bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural basis for enhanced infectivity and immune evasion of SARS-CoV-2 variants
Authors: Cai Yongfei , Zhang Jun , Xiao Tianshu , Lavine Christy L. , Rawson Shaun , Peng Hanqin , Zhu Haisun , Anand Krishna , Tong Pei , Gautam Avneesh , Lu Shen , Sterling Sarah M. , Walsh Richard M. , Rits-Volloch Sophia , Lu Jianming , Wesemann Duane R. , Yang Wei , Seaman Michael S. , Chen Bing 
Published: April 2021

AbstractSeveral fast-spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become the dominant circulating strains that continue to fuel the COVID-19 pandemic despite intensive vaccination efforts throughout the world. We report here cryo-EM structures of the full-length spike (S) trimers of the B.1.1.7 and B.1.351 variants, as well as their biochemical and antigenic properties. Mutations in the B.1.1.7 protein increase the accessibility of its receptor binding domain and also the binding affinity for receptor angiotensin-converting enzyme 2 (ACE2). The enhanced receptor engagement can account for the increased transmissibility and risk of mortality as the variant may begin to infect efficiently infect additional cell types expressing low levels of ACE2. The B.1.351 variant has evolved to reshape antigenic surfaces of the major neutralizing sites on the S protein, rendering complete resistance to some potent neutralizing antibodies. These findings provide structural details on how the wide spread of SARS-CoV-2 enables rapid evolution to enhance viral fitness and immune evasion. They may guide intervention strategies to control the pandemic.
Dysfunctional vascular smooth muscle cells mediate early and late-stage neuroinflammation and Tau hyperphosphorylation
Authors: Aguilar-Pineda Jorge A. , Vera-Lopez Karin J. , Shrivastava Pallavi , Nieto-Montesinos Rita , Chávez-Fumagalli Miguel A. , Davila Del-Carpio Gonzalo , Valdez Badhin Gomez , Miller Clint L. , Malhotra Rajeev , Lindsay Mark E. , Lino Cardenas Christian L. 
Published: April 2021

SUMMARYDespite the emerging evidence implying early vascular contributions to neurogenerative syndromes, the role of vascular smooth muscle cells (VSMCs) in the pathogenesis of Alzheimer’s disease is still not well understood. Herein, we show that VSMCs in brains of AD patients and the animal model of the disease, are deficient in multiple VSMC-contractile markers which correlated with Tau accumulation in brain arterioles.Ex vivoandin vitroexperiments demonstrated that VSMCs undergo dramatic phenotypic transitions under AD-like conditions, adopting pro-inflammatory and synthetic phenotypes. Notably, these changes coincided with Tau hyperphosphorylation at residues Y18, T205 and S262. We also observed that loss of VSMC markers occurred in an age-dependent manner, and that expression of Sm22α and α-Sma proteins were inversely correlated with CD68 and Tau accumulation in brain arterioles of 3xTg-AD mice. Together, these findings further support the contribution of VSMCs in AD pathogenesis, and nominate VSMCs as potential novel therapeutic target in AD.Graphical Abstract
Males perceive honest information from female released sex pheromone in a moth
Authors: Yiftach Golov , Alexander Liberzon , Roi Gurka , Victoria Soroker , Russell Jurenka , Ally R Harari 
Published: April 2021

AbstractThere is accumulating evidence that male insects advertise their quality to conspecific females through pheromones. However, most studies of female released sex pheromone assume information transfer regarding merely the species of the female and her mating status. We show that more and precise information is conveyed through the female sex pheromone, positioning it as an honest sexual trait. We demonstrate that females in bad physical conditions (small, starved or old) lay significantly fewer eggs than females in good conditions (large, fed or young). The ratio of the sex pheromone blend in gland extracts of female pink bollworm moths accurately describes the female phenotypic condition whereas the pheromone amount in the glands fails to provide an honest signal of quality. Moreover, males use the female released pheromone blend to choose their mates and approach females that signal higher reproductive potential. In addition, surrogating the female effect, using synthetic pheromone blend that represents that of higher quality females (0.6:0.4 ZZ:ZE) more males were attracted to this blend than to the blend representing the population mean (0.5:0.5 ZZ:ZE). Both, female advertisement for males and the male choosiness, suggest that pheromones have evolved as sexual traits under directional, sexual selection.
Transcriptional Inactivation of TP53 and the BMP Pathway Mediates Therapy-induced Dedifferentiation and Metastasis in Prostate Cancer
Authors: Han Hyunho , Wang Yan , Curto Josue , Gurrapu Sreeharsha , Laudato Sara , Rumandla Alekya , Chakraborty Goutam , Wang Xiaobo , Chen Hong , Jiang Yan , Kumar Dhiraj , Caggiano Emily , Zhang Boyu , Ji Yan , Maity Sankar N. , Hu Min , Bai Shanshan , Aparicio Ana , Efstathiou Eleni , Logothetis Christopher J. , Navin Nicholas , Navone Nora , Chen Yu , Giancotti Filippo G. 
Published: April 2021

SummaryUnsupervised clustering and deconvolution analysis identifies a novel subtype of M-CRPC endowed with hybrid epithelial/mesenchymal (E/M) and luminal progenitor-like traits (Mesenchymal and Stem-like PC, MSPC). Analysis of patient datasets and mechanistic studies indicate that MSPC arises as a consequence of therapy-induced lineage plasticity. AR blockade instigates two separate and complementary processes: 1) transcriptional silencing ofTP53and hence acquisition of hybrid E/M and stem-like traits; and 2) inhibition of the BMP signaling, which promotes resistance to the pro-apoptotic and anti-proliferative effects of AR inhibition. The drug-tolerant prostate cancer cells generated through reprogramming are rescued by neuregulin and generate metastases in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibit efficacy in preclinical models of mixed ARPC/MSPC or MSPC, respectively. These results identify a novel subtype of M-CRPC, trace its origin to therapy-induced lineage plasticity, and reveal its dependency on HER2/3 signaling.
Towards a causal role of Broca’s area in language: A TMS-EEG study on syntactic prediction
Authors: Maran Matteo , Numssen Ole , Hartwigsen Gesa , Friederici Angela D. , Zaccarella Emiliano 
Published: April 2021

ABSTRACTCategorical predictions have been proposed as the key mechanism supporting the fast pace of syntactic composition in human language. Accordingly, grammar-based expectations facilitate the analysis of incoming syntactic information—e.g., hearing the determiner “the” enhances the prediction of a noun—which is then checked against a single or few other word categories. Previous functional neuroimaging studies point towards Broca’s area in the left inferior frontal gyrus (IFG) as one fundamental cortical region involved in categorical prediction during on-line language processing. Causal evidence for this hypothesis is however still missing. In this study, we combined Electroencephalography (EEG) and Transcranial Magnetic Stimulation (TMS) to test whether Broca’s area is functionally relevant in predictive mechanisms for language. Specifically, we transiently perturbed Broca’s area during the categorical prediction phase in two-word constructions, while simultaneously measuring the Event-Related Potential (ERP) correlates of syntactic composition. We reasoned that if Broca’s area is involved in predictive mechanisms for syntax, disruptive TMS during the processing of the first word (determiner/pronoun) would mitigate the difference in ERP responses for predicted and unpredicted categories when composing basic phrases and sentences. Contrary to our hypothesis, perturbation of Broca’s area at the predictive stage did not affect the ERP correlates of basic composition. The correlation strength between the electrical field induced by TMS and the magnitude of the EEG response on the scalp further confirmed this pattern. We discuss the present results in light of an alternative account of the role of Broca’s area in syntactic composition, namely the bottom-up integration of words into constituents.
Time grid-based isomer specific N-glycan analysis and detection of bi-secting Lewis X in human brain
Authors: Helm Johannes , Gruber Clemens , Thader Andreas , Urteil Jonathan , Führer Johannes , Stenitzer David , Maresch Daniel , Neumann Laura , Pabst Martin , Altmann Friedrich 
Published: April 2021

ABSTRACTThe importance of protein glycosylation in the biomedical field demands for methods capable of resolving and identifying isomeric structures of N-glycans. However, the unambiguous identification of isomeric structures from complex mixtures is currently not reasonably realized even by the most sophisticated approaches. Here we present a novel approach which uses stable isotope labelled reference N-glycans to establish a retention time grid (glyco-TiGr) on porous graphitized carbon. This furthermore enables retention as the primary criterion for the structural assignment of isomeric N-glycans.Moreover, we biosynthesized forty natural isomers of the fundamental N-glycan type consisting of five hexoses, four N-acetylhexosamines and one fucose residue. Nearly all of these isomers occupied unique positions on the retention time grid. Reference glycan assisted retention time determination with deci-minute accuracy narrowed the assignment space to very few, often only one possible glycan isomer.Application of the glyco-TiGr approach revealed yet undescribed isomers of Lewis x determinants in multimeric human IgA and hybrid type N-glycans in human brain with galactose and even fucose linked to the bisecting N-acetylglucosamine. Thus, the brain N-glycome displayed a degree of sophistication commensurate with this organ’s role.
Developmental series of gene expression clarifies maternal mRNA provisioning and maternal-to-zygotic transition in the reef-building coralMontipora capitata
Authors: Chille E , Strand E , Neder M , Schmidt V , Sherman M , Mass T , Putnam HM 
Published: April 2021

AbstractBackgroundMaternal mRNA provisioning of oocytes regulates early embryogenesis. Maternal transcripts are degraded as zygotic genome activation (ZGA) intensifies, a phenomenon known as the maternal-to-zygotic transition (MZT). Here, we examine gene expression over nine developmental stages in the Pacific rice coral,Montipora capitata, from eggs and embryos at 1, 4, 9, 14, 22, and 36 hours-post-fertilization (hpf), as well as swimming larvae (9d), and adult colonies.ResultsWeighted Gene Coexpression Network Analysis revealed four expression peaks, identifying the maternal complement, two waves of the MZT, and adult expression. Gene ontology enrichment revealed maternal mRNAs are dominated by cell division, methylation, biosynthesis, metabolism, and protein/RNA processing and transport functions. The first MZT wave occurs from ∼4-14 hpf and is enriched in terms related to biosynthesis, methylation, cell division, and transcription. In contrast, functional enrichment in the second MZT wave, or ZGA, from 22 hpf-9dpf, includes ion/peptide transport and cell signaling. Finally, adult expression is enriched for functions related to signaling, metabolism, and ion/peptide transport. Our proposed MZT timing is further supported by expression of enzymes involved in zygotic transcriptional repression (Kaiso) and activation (Sox2), which peak at 14 hpf and 22 hpf, respectively. Further, DNA methylation writing (DNMT3a) and removing enzymes (TET1) peak and remain stable past ∼4 hpf, indicating that methylome programming occurs before 4 hpf.ConclusionsOur high-resolution insight into the coral maternal mRNA and MZT provides essential information regarding setting the stage for, and the sensitivity of, developmental success and parental carryover effects under increasing environmental stress.
INO-4800 DNA Vaccine Induces Neutralizing Antibodies and T cell Activity Against Global SARS-CoV-2 Variants
Authors: Andrade Viviane M. , Christensen-Quick Aaron , Agnes Joseph , Tur Jared , Reed Charles , Kalia Richa , Marrero Idania , Elwood Dustin , Schultheis Katherine , Purwar Mansi , Reuschel Emma , McMullan Trevor , Pezzoli Patrick , Kraynyak Kim , Sylvester Albert , Mammen Mammen P. , Tebas Pablo , Kim J. Joseph , Weiner David B. , Smith Trevor R.F. , Ramos Stephanie J. , Humeau Laurent M. , Boyer Jean D. , Broderick Kate E. 
Published: April 2021

AbstractGlobal surveillance has identified emerging SARS-CoV-2 variants of concern (VOC) associated with broadened host specificity, pathogenicity, and immune evasion to vaccine induced immunity. Here we compared humoral and cellular responses against SARS-CoV-2 VOC in subjects immunized with the DNA vaccine, INO-4800. INO-4800 vaccination induced neutralizing antibodies against all variants tested, with reduced levels detected against B.1.351. IFNγ T cell responses were fully maintained against all variants tested.
Phosphorus stress induces the synthesis of novel glycolipids inPseudomonas aeruginosathat confer protection against a last-resort antibiotic
Authors: Jones Rebekah A. , Shropshire Holly , Zhao Caimeng , Murphy Andrew , Lidbury Ian , Wei Tao , Scanlan David J , Chen Yin 
Published: April 2021

AbstractPseudomonas aeruginosais a nosocomial pathogen with a prevalence in immunocompromised individuals and is particularly abundant in the lung microbiome of cystic fibrosis patients. A clinically important adaptation for bacterial pathogens during infection is their ability to survive and proliferate under phosphorus (P) limited growth conditions. Here, we demonstrate thatP. aeruginosaadapts to P-limitation by substituting membrane glycerophospholipids with sugar-containing glycolipids through a lipid renovation pathway involving a phospholipase and two glycosyltransferases. Combining bacterial genetics and multi-omics (proteomics, lipidomics and metatranscriptomic analyses), we show that the surrogate glycolipids monoglycosyldiacylglycerol and glucuronic acid-diacylglycerol are synthesised through the action of a new phospholipase (PA3219) and two glycosyltransferases (PA3218 and PA0842). Comparative genomic analyses revealed that this pathway is strictly conserved in allP. aeruginosastrains isolated from a range of clinical and environmental settings and actively expressed in the metatranscriptome of a cystic fibrosis patient. Importantly, this phospholipid-to-glycolipid transition comes with significant ecophysiological consequence in terms of antibiotic sensitivity. Mutants defective in glycolipid synthesis survive poorly when challenged with polymyxin B, a last-resort antibiotic for treating multi-drug resistantP. aeruginosa. Thus, we demonstrate an intriguing link between adaptation to environmental stress (nutrient availability) and antibiotic resistance, mediated through membrane lipid renovation that is an important new facet in our understanding of the ecophysiology of this bacterium in the lung microbiome of cystic fibrosis patients.ClassificationIntegrated genomics and post-genomics approaches in microbial ecology
Maternal and zygotic factors sequentially shape the tissue regionalization of chromatin landscapes in early vertebrate embryos
Authors: Paraiso Kitt D. , Blitz Ira L. , Cho Ken W.Y. 
Published: April 2021

AbstractOne of the first steps in cellular differentiation of vertebrate embryos is the formation of the three germ layers. Maternal pioneer transcription factors (TFs) bind to the regulatory regions of the embryonic genome prior to zygotic genome activation and initiate germ layer specification. While the involvement of maternal TFs in establishing epigenetic marks in whole embryos was addressed previously, how early pluripotent cells acquire spatially restricted epigenetic identity in embryos remain unknown. Here, we report that the H3K4me1 enhancer mark in each germ layer becomes distinct in germ layer specific regulatory regions, forming super-enhancers (SEs), by early gastrula stage. Distinct SEs are established in these germ layers near robustly regulated germ layer identity genes, suggesting that SEs are important for the canalization of development. Establishment of these enhancers requires a sequential function of maternal and zygotic TFs. By knocking down the expression of a critical set of maternal endodermal TFs, an overwhelming majority of the endodermal H3K4me1 marks are lost. Interestingly, this disappearance of endodermal marking coincides with the appearance of ectodermal and mesodermal H3K4me1 marks in the endoderm, suggesting a transformation in the chromatin state of these nuclei towards a more ecto-mesodermal state.De novomotif analysis to identify TFs responsible for the transformation recovers a profile for endodermal maternal TFs as well as their downstream target TFs. We demonstrate the importance of coordinated activities of maternal and zygotic TFs in defining a spatially resolved dynamic process of chromatin state establishment.
Associations between recurrent mutations and blast immunophenotype in acute myeloid leukemia
Authors: Kuželová Kateřina , Brodská Barbora , Marková Jana , Petráčková Martina , Ransdorfová Šárka , Gašová Zdenka , Šálek Cyril 
Published: April 2021

AbstractThe immune system undoubtly plays an important role in final elimination of residual leukemic cells during acute myeloid leukemia (AML) therapy. However, the anti-leukemia immune response can be inhibited by a variety of mechanisms enabling immune escape and eventual disease relapse. We analyzed selected markers of immune escape on AML cells at diagnosis (N = 53) and used them for hierarchical clustering analysis, which yielded distinct clusters with different incidence of mutations in nucleophosmin 1 (NPM1) and in the methyltransferase DNMT3A. More detailed analysis showed that in the absence of DNMT3A mutation, NPM1 mutation is associated with decreased HLA expression and also with low levels of other markers (CLIP, PD-L1, TIM-3). On the other hand, samples with concomitant DNMT3A mutation had high CLIP surface amount suggesting reduced antigen presentation. Higher CLIP exposition was also found in patients with internal tandem duplications in FLT3 (FLT3-ITD). TIM-3 transcript correlated not only with TIM-3 protein surface amount, but also with CLIP and PD-L1, suggesting acquisition of a complex immunoresistant phenotype. Our results indicate that AML genotype is to some extent related to the blast immunophenotype, and the established predictive values of particular mutations might also reflect an inherent cell resistance to the immune system.
Effects of tumor mutation burden on the antigen presentation pathway
Authors: Garcia-Rivera Enrique M. , Park Jiho , Desai Aakash , Boidot Romain , Chevrier Sandy , Truntzer Caroline , Ghiringhelli François , Borad Mitesh , Mansfield Aaron S. 
Published: April 2021

AbstractTumor mutation burden (TMB) is used to select patients to receive immune checkpoint inhibitors (ICIs) but has mixed predictive capabilities. We hypothesized that inactivation of antigen presenting genes (APGs) that result from increased TMBs would result in inherent resistance to ICIs. We observed that somatic mutations in APGs were associated with increasing TMBs across 9,418 tumor samples of 33 different histological subtypes. In adenocarcinomas of the lung,ITGAXandCD1Bwere some of the most commonly mutated APGs. In 62 patients with non-small cell lung cancers treated with a PD-1 inhibitor in second or later lines of therapy, there was an association of increased TMB with mutations in APGs; however, mutations in one or more APGs were associated with improved progression-free survival. Contrary to our hypothesis, mutations in APGs were associated with improved progression-free survival with nivolumab, possibly due to the involvement of single alleles rather than complete loss.
Pattern Detection in Multiple Genome Sequences with Applications: The Case of All SARS-CoV-2 Complete Variants
Authors: Xylogiannopoulos Konstantinos F. 
Published: April 2021

AbstractPattern detection and string matching are fundamental problems in computer science and the accelerated expansion of bioinformatics and computational biology have made them a core topic for both disciplines. The SARS-CoV-2 pandemic has made such problems more demanding with hundreds or thousands of new genome variants discovered every week, because of constant mutations, and the need for fast and accurate analyses. Medicines and, mostly, vaccines must be altered to adapt and efficiently address mutations. The need of computational tools for genomic analysis, such as sequence alignment, is very important, although, in most cases the resources and computational power needed is vast. The presented data structures and algorithms, specifically built for text mining and pattern detection, can help to address efficiently several bioinformatics problems. With a single execution of advanced algorithms, with limited space and time complexity, it is possible to acquire knowledge on all repeated patterns that exist in multiple genome sequences and this information can be used for further meta analyses. The potentials of the presented solutions are demonstrated with the analysis of more than 55,000 SARS-CoV-2 genome sequences (collected on March 10, 2021) and the detection of all repeated patterns with length up to 60 nucleotides in these sequences, something practically impossible with other algorithms due to its complexity. These results can be used to help provide answers to questions such as all variants common patterns, sequence alignment, palindromes and tandem repeats detection, genome comparisons, etc.
T1TAdb: the database of Type I Toxin-Antitoxin systems
Authors: Tourasse Nicolas J. , Darfeuille Fabien 
Published: April 2021

AbstractType I toxin-antitoxin (T1TA) systems constitute a large class of genetic modules with antisense RNA (asRNA)-mediated regulation of gene expression. They are widespread in bacteria and consist of an mRNA coding for a toxic protein and a noncoding asRNA that acts as an antitoxin preventing the synthesis of the toxin by directly basepairing to its cognate mRNA. The co- and post-transcriptional regulation of T1TA systems is intimately linked to RNA sequence and structure, therefore it is essential to have an accurate annotation of the mRNA and asRNA molecules to understand this regulation. However, most T1TA systems have been identified by means of bioinformatic analyses solely based on the toxin protein sequences, and there is no central repository of information on their specific RNA features. Here we present the first database dedicated to type I TA systems, named T1TAdb. It is an open-access web database (https://d-lab.arna.cnrs.fr/t1tadb) with a collection of ~1,900 loci in ~500 bacterial strains in which a toxin-coding sequence has been previously identified. RNA molecules were annotated with a bioinformatic procedure based on key determinants of the mRNA structure and the genetic organization of the T1TA loci. Besides RNA and protein secondary structure predictions, T1TAdb also identifies promoter, ribosome-binding, and mRNA-asRNA interaction sites. It also includes tools for comparative analysis, such as sequence similarity search and computation of structural multiple alignments, which are annotated with covariation information. To our knowledge, T1TAdb represents the largest collection of features, sequences, and structural annotations on this class of genetic modules.