroundHyperinflammation is a key feature of the pathogenesis of COVID-19 with a central role of the interleukin-6 pathway. We aimed to study the impact of the IL-6 receptor antagonist tocilizumab on the outcome of patients admitted to the intensive care unit (ICU) with acute respiratory distress syndrome (ARDS) related to COVID-19.MethodsEighty-seven patients with confirmed SARS-CoV-2 infection and moderate to severe ARDS were included (n tocilizumab = 29, n controls = 58). A matched cohort was created using a propensity score. The primary endpoint was 30-day all-cause mortality, secondary endpoints included ventilation-free days and length of stay.ResultsNo difference was found in 30-day all-cause mortality in patients treated with tocilizumab compared to controls (17.2% vs. 32.8%, p = 0.2; HR = 0.52 [0.19 - 1.39], p = 0.19). Ventilator-free days were 19.0 (IQR 12.5 - 20.0) versus 9 (IQR 0.0 - 18.5; p = 0.04), respectively. A higher rate of freedom from mechanical ventilation at 30 days was achieved in patients receiving tocilizumab (HR 2.83 [1.48 - 5.40], p < 0.002). Median length of stay in ICU and total length of stay were reduced by 8 and 9.5 days in patients treated with tocilizumab. Similar results were obtained in the analysis of the propensity score matched cohort.ConclusionsTreatment of critically ill patients with ARDS due to COVID-19 with tocilizumab was not associated with reduced 30-day all-cause mortality, but shorter duration on ventilatory support as well as shorter overall length of stay in hospital and in ICU.
Disease severity dictates SARS-CoV-2-specific neutralizing antibody responses in COVID-19
Authors: Chen Xiangyu , Pan Zhiwei , Yue Shuai , Yu Fei , Zhang Junsong , Yang Yang , Li Ren , Liu Bingfeng , Yang Xiaofan , Gao Leiqiong , Li Zhirong , Lin Yao , Huang Qizhao , Xu Lifan , Tang Jianfang , Hu Li , Zhao Jing , Liu Pinghuang , Zhang Guozhong , Chen Yaokai , Deng Kai , Ye Lilin 
Published: July 2020

AbstractCOVID-19 patients exhibit differential disease severity after SARS-CoV-2 infection. It is currently unknown as to the correlation between the magnitude of neutralizing antibody (NAb) responses and the disease severity in COVID-19 patients. In a cohort of 59 recovered patients with disease severity including severe, moderate, mild and asymptomatic, we observed the positive correlation between serum neutralizing capacity and disease severity, in particular, the highest NAb capacity in sera from the patients with severe disease, while a lack of ability of asymptomatic patients to mount competent NAbs. Furthermore, the compositions of NAb subtypes were also different between recovered patients with severe symptoms and with mild-to-moderate symptoms. These results reveal the tremendous heterogeneity of SARS-CoV-2-specific NAb responses and their correlations to disease severity, highlighting the needs of future vaccination in COVID-19 patients recovered from asymptomatic or mild illness.
On the Digital Psychopharmacology of Valproic Acid in Mice
Authors: Bass John Samuel , Tuo Anney , Ton Linh , Jankovic Miranda J. , Kapadia Paarth K. , Schirmer Catharina , Krishnan Vaishnav 
Published: July 2020

AbstractObjectiveAntiepileptic drugs (AEDs) require daily ingestion for maximal seizure prophylaxis. Adverse psychiatric consequences of AEDs present as: (i) reversible changes in mood, anger, anxiety and/or irritability that often necessitate drug discontinuation, and (ii) autism and/or cognitive/psychomotor developmental delays following fetal exposure. Technical advances in quantifying naturalistic rodent behaviors may provide sensitive preclinical estimates of AED psychiatric tolerability and neuropsychiatric teratogenicity.MethodsUsing instrumented home-cage monitoring, we assessed how valproic acid (VPA, dissolved in sweetened drinking water) alters home-cage behavior in adult C57BL/6J mice and in the adult offspring of VPA-exposed breeder pairs. By utilizing a pup open field assay, we also examined how prenatal VPA exposure impacts early spontaneous exploratory behavior.ResultsAt 500-600mg/kg/d, chronic VPA produced hyperphagia and increased wheel-running without impacting sleep, activity and measures of risk aversion. When applied chronically to breeder pairs of mice, VPA prolonged the latency to viable litters without affecting litter size. Two-week old VPA-exposed pups displayed open field hypoactivity without alterations in thigmotaxis. As adults, prenatal VPA-exposed mice displayed active state fragmentation, hypophagia and increased wheel running, together with subtle alterations in home-cage dyadic behavior.InterpretationThrough automated home-cage assessments of C57BL/6J mice, we capture an ethologically centered psychopharmacological profile of enterally administered VPA that is aligned with human clinical experience. By characterizing the effects of pangestational VPA exposure, we discover novel murine expressions of pervasive neurodevelopment. Incorporating rigorous comprehensive assessments of neuropsychiatric tolerability may inform the design of future AEDs with improved neuropsychiatric safety profiles, both for patients and their offspring.
The malaria metabolite HMBPP does not trigger erythrocyte terpene production
Authors: Miller Justin J. , Odom John Audrey R. 
Published: July 2020

AbstractInfection with malarial parasites renders hosts more mosquito attractive than their uninfected, healthy, counterparts. One volatile organic compound, α-pinene, is associated withPlasmodiumspp. infection in multiple studies and is a known mosquito attractant. However, how malarial infection results in elevated levels of host-associated α-pinene remains unclear. One study suggests that erythrocyte exposure to the malarial metabolite, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), results in increased levels of α-pinene. Here, we establish that endogenous levels of α-pinene are present in human erythrocytes, that these levels vary widely by erythrocyte donor, and that α-pinene levels are not altered by HMBPP treatment.
Generation of nonhuman primate retinitis pigmentosa model byin situknockout ofRHOin rhesus macaque retina
Authors: Li Shouzhen , Hu Yingzhou , Li Yunqin , Hu Min , Wang Wenchao , Ma Yuqian , Cai Yuan , Wei Min , Yao Yichuan , Wang Yun , Dong Kai , Gu Yonghao , Zhao Huan , Bao Jin , Qiu Zilong , Zhang Mei , Hu Xintian , Xue Tian 
Published: July 2020

AbstractRetinitis pigmentosa (RP) is a form of inherited retinal degenerative disease that ultimately involves the macula, which is present in primates but not in the rodents. Therefore, creating nonhuman primate (NHP) models of RP is of critical importance to study its mechanism of pathogenesis and to evaluate potential therapeutic options in the future. Here we applied adeno-associated virus (AAV)-delivered CRISPR/SaCas9 technology to knockout theRHOgene in the retinae of the adult rhesus macaque (Macaca mulatta) to investigate the hypothesis whether non-germline mutation of theRHOgene is sufficient to recapitulate RP. Through a series of studies, we were able to demonstrate successful somatic editing of theRHOgene and reduced RHO protein expression. More importantly, the mutant macaque retinae displayed clinical RP phenotypes, including photoreceptor degeneration, retinal thinning, abnormal rod subcellular structures, and reduced photoresponse. Therefore, we suggest somatic editing of theRHOgene is able to phenocopy RP, and the reduced time span in generating NHP mutant accelerates RP research and expands the utility of NHP model for human disease study.
E-cigarettes compromise the gut barrier and trigger gut inflammation
Authors: Sharma Aditi , Lee Jasper , Fonseca Ayden G. , Moshensky Alex , Kothari Taha , Sayed Ibrahim M. , Ibeawuchi Stella-Rita , Pranadinata Rama F. , Ear Jason , Sahoo Debashis , Crotty-Alexander Laura E. , Ghosh Pradipta , Das Soumita 
Published: July 2020

ABSTRACTE-cigarette and vaping device use continue to rise, particularly in adolescents and young adults, but the safety of inhaling the multitude of chemicals within e-cigarette aerosols has been questioned. While several studies have evaluated vaping effects on the lungs and heart; effects on the gastrointestinal tract remain unknown. Using established murine models of acute (1 week) and chronic (3 month) daily e-cigarette aerosol inhalation, both with nicotine-containing and vehicle control e-liquids, murine colon transcriptomics and organoid co-culture models, we assessed the effects of e-cigarette use on the gut barrier and mucosal health. Histologic analyses revealed that chronic exposure to nicotine-free e-cigarette aerosols induced mucosal inflammation. Transcriptome analyses revealed that chronic, but not acute, nicotine-free e-cigarette use significantly reduced expression of tight junction markers, including occluding, and drove expression of pro-inflammatory cytokines. Exposure of murine and human enteroid-derived monolayers (EDMs) to nicotine-free e-cigarette aerosols alone, or in co-culture with invasiveE. coli,confirmed that repetitive exposure was sufficient to recapitulate the key findings observedin vivo, i.e., barrier-disruption, downregulation of occludin, inflammation, and an accentuated risk of and response to bacterial infection. These data highlight an unexpected harmful effect of e-cigarette use on the gut barrier and pinpoint non-nicotine chemical components common across >90% of e-cigarette e-liquids as the source of harm. Given the ever-expanding importance of the integrity of the gut barrier for host fitness, and impact of gut mucosal inflammation on a multitude of chronic diseases, these findings are broadly relevant to medicine and public health.SIGNIFICANCEThe safety of electronic cigarettes has been questioned amidst emerging evidence that they may derail our immune system and increase our susceptibility to infections. Despite these insights, their impact on the most critical entity that separates trillions of microbes from the largest immune system in our body, i.e., the gut barrier, remains unexplored. Using a combination of mouse models, gut transcriptomics, and murine and human gut-derived organoids, here we show that chronic exposure to aerosols of electronic-cigarette disrupts the gut barrier, increases its susceptibility to bacterial infections and triggers inflammation. Given the importance of the gut barrier in the maintenance of immune homeostasis, these findings provide valuable insights into the potential long-term harmful effects of electronic cigarettes on health.
Signatures of neutral evolution in exponentially growing tumors: a theoretical perspective
Authors: Tung Hwai-Ray , Durrett Rick 
Published: July 2020

AbstractWe investigate the site frequency spectrum in the two-type model of clonal evolution. If the fitnesses of the two types are λ0< λ1then the site frequency spectrum isc/fαwhereα= λ0/λ1. This is due to the advantageous mutations that produce the founders of the type 1 population. Mutations within the growing type 0 and type 1 populations follow the 1/flaw. Our results show that neutral evolution can be distinguished from the two-type model using the site frequency spectrum.
SARS-CoV-2 Spike Protein Interacts with Multiple Innate Immune Receptors
Authors: Gao Chao , Zeng Junwei , Jia Nan , Stavenhagen Kathrin , Matsumoto Yasuyuki , Zhang Hua , Li Jiang , Hume Adam J. , Mühlberger Elke , van Die Irma , Kwan Julian , Tantisira Kelan , Emili Andrew , Cummings Richard D. 
Published: July 2020

AbstractThe spike (S) glycoprotein in the envelope of SARS-CoV-2 is densely glycosylated but the functions of its glycosylation are unknown. Here we demonstrate that S is recognized in a glycan-dependent manner by multiple innate immune receptors including the mannose receptor MR/CD206, DC-SIGN/CD209, L-SIGN/CD209L, and MGL/CLEC10A/CD301. Single-cell RNA sequencing analyses indicate that such receptors are highly expressed in innate immune cells in tissues susceptible to SARS-CoV-2 infection. Binding of the above receptors to S is characterized by affinities in the picomolar range and consistent with S glycosylation analysis demonstrating a variety of N- and O-glycans as receptor ligands. These results indicate multiple routes for SARS-CoV-2 to interact with human cells and suggest alternative strategies for therapeutic intervention.
Noise regularization removes correlation artifacts in single-cell RNA-seq data preprocessing
Authors: Zhang Ruoyu , Atwal Gurinder S. , Lim Wei Keat 
Published: July 2020

AbstractWith the rapid advancement of single-cell RNA-seq (scRNA-seq) technology, many data preprocessing methods have been proposed to address numerous systematic errors and technical variabilities inherent in this technology. While these methods have been demonstrated to be effective in recovering individual gene expression, the suitability to the inference of gene-gene associations and subsequent gene networks reconstruction have not been systemically investigated. In this study, we benchmarked five representative scRNA-seq normalization/imputation methods on human cell atlas bone marrow data with respect to their impact on inferred gene-gene associations. Our results suggested that a considerable amount of spurious correlations was introduced during the data preprocessing steps due to over-smoothing of the raw data. We proposed a model-agnostic noise regularization method that can effectively eliminate the correlation artifacts. The noise regularized gene-gene correlations were further used to reconstruct gene co-expression network and successfully revealed several known immune cell modules.
A Next Generation Bivalent Human Ad5 COVID-19 Vaccine Delivering Both Spike and Nucleocapsid Antigens Elicits Th1 Dominant CD4+, CD8+ T-cell and Neutralizing Antibody Responses
Authors: Rice Adrian , Verma Mohit , Shin Annie , Zakin Lise , Sieling Peter , Tanaka Shiho , Adisetiyo Helty , Taft Justin , Patel Rosheel , Buta Sofija , Martin-Fernandez Marta , Morimoto Brett , Gabitzsch Elizabeth , Safrit Jeffrey T. , Balint Joseph , Dinkins Kyle , Spilman Patricia , Bogunovic Dusan , Rabizadeh Shahrooz , Niazi Kayvan , Soon-Shiong Patrick 
Published: July 2020

ABSTRACTIn response to the health crisis presented by the COVID-19 pandemic, rapid development of safe and effective vaccines that elicit durable immune responses is imperative. Recent reports have raised the concern that antibodies in COVID-19 convalescent patients may not be long lasting and thus even these individuals may require vaccination. Vaccine candidates currently in clinical testing have focused on the SARS-CoV-2 wild type spike (S) protein (S-WT) as the major antigen of choice and while pre-clinical and early clinical testing have shown that S elicits an antibody response, we believe the optimal vaccine candidate should be capable of inducing robust, durable T-cell responses as well as humoral responses. We report here on a next generation bivalent human adenovirus serotype 5 (hAd5) vaccine capable of inducing immunity in patients with pre-existing adenovirus immunity, comprisingbothan S sequence optimized for cell surface expression (S-Fusion) and a conserved nucleocapsid (N) antigen designed to be transported to the endosomal subcellular compartment, with the potential to generate durable immune protection. Our studies suggest that this bivalent vaccine is optimized for immunogenicity as evidenced by the following findings: (i) The optimized S-Fusion displayed improved S receptor binding domain (RBD) cell surface expression compared to S-WT where little surface expression was detected; (ii) the expressed RBD from S-Fusion retained conformational integrity and recognition by ACE2-Fc; (iii) the viral N protein modified with an enhanced T-cell stimulation domain (ETSD) localized to endosomal/lysosomal subcellular compartments for MHC I/II presentation; and (iv) these optimizations to S and N (S-Fusion and N-ETSD) generated enhancedde novoantigen-specific B cell and CD4+ and CD8+ T-cell responses in antigen-naive pre-clinical models. Both the T-cell and antibody immune responses to S and N demonstrated a T-helper 1 (Th1) bias. The antibody responses were neutralizing as demonstrated by two independent SARS-CoV-2 neutralization assays. Based on these findings, we are advancing this next generation bivalent hAd5 S-Fusion + N-ETSD vaccine as our lead clinical candidate to test for its ability to provide robust, durable cell-mediated and humoral immunity against SARS-CoV-2 infection. Further studies are ongoing to explore utilizing this vaccine construct in oral, intranasal, and sublingual formulations to induce mucosal immunity in addition to cell-mediated and humoral immunity. The ultimate goal of an ideal COVID-19 vaccine is to generate long-term T and B cell memory.
Cullin3 promotes stem cell progeny differentiation by facilitating aPKC-directed asymmetric Numb localization
Authors: Komori Hideyuki , Rives-Quinto Noemi , Han Xu , Anhezini Lucas , Esrig Ari J. , Skeath James B. , Lee Cheng-Yu 
Published: July 2020

SummaryAsymmetric segregation of Numb is a conserved mechanism for regulating Notch-mediated binary cell fate decisions; however, the mechanisms controlling Numb segregation remain unclear. Previous studies have proposed an “exclusion” model, suggesting that atypical protein kinase C (aPKC) negatively regulates Numb cortical localization. Here, we report that aPKC kinase activity positively promotes basal cortical Numb localization during asymmetric division ofDrosophilaneural stem cells (neuroblasts) and that Cullin 3 (Cul3) is required for aPKC-directed basal Numb localization. Innumb-orcul3-mutant brains, decreased levels of Numb segregated into neuroblast progeny failed to downregulate Notch, leading to supernumerary neuroblast formation. Increased aPKC kinase activity suppressed supernumerary neuroblast formation by concentrating residual Numb protein at the basal cortex and in neuroblast progeny, whereas decreased aPKC function enhanced the supernumerary neuroblast phenotype by reducing basal Numb levels. We propose that aPKC and Cul3 promote basal Numb localization, which is required to downregulate Notch signaling and promote differentiation in neuroblast progeny.