bluuebunny/crossref_metadata_2025 huggingface dataset:
Insights into The Codon Usage Bias of 13 Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Isolates from Different Geo-locations
Authors: Khodary Saif M. , Anwar Ali Mostafa
Published: April 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus disease 2019 (COVID-19) which is an infectious disease that spread throughout the world and was declared as a pandemic by the World Health Organization (WHO). In this study, we performed a genome-wide analysis on the codon usage bias (CUB) of 13 SARS-CoV-2 isolates from different geo-locations (countries) in an attempt to characterize it, unravel the main force shaping its pattern, and understand its adaptation toHomo sapiens. Overall results revealed that, SARS-CoV-2 codon usage is slightly biased similarly to other RNA viruses. Nucleotide and dinucleotide compositions displayed a bias toward A/U content in all codon positions and CpU-ended codons preference, respectively. Eight common putative preferred codons were identified, and all of them were A/U-ended (U-ended: 7, A-ended: 1). In addition, natural selection was found to be the main force structuring the codon usage pattern of SARS-CoV-2. However, mutation pressure and other factors such as compositional constraints and hydrophobicity had an undeniable contribution. Two adaptation indices were utilized and indicated that SARS-CoV-2 is moderately adapted toHomo sapienscompared to other human viruses. The outcome of this study may help in understanding the underlying factors involved in the evolution of SARS-CoV-2 and may aid in vaccine design strategies.
The role of thickness inhomogeneities in hierarchical cortical folding
Authors: da Costa Campos Lucas , Hornung Raphael , Gompper Gerhard , Elgeti Jens , Caspers Svenja
Published: April 2020

The morphology of the mammalian brain cortex is highly folded. For long it has been known that specific patterns of folding are necessary for an optimally functioning brain. On the extremes, lissencephaly, a lack of folds in humans, and polymicrogyria, an overly folded brain, can lead to severe mental retardation, short life expectancy, epileptic seizures, and tetraplegia. The construction of a quantitative model on how and why these folds appear during the development of the brain is the first step in understanding the cause of these conditions. In recent years, there have been various attempts to understand and model the mechanisms of brain folding. Previous works have shown that mechanical instabilities play a crucial role in the formation of brain folds, and that the geometry of the fetal brain is one of the main factors in dictating the folding characteristics. However, modeling higher-order folding, one of the main characteristics of the highly gyrencephalic brain, has not been fully tackled. The effects of thickness inhomogeneity in the gyrogenesis of the mammalian brain are studiedin silico. Finite-element simulations of rectangular slabs are performed. The slabs are divided into two distinct regions, where the outer layer mimics the gray matter, and the inner layer the underlying white matter. Differential growth is introduced by growing the top layer tangentially, while keeping the underlying layer untouched. The brain tissue is modeled as a neo-Hookean hyperelastic material. Simulations are performed with both, homogeneous and inhomogeneous cortical thickness. The homogeneous cortex is shown to fold into a single wavelength, as is common for bilayered materials, while the inhomogeneous cortex folds into more complex conformations. In the early stages of development of the inhomogeneous cortex, structures reminiscent of the deep sulci in the brain are obtained. As the cortex continues to develop, secondary undulations, which are shallower and more variable than the structures obtained in earlier gyrification stage emerge, reproducing well-known characteristics of higher-order folding in the mammalian, and particularly the human, brain.
Assessment of a weak mode of bacterial adhesion by applying an electric field
Authors: Araujo George , Zheng Joy , Oh Jae Jong , Tang Jay X.
Published: April 2020

Microbial attachment to surfaces is ubiquitous in nature. Most species of bacteria attach and adhere to surfaces via special appendages such as pili and fimbriae, the roles of which have been extensively studied. Here we report an experiment on pilus-less mutants ofCaulobacter crescentusweakly attached to a plastic surface and subjected to an electric field parallel to the surface. We find that some individual cells transiently but repeatedly adhere to the surface in a stick-slip fashion in the presence of an electric field. Even while transiently detached, these bacteria move significantly slower than the unattached ones in the same field of view undergoing electrophoretic motion. We refer this behavior of repeated and transient attachment as “quasi-attachment”. The speed of the quasi-attached bacteria exhibits large variations, frequently dropping close to zero for short intervals of time. This study suggests applying electric field as a useful method to investigate bacteria-surface interaction, which is significant in broader contexts such as infection and environmental control.

Significance

Interaction between bacteria and surfaces occur widely in nature, including those in industrial, environmental, and medical settings. It is therefore important to understand various mechanisms and factors that affect numerous forms of bacterium-surface interaction, particularly those resulting in adhesion or attachment, be they strong or weak, permanent or transient. This work takes a unique approach to identify a transient and reversible mode of bacterial attachment to a solid surface, by applying an electric field to exert a force for detachment. The force thus exerted proves to reach the amplitude required to detach bacteria of a pilus-less strain that weakly attach to a plastic surface. The method may be applied broadly to investigate bacteria-surface interaction.
Multiple lineages, same molecular basis: task specialization is commonly regulated across all eusocial bee groups
Authors: de Souza Araujo Natalia , Arias Maria Cristina
Published: April 2020

A striking feature of advanced insect societies is the existence of workers that forgo reproduction. Two broad types of workers exist in eusocial bees: nurses which care for their young siblings and the queen, and foragers who guard the nest and forage for food. Comparisons between this two worker subcastes have been performed in honeybees, but data from other bees are scarce. To understand whether similar molecular mechanisms are involved in nurse-forager differences across distinct species, we compared gene expression and DNA methylation profiles between nurses and foragers of the buff-tailed bumblebeeBombus terrestrisand of the stingless beeTetragonisca angustula. These datasets were then discussed comparatively to previous findings on honeybees. Our analyses revealed that although the expression pattern of genes is often species-specific, many of the biological processes and molecular pathways involved are common. Moreover, DNA methylation and gene expression correlation were dependent on the nucleotide context.
RDoC Mechanisms of Transdiagnostic Polygenic Risk for Trajectories of Depression: From Early Adolescence to Adulthood
Authors: Li James J. , Zhang Qi , Lu Qiongshi
Published: April 2020

There is substantial heterogeneity in the development of depression across early adolescence into adulthood. Yet, little is known about the risk factors underlying individual differences in the development of depression. For instance, despite the discovery of genetic variants for depression, there is also significant genetic overlap between depression and other mental disorders. Thus, depression may have etiologically complex (i.e., transdiagnostic) origins when accounting for its heterogeneous developmental presentations. This study examined the association between a transdiagnostic polygenic score for psychopathology (p-factor PGS) and depressive trajectories, spanning early adolescence into adulthood, in the National Longitudinal Study of Adolescent to Adult Health. We also examined whether the Research Domains Criteria (RDoC) negative valence (i.e., negative emotionality), positive valence (i.e., novelty seeking), and cognitive systems (i.e., picture vocabulary) could explain how thep-factor PGS eventuates into the various pathways of depressive development. Four trajectories of depression were identified:low depression(78.9%), low increasing(7.3%), high declining(8.2%), andearly adult peaked(5.7%). Thep-factor PGS was only associated with the trajectory that showed increasing depression over time –low increasing.There was also a specific indirect effect by which the association ofp-factor PGS onearly adult peakedandhigh decliningdepression was partially mediated by negative emotionality, but not by picture vocabulary or novelty seeking. Our findings reinforce the crucial role of development in genetically-informed RDoC models of depression, as there appear to be distinct correlates and risk factors that underlie the various developmental pathways of depression. Clinical implications were also discussed.

General Scientific Summary

There are individual differences in how depression symptoms progress over time, but little is known about the risk factors that underlie these various patterns of development. This study suggests that there are distinct correlates and risk factors that underlie the various developmental pathways of depression. We found that transdiagnostic polygenic risks for psychopathology are directly associated with worsening patterns of adolescent to adult depression and indirectly associated with the less severe patterns of depression via negative emotionality.
Structure of the Visual Signaling Complex between Transducin and Phosphodiesterase 6
Authors: Gao Yang , Eskici Gözde , Ramachandran Sekar , Poitevin Frédéric , Seven Alpay Burak , Panova Ouliana , Skiniotis Georgios , Cerione Richard A.
Published: April 2020

Heterotrimeric G proteins communicate signals from activated G protein-coupled receptors to downstream effector proteins. In the phototransduction pathway responsible for vertebrate vision, the G protein-effector complex is comprised of the GTP-bound transducin α subunit (GαT·GTP) and the cyclic GMP (cGMP) phosphodiesterase 6 (PDE6), which stimulates cGMP hydrolysis to transmit signals to the optic nerve. Here we report a cryo-electron microscopy (cryoEM) structure of PDE6 complexed to GTP-bound GαT. The structure reveals two GαT·GTP subunits engaging the PDE6 hetero-tetramer at both the PDE6 catalytic core and the PDEγ subunits, driving extensive rearrangements to relieve all inhibitory constraints on enzyme catalysis. Analysis of the conformational ensemble in the cryoEM data highlights the dynamic nature of the contacts between the two GαT·GTP subunits and PDE6 that support an alternating-site catalytic mechanism.
VISTA: Virtual ImmunoSTAining for pancreatic disease quantification in murine cohorts
Authors: Ternes Luke , Huang Ge , Lanciault Christian , Thibault Guillaume , Riggers Rachelle , Gray Joe W. , Muschler John , Chang Young Hwan
Published: April 2020

Mechanistic studies of pancreatic disease progression using animal models require objective and quantifiable assessment of tissue changes among animal cohorts. Disease state quantification, however, relies heavily on tissue immunostaining, which can be expensive, labor- and time-intensive, and all too often produces uneven staining that is prone to variable interpretation between experts and inaccurate quantification. Here we develop a fully automated semantic segmentation tool using deep learning for the rapid and objective quantification of histologic features using hematoxylin and eosin (H&E) stained pancreatic tissue sections acquired from murine pancreatic cancer models. The tool was successfully trained to segment and quantify multiple histopathologic features of pancreatic pre-cancer evolution, including normal acinar structures, the ductal phenotype of acinar-to ductal metaplasia (ADM), dysplasia, and the expanding stromal compartment. Disease quantifications produced by our computational tool were highly correlated to the results obtained by immunostaining markers of normal and diseased tissue (DAPI, amylase, and cytokeratins; correlation score= 0.9, 0.95, and 0.91, respectively) and were able to accurately reproduce immunostain patterns. Moreover, our tool was able to distinguish ADM from dysplasia, which are not reliably distinguished by immunostaining, and avoid the pitfalls of uneven or poor-quality staining. Using this tool, we quantified the changes in histologic feature abundance for murine cohorts with oncogenic Kras-driven disease at 2 months and 5 months of age (n=12, n=13). The calculated changes in histologic feature abundance were consistent with biological expectations, showing an expansion of the stromal compartment, a reduction of normal acinar tissue, and an increase in both ADM and dysplasia as disease progresses (p= 2e-6, 6e-7, 4e-4, and 3e-5, respectively). These results demonstrate the tool’s efficacy for accurate and rapid quantification of multiple histologic features using an objective and automated platform. Our tool promises to rapidly accelerate and improve the quantification of altered pancreatic disease progression in animal studies.
LxxIxE-like Motif in Spike Protein of SARS-CoV-2 that is Known to Recruit the Host PP2A-B56 Phosphatase Mimics Artepillin C, an Immunomodulator, of Brazilian Green Propolis
Authors: Maaroufi Halim
Published: April 2020

SARS-CoV-2 is highly contagious and can cause acute respiratory distress syndrome (ARDS) and multiple organ failure that are largely attributed to the cytokine storm. The surface coronavirus spike (S) glycoprotein is considered as a key factor in host specificity because it mediates infection by receptor-recognition and membrane fusion. Here, the analysis of SARS-CoV-2 S protein revealed two B56-binding LxxIxE-like motifs in S1 and S2 subunits that could recruit the host protein phosphatase 2A (PP2A). The motif in S1 subunit is absent in SARS-CoV and MERS-CoV. Phosphatases and kinases are major players in the regulation of pro-inflammatory responses during pathogenic infections. Moreover, studies have shown that viruses target PP2A in order to manipulate host’s antiviral responses. Recent researches have indicated that SARS-CoV-2 is involved in sustained host inflammation. Therefore, by controlling acute inflammation, it is possible to eliminate its dangerous effects on the host. Among efforts to fight COVID-19, the interaction between LxxIxE-like motif and the PP2A-B56-binding pocket could be a target for the discovery and/or development of a bioactive ligand inhibitor for therapeutic purposes. Indeed, a small molecule called Artepillin C (ArtC), a main compound in Brazilian honeybee green propolis, mimics the side chains of LxxLxE motif. Importantly, ArtC is known, among other effects, to have anti-inflammatory activity that makes it an excellent candidate for future clinical trials in COVID-19 patients.
Deducing the N- and O- glycosylation profile of the spike protein of novel coronavirus SARS-CoV-2
Authors: Shajahan Asif , Supekar Nitin T. , Gleinich Anne S. , Azadi Parastoo
Published: April 2020

The current emergence of the novel coronavirus pandemic caused by SARS-CoV-2 demands the development of new therapeutic strategies to prevent rapid progress of mortalities. The coronavirus spike (S) protein, which facilitates viral attachment, entry and membrane fusion is heavily glycosylated and plays a critical role in the elicitation of the host immune response. The spike protein is comprised of two protein subunits (S1 and S2), which together possess 22 potential N-glycosylation sites. Herein, we report the glycosylation mapping on spike protein subunits S1 and S2 expressed on human cells through high resolution mass spectrometry. We have characterized the quantitative N-glycosylation profile on spike protein and interestingly, observed unexpected O-glycosylation modifications on the receptor binding domain (RBD) of spike protein subunit S1. Even though O-glycosylation has been predicted on the spike protein of SARS-CoV-2, this is the first report of experimental data for both the site of O-glycosylation and identity of the O-glycans attached on the subunit S1. Our data on the N- and O-glycosylation is strengthened by extensive manual interpretation of each glycopeptide spectra in addition to using bioinformatics tools to confirm the complexity of glycosylation in the spike protein. The elucidation of the glycan repertoire on the spike protein provides insights into the viral binding studies and more importantly, propels research towards the development of a suitable vaccine candidate.
modleR: a modular workflow to perform ecological niche modeling in R
Authors: Sánchez-Tapia Andrea , Mortara Sara Ribeiro , Bezerra Rocha Diogo Souza , Mendes Barros Felipe Sodré , Gall Guilherme , de Siqueira Marinez Ferreira
Published: April 2020

Ecological niche models (ENM) use the environmental variables associated with the currently known distribution of a species to model its ecological niche and project it into the geographic space. Widely used and misused, ENM has become a common tool for ecologists and decision-makers.

Many ENM platforms have been developed over the years, first as standalone programs, later as packages within script-based programming languages and environments. The democratization of these programming tools and the advent of Open Science brought a growing concern regarding the reproducibility, transparency, robustness, portability, and interoperability in ENM workflows.

ENM workflows have some core components that are replicated between projects. However, they have a large internal variation due to the variety of research questions and applications. Any ecological niche modeling platform should take into account this trade-off between stability and reproducibility on one hand, and flexibility and decision-making on the other.

Here, we presentmodleR, a four-step workflow that wraps some of the common phases executed during an ecological niche model procedure. We have divided the process into (1) data setup, (2) model fitting and projection, (3) partition joining and (4) ensemble modeling (consensus between algorithms).

modleRis highly adaptable and replicable depending on the user’s needs and is open to deeper internal parametrization. It can be used as a testing platform due to its consistent folder structure and its capacity to control some sources of variation while changing others. It can be run in interactive local sessions and in high-performance or high-throughput computational (HPC/HTC) platforms and parallelized by species or algorithms. It can also communicate with other tools in the field, allowing the user to enter and exit the workflow at any phase, and execute complementary routines outside the package. Finally, it records metadata and session information at each step, ensuring reproducibility beyond the use of script-based applications.
Lessons from the analysis of TAD boundary deletions in normal population
Authors: Smol Thomas , Sigé Jérôme , Thuillier Caroline , Frénois Frédéric , Brunelle Perrine , Rama Mélanie , Roche-Lestienne Catherine , Manouvrier-Hanu Sylvie , Petit Florence , Ghoumid Jamal
Published: April 2020

Topologically Associating Domains (TAD)-boundaries induce spatial constraints, allowing interaction between regulatory elements and promoters only within their TAD. Their disruption could lead to disease, through gene-expression deregulation. This mechanism has been shown in only a relatively low number of diseases and a relatively low proportion of patients, raising the possibility of TAD boundary disruption without phenotypical consequence. We investigated, therefore, the occurrence of TAD boundaries disruption in the general population. Coordinates of 307,430 benign deletions from public databases were crossed with 36 Hi-C datasets. Differences in gene content and gene localization were compared in the TADs, according to the possible disruption of their boundaries by a deletion found in the general population. TADs with no deletion encompassing their boundaries (R-TAD) represented 38% of TADs. Enrichment in OMIM genes as well as in morbid genes was observed in R-TADs and genes in R-TADs were found to localize closer to the boundaries. Our results support recent publications tempering the impact of breaking TADs on gene expression with a majority of broken TADs in the general population. A subgroup of R-TAD emerges from this analysis with enrichment in disease genes and their coordinates could be used to annotate CNV from pangenomic approaches to enhance data interpretation.
IL-6 signalling pathway inactivation with siltuximab in patients with COVID-19 respiratory failure: an observational cohort study
Authors: Gritti Giuseppe , Raimondi Federico , Ripamonti Diego , Riva Ivano , Landi Francesco , Alborghetti Leonardo , Frigeni Marco , Damiani Marianna , Micò Caterina , Fagiuoli Stefano , Cosentini Roberto , Lorini Ferdinando Luca , Gandini Lucia , Novelli Luca , Morgan Jonathan P , Owens Benjamin M J , Kanhai Karan J K , Reljanovic Gordana Tonkovic , Rizzi Marco , Di Marco Fabiano , Rambaldi Alessandro
Published: April 2020

Background

Severe COVID-19 is characterised by interstitial pneumonia and hyperinflammation, with elevated levels of pro-inflammatory cytokines, such as IL-6. Effective treatments are urgently needed, and IL-6 is a rational target to reduce hyperinflammation.

Methods

An observational, control cohort, single-centre study initiated at the Papa Giovanni XXIII Hospital in Bergamo, Italy included patients with COVID-19 confirmed by a nasopharyngeal swab positive for severe acute respiratory syndrome coronavirus 2 RNA and interstitial pneumonia requiring ventilatory support. Patients were treated with either best supportive care and siltuximab or best supportive care alone. Propensity score matching was applied to minimise differences in baseline covariates between patient cohorts. The main outcome was mortality in siltuximab-treated patients compared with patients in the matched-control cohort. This study (Siltuximab in Severe COVID-19, SISCO) is registered with ClinicalTrials.gov, identifier NCT04322188.

Findings

Thirty patients received siltuximab, while 188 control patients received only best supportive care. Siltuximab-treated patients were matched to 30 control patients using the propensity score analysis of baseline covariates. The 30-day mortality rate was significantly lower in the siltuximab-treated than the matched-control cohort patients (HR 0·462, 95% CI 0·221– 0·965); p=0·0399). The mean follow-up was 33·3 days (range 7–58 days) for the siltuximab-treated patients and 22·8 days (range 2–45 days) for the control cohort. Sixteen siltuximab-treated patients were discharged from hospital, four remained on mechanical ventilation, and 10 patients died.

Interpretation

Patients with rapidly progressing COVID-19 respiratory failure requiring ventilatory support may benefit from treatment with siltuximab to reduce mortality and cytokine-driven hyperinflammation associated with severe disease. These findings require validation in a randomised controlled clinical trial.

Funding

Papa Giovanni XXIII Hospital and the Italian Association for Cancer Research funded the study. EUSA Pharma supplied siltuximab, and provided funding for data collection, analysis, and development of the publication.
SEIR and Regression Model based COVID-19 outbreak predictions in India
Authors: Gupta Rajan , Pandey Gaurav , Chaudhary Poonam , Pal Saibal
Published: April 2020

COVID-19 pandemic has become a major threat to the country. Till date, well tested medication or antidote is not available to cure this disease. According to WHO reports, COVID-19 is a severe acute respiratory syndrome which is transmitted through respiratory droplets and contact routes. Analysis of this disease requires major attention by the Government to take necessary steps in reducing the effect of this global pandemic. In this study, outbreak of this disease has been analyzed for India till 30th March 2020 and predictions have been made for the number of cases for the next 2 weeks. SEIR model and Regression model have been used for predictions based on the data collected from John Hopkins University repository in the time period of 30th January 2020 to 30th March 2020. The performance of the models was evaluated using RMSLE and achieved 1.52 for SEIR model and 1.75 for the regression model. The RMSLE error rate between SEIR model and Regression model was found to be 2.01. Also, the value of R0 which is the spread of the disease was calculated to be 2.02. Expected cases may rise between 5000-6000 in the next two weeks of time. This study will help the Government and doctors in preparing their plans for the next two weeks. Based on the predictions for short-term interval, these models can be tuned for forecasting in long-term intervals.
Clinical Manifestations of Children with COVID-19: a Systematic Review
Authors: de Souza Tiago H. , Nadal José A. , Nogueira Roberto J. N. , Pereira Ricardo M. , Brandão Marcelo B.
Published: April 2020

Background

The coronavirus disease 2019 (COVID-19) outbreak is an unprecedented global public health challenge, leading to thousands of deaths every day worldwide. Despite the epidemiological importance, clinical patterns of children with COVID-19 remain unclear. The aim of this study was to describe the clinical, laboratorial and radiological characteristics of children with COVID-19.

Methods

The Medline database was searched between December 1st 2019 and April 6th 2020. No language restrictions were applied. Inclusion criteria were: (1) studied patients younger than 18 years old; (2) presented original data from cases of COVID-19 confirmed by reverse-transcription polymerase chain reaction; and (3) contained descriptions of clinical manifestations, laboratory tests or radiological examinations.

Results

A total of 38 studies (1,124 cases) were included. From all the cases, 1,117 had their severity classified: 14.2% were asymptomatic, 36.3% were mild, 46.0% were moderate, 2.1% were severe and 1.2% were critical. The most prevalent symptom was fever (47.5%), followed by cough (41.5%), nasal symptoms (11.2%), diarrhea (8.1%) and nausea/vomiting (7.1%). One hundred forty-five (36.9%) children were diagnosed with pneumonia and 43 (10.9%) upper airway infections were reported. Reduced lymphocyte count were reported in 12.9% of cases. Abnormalities on computed tomography was reported in 63.0% of cases. The most prevalent abnormalities reported were ground glass opacities, patchy shadows and consolidations. Only one death was reported.

Conclusions

Clinical manifestations of children with COVID-19 differ widely from adults cases. Fever and respiratory symptoms should not be considered a hallmark of COVID-19 in children.
Perceptions and behavioural responses of the general public during the COVID-19 pandemic: A cross-sectional survey of UK Adults
Authors: Atchison Christina J , Bowman Leigh , Vrinten Charlotte , Redd Rozlyn , Pristerà Philippa , Eaton Jeffrey W , Ward Helen
Published: April 2020

Objective

To examine risk perceptions and behavioural responses of the UK adult population during the early phase of the COVID-19 epidemic in the UK.

Design

A cross-sectional survey

Setting

Conducted with a nationally representative sample of UK adults within 48 hours of the UK Government advising the public to stop non-essential contact with others and all unnecessary travel.

Participants

2,108 adults living in the UK aged 18 years and over. Data were collected between March 17 and 18 2020.

Main outcome measures

Descriptive statistics for all survey questions, including the number of respondents and the weighted percentages. Logistic regression was used to identify sociodemographic variation in: (1) adoption of social-distancing measures, (2) ability to work from home, and (3) willingness and (4) ability to self-isolate.

Results

Overall, 1,992 (94.2%) respondents reported taking at least one preventive measure: 85.8% washed their hands with soap more frequently; 56.5% avoided crowded areas and 54.5% avoided social events. Adoption of social-distancing measures was higher in those aged over 70 compared to younger adults aged 18 to 34 years (aOR:1.9; 95% CI:1.1 to 3.4). Those with the lowest household income were six times less likely to be able to work from home (aOR:0.16; 95% CI:0.09 to 0.26) and three times less likely to be able to self-isolate (aOR:0.31; 95% CI:0.16 to 0.58). Ability to self-isolate was also lower in black and minority ethnic groups (aOR:0.47; 95% CI:0.27 to 0.82). Willingness to self-isolate was high across all respondents.

Conclusions

The ability to adopt and comply with certain NPIs is lower in the most economically disadvantaged in society. Governments must implement appropriate social and economic policies to mitigate this. By incorporating these differences in NPIs among socio-economic subpopulations into mathematical models of COVID-19 transmission dynamics, our modelling of epidemic outcomes and response to COVID-19 can be improved.
Evaluation of the Anticipated Burden of COVID-19 on Hospital-Based Healthcare Services Across the United States
Authors: Khera Rohan , Jain Snigdha , Lin Zhenqiu , Ross Joseph S. , Krumholz Harlan M
Published: April 2020

Background

Coronavirus disease-19 (COVID-19) is a global pandemic, with the potential to infect nearly 60% of the population. The anticipated spread of the virus requires an urgent appraisal of the capacity of US healthcare services and the identification of states most vulnerable to exceeding their capacity

Methods

In the American Hospital Association survey for 2018, a database of US community hospitals, we identified total inpatient beds, adult intensive care unit (ICU) beds, and airborne isolation rooms across all hospitals in each state of continental US. The burden of COVID-19 hospitalizations was estimated based on a median hospitalization duration of 12 days and was evaluated for a 30-day reporting period.

Results

At 5155 US community hospitals across 48 states in the contiguous US and Washington DC, there were a total of 788,032 inpatient beds, 68,280 adult ICU beds, and 44,222 isolation rooms. The median daily bed occupancy was 62.8% (IQR 58.1%, 66.6%) across states. Nationally, for every 10,000 individuals, there are 24.2 inpatient beds, 2.8 adult ICU beds, and 1.4 isolation beds. There is a 3-fold variation in the number of inpatient beds available across the US, ranging from 16.4 per 10,000 in Oregon to 47 per 10,000 in South Dakota. There was also a similar 3-fold variation in available or non-occupied beds, ranging from 4.7 per 10,000 in Connecticut through 18.3 per 10,000 in North Dakota. The availability of ICU beds is low nationally, ranging from 1.4 per 10,000 in Nevada to 4.7 per 10000 in Washington DC.

Hospitalizations for COVID-19 in a median 0.2% (IQR 0.2 %, 0.3%) of state population, or 1.4% of state’s older adults (1.0%, 1.9%) will require all non-occupied beds. Further, a median 0.6% (0.5%, 0.8%) of state population, or 3.9% (3.1%, 4.6%) of older individuals would require 100% of inpatient beds.

Conclusion

The COVID-19 pandemic is likely to overwhelm the limited number of inpatient and ICU beds for the US population. Hospitals in half of US states would exceed capacity if less than 0.2% of the state population requires hospitalization in any given month.
Mechanical characteristics of ultrafast zebrafish larval swimming muscles
Authors: Mead A. F. , Kennedy G. G. , Palmer B. M. , Ebert A. M. , Warshaw D. M.
Published: April 2020

Zebrafish (Danio rerio) swim within days of fertilization, powered by muscles of the axial myotomes. Forces generated by these muscles can be measured rapidly in whole, intact larval tails by adapting protocols developed forex vivomuscle mechanics. But it is not known how well these measurements reflect the function of the underlying muscle fibers and sarcomeres. Here we consider the anatomy of the 5-day-old, wild-type larval tail, and implement technical modifications to measuring muscle physiology in intact tails. Specifically, we quantify fundamental relationships between force, length, and shortening velocity, and capture the extreme contractile speeds required to swim with tail-beat frequencies of 80-100 Hz. Therefore, we analyze 1000 frames/second movies to track the movement of structures, visible in the transparent tail, which correlate with sarcomere length. We also characterize the passive viscoelastic properties of the preparation to isolate forces contributed by non-muscle structures within the tail. Myotomal muscles generate more than 95% of their maximum isometric stress (76±3 mN/mm2) over the range of muscle lengths usedin vivo. They have rapid twitch kinetics (full width at half-maximum stress: 11±1 msec) and a high twitch to tetanus ratio (0.91±0.05), indicating adaptations for fast excitation-contraction coupling. Although contractile stress is relatively low, myotomal muscles develop high net power (134±20 W/kg at 80 Hz) in cyclical work loop experiments designed to simulate thein vivodynamics of muscle fibers during swimming. When shortening at a constant speed of 7±1 muscle lengths/second, muscles develop 86±2% of isometric stress, while peak instantaneous power during 100Hz work loops occurs at 18±2 muscle lengths/second. These approaches can improve the usefulness of zebrafish as a model system for muscle research by providing a rapid and sensitive functional readout for experimental interventions.

Statement of significance

The zebrafish (Danio rerio) may prove a uniquely efficient model system for characterizing vertebrate muscle physiology. Transparent, drug-permeable larva – each, in essence, a fully functional muscle – can be generated rapidly, inexpensively, and in large numbers. Critically, the zebrafish genome contains homologs of major muscle genes and is highly amenable to manipulation. To reach its potential, reliable (and preferably rapid) means are needed to observe the effects of experimental interventions on larval muscle function. In the present study we show how mechanical measurements made on whole, intact larval tails can provide a readout of fundamental muscle-mechanical properties. Additionally, we show that these muscles are among the fastest ever measured, and therefore worthy of study in their own right.
Diffusion Basis Spectrum Imaging with Deep Neural Network Differentiates Distinct Histology in Pediatric Brain Tumors
Authors: Ye Zezhong , Srinivasa Komal , Lin Joshua , Viox Jeffrey D. , Song Chunyu , Wu Anthony T. , Sun Peng , Song Sheng-Kwei , Dahiya Sonika , Rubin Joshua B.
Published: April 2020

High-grade pediatric brain tumors constitute the highest mortality of cancer-death in children. While conventional MRI has been widely adopted for examining pediatric high-grade brain tumor clinically, accurate neuroimaging detection and differentiation of tumor histopathology for improved diagnosis, surgical planning, and treatment evaluation, remains an unmet need in the clinical management of pediatric brain tumor. We employed a novel Diffusion Histology Imaging (DHI) approach that incorporates diffusion basis spectrum imaging (DBSI) and deep neural network. DHI aims to detect, differentiate, and quantify heterogenous areas in pediatric high-grade brain tumors, which include normal white matter (WM), densely cellular tumor (DC tumor), less densely cellular tumor (LDC tumor), infiltrating edge, necrosis, and hemorrhage. Distinct diffusion metric combination would thus indicate the unique distributions of each distinct tumor histology features. DHI, by incorporating DBSI metrics and the deep neural network algorithm, classified pediatric tumor histology with an overall accuracy of 83.3%. Receiver operating analysis (ROC) analysis suggested DHI’s great capability in distinguishing individual tumor histology with AUC values (95%CI) of 0.983 (0.985-0.989), 0.961 (0.957-0.964), 0.993 (0.992-0.994), 0.953 (0.947-0.958), 0.974 (0.970-0.978) and 0.980 (0.977-0.983) for normal WM, DC tumor, LDC tumor, infiltrating edge, necrosis and hemorrhage, respectively. Our results suggest that DBSI-DNN, or DHI, accurately characterized and classified multiple tumor histologic features in pediatric high-grade brain tumors. If further validated in patients, the novel DHI might emerge as a favorable alternative to the current neuroimaging techniques to better guide biopsy and resection as well as monitor therapeutic response in patients with high-grade brain tumors.
Altered skeletal muscle glucose-fatty acid flux in amyotrophic lateral sclerosis (ALS)
Authors: Steyn Frederik J. , Kirk Siobhan E. , Tefera Tesfaye W. , Xie Teresa Y. , Tracey Timothy J. , Kelk Dean , Wimberger Elyse , Garton Fleur C. , Roberts Llion , Chapman Sarah , Coombes Jeff S. , Leevy W. Matthew , Ferri Alberto , Valle Cristiana , René Frédérique , Loeffler Jean-Philippe , McCombe Pamela A. , Henderson Robert D. , Ngo Shyuan T.
Published: April 2020

Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons, yet an increasing number of studies in both mouse models and patients with ALS suggest that altered metabolic homeostasis is a feature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in ALS. However, our capacity to target specific metabolic pathways or mechanisms requires detailed understanding of metabolic dysregulation in ALS. Here, using the SOD1G93Amouse model of ALS, we demonstrate that an increase in whole-body metabolism occurs at a time when glycolytic muscle exhibits an increased dependence on fatty acid oxidation. Using myotubes derived from muscle of ALS patients, we also show that increased dependence on fatty acid oxidation is associated with increased whole-body energy expenditure. In the present study, increased fatty acid oxidation was associated with slower disease progression. However, we observed considerable heterogeneity in whole-body metabolism and fuel oxidation profiles across our patient cohort. Thus, future studies that decipher specific metabolic changes at an individual patient level are essential for the development of treatments that aim to target metabolic pathways in ALS.
CLUE: a bioinformatic and wet-lab pipeline for multiplexed cloning of custom sgRNA libraries
Authors: Becker Martin , Noll-Puchta Heidi , Amend Diana , Nolte Florian , Fuchs Christiane , Jeremias Irmela , Braun Christian J
Published: April 2020

The systematic perturbation of genomes using CRISPR/Cas9 deciphers gene function at an unprecedented rate, depth and ease. Commercially available sgRNA libraries typically contain tens of thousands of pre-defined constructs, resulting in a complexity challenging to handle. In contrast, custom sgRNA libraries comprise gene sets of self-defined content and size, facilitating experiments under complex conditions such asin vivosystems. To streamline and upscale cloning of custom libraries, we present CLUE, a bioinformatic and wet-lab pipeline for the multiplexed generation of pooled sgRNA libraries. CLUE starts from lists of genes or pasted sequences provided by the user and designs a single synthetic oligonucleotide pool containing various libraries. At the core of the approach, a barcoding strategy for unique primer binding sites allows amplifying different distinct libraries from one single oligonucleotide pool. We prove the approach to be straightforward, versatile and specific, yielding uniform sgRNA distributions in all resulting libraries, virtually devoid of cross-contaminations. Forin silicolibrary multiplexing and design, we established an easy-to-use online platform atwww.crispr-clue.de. All in all, CLUE represents a resource-saving approach to produce numerous high quality custom sgRNA libraries in parallel, which will foster their broad use across molecular biosciences.
Distributed coding of stimulus magnitude in rodent prefrontal cortex
Authors: Henke Josephine , Bunk David , von Werder Dina , Häusler Stefan , Flanagin Virginia L , Thurley Kay
Published: April 2020

As we interact with the external world, we judge magnitudes from sensory information. The estimation of magnitudes has been characterized in primates, yet it is largely unexplored in non-primate species. Here, we show that gerbils that solve a time-interval reproduction task display primate-like magnitude estimation characteristics, most prominently a systematic overestimation of small stimuli and an underestimation of large stimuli, often referred to as regression effect. We investigated the underlying neural mechanisms by recording from medial prefrontal cortex and show that the majority of neurons respond either during the measurement or the reproduction of a time-interval. Cells that are active during both phases display distinct response patterns. We categorize the neural responses into multiple types and demonstrate that only populations with mixed responses can encode the bias of the regression effect. These results reveal the organizing neural principles of magnitude estimation a process important to higher cognitive functions.
Expansion of frozen hybrids in the guppy ectoparasite,Gyrodactylus turnbulli
Authors: Konczal Mateusz , Przesmycka Karolina J. , Mohammed Ryan S. , Hahn Christoph , Cable Jo , Radwan Jacek
Published: April 2020

Hybridization is one of the major factors contributing to the emergence of highly successful parasites. Hybrid vigor can play an important role in this process, but subsequent rounds of recombination in the hybrid population may dilute its effects. Increased fitness of hybrids can, however, be frozen by asexual reproduction. Here, we identify invasion of a “frozen hybrid” genotype in natural populations ofGyrodactylus turnbulli, a facultatively sexual ectoparasitic flatworm that causes significant damage to its fish host. We re-sequenced genomes of these parasites infecting guppies from six Trinidad and Tobago populations, and found surprisingly high discrepancy in genome-wide nucleotide diversity between islands. The elevated heterozygosity on Tobago is maintained by predominantly clonal reproduction of hybrids formed from two diverged genomes. Hybridization has been followed by spread of the hybrids across the island, implying a selective advantage compared to native genotypes. Our results thus highlight that a single outcrossing event may be independently sufficient to cause pathogen expansion.
Weeds are not always evil: crop-weed relationships are context-dependent and cannot fully explain the positive effects of intercropping on yield
Authors: Stefan Laura , Engbersen Nadine , Schoeb Christian
Published: April 2020

Implementing sustainable weed control strategies is a major challenge in agriculture. Intercropping offers a potential solution to control weed pressure by reducing the niche space available for weeds; however, available research on the relationship between crop diversity and weed pressure, and its consequences on crop yield is not fully conclusive yet. In this study, we performed an extensive intercropping experiment using eight crop species and 40 different species mixtures to examine how crop diversity affects weed communities and how the subsequent changes in weeds influence crop yield. Field experiments were carried out in Switzerland and in Spain, which differ drastically in terms of climate and soil, and included monocultures, 2- and 4-species mixtures, and a control treatment without crops. Weed communities were assessed in terms of biomass, species richness and evenness, and community composition. Results indicate that intercropping per se does not reduce weed performance or diversity, but crop species composition does. In particular, the presence of cereals in crop mixtures significantly reduced weed biomass and diversity. Despite the lack of crop diversity effect on weeds, crop yield increased with crop species richness, particularly in Switzerland. Moreover, in Switzerland, where soil resources were abundant, increasing crop yield correlated with increased weed suppression and reduced weed diversity. In Spain, where water and nutrients were limited, crop yield was not related to weed biomass or diversity. Synthesis and applications: We demonstrate that in our study, increased crop yield in mixtures was not due to increased weed suppression in diverse crop communities, but must be the result of other ecological processes. We also show that crop-weed relationships vary across environmental conditions, which emphasizes the need for a better understanding of weed communities' assembly mechanisms, as well as locally adapted weed management strategies.
Reconstitution of intestinal stem cell nichein vitrowith pharmacological inhibitors or L-WRN conditioned medium differentially regulates epithelial proliferation, differentiation and barrier function in rabbit caecum organoids
Authors: Mussard Eloïse , Pouzet Cécile , Helies Virginie , Pascal Géraldine , Fourre Sandra , Cherbuy Claire , Rubio Aude , Vergnolle Nathalie , Combes Sylvie , Beaumont Martin
Published: April 2020

Intestinal organoids are self-organized 3-dimensional (3D) structures formed by a single layer of polarized epithelial cells. This innovativein vitromodel is highly relevant to study physiology of the intestinal epithelium and its role in nutrition and barrier function. However, this model has never been developed in rabbits, while it would have potential applications for biomedical and veterinary research. Here, we cultured rabbit caecum organoids with either pharmacological inhibitors (2Ki medium) or L-WRN cells conditioned medium (L-WRN CM) to reconstitute the intestinal stem cell nichein vitro. Large spherical organoids were obtained with the 2Ki medium and this morphology was associated with a high level of proliferation and stem cells markers gene expression. In contrast, organoids cultured with L-WRN CM had a smaller diameter; a greater cell height and part of them were not spherical. When the L-WRN CM was used at low concentration (5%) for two days, the gene expression of stem cells and proliferation markers were very low, while absorptive and secretory cells markers and antimicrobial peptides were elevated. Epithelial cells within organoids were polarized in 3D cultures with 2Ki medium or L-WRN CM (apical side towards the lumen). We cultured dissociated organoid cells in 2D monolayers, which allowed accessibility to the apical compartment. Under these conditions, actin stress fibers were observed with the 2Ki medium, while perijonctionnal localization of actin was observed with the L-WRN CM suggesting, in 2D cultures as well, a higher differentiation level in the presence of L-WRN CM. In conclusion, rabbit caecum organoids cultured with the 2Ki medium were more proliferative and less differentiated than organoids cultured with L-WRN CM. We propose that organoids cultured with the 2Ki medium could be used to rapidly generatein vitroa large number of rabbit intestinal epithelial stem cells while organoids cultured with the L-WRN CM represent a suitable model to study differentiated rabbit epithelium.