bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethnicity and risk of death in patients hospitalised for COVID-19 infection in the UK: an observational cohort study in an urban catchment area
Authors: Sapey E , Gallier S , Mainey C , Nightingale P , McNulty D , Crothers H , Evison F , Reeves K , Pagano D , Denniston A.K , Nirantharakumar K. , Diggle P , Ball S
Published: May 2020

Background

Studies suggest that certain Black and Asian Minority Ethnic groups experience poorer outcomes from COVID-19 but these studies have not provided insight into potential reasons for this. We hypothesised that outcomes would be poorer for those of South Asian ethnicity hospitalised from a confirmed SARS-CoV-2 infection, once confounding factors, health seeking behaviours and community demographics were considered and that this might reflect a more aggressive disease course in these patients.

Methods

Patients with confirmed SARS-CoV-2 infection requiring admission to University Hospitals Birmingham NHS Foundation Trust(UHB) in Birmingham UK between 10thMarch 2020-17thApril 2020 were included. Standardised Admission Ratio(SAR) and Standardised Mortality Ratio(SMR) were calculated using observed COVID-19 admissions/deaths and 2011 census data. Hazard Ratio (aHR) for mortality was estimated using Cox proportional hazard model adjusting and propensity score matching.

Results

All patients admitted to UHB with COVID-19 during the study period were included (2217 in total). Fifty-eight percent were male, 69.5% White and the majority (80.2%) had co-morbidities. Eighteen and a half percent were of South Asian ethnicity, and these patients were more likely to be younger, have no co-morbidities but twice the prevalence of diabetes than White patients. SAR and SMR suggested more admissions and deaths in South Asian patients than would be predicted and they were more likely to present with severe disease despite no delay in presentation since symptom onset. South Asian ethnicity was associated with an increased risk of death; both by Cox regression (Hazard Ratio 1.4 (95%CI 1.2–1.8) after adjusting for age, sex, deprivation and comorbidities and by propensity score matching, matching for the same factors but categorising ethnicity into South Asian or not (Hazard ratio 1.3 (1.0-1.6)).

Conclusions

Those of South Asian ethnicity appear at risk of worse COVID-19 outcomes, further studies need to establish the underlying mechanistic pathways.
IKONOS: An intelligent tool to support diagnosis of Covid-19 by texture analysis of x-ray images
Authors: Gomes Juliana C. , de F. Barbosa Valter A. , Santana Maira A. , Bandeira Jonathan , Valença Mêuser Jorge Silva , de Souza Ricardo Emmanuel , Ismael Aras Masood , dos Santos Wellington P.
Published: May 2020

In late 2019, the SARS-Cov-2 spread worldwide. The virus has high rates of proliferation and causes severe respiratory symptoms, such as pneumonia. There is still no specific treatment and diagnosis for the disease. The standard diagnostic method for pneumonia is chest X-ray image. There are many advantages to using Covid-19 diagnostic X-rays: low cost, fast and widely available. We propose an intelligent system to support diagnosis by X-ray images. We tested Haralick and Zernike moments for feature extraction. Experiments with classic classifiers were done. Support vector machines stood out, reaching an average accuracy of 89.78%, average recall and sensitivity of 0.8979, and average precision and specificity of 0.8985 and 0.9963 respectively. The system is able to differentiate Covid-19 from viral and bacterial pneumonia, with low computational cost.
A preliminary study on analytical performance of serological assay for SARS-CoV-2 IgM/IgG and application in clinical practice
Authors: Zhou Quan , Zhu Danping , Yan Huacheng , Quan Jingwen , Kuang Zhenzhan , Zhang Weiyun , Huang Ling , Lei Ting , Liu Jiahui , Xiao Bin , Luo Aiwu , Sun Zhaohui , Li Linhai
Published: May 2020

Objective

To investigate the performance of serological test and dynamics of serum antibody with the progress of SARS-CoV-2 infections.

Methods

A total of 419 patients were enrolled including 19 confirmed cases and 400 patients from fever clinics. Their serial serum samples collected during the hospitalization were menstruated for IgM and IgG against SARS-CoV-2 using gold immunochromatographic assay and chemiluminescence immunoassay. We investigated whether thermal inactivation could affect the results of antibody detection. The dynamics of antibodies with the disease progress and false positive factors for antibody testing were also analyzed.

Results

The positive rate of IgG detection was 91.67% and 83.33% using two CLIA, respectively. However, the IgM positive rate was dramatically declined might due to the lack of blood samples at early stages of the disease. The chemiluminescence immunoassay had a favorable but narrow linear range. Our work showed increased IgG values in serums from virus-negative patients and four negative samples were IgG weak-positive after thermal incubation. Our data showed the specificity of viral N+S proteins was higher than single antigen. Unlike generally thought that IgM appeared earlier than IgG, there is no certain chronological order of IgM and IgG seroconversion in COVID-19 patients. It was difficult to detect antibodies in asymptomatic patients suggesting that their low viral loads were not enough to cause immune response. Analysis of common interferent in three IgG false-positive patients, such as rheumatoid factor, proved that false positives were not caused by these interfering substances and antigenic cross-reaction.

Conclusions

Viral serological test is an effective means for SARS-CoV-2 infect detection using both chemiluminescence immunoassay and gold immunochromatographic assay. Chemiluminescence immunoassay against multi-antigens has obvious advantages but still need improve in reducing false positives.
Epidemiological Transition of Covid-19 in India from Higher to Lower HDI States and Territories: Implications for Prevention and Control
Authors: Gupta Rajeev , Dhamija Rajinder K , Gaur Kiran
Published: May 2020

Background & Objective

Social determinants of evolving covid-19 pandemic have not been well studied. To determine trends in transition of this epidemic in India we performed a study in states at various levels of human development index (HDI).

Methods

We used publicly available data sources to track progress of covid-19 epidemic in India in different states and territories where it was reported in significant numbers. The states (n=20) were classified into tertiles of HDI and weekly trends in cases and deaths plotted from 15 March to 2 May 2020. To assess association of HDI with state-level covid-19 burden we performed Pearson’s correlation. Logarithmic trends were evaluated for calculation of projections. A microlevel study was performed in select urban agglomerations for identification of socioeconomic status (SES) differentials.

Results

There is wide regional variation in covid-19 cases and deaths in India from mid-March to early-May 2020. High absolute numbers have been reported from states of Maharashtra, Gujarat, Delhi, Madhya Pradesh, Rajasthan and Tamilnadu. Growth rate in cases and deaths is slow in high HDI states while it has increased rapidly in middle and lower HDI states. In mid-March 2020 there was a strong positive correlation of state-level HDI with weekly covid-19 cases (r= 0.37, 0.40) as well as deaths (r= 0.31, 0.42). This declined by early-May for cases (r= 0.04, 0.06) as well as deaths (r= - 0.005, 0.001) with significant negative logarithmic trend (cases R squared= 0.92; deaths R squared= 0. 84). These trends indicate increasing cases and deaths in low HDI states. Projection reveals that this trend is likely to continue to early-June 2020. Microlevel evaluation shows that urban agglomerations are major focus of the disease in India and it has transited from middle SES to low SES locations.

Conclusion

There is wide variability in burden of covid-19 in India. Slow growth and flattening of curve is observed in high-HDI states while disease is increasing in mid and lower HDI states. Projections reveal that lower HDI states would achieve parity with high HDI states by early-June 2020. Covid-19 is mostly present in urban agglomerations where it has transited from upper-middle to low SES locations. Public health strategies focusing on urban low SES locations and low HDI states are crucial to decrease covid-19 burden in India.
Weather Conditions and COVID-19 Transmission: Estimates and Projections
Authors: Xu Ran , Rahmandad Hazhir , Gupta Marichi , DiGennaro Catherine , Ghaffarzadegan Navid , Jalali Mohammad S.
Published: May 2020

Background

Understanding and projecting the spread of COVID-19 requires reliable estimates of how weather components are associated with the transmission of the virus. Prior research on this topic has been inconclusive. Identifying key challenges to reliable estimation of weather impact on transmission we study this question using one of the largest assembled databases of COVID-19 infections and weather.

Methods

We assemble a dataset that includes virus transmission and weather data across 3,739 locations from December 12, 2019 to April 22, 2020. Using simulation, we identify key challenges to reliable estimation of weather impacts on transmission, design a statistical method to overcome these challenges, and validate it in a blinded simulation study. Using this method and controlling for location-specific response trends we estimate how different weather variables are associated with the reproduction number for COVID-19. We then use the estimates to project the relative weather-related risk of COVID-19 transmission across the world and in large cities.

Results

We show that the delay between exposure and detection of infection complicates the estimation of weather impact on COVID-19 transmission, potentially explaining significant variability in results to-date. Correcting for that distributed delay and offering conservative estimates, we find a negative relationship between temperatures above 25 degrees Celsius and estimated reproduction number (Ȓ), with each degree Celsius associated with a 3.1% (95% CI, 1.5% to 4.8%) reduction inȒ. Higher levels of relative humidity strengthen the negative effect of temperature above 25 degrees. Moreover, one millibar of additional pressure increasesȒby approximately 0.8 percent (95% CI, 0.6% to 1%) at the median pressure (1016 millibars) in our sample. We also find significant positive effects for wind speed, precipitation, and diurnal temperature onȒ. Sensitivity analysis and simulations show that results are robust to multiple assumptions. Despite conservative estimates, weather effects are associated with a 43% change inȒbetween the 5thand 95thpercentile of weather conditions in our sample.

Conclusions

These results provide evidence for the relationship between several weather variables and the spread of COVID-19. However, the (conservatively) estimated relationships are not strong enough to seasonally control the epidemic in most locations.
Multiple early introductions of SARS-CoV-2 into a global travel hub in the Middle East
Authors: Tayoun Ahmad Abou , Loney Tom , Khansaheb Hamda , Ramaswamy Sathishkumar , Harilal Divinlal , Deesi Zulfa Omar , Varghese Rupa Murthy , Al Suwaidi Hanan , Alkhajeh Abdulmajeed , AlDabal Laila Mohamed , Uddin Mohammed , Hamoudi Rifat , Halwani Rabih , Senok Abiola , Hamid Qutayba , Nowotny Norbert , Alsheikh-Ali Alawi
Published: May 2020

International travel played a significant role in the early global spread of SARS-CoV-2. Understanding transmission patterns from different regions of the world will further inform global dynamics of the pandemic. Using data from Dubai in the United Arab Emirates (UAE), a major international travel hub in the Middle East, we establish SARS-CoV-2 full genome sequences from the index and early COVID-19 patients in the UAE. The genome sequences are analysed in the context of virus introductions, chain of transmissions, and possible links to earlier strains from other regions of the world. Phylogenetic analysis showed multiple spatiotemporal introductions of SARS-CoV-2 into the UAE from Asia, Europe, and the Middle East during the early phase of the pandemic. We also provide evidence for early community-based transmission and catalogue new mutations in SARS-CoV-2 strains in the UAE. Our findings contribute to the understanding of the global transmission network of SARS-CoV-2.
Ethnicity, comorbidity, socioeconomic status, and their associations with COVID-19 infection in England: a cohort analysis of UK Biobank data
Authors: Prats-Uribe Albert , Paredes Roger , Prieto-Alhambra Daniel
Published: May 2020

Objectives

Recent data suggest higher COVID-19 rates and severity in Black, Asian, and minority ethnic (BAME) communities. The mechanisms underlying such associations remain unclear. We aimed to study the association between ethnicity and risk of COVID-19 infection and disentangle any correlation with socioeconomic deprivation or previous comorbidity.

Design

Prospective cohort.

Setting

UK Biobank linked to Hospital Episode Statistics (HES) and COVID-19 tests until 14 April 2020.

Participants

UK Biobank participants from England, excluding drop-outs and deaths.

Main measures

COVID-19 infection based on a positive PCR test. Ethnicity was self-reported and classified using Office of National Statistics groups. Socioeconomic status was based on index of multiple deprivation quintiles. Comorbidities were self-reported and completed from HES.

Analyses

Multivariable Poisson analysis to estimate incidence rate ratios of COVID-19 infection according to ethnicity, adjusted for socioeconomic status, alcohol drinking, smoking, body mass index, age, sex, and comorbidity.

Results

415,582 participants were included, with 1,416 tested and 651 positive for COVID-19. The incidence of COVID-19 was 0.61% (95% CI: 0.46%-0.82%) in Black/Black British participants, 0.32% (0.19%-0.56%) in ‘other’ ethnicities, 0.32% (0.23%-0.47%) in Asian/Asian British, 0.30% (0.11%-0.80%) in Chinese, 0.16% (0.06%-0.41%) in mixed, and 0.14% (0.13%-0.15%) in White. Compared with White participants, Black/Black British participants had an adjusted relative risk (RR) of 3.30 (2.39-4.55), Chinese participants 3.00 (1.11-8.06), Asian/Asian British participants 2.04 (1.36-3.07), ‘other’ ethnicities 1.93 (1.08-3.45), and mixed ethnicities 1.07 (0.40-2.86). Socioeconomic status (adjusted RR 1.93 (1.51-2.46) for the most deprived), obesity (adjusted RR 1.04 (1.02-1.05) per kg/m2) and comorbid hypertension, chronic obstructive pulmonary disease, asthma, and specific renal diseases were also associated with increased risk of COVID-19.

Conclusions

COVID-19 rates in the UK are higher in BAME communities, those living in deprived areas, obese patients, and patients with previous comorbidity. Public health strategies are needed to reduce COVID-19 infections among the most susceptible groups.
ProgNet: Covid-19 prognosis using recurrent and convolutional neural networks
Authors: Fakhfakh Mohamed , Bouaziz Bassem , Gargouri Faiez , Chaari Lotfi
Published: May 2020

—Humanity is facing nowadays a dramatic pandemic episode with the Coronavirus propagation over all continents. The Covid-19 disease is still not well characterized, and many research teams all over the world are working on either therapeutic or vaccination issues. Massive testing is one of the main recommendations. In addition to laboratory tests, imagery-based tools are being widely investigated. Artificial intelligence is therefore contributing to the efforts made to face this pandemic phase.

Regarding patients in hospitals, it is important to monitor the evolution of lung pathologies due to the virus. A prognosis is therefore of great interest for doctors to adapt their care strategy. In this paper, we propose a method for Covid-19 prognosis based on deep learning architectures. The proposed method is based on the combination of a convolutional and recurrent neural networks to classify multi-temporal chest X-ray images and predict the evolution of the observed lung pathology. When applied to radiological time-series, promising results are obtained with an accuracy rates higher than 92%.
Mitochondrial cytochromecliberates the nucleophosmin-sequestered ARF tumor suppressor in the nucleolus
Authors: González-Arzola Katiuska , Díaz-Quintana Antonio , Bernardo-García Noelia , Á. Casado-Combreras Miguel , Elena-Real Carlos A. , Velázquez-Cruz Alejandro , Gil-Caballero Sergio , Velázquez-Campoy Adrián , Szulc Elzbieta , Ayala Isabel , Arranz Rocío , Salvatella Xavier , Valpuesta José M. , Hermoso Juan A. , De la Rosa Miguel A. , Díaz-Moreno Irene
Published: May 2020

The alternative reading frame (ARF) protein is crucial in the cellular response to oncogenic stress, being likewise the second most frequently inactivated gene in a wide spectrum of human cancers. ARF is usually sequestered in the nucleolus by the well-known oncogenic nucleophosmin (NPM) protein and is liberated in response to cell damage to exhibit its tumor-suppressor ability. However, the mechanism underlying ARF activation is unknown. Here we show that mitochondria-to-nucleus translocation of cytochromecupon DNA damage leads to the break-off of the NPM-ARF ensemble and subsequent release of ARF from the nucleoli. Our structural and subcellular data support a molecular model in which the hemeprotein triggers the extended-to-compact conformation of NPM and competes with ARF for binding to NPM.
Genetic architecture of a body color cline inDrosophila americana
Authors: Sramkoski Lisa L. , McLaughlin Wesley N. , Cooley Arielle M. , Yuan David C. , John Alisha , Wittkopp Patricia J.
Published: May 2020

Phenotypic variation within a species is often structured geographically in clines. InDrosophila americana, a longitudinal cline for body color exists within North America that appears to be due to local adaptation. Thetanandebonygenes have been hypothesized to contribute to this cline, with alleles of both genes that lighten body color found inD. americana. These alleles are similar in sequence and function to the allele fixed inD. americana’smore lightly pigmented sister species,Drosophila novamexicana. To test this hypothesis, we examined the frequency and geographic distribution ofD. novamexicana-like alleles oftanandebonyinD. americana. Among alleles from over 100 strains ofD. americanaisolated from 21 geographic locations, we failed to identify additional alleles oftanorebonywith as much sequence similarity toD. novamexicanaas the alleles previously described. However, using genetic analysis of 51D. americanastrains derived from 20 geographic locations, we identified one new allele ofebonyand one new allele oftansegregating inD. americanathat are functionally equivalent to theD. novamexicanaallele. An additional 5 alleles oftanalso showed marginal evidence of functional similarity. Given the rarity of these alleles, however, we conclude that they are unlikely to be driving the pigmentation cline. Indeed, phenotypic distributions of the 51 backcross populations analyzed indicate a more complex genetic architecture, with diversity in the number and effects of loci altering pigmentation observed both within and among populations ofD. americana. This genetic heterogeneity poses a challenge to association studies and genomic scans for clinal variation, but might be common in natural populations.
CD8 T cells induce destruction of bone marrow stromal niches and hematopoietic stem cell dysfunction in chronic viral infections
Authors: Isringhausen Stephan , Kovtonyuk Larisa , Suessbier Ute , Kraeutler Nike J. , Gomariz Alvaro , Helbling Patrick M. , Wong Hui Chyn , Nagasawa Takashi , Manz Markus G. , Oxenius Anette , Nombela-Arrieta César
Published: May 2020

Chronic viral infections are associated with hematopoietic suppression and bone marrow (BM) failure, which have been linked to hematopoietic stem cell (HSC) exhaustion. However, how persistent viral infectious challenge and ensuing inflammatory responses target BM tissues and perturb hematopoietic homeostasis remains poorly understood. Here, we combine extensive functional analyses with advanced 3D microscopy to demonstrate that chronic infection with lymphocytic choriomeningitis virus clone 13 results in the long-term impairment of HSC function, concomitant with a persistent destruction of the HSC-supportive stromal networks of mesenchymal CXCL12-abundant reticular cells. During infections, long lasting injuries and aberrant transcriptional programs of the stromal infrastructure diminish the capacity of the BM microenvironment to adequately support HSC maintenance. Mechanistically, BM immunopathology is elicited by virus-specific, activated CD8 T cells, which accumulate in the BM via interferon-dependent mechanisms. Combined inhibition of type I and II IFN pathways completely preempts viral-mediated degeneration of CARc networks and protects HSCs from persistent dysfunction. Hence, viral infections and ensuing immune reactions chronically interfere with BM function by disrupting essential stromal-derived, hematopoietic-supporting cues.
Conservative route to genome compaction in a miniature annelid
Authors: Martín-Durán José M. , Vellutini Bruno C. , Marlétaz Ferdinand , Cetrangolo Viviana , Cvetesic Nevena , Thiel Daniel , Henriet Simon , Grau-Bové Xavier , Carrillo-Baltodano Allan M. , Gu Wenjia , Kerbl Alexandra , Marquez Yamile , Bekkouche Nicolas , Chourrout Daniel , Gómez-Skarmeta Jose Luis , Irimia Manuel , Lenhard Boris , Worsaae Katrine , Hejnol Andreas
Published: May 2020

The causes and consequences of genome reduction in animals are unclear, because our understanding of this process mostly relies on lineages with often exceptionally high rates of evolution. Here, we decode the compact 73.8 Mb genome of Dimorphilus gyrociliatus, a meiobenthic segmented worm. The D. gyrociliatus genome retains traits classically associated with larger and slower-evolving genomes, such as an ordered, intact Hox cluster, a generally conserved developmental toolkit, and traces of ancestral bilaterian linkage. Unlike some other animals with small genomes, the analysis of the D. gyrociliatus epigenome revealed canonical features of genome regulation, excluding the presence of operons and trans-splicing. Instead, the gene dense D. gyrociliatus genome presents a divergent Myc pathway, a key physiological regulator of growth, proliferation, and genome stability in animals. Altogether, our results uncover a conservative route to genome compaction in annelids, reminiscent of that observed in the vertebrate Takifugu rubripes.
Efficient Estimation of Large-Scale Spatial Capture-Recapture Models
Authors: Turek Daniel , Milleret Cyril , Ergon Torbjørn , Brøseth Henrik , de Valpine Perry
Published: May 2020

Capture-recapture methods are a common tool in ecological statistics, which have been extended to spatial capture-recapture models for data accompanied by location information. However, standard formulations of these models can be unwieldy and computationally intractable for large spatial scales, many individuals, and/or activity center movement. We provide a cumulative series of methods that yield dramatic improvements in Markov chain Monte Carlo (MCMC) estimation for two examples. These include removing unnecessary computations, integrating out latent states, vectorizing declarations, and restricting calculations to the locality of individuals. Our approaches leverage the flexibility provided by thenimbleR package. In our first example, we demonstrate an improvement in MCMC efficiency (the rate of generating effectively independent posterior samples) by a factor of 100. In our second example, we reduce the computing time required to generate 10,000 posterior samples from 4.5 hours down to five minutes, and realize an increase in MCMC efficiency by a factor of 25. We also explain how these approaches can be applied generally to other spatially-indexed hierarchical models. R code is provided for all examples, as well as an executable web-appendix.
A metabolic CRISPR-Cas9 screen in Chinese hamster ovary cells identifies glutamine-sensitive genes
Authors: la Cour Karottki Karen Julie , Hefzi Hooman , Li Songyuan , Pedersen Lasse Ebdrup , Spahn Philipp , Joshi Chintan , Ruckerbauer David , Bort Juan Hernandez , Thomas Alex , Lee Jae Seong , Borth Nicole , Lee Gyun Min , Kildegaard Helene Faustrup , Lewis Nathan E.
Published: May 2020

Over the past decades, optimization of media formulation and feeding strategies have fueled a many-fold improvement in CHO-based biopharmaceutical production. While Design of Experiments (DOE) and media screens have led to many advances, genome editing offers another avenue for enhancing cell metabolism and bioproduction. However the complexity of metabolism, involving thousands of genes, makes it unclear which engineering strategies will result in desired traits. Here we developed a comprehensive pooled CRISPR screen for CHO cell metabolism, including ∼16,000 gRNAs against ∼2500 metabolic enzymes and regulators. We demonstrated the value of this screen by identifying a glutamine response network in CHO cells. Glutamine is particularly important since it is often substantially over-fed to drive increased TCA cycle flux but can lead to accumulation of toxic ammonia. Within the glutamine-response network, the deletion of a novel and poorly characterized lipase,Abhd11, was found to substantially increase growth in glutamine-free media by altering the regulation of the TCA cycle. Thus, the screen provides an invaluable targeted platform to comprehensively study genes involved in any metabolic trait.
Stable kinetochore–microtubule attachments restrict MTOC position and spindle elongation in acentrosomal oocytes
Authors: Courtois Aurélien , Yoshida Shuhei , Kitajima Tomoya S.
Published: May 2020

In mouse oocytes, acentriolar MTOCs functionally replace centrosomes and act as microtubule nucleation sites. Microtubules nucleated from MTOCs initially assemble into an unorganized ball-like structure, which then transforms into a bipolar spindle carrying MTOCs at its poles, a process called spindle bipolarization. In mouse oocytes, spindle bipolarization is promoted by kinetochores but the mechanism by which kinetochore–microtubule attachments contribute to spindle bipolarity remains unclear. This study demonstrates that the stability of kinetochore–microtubule attachment is essential for confining MTOC positions at the spindle poles and for limiting spindle elongation. MTOC sorting is gradual and continues even in the metaphase spindle. When stable kinetochore–microtubule attachments are disrupted, the spindle is unable to restrict MTOCs at its poles and fails to terminate its elongation. Stable kinetochore fibers are directly connected to MTOCs and to the spindle poles, and thus may serve as a measure that defines proper spindle length. These findings reinforce the hypothesis that kinetochores act as scaffolds for acentrosomal spindle bipolarity.
Single-cell atlas of human developing and azoospermia patients’ testicles reveals the roadmap and defects in somatic microenvironment
Authors: Zhao LiangYu , Yao ChenCheng , Xing XiaoYu , Jing Tao , Li Peng , Zhu ZiJue , Yang Chao , Zhai Jing , Tian RuHui , Chen HuiXing , Luo JiaQiang , Liu NaChuan , Deng ZhiWen , Lin XiaoHan , Li Na , Fang Jing , Sun Jie , Wang ChenChen , Zhou Zhi , Li Zheng
Published: May 2020

Non-obstructive azoospermia (NOA) affects 1% of men. However, the unknowns of NOA pathogenesis and even normal spermatogenic microenvironment establishment severely limit the clinical efficacy of NOA treatment. We profiled > 80,000 human testicular single-cell transcriptomes from 10 healthy donors spanning the range from infant to adult and 7 NOA patients. Sertoli cells, which form the scaffold in the testicular microenvironment, exhibited the most obvious damages in NOA patients. We identified the roadmap of Sertoli cell maturation. Notably, Sertoli cells of patients with congenital causes (Klinefelter syndrome and Y chromosome microdeletions) are mature but with abnormal immune response, while the cells in idiopathic NOA (iNOA) are basically physiologically immature. Furthermore, inhibition of Wnt signaling promotes the maturation of Sertoli cells from iNOA patients, allowing these cells to regain their ability to support germ cell survival. We provide a novel perspective on the development of diagnostic methods and therapeutic targets for NOA.
Thermogenic genes are blunted whereas brown adipose tissue identity is preserved in human obesity
Authors: Jespersen Naja Z. , Andersen Maja W. , Jensen Verena H. , Stærkær Thit W , Severinsen Mai C.K. , Peijs Lone , Soares Ricardo , Forss Isabel , Andersen Eline S. , Hahn Christoffer H. , Homøe Preben , Mandrup Susanne , Pedersen Bente K. , Nielsen Søren , Scheele Camilla
Published: May 2020

Obesity associates with a reduction in cold-induced glucose tracer uptake in brown adipose tissue in humans, suggesting loss of thermogenic capacity. We therefore hypothesized that a whitening of BAT occurs in obesity and assessed the molecular characteristics of deep neck BAT in a cohort of 24 normal weight, 24 overweight and 22 obese individuals in comparison with subcutaneous abdominal white adipose tissue (WAT). We found that the major marker of BAT thermogenesis,UCP1, was associated with central but not general obesity. We performed transcriptomic analysis of BAT in a cohort of 27 individuals classified as normal weight, over-weight or obese, and additionally four subjects with type 2 diabetes (T2DM), dispersed among the 3 BMI groups. We identified 3204 differentially expressed genes between BAT and WAT in samples from normal weight individuals, including genes involved in thermogenesis, but also revealing differences in developmental and immune system related genes. In BAT from individuals with overweight or obesity, 202 genes were downregulated and 66 of these were involved in cellular respiratory pathways, likely reflecting previously observed reduction in thermogenic function with obesity. Importantly, most BAT selective genes werenotaffected, and isolated adipose progenitors differentiated into thermogenic adipocytes with equal frequency regardless of BMI group. In conclusion, our data suggest a retained BAT identity, with a selective reduction of thermogenic genes, in human obesity.
Novel NGS Pipeline for Virus Discovery from a Wide Spectrum of Hosts and Sample Types
Authors: Plyusnin Ilya , Kant Ravi , Jääskeläinen Anne J. , Sironen Tarja , Holm Liisa , Vapalahti Olli , Smura Teemu
Published: May 2020

The study of the microbiome data holds great potential for elucidating the biological and metabolic functioning of living organisms and their role in the environment. Metagenomic analyses have shown that humans, along with e.g. domestic animals, wildlife and arthropods, are colonized by an immense community of viruses. The current Coronavirus pandemic (COVID-19) heightens the need to rapidly detect previously unknown viruses in an unbiased way. The increasing availability of metagenomic data in this era of next-generation sequencing (NGS), along with increasingly affordable sequencing technologies, highlight the need for reliable and comprehensive methods to manage such data. In this article, we present a novel stand-alone pipeline called LAZYPIPE for identifying both previously known and novel viruses in host-associated or environmental samples and give examples of virus discovery based on it. LAZYPIPE is a Unix-based pipeline for automated assembling and taxonomic profiling of NGS libraries implemented as a collection of C++, Perl, and R scripts.
Lung biopsy cells transcriptional landscape from COVID-19 patient stratified lung injury in SARS-CoV-2 infection through impaired pulmonary surfactant metabolism
Authors: Islam Abul Bashar Mir Md. Khademul , Khan Md. Abdullah-Al-Kamran
Published: May 2020

Clinical management of COVID-19 is still complicated due to the lack of therapeutic interventions to reduce the breathing problems, respiratory complications and acute lung injury – which are the major complications of most of the mild to critically affected patients and the molecular mechanisms behind these clinical features are still largely unknown. In this study, we have used the RNA-seq gene expression pattern in the COVID-19 affected lung biopsy cells and compared it with the effects observed in typical cell lines infected with SARS-CoV-2 and SARS-CoV. We performed functional overrepresentation analyses using these differentially expressed genes to signify the processes/pathways which could be deregulated during SARS-CoV-2 infection resulting in the symptomatic impairments observed in COVID-19. Our results showed that the significantly altered processes include inflammatory responses, antiviral cytokine signaling, interferon responses, and interleukin signaling etc. along with downmodulated processes related to lung’s functionality like-responses to hypoxia, lung development, respiratory processes, cholesterol biosynthesis and surfactant metabolism. We also found that the viral protein interacting host’s proteins involved in similar pathways like: respiratory failure, lung diseases, asthma, and hypoxia responses etc., suggesting viral proteins might be deregulating the processes related to acute lung injury/breathing complications in COVID-19 patients. Protein-protein interaction networks of these processes and map of gene expression of deregulated genes revealed that several viral proteins can directly or indirectly modulate the host genes/proteins of those lung related processes along with several host transcription factors and miRNAs. Surfactant proteins and their regulators SPD, SPC, TTF1 etc. which maintains the stability of the pulmonary tissue are found to be downregulated through viral NSP5, NSP12 that could lead to deficient gaseous exchange by the surface films. Mitochondrial dysfunction owing to the aberration of NDUFA10, NDUFAF5, SAMM50 etc. by NSP12; abnormal thrombosis in lungs through atypical PLAT, EGR1 functions by viral ORF8, NSP12; dulled hypoxia responses due to unusual shift in HIF-1 downstream signaling might be the causative elements behind the acute lung injury in COVID-19 patients. Our study put forward a distinct mechanism of probable virus induced lung damage apart from cytokine storm and advocate the need of further research for alternate therapy in this direction.
A low-cost pipeline for soil microbiome profiling
Authors: Bollmann-Giolai Anita , Giolai Michael , Heavens Darren , Macaulay Iain , Malone Jacob , Clark Matthew D.
Published: May 2020

Background

Common bottlenecks in environmental microbiome studies are the consumable and personnel costs necessary for genomic DNA extraction and sequencing library construction. This is harder for challenging environmental samples such as soil, which is rich in PCR inhibitors. To address this, we have established a low-cost genomic DNA extraction method for inhibitor rich samples alongside an Illumina-compatible 16S and ITS rRNA gene amplicon library preparation workflow that uses common laboratory equipment. We evaluated the performance of our genomic DNA extraction method against two leading commercial soil genomic DNA kits (MoBio PowerSoil® and MP Biomedicals™ FastDNA™ SPIN) and a recently published non-commercial extraction method by Zou et al. (2017). Our benchmarking experiment used four different soil types (coniferous, broad leafed, and mixed forest plus a standardised cereal crop compost mix) assessing the quality and quantity of the extracted genomic DNA by analysing sequence variants of 16S V4 and ITS rRNA amplicons.

Results

We found that our genomic DNA extraction method compares well to both commercially available genomic DNA extraction kits in DNA quality and quantity. The MoBio PowerSoil® kit, which relies on silica column-based DNA extraction with extensive washing delivered the cleanest genomic DNA e.g. best A260:A280 and A260:A230 absorbance ratios. The MP Biomedicals™ FastDNA™ SPIN kit, which uses a large amount of binding material, yielded the most genomic DNA. Our method fits between the two commercial kits, producing both good yields and clean genomic DNA with fragment sizes of approximately 10 kb. Comparative analysis of detected amplicon sequence variants shows that our method correlates well with the two commercial kits.

Conclusion

Here we present a low-cost genomic DNA extraction method for inhibitor rich sample types such as soil that can be coupled to an Illumina-compatible simple two step amplicon library construction workflow for 16S V4 and ITS marker genes. Our method delivers high quality genomic DNA at a fraction of the cost of commercial kits and enables cost-effective, large scale amplicon sequencing projects. Notably our extracted gDNA molecules are long enough to be suitable for downstream techniques such as full gene sequencing or even metagenomics shotgun approaches using long reads (PacBio or Nanopore), 10x Genomics linked reads, Dovetail genomics etc.
Methods for quantitative susceptibility and R2* mapping in whole post-mortem brains at 7T
Authors: Wang Chaoyue , Foxley Sean , Ansorge Olaf , Bangerter-Christensen Sarah , Chiew Mark , Leonte Anna , Menke Ricarda AL , Mollink Jeroen , Pallebage-Gamarallage Menuka , Turner Martin R , Miller Karla L , Tendler Benjamin C.
Published: May 2020

Susceptibility weighted magnetic resonance imaging (MRI) is sensitive to the local concentration of iron and myelin. Here, we describe a robust image processing pipeline for quantitative susceptibility mapping (QSM) and R2* mapping of fixed post-mortem, whole-brain data. Using this pipeline, we compare the resulting quantitative maps in brains from patients with amyotrophic lateral sclerosis (ALS) and controls, with validation against iron and myelin histology.

Twelve post-mortem brains were scanned with a multi-echo gradient echo sequence at 7T, from which susceptibility and R2* maps were generated. Semi-quantitative histological analysis for ferritin (the principal iron storage protein) and myelin proteolipid protein was performed in the primary motor, anterior cingulate and visual cortices.

Magnetic susceptibility and R2* values in primary motor cortex were higher in ALS compared to control brains. Magnetic susceptibility and R2* showed positive correlations with both myelin and ferritin estimates from histology. Four out of nine ALS brains exhibited clearly visible hyperintense susceptibility and R2* values in the primary motor cortex.

Our results demonstrate the potential for MRI-histology studies in whole, fixed post-mortem brains to investigate the biophysical source of susceptibility weighted MRI signals in neurodegenerative diseases like ALS.
3D Additive Manufactured Composite Scaffolds with Antibiotic-loaded Lamellar Fillers for Bone Infection Prevention and Tissue Regeneration
Authors: Cámara-Torres María , Duarte Stacy , Sinha Ravi , Egizabal Ainhoa , Álvarez Noelia , Bastianini Maria , Sisani Michele , Scopece Paolo , Scatto Marco , Bonetto Alessandro , Marcomini Antonio , Sanchez Alberto , Patelli Alessandro , Mota Carlos , Moroni Lorenzo
Published: May 2020

Bone infections following open bone fracture or implant surgery remain a challenge in the orthopedics field. In order to avoid high doses of systemic drug administration, optimized local antibiotic release from scaffolds is required. 3D additive manufactured (AM) scaffolds made with biodegradable polymers are ideal to support bone healing in non-union scenarios and can be given antimicrobial properties by the incorporation of antibiotics. In this study, ciprofloxacin and gentamicin intercalated in the interlamellar spaces of magnesium aluminum layered double hydroxides (MgAl) and α-zirconium phosphates (ZrP), respectively, are dispersed within a thermoplastic polymer by melt compounding and subsequently processed via high temperature melt extrusion AM (∼190 °C) into 3D scaffolds. The inorganic fillers enable a sustained antibiotics release through the polymer matrix, controlled by antibiotics counterions exchange or pH conditions. Importantly, both antibiotics retain their functionality after the manufacturing process at high temperatures, as verified by their activity against both Gram + and Gram − bacterial strains. Moreover, scaffolds loaded with filler-antibiotic do not impair human mesenchymal stromal cells osteogenic differentiation, allowing matrix mineralization and the expression of relevant osteogenic markers. Overall, these results suggest the possibility of fabricating dual functionality 3D scaffolds via high temperature melt extrusion for bone regeneration and infection prevention.
Structural basis of ClpXP recognition and unfolding of ssrA-tagged substrates
Authors: Fei Xue , Bell Tristan A , Barkow Sarah R , Baker Tania A , Sauer Robert T
Published: May 2020

When ribosomes fail to complete normal translation, all cells have mechanisms to ensure degradation of the resulting partial proteins to safeguard proteome integrity. InE. coliand other eubacteria, the tmRNA system rescues stalled ribosomes and adds an ssrA tag or degron to the C-terminus of the incomplete protein, which directs degradation by the AAA+ ClpXP protease. Here, we present cryo-EM structures of ClpXP bound to the ssrA degron. C-terminal residues of the ssrA degron initially bind in the top of an otherwise closed ClpX axial channel and subsequently move deeper into an open channel. For short-degron protein substrates, we show that unfolding can occur directly from the initial closed-channel complex. For longer-degron substrates, our studies illuminate how ClpXP transitions from specific recognition into a nonspecific unfolding and translocation machine. Many AAA+ proteases and protein-remodeling motors are likely to employ similar multistep recognition and engagement strategies.
Mobility and infectiousness in the spatial spread of an emerging fungal pathogen
Authors: Langwig Kate E. , White J. Paul , Parise Katy L. , Kaarakka Heather M. , Redell Jennifer A. , DePue John E. , Scullon William H. , Foster Jeffrey T. , Kilpatrick A. Marm , Hoyt Joseph R.
Published: May 2020

Emerging infectious diseases can have devastating effects on host communities, causing population collapse and species extinctions. The timing of novel pathogen arrival into naïve species communities can have consequential effects that shape the trajectory of epidemics through populations. Pathogen introductions are often presumed to occur when hosts are highly mobile. However, spread patterns can be influenced by a multitude of other factors including host body condition and infectiousness.

White-nose syndrome (WNS) is a seasonal emerging infectious disease of bats, which is caused by the fungal pathogenPseudogymnoascus destructans. Within-site transmission ofP. destructansprimarily occurs over winter, however the influence of bat mobility and infectiousness on the seasonal timing of pathogen spread to new populations is unknown. We combined data on host population dynamics and pathogen transmission from 22 bat communities to investigate the timing of pathogen arrival and the consequences of varying pathogen arrival times on disease impacts.

We found that midwinter arrival of the fungus predominated spread patterns, suggesting that bats were most likely to spreadP. destructanswhen they are highly infectious, but have reduced mobility. In communities whereP. destructanswas detected in early winter, one species suffered higher fungal burdens and experienced more severe declines than at sites where the pathogen was detected later in the winter, suggesting that the timing of pathogen introduction had consequential effects for some bat communities. We also found evidence of source-sink population dynamics over winter, suggesting some movement among sites occurs during hibernation, even though bats at northern latitudes were thought to be fairly immobile during this period. Winter emergence behavior symptomatic of white-nose syndrome may further exacerbate these winter bat movements to uninfected areas.

Our results suggest that low infectiousness during host migration may have reduced the rate of expansion of this deadly pathogen, and that elevated infectiousness during winter plays a key role in seasonal transmission. Furthermore, our results highlight the importance of both accurate estimation of the timing of pathogen spread and the consequences of varying arrival times to prevent and mitigate the effects of infectious diseases.
Comparative severity analysis of colitis in C57BL/6 than BALB/c mice: A novel and rapid model of DSS induced colitis
Authors: Mukhopadhyay Sohini , Aich Palok
Published: May 2020

Colitis is a complex and multifactorial disease with unknown etiology. To understand colitis, a number of models were developed in mouse. Colitis, in these models, was induced using either chemicals or select bacteria. Dextran sulfate sodium (DSS) induced colitis model was used widely, over other models, because of the simpler properties of DSS and similarities of the model with colitis in humans. The available models of DSS induced colitis require either longer time to understand the chronic stages of the disease or a shorter time period to study the acute phase. Currently, no composite models exist that can be used to study the acute, chronic and recovery stages of colitis within a reasonably shorter period of time. In the current study, we have developed a newer model system in two differently immune biased (Th-1 and Th-2) mice strains using DSS. We have developed the DSS model to compare the response in C57BL/6 (Th1 biased) and BALB/c (Th2 biased) mice models. We have standardized the dosage for both C57BL/6 and BALB/c mice with zero mortality rates. Using the model developed we studied the acute, chronic and recovery phases of colitis. The differential responses of C57BL/6 and BALB/c revealed that the disease was more severe in C57Bl/6. BALB/c, on the contrary, recovered from the diseased condition more quickly. The current report will further help to unravel the disease etiology based on immunological background of the host.
Werewolf, there wolf: variants inHairlessassociated with hypotrichia and roaning in the lykoi cat breed
Authors: Buckley Reuben M. , Gandolfi Barbara , Creighton Erica K. , Pyne Connor A. , LeRoy Michelle L. , Senter David A. , Bouhan Delia M. , Gobble Johnny R. , Abitbol Marie , Lyons Leslie A. ,   99 Lives Consortium
Published: May 2020

A variety of cat breeds have been developed via novelty selection on aesthetic, dermatological traits, such as coat colors and fur types. A recently developed breed, the lykoi, was bred from cats with a sparse hair coat with roaning, implying full color and all white hairs. The lykoi phenotype is a form of hypotrichia, presenting as significant reduction in the average numbers of follicles per hair follicle group as compared to domestic shorthair cats, a mild to severe perifollicular to mural lymphocytic infiltration in 77% of observed hair follicle groups, and the follicles are often miniaturized, dilated, and dysplastic. Whole genome sequencing was conducted on a single lykoi cat that was a cross between two independently ascertained lineages. Comparison to the 99 Lives dataset of 194 non-lykoi cats suggested two variants in the cat homolog forHairless(HR:lysine demethylase and nuclear receptor corepressor) as candidate causal variants. The lykoi cat was a compound heterozygote for two loss of function variants inHR, an exon 3 c.1255_1256dupGT (chrB1:36040783), which should produce a stop codon at amino acid 420 (p.Gln420Serfs*100) and, an exon 18 c.3389insGACA (chrB1:36051555), which should produce a stop codon at amino acid position 1130 (p.Ser1130Argfs*29). Ascertainment of 14 additional cats from founder lineages from Canada, France and different areas of the USA identified four additional loss of functionHRvariants likely causing the highly similar phenotypic hair coat across the diverse cats. The novel variants inHRfor cat hypotrichia can now be established between minor differences in the phenotypic presentations.