bluuebunny/crossref_metadata_2025_split huggingface dataset:
KLF2 is a therapeutic target for COVID-19 induced endothelial dysfunction
Authors: Xu Suowen , Luo Sihui , Zheng Xueying , Weng Jianping 
Published: February 2021

AbstractCoronavirus disease 2019 (COVID-19) is regarded as an endothelial disease (endothelialitis) with its mechanism being incompletely understood. Emerging evidence has demonstrated that the endothelium represents the Achilles' heel in COVID-19 patients and that endothelial dysfunction precipitates COVID-19 and accompanying multi-organ injuries. Thus, pharmacotherapies targeting endothelial dysfunction have potential to ameliorate COVID-19 and its cardiovascular complications. Primary human umbilical vein endothelial cells (HUVECs) and human pulmonary microvascular endothelial cells (HPMECs) were treated with serum from control subjects or COVID-19 patients. Downstream monocyte adhesion and associated gene/protein expression was evaluated in endothelial cells exposed to COVID-19 patient serum in the presence of KLF2 activator (Atorvastatin) or KLF2 overexpression by an adenoviral vector. Here, we demonstrate that the expression of KLF2 was significantly reduced and monocyte adhesion was increased in endothelial cells treated with COVID-19 patient serum due to elevated levels of pro-adhesive molecules, ICAM1 and VCAM1. IL-1β and TNF-α, two cytokines observed in cytokine release syndrome in COVID-19 patients, decreased KLF2 gene expression. Next-generation RNA-sequencing data showed that atorvastatin treatment leads to a cardiovascular protective transcriptome associated with improved endothelial function (vasodilation, anti-inflammation, antioxidant status, anti-thrombosis/-coagulation, anti-fibrosis and reduced angiogenesis). Treatment of HPMECs with atorvastatin or KLF2 adenovirus ameliorate COVID-19 serum-induced increase in endothelial inflammation and monocyte adhesion by increasing KLF2 expression. Altogether, the present study demonstrates that genetic and pharmacological activation of KLF2 represses COVID-19 associated endothelial dysfunction, heralding a potentially new direction to treat endothelialitis accompanying COVID-19.
CheSPI: Chemical shift Secondary structure Population Inference
Authors: Nielsen Jakob Toudahl , Mulder Frans A.A. 
Published: February 2021

AbstractNMR chemical shifts (CSs) are delicate reporters of local protein structure, and recent advances in random coil CS (RCCS) prediction and interpretation now offer the compelling prospect of inferring small populations of structure from small deviations from RCCSs. Here, we present CheSPI, a simple and efficient method that provides unbiased and sensitive aggregate measures of local structure and disorder. It is demonstrated that CheSPI can predict even very small amounts of residual structure and robustly delineate subtle differences into four structural classes for intrinsically disordered proteins. For structured regions and proteins, CheSPI can assign up to eight structural classes, which coincide with the well-known DSSP classification. The program is freely available, and can either be invoked from URLwww.protein-nmr.orgas a web implementation, or run locally from command line as a python program. CheSPI generates comprehensive numeric and graphical output for intuitive annotation and visualization of protein structures. A number of examples are provided.
Target enrichment and extensive population sampling help untangle the recent, rapid radiation of Oenothera sect. Calylophus
Authors: Cooper Benjamin J. , Moore Michael J. , Douglas Norman A. , Wagner Warren L. , Johnson Matthew G. , Overson Rick P. , McDonnell Angela J. , Levin Rachel A. , Raguso Robert A. , Olvera Hilda Flores , Ochoterena Helga , Fant Jeremie B. , Skogen Krissa A. , Wickett Norman J. 
Published: February 2021

ABSTRACTOenothera sect. Calylophus is a North American group of 13 recognized taxa in the evening primrose family (Onagraceae) with an evolutionary history that may include independent origins of bee pollination, edaphic endemism, and permanent translocation heterozygosity. Like other groups that radiated relatively recently and rapidly, taxon boundaries within Oenothera sect. Calylophus have remained challenging to circumscribe. In this study, we used target enrichment, flanking non-coding regions, summary coalescent methods, tests for gene flow modified for target-enrichment data, and morphometric analysis to reconstruct phylogenetic hypotheses, evaluate current taxon circumscriptions, and examine character evolution in Oenothera sect. Calylophus. Because sect. Calylophus comprises a clade with a relatively restricted geographic range, we were able to extensively sample across the range of geographic and morphological diversity in the group. We found that the combination of exons and flanking non-coding regions led to improved support for species relationships. We reconstructed potential hybrid origins of some accessions and note that if processes such as hybridization are not taken into account, the number of inferred evolutionary transitions may be artificially inflated. We recovered strong evidence for multiple origins of the evolution of bee pollination from ancestral hawkmoth pollination, the evolution of edaphic specialization on gypsum, and permanent translocation heterozygosity. This study applies newly emerging techniques alongside dense infraspecific sampling and morphological analyses to effectively address a relatively common but recalcitrant problem in evolutionary biology.
Widespread cryptic variation in genetic architecture between the sexes
Authors: van der Bijl Wouter , Mank Judith E. 
Published: February 2021

AbstractThe majority of the genome is shared between the sexes, and it is expected that the genetic architecture of most traits is shared as well. This common architecture has been viewed as a major source of constraint on the evolution of sexual dimorphism (SD). SD is nonetheless common in nature, leading to assumptions that it results from differential regulation of shared genetic architecture. Here, we study the effect of thousands of gene knock-out mutations on 202 mouse phenotypes to explore how regulatory variation affects SD. We show that many traits are dimorphic to some extent, and that a surprising proportion of knock-outs have sex-specific phenotypic effects. Many traits, regardless whether they are monomorphic or dimorphic, harbor cryptic differences in genetic architecture between the sexes, resulting in sexually discordant phenotypic effects from sexually concordant regulatory changes. This provides an alternative route to dimorphism through sex-specific genetic architecture, rather than differential regulation of shared architecture.
Modulating the properties of DNA-SWCNT sensors using chemically modified DNA
Authors: Gillen Alice J. , Lambert Benjamin P. , Antonucci Alessandra , Molina-Romero Daniel , Boghossian Ardemis A. 
Published: February 2021

AbstractProperties of SWCNT-based sensors such as brightness and detection capabilities strongly depend on the characteristics of the wrapping used to suspend the nanotubes. In this study, we explore ways to modify the properties of DNA-SWCNT sensors by using chemically modified DNA sequences, with the aim of creating sensors more suitable for use in in vivo and in vitro applications. We show that both the fluorescence intensity and sensor reactivity are strongly impacted not only by the chemical modification of the DNA but also by the method of preparation. In the absence of modifications, the sensors prepared using MeOH-assisted surfactant exchange exhibited higher overall fluorescence compared to those prepared by direct sonication. However, we demonstrate that the incorporation of chemical modifications in the DNA sequence could be used to enhance the fluorescence intensity of sonicated samples. We attribute these improvements to both a change in dispersion efficiency as well as to a change in SWCNT chirality distribution.Furthermore, despite their higher intensities, the response capabilities of sensors prepared by MeOH-assisted surfactant exchange were shown to be significantly reduced compared to their sonicated counterparts. Sonicated sensors exhibited a globally higher turn-on response towards dopamine compared to the exchanged samples, with modified samples retaining their relative intensity enhancement. As the increases in fluorescence intensity were achieved without needing to alter the base sequence of the DNA wrapping or to add any exogenous compounds, these modifications can - in theory - be applied to nearly any DNA sequence to increase the brightness and penetration depths of a variety of DNA-SWCNT sensors without affecting biocompatibility or reducing the near-limitless sequence space available. This makes these sensors an attractive alternative for dopamine sensing in vitro and in vivo by enabling significantly higher penetration depths and shorter laser exposure times.
Prediction of nanographene binding-scores to trout cellular receptors and cytochromes
Authors: Connolly M. C. , Navas J.M. , Coll J. 
Published: February 2021

AbstractTo address the increasing concerns surrounding possible impacts of graphene-related materials on the aquatic environment, this study focused on computational predictions of binding between models of graphenes in the nm size range (nanographenes, nGs) and the aryl-hydrocarbon receptor (tAHR) and P450 cytochromes (tCYPs) of rainbow trout (Oncorhynchus mykiss). The tAHR plays a key role in the induction of detoxifying and early immune responses and tCYPs are essential for detoxifying planar hydrophobic chemicals such as nGs. After 3D modelling of those trout proteins, docking algorithms predicted the size-dependance profiles of nGs binding-scores to tAHR and tCYPs in the low nM range (high binding-affinities). Virtual oxidations of nGs to nGOs (carboxy-, epoxy-and/or hydroxy-oxidations) further lowered the corresponding binding-scores in level/type-oxidation manners. Among all the tCYPs, the tCYP3AR (the equivalent to human CYP3A4) was identified as a potential key interaction enzyme for nGs because of its lower binding-scores. These results implicate a possible processing pathway to be further probed through in vitro and in vivo experimentation. Together the information generated can be pivotal for the design of safer graphene-related materials for a variety of applications and help to understand their detoxification in aquatic vertebrates.
Comparative analysis of 16S rRNA gene and metagenome sequencing in pediatric gut microbiomes
Authors: Peterson Danielle , Bonham Kevin S. , Rowland Sophie , Pattanayak Cassandra W. ,   RESONANCE Consortium, Klepac-Ceraj Vanja 
Published: February 2021

AbstractThe colonization of the human gut microbiome begins at birth, and, over time, these microbial communities become increasingly complex. Most of what we currently know about the human microbiome, especially in early stages of development, was described using culture-independent sequencing methods that allow us to identify the taxonomic composition of microbial communities using genomic techniques, such as amplicon or shotgun metagenomic sequencing. Each method has distinct tradeoffs, but there has not been a direct comparison of the utility of these methods in stool samples from very young children, which have different features than those of adults. We compared the effects of profiling the human infant gut microbiome with 16S rRNA amplicon versus shotgun metagenomic sequencing techniques in 130 fecal samples; younger than 15, 15-30, and older than 30 months of age. We demonstrate that observed changes in alpha-diversity and beta-diversity with age occur to similar extents using both profiling methods. We also show that 16S rRNA profiling identified a larger number of genera and we find several genera that are missed or underrepresented by each profiling method. We present the link between alpha diversity and shotgun metagenomic sequencing depth for children of different ages. These findings provide a guide for selecting an appropriate method and sequencing depth for the three studied age groups.
Condensates in RNA Repeat Sequences are Heterogeneously Organized and Exhibit Reptation-like Dynamics
Authors: Nguyen Hung T. , Hori Naoto , Thirumalai D. 
Published: February 2021

ABSTRACTAlthough it is known that RNA undergoes liquid–liquid phase separation (LLPS), the interplay between the molecular driving forces and the emergent features of the condensates, such as their morphologies and dynamical properties, is not well understood. We introduce a coarse-grained model to simulate phase separation of trinucleotide repeat RNAs, which are implicated in neurological disorders such as Huntington disease and amyotrophic lateral sclerosis. After establishing that the simulations reproduce key experimental findings (length and concentration dependence of the phase transition in (CAG)nrepeats), we show that once recruited inside the liquid droplets, the monomers transition from hairpin-like structures to extended states. Interactions between the monomers in the condensates result in the formation of an intricate and dense intermolecular network, which severely restrains the fluctuations and mobilities of the RNAs inside large droplets. In the largest densely packed high viscosity droplets, the mobility of RNA chains is best characterized by reptation, reminiscent of the dynamics in polymer melts. Our work provides a microscopic framework for understanding liquid–liquid phase separation in RNA, which is not easily discernible in current experiments.
Ku70 suppresses alternative end-joining in G1-arrested progenitor B cells
Authors: Liang Zhuoyi , Kumar Vipul , Le Bouteiller Marie , Zurita Jeffrey , Kenrick Josefin , Lin Sherry G. , Lou Jiangman , Hu Jianqiao , Ye Adam Yongxin , Boboila Cristian , Alt Frederick W. , Frock Richard L. 
Published: February 2021

AbstractClassical nonhomologous end-joining (C-NHEJ) repairs DNA double-stranded breaks (DSBs) throughout interphase but predominates in G1-phase when homologous recombination is unavailable. Complexes containing the Ku70/80 (“Ku”) and XRCC4/Ligase IV (Lig4) core C-NHEJ factors are required, respectively, for sensing and joining DSBs. While XRCC4/Ligase IV are absolutely required for joining RAG1/2-endonucease (“RAG”)-initiated DSBs during V(D)J recombination in G1-phase progenitor lymphocytes, cycling cells deficient for XRCC4/Ligase IV also can join chromosomal DSBs by alternative end-joining (A-EJ) pathways. Restriction of V(D)J recombination by XRCC4/Ligase IV-mediated joining has been attributed to RAG shepherding V(D)J DSBs exclusively into the C-NHEJ pathway. Here, we report that A-EJ of DSB ends generated by RAG1/2, Cas9:gRNA and Zinc finger endonucleases in Lig4-deficient G1-arrested progenitor B cell lines is suppressed by Ku. Thus, while diverse DSBs remain largely as free broken ends in Lig4-deficient G1-arrested progenitor B cells, deletion of Ku70 increases DSB rejoining and translocation levels to those observed in Ku70-deficient counterparts. Correspondingly, while RAG-initiated V(D)J DSB joining is abrogated in Lig4-deficient G1-arrested progenitor B cell lines, joining of RAG-generated DSBs in Ku70-deficient and Ku70/Lig4 double-deficient lines occurs through a translocation-like A-EJ mechanism. Thus, in G1-arrested, Lig4-deficient progenitor B cells are functionally end-joining suppressed due to Ku-dependent blockage of A-EJ, potentially, in association with G1-phase down-regulation of Ligase1. Finally, we suggest that differential impacts of Ku-deficiency versus Lig4-deficiency on V(D)J recombination, neuronal apoptosis, and embryonic development results from Ku-mediated inhibition of A-EJ in the G1 cell cycle phase in Lig4-defcient developing lymphocyte and neuronal cells.Significance StatementAlternative end-joining (A-EJ) is implicated in oncogenic translocations and mediating DNA double-strand break (DSB) repair in cycling cells when classical nonhomologous endjoining (C-NHEJ) factors of the C-NHEJ Ligase complex are absent. However, V(D)J recombination-associated DSBs that occur in G1 cell cycle-phase progenitor lymphocytes are joined exclusively by the C-NHEJ pathway. Until now, however, the overall mechanisms that join general DSBs in G1-phase progenitor B cells had not been fully elucidated. Here, we report that Ku, a core C-NHEJ double-strand break recognition complex, directs repair of a variety of different targeted DSBs towards C-NHEJ and suppresses A-EJ in G1-phase cells. We suggest this Ku activity explains how Ku-deficiency can rescue the neuronal development and embryonic lethality phenotype of Ligase 4-deficient mice.
Structure-based prediction of HDAC6 substrates validated by enzymatic assay reveals determinants of promiscuity and detects new potential substrates
Authors: Varga Julia K. , Diffley Kelsey , Welker Leng Katherine R. , Fierke Carol A. , Schueler-Furman Ora 
Published: February 2021

SummaryHistone deacetylases play important biological roles well beyond the deacetylation of histone tails. In particular, HDAC6 is involved in multiple cellular processes such as apoptosis, cytoskeleton reorganization, and protein folding, affecting substrates such as α-tubulin, Hsp90 and cortactin proteins. We have applied a biochemical enzymatic assay to measure the activity of HDAC6 on a set of candidate unlabeled peptides. These served for the calibration of a structure-based substrate prediction protocol, Rosetta FlexPepBind, previously used for the successful substrate prediction of HDAC8 and other enzymes. A proteome-wide screen of reported acetylation sites using our calibrated protocol together with the enzymatic assay provide new peptide substrates and avenues to novel potential functional regulatory roles of this promiscuous, multi-faceted enzyme. In particular, we propose novel regulatory roles of HDAC6 in tumorigenesis and cancer cell survival via the regulation of the EGFR/Akt pathway activation process. The calibration process and comparison of the results between HDAC6 and HDAC8 highlight structural differences that explain the established promiscuity of HDAC6.
Mechanical mapping of mammalian follicle development using Brillouin microscopy
Authors: Chan Chii Jou , Bevilacqua Carlo , Prevedel Robert 
Published: February 2021

AbstractIn early mammalian development, the maturation of follicles containing the immature oocytes is an important biological process as the functional oocytes provide the bulk genetic and cytoplasmic materials for successful reproduction. Despite recent work demonstrating the regulatory role of mechanical stress in oocyte growth, quantitative studies of ovarian mechanical properties remain lacking bothin vivoandex vivo. In this work, we quantify the material properties of ooplasm, follicles and connective tissues in intact mouse ovaries at distinct stages of follicle development using Brillouin microscopy, a non-invasive tool to probe mechanics in three-dimensional (3D) tissues. We find that the ovarian cortex and its interior stroma have distinct material properties associated with extracellular matrix deposition, and that intra-follicular mechanical compartments emerge during follicle maturation. Our work provides a novel approach to study the role of mechanics in follicle morphogenesis and pave the way for future understanding of mechanotransduction in reproductive biology, with potential implications for infertility diagnosis and treatment.
Longitudinally stable, brain-based predictive models mediate the relationships between childhood cognition and socio-demographic, psychological and genetic factors
Authors: Pat Narun , Wang Yue , Anney Richard , Riglin Lucy , Thapar Anita , Stringaris Argyris 
Published: February 2021

AbstractCognitive abilities are one of the major transdiagnostic domains in the National Institute of Mental Health’s Research Domain Criteria (RDoC). Following RDoC’s integrative approach, we aimed to develop brain-based predictive models for cognitive abilities that a) are developmentally stable over years during adolescence and b) account for the relationships between cognitive abilities and socio-demographic, psychological and genetic factors. For this, we leveraged the unique power of the large-scale, longitudinal data from the Adolescent Brain Cognitive Development (ABCD) study (n ∼11k) and combined MRI data across modalities (task-fMRI from three tasks, resting-state fMRI, structural MRI, DTI) using machine-learning. Our brain-based, predictive models for cognitive abilities were stable across two years during young adolescence and generalisable to different sites, partially predicting childhood cognition at around 20% of the variance. Moreover, our use of ‘opportunistic stacking’ allowed the model to handle missing values, reducing the exclusion from around 80% to around 5% of the data. We found fronto-parietal networks during a working-memory task to drive childhood-cognition prediction. The brain-based, predictive models significantly, albeit partially, accounted for variance in childhood cognition due to (1) key socio-demographic and psychological factors (proportion mediated=18.65% [17.29%-20.12%]) and (2) genetic variation, as reflected by the polygenic score of cognition (proportion mediated=15.6% [11%-20.7%]). Thus, our brain-based predictive models for cognitive abilities facilitate the development of a robust, transdiagnostic research tool for cognition at the neural level in keeping with the RDoC’s integrative framework.Key PointsUsing opportunistic stacking and multimodal MRI, we developed brain-based predictive models for children’s cognitive abilities that were longitudinally stable, generalisable to different sites and robust against missing data.Our brain-based models were able to partially mediate the relationships of childhood cognitive abilities with the socio-demographic, psychological and genetic factors.Our approach should pave the way for future researchers to employ multimodal MRI as a tool for the brain-based indicator of cognitive abilities, according to the integrative RDoC framework.
Interaural Time Difference Tuning in the Rat Inferior Colliculus is Predictive of Behavioral Sensitivity
Authors: Li Kongyan , Rajendran Vani G. , Mishra Ambika Prasad , Chan Chloe H.K. , Schnupp Jan W. H. 
Published: February 2021

AbstractRecent studies have shown that rats are a useful model for binaural cochlear implant (CI) research, with behavioral sensitivity to interaural time differences (ITDs) of CI stimuli which are better than those of human patients. Here, we characterize ITD tuning in the rat inferior colliculus (IC) and explore whether quality of tuning can predict behavioral performance. We recorded IC responses to stimuli of varying pulse rates and envelope types and quantified both mutual information (MI) and neurald′ as measures of ITD sensitivity. Neurald′ values paralleled behavioral ones, declining with increasing click rates or when envelopes changed from rectangular to Hanning windows. While MI values increased with experience, neurald′ did not. However, neurald′ values correlated much better with behavioral performance than MI. Thus, neurald′ appears to be a particularly well suited to predicting how stimulus parameters will impact behavioral performance.