bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic review of reviews of symptoms and signs of COVID-19 in children and adolescents
Authors: Viner Russell , Ward Joseph , Hudson Lee , Ashe Melissa , Patel Sanjay , Hargreaves Dougal , Whittaker Elizabeth
Published: October 2020

Objective

To undertake a systematic review of reviews of the prevalence of symptoms and signs of COVID-19 in those aged under 20 years?

Design

Narrative systematic review of reviews. PubMed, medRxiv, Europe PMC and COVID-19 Living Evidence Database were searched on 9 October 2020.

Setting

All settings, including hospitalised and community settings.

Patients

CYP under age 20 years with laboratory-proven COVID-19.

Study review, data extraction and quality

Potentially eligible articles were reviewed on title and abstract by one reviewer. Quality was assessed using the modified AMSTARS criteria and data were extracted from included studies by two reviewers.

Main outcome measures

Prevalence of symptoms and signs of COVID-19

Results

1325 studies were identified and 18 reviews were included. Eight were high quality, 7 medium and 3 low quality. All reviews were dominated by studies of hospitalised children. The proportion who were asymptomatic ranged from 14.6 to 42%. Fever and cough were the commonest symptoms; proportions with fever ranged from 46 to 64.2% and with cough from 32 to 55.9%. All other symptoms or signs including rhinorrhoea, sore throat, headache, fatigue/myalgia and gastrointestinal symptoms including diarrhoea and vomiting are infrequent, occurring in less than 10-20%.

Conclusions

Fever and cough are the most common symptoms in CYP with COVID-19, with other symptoms infrequent. Further research on symptoms in community samples are needed to inform pragmatic identification and testing programmes for CYP.
Increase in anticholinergic burden in the UK from 1990 to 2015: a UK Biobank study
Authors: Mur J. , Cox S. R. , Marioni R. E. , Muniz-Terrera G. , Russ T. C.
Published: October 2020

Background

The use of prescription drugs with anticholinergic properties has been associated with multiple negative health outcomes in older people. Moreover, recent evidence suggests that associated adverse effects may occur even decades after stopping anticholinergic use. Despite the implicated importance of examining longitudinal patterns of anticholinergic prescribing for different age groups, few such data are available.

Methods

We performed an age-period-cohort analysis to study trends in anticholinergic burden between the years 1990 and 2015 utilising data from >220,000 UK Biobank participants with linked prescription data from primary care.

Results

Anticholinergic burden in the sample increased between three- and nine-fold over 25 years and was significant for both period/cohort- and age-effects across all models. When adjusted for total number of prescriptions, the effect of age reversed. Anticholinergic burden was also associated with various lifestyle- and demographic factors.

Conclusions

The increase in anticholinergic prescribing is mostly due to an increase in polypharmacy and is attributable to both ageing of participants, as well as period/cohort-related changes in prescribing practices. There is evidence for deprescribing of anticholinergic medications in older age. Further research is needed to clarify the implications of rising anticholinergic use for public health and to contextualise this rise in light of other relevant prescribing practices.
National Routine Adult Immunization Programs among World Health Organization Member States: An Assessment of Health Systems to Deploy Future SARS-CoV-2 Vaccines
Authors: Williams Sarah R. , Driscoll Amanda J. , LeBuhn Hanna M. , Chen Wilbur H. , Neuzil Kathleen M. , Ortiz Justin R.
Published: October 2020

Introduction

As the SARS-CoV-2 pandemic disproportionately affects older adults, future pandemic vaccine response will rely on existing adult immunization infrastructures.

Methods

We evaluated the 2018 WHO/UNICEF Joint Reporting Form on Immunization for country reports on adult immunization programs. We described countries with programs and used multivariable regression to identify independent factors associated with having them.

Results

Of 194 WHO Member States, 120 (62%) reported having any adult vaccination program. The Americas and Europe had the most adult immunization programs, most commonly Hepatitis B and influenza vaccines (>45% and >90% of countries). Africa and South-East Asia had the fewest adult immunization programs, with <11% of countries reporting any adult immunization programs for influenza or hepatitis vaccines, and none for pneumococcal vaccines. In bivariate analyses, high- or upper-middle income, introduction of new or underused vaccines, having achieved pediatric vaccine coverage goals, and meeting National Immunization Technical Advisory Groups basic functional indicators were significantly associated (p<0.001) with having any adult immunization programs. In multivariable analyses, the factor most strongly associated with adult immunization programs was country income, with high- or upper-middle income countries significantly more likely to report having a program (aOR 19.3, 95% CI 6.5, 57.7).

Discussion

That 38% of countries lack functional platforms for adult immunization has major implications for future SARS-CoV-2 vaccine deployment. Systems for vaccine storage and handling, delivery, and waste management for adult immunization do not exist in much of the world. Developing countries should strengthen immunization programs to reach adults with SARS-CoV-2 vaccines when they become available.
Phosphate dysregulation via the XPR1:KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer
Authors: Bondeson Daniel P , Paolella Brenton R , Asfaw Adhana , Rothberg Michael , Skipper Thomas , Langan Carly , Gonzalez Alfredo , Surface Lauren E , Ito Kentaro , Kazachkova Mariya , Colgan William N , Warren Allison , Dempster Josh , Burger Mike , Ericsson Maria , Tang Andrew , Fung Iris , Chambers Emily S , Abdusamad Mai , Dumont Nancy , Doench John G , Piccioni Federica , Root David E , Boehm Jesse , Hahn William C , Mannstadt Michael , McFarland James M , Vazquez Francisca , Golub Todd R
Published: October 2020

Clinical outcomes for patients with ovarian and uterine cancers have not improved greatly in the past twenty years. To identify ovarian and uterine cancer vulnerabilities, we analyzed genome-scale CRISPR/ Cas9 loss-of-function screens across 739 human cancer cell lines. We found that many ovarian cancer cell lines overexpress the phosphate importer SLC34A2, which renders them sensitive to loss of the phosphate exporter XPR1. We extensively validated the XPR1 vulnerability in cancer cell lines and found that the XPR1 dependency was retained in vivo. Overexpression of SLC34A2 is frequently observed in tumor samples and is regulated by PAX8 -a transcription factor required for ovarian cancer survival. XPR1 overexpression and copy number amplifications are also frequently observed. Mechanistically, SLC34A2 overexpression and impaired phosphate efflux leads to the accumulation of intracellular phosphate and cell death. We further show that proper localization and phosphate efflux by XPR1 requires a novel binding partner, KIDINS220. Loss of either XPR1 or KIDINS220 results in acidic vacuolar structures which precede cell death. These data point to the XPR1:KIDINS220 complex - and phosphate dysregulation more broadly -as a therapeutic vulnerability in ovarian cancer.
The dynamic, combinatorial cis-regulatory lexicon of epidermal differentiation
Authors: Kim Daniel , Risca Viviana , Reynolds David , Chappell James , Rubin Adam , Jung Namyoung , Donohue Laura , Kathiria Arwa , Shi Minyi , Zhao Zhixin , Deep Harsh , Chang Howard Y. , Snyder Michael P. , Greenleaf William J. , Kundaje Anshul , Khavari Paul A.
Published: October 2020

Transcription factors (TFs) bind DNA sequence motif vocabularies in cis-regulatory elements (CREs) to modulate chromatin state and gene expression during cell state transitions. A quantitative understanding of how motif lexicons influence dynamic regulatory activity has been elusive due to the combinatorial nature of the cis-regulatory code. To address this, we undertook multi-omic data profiling of chromatin and expression dynamics across epidermal differentiation to identify 40,103 dynamic CREs associated with 3,609 dynamically expressed genes, then applied an interpretable deep learning framework to model the cis-regulatory logic of chromatin accessibility. This identified cooperative DNA sequence rules in dynamic CREs regulating synchronous gene modules with diverse roles in skin differentiation. Massively parallel reporter analysis validated temporal dynamics and cooperative cis-regulatory logic. Variants linked to human polygenic skin disease were enriched in these time-dependent combinatorial motif rules. This integrative approach reveals the combinatorial cis-regulatory lexicon of epidermal differentiation and represents a general framework for deciphering the organizational principles of the cis-regulatory code in dynamic gene regulation.

HIGHLIGHTS

An integrative multi-omic resource profiling chromatin and expression dynamics across keratinocyte differentiation

Predictive deep learning models of chromatin dynamics reveal a high-resolution cis-regulatory DNA motif lexicon of epidermal differentiation

Model interpretation enables discovery of combinatorial cis-regulatory logic of homotypic and heterotypic motif combinations

Massively parallel reporter experiments validate temporal dynamics and cis-regulatory logic of the combinatorial motif lexicon
Transdermal patch containing physostigmine and procyclidine protects rhesus monkeys against VX intoxication
Authors: Song Young Jo
Published: October 2020

VX is an organophosphate cholinesterase inhibitor known as a chemical warfare agent. This study was designed 1) to determine the acute toxicity of VX in male rhesus monkeys by subcutaneous administration, 2) to evaluate the efficacy of a transdermal patch containing physostigmine and procyclidine. The median lethal dose (LD50) of the subcutaneous injection of VX was 15.409 ug/kg, which was calculated using the up-and-down dose selection procedure based on deaths occurring within 48 h. To test the efficacy of the transdermal patch, rhesus monkeys were treated with a patch (5×5 cm2) alone or in combination with post-exposure therapy comprising atropine plus 2-pralidoxime (2-PAM), and then administered subcutaneous injection of VX at various doses. The rhesus monkeys pretreated with the patch alone were 100% protected against 1.5×LD50of VX, while the rhesus monkeys treated with the patch, atropine, and 2-PAM were 100% protected against 50×LD50of VX. This study demonstrated that patch pretreatment in conjunction with atropine and 2-PAM treatment is an effective regimen against high doses of VX.
NetworkExtinction: an R package to simulate extinction’s propagation and rewiring potential in ecological networks
Authors: Ávila-Thieme M.Isidora , Corcoran Derek , Kusch Erik , Castillo Simón P. , Valdovinos Fernanda S. , Navarrete Sergio A. , Marquet Pablo A.
Published: October 2020

Earth’s biosphere is currently undergoing drastic reorganisation as a consequence of the sixth mass extinction brought on by the Anthropocene. Impacts of local and regional extirpation of species have been demonstrated to propagate through the complex interaction networks they are part of, subsequently leading to secondary extinctions, exacerbating biodiversity loss. Contemporary ecological theory has developed several measures to analyse the structure and robustness of ecological networks under biodiversity loss. However, a toolbox for direct simulation and quantification of extinction cascades and the creation of novel interactions (i.e. rewiring) remains absent.

Here, we presentNetworkExtinction- a novel R package which we have developed to explore the propagation of species extinctions sequences through ecological networks as well as quantify the effects of rewiring potential in response to primary species extinctions. WithNetworkExtinctionwe have integrated ecological theory and computational simulations to develop functionality with which users may analyze and visualize the structure and robustness of ecological networks. The core functions introduced withNetworkExtinctionfocus on simulations of sequential primary extinctions and associated secondary extinctions while allowing for user-specified secondary extinction thresholds and realisation of rewiring potential.

With the packageNetworkExtinction,users can estimate the robustness of ecological networks after performing species extinction routines based on several algorithms. Moreover, users can compare the number of simulated secondary extinctions against a null model of random extinctions. In-built visualizations enable graphing topological indices calculated by the deletion sequence functions after each simulation step. Finally, the user can define the degree distribution of the network by fitting different common distributions. Here, we illustrate the use of the package and its outputs by analyzing a Chilean coastal marine food web.

NetworkExtinctionis a compact and easy-to-use R package with which users can quantify changes in ecological network structure in response to different patterns of species loss, thresholds, and rewiring potential. Therefore, this package is particularly useful to evaluate ecosystem responses to anthropogenic and environmental perturbations that produce non-random species extinctions.
CD4 and CD8 co-receptors modulate functional avidity of CD1b-restricted T cells
Authors: James Charlotte A. , Xu Yuexin , Aguilar Melissa S. , Jing Lichen , Layton Erik D. , Gilleron Martine , Minnaard Adriaan J. , Scriba Thomas J. , Day Cheryl L. , Warren Edus H. , Koelle David M. , Seshadri Chetan
Published: October 2020

CD4 and CD8 co-receptors define distinct lineages of T cells restricted by major histocompatibility complex (MHC) Class II and I molecules, respectively. Co-receptors interact with the T cell receptor (TCR) at the surface of MHC-restricted T cells to facilitate antigen recognition, thymic selection, and functional differentiation. T cells also recognize lipid antigens presented by CD1 molecules, but the role that CD4 and CD8 play in lipid antigen recognition is unknown. We studied the effect of CD4 and CD8 on the avidity, activation, and function of T cells specific for two CD1b-presented mycobacterial lipid antigens, glucose monomycolate (GMM) and diacylated sulfoglycolipids (SGL). In a human cohort study using SGL-loaded CD1b tetramers, we discovered a hierarchy among SGL-specific T cells in which T cells expressing the CD4 or CD8 co-receptor stain with a higher tetramer mean fluorescence intensity (MFI) than CD4-CD8- T cells. To determine the role of the TCR co-receptor in lipid antigen recognition, we exogenously expressed GMM and SGL-specific TCRs in Jurkat or polyclonal T cells and quantified tetramer staining and activation thresholds. Transduced CD4+ primary T cells bound the lipid-loaded CD1b tetramer with a higher MFI than CD8+ primary T cells, and transduced CD8+ Jurkat cells bound the SGL-CD1b tetramer with higher MFI than CD4-CD8- Jurkat cells. The presence of either co-receptor also decreased the threshold for IFN-γ secretion. Further, co-receptor expression increased surface expression of CD3ε, suggesting a mechanism for increased tetramer binding and activation. Finally, we used single-cell sequencing to define the TCR repertoire andex vivofunctional profiles of SGL-specific T cells from individuals with M.tb disease. We found that CD8+ T cells specific for SGL express canonical markers associated with cytotoxic T lymphocytes, while CD4+ T cells could be classified as T regulatory or T follicular helper cells. Among SGL-specific T cells, only those expressing the CD4 co-receptor also expressed Ki67, suggesting that they were actively proliferating at the time of sample collection. Together, these data reveal that expression of CD4 and CD8 co-receptor modulates TCR avidity for lipid antigen, leading to functional diversity and differences inin vivoproliferation during M.tb disease.
Cardiovascular Disease Related Proteomic Biomarkers of Alcohol Consumption
Authors: Sun Xianbang , Ho Jennifer E. , Gao He , Evangelou Evangelos , Yao Chen , Huan Tianxiao , Hwang Shih-Jen , Courchesne Paul , Larson Martin G. , Levy Daniel , Ma Jiantao , Liu Chunyu
Published: October 2020

The relationship between alcohol consumption, circulating proteins, and cardiovascular disease (CVD) risk has not been well studied. We performed association analyses of alcohol consumption with three CVD risk factors and 71 CVD-related circulating proteins measured in 6,745 Framingham Heart Study participants (mean age, 49 years; 53% women). We found that an increase in alcohol consumption was associated with a higher risk of incident hypertension (P=7.2E-3) but a lower risk of incident obesity (P=5.7E-4) and type 2 diabetes (P=1.4E-5) in a 14-year of follow-up. Using independent discovery (n=4,348) and validation (n=2,397) samples, we identified 20 alcohol-associated proteins (FDR<0.05 in discovery and P<0.05/n in validation), with majority (18 of 20 proteins) inversely associated with alcohol consumption. The alcohol-protein associations remained similar after removing heavy drinkers. Four proteins demonstrated consistent triangular relationships, as expected, with alcohol consumption and CVD risk factors. For example, a greater level of APOA1, which was associated with a higher alcohol consumption (P=1.2E-65), was associated with a lower risk of type 2 diabetes (P=3.1E-5). However, several others showed inconsistent triangular relationships, e.g., a greater level of GDF15, which was associated with a lower alcohol consumption (P=1.0E-13), was associated with an increased risk of hypertension (P=2.4E-4). In conclusion, we identified 20 alcohol-associated proteins and demonstrated complex relationships between alcohol consumption, circulating proteins and CVD risk factors. Future studies with integration of more proteomic markers and larger sample size are warranted to unravel the complex relationship between alcohol consumption and CVD risk.
Safe linkage of cohort and population-based register data in a genome-wide association study on health care expenditure
Authors: de Zeeuw Eveline L. , Voort Lykle , Schoonhoven Ruurd , Nivard Michel G. , Emery Thomas , Hottenga Jouke-Jan , Willemsen Gonneke A.H.M. , Dykstra Pearl A. , Zarrabi Narges , Kartopawiro John D. , Boomsma Dorret I.
Published: October 2020

Background

There are research questions whose answers require record linkage of multiple databases which may be characterized by limited options for full data sharing. For this purpose, the Open Data Infrastructure for Social Science and Economic Innovations (ODISSEI) consortium has supported the development of the ODISSEI Secure Supercomputer (OSSC) platform that allows researchers to link cohort data to data from Statistics Netherlands and run analyses in a high performance computing (HPC) environment.

Methods

After successful record linkage genome-wide association (GWA) analyses were carried out on expenditure for total health, mental health, primary and hospital care and medication. Record linkage for genotype data from 16,726 participants from the Netherlands Twin Register (NTR) with data from Statistics Netherlands was accomplished in the secure OSSC platform, followed by gene-based tests and estimation of total and SNP-based heritability.

Results

The total heritability of expenditure ranged between 29.4 (SE 0.8) and 37.5 (SE 0.8) per cent, but GWA analyses did not identify single SNPs or genes that were genome-wide significantly associated with health care expenditure. SNP-based heritability was between 0.0 (SE 3.5) and 5.4 (SE 4.0) per cent and was different from zero for mental health care and primary care expenditure.

Conclusions

We successfully linked genotype data to administrative health care expenditure data from Statistics Netherlands and performed a series of analyses on health care expenditure. The OSSC platform offers secure possibilities for analysing linked data in large-scale and realizing sample sizes required for GWA studies, providing invaluable opportunities to answer many new research questions.

Key messages

Cohort data of the Netherlands Twin Register were safely linked to population-based register data of Statistics Netherlands

On the ODISSEI Secure Supercomputer (OSSC) platform genome-wide association analyses were carried out on linked genotype and health care expenditure data

Variation in health care expenditure was for approximately one third explained by family-based heritability, but SNP-heritability based on genetic similarity across unrelated individuals explained only a very small proportion of variance

The newly developed platform can serve as a prototype for realizing genome-wide association studies with sensitive data
ALS-linked mutations impair UBQLN2 stress-induced biomolecular condensate assembly in cells
Authors: Riley Julia F. , Hehnly Heidi , Castañeda Carlos A.
Published: October 2020

Mutations in Ubiquilin-2 (UBQLN2), a ubiquitin-binding shuttle protein involved in several protein quality control processes, can lead to amyotrophic lateral sclerosis (ALS). We previously found that wild-type UBQLN2 forms dynamic, membraneless biomolecular condensates upon cellular stress, and undergoes liquid-liquid phase separationin vitro. However, the impact of ALS-linked mutations on UBQLN2 condensate formation in cells is unknown. Here, we employ live-cell imaging with photokinetic analysis to investigate how five patient-derived ALS-linked mutations in UBQLN2 impact stress-induced UBQLN2 condensate assembly and condensate material properties. Both wild-type and mutant UBQLN2 condensates are generally cytoplasmic and liquid-like. However, cells transfected with mutant UBQLN2 contain fewer stress-induced UBQLN2 condensates than those with wild-type UBQLN2. Most strikingly, ectopically expressed P506T UBQLN2 forms the lowest number of stress-induced condensates of all UBQLN2 mutants, and these condensates are significantly smaller than those of wild-type UBQLN2. Fluorescence recovery after photobleaching (FRAP) analysis of UBQLN2 condensates revealed higher immobile fractions for UBQLN2 mutants, especially P506T. P497S and P497H mutations differentially impact condensate properties, demonstrating that the effects of ALS-linked mutations are both position- and amino acid-dependent. Collectively, our data show that disease mutations hinder assembly and alter viscoelastic properties of stress-induced UBQLN2 condensates, potentially leading to aggregates commonly observed in ALS.
The Almond plumage color pattern is associated with eye pigmentation defects in the domestic pigeon (Columba livia)
Authors: Bruders Rebecca , Sidesinger Max , Shapiro Michael D.
Published: October 2020

Changes in epidermal pigmentation are associated with eye defects in humans and other vertebrates. In the rock pigeon (Columba livia), the sex-linked Almond color pattern is characterized by hypopigmentation of epidermal structures. The trait is controlled by the classicalStipper(St) locus, and homozygous (ZStZSt) Almond males often have severe eye defects. Heterozygous (ZStZ+) and hemizygous (ZStW) pigeons do not typically have obvious eye defects, suggesting that higher dosage of the mutant allele is deleterious. Because Almond pigeons have pronounced hypopigmentation in epidermal structures, we hypothesized that they might also have reduced eye pigmentation. Here, we examined pigmentation in the iris, ciliary body, anterior retinal pigmented epithelium (RPE), and posterior RPE in pigeons with and without Almond alleles. We found that pigmentation of anterior segment structures was reduced in birds with at least one Almond allele. However, posterior eye pigmentation was substantially reduced only in homozygous Almond birds. We postulate that the gradient of effects on eye pigmentation is due to the different embryological origins of anterior and posterior eye pigment-producing cells.
Subcellular sequencing of single neurons reveals the dendritic transcriptome of GABAergic interneurons
Authors: Perez Julio D. , tom Dieck Susanne , Alvarez-Castelao Beatriz , Chan Ivy C.W. , Schuman Erin M.
Published: October 2020

The localization and translation of mRNAs to dendrites and axons maintains and modifies the local proteome of neurons, and is essential for synaptic plasticity. Although significant efforts have allowed the identification of localized mRNAs in excitatory neurons, it is still unclear whether interneurons also localize a large population of mRNAs. In addition, the variability in the population of localized mRNAs within and between cell-types is unknown. Here we developed a method for the transcriptomic characterization of a single neuron’s subcellular compartments, which combines laser capture microdissection with scRNA-seq. This allowed us to separately profile the dendritic and somatic transcriptomes of individual rat hippocampal neurons and investigate the relation in mRNA abundances between the soma and dendrites of single glutamatergic and GABAergic neurons. We identified two types of glutamatergic and three types of GABAergic interneurons and we found that, like their excitatory counterparts, interneurons contain a rich repertoire of ~4000 mRNAs. The individual somatic transcriptomes exhibited more cell type-specific features than their associated dendritic transcriptomes. The detection and abundance of dendritic mRNAs was not always simply predicted by their somatic counterparts. Finally, using cell-type specific metabolic labelling of isolated neurites, we demonstrated that the processes not only of Glutamatergic but also of GABAergic neurons are capable of local translation, suggesting mRNA localization and local translation is a general property of neurons.
Stability of ripple events during task engagement in human hippocampus
Authors: Chen Yvonne Y. , Yoshor Daniel , Sheth Sameer A. , Foster Brett L.
Published: October 2020

Periods of cognitive disengagement, such as rest or sleep, are thought to support the progressive consolidation of episodic memories. During these states, the hippocampus displays transient high-frequency oscillatory bursts, known as ripples, which are thought to promote interactions with the neocortex, consolidating memory traces. More recent findings have suggested ripples in the human hippocampus may also occur during task engagement, particularly for tasks requiring episodic memory processes. However, it is unclear if hippocampal ripples occur during other cognitive states or whether ripple properties are modulated by specific types of task demands. In addition, identifying genuine hippocampal ripple events in the human brain can be methodological challenging. To address these questions, we used intracranial recordings from the human hippocampus to quantify ripple events across perceptual, memory and resting task states. Using spectro-temporal identification of hippocampal ripples, we observed highly similar ripple event properties across tasks, with a modest yet significant increase in ripple properties (rate, duration & amplitude) during resting task states. These ripple event attributes did not differ between hemisphere, nor across or within the time of day examined. Supporting data further highlighted that while hippocampal ripples occurred during all task states, these rates were typically lower than that observed during sleep. Together, these findings highlight that hippocampal ripples occur consistently, but sparsely, during a broad range of cognitive task states. Such findings may be incorporated into existing models of systems consolidation, whereby hippocampal ripples help to initially establish latent memory traces.
AniProtDB: A Collection of Uniformly Generated Metazoan Proteomes for Comparative Genomics Studies
Authors: Barreira Sofia N. , Nguyen Anh-Dao , Fredriksen Mark T. , Wolfsberg Tyra G. , Moreland R. Travis , Baxevanis Andreas D.
Published: October 2020

To address the void in the availability of high-quality proteomic data traversing the animal tree, we have implemented a pipeline for generatingde novoassemblies based on publicly available data from the NCBI Sequence Read Archive, yielding a comprehensive collection of proteomes from 100 species spanning 21 animal phyla. We have also created the Animal Proteome Database (AniProtDB), a resource providing open access to this collection of high-quality metazoan proteomes, along with information on predicted proteins and protein domains for each taxonomic classification and the ability to perform sequence similarity searches against all proteomes generated using this pipeline. This solution vastly increases the utility of these data by removing the barrier to access for research groups who do not have the expertise or resources to generate these data themselves and enables the use of data from non-traditional research organisms that have the potential to address key questions in biomedicine.

Database URL

https://research.nhgri.nih.gov/aniprotdb
Mitochondrial fission governed by Drp1 regulates exogenous fatty acid usage and storage
Authors: Song Jae Eun , Alves Tiago C. , Stutz Bernardo , Sestan-Pesa Matija , Kilian Nicole , Diano Sabrina , Kibbey Richard G. , Horvath Tamas L.
Published: October 2020

The bioenergetic function of mitochondrial fission is associated with uncoupled respiration or elimination of damaged mitochondria to maintain a healthy mitochondrial population. In the presence of a high abundance of exogenous fatty acids, cells can either store fatty acids in lipid droplets or oxidize them in mitochondria. Even though carnitine palmitoyltransferase-1 (CPT1) controls the respiratory capacity of mitochondria in fatty acid oxidation, we observed that it did not dictate the balance of storage and usage of lipids in HeLa cells. On the other hand, inhibition of mitochondrial fission by silencing dynamic-related protein 1 (DRP1) resulted in an increase in fatty acid content of lipid droplets and a decrease in fatty acid oxidation. Mitochondrial fission was not only reflective of the amount of exogenous fatty acid being processed by mitochondria, but also found to be actively involved in the distribution of fatty acids between mitochondria and lipid droplets. Our data reveals a novel function for mitochondrial fission in balancing exogenous fatty acids between usage and storage, assigning a role for mitochondrial dynamics in control of intracellular fuel utilization and partitioning.
Strain population structure varies widely across bacterial species and predicts strain colonization in unrelated individuals
Authors: Faith Jeremiah J. , Chen-Liaw Alice , Aggarwala Varun , Kaakoush Nadeem O. , Borody Thomas J. , Mitchell Hazel , Kamm Michael A. , Paramsothy Sudarshan , Snitkin Evan S. , Mogno Ilaria
Published: October 2020

The population structure of strains within a bacterial species is poorly defined, despite the functional importance of strain variation in the human gut microbiota on health. Here we analyzed >1000 sequenced bacterial strains from the fecal microbiota of 47 individuals from two countries and combined them with >150,000 bacterial genomes from NCBI to quantify the strain population size of different bacterial species, as well as the frequency of finding the same strain colonized in unrelated individuals who had no opportunities for direct microbial strain transmission. Strain population sizes ranged from tens to over one-hundred thousand per species. Prevalent strains in common gut microbiota species with small population sizes were the most likely to be harbored in two or more unrelated individuals. The finite strain population size of certain species creates the opportunity to comprehensively sequence the entirety of these species’ prevalent strains and associate their presence in different individuals with health outcomes.
Multiple time-scales of decision making in the hippocampus and prefrontal cortex
Authors: Tang Wenbo , Shin Justin D. , Jadhav Shantanu P.
Published: October 2020

The prefrontal cortex and hippocampus are crucial for memory-guided decision-making. Neural activity in the hippocampus exhibits place-cell sequences at multiple timescales, including slow behavioral sequences (∼seconds) and fast theta sequences (∼100-200 ms) within theta oscillation cycles. How prefrontal ensembles interact with hippocampal sequences to support decision-making is unclear. Here, we examined simultaneous hippocampal and prefrontal ensemble activity during learning of a spatial working-memory decision task. We found clear theta sequences in prefrontal cortex, nested within its behavioral sequences. In both regions, behavioral sequences maintained representations of current goals during navigation. In contrast, hippocampal theta sequences encoded alternatives for deliberation, and were coordinated with prefrontal theta sequences that predicted upcoming choices. During error trials, these representations were preserved to guide ongoing behavior, whereas replay sequences during inter-trial periods were impaired prior to navigation. These results establish cooperative interaction between hippocampal and prefrontal sequences at multiple timescales for memory-guided decision making.
Meta-GWAS for quantitative trait loci identification in soybean
Authors: Shook Johnathon M. , Zhang Jiaoping , Jones Sarah E. , Singh Arti , Diers Brian W. , Singh Asheesh K.
Published: October 2020

We report a meta-Genome Wide Association Study involving 73 published studies in soybean (Glycine maxL. [Merr.]) covering 17,556 unique accessions, with improved statistical power for robust detection of loci associated with a broad range of traits.De novoGWAS and meta-analysis were conducted for composition traits including fatty acid and amino acid composition traits, disease resistance traits, and agronomic traits including seed yield, plant height, stem lodging, seed weight, seed mottling, seed quality, flowering timing, and pod shattering. To examine differences in detectability and test statistical power between single- and multi-environment GWAS, comparison of meta-GWAS results to those from the constituent experiments were performed. Using meta-GWAS analysis and the analysis of individual studies, we report 483 quantitative trait loci (QTL) at 393 unique loci. Using stringent criteria to detect significant marker trait associations, 66 candidate genes were identified, including 17 candidate genes for agronomic traits, 19 for seed related traits, and 33 for disease reaction traits. This study identified potentially valuable candidate genes that affect multiple traits. The success in narrowing down the genomic region for some loci through overlapping mapping results of multiple studies is a promising avenue for community-based studies and plant breeding applications.
Global distribution patterns of marine nitrogen-fixers by imaging and molecular methods
Authors: Karlusich Juan José Pierella , Pelletier Eric , Lombard Fabien , Carsique Madeline , Dvorak Etienne , Colin Sébastien , Picheral Marc , Cornejo-Castillo Francisco M. , Acinas Silvia G. , Pepperkok Rainer , Karsenti Eric , de Vargas Colomban , Wincker Patrick , Bowler Chris , Foster Rachel A
Published: October 2020

Biological nitrogen fixation plays a critical role in marine primary production, yet, our understanding of marine N2-fixers (diazotrophs) is hindered by limited observations. Here, we developed a quantitative image analysis pipeline in concert with mapping of molecular markers for mining >2,000,000 images and >1,300 metagenomes in surface, deep chlorophyll maximum and mesopelagic samples across 6 size fractions (<0.2-2000 μm). Imaging and PCR-free molecular data were remarkably congruent. Sequences from diazotrophs were detected from the ultrasmall bacterioplankton (<0.2 μm) to mesoplankton (180-2000 μm), while images predicted symbiotic and colonial-forming diazotrophs (>20 µm). Imaging and molecular data estimated that polyploidy can significantly impact gene abundances of symbiotic vs colonial-forming diazotrophs. In general our results support the canonical view that larger sized diazotrophs (>10 μm) dominate the tropical belts, while sequences from unicellular cyanobacterial and non-cyanobacterial diazotrophs were globally distributed in surface and the mesopelagic. Co-occurring diazotrophic lineages of different lifestyles were frequently encountered, and several new high density regions of diazotrophs were identified in the global ocean. Overall, this work provides an update of marine diazotroph biogeographical diversity and contributes a new bio-imaging-informatic workflow.
Subcellular relocalization and nuclear redistribution of the RNA methyltransferases TRMT1 and TRMT1L upon neuronal activation
Authors: Jonkhout Nicky , Cruciani Sonia , Vieira Helaine Graziele Santos , Tran Julia , Liu Huanle , Liu Ganqiang , Pickford Russell , Kaczorowski Dominik , Franco Gloria R. , Vauti Franz , Camacho Noelia , Abedini Seyedeh Sedigheh , Najmabadi Hossein , de Pouplana Lluís Ribas , Christ Daniel , Schonrock Nicole , Mattick John S. , Novoa Eva Maria
Published: October 2020

RNA modifications are dynamic chemical entities that regulate RNA fate, and an avenue for environmental response in neuronal function. However, which RNA modifications may be playing a role in neuronal plasticity and environmental responses is largely unknown. Here we characterize the biochemical function and cellular dynamics of two human RNA methyltransferases previously associated with neurological dysfunction, TRMT1 and its homolog, TRMT1-like(TRMT1L). Using a combination of next-generation sequencing, LC-MS/MS, patient-derived cell lines and knockout mouse models, we confirm the previously reported dimethylguanosine (m2,2G) activity of TRMT1 in tRNAs, as well as reveal that TRMT1L, whose activity was unknown, is responsible for methylating a subset of cytosolic tRNAAla(AGC) isoacceptors at position 26. Using a cellularin vitromodel that mimics neuronal activation and long term potentiation, we find that both TRMT1 and TRMT1L change their subcellular localization upon neuronal activation. Specifically, we observe a major subcellular relocalization from mitochondria and other cytoplasmic domains (TRMT1) and nucleoli (TRMT1L) to different small punctate compartments in the nucleus, which are as yet uncharacterized. This phenomenon does not occur upon heat shock, suggesting that the relocalization of TRMT1 and TRMT1L is not a general reaction to stress, but rather a specific response to neuronal activation. Our results suggest that subcellular relocalization of RNA modification enzymes play a role in neuronal plasticity and transmission of information, presumably by addressing new targets.
PATRIOT: A pipeline for tracing identical-by-descent chromosome segments to improve genomic prediction in self-pollinating crop species
Authors: Shook Johnathon M. , Lourenco Daniela , Singh Asheesh K.
Published: October 2020

The lowering genotyping cost is ushering in a wider interest and adoption of genomic prediction and selection in plant breeding programs worldwide. However, improper conflation of historical and recent linkage disequilibrium between markers and genes restricts high accuracy of genomic prediction (GP). Multiple ancestors may share a common haplotype surrounding a gene, without sharing the same allele of that gene. This prevents parsing out genetic effects associated with the underlying allele of that gene among the set of ancestral haplotypes. We present ‘Parental Allele Tracing, Recombination Identification, and Optimal predicTion’ (i.e., PATRIOT) approach that utilizes marker data to allow for a rapid identification of lines carrying specific alleles, increases the accuracy of genomic relatedness and diversity estimates, and improves genomic prediction. Leveraging identity by descent, PATRIOT showed an improvement in GP accuracy by 16.6% compared to the traditional rrBLUP method. This approach will help to increase the rate of genetic gain and allow available information to be more effectively utilized within breeding programs.
Meet me in the middle: brain-behavior mediation analysis for fMRI experiments
Authors: Brochard Jules , Daunizeau Jean
Published: October 2020

Functional outcomes (e.g., subjective percepts, emotions, memory retrievals, decisions, etc…) are partly determined by external stimuli and/or cues. But they may also be strongly influenced by (trial-by-trial) uncontrolled variations in brain responses to incoming information. In turn, this variability provides information regarding how stimuli and/or cues are processed by the brain to shape behavioral responses. This can be exploited by brain-behavior mediation analysis to make specific claims regarding the contribution of brain regions to functionally-relevant input-output transformations. In this work, we address four challenges of this type of approach, when applied in the context of mass-univariate fMRI data analysis: (i) we quantify the specificity and sensitivity profiles of different variants of mediation statistical tests, (ii) we evaluate their robustness to hemo-dynamic and other confounds, (iii) we identify the sorts of brain mediators that one can expect to detect, and (iv) we disclose possible interpretational issues and address them using complementary information-theoretic approaches.En passant, we propose a computationally efficient algorithmic implementation of the approach that is amenable to whole-brain exploratory analysis. We also demonstrate the strengths and weaknesses of brain-behavior mediation analysis in the context of an fMRI study of decision under risk. Finally, we discuss the limitations and possible extensions of the approach.
Chromatin conformation capture (Hi-C) sequencing of patient-derived xenografts: analysis guidelines
Authors: Dozmorov Mikhail G. , Tyc Katarzyna M. , Sheffield Nathan C. , Boyd David C. , Olex Amy L. , Reed Jason , Harrell J. Chuck
Published: October 2020

Sequencing of patient-derived xenograft (PDX) mouse models allows investigation of the molecular mechanisms of human tumor samples engrafted in a mouse host. Thus, both human and mouse genetic material is sequenced. Several methods have been developed to remove mouse sequencing reads from RNA-seq or exome sequencing PDX data and improve the downstream signal. However, for more recent chromatin conformation capture technologies (Hi-C), the effect of mouse reads remains undefined.

We evaluated the effect of mouse read removal on the quality of Hi-C data using in silico created PDX Hi-C data with 10% and 30% mouse reads. Additionally, we generated two experimental PDX Hi-C datasets using different library preparation strategies. We evaluated three alignment strategies (Direct, Xenome, Combined) and three processing pipelines (Juicer, HiC-Pro, HiCExplorer) on the quality of Hi-C data.

Removal of mouse reads had little-to-no effect on data quality than the results obtained with Direct alignment strategy. Juicer pipeline extracted the most useful information from PDX Hi-C data. However, library preparation strategy had the largest effect on all quality metrics. Together, our study presents comprehensive guidelines on PDX Hi-C data processing.
Key Nucleation Stages and Associated Molecular Determinants and Processes in pH-Induced Formation of Amyloid Beta Oligomers as Revealed by High-Speed AFM
Authors: Feng Lei , Watanabe Hiroki , Molino Paul J. , Wallace Gordon G. , Phung Son L. , Uchihashi Takayuki , Higgins Michael J.
Published: October 2020

Non-fibrillar oligomers formed via nucleation from amyloid beta (AB) peptides are currently implicated in the neurotoxicity of Alzheimer’s disease. Thus, shedding light on the molecular mechanisms underlying their formation is important for identifying targets for drug therapies. This is however an enduring challenge due to the inability to detect AB nucleation processes in the lag phase from bulk kinetic assays, while time-course analyses using a series of peptide solutions involve the discontinuous observation of dynamic nucleation processes and pathways. In this study, by adjusting the pH of AB42 peptide samples while simultaneously imaging with high-speed atomic force microscopy (HS-AFM), we show the in-situ, continuous visualization of dynamic AB42 nucleation at the molecular level. The process reveals a pH-induced saturation regime, enabling a critical monomer substrate concentration to initiate the birth of nucleation. A number of key nucleation phases are identified, including pre-nucleation, saturation regime (mass surface adsorption), nucleation and post-nucleation growth, eventually leading to the formation of predominately oligomer species. HS-AFM observations further reveal the distinct, molecular processes associated with each nucleation phase that constitute the path-dependent formation of different AB species, namely an intial monomer “diffuse-like” surface layer, followed by the emergence of nuclei and then subsequent formation and growth of new complexes and oligomers. In particular, the ability of individual nuclei to undergo surface diffusion and establish new complexes via binding interactions with other species encountered in the system was found to be a significant mechanism influencing the growth of oligomers. Herein, the study contributes to current AB nucleation theories by ascribing new molecular mechanisms. More generally, the knowledge gained from single molecule techniques can greatly assist in our current understanding of various biological processes of AB peptide such as nucleation, growth, aggregation and their related kinetic pathways.
Relative time constraints improve molecular dating
Authors: Szöllősi Gergely J. , Höhna Sebastian , Williams Tom A. , Schrempf Dominik , Daubin Vincent , Boussau Bastien
Published: October 2020

Dating the tree of life is central to understanding the evolution of life on Earth. Molecular clocks calibrated with fossils represent the state of the art for inferring the ages of major groups. Yet, other information on the timing of species diversification can be used to date the tree of life. For example, horizontal gene transfer events and ancient coevolutionary relationships such as (endo)symbioses can imply temporal relationships between two nodes in a phylogeny (Davín et al. 2018). These alternative sources of temporal constraints can be particularly helpful when the geological record is sparse, e.g. for microorganisms, which represent the vast majority of extant and extinct biodiversity.

Here, we present a new method to combine fossil calibrations and relative age constraints to estimate chronograms. We provide an implementation of relative age constraints in RevBayes (Höhna et al. 2016) that can be combined in a modular manner with the wide range of molecular dating methods available in the software.

We use both realistic simulations and empirical datasets of 40 Cyanobacteria and 62 Archaea to evaluate our method. We show that the combination of relative age constraints with fossil calibrations significantly improves the estimation of node ages.
Identification and validation of a ferroptosis-related genes based prognostic signature for prostate cancer
Authors: Liu Huan , Gao Lei , Li Jie , Zhai Tingshuai , Xie Tiancheng , Xu Yunfei
Published: October 2020

Ferroptosis, an iron-dependent form of selective cell death, involves in the development of many cancers. However, systematic analysis of ferroptosis related genes (FRGs) in prostate cancer (PCa) remains to be clarified. In our research, we collected the mRNA expression profiles and clinical information of PCa patients from TCGA and MSKCC databases. The univariate, LASSO and multivariate Cox regression method were performed to construct prognostic signature in TCGA cohort. Seven FRGs, AKR1C3, ALOXE3, ATP5MC3, CARS1, MT1G, PTGS2, TFRC, were included to establish the risk model, which was validated in MSKCC dataset. Subsequently, we found that high risk group was strongly correlated with copy number alteration load, tumor burden mutation, immune cell infiltration, mRNAsi, immuetherapy and bicalutamide response. Finally, it was identified that overexpression of TFRC could induce proliferation and invasion in PCa cell linesin vitro.These results demonstrated that this risk model based on recurrence free survival (RFS) could accurately predict prognosis in PCa patients, suggesting that FRGs are promising prognostic biomarkers and drug target genes for PCa patients.