bluuebunny/crossref_metadata_2025 huggingface dataset:
In-depth analysis of Bacillus anthracis 16S rRNA genes and transcripts reveals intra- and intergenomic diversity and facilitates anthrax detection
Authors: Braun Peter , Zimmermann Fee , Walter Mathias C. , Mantel Sonja , Aistleitner Karin , Stürz Inga , Grass Gregor , Stoecker Kilian
Published: August 2021

Analysis of 16S ribosomal RNA (rRNA) genes provides a central means of taxonomic classification of bacterial species. Based on presumed sequence identity among species of the Bacillus cereus sensu lato group, the 16S rRNA genes of B. anthracis have been considered unsuitable for diagnosis of the anthrax pathogen. With the recent identification of a single nucleotide polymorphism in some 16S rRNA gene copies, specific identification of B. anthracis becomes feasible. Here, we designed and evaluated a set of in situ-, in vitro- and in silico-assays to assess the yet unknown 16S-state of B. anthracis from different perspectives. Using a combination of digital PCR, fluorescence in situ hybridization, long-read genome sequencing and bioinformatics we were able to detect and quantify a unique 16S rRNA gene allele of B. anthracis (16S-BA-allele). This allele was found in all available B.anthracis genomes and may facilitate differentiation of the pathogen from any close relative. Bioinformatics analysis of 959 B. anthracis genome data-sets inferred that abundances and genomic arrangements of the 16S-BA-allele and the entire rRNA operon copy-numbers differ considerably between strains. Expression ratios of 16S-BA-alleles were proportional to the respective genomic allele copy-numbers. The findings and experimental tools presented here provide detailed insights into the intra- and intergenomic diversity of 16S rRNA genes and may pave the way for improved identification of B. anthracis and other pathogens with diverse rRNA operons.
Population normalisation in wastewater-based epidemiology for improved understanding of SARS-CoV-2 prevalence: A multi-site study
Authors: Sweetapple Chris , Wade Matthew J. , Grimsley Jasmine M. S. , Bunce Joshua T. , Melville-Shreeve Peter , Chen Albert S.
Published: August 2021

This paper aims to determine whether population normalisation significantly alters the SARS-CoV-2 trends revealed by wastewater-based epidemiology, and whether it is beneficial and/or necessary to provide an understanding of prevalence from wastewater SARS-CoV-2 concentrations. It uses wastewater SARS-CoV-2 data collected from 394 sampling sites, and implements normalisation based on concentrations of a) ammoniacal nitrogen, and b) orthophosphate. Wastewater SARS-CoV-2 metrics are evaluated at a site and aggregated level against three indicators prevalence, based on positivity rates from the Office for National Statistics Coronavirus Infection Survey and test results reported by NHS Test and Trace. Normalisation is shown to have little impact on the overall trends in the wastewater SARS-CoV-2 data on average. However, significant variability between the impact of population normalisation at different sites, which is not evident from previous WBE studies focussed on a single site, is also revealed. Critically, it is demonstrated that while the impact of normalisation on SARS-CoV-2 trends is small on average, it is not reasonable to conclude that it is always insignificant. When averaged across many sites, normalisation strengthens the correlation between wastewater SARS-CoV-2 data and indicators of prevalence; however, confidence in the improvement is low. Lastly, it is noted that most data were collected during periods of national lockdown and/or local restrictions, and thus the impacts and benefits of population normalisation are expected to be higher when normal travel habits resume.
Increased brain atrophy over 3 years in stroke survivors is linked to early post-stroke cognitive impairment
Authors: Brodtmann Amy , Werden Emilio , Khlif Mohamed Salah , Bird Laura J. , Egorova Natalia , Veldsman Michele , Pardoe Heath , Jackson Graeme , Bradshaw Jennifer , Darby David , Cumming Toby , Churilov Leonid , Donnan Geoffrey
Published: August 2021

Background

Stroke survivors are at high risk of dementia, associated with increasing age and vascular burden and with pre-existing cognitive impairment, older age. Brain atrophy patterns are recognised as signatures of neurodegenerative conditions, but the natural history of brain atrophy after stroke remains poorly described. We sought to determine whether stroke survivors who were cognitively normal at time of stroke had greater total brain (TBV) and hippocampal volume (HV) loss over 3 years than controls. We examined whether stroke survivors who were cognitively impaired (CI) at 3 months following their stroke had greater brain volume loss than cognitively normal (CN) stroke participants.

Methods

Cognition And Neocortical Volume After Stroke (CANVAS) study is a multi-centre cohort study of first-ever or recurrent adult ischaemic stroke participants compared to age- and sex-matched community controls. Participants were followed with MRI and cognitive assessments over 3 years and were free of a history of cognitive impairment or decline at inclusion. Our primary outcome measure was TBV change between 3 months and 3 years; secondary outcomes were TBV and HV change comparing CI and CN participants. We investigated associations between group status and brain volume change using a baseline-volume adjusted linear regression model with robust standard error.

Results

Ninety-three stroke (26 women, 66.7±12 years) and 39 control participants (15 women, 68.7±7 years) were available at 3 years. TBV loss in stroke patients was greater than controls: stroke mean (M)=20.3cm3±SD14.8cm3; controls M=14.2cm3±SD13.2cm3; (adjusted mean difference 7.88 95%CI [2.84,12.91] p-value=0.002). TBV decline was greater in those stroke participants who were cognitively impaired (M=30.7cm3; SD=14.2cm3) at 3 months (M=19.6cm3; SD=13.8cm3); (adjusted mean difference 10.42; 95%CI [3.04,17.80], p-value=0.006). No statistically significant differences in HV change were observed.

Conclusions

Ischaemic stroke survivors exhibit greater neurodegeneration compared to stroke-free controls. Brain atrophy is greater in stroke participants who were cognitively impaired people early after their stroke. Early cognitive impairment may predict greater subsequent atrophy, reflecting the combined impacts of stroke and vascular brain burden. Atrophy rates could serve as a useful biomarker for trials testing interventions to reduce post-stroke cognitive impairment.
Association of Systemic Immune-inflammation Index With Short-Term Mortality of Congestive Heart Failure: A Retrospective Cohort Study
Authors: Tang Yiyang , Zeng Xiaofang , Feng Yilu , Chen Qin , Liu Zhenghui , Luo Hui , Zha Lihuang , Yu Zaixin
Published: August 2021

Purpose

The present study aimed to clarify the potential predictive significance of Systemic immune-inflammation index (SII) in assessing the poor prognosis of critically ill patients with congestive heart failure (CHF).

Methods

Detailed clinical data were extracted from the Multiparameter Intelligent Monitoring in Intensive Care III database after gaining access and building the local platform. The 30- and 90-day and hospital all-cause mortalities of the patient was the primary outcome, and the readmission rate and the occurrence of major cardiovascular adverse events (MACEs) were the secondary outcomes. the Cox proportional hazard model and Logistic regression analysis were selected to reveal the relationship between SII level and the research outcome. Further, the propensity score matching (PSM) analysis was performed to improve the reliability of results by reducing the imbalance across groups.

Results

There were a total of 4606 subjects who passed the screening process and entered the subsequent analysis. Multivariate regression analysis showed that after adjusting for possible confounders, including age, heart rate, and albumin, etc., the high level of SII was independently associated with 30- and 90-day and hospital mortalities (tertile 3 versus tertile 1: HR, 95% CIs: 1.23, 1.04-1.45; 1.21, 1.06-1.39; 1.26, 1.05-1.50) and the incidence of MACEs (tertile 3 versus tertile 1: OR, 95% CI: 1.39, 1.12-1.73) in critically ill patients with CHF, but no significant correlation was found between SII and the readmission rate. Consistently, patients with high SII level still presented a significantly higher short-term mortality than patients with low SII in the PSM subset.

Conclusion

In critically ill patients with CHF, high level of SII could effectively predict high 30- and 90-day and hospital mortalities, as well as the high risk of occurrence of MACEs.
Thekpc-13’UTR facilitates dendritic transport and translation of mRNAs for dendrite arborization of a mechanosensory neuron important for male courtship
Authors: Shih Mushaine , Zou Yan , Ferreira Tarsis , Suzuki Nobuko , Kim Eunseo , Chuang Chiou-Fen , Chang Chieh
Published: August 2021

A recently reported Schizophrenia-associated genetic variant in the 3’UTR of the human furin gene, a homolog ofC. elegans kpc-1, highlights an important role of the furin 3’UTR in neuronal development(1). We isolate threekpc-1mutants that display abnormal dendrite arborization in PVD neurons and defective male mating behaviors. We show that thekpc-13’UTR participates in dendrite branching and self-avoidance. Thekpc-13’UTR facilitates mRNA localization to branching points and contact points between sibling dendrites and promotes local protein synthesis. We identify a secondary structural motif in thekpc-13’UTR required for dendrite self-avoidance. Animals withdma-1receptor over-expression exhibit similar dendrite branching and self-avoidance defects that are suppressed withkpc-1over-expression. Our results support a model in which KPC-1 proteins are synthesized at branching points and contact points to locally down-regulate DMA-1 receptors to promote dendrite branching and self-avoidance of a mechanosensory neuron important for male courtship.
Deep learning model of somatic hypermutation reveals importance of sequence context beyond targeting of AID and Polη hotspots
Authors: Tang Catherine , Krantsevich Artem , MacCarthy Thomas
Published: August 2021

B-cells undergo somatic hypermutation (SHM) of the Immunoglobulin (Ig) variable region to generate high-affinity antibodies. SHM relies on the activity of activation-induced deaminase (AID), which mutates C>U preferentially targeting WRC(W=A/T, R=A/G) hotspots. Downstream mutations at WAPolymerase η hotspots contribute further mutations. Computational models of SHM can describe the probability of mutations essential for vaccine responses. Previous studies using short subsequences (k-mers) failed to explain divergent mutability for the samek-mer. We developed the DeepSHM (Deep learning on SHM) model usingk-mers of size 5-21, improving accuracy over previous models. Interpretation of DeepSHM identified an extended DWRCT (D=A/G/T) motif with particularly high mutability. Increased mutability was further associated with lower surrounding G content. Our model also discovered a conserved AGYCTGGGGG (Y=C/T) motif within FW1 of IGHV3 family genes with unusually high T>G substitution rates. Thus, a wider sequence context increases predictive power and identifies novel features that drive mutational targeting.
A rear-engine drives adherent tissue migration in vivo
Authors: Yamaguchi Naoya , Zhang Ziyi , Schneider Teseo , Wang Biran , Panozzo Daniele , Knaut Holger
Published: August 2021

During animal embryogenesis, homeostasis and disease, tissues push and pull on their surroundings to move forward. Although the force-generating machinery is known, it is unknown how tissues exert physical stresses on their substrate to generate motion in vivo. Here, we identify the force transmission machinery, the substrate, and the stresses that a tissue, the zebrafish posterior lateral line primordium, generates during its migration. We find that the primordium couples actin flow through integrins to the basement membrane for forward movement. Talin/integrin-mediated coupling is required for efficient migration and its loss is partly compensated for by increased actin flow. Using Embryogram, an approach to measure stresses in vivo, we show that the primordium’s rear exerts high stresses, indicating that this tissue pushes itself forward with its back. This unexpected strategy likely also underlies the motion of other tissues in animals
NanoNet: Rapid end-to-end nanobody modeling by deep learning at sub angstrom resolution
Authors: Cohen Tomer , Halfon Matan , Schneidman-Duhovny Dina
Published: August 2021

Antibodies are a rapidly growing class of therapeutics. Recently, single domain camelid VHH antibodies, and their recognition nanobody domain (Nb) appeared as a cost-effective highly stable alternative to full-length antibodies. There is a growing need for high-throughput epitope mapping based on accurate structural modeling of the variable domains that share a common fold and differ in the Complementarity Determining Regions (CDRs). We develop a deep learning end-to-end model, NanoNet, that given a sequence directly produces the 3D coordinates of the Cɑ atoms of the entire VH domain. For the Nb test set, NanoNet achieves 1.7Å overall average RMSD and 3.0Å average RMSD for the most variable CDR3 loops. The accuracy for antibody VH domains is even higher: overall average RMSD < 1Å and 2.2Å RMSD for CDR3. NanoNet runtimes allow generation of ~1M nanobody structures in less than an hour on a standard CPU computer enabling high-throughput structure modeling.
The impact of eye closure on anticipatory alpha activity in a tactile discrimination task
Authors: ElShafei Hesham A. , Orlemann Corinne , Haegens Saskia
Published: August 2021

One of the very first observations made regarding alpha oscillations (8–14 Hz), is that they increase in power over posterior areas when awake participants close their eyes. Recent work, especially in the context of (spatial) attention, suggests that alpha activity reflects a mechanism of functional inhibition. However, it remains unclear how eye closure impacts anticipatory alpha modulation observed in attention paradigms, and how this affects subsequent behavioral performance. Here, we recorded magnetoencephalography (MEG) in 33 human participants performing a tactile discrimination task with their eyes open vs. closed. We replicated the hallmarks of previous somatosensory spatial attention studies: alpha lateralization across the somatosensory cortices as well as alpha increase over posterior regions. Furthermore, we found that eye closure leads to (i) reduced task performance, (ii) widespread increase in alpha power, and (iii) reduced anticipatory visual alpha modulation (iv) with no effect on somatosensory alpha lateralization. Regardless of whether participants had their eyes open or closed, increased posterior alpha power and somatosensory alpha lateralization improved their performance. Thus, we provide evidence that eye closure does not alter the impact of anticipatory alpha modulations on behavioral performance. We propose there is an optimal posterior alpha level for somatosensory task performance, which can be achieved through a combination of eye closure and top-down anticipatory attention.

Significance Statement

Alpha oscillations are dominant when awake participants have their eyes closed. Furthermore, alpha is known to modulate with anticipatory attention, and has been ascribed a role of active functional inhibition. Surprisingly, the link between anticipatory alpha and eye closure remains unclear. Here we collected MEG data while human participants performed a tactile discrimination task either with their eyes open or closed. Eye closure led to a widespread increase in alpha power, and affected anticipatory visual alpha modulation but not somatosensory alpha lateralization. Importantly, eye closure did not affect the correlation between alpha and task performance. Our findings provide novel insights into how eye closure impacts anticipatory alpha modulation, and how optimal alpha levels for task performance can be achieved differently.
Learning directed acyclic graphs for ligands and receptors based on spatially resolved transcriptomic analysis of ovarian cancer
Authors: Chowdhury Shrabanti , Ferri-Borgogno Sammy , Calinawan Anna P , Yang Peng , Wang Wenyi , Peng Jie , Mok Samuel C , Wang Pei
Published: August 2021

To unravel the mechanism of immune activation and suppression within tumors, a critical step is to identify transcriptional signals governing cell-cell communication between tumor and immune/stromal cells in the tumor microenvironment. Central to this communication are interactions between secreted ligands and cell-surface receptors, creating a highly connected signaling network among cells. Recent advancement in in situ-omics profiling, particularly spatial transcriptomic (ST) technology, provide unique opportunities to directly characterize ligand-receptor signaling networks that powers cell-cell communication. In this paper, we propose a novel statistical method,LRnetST, to characterize the ligand-receptor interaction networks between adjacent tumor and stroma cells based on ST data.LRnetSTutilizes a directed acyclic graph (DAG) model with a novel treatment to handle the zero-inflated distribution observed in the ST data. It also leverages existing ligand-receptor regulation databases as prior information, and employs a bootstrap aggregation strategy to achieve robust network estimation. Application ofLRnetSTto ST data of high-grade serous ovarian tumor samples revealed both common and distinct ligand-receptor regulations across different tumors. Some of these interactions were validated through a MERFISH data set of independent ovarian tumor samples. These results cast light on biological processes relating to the communication between tumor and immune/stromal cells in ovarian tumors. An open-source R package ofLRnetSTis available on GitHub athttps://github.com/jie108/LRnetST.
A flux-based machine learning model to simulate the impact of pathogen metabolic heterogeneity on drug interactions
Authors: Chung Carolina H. , Chandrasekaran Sriram
Published: August 2021

Abstract

Drug combinations are a promising strategy to counter antibiotic resistance. However, current experimental and computational approaches do not account for the entire complexity involved in combination therapy design, such as the effect of pathogen metabolic heterogeneity, changes in the growth environment, drug treatment order and time interval. To address these limitations, we present a comprehensive approach that uses genome-scale metabolic modeling and machine learning to guide combination therapy design. Our mechanistic approach (a) accommodates diverse data types, (b) accounts for time- and order-specific interactions, and (c) accurately predicts drug interactions in various growth conditions and their robustness to pathogen metabolic heterogeneity. Our approach achieved high accuracy (AUC = 0.83 for synergy, AUC = 0.98 for antagonism) in predicting drug interactions forE. colicultured in 57 metabolic conditions based on experimental validation. The entropy in bacterial metabolic response was predictive of combination therapy outcomes across time scales and growth conditions. Simulation of metabolic heterogeneity using population FBA identified two sub-populations ofE. colicells defined by the levels of three proteins (eno, fadB and fabD) in glycolysis and lipid metabolism that influence cell tolerance to a broad range of antibiotic combinations. Analysis of the vast landscape of condition-specific drug interactions revealed a set of 24 robustly synergistic drug combinations with potential for clinical use.

Significance

Worldwide, 700,000 people die each year from drug-resistant infections. Drug combinations have great potential to reduce the spread of drug-resistant bacteria. However, their potency is impacted by both the pathogen growth environment and the heterogeneity in pathogen metabolism. The metabolic heterogeneity in a pathogen population allows them to survive antibiotic treatment. Here we present a flexible machine-learning framework that utilizes diverse data types to effectively search through the large design space of both sequential and simultaneous combination therapies across hundreds of simulated growth conditions and pathogen metabolic states. Our approach can serve as a useful guide for the selection of robustly synergistic drug combinations.
The amyloid concentric β-barrel hypothesis: Models of amyloid beta 42 oligomers and annular protofibrils
Authors: Durell Stewart R. , Kayed Rakez , Guy H. Robert
Published: August 2021

Amyloid beta (Aβ) peptides, a major contributor to Alzheimers disease, occur in differing lengths, each of which forms a multitude of assembly types. The most toxic soluble oligomers are formed by Aβ42; some of which have antiparallel β-sheets. Previously, our group proposed molecular models of Aβ42 hexamers in which the C-terminus third of the peptide (S3) forms an antiparallel 6-stranded β-barrel that is surrounded by an antiparallel barrel formed by the more polar N-terminus (S1) and middle (S2) portions. These hexamers were proposed to act as seeds from which dodecamers, octadecamers, both smooth and beaded annular protofibrils, and transmembrane channels form. Since then, numerous aspects of our models have been supported by experimental findings. Recently, NMR-based structures have been proposed for Aβ42 tetramers and octamers, and NMR studies have been reported for oligomers composed of ~ 32 monomers. Here we propose a range of concentric β-barrel models and compare their dimensions to image-averaged electron micrographs of both beaded annular protofibrils (bAPFs) and smooth annular protofibrils (sAPFs) of Aβ42. The smaller oligomers have 6, 8, 12, 16, and 18 monomers. These beads string together to form necklace-like bAPFs. These gradually morph into sAPFs in which a S3 β-barrel is shielded on one or both sides by β-barrels formed from S1 and S2 segments.
Cross-organ transcriptomic comparison reveals universal factors during maturation
Authors: Kambhampati Sandeep , Murphy Sean A. , Uosaki Hideki , Kwon Chulan
Published: August 2021

Various cell types can be derived from stem cells. However, these cells are immature and do not match their adult counterparts in functional capabilities, limiting their use in disease modeling and cell therapies. Thus, it is crucial to understand the mechanisms of maturation in vivo. However, it is unknown if there are genes and pathways conserved across organs during maturation. To address this, we performed a time-series analysis of the transcriptome of the mouse heart, brain, liver, and kidney and analyzed their trajectories over time. In addition, gene regulatory networks were reconstructed to determine overlapping expression patterns. Based on these, we identified commonly upregulated and downregulated pathways across all four organs. Key upstream regulators were also predicted based on the temporal expression of downstream genes. These findings suggest the presence of universal regulators during organ maturation, which may help us develop a general strategy to mature stem cell-derived cells in vitro.
Synaptic plasticity is predicted by spatiotemporal firing rate patterns and robust to in vivo-like variability
Authors: Dorman Daniel B. , Blackwell Kim T.
Published: August 2021

Synaptic plasticity, the experience-induced change in connections between neurons, underlies learning and memory in the brain. Most of our understanding of synaptic plasticity derives from in vitro experiments with precisely repeated stimulus patterns; however, neurons exhibit significant variability in vivo during repeated experiences. Further, the spatial pattern of synaptic inputs to the dendritic tree influences synaptic plasticity, yet is not considered in most synaptic plasticity rules. Here, we address the sensitivity of plasticity to trial-to-trial variability and delineate how spatiotemporal synaptic input patterns produce plasticity with in vivo-like conditions using a data-driven computational model with a calcium-based plasticity rule. Using in vivo spike train recordings as inputs, we show that plasticity is strongly robust to trial-to-trial variability of spike timing, and derive general synaptic plasticity rules describing how spatiotemporal patterns of synaptic inputs control the magnitude and direction of plasticity. Specifically, a high temporal input firing rate to a synapse late in a trial correlated with neighboring synaptic activity produces potentiation, while an earlier, moderate firing rate that is negatively correlated with neighboring synaptic activity produces depression. Together, our results reveal that calcium dynamics can unify diverse plasticity rules and reveal how spatiotemporal firing rate patterns control synaptic plasticity.
The decoy SNARE Tomosyn sets tonic versus phasic release properties and is required for homeostatic synaptic plasticity
Authors: Sauvola Chad W. , Akbergenova Yulia , Cunningham Karen L. , Aponte-Santiago Nicole A. , Littleton J. Troy
Published: August 2021

Synaptic vesicle release probability (Pr) is a key presynaptic determinant of synaptic strength established by cell intrinsic properties and further refined by plasticity. To characterize mechanisms that generate Pr heterogeneity between distinct neuronal populations, we examined glutamatergic tonic (Ib) and phasic (Is) motoneurons in Drosophila with stereotyped differences in Pr and synaptic plasticity. We found the decoy SNARE Tomosyn is differentially expressed between these motoneuron subclasses and contributes to intrinsic differences in their synaptic output. Tomosyn expression enables tonic release in Ib motoneurons by reducing SNARE complex formation and suppressing Pr to generate decreased levels of synaptic vesicle fusion and enhanced resistance to synaptic fatigue. In contrast, phasic release dominates when Tomosyn expression is low, enabling high intrinsic Pr at Is terminals at the expense of sustained release and robust presynaptic potentiation. In addition, loss of Tomosyn disrupts the ability of tonic synapses to undergo presynaptic homeostatic potentiation (PHP).
A pathogenic DYT-THAP1 dystonia mutation causes hypomyelination and loss of YY1 binding
Authors: Yellajoshyula Dhananjay , Rogers Abigail E. , Kim Audrey J. , Kim Sumin , Pappas Samuel S. , Dauer William T.
Published: August 2021

Dystonia is a disabling disease that manifests as prolonged involuntary twisting movements. DYT-THAP1 is an inherited form of isolated dystonia caused by mutations in THAP1 encoding the transcription factor THAP1. The phe81leu (F81L) missense mutation is representative of a category of poorly understood mutations that do not occur on residues critical for DNA binding. Here, we demonstrate that the F81L mutation (THAP1F81L) impairs THAP1 transcriptional activity and disrupts CNS myelination. Strikingly, THAP1F81L exhibits normal DNA binding but causes a significantly reduced DNA binding of YY1, its transcriptional partner that also has an established role in oligodendrocyte lineage progression. Our results suggest a model of molecular pathogenesis whereby THAP1F81L normally binds DNA but is unable to efficiently organize an active transcription complex.
Pediatric SARS-CoV-2 seroprevalence in Arkansas over the first year of the COVID-19 pandemic
Authors: Boehme Karl W. , Kennedy Joshua L. , Snowden Jessica , Owens Shana M. , Kouassi Marianne , Mann Ryan L. , Paredes Amairani , Putt Claire , James Laura , Jin Jing , Du Ruofei , Kirkpatrick Catherine , Modi Zeel , Caid Katherine , Zohoori Namvar , Kothari Atul , Boyanton Bobby L. , Forrest J. Craig
Published: August 2021

Background

SARS-CoV-2 seroprevalence studies have largely focused on adults but little is known about spread in children. We determined SARS-CoV-2 seroprevalence in children and adolescents from Arkansas over the first year of the COVID-19 pandemic.

Methods

We tested remnant serum samples from children from 1–18 years who visited Arkansas hospitals or clinics for non-COVID19-related reasons from April, 2020 through April, 2021 for SARS-CoV-2 antibodies. We used univariable and multivariable regression models to determine association between seropositivity and participant characteristics.

Results

Among 2400 participants, seroprevalence rose from 7.9% in April/May 2020 (95% CI, 4.9-10.9%) to 25.8% in April 2021 (95% CI, 22.2-29.3%). Hispanic and black children had a significantly higher association with antibody positivity than white children in multiple sampling periods.

Conclusions

By spring 2021, most children in Arkansas had not been infected with SARS-CoV-2. With the emergence of SARS-CoV-2 variants, recognition of long-term effects of COVID-19, and the lack of an authorized pediatric SARS-CoV-2 vaccine, these results highlight the importance of including children in SARS-CoV-2 public health, clinical care, and research strategies. These findings are important for state and local officials as they consider measures to limit SARS-CoV-2 spread in schools and daycares for the 2021–2022 school year.
Strategies to Estimate Prevalence of SARS-CoV-2 Antibodies in a Texas Vulnerable Population: Results from Phase I of the Texas Coronavirus Antibody REsponse Survey (TX CARES)
Authors: Valerio-Shewmaker Melissa , DeSantis Stacia , Swartz Michael , Yaseen Ashraf , Gonzalez Michael O. , Kohl Harold W. , Kelder Steven H. , Messiah Sarah E. , Aguillard Kimberly A. , Breaux Camille , Wu Leqing , Shuford Jennifer , Pont Stephen , Lakey David , Boerwinkle Eric
Published: August 2021

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and immunity remains uncertain in populations. The state of Texas ranks 2ndin infection with over 2.71 million cases and has seen a disproportionate rate of death across the state. The TX CARES project was funded by the state of Texas to estimate the prevalence of SARS-CoV-2 antibody status in children and adults.

Materials and Methods

The TX CARES (Texas Coronavirus Antibody Response Survey) is an ongoing prospective population-based convenience sample from the Texas general population that commenced in October 2020. Volunteer participants are recruited across the state to participate in a 3-time point data collection TX CARES to assess antibody response over time. We use the Roche Elecsys® Anti-SARS-CoV-2 Immunoassay to determine SARS-CoV-2 antibody status.

Results

The crude antibody positivity prevalence in Phase I was 26.1% (80/307). The fully adjusted seroprevalence of the sample was 31.5%. Specifically, 41.1% of males and 21.9% of females were seropositive. For age categories, 33.5% of those 18-34; 24.4% of those 35-44; 33.2% of those 45-54; and 32.8% of those 55+ were seropositive. In this sample,42.2% (89/211) of those negative for the antibody test reported having had a COVID-19 test.

Conclusions

In this survey we enrolled and analyzed data for 319 participants, demonstrating a high survey and antibody test completion rate, and ability to implement a questionnaire and SARS-CoV-2 antibody testing within FQHC clinical settings. We were also able to determine our capability to estimate the cross-sectional seroprevalence within Texas’s FQHC clinical settings. The crude positivity prevalence for SARS-CoV-2 antibodies in this sample was 26.1% indicating potentially high exposure to COVID-19 for FQHC clinic employees and patients. These methods are being used to guide the completion of a large longitudinal survey in the state of Texas with implications for practice and population health.
Perceived racial discrimination and eating habits: Systematic review and conceptual models
Authors: Rodrigues Ylana Elias , Fanton Marcos , Novossat Ricardo Suñé , Canuto Raquel
Published: August 2021

Context

there is no systematic organization of the available evidence about the relationship between racial discrimination and eating habits. Also, there is no consensus about its causal mechanism.

Objectives

a systematic review was conducted to synthesize evidence on the association between perceived racial discrimination and eating habits (eating behavior and food consumption). A conceptual model was developed to depict the most common mechanisms used to explain this association.

Data Sources

articles and dissertations were retrieved from the PubMed, EMBASE, Lilacs, and PsycINFO databases from inception to January 2021.

Data Analysis

19 studies were included. The assessment of methodological quality was conducted using the Newcastle-Ottawa Scale. On average, the studies showed a methodological quality of 66%. Forty-six associations were evaluated. There were 38 associations between perceived racial discrimination and negative eating habits, 29 concerning eating behavior, and 17 regarding food consumption.

Conclusions

perceived racial discrimination negatively affects eating habits. A broader conceptual framework based on ecosocial theory is suggested to guide future research that would include different racial discrimination dimensions, such as internalized and structural.
Distinctive neural correlates of phonological processing and reading impairment in fetal alcohol-exposed adolescents with and without facial dysmorphology
Authors: Yu Xi , Dunstan Jade , Jacobson Sandra W. , Molteno Christopher D. , Lindinger Nadine M. , Turesky Theodore K. , Meintjes Ernesta M. , Jacobson Joseph L. , Gaab Nadine
Published: August 2021

Abstract

Background

Prenatal alcohol exposure (PAE) has been linked to atypical brain development and a wide range of cognitive and behavioral impairments, including poor reading performance in childhood and adolescence. However, little is known about how structural and/or functional teratogenesis in the brain mediate reading impairment in fetal alcohol spectrum disorders (FASD) and whether neural correlates of reading and phonological processing differ between FASD subtypes with different clinical presentations in facial morphology.

Methods

The current study utilized functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to characterize functional and structural mechanisms mediating reading deficits in 26 syndromal adolescents with PAE-related facial dysmorphology (i.e., fetal alcohol syndrome (FAS) or partial FAS (PFAS)) and 30 heavily exposed (HE) without this dysmorphology, in comparison with 19 typically developing controls. Importantly, the levels of PAE and reading ability were comparable between the FAS/PFAS and HE groups in the current study.

Results

Compared to the nonsyndromal HE and control groups, the syndromal adolescents showed greater activation in the right precentral gyrus during an fMRI phonological processing task and rightward lateralization in an important reading-related tract (inferior longitudinal fasciculus, ILF), suggesting an atypical reliance on the right hemisphere during reading. By contrast, in the HE group, better reading skills were associated with increased neural activation in the left angular gyrus (LAG) and higher fractional anisotropy in the white matter organization of the left ILF. However, the brain function-behavior relation was weaker in the HE than among the controls, suggesting less efficient function of the typical reading neural network that may contribute to the observed reading impairments.

Conclusions

Our findings provide the first evidence for the distinctive functional and structural mechanisms underlying atypical reading and phonological processing in PAE adolescents with and without FAS facial dysmorphology.

Highlights

Prenatal alcohol exposure is associated with altered neural reading networks

FASD subtypes exhibit distinctive neural correlates of phonological processing

Greater right-hemispheric reliance was observed in FASD with facial dysmorphology

Non-syndromal FASD showed deficits in the typical left-hemispheric reading network
Specific telomere protection ensured by FOXO3a upon genotoxic stress and during aging
Authors: Burbano Maria Sol Jacome , Robin Jérome , Bauwens Serge , Martin Marjorie , Donati Emma , Martínez Lucia , Sacconi Sabrina , Magdinier Frédérique , Gilson Eric
Published: August 2021

Longevity is determined by diverse signaling pathways including telomere protection and homeostasis master regulators like FOXO3a. We previously showed that the telomeric repeat binding factor 2 (TRF2) expression decreases with age in human skeletal muscle and that, surprisingly, its loss in myofibers does not trigger telomere deprotection. We reveal here that inTERF2-compromised myotubes, FOXO3a is recruited to telomeres where it acts as a protective factor against ATM-dependent DNA damage activation. Moreover, we show that FOXO3a-telomere association increases with age in human skeletal muscle biopsies. In mitotic fibroblasts, the telomere protective properties of FOXO3a are operative if the cells are treated with bleomycin. The telomere function of FOXO3a does not require its Forkhead DNA binding domain but the CR2C. Overall, these findings demonstrate a direct connection between two key longevity pathways, FOXO3a and telomere protection. This unveils an unexpected higher level of integration in the regulation of longevity signaling pathway.
The role of Musashi-1 in CEP290 c.2991+1655A>G cryptic exon splicing in Leber Congenital Amaurosis
Authors: Ottaviani Daniele , Lane Amelia , Jovanovic Katarina , Gardner Jessica C. , Sladen Paul E. , Hau Kwan L. , Panes Anna Brugulat , Guarascio Rosellina , Hardcastle Alison J. , Cheetham Michael E.
Published: August 2021

Human photoreceptors maximise alternative exon splicing to generate a unique set of gene isoforms. Conversely, the inclusion of a cryptic exon caused by the c.2991+1655A>G deep intronic change in CEP290 occurs in the human retina leading to Leber Congenital Amaurosis (LCA10). The RNA-binding protein Musashi-1 (MSI1) is a key component of alternative splicing in the developing mouse retina. Here we investigated the role of MSI1 in human photoreceptor-specific splicing and its potential role in CEP290 aberrant splicing disease. Alternative splicing was studied using human induced pluripotent stem cell derived 3D retinal organoid and RPE RNA-seq datasets and several photoreceptor gene isoforms were identified. Their temporal expression was resolved in control 3D retinal organoids in comparison to development and differentiation markers. Morpholino knockdown of MSI1 in control retinal organoids reduced the expression of several photoreceptor differentiation markers and the inclusion of photoreceptor-specific exons. Nonetheless, MSI1 knockdown in homozygous CEP290 c.2991+1655A>G LCA10 retinal organoids did not affect the inclusion of the LCA10-associated cryptic exon. These results show that while MSI1 is important for photoreceptor alternative splicing and homeostasis, it is not a major driver of the recognition of the CEP290 cryptic splice site and the manifestation of LCA10.

HIGHLIGHTS

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The human retina expresses a unique set of gene isoforms

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Musashi-1 regulates alternative splicing in 3D human retinal organoids

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Musashi-1 knockdown in 3D retinal organoids affects gene splicing and homeostasis in photoreceptors

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Musashi-1 may regulate alternative splicing of cryptic exons in retina but not in LCA10
Analysis of 329,942 SARS-CoV-2 records retrieved from GISAID database
Authors: Zelenova Maria , Ivanova Anna , Semyonov Semyon , Gankin Yuriy
Published: August 2021

Background

The 31st of December 2019 was when the World Health Organization received a report about an outbreak of pneumonia of unknown etiology in the Chinese city of Wuhan. The outbreak was the result of the novel virus labeled as SARS-CoV-2, which spread to about 220 countries and caused approximately 3,311,780 deaths, infecting more than 159,319,384 people by May 12th, of 2021. The virus caused a worldwide pandemic leading to panic, quarantines, and lockdowns – although none of its predecessors from the coronavirus family have ever achieved such a scale. The key to understanding the global success of SARS-CoV-2 is hidden in its genome.

Materials and Methods

We retrieved data for 329,942 SARS-CoV-2 records uploaded to the GISAID database from the beginning of the pandemic until the 8th of January 2021. To process the data, a Python variant detection script was developed, using pairwise2 from the BioPython library. Pandas, Matplotlib, and Seaborn, were applied to visualize the data. Genomic coordinates were obtained from the UCSC Genome Browser (https://genome.ucsc.edu/). Sequence alignments were performed for every gene separately. Genomes less than 26,000 nucleotides long were excluded from the research. Clustering was performed using HDBScan.

Results

Here, we addressed the genetic variability of SARS-CoV-2 using 329,942 worldwide samples. The analysis yielded 155 genome variations (SNPs and deletions) in more than 0.3% of the sequences. Nine common SNPs were present in more than 20% of the samples. Clustering results suggested that a proportion of people (2.46%) were infected with a distinct subtype of the B.1.1.7 variant. The subtype may be characterized by four to six additional mutations, with four being a more frequent option (G28881A, G28882A, and G28883С in the N gene, A23403G in S, A28095T in ORF8, G25437T in ORF3a). Two clusters were formed by mutations in the samples uploaded predominantly by Denmark and Australia, which may indicate the emergence of “Danish” and “Australian” variants. Five clusters were linked to increased/decreased age, shifted gender ratio, or both. According to a correlation coefficient matrix, 69 mutations correlate with at least one other mutation (correlation coefficient greater than 0.7). We also addressed the completeness of the GISAID database, where between 77% and 93% of the fields were either left blank or filled incorrectly. Metadata mining analysis has led to a hypothesis about gender inequality in medical care in certain countries. Finally, we found ORF6 and E as the most conserved genes (96.15% and 94.66% of the sequences totally match the reference, respectively), making them potential targets for vaccines and treatment. Our results indicate areas of the SARS-CoV-2 genome that researchers can focus on for further structural and functional analysis.
Probing the stability of the SpCas9-DNA complex after cleavage
Authors: Aldag Pierre , Welzel Fabian , Jakob Leonhard , Schmidbauer Andreas , Rutkauskas Marius , Fettes Fergus , Grohmann Dina , Seidel Ralf
Published: August 2021

CRISPR-Cas9 is a ribonucleoprotein complex that sequence-specifically binds and cleaves double-stranded DNA. Wildtype Cas9 as well as its nickase and cleavage-incompetent mutants have been used in various biological techniques due to their versatility and programmable specificity. Cas9 has been shown to bind very stably to DNA even after cleavage of the individual DNA strands, inhibiting further turnovers and considerably slowing down in-vivo repair processes. This poses an obstacle in genome editing applications. Here, we employed single-molecule magnetic tweezers to investigate the binding stability of different S. pyogenes Cas9 variants after cleavage by challenging them with supercoiling. We find that different release mechanisms occur depending on which DNA strand is cleaved. After non-target strand cleavage, supercoils are immediately but slowly released by swiveling of the non-target strand around the DNA with friction. Consequently, Cas9 and its non-target strand nicking mutant stay stably bound to the DNA for many hours even at elevated torsional stress. After target-strand cleavage, supercoils are only removed after the collapse of the R-loop. We identified several states with different stabilities of the R-loop. Most importantly, we find that the post-cleavage state of Cas9 exhibits a higher stability compared to the pre-cleavage state. This suggests that Cas9 has evolved to remain tightly bound to its cut target.
Dataset on Emotion with Naturalistic Stimuli (DENS) on Indian Samples
Authors: Mishra Sudhakar , Asif Mohammad , Srinivasan Narayanan , Tiwary Uma Shanker
Published: August 2021

Emotions are constructed and emerge through the dynamic interaction of multiple components. It is difficult to capture the dynamics using static or artificial stimuli. Hence, there is a need for an experiment paradigm using ecologically valid film stimuli. The data set described in this work results from an attempt to capture felt emotional experience at a particular point in time using physiological measures like EEG, ECG and EMG as well as self-reported scales. Sixteen emotional film stimuli were used from the film stimuli dataset validated in the Indian population. Participants self-reported the felt emotional category. Both the raw and pre-processed data are provided along with the pre-processing pipeline. The paradigm we have adopted is new which we have termed as Emotional Event Marker Paradigm (EEMP). Hence, the dataset has unique information about temporal markers of emotional experiences while watching the film stimuli, which is not available with any data to date. It is the first EEG data with emotional film stimuli on the Indian population. This data can be utilized to study dynamic activation and connectivity in a whole-brain source localization study, understand the mutual interactions between the central and autonomic nervous system, understand temporal hierarchy using multi-resolution tools, and perform machine learning-based classification and complex networks analysis associated with emotions.
AATF/Che-1, a new component of paraspeckles, controls R-loops formation and Interferon activation in Multiple Myeloma
Authors: Bruno Tiziana , Corleone Giacomo , Cortile Clelia , Nicola Francesca De , Catena Valeria , Fabretti Francesca , Gumenyuk Svitlana , Pisani Francesco , Mengarelli Andrea , Passananti Claudio , Fanciulli Maurizio
Published: August 2021

Multiple myeloma (MM) is a hematological neoplasm of plasma cells characterized by abnormal production of immunoglobulins. Che-1/AATF (Che-1) is an RNA binding protein involved in transcription regulation and is highly expressed in this malignancy. Here we experimentally show that Che-1 interacts with paraspeckle components, including the lncRNA NEAT1_2 (NEAT1), which serves as the seed for the maintenance of these structures. Che-1 and NEAT1 localize on R-loops, three-stranded RNA:DNA hybrids structures involved in DNA transcription and repair. Depletion of Che-1 produces a marked accumulation of RNA:DNA hybrids sustaining activation of a systemic inflammatory response. We provide evidence that high levels of Unfolded Protein Response (UPR) in MM cells induces RNA:DNA hybrids and an interferon (IFN) gene signature. We found that MM patients exhibit elevated R-loops levels and paraspeckle genes mRNAs increase linearly to MM progression. Strikingly, patients showing elevated IFN genes signature are associated with a marked poor prognosis. Overall, these findings delineate that elevated R-loops accumulation and inflammatory signaling may contribute to MM progression and that Che-1/NEAT1 plays an essential role in maintaining R-loops homeostasis by preventing excessive inflammatory signaling.