bluuebunny/crossref_metadata_2025 huggingface dataset:
starmapVR: immersive visualisation of single cell spatial omic data
Authors: Yang Andrian , Yao Yu , Fang Xiunan , Li Jianfu , Xia Yongyan , Kwok Crystal S. M. , Lo Michelle C. K. , Siu Dickson M. D. , Tsia Kevin K. , Ho Joshua W. K.
Published: September 2020

Motivation

Advances in high throughput single-cell and spatial omic technologies have enabled the profiling of molecular expression and phenotypic properties of hundreds of thousands of individual cells in the context of their two dimensional (2D) or three dimensional (3D) spatial endogenous arrangement. However, current visualisation techniques do not allow for effective display and exploration of the single cell data in their spatial context. With the widespread availability of low-cost virtual reality (VR) gadgets, such as Google Cardboard, we propose that an immersive visualisation strategy is useful.

Results

We present starmapVR, a light-weight, cross-platform, web-based tool for visualising single-cell and spatial omic data. starmapVR supports a number of interaction methods, such as keyboard, mouse, wireless controller and voice control. The tool visualises single cells in a 3D space and each cell can be represented by a star plot (for molecular expression, phenotypic properties) or image (for single cell imaging). For spatial transcriptomic data, the 2D single cell expression data can be visualised alongside the histological image in a 2.5D format. The application of starmapVR is demonstrated through a series of case studies. Its scalability has been carefully evaluated across different platforms.

Availability and implementation

starmapVR is freely accessible athttps://holab-hku.github.io/starmapVR, with the corresponding source code available athttps://github.com/holab-hku/starmapVRunder the open source MIT license.

Supplementary Information

Supplementary data are available atBioinformaticsonline.
Utility of Olfactory test as screening tool for COVID-19: A pilot study
Authors: Khare Pragyanshu , Munish Chander Atul , Agrawal Kanhaiya , Singh Jayant Satyam , Mukherjee Soham , Yadav Kamalendra , Gupta Rahul , Chaudhary Shakun , Srivastava Sumit , Muralidharan Sanuj , Mohan Rijin , Chaudhary Shikha , Pal Rimesh , Bansal Sandeep , Kondepudi Kanthi Kiran , Puri Govardhan Dutt , Bishnoi Mahendra , Kumar Bhadada Sanjay
Published: September 2020

Loss of smell function (Anosmia) is reported to be associated with novel coronavirus disease 2019 (COVID-19) infection. The present study was designed to evaluate the effectiveness of an indigenously developed prototype smell test to identify/diagnose asymptomatic COVID-19 positive individuals. A panel of five different odorants belonging to Indian household with unique and mutually exclusive odor were used to develop prototype kit to test the hypothesis. The developed prototype kit was tested at 2 centers (N = 49 and 34) with slight modifications. Simultaneously, the kit was also tested on 55 (N = 35 and 20) healthy controls. Our results indicate that otherwise asymptomatic COVID-19 positive individuals were having quantifiable deficit in smell sensation. Interestingly, the variable sensitivity of different odorants was observed in different patients. None of the healthy controls reported difficulty in sensing any of the odorant, whereas, some of healthy controls did misidentify the odorants. Overall, the present study provides a preliminary data that loss in smell sensation for various odorants can be exploited as a quick and affordable screening test to identify infected cases among at risk individuals.
Impact of baseline cases of cough and fever on UK COVID-19 diagnostic testing rates: estimates from the Bug Watch community cohort study
Authors: Eyre Max T , Burns Rachel , Kirkby Victoria , Smith Catherine , Denaxas Spiros , Nguyen Vincent , Hayward Andrew , Shallcross Laura , Fragaszy Ellen , Aldridge Robert W
Published: September 2020

Background

Diagnostic testing forms a major part of the UK’s response to the current COVID-19 pandemic with tests offered to people with a continuous cough, high temperature or anosmia. Testing capacity must be sufficient during the winter respiratory season when levels of cough and fever are high due to non-COVID-19 causes. This study aims to make predictions about the contribution of baseline cough or fever to future testing demand in the UK.

Methods

In this analysis of the Bug Watch prospective community cohort study, we estimated the incidence of cough or fever in England in 2018–2019. We then estimated the COVID-19 diagnostic testing rates required in the UK for baseline cough or fever cases for the period July 2020-June 2021. This was explored for different rates of the population requesting tests and four second wave scenarios and then compared to current national capacity.

Results

The baseline incidence of cough or fever in the UK is expected to rise rapidly from 154,554 (95%CI 103,083 – 231,725) cases per day in August 2020 to 250,708 (95%CI 181,095 – 347,080) in September, peaking at 444,660 (95%CI 353,084 – 559,988) in December. If 80% of baseline cough or fever cases request tests, average daily UK testing demand would exceed current capacity for five consecutive months (October 2020 to February 2021), with a peak demand of 147,240 (95%CI 73,978 – 239,502) tests per day above capacity in December 2020.

Conclusions

Our results show that current national COVID-19 testing capacity is likely to be exceeded by demand due to baseline cough and fever alone. This study highlights that the UK’s response to the COVID-19 pandemic must ensure that a high proportion of people with symptoms request tests, and that testing capacity is immediately scaled up to meet this high predicted demand.
Composite trait Mendelian Randomization reveals distinct metabolic and lifestyle consequences of differences in body shape
Authors: Sulc Jonathan , Sonrel Anthony , Mounier Ninon , Auwerx Chiara , Marouli Eirini , Darrous Liza , Draganski Bogdan , Kilpeläinen Tuomas O. , Joshi Peter , Loos Ruth J.F. , Kutalik Zoltán
Published: September 2020

Obesity is a major risk factor for a wide range of cardiometabolic diseases, however the impact of specific aspects of body morphology remains poorly understood. We combined the GWAS summary statistics of fourteen anthropometric traits from UK Biobank through principal component analysis to reveal four major independent axes summarizing 99% of genetically driven variation in body shape and size: overall body size, adiposity, predisposition to abdominal fat deposition, and lean mass. Enrichment analyses suggest that body size and adiposity are affected by genes involved in neuronal signaling, whereas body fat distribution and lean mass are dependent on genes involved in morphogenesis and energy homeostasis. Using Mendelian randomization, we found that although both body size and adiposity contribute to the consequences of BMI, many of their effects are distinct, such as body size increasing the risk of diseases of the veins (b ≥ 0.044, p ≤ 8.9*10-10) and cardiac arrhythmia (b = 0.06, p = 4.2*10-17) while adiposity instead increased the risk of ischemic heart disease (b = 0.079, p = 8.2*10-21). The body mass-neutral component predisposing to abdominal fat deposition, likely reflecting a shift from subcutaneous to visceral fat, exhibited health effects that were weaker but specifically linked to lipotoxicity, such as ischemic heart disease (b = 0.067, p = 9.4*10-14) and diabetes (b = 0.082, p = 5.9*10-19). Combining their predicted effects significantly improved the prediction of obesity-related diseases, even when applied out-of-population (p < 10-10). The presented decomposition approach sheds light on the biological mechanisms underlying the remarkably heterogeneous nature of body morphology as well as its consequences on health and lifestyle.
Exploring linkages between drought and HIV treatment adherence in Africa: A Systematic Review
Authors: Orievulu Kingsley , Ayeb-Karlsson Sonja , Ngema Sthembile , Baisley Kathy , Tanser Frank , Ngwenya Nothando , Seeley Janet , Hanekom Willem , Herbst Kobus , Kniveton Dominic , Iwuji Collins
Published: September 2020

Climate change is directly and indirectly linked to human health, including through access to treatment and care. Our systematic review presents a ‘systems’ understanding of the nexus between drought and antiretroviral treatment (ART) adherence in HIV-positive individuals in the African setting. Narrative synthesis of 111 studies retrieved from Web of Science, PubMed/Medline, and PsycINFO suggests that economic and livelihoods conditions, comorbidities and ART regimens, human mobility, and psycho-behavioural dispositions and support systems interact in complex ways in the drought-ART adherence nexus in Africa. Economic and livelihood-related challenges appear to impose the strongest impact on human interactions, actions and systems that culminate in non-adherence. Indeed, the complex pathways identified by our systems approach emphasise the need for more integrated research approaches to understanding this phenomenon and develop interventions.
COVID-19 hospitalizations in Brazil’s Unified Health System (SUS)
Authors: de Andrade Carla Lourenço Tavares , de Aguiar Pereira Claudia Cristina , Martins Mônica , Lima Sheyla Maria Lemos , Portela Margareth Crisóstomo
Published: September 2020

Objective

To study the profile of hospitalizations due to COVID-19 in the Unified Health System (SUS) in Brazil and to identify factors associated with hospital mortality related to the disease.

Methods

Cross-sectional study, based on secondary data on COVID-19 hospitalizations that occurred in SUS, between the last days of February and June. Patients aged 18 years or older, with primary or secondary diagnoses indicative of COVID-19 were included. Bivariate analyses were performed and generalized linear mixed models (GLMM) were estimated with random effects intercept. The modeling followed three steps, including: attributes of the patients; elements of the care process; and characteristics of the hospital and place of hospitalization.

Results

89,405 hospitalizations were observed, of which 24.4% resulted in death. COVID-19 patients hospitalized in SUS were predominantly male (56.5%), with a mean age of 58.9 years. The length of stay ranged from less than 24 hours to 114 days, with a mean of 6.9 (±6.5) days. Of the total number of hospitalizations, 22.6% reported ICU use. The chances of hospital death among men were 16.8% higher than among women and increased with age. Black individuals had a higher chance of death. The behavior of the Charlson and Elixhauser indices was consistent with the hypothesis of a higher risk of death among patients with comorbidities, and obesity had an independent effect on increasing this risk. Some states had a higher risk of hospital death from COVID-19, such as Amazonas and Rio de Janeiro. The chances of hospital death were 72.1% higher in municipalities with at least 100,000 inhabitants and being hospitalized in the municipality of residence was a protective factor.

Conclusion

There was wide variation in hospital COVID-19 mortality in the SUS, associated with demographic and clinical factors, social inequality and differences in the structure of services and quality of health care.
Swab pooling for large-scale RT-qPCR screening of SARS-CoV-2
Authors: Paula Christoff Ana , Cruz Giuliano Netto Flores , Sereia Aline Fernanda Rodrigues , Boberg Dellyana Rodrigues , Bastiani Daniela Carolina de , Yamanaka Laís Eiko , Fongaro Gislaine , Stoco Patrícia Hermes , Bazzo Maria Luiza , Grisard Edmundo Carlos , Hernandes Camila , de Oliveira Luiz Felipe Valter
Published: September 2020

Pool testing has been proposed as an alternative for large-scale SARS-CoV-2 screening. However, dilution factors proportional to the number of pooled samples have been a source of major concern regarding its diagnostic performance. Further, sample pooling can lead to increased laboratory workload and operational complexity. Therefore, pooling strategies that minimize sample dilution, loss of sensitivity, and laboratory overload are needed to allow reliable and large-scale screenings of SARS-CoV-2. Here, we describe a pooling procedure in which nasopharyngeal swabs are pooled together at the time of sample collection (swab pooling), decreasing laboratory manipulation and minimizing dilution of the viral RNA present in the samples. Paired analysis of pooled and individual samples from 613 patients revealed 94 positive individual tests. Having individual testing as a reference, no false-positives or false-negatives were observed for swab pooling. A Bayesian model estimated a sensitivity of 99% (Cr.I. 96.9% to 100%) and a specificity of 99.8% (Cr.I. 99.4% to 100%) for the swab pooling procedure. Data from additional 18,922 patients screened with swab pooling were included for further quantitative analysis. Mean Cq differences between individual and corresponding pool samples ranged from 0.1 Cq (Cr.I. –0.98 to 1.17) to 2.09 Cq (Cr.I. 1.24 to 2.94). Overall, 19,535 asymptomatic and presymptomatic patients were screened using 4,400 RT-qPCR assays, resulting in 246 positive patients (positivity rate 1.26%). This corresponds to an increase of 4.4 times in laboratory capacity and a reduction of 77% in required tests. Finally, these data demonstrate that swab pooling can significantly minimize sample dilution and sensitivity issues commonly seen in its traditional counterpart. Therefore, swab pooling represents a major alternative for reliable and large-scale screening of SARS-CoV-2 in low prevalence populations.
Assessment of COVID-19 Pandemic in Nepal: A Lockdown Scenario Analysis
Authors: Sharma Kusum , Banstola Amrit , Parajuli Rishi Ram
Published: September 2020

The Government of Nepal issued a nationwide lockdown from 24 March to 21 July 2020, prohibiting domestic and international travels, closure of the border and non-essential services. There were only two confirmed cases from 610 Reverse Transcription Polymerase Chain Reaction (RT-PCR) tests and no fatalities when the government introduced nationwide lockdown. This study aimed to explore the overall scenario of COVID-19 including spatial distribution of cases; government efforts, and impact on public health, socio-economy, and education during the lockdown in Nepal. We collated and analysed data using official figures from the Nepalese Ministry of Health and Population. Nepal had performed 7,791 RT-PCR tests for COVID-19, the highest number of tests during the lockdown. It has recorded its highest daily rise in coronavirus infections with a total of 740 new cases from the total of 4,483 RT-PCR tests performed on a single day. Nepal had reported a total of 17,994 positive cases and 40 deaths at the end of lockdown. The spatial distribution clearly shows that the cases were rapidly spreading from the southern part of the country where most points of entry and exit from India are located. To contain the spread of the virus, the government has also initiated various preventive measures and strategies during the lockdown. The Government of Nepal needs to allocate more resources, increase its capacity to test and trace, establish dedicated isolation and quarantine facility and impose local restrictions such as a local lockdown based on risk assessment rather than a nationwide lockdown.
Inter-specific Variability in Demographic Processes Affects Abundance-Occupancy Relationships
Authors: Şen Bilgecan , Akçakaya H. Reşit
Published: September 2020

Species with large local abundances tend to occupy more sites. One of the mechanisms proposed to explain this widely reported inter-specific relationship is a cross-scale hypothesis based on dynamics at the population level. Called the vital rates mechanism, it uses within-population demographic processes of population growth and density dependence to predict when inter-specific abundance-occupancy relationships can arise and when these relationships can weaken and even turn negative. Even though the vital rates mechanism is mathematically simple, its predictions has never been tested directly because of the difficulty estimating the demographic parameters involved. Here, using a recently introduced mark-recapture analysis method, we show that there is a weakly positive relationship between abundance and occupancy among 17 bird species. Our results are consistent with the predictions of the vital rate mechanism regarding the demographic processes that are expected to weaken this relationship. Specifically, we find that intrinsic growth rate and local abundance are weakly correlated; and density dependence strength shows considerable variation across species. Variability in density dependence strength is related to variability in species-level local average abundance and intrinsic growth rate; species with lower growth rate have higher abundance and are strongly regulated by density dependent processes, especially acting on survival rates. Species with higher growth rate, on average, have lower abundance and are more weakly regulated by density dependent processes especially acting on fecundity. More generally, our findings support a cross scale mechanism of macroecological abundance-occupancy relationship emerging from density-dependent dynamics at the population level.
A SARS-CoV-2 – host proximity interactome
Authors: Samavarchi-Tehrani Payman , Abdouni Hala , Knight James D.R. , Astori Audrey , Samson Reuben , Lin Zhen-Yuan , Kim Dae-Kyum , Knapp Jennifer J. , St-Germain Jonathan , Go Christopher D. , Larsen Brett , Wong Cassandra J. , Cassonnet Patricia , Demeret Caroline , Jacob Yves , Roth Frederick P. , Raught Brian , Gingras Anne-Claude
Published: September 2020

Viral replication is dependent on interactions between viral polypeptides and host proteins. Identifying virus-host protein interactions can thus uncover unique opportunities for interfering with the virus life cycle via novel drug compounds or drug repurposing. Importantly, many viral-host protein interactions take place at intracellular membranes and poorly soluble organelles, which are difficult to profile using classical biochemical purification approaches. Applying proximity-dependent biotinylation (BioID) with the fast-acting miniTurbo enzyme to 27 SARS-CoV-2 proteins in a lung adenocarcinoma cell line (A549), we detected 7810 proximity interactions (7382 of which are new for SARS-CoV-2) with 2242 host proteins (results available at covid19interactome.org). These results complement and dramatically expand upon recent affinity purification-based studies identifying stable host-virus protein complexes, and offer an unparalleled view of membrane-associated processes critical for viral production. Host cell organellar markers were also subjected to BioID in parallel, allowing us to propose modes of action for several viral proteins in the context of host proteome remodelling. In summary, our dataset identifies numerous high confidence proximity partners for SARS-CoV-2 viral proteins, and describes potential mechanisms for their effects on specific host cell functions.
No evidence for differential gene expression in major depressive disorder PBMCs, but robust evidence of elevated biological ageing
Authors: Cole John J. , McColl Alison , Shaw Robin , Lynall Mary-Ellen , Cowen Philip J , de Boer Peter , Drevets Wayne C , Harrison Neil , Pariante Carmine , Pointon Linda ,   NIMA consortium, Goodyear Carl , Bullmore Edward , Cavanagh Jonathan
Published: September 2020

Background

The increasingly compelling data supporting the involvement of immunobiological mechanisms in Major Depressive Disorder (MDD) might provide some explanation of the variance in this heterogeneous condition. Peripheral blood measures of cytokines and chemokines constitute the bulk of evidence with consistent meta-analytic data implicating raised proinflammatory cytokines such as IL6, IL1β and TNF. Among the potential mechanisms linking immunobiological changes to affective neurobiology is the accelerated biological ageing seen in MDD, particularly via the senescence associated secretory phenotype (SASP). However, the cellular source of immunobiological markers remains unclear.

Aims

Pre-clinical evidence suggests a role for peripheral blood mononuclear cells (PBMC), thus here we aimed to explore the transcriptomic profile using RNA sequencing in PBMCs in a clinical sample of people with various levels of depression and treatment response comparing it with that in healthy controls (HCs).

Method

Transcriptomic analysis of peripheral blood mononuclear cells.

Results

The data showed no robust signal differentiating MDD and HCs. There was, however, significant evidence of elevated biological ageing in MDD vs HC.

Conclusions

Future work should endeavour to expand clinical sample sizes and reduce clinical heterogeneity. The exploration of RNA-seq signatures in other leukocyte populations and advances in RNA sequencing at the level of the single cell may help uncover more subtle differences. However, currently the subtlety of any PBMC signature mitigates against its convincing use as a diagnostic or predictive biomarker.

Highlights

PBMCs showed no differential transcriptomic signature between depressed cases and healthy controls suggesting that the cellular source of the immune signature seen in depression may be from a different cell group.

There was significant evidence of accelerated biological ageing in major depression compared to healthy controls.
Using human genetics to understand the causes and consequences of circulating cardiac troponin I in the general population
Authors: Moksnes Marta R , Røsjø Helge , Richmond Anne , Lyngbakken Magnus N , Graham Sarah E , Hansen Ailin Falkmo , Wolford Brooke N , Taliun Sarah A Gagliano , LeFaive Jonathon , Rasheed Humaira , Thomas Laurent F , Zhou Wei , Surakka Ida , Douville Nicholas J , Campbell Archie , Porteous David J , Welsh Paul , Sattar Naveed , Smith George Davey , Fritsche Lars G , Nielsen Jonas B , Åsvold Bjørn Olav , Hveem Kristian , Hayward Caroline , Willer Cristen J , Brumpton Ben M , Omland Torbjørn
Published: September 2020

Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes is unclear. We combine data from the Trøndelag Health Study and the Generation Scotland Scottish Family Health Study and perform a genome-wide association study of highsensitivity cTnI concentrations with 48 115 individuals.

We identified 12 genetic loci (8 novel) associated with cTnI concentrations. Associated protein-altering variants highlighted putative functional genes:CAND2, HABP2, ANO5, APOH, FHOD3, TNFAIP2, KLKB1andLMAN1. Using two-sample Mendelian randomization we confirmed the non-causal role of cTnI in acute myocardial infarction, but could not rule out a causal role for cTnI in heart failure. Using genetically informed methods for causal inference of cTnI helps inform the role and value of measuring cTnI in the general population.
Monocyte-chemoattractant protein-1 Levels in Human Atherosclerosis Associate with Plaque Vulnerability
Authors: Georgakis Marios K. , van der Laan Sander W. , Asare Yaw , Mekke Joost M. , Haitjema Saskia , Schoneveld Arjan H. , de Kleijn Dominique P.V. , de Borst Gert J. , Pasterkamp Gerard , Dichgans Martin
Published: September 2020

Monocyte chemoattractant protein-1 (MCP-1) recruits monocytes to the atherosclerotic plaque. While experimental,1–6genetic,7and observational8,9data support a key role of MCP-1 in atherosclerosis, the translational potential of targeting MCP-1 signaling for lowering vascular risk is limited by the lack of data on plaque MCP-1 activity in human atherosclerosis. Here, we measured MCP-1 levels in human plaque samples from 1,199 patients undergoing carotid endarterectomy and explored associations with histopathological, molecular, and clinical features of plaque vulnerability. MCP-1 plaque levels were associated with histopathological hallmarks of plaque vulnerability (large lipid core, low collagen, high macrophage burden, low smooth muscle cell burden, intraplaque hemorrhage) as well as molecular markers of plaque inflammation and matrix turnover, clinical plaque instability, and periprocedural stroke during plaque removal. Collectively, our findings highlight a role of MCP-1 in human plaque vulnerability and suggest that interfering with MCP-1 signaling in patients with established atherosclerosis could lower vascular risk.
Nucleo-cytoplasmic shuttling of splicing factor SRSF1 is required for development and cilia function
Authors: Haward Fiona , Maslon Magdalena M. , Yeyati Patricia L. , Bellora Nicolas , Hansen Jan N. , Aitken Stuart , Lawson Jennifer , von Kriegsheim Alex , Wachten Dagmar , Mill Pleasantine , Adams Ian R. , Cáceres Javier F.
Published: September 2020

Shuttling RNA-binding proteins coordinate nuclear and cytoplasmic steps of gene expression. The SR family proteins regulate RNA splicing in the nucleus and a subset of them, including SRSF1, shuttles between the nucleus and cytoplasm affecting post-splicing processes. However, the physiological significance of this remains unclear. Here, we used genome editing to knock-in a nuclear retention signal (NRS) inSrsf1to create a mouse model harboring an SRSF1 protein that is retained exclusively in the nucleus.Srsf1NRS/NRSmutants displayed small body size, hydrocephalus and immotile sperm, all traits associated with ciliary defects. We observed reduced translation of a subset of mRNAs and decreased abundance of proteins involved in multiciliogenesis, with disruption of ciliary ultrastructure and motility in cells derived from this mouse model. These results demonstrate that SRSF1 shuttling is used to reprogram gene expression networks in the context of high cellular demands, as observed here, during motile ciliogenesis.
Preclinical efficacy and safety analysis of gamma-irradiated inactivated SARS-CoV-2 vaccine candidates
Authors: Sir Karakus Gozde , Tastan Cihan , Dilek Kancagi Derya , Yurtsever Bulut , Tumentemur Gamze , Demir Sevda , Dilek Turan Raife , Abanuz Selen , Cakirsoy Didem , Seyis Utku , Ozer Samed , Elibol Omer , Elek Muhammer , Ertop Gurcan , Arbak Serap , Acikel Elmas Merve , Hemsinlioglu Cansu , Sesin Kocagoz Ayse , Hatirnaz Ng Ozden , Akyoney Sezer , Sahin Ilayda , Ozbek Ugur , Telci Dilek , Sahin Fikrettin , Yalcin Koray , Ratip Siret , Ovali Ercument
Published: September 2020

COVID-19 outbreak caused by SARS-CoV-2 created an unprecedented health crisis since there is no vaccine for this novel virus. Therefore, SARS-CoV-2 vaccines have become crucial for reducing morbidity and mortality. In this study, in vitro and in vivo safety and efficacy analyzes of lyophilized vaccine candidates inactivated by gamma-irradiation were performed. The candidate vaccines in this study were OZG-3861 version 1 (V1), an inactivated SARS-CoV-2 virus vaccine, and SK-01 version 1 (V1), a GM-CSF adjuvant added vaccine. The candidate vaccines were applied intradermally to BALB/c mice to assess toxicity and immunogenicity. Preliminary results in vaccinated mice are reported in this study. Especially, the vaccine models containing GM-CSF caused significant antibody production with neutralization capacity in absence of the antibody-dependent enhancement feature, when considered in terms of T and B cell responses. Another important finding was that the presence of adjuvant was more important in T cell in comparison with B cell response. Vaccinated mice showed T cell response upon restimulation with whole inactivated SARS-CoV-2 or peptide pool. This study shows that the vaccines are effective and leads us to start the challenge test to investigate the gamma-irradiated inactivated vaccine candidates for infective SARS-CoV-2 virus in humanized ACE2+ mice.
Proteomics profiling of human synovial fluid suggests global increased protein interplay in early-osteoarthritis (OA) and lost in late-stage OA
Authors: Ali Neserin , Turkiewicz Aleksandra , Hughes Velocity , Folkesson Elin , Tjörnstand Jon , Neuman Paul , Önnerfjord Patrik , Englund Martin
Published: September 2020

The underlying molecular mechanisms in osteoarthritis (OA) development are largely unknown. This study explores the proteome and the pairwise interplay of proteins on a global level in synovial fluid from patients with late-stage knee OA (arthroplasty), early knee OA (arthroscopy due to degenerative meniscal tear) and from deceased controls without knee OA.

Synovial fluid samples were analyzed using state-of-the-art mass spectrometry with data-independent acquisition. The differential expression of the proteins detected was clustered and evaluated with data mining strategies and a multilevel model. Group-specific slopes of associations were estimated between expressions of each pair of identified proteins to assess the co-expression (i.e. interplay) between the proteins in each group.

More proteins were increased in early-OA vs controls than late-stage OA vs controls. For most of these proteins, the fold changes between late-stage OA vs controls and early stage OA vs controls were remarkably similar suggesting potential involvement in the OA process. Further, for the first time this study illustrated distinct patterns in protein co-expression suggesting that the global interplay between the protein machinery is increased in early-OA and lost in late-stage OA. Further efforts should probably focus on earlier stages of the disease than previously considered.
Multi-BIRW: a network-based algorithm for drug repurposing
Authors: Ferraro Luigi
Published: September 2020

This paper is based onComputational Biologywith an eye towards medicine. In fact our aim is to identify new indications for existing drugs with a computational approach usingSystems Biology, in order to speed up the market entry, avoiding some phases of drug development (for example toxicity tests) and with a lower cost.

The method that we will discuss exploits the concept ofRandom Walkin a heterogeneous network, formed by a drug-drug and disease-disease similarity and known drug-disease associations. This is done by combining different types of data in order to connect more effectively two drugs or two diseases with a similarity score. At the end we integrate the known associations between drugs and diseases with the purpose of finding similarity values of new couples.
Error-related cognitive control and behavioural adaptation mechanisms in the context of motor functioning and anxiety
Authors: Topor Marta , Opitz Bertram , Leonard Hayley C.
Published: September 2020

Previous research suggests that there is an interaction between cognitive and motor processes. This has been investigated throughout development and in different conditions related to motor impairment. The current study addressed a gap in the literature by investigating this interaction in the general population of healthy adults with different profiles of motor proficiency by focusing on error-related cognitive control and behavioural adaptation mechanisms. In addition, the impact of these processes was assessed in terms of experienced anxiety. Forty healthy adults were divided into high and low motor proficiency groups based on an assessment of their motor skills. Using electroencephalography (EEG) during a flanker task, error-related negativity (ERN) was measured as the neural indicator of cognitive control. Post-error slowing (PES) was measured to represent behavioural adaptation. Participants also completed an anxiety assessment questionnaire. Participants in the high motor proficiency group achieved better task accuracy and showed relatively enhanced cognitive control through increased ERN. Contrastingly, individuals in the lower motor proficiency group achieved poorer accuracy whilst showing some evidence of compensation through increased PES. Anxiety was found to be associated with motor functioning, but the study could not provide evidence that this was related to cognitive or behavioural control mechanisms. The interaction between cognitive and motor processes observed in this study is unique for healthy and sub-clinical populations and provides a baseline for the interpretation of similar investigations in individuals with motor disorders.
Sense organ formation and identity are controlled by divergent mechanisms in insects
Authors: Klann Marleen , Schacht Magdalena Ines , Benton Matthew Alan , Stollewerk Angelika
Published: September 2020

Insects and other arthropods utilise external sensory structures for mechanosensory, olfactory and gustatory reception. These sense organs have characteristic shapes related to their function, and in many cases are distributed in a fixed pattern so that they are identifiable individually. InDrosophila melanogaster, the identity of sense organs is regulated by specific combinations of transcription factors. In other arthropods, however, sense organ subtypes cannot be linked to the same code of gene expression. This raises the questions of how sense organ diversity has evolved in arthropods, and if theD. melanogastersubtype identity principle is representative for insects. To address these questions, we analyse sense organ development in another insect, the flour beetleTribolium castaneum.We show that in contrast toD. melanogaster,T. castaneumsense organs cannot be categorised based on their requirement for individual or combinations of the conserved sense organ transcription factors such ascutandpox-neuroand members of the Achaete-Scute (Tc ASH,Tc asense) and Atonal family (Tc atonal,Tc cato,Tc amos). Rather, these genes are required for the specification of sense organ precursors and the development and differentiation of sensory cell types in diverse external sensilla. Based on our findings and past research, we present an evolutionary scenario suggesting that sensory organs have diversified from a default state through subsequent recruitment of sensory genes to the different sense organ specification processes. A specific role for genes in subtype identity has evolved as a secondary effect of the function of these genes in individual or subsets of sense organs, which can largely not be aligned with morphological or functional categories.
Genomic divergence and differential gene expression between crustacean ecotypes across a marine thermal gradient
Authors: Emami-Khoyi Arsalan , Knapp Ingrid S. , Monsanto Daniela M. , van Vuuren Bettine Jansen , Toonen Robert J. , Teske Peter R.
Published: September 2020

Environmental gradients between marine biogeographical provinces separate distinct faunal communities; in the absence of absolute dispersal barriers numerous species nonetheless occur on either side of such boundaries. While the regional populations of such widespread species tend to be morphologically indistinguishable from each other, genetic evidence suggests that they represent unique ecotypes, and likely even cryptic species, that may be uniquely adapted to their local environment. Here, we explored genomic divergence in four sympatric southern African decapod crustaceans whose ranges span the boundary between the cool-temperate west coast (south-eastern Atlantic) and the warm-temperate south coast (south-western Indian Ocean) near the southern tip of the African continent. Using genome-wide data, we found that all four species comprise distinct west- and south coast ecotypes, with molecular dating suggesting divergence during the Pleistocene. Using transcriptomic data from one of the decapod crustaceans, we further found a clear difference in gene expression profiles between the west- and south coast ecotypes. This was particularly clear in the individual from the south coast, which experienced a ‘transcriptomic shock’ at low temperatures that are more typical of the west coast and may explain their absence from that coastline. Our results shed new light on the processes involved in driving genomic divergence and incipient speciation.
Multimerization- and glycosylation-dependent receptor binding of SARS-CoV-2 spike proteins
Authors: Bouwman Kim M. , Tomris Ilhan , Turner Hannah L. , van der Woude Roosmarijn , Bosman Gerlof P. , Rockx Barry , Herfst Sander , Haagmans Bart L. , Ward Andrew B. , Boons Geert-Jan , de Vries Robert P.
Published: September 2020

Receptor binding studies using recombinant SARS-CoV proteins have been hampered due to challenges in approaches creating spike protein or domains thereof, that recapitulate receptor binding properties of native viruses. We hypothesized that trimeric RBD proteins would be suitable candidates to study receptor binding properties of SARS-CoV-1 and -2. Here we created monomeric and trimeric fluorescent RBD proteins, derived from adherent HEK293T, as well as in GnTI mutant cells, to analyze the effect of complex vs high mannose glycosylation on receptor binding. The results demonstrate that trimeric fully glycosylated proteins are superior in receptor binding compared to monomeric and immaturely glycosylated variants. Although differences in binding to commonly used cell lines were minimal between the different RBD preparations, substantial differences were observed when respiratory tissues of experimental animals were stained. The RBD trimers demonstrated distinct ACE2 expression profiles in bronchiolar ducts and confirmed the higher binding affinity of SARS-CoV-2 over SARS-CoV-1. Our results show that fully glycosylated trimeric RBD proteins are attractive to analyze receptor binding and explore ACE2 expression profiles in tissues.
The kinesin-8 member Kif19 alters microtubule dynamics, suppresses cell adhesion, and promotes cancer cell invasion
Authors: Eisenberg Samuel C. , Dey Abhinav , Birnbaum Rayna , Sharp David J.
Published: September 2020

Metastasis is one of the deadliest aspects of cancer. Initial Metastatic spread is dependent on the detachment and dissemination of cells from a parent tumor, and invasion into the surrounding tissue. In this study, we characterize the kinesin-8 member Kif19 as a promoter of cancer cell invasion that suppresses cell-cell adherens junctions and cell-matrix focal adhesions. Initial analysis of publicly available cancer patient data sets demonstrated that Kif19 expression correlates with worse overall survival probability in several cancers and that Kif19 expression is increased in metastases of colorectal and breast carcinoma compared to the primary tumor. Depletion of Kif19 from two human cancer cell lines (DMS53 and MDA-MB-231) did not alter viability, but decreased the cells’ ability to invade a Matrigel matrix by half and impaired the invasion of spheroids into a primary cell monolayer. Ectopically expressed Kif19 localized to, and partially depolymerized, microtubules in the cell periphery. However, Kif19 depletion increased microtubule dynamicity and sensitivity to pharmacological depolymerization without altering total microtubule polymer levels. These data indicate that Kif19 can both depolymerize and stabilize microtubules. Given this activity, we then studied Kif19’s effect on focal adhesions and adherens junctions, which are both regulated by microtubule dynamics. Kif19 knockdown increased the proportion of cell surface area covered by Vinculin focal adhesions. Further, Kif19 depletion increased whole cell E-cadherin expression and the accumulation of E-cadherin at cell-cell adherens junctions. Conversely, ectopic overexpression of full-length Kif19 led to proportionally smaller focal adhesions and impaired E-cadherin accumulation at cell-cell junctions. Our current hypothesis is that aberrant Kif19 expression in cancer alters focal adhesion dynamics and suppresses E-cadherin expression, which enhance cell invasiveness. Further, we propose that these changes in cell adhesion are due to modification of peripheral microtubule dynamics by Kif19, potentially through disruption of local rho GTPase activity.
De novo virus inference and host prediction from metagenome using CRISPR spacers
Authors: Sugimoto Ryota , Nishimura Luca , Thanh Phuong Nguyen , Ito Jumpei , Parrish Nicholas F. , Mori Hiroshi , Kurokawa Ken , Nakaoka Hirofumi , Inoue Ituro
Published: September 2020

Viruses are the most numerous biological entity, existing in all environments and infecting all cellular organisms. Compared with cellular life, the evolution and origin of viruses are poorly understood; viruses are enormously diverse and most lack sequence similarity to cellular genes. To uncover viral sequences without relying on either reference viral sequences from databases or marker genes known to characterize specific viral taxa, we developed an analysis pipeline for virus inference based on clustered regularly interspaced short palindromic repeats (CRISPR). CRISPR is a prokaryotic nucleic acid restriction system that stores memory of previous exposure. Our protocol can infer viral sequences targeted by CRISPR and predict their hosts using unassembled short-read metagenomic sequencing data. Analysing human gut metagenomic data, we extracted 11,391 terminally redundant CRISPR-targeted sequences which are likely complete circular genomes of viruses or plasmids. The sequences include 257 complete crAssphage family genomes, 11 genomes larger than 200 kilobases, 766 genomes ofMicroviridaespecies, 114 genomes ofInoviridaespecies and many entirely novel genomes of unknown taxa. We predicted the host(s) of approximately 70% of discovered genomes by linking protospacers to taxonomically assigned CRISPR direct repeats. These results support that our protocol is efficient for de novo inference of viral genomes and host prediction. In addition, we investigated the origin of the diversity-generating retroelement (DGR) locus of the crAssphage family. Phylogenetic analysis and gene locus comparisons indicate that DGR is orthologous in human gut crAssphages and shares a common ancestor with baboon-derived crAssphage; however, the locus has likely been lost in multiple lineages recently.
Shulin packages axonemal outer dynein arms for ciliary targeting
Authors: Mali Girish R. , Abid Ali Ferdos , Lau Clinton K. , Begum Farida , Skehel Mark , Carter Andrew P.
Published: September 2020

The main force generators in eukaryotic cilia and flagella are axonemal outer dynein arms (ODAs). During cilio-genesis, these ∼1.8 MDa complexes are assembled in the cytoplasm and targeted to cilia via an unknown mechanism. Here we use the ciliateTetrahymenato identify two novel factors (Q22YU3 and Q22MS1) which bind ODAs in the cytoplasm and are required for their delivery to cilia. We show that Q22YU3, which we name Shulin, locks the ODA motor domains into a closed conformation and inhibits motor activity. Cryo-EM reveals how Shulin stabilizes this compact form of ODAs by binding to the dynein tails. Our findings provide a molecular explanation for how newly assembled dyneins are packaged for delivery to the cilia.
Improvements to the ARTIC multiplex PCR method for SARS-CoV-2 genome sequencing using nanopore
Authors: Tyson John R , James Phillip , Stoddart David , Sparks Natalie , Wickenhagen Arthur , Hall Grant , Choi Ji Hyun , Lapointe Hope , Kamelian Kimia , Smith Andrew D , Prystajecky Natalie , Goodfellow Ian , Wilson Sam J , Harrigan Richard , Snutch Terrance P , Loman Nicholas J , Quick Joshua
Published: September 2020

Genome sequencing has been widely deployed to study the evolution of SARS-CoV-2 with more than 90,000 genome sequences uploaded to the GISAID database. We published a method for SARS-CoV-2 genome sequencing (https://www.protocols.io/view/ncov-2019-sequencing-protocol-bbmuik6w) online on January 22, 2020. This approach has rapidly become the most popular method for sequencing SARS-CoV-2 due to its simplicity and cost-effectiveness. Here we present improvements to the original protocol: i) an updated primer scheme with 22 additional primers to improve genome coverage, ii) a streamlined library preparation workflow which improves demultiplexing rate for up to 96 samples and reduces hands-on time by several hours and iii) cost savings which bring the reagent cost down to £10 per sample making it practical for individual labs to sequence thousands of SARS-CoV-2 genomes to support national and international genomic epidemiology efforts.
Dynamics of the HD regulatory subdomain of PARP-1; substrate access and allostery in PARP activation and inhibition
Authors: Ogden Tom E.H. , Yang Ji-Chun , Schimpl Marianne , Easton Laura E. , Underwood Elizabeth , Rawlins Philip B. , McCauley Michael M. , Langelier Marie-France , Pascal John M. , Embrey Kevin J. , Neuhaus David
Published: September 2020

PARP-1 is a key early responder to DNA damage in eukaryotic cells. An allosteric mechanism links initial sensing of DNA single-strand breaks by PARP-1’s F1 and F2 domainsviaa process of further domain assembly to activation of the catalytic domain (CAT); synthesis and attachment of poly(ADP-ribose) (PAR) chains to protein sidechains then signals for assembly of DNA repair components. A key component in transmission of the allosteric signal is the HD subdomain of CAT, which alone bridges between the assembled DNA-binding domains and the active site in the ART subdomain of CAT. Here we present a study of isolated CAT domain from human PARP-1, using NMR-based dynamics experiments to analyse WT apo-protein as well as a set of inhibitor complexes (with veliparib, olaparib, talazoparib and EB-47) and point mutants (L713F, L765A and L765F), together with new crystal structures of the free CAT domain and inhibitor complexes. Variations in both dynamics and structures amongst these species point to a model for full-length PARP-1 activation where first DNA binding and then substrate interaction successively destabilise the folded structure of the HD subdomain to the point where its steric blockade of the active site is released and PAR synthesis can proceed.
Unsupervised clustering analysis of SARS-Cov-2 population structure reveals six major subtypes at early stage across the world
Authors: Li Yawei , Liu Qingyun , Zeng Zexian , Luo Yuan
Published: September 2020

Identifying the population structure of the newly emerged coronavirus SARS-CoV-2 has significant potential to inform public health management and diagnosis. As SARS-CoV-2 sequencing data accrued, grouping them into clusters is important for organizing the landscape of the population structure of the virus. Due to the limited prior information on the newly emerged coronavirus, we utilized four different clustering algorithms to group 16,873 SARS-CoV-2 strains, which automatically enables the identification of spatial structure for SARS-CoV-2. A total of six distinct genomic clusters were identified using mutation profiles as input features. Comparison of the clustering results reveals that the four algorithms produced highly consistent results, but the state-of-the-art unsupervised deep learning clustering algorithm performed best and produced the smallest intra-cluster pairwise genetic distances. The varied proportions of the six clusters within different continents revealed specific geographical distributions. In particular, our analysis found that Oceania was the only continent on which the strains were dispersively distributed into six clusters. In summary, this study provides a concrete framework for the use of clustering methods to study the global population structure of SARS-CoV-2. In addition, clustering methods can be used for future studies of variant population structures in specific regions of these fast-growing viruses.