bluuebunny/crossref_metadata_2025 huggingface dataset:
Heterologous vaccination strategy for containing COVID-19 pandemic
Authors: Lin Ang , Liu JingJing , Ma Xiaopin , Zhao Fanfan , Yu Bo , He Jiaxin , Shen Mingyun , Huang Lei , Tang Hongming , Jiang Erpeng , Wang Yue , Cui Pingfang , Zhang Yujian , Yao Weiguo , Zhang Aihua , Wang Youchun , Li Yuhua , Huang Weijin , Li Qihan , Liu Zhongmin , Li Hangwen
Published: May 2021

An unequitable vaccine allocation and continuously emerging SARS-CoV-2 variants pose challenges to contain the pandemic, which underscores the need for licensing more vaccine candidates, increasing manufacturing capacity and implementing better immunization strategy. Here, we report data from a proof-of-concept investigation in two healthy individuals who received two doses of inactivated whole-virus COVID-19 vaccines, followed by a single heterologous boost vaccination after 7 months with an mRNA vaccine candidate (LPP-Spike-mRNA) developed by Stemirna Therapeutics. Following the boost, Spike-specific antibody (Ab), memory B cell and T cell responses were significantly increased. These findings indicate that a heterologous immunization strategy combining inactivated and mRNA vaccines can generate robust vaccine responses and therefore provide a rational and effective vaccination regimen.
A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program
Authors: Verma Anurag , Tsao Noah , Thomann Lauren , Ho Yuk-Lam , Iyengar Sudha , Luoh Shiuh-Wen , Carr Rotonya , Crawford Dana , Efird Jimmy T. , Huffman Jennifer , Hung Adriana , Ivey Kerry , Levin Michael , Lynch Julie , Natarajan Pradeep , Pyarajan Saiju , Bick Alexander , Costa Lauren , Genovese Giulio , Hauger Richard , Madduri Ravi , Pathak Gita , Polimanti Renato , Voight Benjamin , Vujkovic Marijana , Zekavat Maryam , Zhao Hongyu , Ritchie Marylyn D ,   VA Million Veteran Program COVID-19 Science Initiative, Chang Kyong-Mi , Cho Kelly , Casas Juan P. , Tsao Philip S. , Gaziano J. Michael , O’Donnell Christopher , Damrauer Scott , Liao Katherine
Published: May 2021

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n=35) or hospitalization (n=42) due to severe COVID-19 using genome-wide association summary from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828= 53 and nrs505922=59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p=1.32 × 10−199), and thrombosis ORrs505922 1.33, p=2.2 ×10−265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p=4.12 × 10−191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p=2.26× 10−12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p=6.48 ×10−23, lupus OR 0.84, p=3.97 × 10−06. PheWAS stratified by genetic ancestry demonstrated differences in genotype-phenotype associations across ancestry. LMNA (rs581342) associated with neutropenia OR 1.29 p=4.1 × 10−13 among Veterans of African ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.
Synergistic associations of cognitive and motor impairments with functional outcome in covert cerebral small vessel disease
Authors: Jokinen Hanna , Laakso Hanna M. , Ahlström Matti , Arola Anne , Lempiäinen Juha , Pitkänen Johanna , Paajanen Teemu , Sikkes Sietske A. M. , Koikkalainen Juha , Lötjönen Jyrki , Korvenoja Antti , Erkinjuntti Timo , Melkas Susanna
Published: May 2021

Objective

Cognitive and motor impairments are the key clinical manifestations of cerebral small vessel disease (SVD), but their interrelations and combined effects on functional outcome have not been elucidated. We investigated the associations between cognitive and motor functions and their interactions and mediating effects on instrumental activities of daily living (IADL) and quality of life in older individuals with various degrees of white matter hyperintensities (WMH).

Methods

Participants of the Helsinki Small Vessel Disease Study (n=152) were assessed according to an extensive clinical, neuropsychological and MRI protocol. Cognitive composite scores for global cognition, processing speed, executive functions and memory were constructed from multiple tests within each domain. Physical examination included measures of gait speed, balance (single-leg-stance) and functional mobility (timed-up-and-go test). IADL was evaluated with a proxy-based Amsterdam IADL questionnaire and quality of life with a self-report EUROHIS-Qol index. Volumes of WMH and gray matter (GM) were obtained with automated segmentation. Sets of linear regression analyses were used to model the associations between motor and cognitive performances, WMH and GM volumes, and IADL and quality of life.

Results

Domain-specific cognitive and motor functions had strong interrelations with each other, and they were significantly associated with IADL, quality of life as well as WMH and GM volumes. A consistent pattern on significant interactions between cognitive and motor functions was found on IADL, but not on quality of life. In particular, low cognitive scores together with decline in the timed-up-and-go test and gait speed were strongly related to impaired IADL. The association of WMH volume with IADL was mediated by global cognition, whereas the association of GM volume with IADL was mediated by global cognition and timed up-and-go performance.

Conclusion

The results highlight the complex interplay and synergism between motor and cognitive abilities on functional outcome in SVD. The combined effect of motor and cognitive disturbances on IADL is likely to be greater than the individual effects of each of the two impairments. WMH and brain atrophy contribute to disability through cognitive and motor impairment.
Risk factors for early childhood growth faltering in rural Cambodia
Authors: Lai Amanda , Velez Irene , Ambikapathi Ramya , Seng Krisna , Cumming Oliver , Brown Joe
Published: May 2021

Introduction

Inadequate nutrition in early life and exposure to sanitation-related enteric pathogens have been linked to poor growth outcomes in children. Despite rapid development in Cambodia, high prevalence of growth faltering and stunting continue to persist. This study aimed to assess nutrition and WASH variables and their association with nutritional status of children under 24 months in rural Cambodia.

Methods

We conducted surveys in 491 villages across 55 rural communes in Cambodia in September 2016 to measure associations between child, household, and community-level risk factors for stunting and length-for-age z-score (LAZ). A primary survey measured child-level variables, including anthropometric measures and risk factors for growth faltering and stunting, for 4,036 children under 24 months of age from 3,877 households (approximately 8 households per village). For LAZ, we calculated bivariate and adjusted associations (as mean differences) with 95% confidence intervals using generalised estimating equations (GEEs) to fit linear regression models with robust standard errors. For stunting, we calculated unadjusted and adjusted prevalence ratios (PRs) with 95% confidence intervals using GEEs to fit Poisson regression models with robust standard errors. For all models assessing effects of household-level variables, we used GEEs to account for clustering at the village level.

Results

After adjustment for potential confounding, presence of water and soap at a household’s handwashing station was found to be significantly associated (p<0.05) with increased LAZ (adjusted mean difference in LAZ +0.10, 95% CI: 0.03, 0.16), and household use of an improved drinking water source was associated with less stunting in children compared to households that did not use an improved source of drinking water (aPR 0.81, 95% CI: 0.66, 0.98); breastfeeding was associated with a lower LAZ score (−0.16, 95% CI: −0.27, −0.05). No other feeding practices (i.e., dietary diversity, meal frequency, minimum acceptable diet) or sanitation variables (i.e., household’s safe disposal of child stools, household-level sanitation, community-level sanitation) were associated with LAZ scores or stunting in children under 24 months of age. In an age-stratified analysis, children under 12 months of age were longer (LAZ +0.12, 95% CI: 0.02, 0.21) if there was presence of water and soap at the household handwashing station; at the community level, higher prevalence of shared sanitation (percentage of households in a village who report to use shared sanitation facilities) was negatively associated with child length (LAZ - 0.36, 95% CI: −0.66, −0.07).
Combined Metabolic Activators Reduces Liver Fat in Nonalcoholic Fatty Liver Disease Patients
Authors: Zeybel Mujdat , Altay Ozlem , Arif Muhammad , Li Xiangyu , Yang Hong , Fredolini Claudia , Akyildiz Murat , Saglam Burcin , Gonenli Mehmet Gokhan , Ural Dilek , Kim Woonghee , Schwenk Jochen M. , Zhang Cheng , Shoaie Saeed , Nielsen Jens , Uhlén Mathias , Borén Jan , Mardinoglu Adil
Published: May 2021

Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMA) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo-controlled 10-week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomics data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host-microbiome interactions. In conclusion, we observed that CMA can be used develop a pharmacological treatment strategy in NAFLD patients.
Electronic early notification of sepsis in hospitalized ward patients: a study protocol for a stepped-wedge cluster randomized controlled trial
Authors: Arabi Yaseen M , Saawi Abdulmohsen Al , Zahrani Mohammed Al , Khathaami Ali Al , AlHazme Raed H , Mutrafy Abdullah Al , Qarni Ali Al , Shouabi Ahmed Al , Qasim Eman Al , Abdukahil Sheryl Ann , Al-Rabeeah Fawaz Q , Ghamdi Huda Al , Ghamdi Ebtisam Al , Alansari Mariam , Abuelgasim Khadega A , Alattasi Abdulaleem , Alchin John , Al-Dorzi Hasan M , Ghamdi Abdulaziz A , Al-Hameed Fahad , Alharbi Ahmad , Hussein Mohamed , Jastaniah Wasil , AlKatheri Mufareh Edah , AlMarhabi Hassan , Mustafa Hani T , Jones Joan , Al-Qahtani Saad , Qahtani Shaher , Qureshi Ahmad S , Salih Salih Bin , Alselaim Nahar , Tashkandi Nabeeha , Vishwakarma Ramesh Kumar , AlWafi Emad , Alyami Ali H , Yousef Zeyad Al ,   for the SCREEN Trial Group
Published: May 2021

Background

To examine the effect of screening for sepsis using an electronic sepsis alert versus no alert in hospitalized patients admitted to wards on hospital mortality.

Methods

This study is conducted in 45 medical-surgical-oncology wards in five hospitals. Based on the quick Sequential Organ Failure Assessment (qSOFA), an electronic alert has been developed in the hospital Electronic Medical Record system. The alert system sends notifications of “Possible Sepsis Alert” to the bedside nurse, charge nurse, and primary medical team and requires an acknowledgment in the health information system from the bedside nurse and physician. In addition, data on the alert are displayed on management dashboards for each ward. Initially, all wards had a masked alert for 2 months. Hospital wards are then allocated in a randomized fashion to either active or masked alert, such that the alert is activated in five new randomly selected wards every two months until all wards have the active alert. The primary endpoint is in-hospital mortality by 90 days.

Discussion

The trial has started in October 2019 and is expected to continue for 22 months enrolling more than 62550 hospitalized patients.

Trial registration

ClinicalTrials.govNCT04078594. Registered on September 6, 2019,https://clinicaltrials.gov/ct2/show/NCT04078594
Modeling third waves of Covid-19 spread with piecewise differential and integral operators: Turkey, Spain and Czechia
Authors: Atangana Abdon , İğret Araz Seda
Published: May 2021

Several collected data representing the spread of some infectious disease have demonstrated that the spread does not really exhibit homogeneous spread. Clear examples can include the spread of Spanish flu and Covid-19. Collected data depicting numbers of daily new infections in the case of Covid-19 from countries like Turkey, Spain show three waves with different spread patterns. A clear indication of crossover behaviors. While modelers have suggested many mathematical models to depicting these behaviors, it becomes clear that their mathematical models cannot really capture the crossover behaviors, especially passage from deterministic resetting to stochastics. Very recently Atangana and Seda have suggested a concept of piecewise modeling consisting in defining a differential operator piece-wisely, the idea was first in chaos and outstanding patterns were captured. In this paper, we extend this concept to the field of epidemiology with the aim to depict waves with different patterns. Due to the novelty of this concept, a different approach to insure the existence and uniqueness of system solutions are presented. A piecewise numerical approach is presented to derive numerical solutions of such models. An illustrative example is presented and compared with collected data from 3 different countries including Turkey, Spain and Czechia. The obtained results let no doubt for us to conclude that this concept is a new window that will help mankind to better understand nature.
Virus-Dependent Immune Conditioning of Tissue Microenvironments
Authors: Jiang Sizun , Chan Chi Ngai , Rovira-Clave Xavier , Chen Han , Bai Yunhao , Zhu Bokai , McCaffrey Erin , Greenwald Noah F. , Liu Candace , Barlow Graham L , Weirather Jason L. , Oliveria John Paul , Philips Darci , Mukherjee Nilanjan , Busman-Sahay Kathleen , Nekorchuk Michael , Terry Margaret , Younger Skyler , Bosse Marc , Demeter Janos , Golstev Yury , McIlwain David Robert , Angelo Michael , Estes Jacob D. , Nolan Garry P.
Published: May 2021

A thorough understanding of complex spatial host-disease interactions in situ is necessary in order to develop effective preventative measures and therapeutic strategies. Here, we developed Protein And Nucleic acid IN situ Imaging (PANINI) and coupled it with Multiplexed Ion Beam Imaging (MIBI) to sensitively and simultaneously quantify DNA, RNA, and protein levels within the microenvironments of tissue compartments. The PANINI-MIBI approach was used to measure over 30 parameters simultaneously across large sections of archival lymphoid tissues from non-human primates that were healthy or infected with simian immunodeficiency virus (SIV), a model that accurately recapitulates human immunodeficiency virus infection (HIV). This enabled multiplexed dissection of cellular phenotypes, functional markers, viral DNA integration events, and viral RNA transcripts as resulting from viral infection. The results demonstrated immune coordination from an unexpected upregulation of IL10 in B cells in response to SIV infection that correlated with macrophage M2 polarization, thus conditioning a potential immunosuppressive environment that allows for viral production. This multiplexed imaging strategy also allowed characterization of the coordinated microenvironment around latently or actively infected cells to provide mechanistic insights into the process of viral latency. The spatial multi-modal framework presented here is applicable to deciphering tissue responses in other infectious diseases and tumor biology.
Partial reprogramming restores youthful gene expression through transient suppression of cell identity
Authors: Roux Antoine , Zhang Chunlian , Paw Jonathan , Solorio José-Zavalara , Vijay Twaritha , Kolumam Ganesh , Kenyon Cynthia , Kimmel Jacob C.
Published: May 2021

Transient induction of pluripotent reprogramming factors has been reported to reverse some features of aging in mammalian cells and tissues. However, the impact of transient reprogramming on somatic cell identity programs and the necessity of individual pluripotency factors remain unknown. Here, we mapped trajectories of transient reprogramming in young and aged cells from multiple murine cell types using single cell transcriptomics to address these questions. We found that transient reprogramming restored youthful gene expression in adipocytes and mesenchymal stem cells but also temporarily suppressed somatic cell identity programs. We further screened Yamanaka Factor subsets and found that many combinations had an impact on aging gene expression and suppressed somatic identity, but that these effects were not tightly entangled. We also found that a transient reprogramming approach inspired by amphibian regeneration restored youthful gene expression in aged myogenic cells. Our results suggest that transient pluripotent reprogramming poses a neoplastic risk, but that restoration of youthful gene expression can be achieved with alternative strategies.
In vivo direct imaging of neuronal activity at high temporo-spatial resolution
Authors: Toi Phan Tan , Jang Hyun Jae , Min Kyeongseon , Kim Sung-Phil , Lee Seung-Kyun , Lee Jongho , Kwag Jeehyun , Park Jang-Yeon
Published: May 2021

There has been a longstanding demand for noninvasive neuroimaging methods capable of detecting neuronal activity at both high temporal and spatial resolution. Here, we propose a novel method that enables Direct Imaging of Neuronal Activity for functional MRI (termed DIANA-fMRI) that can dynamically image spiking activity in milliseconds precision, while retaining the original benefit of high spatial resolution of MRI. DIANA-fMRI was demonstrated through in vivo mice brain imaging at 9.4 T applying electrical whisker-pad stimulation, directly imaging the spiking activity as well as capturing its sequential propagation along the thalamocortical pathway, as further confirmed through in vivo spike recording and optogenetics. DIANA-fMRI will open up new avenues in brain science by providing a deeper understanding of the brain’s functional organization including neural networks.
Molecular architecture determines brain delivery of a transferrin-receptor targeted lysosomal enzyme
Authors: Arguello Annie , Mahon Cathal S. , Calvert Meredith E. K. , Chan Darren , Dugas Jason C. , Pizzo Michelle E. , Thomsen Elliot R. , Chau Roni , Damo Lorna A. , Duque Joseph , Earr Timothy , Fang Meng , Giese Tina , Kim Do Jin , Liang Nicholas , Lopez Isabel A. , Nguyen Hoang N. , Solanoy Hilda , Tsogtbaatar Buyankhishig , Ullman Julie C. , Wang Junhua , Dennis Mark S. , Diaz Dolores , Gunasekaran Kannan , Henne Kirk R. , Lewcock Joseph W. , Sanchez Pascal E. , Troyer Matthew D. , Harris Jeffrey M. , Scearce-Levie Kimberly , Shan Lu , Watts Ryan J. , Thorne Robert G. , Henry Anastasia G. , Kariolis Mihalis S.
Published: May 2021

Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse biotherapeutics to platforms that bind the transferrin receptor (TfR), a brain endothelial cell target, to facilitate receptor-mediated transcytosis across the BBB. Here, we characterized the pharmacological behavior of two distinct TfR-targeted platforms fused to iduronate 2-sulfatase (IDS), a lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared the relative brain exposures and functional activities of both approaches in mouse models. IDS fused to a moderate-affinity, monovalent TfR binding enzyme transport vehicle (ETV:IDS) resulted in widespread brain exposure, internalization by parenchymal cells, and significant substrate reduction in the CNS of an MPS II mouse model. In contrast, IDS fused to a standard high-affinity bivalent antibody (IgG:IDS) resulted in lower brain uptake, limited biodistribution beyond brain endothelial cells, and reduced brain substrate reduction. These results highlight important features likely to impact the clinical development of TfR-targeting platforms in MPS II and potentially other CNS diseases.

Brain delivery, biodistribution and pharmacodynamics of a lysosomal enzyme fused to a moderate-affinity transferrin receptor-directed blood-brain barrier enzyme transport vehicle are superior to a traditional high-affinity anti-TfR monoclonal antibody fusion.
PARROT: a flexible recurrent neural network framework for analysis of large protein datasets
Authors: Griffith Daniel , Holehouse Alex S.
Published: May 2021

The rise of high-throughput experiments has transformed how scientists approach biological questions. The ubiquity of large-scale assays that can test thousands of samples in a day has necessitated the development of new computational approaches to interpret this data. Among these tools, machine learning approaches are increasingly being utilized due to their ability to infer complex non-linear patterns from high-dimensional data. Despite their effectiveness, machine learning (and in particular deep learning) approaches are not always accessible or easy to implement for those with limited computational expertise. Here we present PARROT, a general framework for training and applying deep learning-based predictors on large protein datasets. Using an internal recurrent neural network architecture, PARROT is capable of tackling both classification and regression tasks while only requiring raw protein sequences as input. We showcase the potential uses of PARROT on three diverse machine learning tasks: predicting phosphorylation sites, predicting transcriptional activation function of peptides generated by high-throughput reporter assays, and predicting the fibrillization propensity of amyloid beta with data generated by deep mutational scanning. Through these examples, we demonstrate that PARROT is easy to use, performs comparably to state-of-the-art computational tools, and is applicable for a wide array of biological problems.
Novel feature selection method via kernel tensor decomposition for improved multi-omics data analysis
Authors: Taguchi Y-h. , Turki Turki
Published: May 2021

Background

Feature selection of multi-omics data analysis remains challenging owing to the size of omics datasets, comprising approximately 102–105features. In particular, appropriate methods to weight individual omics datasets are unclear, and the approach adopted has substantial consequences for feature selection. In this study, we extended a recently proposed kernel tensor decomposition (KTD)-based unsupervised feature extraction (FE) method to integrate multi-omics datasets obtained from common samples in a weight-free manner.

Method

KTD-based unsupervised FE was reformatted as the collection of kernelized tensors sharing common samples, which was applied to synthetic and real datasets.

Results

The proposed advanced KTD-based unsupervised FE method showed comparative performance to that of the previously proposed KTD method, as well as tensor decomposition-based unsupervised FE, but required reduced memory and central processing unit time. Moreover, this advanced KTD method, specifically designed for multi-omics analysis, attributesP-values to features, which is rare for existing multi-omics–oriented methods.

Conclusions

The sample R code is available athttps://github.com/tagtag/MultiR/
Depression-like state induced by low-frequency repetitive transcranial magnetic stimulation to ventral medial frontal cortex in monkeys
Authors: Nakamura Shinya , Kishimoto Yodai , Sekino Masaki , Nakamura Motoaki , Tsutsui Ken-Ichiro
Published: May 2021

The medial frontal cortex (MFC), especially its ventral part, has long been of great interest with respect to the pathology of mood disorders. A number of human brain imaging studies have demonstrated the abnormalities of this brain region in patients with mood disorders, however, whether it is critically involved in the pathogenesis of such disorders remains to be fully elucidated. In this study, we conducted a causal study to investigate how the suppression of neural activity in the ventral region of the MFC (vMFC) affects the behavioral and physiological states of monkeys by using repetitive transcranial magnetic stimulation (rTMS). By using low-frequency rTMS (LF-rTMS) as an inhibitory intervention, we found that LF-rTMS targeting the vMFC induced a depression-like state in monkeys, which was characterized by a reduced spontaneous behavioral activity, increased plasma cortisol level, impaired sociability, and decreased motivation level. On the other hand, no such significant changes in behavioral and physiological states were observed when targeting the other MFC regions, dorsal or posterior. We further found that the administration of an antidepressant agent, ketamine, ameliorated the abnormal behavioral and physiological states induced by the LF-rTMS intervention. These findings indicate the causal involvement of the vMFC in the regulation of mood and affect and the validity of the LF-rTMS-induced dysfunction of the vMFC as a nonhuman primate model of the depression-like state.
ChAlPred: A Web Server for Prediction of Allergenicity of Chemical Compounds
Authors: Sharma Neelam , Patiyal Sumeet , Dhall Anjali , Devi Naorem Leimarembi , Raghava Gajendra P. S.
Published: May 2021

Allergy is the abrupt reaction of the immune system that may occur after the exposure with allergens like protein/peptide or chemical allergens. In past number of methods of have been developed for classifying the protein/peptide based allergen. To the best of our knowledge, there is no method to classify the allergenicity of chemical compound. Here, we have proposed a method named “ChAlPred”, which can be used to fill the gap for predicting the chemical compound that might cause allergy. In this study, we have obtained the dataset of 403 allergen and 1074 non-allergen chemical compounds and used 2D, 3D and FP descriptors to train, test and validate our prediction models. The fingerprint analysis of the dataset indicates that PubChemFP129 and GraphFP1014 are more frequent in the allergenic chemical compounds, whereas KRFP890 is highly present in non-allergenic chemical compounds. Our XGB based model achieved the AUC of 0.89 on validation dataset using 2D descriptors. RF based model has outperformed other classifiers using 3D descriptors (AUC = 0.85), FP descriptors (AUC = 0.92), combined descriptors (AUC = 0.93), and hybrid model (AUC = 0.92) on validation dataset. In addition, we have also reported some FDA-approved drugs like Cefuroxime, Spironolactone, and Tioconazole which can cause the allergic symptoms. A user user-friendly web server named “ChAlPred” has been developed to predict the chemical allergens. It can be easily accessed at https://webs.iiitd.edu.in/raghava/chalpred/.
Optimal spatial monitoring of populations described by reaction-diffusion models
Authors: Parisey Nicolas , Leclerc Melen , Adamczyk-Chauvat Katarzyna
Published: May 2021

Using spatialised population measurements and related geographic habitat data, it is quite feasible nowadays to derive parsimonious spatially explicit population models and to carry on their parameter estimation. To achieve such goal, reaction-diffusion models are fairly common in conservation biology and agricultural plant health where they are used, for example, for landscape planning or epidemiological surveillance. Unfortunately, if the mathematical methods and computational power are readily available, biological measurements are not. Despite the high throughput of some habitat related remote sensors, the experimental cost of biological measurements are, in our view, one of the worst bottleneck against a widespread usage of reaction-diffusion models. Hence, in this paper, we will recall some classical methods for optimal experimental design that we deem useful to spatial ecologist. Using two case studies, one in landscape ecology and one in conservation biology, we will show how to constructa prioriexperimental design minimizing variance of parameter estimates, enabling optimal experimental setup with pre and post hoc filtering for accommodating additional constraints.
Tools for accurate post hoc determination of marker location within whole-brain microscopy images
Authors: Tyson Adam L. , Vélez-Fort Mateo , Rousseau Charly V. , Cossell Lee , Tsitoura Chryssanthi , Obenhaus Horst A. , Claudi Federico , Lenzi Stephen C. , Branco Tiago , Margrie Troy W.
Published: May 2021

To interpret in vivo experiments designed to understand brain function, high-resolution whole-brain microscopy provides a means for post hoc determination of the location of implanted devices and recorded cells in three dimensional brain space that is a critical step for data interrogation. Here we have developed Python-based tools (brainreg and brainreg-segment) to accurately map, in a common coordinate space, the position of dye-labelled probe tracks and two-photon imaged cell populations expressing fluorescent protein. The precise location of probes and cells were validated using physiological recordings and human raters that indicate accuracy levels to less than 70µm. These flexible, open-source methodologies are expected to further evolve with need and to deliver the anatomical precision that is necessary for understanding the functional architecture of the brain.
recount3: summaries and queries for large-scale RNA-seq expression and splicing
Authors: Wilks Christopher , Zheng Shijie C. , Chen Feng Yong , Charles Rone , Solomon Brad , Ling Jonathan P. , Imada Eddie Luidy , Zhang David , Joseph Lance , Leek Jeffrey T. , Jaffe Andrew E. , Nellore Abhinav , Collado-Torres Leonardo , Hansen Kasper D. , Langmead Ben
Published: May 2021

We present recount3, a resource consisting of over 750,000 publicly available human and mouse RNA sequencing (RNA-seq) samples uniformly processed by our new Monorail analysis pipeline. To facilitate access to the data, we provide the recount3 and snapcount R/Bioconductor packages as well as complementary web resources. Using these tools, data can be downloaded as study-level summaries or queried for specific exon-exon junctions, genes, samples, or other features. Monorail can be used to process local and/or private data, allowing results to be directly compared to any study in recount3. Taken together, our tools help biologists maximize the utility of publicly available RNA-seq data, especially to improve their understanding of newly collected data. recount3 is available from http://rna.recount.bio.
Silencing Doublesex expression triggers three-level pheromonal feminization in Nasonia males
Authors: Wang Yidong , Sun Weizhao , Fleischmann Sonja , Millar Jocelyn G. , Ruther Joachim , Verhulst Eveline C
Published: May 2021

The transcription factor Doublesex (Dsx) has a conserved function in controlling sexual morphological differences in insects, but our knowledge on its role in regulating sexual behavior is widely limited to Drosophila. Here, we show in the parasitoid wasp Nasonia vitripennis that males whose Dsx gene had been silenced by RNA interference (NvDsx-i) underwent a three-level pheromonal feminization: (1) NvDsx-i males were no longer able to attract females from a distance, owing to drastically reduced titers of the abdominal long-range sex pheromone. (2) NvDsx-i males were courted by wild-type males like females which correlated with a lower abundance of alkenes in their cuticular hydrocarbon (CHC) profiles. Supplementation of NvDsx-i male CHC profiles with realistic amounts of synthetic (Z)-9-hentriacontene (Z9C31), the most significantly reduced alkene in NvDsx-i males, interrupted courtship by wild-type conspecific males. Supplementation of female CHC profiles with Z9C31 reduced courtship and mating attempts by wild-type males. These results prove that Z9C31 is crucial for sex discrimination in Nasonia. (3) Nvdsx-i males were hampered in eliciting female receptivity during courtship and thus experienced severely reduced mating success, suggesting that they are unable to produce the hitherto unidentified oral aphrodisiac pheromone reported in N. vitripennis males. We conclude that Dsx is a multi-level key regulator of pheromone-mediated sexual communication in N. vitripennis. Silencing Dsx by RNA interference provides a new avenue for unraveling the molecular mechanisms underlying the pheromone-mediated sexual communication in insects.
A proteomics sample metadata representation for multiomics integration, and big data analysis
Authors: Dai Chengxin , Füllgrabe Anja , Pfeuffer Julianus , Solovyeva Elizaveta , Deng Jingwen , Moreno Pablo , Kamatchinathan Selvakumar , Kundu Deepti Jaiswal , George Nancy , Fexova Silvie , Grüning Björn , Föll Melanie Christine , Griss Johannes , Vaudel Marc , Audain Enrique , Locard-Paulet Marie , Turewicz Michael , Eisenacher Martin , Uszkoreit Julian , Van Den Bossche Tim , Schwämmle Veit , Webel Henry , Schulze Stefan , Bouyssié David , Jayaram Savita , Duggineni Vinay Kumar , Samaras Patroklos , Wilhelm Mathias , Choi Meena , Wang Mingxun , Kohlbacher Oliver , Brazma Alvis , Papatheodorou Irene , Bandeira Nuno , Deutsch Eric W. , Vizcaíno Juan Antonio , Bai Mingze , Sachsenberg Timo , Levitsky Lev , Perez-Riverol Yasset
Published: May 2021

The amount of public proteomics data is increasing at an extraordinary rate. Hundreds of datasets are submitted each month to ProteomeXchange repositories, representing many types of proteomics studies, focusing on different aspects such as quantitative experiments, post-translational modifications, protein-protein interactions, or subcellular localization, among many others. For every proteomics dataset, two levels of data are captured: the dataset description, and the data files (encoded in different file formats). Whereas the dataset description and data file formats are supported by all ProteomeXchange partner repositories, there is no standardized format to properly describe the sample metadata and their relationship with the dataset files in a way that fully allows their understanding or re-analysis. It is left to the user’s choice whether to provide or not an ad hoc document containing this information. Therefore, in many cases, understanding the study design and data requires going back to the associated publication. This can be tedious and may be restricted in the case of non-open access publications. In many cases, this problem limits the generalization and reuse of public proteomics data.

Here we present a standard representation for sample metadata tailored to proteomics datasets produced by the HUPO Proteomics Standards Initiative and supported by ProteomeXchange resources. We repurposed the existing data format MAGE-TAB used routinely in the transcriptomics field to represent and annotate proteomics datasets. MAGETAB-Proteomics defines a set of annotation rules that the datasets submitted to ProteomeXchange should follow, ranging from sample properties to data analysis protocols. We also introduce a crowdsourcing project that enabled the manual curation of over 200 public datasets using MAGE-TAB-Proteomics. In addition, we describe an ecosystem of tools and libraries that were developed to validate and submit sample metadata-related information to ProteomeXchange. We expect that these tools will improve the reproducibility of published results and facilitate the reanalysis and integration of public proteomics datasets.
Vcflib and tools for processing the VCF variant call format
Authors: Garrison Erik , Kronenberg Zev N. , Dawson Eric T. , Pedersen Brent S. , Prins Pjotr
Published: May 2021

Since its introduction in 2011 the variant call format (VCF) has been widely adopted for processing DNA and RNA variants in practically all population studies — as well as in somatic and germline mutation studies. VCF can present single nucleotide variants, multi-nucleotide variants, insertions and deletions, and simple structural variants called against a reference genome. Here we present over 125 useful and much used free and open source software tools and libraries, part of vcflib tools and bio-vcf. We also highlight cyvcf2, hts-nim and slivar tools. Application is typically in the comparison, filtering, normalisation, smoothing, annotation, statistics, visualisation and exporting of variants. Our tools run daily and invisibly in pipelines and countless shell scripts. Our tools are part of a wider bioinformatics ecosystem and we consider it very important to make these tools available as free and open source software to all bioinformaticians so they can be deployed through software distributions, such as Debian, GNU Guix and Bioconda. vcflib, for example, was installed over 40,000 times and bio-vcf was installed over 15,000 times through Bioconda by December 2020. We shortly discuss the design of VCF, lessons learnt, and how we can address more complex variation that can not easily be represented by the VCF format. All source code is published under free and open source software licenses and can be downloaded and installed from https://github.com/vcflib.

Author summary

Most bioinformatics workflows deal with DNA/RNA variations that are typically represented in the variant call format (VCF) — a file format that describes mutations (SNP and MNP), insertions and deletions (INDEL) against a reference genome. Here we present a wide range of free and open source software tools that are used in biomedical sequencing workflows around the world today.
Distribution-free complex hypothesis testing for single-cell RNA-seq differential expression analysis
Authors: Gauthier Marine , Agniel Denis , Thiébaut Rodolphe , Hejblum Boris P.
Published: May 2021

Summary

State-of-the-art methods for single-cell RNA sequencing (scRNA-seq) Differential Expression Analysis (DEA) often rely on strong distributional assumptions that are difficult to verify in practice. Furthermore, while the increasing complexity of clinical and biological single-cell studies calls for greater tool versatility, the majority of existing methods only tackle the comparison between two conditions. We propose a novel, distribution-free, and flexible approach to DEA for single-cell RNA-seq data. This new method, called ccdf, tests the association of each gene expression with one or many variables of interest (that can be either continuous or discrete), while potentially adjusting for additional covariates. To test such complex hypotheses,ccdfuses a conditional independence test relying on the conditional cumulative distribution function, estimated through multiple regressions. We provide the asymptotic distribution of theccdftest statistic as well as a permutation test (when the number of observed cells is not sufficiently large).ccdfsubstantially expands the possibilities for scRNA-seq DEA studies: it obtains good statistical performance in various simulation scenarios considering complex experimental designs (i.e.beyond the two condition comparison), while retaining competitive performance with state-of-the-art methods in a two-condition benchmark. We applyccdfto a large publicly available scRNA-seq dataset of 84,140 SARS-CoV-2 reactive CD8+ T cells, in order to identify the diffentially expressed genes across 3 groups of COVID-19 severity (mild, hospitalized, and ICU) while accounting for seven different cellular subpopulations.
ROS-Degradable Polythioketal Urethane Foam Dressings to Promote Porcine Skin Wound Repair
Authors: Patil Prarthana , Russo Katherine A. , McCune Joshua T. , Pollins Alonda C. , Cottam Matthew A. , Dollinger Bryan R. , Colazo Juan M. , Yu Fang , Martin John R. , Gupta Mukesh K. , Cardwell Nancy L. , Davidson Jeffrey M. , Thompson Callie M. , Barbul Adrian , Hasty Alyssa M. , Guelcher Scott A. , Duvall Craig L.
Published: May 2021

Impaired skin healing and progression into chronic wounds is a prevalent and growing medical problem. Porous, resorbable biomaterials can be used as temporary substrates placed into skin defects to support cell infiltration, neo-tissue formation, and remodeling of nonhealing wounds. Naturally-derived biomaterials have promising healing benefits, but their low mechanical properties and exuberant costs limit their performance and use. Synthetic materials can be affordably manufactured and tuned across a broader range of physiochemical properties, but opportunities remain for tailoring them for ideal host immune and regenerative responses. Polyesters are the most clinically-tested class of synthetic biomaterials, but their hydrolysis releases acidic degradation products that can cause autocatalytic degradation processes that are poorly controlled and are not tied to cellular or other biologic activities. Here, we systemically explored a series of ROS-degradable polythioketal (PTK) urethane (UR) foams with varied hydrophilicity as an alternative class of synthetic biomaterials for wound healing. It was found that the most hydrophilic PTK- UR variant, which had 7 ethylene glycol (EG7) repeats flanking each side of each thioketal bond, had the highest ROS reactivity of the PTK-URs tested. In an in vivo porcine excisional skin wound healing model, hydrophilic EG7 PTK-UR foams more effectively promoted tissue integration, ECM deposition, and re- epithelialization of full-thickness skin wound compared to more hydrophobic PTK-UR variants. Resolution of type 1 inflammation and lower foreign body response to scaffold remnants was also observed for EG7 versus more hydrophobic PTK-UR scaffolds. Finally, porcine wound healing studies showed that EG7 PTK-UR foams had similar wound healing response to a collagen-based clinical gold standard product, Integra Bilayer Wound Matrix (BWM), while outperforming polyester UR foam-based NovoSorb Biodegradable Temporizing Matrix (BTM) with respect to increased ECM production, vascularization, and biomaterial-associated immune phenotype. In sum, PTK-UR foams warrant further development toward a new class of synthetic biomaterial foams for skin wound healing applications.
Repertoire of naturally acquired maternal antibodies transferred to infants for protection against shigellosis
Authors: Ndungo Esther , Andronescu Liana R. , Buchwald Andrea G , Lemme-Dumit Jose M. , Mawindo Patricia , Kapoor Neeraj , Fairman Jeff , Laufer Miriam K. , Pasetti Marcela F.
Published: May 2021

Shigellais the second leading cause of diarrheal diseases, accounting for >200,000 infections and >50,000 deaths in children under 5 years of age annually worldwide. The incidence ofShigella-induced diarrhea is relatively low during the first year of life and increases substantially, reaching its peak between 11 to 24 months of age. This epidemiological trend hints at an early protective immunity of maternal origin and an increase in disease incidence when maternally acquired immunity wanes. The magnitude, type, antigenic diversity, and antimicrobial activity of maternal antibodies transferred via placenta that can prevent shigellosis during early infancy are not known. To address this knowledge gap,Shigella-specific antibodies directed against the lipopolysaccharide (LPS) and virulence factors (IpaB, IpaC, IpaD, IpaH, and VirG), and antibody-mediated serum bactericidal (SBA) and opsonophagocytic killing antibody (OPKA) activity were measured in maternal and cord blood sera from a longitudinal cohort of mother-infant pairs living in rural Malawi. Protein-specific (very high levels) andShigellaLPS IgG were detected in maternal and cord blood sera; efficiency of placental transfer was 100% and 60%, respectively, and had preferential IgG subclass distribution (protein-specific IgG1 > LPS-specific IgG2). In contrast, SBA and OPKA activity in cord blood was substantially lower as compared to maternal serum and varied amongShigellaserotypes. LPS was identified as the primary target of SBA and OPKA activity. Maternal sera had remarkably elevatedShigella flexneri2a LPS IgM, indicative of recent exposure. Our study revealed a broad repertoire of maternally acquired antibodies in infants living in aShigella-endemic region and highlights the abundance of protein-specific antibodies and their likely contribution to disease prevention during the first months of life. These results contribute new knowledge on maternal infant immunity and target antigens that can inform the development of vaccines or therapeutics that can extend protection after maternally transferred immunity wanes.
Rapamycin induced hyperglycemia is associated with exacerbated age-related osteoarthritis
Authors: Minton Dennis M. , Elliehausen Christian J. , Javors Martin A. , Santangello Kelly S. , Konopka Adam R.
Published: May 2021

Background

The objective of this study was to determine if mechanistic target of rapamycin (mTOR) inhibition with or without AMP-activated protein kinase (AMPK) activation can protect against primary, age-related OA.

Design

Dunkin-Hartley guinea pigs develop mild primary OA pathology by 5-months of age that progresses to moderate OA by 8-months of age. At 5-months, guinea pigs sacrificed as young control (n=3) or were fed either a control diet (n=8), a diet enriched with the mTOR-inhibitor rapamycin (Rap, 14ppm, n=8), or Rap with the AMPK-activator metformin (Rap+Met, 1000ppm, n=8) for 12 weeks. Knee joints were evaluated by OARSI scoring, micro-computed tomography, and immunohistochemistry. Glenohumeral articular cartilage was collected for western blotting.

Results

Rap and Rap+Met treated guinea pigs displayed lower body weight than control. Rap and Rap+Met inhibited articular cartilage mTORC1 but not mTORC2 signaling. Rap+Met, but not Rap alone, stimulated AMPK. Despite lower body weight and articular cartilage mTORC1 inhibition, Rap and Rap+Met treated guinea pigs had greater OA severity in the medial tibial plateau due to articular cartilage structural damage and/or proteoglycan loss. Rap and Rap+Met increased plasma glucose compared to control. Plasma glucose concentration was positively correlated with proteoglycan loss, suggesting hyperglycemic stress may have contributed to worsened OA.

Conclusions

This is the first study to show that Rap induced increase in plasma glucose was associated with greater OA severity. Further, articular cartilage mTORC1 inhibition and bodyweight reduction by dietary Rap and Rap+Met did not protect against primary OA during the prevailing hyperglycemia.