bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic significance of PD-L1 in advanced non-small cell lung carcinoma
Authors: Zhao Yanjie , Shi Feng , Zhou Quan , Li Yuchen , Wu Jiangping , Wang Ruibin , Song Qingkun
Published: November 2020

This study aimed to investigate the prognostic value of PD-L1 in Chinese patients with non-small cell lung carcinoma (NSCLC).

In this retrospective study, 97 patients with NSCLC were consecutively recruited. The expression profiling of PD-1, PD-L1, p53 and Ki-67 was detected by immunohistochemistry. Median survival time was estimated by Kaplan–Meier survival curve with log-rank test. Risk factors were evaluated by Cox Proportional Hazards regression models.

The median tumor size was larger (3.5 cm) among patients with positive PD-L1 expression, compared to those with negative expression (2.0 cm; P < .01). Compared to those with negative PD-L1 expression, patients with positive PD-L1 expression had significantly higher rates of nerve invasion (26.3% vs 5.0%; P < .01), blood vessel invasion (47.4% vs 20.0%; P < .01) and lymph node metastasis (64.9% vs 27.5%; P < .01), more advanced tumor stage (P < .01) and Ki-67 index (P < .01). PD-L1 expression status was not significantly associated with disease-free (DFS) or overall survival (OS). However, for patients with advanced disease, PD-L1 positive expression was related to worse outcome (HR: 4.13; 95% CI: 1.06–16.12).

Positive PD-L1 expression is associated with more aggressive pathological features and poorer prognosis in advanced stage NSCLC.
Characteristics of blood glucose distribution in a health examination population in Sichuan (2009–2017)
Authors: Ding Fei , Nie Xin , Liao Jing , He Yong , Li Guixing
Published: November 2020

The prevalence of diabetes mellitus and impaired fasting glucose is rapidly increasing in the recent years. Hyperglycemia associated atherosclerosis and other complications are posing a serious threat to human health. The present study aimed to analyze the blood glucose distribution characteristics within a large size of health examination population of Sichuan province, China.

This was a retrospective study conducted in 878,019 subjects (483,914 males and 394,105 females) aged more than 18 years old from the Health Examination Center at West China Hospital, Sichuan University during 2009 to 2017. The blood glucose levels were compared in different age groups and different years.

The blood glucose levels were significantly increased in recent years. The percentage of cases with high glucose levels was significantly higher in males than that in females since 2009 to 2017. Moreover, the blood glucose levels and the percentage of high glucose levels in aged population were significantly higher than those in younger population every year.

The health examination population showed increased percentage of blood glucose levels, and so regular physical examination and glucose control are highly important in aged population.
Venous Thromboembolism in Hospitalized COVID-19 Patients
Authors: Sridharan Gurusaravanan Kutti , Vegunta Radhakrishna , Rokkam Venkata Ram Pradeep , Meyyur Aravamudan Veeraraghavan , Vegunta Rathnamitreyee , Khan Shahab R. , Ponnada Suresh , Boregowda Umesha , Prudhvi Kalyan , Chamarthi Gajapathiraju , Mohan Babu P.
Published: November 2020

Background:

Venous thromboembolism (VTE) is increasingly reported in seriously ill patients with COVID-19 infection. Incidence of VTE has been reported before and results varied widely in study cohorts.

Area of uncertainty:

Incidence of major VTE (segmental pulmonary embolism and above and proximal deep vein thrombosis) which is a contributor to mortality and morbidity is not known. Also, data is unclear on the optimal anticoagulation regimen to prevent VTE.

Data sources:

Multiple databases including PubMed were searched until May 12, 2020, to include studies reporting VTE in hospitalized COVID-19 adult patients. MOOSE guidelines were followed in selection, and 11 studies were included. We conducted a systematic review and meta-analysis to quantitatively assess the VTE burden in hospitalized COVID-19 patients and potential benefits of therapeutic dosing of anticoagulation compared with prophylaxis dosing for VTE prevention.

Therapeutic advances:

Many societies and experts recommend routine prophylactic anticoagulation with heparin for VTE prevention in hospitalized COVID-19 patients. In this meta-analysis, the pooled rate of major VTE was 12.5% in hospitalized patients and 17.2% in intensive care unit patients. When therapeutic anticoagulation dosing was compared with prophylactic anticoagulation, the pooled odds ratio of VTE was 0.33 (95% confidence interval 0.14–0.75; P = 0.008, I2 = 0%) suggesting statistical significance with therapeutic dosing of anticoagulation for primary prevention of VTE in all hospitalized patients. However, this should be interpreted with caution as the bleeding events and safety profile could not be ascertained because of lack of adequate information. We recommend applying this finding to hospitalized COVID 19 patients only after carefully weighing individual bleeding risks and benefits.

Conclusion:

Major VTE events, especially pulmonary embolism, seem to be high in COVID-19 patients admitted to the intensive care unit. Therapeutic anticoagulation dosing seems to significantly benefit the odds of preventing any VTE when compared with prophylactic dosing in all hospitalized patients.
Gut Microbiome
Authors: Jain Vandana , Alexander Emma C. , Burford Charlotte , Verma Anita , Dhawan Anil
Published: November 2020

Biliary atresia (BA) is a fibro‐obliterative condition of the biliary tree, presenting in infancy. The bilioenteric conduit formed at Kasai portoenterostomy (KPE), achieves restoration of bile flow in approximately 60% of infants. Even if the operation is successful, cirrhosis and its associated complications are, however, common. BA remains the leading cause for liver transplantation (LT) in children. Antibiotic, choleretic, and steroid therapy post‐KPE have not convincingly reduced LT rates. Advances in molecular technology have enabled characterisation of the encoded genes of the gut microbiota (gut microbiome). The gut microbiome plays an important role in host metabolism, nutrition, and immune function, with alterations in its diversity and/or composition, known as dysbiosis, being described in disease states, including liver disease. Liver‐gut microbiome exploration in adulthood largely focuses on nonalcoholic liver disease, cirrhosis (mainly alcohol‐ or viral‐based aetiology) and cholestatic liver diseases (eg, primary sclerosing cholangitis), with microbial signatures correlating to disease severity. Investigation of the gut microbiota in BA had been limited to culture‐based methodology, but molecular studies are emerging, and although in their infancy, highlight a potential pathogenic role for Enterobacteriaceae and Streptococcus, and a potential beneficial role for Bifidobacteria. Bacterial translocation, and the production of gut microbiome‐derived metabolites, are key host‐microbiome‐mechanistic pathways in liver disease pathogenesis. Microbiome‐targeted therapeutics for liver disease are in development, with faecal microbiota transplantation showing promise in cirrhosis. Could the gut microbiome be a novel modifiable risk factor in BA, reducing the need for LT?
A Mixed Methods Study of Senior Medical Student Help Calling in an Individual, Acute Care Simulation Experience
Authors: Young Timothy P. , Estes Molly , Shank Thomas , Smith Dustin D. , Kuntz Heather M.
Published: November 2020

Introduction

The ability to appropriately seek help is a key skill for medical students transitioning to residency. We designed a simulation activity for senior medical students and became interested in studying help calling behaviors and attitudes.

Methods

We collected quantitative data regarding help calling for 2 simulation cases and qualitative data using a survey. We undertook a structured thematic analysis based on grounded theory methodology. We identified and compared groups who did and did not call for help.

Results

One hundred thirty-four students participated and 122 (91%) completed an evaluation. More students called for help without prompting in the second case (34/134, 25% in first case; 110/134, 82% in second case, P < 0.001). Most students did not call for help in the first case but called in the second case (81, 60%). Our qualitative analysis identified 5 themes: (1) students seek to avoid shame and burdening their team, (2) prior institutional simulation and testing experience may imprint help calling behaviors, (3) students view help calling primarily through an individual lens, (4) students overestimate the complexity of the help calling process, and (5) the simulation environment and intentional experimentation make it difficult to observe natural behavior. When compared with help callers, more non–help callers had phrases coded as “perception of expectations” (37% vs. 10%, P = 0.03).

Conclusions

Learners participating in simulation exercises designed to promote help-calling behaviors face training-based barriers related to shame and the desire for autonomy and simulation-based challenges related to assessment.
“Talk-Through Walk-Through”—A Simulation Approach Adapted During Preparation for COVID-19
Authors: Lee Matthew , Chen Stephanie , Tosif Shervin , Graham Jonathon
Published: November 2020

Summary Statement

Talk-through walk-through is a simulation format that enables the rapid development and improvement of complex systems for patient care. This approach was adapted from task analysis literature and used to develop and test processes for the safe management of COVID-19 patients. Talk-through walk-through is a 2-part process that is paired with a simulated clinical scenario. The talk-through focuses on identifying and solving major process issues and establishing a shared mental model. The walk-through tests these proposed solutions and identifies previously unanticipated system and process challenges. The talk-through walk-through approach enables process development and testing in a single session, making it particularly valuable for patient care systems that involve multiple locations and healthcare disciplines, and where the availability of these disciplines and time are scarce.
Quantifying relative virulence: when μ
max fails and AUC alone just is not enough
Authors: Ceballos Ruben Michael , Stacy Carson Len
Published: November 2020

A challenge in virology is quantifying relative virulence (V
R) between two (or more) viruses that exhibit different replication dynamics in a given susceptible host. Host growth curve analysis is often used to mathematically characterize virus–host interactions and to quantify the magnitude of detriment to host due to viral infection. Quantifying V
R using canonical parameters, like maximum specific growth rate (μ
max), can fail to provide reliable information regarding virulence. Although area-under-the-curve (AUC) calculations are more robust, they are sensitive to limit selection. Using empirical data from Sulfolobus Spindle-shaped Virus (SSV) infections, we introduce a novel, simple metric that has proven to be more robust than existing methods for assessing V
R. This metric (I
SC) accurately aligns biological phenomena with quantified metrics to determine V
R. It also addresses a gap in virology by permitting comparisons between different non-lytic virus infections or non-lytic versus lytic virus infections on a given host in single-virus/single-host infections.
Transcriptomics reveal core activities of the plant growth-promoting bacterium Delftia acidovorans RAY209 during interaction with canola and soybean roots
Authors: Suchan Danae M. , Bergsveinson Jordyn , Manzon Lori , Pierce Alexa , Kryachko Yuriy , Korber Darren , Tan Yifang , Tambalo Dinah D. , Khan Nurul H. , Whiting Michael , Yost Christopher K.
Published: November 2020

The plant growth-promoting rhizobacterium

Delftia acidovorans

RAY209 is capable of establishing strong root attachment during early plant development at 7 days post-inoculation. The transcriptional response of RAY209 was measured using RNA-seq during early (day 2) and sustained (day 7) root colonization of canola plants, capturing RAY209 differentiation from a medium-suspended cell state to a strongly root-attached cell state. Transcriptomic data was collected in an identical manner during RAY209 interaction with soybean roots to explore the putative root colonization response to this globally relevant crop. Analysis indicated there is an increased number of significantly differentially expressed genes between medium-suspended and root-attached cells during early soybean root colonization relative to sustained colonization, while the opposite temporal pattern was observed for canola root colonization. Regardless of the plant host, root-attached RAY209 cells exhibited the least amount of differential gene expression between early and sustained root colonization. Root-attached cells of either canola or soybean roots expressed high levels of a fasciclin gene homolog encoding an adhesion protein, as well as genes encoding hydrolases, multiple biosynthetic processes, and membrane transport. Notably, while RAY209 ABC transporter genes of similar function were transcribed during attachment to either canola or soybean roots, several transporter genes were uniquely differentially expressed during colonization of the respective plant hosts. In turn, both canola and soybean plants expressed genes encoding pectin lyase and hydrolases – enzymes with purported function in remodelling extracellular matrices in response to RAY209 colonization. RAY209 exhibited both a core regulatory response and a planthost-specific regulatory response to root colonization, indicating that RAY209 specifically adjusts its cellular activities to adapt to the canola and soybean root environments. This transcriptomic data defines the basic RAY209 response as both a canola and soybean commercial crop and seed inoculant.
Early epidemiological analysis of the 2019-nCoV outbreak based on a crowdsourced data
Authors: Sun Kaiyuan , Chen Jenny , Viboud Cécile
Published: November 2020

As the outbreak of novel 2019 coronavirus (2019-nCoV) progresses within China and beyond, there is a need for rapidly available epidemiological data to guide situational awareness and intervention strategies. Here we present an effort to compile epidemiological information on 2019-nCoV from media news reports and a physician community website (dxy.cn) between Jan 20, 2020 and Jan 30, 2020, as the outbreak entered its 7thweek. We compiled a line list of patients reported in China and internationally and daily case counts by Chinese province. We describe the demographics, hospitalization and reporting delays for 288 patients, over time and geographically. We find a decrease in case detection lags in provinces outside of Wuhan and internationally, compared to Wuhan, and after Jan 18, 2020, as outbreak awareness increased. The rapid progression of reported cases in different provinces of China is consistent with local transmission beyond Wuhan. The age profile of cases points at a deficit among children under 15 years of age, possibly related to prior immunity with related coronavirus or behavioral differences. Overall, our datasets, which have been publicly available since Jan 21, 2020, align with official reports from Chinese authorities published more than a week later. Availability of publicly available datasets in the early stages of an outbreak is important to encourage disease modeling efforts by independent academic modeling teams and provide robust evidence to guide interventions.
Using Community Science to Reveal the Global Chemogeography of River Metabolomes
Authors: Garayburu-Caruso Vanessa A. , Danczak Robert E. , Stegen James C. , Renteria Lupita , Mccall Marcy , Goldman Amy E. , Chu Rosalie K. , Toyoda Jason , Resch Charles T. , Torgeson Joshua M. , Wells Jacqueline , Fansler Sarah , Kumar Swatantar , Graham Emily B.
Published: November 2020

River corridor metabolomes reflect organic matter (OM) processing that drives aquatic biogeochemical cycles. Recent work highlights the power of ultrahigh-resolution mass spectrometry for understanding metabolome composition and river corridor metabolism. However, there have been no studies on the global chemogeography of surface water and sediment metabolomes using ultrahigh-resolution techniques. Here, we describe a community science effort from the Worldwide Hydrobiogeochemistry Observation Network for Dynamic River Systems (WHONDRS) consortium to characterize global metabolomes in surface water and sediment that span multiple stream orders and biomes. We describe the distribution of key aspects of metabolomes including elemental groups, chemical classes, indices, and inferred biochemical transformations. We show that metabolomes significantly differ across surface water and sediment and that surface water metabolomes are more rich and variable. We also use inferred biochemical transformations to identify core metabolic processes shared among surface water and sediment. Finally, we observe significant spatial variation in sediment metabolites between rivers in the eastern and western portions of the contiguous United States. Our work not only provides a basis for understanding global patterns in river corridor biogeochemical cycles but also demonstrates that community science endeavors can enable global research projects that are unfeasible with traditional research models.
The evolution of latitudinal ranges in reef-associated fishes: heritability, limits, and inverse Rapoport’s rule
Authors: Pie Marcio R. , Divieso Raquel , Caron Fernanda S. , Siqueira Alexandre C. , Barneche Diego R. , Luiz Osmar J.
Published: November 2020

Aim

Variation in the size and position of geographical ranges is a key variable that underlies most biogeographical patterns. However, relatively little is known in terms of general principles driving their evolution, particularly in the marine realm. In this study we explore several fundamental properties regarding the evolution of reef fish latitudinal ranges, namely the degree of similarity in range size between ancestor and descendant lineages (i.e. phylogenetic signal); the evolution of range limits; and the latitudinal distribution of range sizes, particularly with respect to Rapoport’s rule.

Location

Global.

Taxon

Reef-associated fishes.

Methods

We integrate data on the latitudinal distribution and evolutionary history of 5,071 reef fish species with phylogenetic comparative methods to assess the level of phylogenetic signal in latitudinal range size, low- and high-latitude limits, and range midpoints, and to estimate rates of evolution of those traits. Finally, we test whether latitudinal ranges become smaller near the equator, as predicted by Rapoport’s rule, using phylogenetic generalized least squares.

Results

There were varying levels of phylogenetic signal in latitudinal range size, low- and high-latitude limits, and range midpoints. Despite these differences, latitudinal midpoints were consistently shown to have the highest phylogenetic signal among all measured geographic features. Interestingly, the position of high-latitude limits in general evolved at substantially faster rates than their low-latitude counterparts. Finally, we confirm for the first time the existence of an inverse Rapoport’s rule in reef-associated fishes using phylogenetic comparative methods. Indeed, mean latitudinal range size of tropical species is nearly twice the size of their temperate counterparts (2067±1431 km vs. 1168±725 km, respectively).

Main conclusions

We uncovered several congruent patterns in phylogenetic signal and rates of evolution of latitudinal ranges, despite vastly disparate biogeographical distributions and ecological differences between the studied fish lineages. Such broad congruence across different taxa and oceans, as well as with previous data from terrestrial environments, suggests that the observed patterns might represent general principles governing geographical range evolution.
COVID-19’s U.S. Temperature Response Profile
Authors: Carson Richard T. , Carson Samuel L. , Dye Thayne Keegan , Mayfield Samuel A. , Moyer Daniel C. , A. (Alex) Yu Chu
Published: November 2020

We estimate the U.S. temperature response curve for COVID-19 and show transmission is highly sensitive to temperature variation despite summer outbreaks widely assumed to show otherwise. By largely replacing the daily death counts states initially reported with counts based on death certificate date, we build a week-ahead statistical forecasting model that explains most of the daily variation (R2 = 0.97) and isolates COVID-19’s temperature response profile (p < 0.001). These counts normalized at 31°C (U.S. mid-summer average) scale up to nearly 160% at 5°C. Positive cases are more temperature sensitive, scaling up to almost 400% between 31°C and 5°C. Dynamic feedback amplifies these effects, suggesting that cooling temperatures are likely to the substantially increase COVID-19 transmission.

Article Summary Line

COVID-19’s temperature response profile is reliably estimated using re-assembled state-reported data and suggests the onset of cold weather will amplify its spread.
Fast and accurate estimation of species-specific diversification rates using data augmentation
Authors: Maliet Odile , Morlon Hélène
Published: November 2020

1

Diversification rates vary across species as a response to various factors, including environmental conditions and species-specific features. Phylogenetic models that allow accounting for and quantifying this heterogeneity in diversification rates have proven particularly useful for understanding clades diversification. Recently, we introduced the cladogenetic diversification rate shift model (ClaDS), which allows inferring subtle rate variations across lineages. Here we present a new inference technique for this model that considerably reduces computation time through the use of data augmentation and provide an implementation of this method in Julia. In addition to drastically reducing computation time, this new inference approach provides a posterior distribution of the augmented data, that is the tree with extinct and unsampled lineages as well as associated diversification rates. In particular, this allows extracting the distribution through time of both the mean rate and the number of lineages. We assess the statistical performances of our approach using simulations and illustrate its application on the entire bird radiation.
Spatial structure impacts adaptive therapy by shaping intra-tumoral competition
Authors: Strobl Maximilian A. R. , Gallaher Jill , West Jeffrey , Robertson-Tessi Mark , Maini Philip K. , Anderson Alexander R. A.
Published: November 2020

(1) Background: Adaptive therapy aims to tackle cancer drug resistance by leveraging intra-tumoral competition between drug-sensitive and resistant cells. Motivated by promising results in prostate cancer there is growing interest in extending this approach to other cancers. Here we present a theoretical study of intra-tumoral competition during adaptive therapy, to identify under which circumstances it will be superior to aggressive treatment; (2) Methods: We use a 2-D, on-lattice, agent-based tumour model to examine the impact of different microenvironmental factors on the comparison between continuous drug administration and adaptive therapy. (3) Results: We show that the degree of crowding, the initial resistance fraction, the presence of resistance costs, and the rate of tumour cell turnover are key determinants of the benefit of adaptive therapy, and we study in detail how these factors alter competition between cells. We find that intra-specific competition between resistant cells plays an unexpectedly important role in the ability to control resistance. To conclude we show how differences in resistance cost and turnover change the tumour’s spatial organisation and may explain differences in cycling speed observed in a cohort of 67 prostate cancer patients undergoing intermittent androgen deprivation therapy; (4) Conclusion: Our work provides insights into how adaptive therapy leverages inter- and intra-specific competition to control resistance, and shows that the tumour’s spatial architecture will likely be an important factor in determining the quantitative benefit of adaptive therapy in patients.
Targeted long-read sequencing resolves complex structural variants and identifies missing disease-causing variants
Authors: Miller Danny E. , Sulovari Arvis , Wang Tianyun , Loucks Hailey , Hoekzema Kendra , Munson Katherine M. , Lewis Alexandra P. , Fuerte Edith P. Almanza , Paschal Catherine R. , Thies Jenny , Bennett James T. , Glass Ian , Dipple Katrina M. , Patterson Karynne , Bonkowski Emily S. , Nelson Zoe , Squire Audrey , Sikes Megan , Beckman Erika , Bennett Robin L. , Earl Dawn , Lee Winston , Allikmets Rando , Perlman Seth J. , Chow Penny , Hing Anne V. , Adam Margaret P. , Sun Angela , Lam Christina , Chang Irene ,   University of Washington Center for Mendelian Genomics, Cherry Tim , Chong Jessica X. , Bamshad Michael J. , Nickerson Deborah A. , Mefford Heather C. , Doherty Dan , Eichler Evan E.
Published: November 2020

BACKGROUND

Despite widespread availability of clinical genetic testing, many individuals with suspected genetic conditions do not have a precise diagnosis. This limits their opportunity to take advantage of state-of-the-art treatments. In such instances, testing sometimes reveals difficult-to-evaluate complex structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in specific genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted.

METHODS

Targeted long-read sequencing (T-LRS) was performed on 33 individuals using Read Until on the Oxford Nanopore platform. This method allowed us to computationally target up to 100 Mbp of sequence per experiment, resulting in an average of 20x coverage of target regions, a 500% increase over background. We analyzed patient DNA for pathogenic substitutions, structural variants, and methylation differences using a single data source.

RESULTS

The effectiveness of T-LRS was validated by detecting all genomic aberrations, including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences, previously identified by prior clinical testing. In 6/7 individuals who had complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, which led, in one case, to a change in clinical management. In nine individuals with suspected Mendelian conditions who lacked a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in five and variants of uncertain significance in two others.

CONCLUSIONS

T-LRS can accurately predict pathogenic copy number variants and triplet repeat expansions, resolve complex rearrangements, and identify single-nucleotide variants not detected by other technologies, including short-read sequencing. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority candidate genes and regions or to further evaluate complex clinical testing results. The application of T-LRS will likely increase the diagnostic rate of rare disorders.
Protein Structural Alignments From Sequence
Authors: Morton James T. , Strauss Charlie E. M. , Blackwell Robert , Berenberg Daniel , Gligorijevic Vladimir , Bonneau Richard
Published: November 2020

Computing sequence similarity is a fundamental task in biology, with alignment forming the basis for the annotation of genes and genomes and providing the core data structures for evolutionary analysis. Standard approaches are a mainstay of modern molecular biology and rely on variations of edit distance to obtain explicit alignments between pairs of biological sequences. However, sequence alignment algorithms struggle with remote homology tasks and cannot identify similarities between many pairs of proteins with similar structures and likely homology. Recent work suggests that using machine learning language models can improve remote homology detection. To this end, we introduce DeepBLAST, that obtains explicit alignments from residue embeddings learned from a protein language model integrated into an end-to-end differentiable alignment framework. This approach can be accelerated on the GPU architectures and outperforms conventional sequence alignment techniques in terms of both speed and accuracy when identifying structurally similar proteins.
Molecular Evolution of Podocyte Slit-diaphragm Proteins
Authors: Mulukala NSK , Kambhampati V , Qadri SAH , Pasupulati AK
Published: November 2020

Vertebrates kidneys contribute to the homeostasis by regulating electrolyte, acid-base balance, and prevent protein loss into the urine. Glomerular podocytes constitute blood-urine barrier and podocyte slit-diaphragm, a modified tight junction contributes to the glomerular permselectivity. Nephrin, podocin, CD2AP, and TRPC6 are considered to be crucial members, which largely interact with each other and contribute to the structural and functional integrity of the slit-diaphragm. In this study, we analyzed the distribution of these four-key slit-diaphragm proteins across the organisms for which the genome sequence is available. We found that nephrin has a diverse distribution ranging from nematodes to higher vertebrates whereas podocin, CD2AP, and TRPC6 are predominantly restricted to the vertebrates. In the invertebrates nephrin and its orthologs consist of more immunoglobulin-3 and immunoglobulin-5 domains when compared to the vertebrates wherein, CD80-like C2-set Ig2 domains were predominant. Src Homology-3 (SH3) domain of CD2AP and SPFH domain of podocin are highly conserved among vertebrates. Although the majority of the TRPC6 and its orthologs had conserved ankyrin repeats, TRP, and ion transport domains, the orthologs of TRPC6 present inRhincodon typusandAcanthaster plancido not possess the ankyrin repeats. Intrinsically unstructured regions (IURs), which are considered to contribute to the interactions among these proteins are largely conserved among orthologs of these proteins, suggesting the importance of IURs in the protein complexes that constitute slit-diaphragm. This study for the first time reports the evolutionary insights of vertebrate slit-diaphragm proteins and its invertebrate orthologs.
Temperature-dependence of spontaneous mutation rates
Authors: Waldvogel Ann-Marie , Pfenninger Markus
Published: November 2020

Mutation is the source of genetic variation and the fundament of evolution. At the interphase of ecology and evolution, temperature has long been suggested to have a direct impact on realised spontaneous mutation rates. The question is whether mutation rates can be a species-specific constant under variable environmental conditions, such as variation of the ambient temperature. By combining mutation accumulation with whole genome sequencing in a multicellular organism, we provide empirical support to reject this null hypothesis. Instead mutation rates depend on temperature in a U-shaped manner with increasing rates towards both temperature extremes. This relation has important implications for mutation dependent processes in molecular evolution, processes shaping the evolution of mutation rates and even the evolution of biodiversity as such.
A region-based method for causal mediation analysis of DNA methylation data
Authors: Yan Qi , Forno Erick , Celedón Juan C. , Chen Wei
Published: November 2020

Exposure to environmental factors can affect DNA methylation at a CpG site or a genomic region, which can then affect an outcome. In other words, environmental effects on an outcome could be mediated by DNA methylation. To date, single CpG site-based mediation analysis has been employed extensively. More recently, however, there has been considerable interest on studying differentially methylated regions (DMRs), both because DMRs are more likely to have functional effects than single CpG sites and because testing DMRs reduces multiple testing. In this report, we propose a novel causal mediation approach under the counterfactual framework to test the significance of total, direct and indirect effects of predictors on response variable with a methylated region (MR) as the mediator (denoted as MR-Mediation). Functional linear transformation is used to reduce the possible high dimension of the CpG sites in a predefined methylated region and to account for their location information. In our simulation studies, MR-Mediation retained the desired Type I error rates for total, direct and indirect effect tests, for both continuous and binary outcomes. Furthermore, MR-Mediation had better power performance than testing mean methylation level as the mediator in most considered scenarios, especially for indirect effect (i.e., mediated effect) test, which could be more interesting than the other two effect tests. We further illustrate our proposed method by analyzing the methylation mediated effect of exposure to gun violence on total immunoglobulin E (IgE) or atopic asthma among participants in the Epigenetic Variation and Childhood Asthma in Puerto Ricans (EVA-PR) study.
Fin sweep angle does not determine flapping propulsive performance
Authors: Zurman-Nasution Andhini N. , Ganapathisubramani Bharathram , Weymouth Gabriel D.
Published: November 2020

The importance of the leading-edge sweep angle of propulsive surfaces used by unsteady swimming and flying animals has been an issue of debate for many years, spurring studies in biology, engineering, and robotics with mixed conclusions. In this work, we provide results from three-dimensional simulations of finite foils undergoing tail-like (pitch-heave) and flipper-like (twist-roll) kinematics for a range of sweep angles based on a large range of animal data while carefully controlling all other parameters. Our primary finding is the negligible 0.043 maximum correlation between the sweep angle and the propulsive force and power for both tail-like and flipper-like motions. This indicates that fish tails and mammal flukes with similar range and size can have a large range of potential sweep angles without significant negative propulsive impact. Although there is a slight benefit toavoidinglarge sweep angles, this is easily compensated by adjusting the fin’s motion parameters such as flapping frequency, amplitude and maximum angle of attack to gain higher thrust and efficiency.
Lymphocyte-Specific Biomarkers Associated with Preterm Birth and Bronchopulmonary Dysplasia
Authors: Bhattacharya Soumyaroop , Mereness Jared A. , Baran Andrea M. , Misra Ravi S. , Peterson Derick R. , Ryan Rita M. , Reynolds Anne Marie , Pryhuber Gloria S. , Mariani Thomas J.
Published: November 2020

Many premature babies who are born with neonatal respiratory distress syndrome (RDS) go on to develop Bronchopulmonary Dysplasia (BPD) and later Post-Prematurity Respiratory Disease (PRD) at one year corrected age, characterized by persistent or recurrent lower respiratory tract symptoms frequently related to inflammation and viral infection. Transcriptomic profiles were generated from sorted peripheral blood CD8+ T cells of preterm and full-term infants enrolled with consent in the NHLBI Prematurity and Respiratory Outcomes Program (PROP) at the University of Rochester and the University at Buffalo. We identified outcome-related gene expression patterns following standard methods to identify markers for oxygen utilization and BPD as outcomes in extremely premature infants. We further identified predictor gene sets for BPD based on transcriptomic data adjusted for gestational age at birth (GAB).

RNA-Seq analysis was completed for CD8+ T cells from 145 subjects. Among the subjects with highest risk for BPD (born at <29 weeks gestational age (GA); n=72), 501 genes were associated with oxygen utilization. In the same set of subjects, 571 genes were differentially expressed in subjects with a diagnosis of BPD and 105 genes were different in BPD subjects as defined by physiologic challenge. A set of 92 genes could predict BPD with a moderately high degree of accuracy. We consistently observed dysregulation of NRF2, HIPPO and CD40-associated pathways in BPD. Using gene expression data from both premature and full-term subjects (n=116), we identified a 28 gene set that predicted the PRD status with a moderately high level of accuracy.

Transcriptomic data from sort-purified peripheral blood CD8+ T cells from 145 preterm and full-term infants identified sets of molecular markers associated with independent development of BPD in extremely premature infants at high risk for the disease and of PRD among the preterm and full-term subjects.
Immunodominant T-cell epitopes from the SARS-CoV-2 spike antigen reveal robust pre-existing T-cell immunity in unexposed individuals
Authors: Mahajan Swapnil , Kode Vasumathi , Bhojak Keshav , Magdalene Coral M. , Lee Kayla , Manoharan Malini , Ramesh Athulya , Sudheendra HV , Srivastava Ankita , Sathian Rekha , Khan Tahira , Kumar Prasanna , Chakraborty Papia , Chaudhuri Amitabha
Published: November 2020

The COVID-19 pandemic has revealed a range of disease phenotypes in infected patients with asymptomatic, mild or severe clinical outcomes, but the mechanisms that determine such variable outcomes remain unresolved. In this study, we identified immunodominant CD8 T-cell epitopes in the RBD and the non-RBD domain of the spike antigen using a novel TCR-binding algorithm. A selected pool of 11 predicted epitopes induced robust T-cell activation in unexposed donors demonstrating pre-existing CD4 and CD8 T-cell immunity to SARS-CoV-2 antigen. The T-cell reactivity to the predicted epitopes was higher than the Spike-S1 and S2 peptide pools containing 157 and 158 peptides both in unexposed donors and in convalescent patients suggesting that strong T-cell epitopes are likely to be missed when larger peptide pools are used in assays. A key finding of our study is that pre-existing T-cell immunity to SARS-CoV-2 is contributed by TCRs that recognize common viral antigens such as Influenza and CMV, even though the viral epitopes lack sequence identity to the SARS-CoV-2 epitopes. This finding is in contrast to multiple published studies in which pre-existing T-cell immunity is suggested to arise from shared epitopes between SARS-CoV-2 and other common cold-causing coronaviruses. Whether the presence of pre-existing T-cell immunity provides protection against COVID-19 or contributes to severe disease phenotype remains to be determined in a larger cohort. However, our findings raise the expectation that a significant majority of the global population is likely to have SARS-CoV-2 reactive T-cells because of prior exposure to flu and CMV viruses, in addition to common cold-causing coronaviruses.
Molecular physiology of pumiliotoxin sequestration in a poison frog
Authors: Alvarez-Buylla Aurora , Payne Cheyenne Y. , Vidoudez Charles , Trauger Sunia A. , O’Connell Lauren A.
Published: November 2020

Poison frogs bioaccumulate alkaloids for chemical defense from their arthropod diet. Although many alkaloids are accumulated without modification, some poison frog species can metabolize pumiliotoxin (PTX251D) into the more potent allopumiliotoxin (aPTX267A). Despite extensive research characterizing the chemical arsenal of poison frogs, the physiological mechanisms involved in the sequestration and metabolism of individual alkaloids remain unclear. We first performed a feeding experiment with the Dyeing poison frog (Dendrobates tinctorius) to ask if this species can metabolize PTX251Dinto aPTX267Aand what gene expression changes are associated with PTX251Dexposure in the intestines, liver, and skin. We found thatD. tinctoriuscan metabolize PTX251Dinto aPTX267A, and that PTX251Dexposure changed the expression level of genes involved in immune system function and small molecule metabolism and transport. To better understand the functional significance of these changes in gene expression, we then conducted a series of high-throughput screens to determine the molecular targets of PTX251Dand identify potential proteins responsible for metabolism of PTX251Dinto aPTX267A. Although screens of PTX251Dbinding human voltage-gated ion channels and G-protein coupled receptors were inconclusive, we identified human CYP2D6 as a rapid metabolizer of PTX251Din a cytochrome P450 screen. Furthermore, a CYP2D6-like gene had increased expression in the intestines of animals fed PTX, suggesting this protein may be involved in PTX metabolism. These results show that individual alkaloids can modify gene expression across tissues, including genes involved in alkaloid metabolism. More broadly, this work suggests that specific alkaloid classes in wild diets may induce physiological changes for targeted accumulation and metabolism.
Comparing the diversity and relative abundance of free and particle-associated aquatic viruses
Authors: Palermo Christine N. , Shea Dylan W. , Short Steven M.
Published: November 2020

Metagenomics has enabled rapid increases in virus discovery, in turn permitting revisions of viral taxonomy and our understanding of the ecology of viruses and their hosts. Inspired by recent discoveries of large viruses prevalent in the environment, we re-assessed the longstanding approach of filtering water through small pore-size filters to separate viruses from cells before sequencing. We studied assembled contigs derived from < 0.45 μm and > 0.45 μm size fractions that were annotated as viral to determine the diversity and relative abundances of virus groups from each fraction. Virus communities were vastly different when comparing the size fractions, indicating that analysis of either fraction alone would provide only a partial perspective of environmental viruses. At the level of virus order/family we observed highly diverse and distinct virus communities in the > 0.45 μm size fractions, whereas the < 0.45 μm size fractions were comprised primarily of highly diverse Caudovirales. The relative abundances of Caudovirales for which hosts could be inferred varied widely between size fractions with higher relative abundances of cyanophages in the > 0.45 μm size fractions potentially indicating replication within cells during ongoing infections. Many of theMimiviridaeandPhycodnaviridae, and allIridoviridaeandPoxviridaewere detected exclusively in the often disregarded > 0.45 μm size fractions. In addition to observing unique virus communities associated with each size fraction, we detected viruses common to both fractions and argue that these are candidates for further exploration because they may be the product of ongoing or recent lytic events.

IMPORTANCE

Most studies of aquatic virus communities analyze DNA sequences derived from the smaller, “free virus” size fraction. Our study demonstrates that analysis of virus communities using only the smaller size fraction can lead to erroneously low diversity estimates for many of the larger viruses such asMimiviridae, Phycodnaviridae, Iridoviridae, andPoxviridae, whereas analyzing only the larger, > 0.45 μm size fraction can lead to underestimates of Caudovirales diversity and relative abundance. Similarly, our data shows that examining only the smaller size fraction can lead to underestimation of virophage and cyanophage relative abundances that could, in turn, cause researchers to assume their limited ecological importance. Given the considerable differences we observed in this study, we recommend cautious interpretations of environmental virus community assemblages and dynamics when based on metagenomic data derived from different size fractions.
NUTRITIONAL IMMUNITY, ZINC SUFFICIENCY AND COVID-19 MORTALITY IN SOCIALLY SIMILAR EUROPEAN POPULATIONS
Authors: Singh Samer , Diwaker Amita , Singh Brijesh P. , Singh Rakesh K.
Published: November 2020

The impact of Zinc (Zn) sufficiency/supplementation on COVID-19 associated mortality and incidence (SARS-CoV-2 infections) remains unknown. During an infection, the levels of free Zn are reduced as part of ‘nutritional immunity’ to limit the growth and replication of pathogen and the ensuing inflammatory damage. Considering its key role in immune competency and frequently recorded deficiency in large sections of different populations, Zn has been prescribed for both prophylactic and therapeutic purposes in COVID-19 without any corroborating evidence for its protective role. Multiple trials are underway evaluating the effect of Zn supplementation on COVID-19 outcome in patients getting standard of care treatment. However, the trial designs presumably lack the power to identify negative effects of Zn supplementation, especially in the vulnerable groups of elderly and patients with comorbidities (contributing 9 out of 10 deaths; up to >8000-fold higher mortality). In this study, we have analyzed COVID-19 mortality and incidence (case) data from 23 socially similar European populations with comparable confounders (population: 522.47 million; experiencing up to >150 fold difference in death rates) and at the matching stage of the pandemic (12 March - 26 June 2020; 1st wave of COVID-19 incidence and mortality). Our results suggest a positive correlation between populations’ Zn-sufficiency status and COVID-19 mortality (r(23): 0.7893–0.6849, p-value<0.0003) as well as incidence [r(23):0.8084 to 0.5658; p-value<0.005]. The observed association is contrary to what would be expected if Zn sufficiency was protective in COVID-19. Thus, controlled trials or retrospective analyses of the adverse event patients’ data should be undertaken to correctly guide the practice of Zn supplementation in COVID-19.
Rad51 paralog complex Rad55–Rad57 acts as a molecular chaperone during homologous recombination
Authors: Roy Upasana , Kwon Youngho , Marie Lea , Symington Lorraine , Sung Patrick , Lisby Michael , Greene Eric C.
Published: November 2020

Homologous recombination (HR) is essential for the maintenance of genome integrity. Rad51 paralogs fulfill a conserved, but undefined role in HR, and their mutations are associated with increased cancer risk in humans. Here, we use single–molecule imaging to reveal that theSaccharomyces cerevisiaeRad51 paralog complex Rad55–Rad57 promotes the assembly of Rad51 recombinase filaments through transient interactions, providing evidence that it acts as a classical molecular chaperone. Srs2 is an ATP–dependent anti–recombinase that downregulates HR by actively dismantling Rad51 filaments. Contrary to the current model, we find that Rad55– Rad57 does not physically block the movement of Srs2. Instead, Rad55–Rad57 promotes rapid re– assembly of Rad51 filaments after their disruption by Srs2. Our findings support a model in which Rad51 is in flux between free and ssDNA–bound states, the rate of which is dynamically controlled though the opposing actions of Rad55–Rad57 and Srs2.
Epigenomic reprogramming of repetitive noncoding RNAs and IFN-stimulated genes by mutant KRAS
Authors: Reggiardo Roman E. , Maroli Sreelakshmi Velandi , Halasz Haley , Ozen Mehmet , Carrillo David , LaMontagne Erin , Whitehead Lila , Kim Eejung , Malik Shivani , Fernandes Jason , Marinov Georgi , Collisson Eric , Demirci Utkan , Kim Daniel H.
Published: November 2020

RAS genes are the most frequently mutated oncogenes in cancer. However, the effects of oncogenic RAS signaling on the noncoding transcriptome are unclear. We analyzed the transcriptomes of human airway epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated noncoding RNAs. We found that oncogenic KRAS upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements. These repetitive noncoding RNAs exhibit differential RNA editing in single cells, are released in extracellular vesicles, and are known targets of KRAB zinc-finger proteins, which are broadly down-regulated in mutant KRAS cells and lung adenocarcinomas. Moreover, mutant KRAS induces IFN-stimulated genes through both epigenetic and RNA-based mechanisms. Our results reveal that mutant KRAS remodels the noncoding transcriptome through epigenomic reprogramming, expanding the scope of genomic elements regulated by this fundamental signaling pathway and revealing how mutant KRAS induces an intrinsic IFN-stimulated gene signature often seen in ADAR-dependent cancers.