bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of sex, season and environmental air quality on experimental human pneumococcal carriage acquisition
Authors: Cheliotis Katerina S. , Jewell Christopher P. , Solórzano Carla , Urban Britta , Collins Andrea M. , Mitsi Elena , Pojar Sherin , Nikolaou Elissavet , German Esther L. , Reiné Jesús , Gordon Stephen B. , Jochems Simon P. , Rylance Jamie , Ferreira Daniela M. 
Published: October 2021

AbstractStreptococcus pneumoniae (pneumococcus) is the most common identified bacterial cause of pneumonia, and the leading infectious cause of death in children under five years of age worldwide. Pneumococcal disease follows a seasonal pattern with increased incidence during winter. Pneumonia burden is also associated with poor air quality. Nasopharyngeal carriage of the bacterium is a pre-requisite of invasive disease.We aimed to determine if susceptibility to nasopharyngeal pneumococcal carriage varied by season, and which environmental factors might explain such variation. We also evaluated the influence of sex on susceptibility of carriage. We collated data from five studies in which human volunteers underwent intranasal pneumococcal challenge. Generalised linear mixed effects models were used to identify factors associated with altered risk of carriage acquisition, specifically climate and air-quality data.During 2011-2017, 374 healthy adults were challenged with type 6B pneumococcus. Odds of carriage were significantly lower in males (OR, 0.61; 95% CI, 0.40-0.92; p = 0.02), and higher with cooler temperatures (OR, 0.79; 95% CI, 0.63-0.99; p = 0.04). Likelihood of carriage also associated with lower concentrations of local fine particulate matter concentrations (PM2.5) and increased local rainfall.In contrast to epidemiologic series, experimental challenge allowed us to test propensity to acquisition during controlled exposures; immunologic explanations for sex and climatic differences should be sought.
Patch2Self denoising of diffusion MRI in the cervical spinal cord improves intra-cord contrast, signal modelling, repeatability, and feature conspicuity
Authors: Schilling Kurt G. , Fadnavis Shreyas , Batson Joshua , Visagie Mereze , Combes Anna J.E. , McKnight Colin D. , Bagnato Francesca , Garyfallidis Eleftherios , Landman Bennett A. , Smith Seth A. , O’Grady Kristin P. 
Published: October 2021

AbstractQuantitative diffusion MRI (dMRI) is a promising technique for evaluating the spinal cord in health and disease. However, low signal-to-noise ratio (SNR) can impede interpretation and quantification of these images. The purpose of this study is to evaluate a denoising approach, Patch2Self, to improve the quality, reliability, and accuracy of quantitative diffusion MRI of the spinal cord. Patch2Self is a self-supervised learning-based denoising method that leverages statistical independence of noise to suppress signal components strictly originating from random fluctuations. We conduct three experiments to validate the denoising performance of Patch2Self on clinical-quality, single-shell dMRI acquisitions with a small number of gradient directions: 1) inter-session scanrescan in healthy volunteers to evaluate enhancements in image contrast and model fitting; 2) repeated intra-session scans in a healthy volunteer to compare signal averaging to Patch2Self; and 3) assessment of spinal cord lesion conspicuity in a multiple sclerosis group. We find that Patch2Self improves intra-cord contrast, signal modeling, SNR, and lesion conspicuity within the spinal cord. This denoising approach holds promise for facilitating reliable diffusion measurements in the spinal cord to investigate biological and pathological processes.
Proteasome-associated ubiquitin ligase relays target plant hormone-specific transcriptional activators
Authors: Wang Zhishuo , Orosa-Puente Beatriz , Nomoto Mika , Grey Heather , Potuschak Thomas , Matsuura Takakazu , Mori Izumi C. , Tada Yasuomi , Genschik Pascal , Spoel Steven H. 
Published: October 2021

AbstractThe ubiquitin-proteasome system is vital to hormone-mediated developmental and stress responses in plants. Ubiquitin ligases target hormone-specific transcriptional activators (TAs) for degradation, but how TAs are processed by proteasomes remains unknown. We report that in Arabidopsis the salicylic acid-and ethylene-responsive TAs, NPR1 and EIN3, are relayed from pathway-specific ubiquitin ligases to proteasome-associated HECT-type UPL3/4 ligases. Activity and stability of NPR1 was regulated by sequential action of three ubiquitin ligases, including UPL3/4, while proteasome processing of EIN3 required physical handover between ethylene-responsive SCFEBF2 and UPL3/4 ligases. Consequently, UPL3/4 controlled extensive hormone-induced developmental and stress-responsive transcriptional programmes. Thus, our findings identify unknown ubiquitin ligase relays that terminate with proteasome-associated HECT-type ligases, which may be a universal mechanism for processive degradation of proteasome-targeted TAs and other substrates.One-Sentence SummaryTranscriptional activators are targeted by proteasomal ubiquitin ligase relays that control their activity and stability.
Inter-subunit Crosstalk via PDZ Synergistically Governs Allosteric Activation of Proapoptotic HtrA2
Authors: Parui Aasna L. , Mishra Vandana , Dutta Shubhankar , Bhaumik Prasenjit , Bose Kakoli 
Published: October 2021

SUMMARYMitochondrial serine protease – High temperature requirement A2 (HtrA2), is associated with various diseases including neurodegenerative disorders and cancer. Despite availability of structural details, the reports on HtrA2’s mechanistic regulation that varies with the type of activation signals still remain non-concordant. To expound the role of regulatory PDZ domains in promoting synergistic coordination between HtrA2 subunits, we generated heterotrimeric HtrA2 variants comprising different numbers of PDZs and/or active-site mutations. Sequential deletion of PDZs from the trimeric ensemble significantly affected its residual activity in a way that proffered a hypothesis advocating intermolecular allosteric crosstalk via PDZ domains in trimeric HtrA2. Furthermore, structural and computational snapshots affirmed the role of PDZs in secondary structural element formation and coordinated reorganization of the N-terminal region and regulatory loops. Therefore, apart from providing cues for devising structure-guided therapeutic strategies, this study establishes a physiologically relevant working model of complex allosteric regulation through a multifaceted trans-mediated cooperatively-shared energy landscape.
Stochastic variational variable selection for high-dimensional microbiome data
Authors: Dang Tung , Kumaishi Kie , Usui Erika , Kobori Shungo , Sato Takumi , Toda Yusuke , Yamasaki Yuji , Tsujimoto Hisashi , Ichihashi Yasunori , Iwata Hiroyoshi 
Published: October 2021

AbstractBackgroundThe rapid and accurate identification of a minimal-size core set of representative microbial species plays an important role in the clustering of microbial community data and interpretation of clustering results. However, the huge dimensionality of microbial metagenomics datasets is a major challenge for the existing methods such as Dirichlet multinomial mixture (DMM) models. In the framework of the existing methods, the computational burden of identifying a small number of representative species from a large number of observed species remains a challenge.ResultsWe proposed a novel framework to improve the performance of the widely used DMM approach by combining three ideas: (i) we extended the finite DMM model to an infinite case by considering Dirichlet process mixtures and estimating the number of clusters as a random variables; (ii) we proposed an indicator variable to identify representative operational taxonomic units that substantially contribute to the differentiation among clusters; and (iii) to address the computational burden of high-dimensional microbiome data, we proposed a stochastic variational inference, which approximates the posterior distribution using a controllable distribution called variational distribution, and stochastic optimization algorithms for fast computation. Using the proposed method, stochastic variational variable selection (SVVS), we analyzed the root microbiome data collected in our soybean field experiment, the human gut microbiome data from three published datasets of large-scale case-control studies and the healthy human microbiome data from the Human Microbiome Project.ConclusionsSVVS demonstrated a better performance and significantly faster computation than those of the existing methods in all cases of testing datasets. In particular, SVVS is the only method that can analyze massive high-dimensional microbial data with more than 50,000 microbial species and 1,000 samples. Furthermore, recent microbiome studies have suggested that selection of the microbial species used as a core set is important.
Evidence for the Emergence of β-Trefoils by ‘Peptide Budding’ from an IgG-like β-Sandwich
Authors: Longo Liam M. , Kolodny Rachel , McGlynn Shawn E. 
Published: October 2021

AbstractAs sequence and structure comparison algorithms gain sensitivity, the intrinsic interconnectedness of the protein universe has become increasingly apparent. Despite this general trend, β-trefoils have emerged as an uncommon counterexample: They are an isolated protein lineage for which few, if any, sequence or structure associations to other lineages have been identified. If β-trefoils are, in fact, remote islands in sequence-structure space, it implies that the oligomerizing peptide that founded the β-trefoil lineage itself arose de novo. To better understand β-trefoil evolution, and to probe the limits of fragment sharing across the protein universe, we identified both ‘β-trefoil bridging themes’ (evolutionarily-related sequence segments) and ‘β-trefoil-like motifs’ (structure motifs with a hallmark feature of the β-trefoil architecture) in multiple, ostensibly unrelated, protein lineages. The success of the present approach stems, in part, from considering β-trefoil sequence segments or structure motifs rather than the β-trefoil architecture as a whole, as has been done previously. The newly uncovered inter-lineage connections presented here suggest a novel hypothesis about the origins of the β-trefoil fold itself – namely, that it is a derived fold formed by ‘budding’ from an Immunoglobulin-like β-sandwich protein. These results demonstrate how the emergence of a folded domain from a peptide need not be a signature of antiquity and underpin an emerging truth: few protein lineages escape nature’s sewing table.
Integrative analysis of scRNAs-seq and scATAC-seq revealed transit-amplifying thymic epithelial cells expressing autoimmune regulator
Authors: Miyao Takahisa , Miyauchi Maki , Kelly S. Thomas , Terooatea Tommy W. , Ishikawa Tatsuya , Oh Eugene , Hirai Sotaro , Horie Kenta , Takakura Yuki , Ohki Houko , Hayama Mio , Maruyama Yuya , Seki Takao , Yabukami Haruka , Yoshida Masaki , Inoue Azusa , Sakaue-Sawano Asako , Miyawaki Atsushi , Muratani Masafumi , Minoda Aki , Akiyama Nobuko , Akiyama Taishin 
Published: October 2021

SummaryMedullary thymic epithelial cells (mTECs) are critical for self-tolerance induction in T cells via promiscuous expression of tissue-specific antigens (TSAs), which are controlled by transcriptional regulator AIRE. Whereas AIRE-expressing (Aire+) mTECs undergo constant turnover in the adult thymus, mechanisms underlying differentiation of postnatal mTECs remain to be discovered. Integrative analysis of single-cell assays for transposase accessible chromatin (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) suggested the presence of proliferating mTECs with a specific chromatin structure, which express high levels of Aire and co-stimulatory molecules CD80 (Aire+CD80hi). Proliferating Aire+CD80hi mTECs detected by using Fucci technology express a minimal level of Aire-dependent TSAs and are converted into quiescent Aire+CD80hi mTECs expressing high levels of TSAs after a transit amplification. These data provide evidence for the existence of transit amplifying Aire+mTEC precursors during Aire+mTEC differentiation process of the postnatal thymus.
All-trans retinoic acid induces GADD34 gene expression via transcriptional regulation by Six1-TLE3 and post-transcriptional regulation by p38-TTP in skeletal muscle
Authors: Adachi Yuichiro , Masuda Masashi , Sakakibara Iori , Uchida Takayuki , Niida Yuki , Mori Yuki , Kamei Yuki , Okumura Yosuke , Ohminami Hirokazu , Ohnishi Kohta , Yamanaka-Okumura Hisami , Nikawa Takeshi , Taketani Yutaka 
Published: October 2021

AbstractAll-trans retinoic acid (ATRA) increases the sensitivity to unfolded protein response (UPR) in differentiating leukemic blasts. The downstream transcriptional factors of PERK, a major arm of UPR, regulates muscle differentiation. However, the role of growth arrest and DNA damage-inducible protein 34 (GADD34), one of the downstream factors of PERK, and the effects of ATRA on GADD34 expression in muscle remain unclear. In this study, we identified ATRA increased the GADD34 expression independent of the PERK signal in the gastrocnemius muscle of mice. ATRA up-regulated GADD34 expression through the transcriptional activation of it via inhibiting the interaction of homeobox Six1 and transcription co-repressor TLE3 with the MEF3-binding site on the GADD34 gene promoter in myoblasts. ATRA also inhibited the interaction of TTP, which induces mRNA degradation, with AU-rich element on GADD34 mRNA via p38 MAPK, resulting in the instability of GADD34 mRNA. Overexpressed GADD34 in myoblasts changes the type of myosin heavy chain in myotubes. These results suggest ATRA increases GADD34 expression via transcriptional and post-transcriptional regulation in myoblasts, which changes muscle fiber type in myotubes.
Dalpiciclib and Pyrotinib Exert Synergistic Antitumor Effects in Triple Positive Breast Cancer
Authors: Bu Jiawen , Zhang Yixiao , Niu Nan , Bi Kewei , Sun Lisha , Qiao Xinbo , Wang Yimin , Zhang Yinan , Jiang Xiaofan , Wang Dan , Ma Qingtian , Li Huajun , Liu Caigang 
Published: October 2021

AbstractBackgroundThe therapeutic benefit of the standard combination of anti-HER2 and chemotherapy in triple-positive breast cancer (TPBC) is limited even after the addition of endocrine therapy to the regimen. Therefore, treatment optimization is required urgently.MethodsThrough the drug sensitivity test, the drug combination efficacy of anti-HER2 drug, endocrine drug and CDK4/6 inhibitor to BT474 cells were tested. The underlying molecular mechanisms were investigated using immunofluorescence, western blot analysis, immunohistochemical staining and cell cycle analysis. Potential biomarker which may indicate the responsiveness to drug treatment in triple positive breast cancer was selected out using RNA-sequence and tested using immunohistochemical staining.ResultsWe found that pyrotinib combined with dalpiciclib showed better efficacy than pyrotinib combined with tamoxifen in BT474 cells. Degradation of HER2 could enhance ER nuclear transportation, whereas cell cycle blockers could reverse this process. This may be the underlying mechanism by which the addition of dalpiciclib was more beneficial than the addition of pyrotinib plus tamoxifen. Furthermore, CALML5 was revealed to be a potential indicator of responsiveness to anti-HER2 therapy plus CDK4/6 inhibition in triple positive breast cancer.ConclusionOur study provided evidence for the introduction of CDK4/6 inhibitor in the treatment of TPBC and indicated that the combination of anti-HER2 therapy and cell cycle blockers may be a better strategy for TPBC treatment.FundingThis study was supported by the National Natural Science Foundation of China (#U20A20381, #81872159)
The zinc-binding motif in tankyrases is required for the structural integrity and proper function of the catalytic domain
Authors: Sowa Sven T. , Lehtiö Lari 
Published: October 2021

AbstractTankyrases are ADP-ribosylating enzymes that regulate many physiological processes in the cell and they are therefore possible drug targets for cancer and fibrotic diseases. The catalytic ADP-ribosyl-transferase domain of tankyrases contains a unique zinc-binding motif of unknown function. Recently, this motif was suggested to be involved in the catalytic activity of tankyrases. In this work, we set out to study the effect of the zinc-binding motif on activity, stability and structure of human tankyrases. We generated mutants of human TNKS1 and TNKS2 abolishing the zinc-binding capabilities and characterized the proteins biochemically and biophysically in vitro. We further generated a crystal structure of TNKS2, in which the zinc ion was oxidatively removed. Our work shows that the zinc-binding motif in tankyrases is a crucial structural element which is particularly important for the structural integrity of the acceptor site. While mutation of the motif rendered TNKS1 inactive likely due to introduction of major structural defects, the TNKS2 mutant remained active and displayed a different activity profile compared to the wild type.
Detection of Cell-Cell Interactions via Photocatalytic Cell Tagging
Authors: Oslund Rob C. , Reyes-Robles Tamara , White Cory H. , Tomlinson Jake H. , Crotty Kelly A. , Bowman Edward P. , Chang Dan , Peterson Vanessa M. , Li Lixia , Frutos Silvia , Vila-Perelló Miquel , Vlerick David , Cromie Karen , Perlman David H. , O’Hara Samantha D. , Roberts Lee R. , Piizzi Grazia , Hett Erik C. , Hazuda Daria J. , Fadeyi Olugbeminiyi O. 
Published: October 2021

AbstractCell-cell interactions drive essential biological processes critical to cell and tissue development, function, pathology, and disease outcome. The growing appreciation of immune cell interactions within disease environments has led to significant efforts to develop protein- and cell-based therapeutic strategies. A better understanding of these cell-cell interactions will enable the development of effective immunotherapies. However, characterizing these complex cellular interactions at molecular resolution in their native biological contexts remains challenging. To address this, we introduce photocatalytic cell tagging (PhoTag), a modality agnostic platform for profiling cell-cell interactions. Using photoactivatable flavin-based cofactors, we generate phenoxy radical tags for targeted labeling at the cell surface. Through various targeting modalities (e.g. MHC-Multimer, antibody, single domain antibody (VHH)) we deliver a flavin photocatalyst for cell tagging within monoculture, co-culture, and peripheral blood mononuclear cells. PhoTag enables highly selective tagging of the immune synapse between an immune cell and an antigen-presenting cell through targeted labeling at the cell-cell junction. This allowed for the ability to profile gene expression-level differences between interacting and bystander cell populations. Given the modality agnostic and spatio-temporal nature of PhoTag, we envision its broad utilization to detect and profile intercellular interactions within an immune synapse and other confined cellular regions for any biological system.
Slow TCA flux implies low ATP production in tumors
Authors: Bartman Caroline R. , Shen Yihui , Lee Won Dong , TeSlaa Tara , Jankowski Connor S.R. , Wang Lin , Yang Lifeng , Roichman Asael , Bhatt Vrushank , Lan Taijin , Hu Zhixian , Xing Xi , Lu Wenyun , Guo Jessie Yanxiang , Rabinowitz Joshua D. 
Published: October 2021

SummaryThe tricarboxylic acid (TCA) cycle oxidizes carbon substrates to carbon dioxide, with the resulting high energy electrons fed into the electron transport chain to produce ATP by oxidative phosphorylation. Healthy tissues derive most of their ATP from oxidative metabolism, and the remainder from glycolysis. The corresponding balance in tumors remains unclear. Tumors upregulate aerobic glycolysis (the Warburg effect), yet they also typically require an intact TCA cycle and electron transport chain1–6. Recent studies have measured which nutrients contribute carbon to the tumor TCA metabolites7,8, but not tumor TCA flux: how fast the cycle turns. Here, we develop and validate an in vivo dynamic isotope tracing-mass spectrometry strategy for TCA flux quantitation, which we apply to all major mouse organs and to five tumor models. We show that, compared to the tissue of origin, tumor TCA flux is markedly suppressed. Complementary glycolytic flux measurements confirm tumor glycolysis acceleration, but the majority of tumor ATP is nevertheless made aerobically, and total tumor ATP production is suppressed compared to healthy tissues. In murine pancreatic cancer, this is accommodated by downregulation of the major energy-using pathway in the healthy exocrine pancreas, protein synthesis. Thus, instead of being hypermetabolic as commonly assumed, tumors apparently make ATP at a lower than normal rate. We propose that, as cells de-differentiate into cancer, they eschew ATP-intensive processes characteristic of the host tissue, and that the resulting suppressed ATP demand contributes to the Warburg effect and facilitates cancer growth in the nutrient-poor tumor microenvironment.
Correcting Methylation Calls in Clinically Relevant Low-Mappability Regions
Authors: Kumar Caiden M. , Ryan Devon P. , Langhorst Bradley W. 
Published: October 2021

AbstractDNA methylation is an important component in vital biological functions such as embryonic development, carcinogenesis, and heritable regulation. Accurate methods to assess genomic methylation status are crucial to its effective use in many scenarios, especially in the detection and diagnosis of disease. Methylation aligners, such as Bismark and bwa-meth, frequently assign significantly higher MapQ values than can be supported by the uniqueness of the region reads are mapped to. These incorrectly high MapQs result in inappropriate methylation calling in repetitive regions. We observe reads that should map to separate locations (possibly having different methylation states) actually end up mapping to the same locus, causing apparent mixed methylation at such loci. Methylation calling can be improved by using Bismap mappability data to filter out insufficiently unique reads. However, simply filtering out Cs in insufficiently unique regions is not adequate as it is prone to over-filtering Cs in small mappability dips. These Cs can in fact often be called using reads anchored in a nearby mappable region. We have created a new feature for the MethylDackel methylation caller to perform read-based filtering. This new methylation calling method resolves some of the apparent mixed methylation to either 0% or 100% methylation and removes many unsupportable methylation calls. We examined methylation calls with and without read-based filtering in or near the 7830 genes containing ClinVar variants in a methylation sequencing data set from the NA12878 cell line. Use of this improved method corrected 41,143 mixed methylation Cs to 0% methylation, and 22,345 to 100% methylation throughout the genome.