bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inferring CTCF binding patterns and anchored loops across human tissues and cell types
Authors: Xu Hang , Yi Xianfu , Wang Wei , Chu Xinlei , Zhang Shijie , Dong Xiaobao , Wang Zhao , Wang Jianhua , Zhou Yao , Zhao Ke , Yao Hongcheng , Nan Zheng , Wang Junwen , Plewczynski Dariusz , Sham Pak Chung , Chen Kexin , Huang Dandan , Li Mulin Jun 
Published: June 2022

AbstractCCCTC-binding factor (CTCF) is a transcription regulator which is involved in many cellular processes. How CTCF recognizes DNA sequence to exert chromosome barrier or enhancer blocking effects remains to be fully interrogated. Despite many computational tools were developed to predict CTCF-mediated loops qualitatively or quantitatively, few could specially evaluate the regulatory potential of DNA sequence at CTCF binding sites (CBSs) and how it affects chromatin loop formation. Here, we developed a deep learning model, DeepAnchor, to precisely characterize the binding patterns for different types of CBSs. By incorporating base-wise genomic/epigenomic features, we revealed distinct chromatin and sequence features for CTCF-mediated insulation and looping at a high resolution, such as two sequence motifs flanking the core CTCF motif at loop-associated CBSs. Besides, we leveraged the predicted anchor score to optimize the loop extrusion model and achieved the best performance in predicting CTCF-anchored loops. We established a compendium of context-specific CTCF-anchored loops across 52 human tissue/cell types and found that genomic disruption of CTCF-anchored loops may represent a general causal mechanism of disease pathogenesis. These computational models, together with the established resource, could facilitate the mechanistic research on how the CTCF-mediatedcis-regulatory elements (CREs) shapes context-specific gene regulation in cell development and disease progression.
A library of promoter-gfpfusion reporters for studying systemic expression pattern of cyclic-di-GMP metabolism-related genes inPseudomonas aeruginosa
Authors: Liu Dejian , Wang Di , Wei Qing , Zhang Yu , Ma Luyan Z 
Published: June 2022

AbstractThe opportunistic pathogenPseudomonas aeruginosais an environmental microorganism, which is notorious for its resistance or tolerance to antibiotics due to the formation of biofilms. Cyclic diguanosine monophosphate (c-di-GMP) is a bacterial second messenger that plays critical roles in biofilm formation.P. aeruginosacontains 41 genes that encode enzymes to participate in the metabolism of c-di-GMP (biosynthesis or degradation), yet it lacks tools to investigate the systemic expression pattern of those genes. Here, we constructed a promoter-gfptranscriptional fusion reporters’ library that consists of 41 reporter plasmids. Each plasmid contains a promoter of correspondingc-di-GMPmetabolism-related (CMR) genes fromP. aeruginosaPAO1 strain, thus each promoter-Gfp fusion reporter can be used to detect the promotor’ activity as well as the transcription of corresponding gene. The promoters’ activity was tested inP. aeruginosaandEscherichia colirespectively. Among the 41 genes, the promoter of 26 genes showed activity in bothP. aeruginosaandE. coli. The library was applied to determine the influence of different temperatures, growth media, and sub-inhibitory concentrations of antibiotics on transcriptional profile of the 41 CMR genes inP. aeruginosa. The results showed different growth conditions did impact different genes’ transcription, while the promoter’ activity of a few genes kept at the same level under several different growth conditions. In summary, we provided a promoter-gfpfusion reporters’ library for systemic monitoring or study of the regulation of CMR genes inP. aeruginosaand the functional promoters can also be used as a bio-brick for synthetic biology studies.ImportanceThe opportunistic pathogenP. aeruginosacan cause acute and chronic infections in humans and it is one of main pathogens in nosocomial infections. Biofilm formation is one of most important causes forP. aeruginosato persist in hosts and evade immune and antibiotic attacks. c-di-GMP is an important second messenger to control biofilm formation. InP. aeruginosa, there are 41 genes that are predicted to participate in the making and breaking this dinucleotide. A major missing information in this field is the systemic expression profile of those genes in response to changing environment. Toward this goal, we constructed a promoter-gfptranscriptional fusion reporters’ library that consists of 41 reporter plasmids, each of which contains a promoter of corresponding c-di-GMP metabolism-related genes inP. aeruginosa. This library provides a helpful tool to understand the complex regulation network related to c-di-GMP and to discover potential therapeutic targets.
Potent clinical predictive and systemic adjuvant therapeutic value of plasma fractalkine in PD-L1/PD-1 blockade immunotherapy for lung cancer
Authors: Bocanegra Ana , Fernández Gonzalo , Ajona Daniel , Arasanz Hugo , Blanco Ester , Zuazo Miren , Chocarro Luisa , Piñeiro-Hermida Sergio , Morente Pilar , Fernández Leticia , Garnica Maider , Remirez Ana , Martinez-Aguillo Maite , Morilla Idoia , Tavira Beatriz , Ramos Pablo , Echaide Miriam , Lasarte Juan José , Montuenga Luis , Vera Ruth , Pio Ruben , Escors David , Kochan Grazyna 
Published: June 2022

AbstractRecent studies highlight the importance of baseline functional immunity for efficacious immune checkpoint blockade therapies. High-dimensional systemic immune profiling was performed in a discovery cohort of 112 non-small cell lung cancer patients undergoing PD-L1/PD-1 blockade immunotherapy. Responders showed high baseline phenotypic diversity of myeloid cell types in peripheral blood, in which elevated activated monocytic cells and decreased granulocytic phenotypes were potent predictive biomarkers. High-throughput profiling of soluble factors in plasma identified fractalkine (FKN), a chemokine involved in immune chemotaxis and adhesion, as a biomarker of myeloid cell diversity in human patients and in murine models, which was found significantly increased in objective responders. Secreted FKN inhibited adenocarcinoma and squamous cell carcinoma growth in vivo through a prominent contribution of systemic effector NK cells, enhanced tumor infiltration with immunostimulatory immune cells and inhibition of MDSCs within tumors. A synergy between FKN and PD-L1/PD-1 blockade immunotherapy was found in murine lung cancer models refractory to anti-PD-L1/anti-PD-1 treatment. Transcriptional data from 515 human lung adenocarcinoma samples independently confirmed the results from the discovery cohort. Importantly, recombinant FKN and tumor expressed-FKN were efficacious in delaying tumor growth in vivo with significant abscopal effects, indicating a potential therapeutic use of FKN in combination with immunotherapies.One Sentence SummarySerum fractalkine as a biomarker of response to immune checkpoint blockade.
Inter- and intra-chromosomal modulators of the APOE ε2 and ε4 effects on the Alzheimer’s disease risk
Authors: Nazarian Alireza , Philipp Ian , Culminskaya Irina , He Liang , Kulminski Alexander M. 
Published: June 2022

AbstractThe mechanisms of incomplete penetrance of risk modifying impacts of apolipoprotein E (APOE) ε2 and ε4 alleles on Alzheimer’s disease (AD) have not been fully understood. We performed genome-wide analysis of differences in linkage disequilibrium (LD) patterns between 6136 AD-affected and 10555 AD-unaffected subjects from five independent studies to explore whether the association of the APOE ε2 allele (encoded by rs7412 polymorphism) and ε4 allele (encoded by rs429358 polymorphism) with AD was modulated by autosomal polymorphisms. The LD analysis identified 24 (mostly inter-chromosomal) and 57 (primarily intra-chromosomal) autosomal polymorphisms with significant differences in LD with either rs7412 or rs429358, respectively, between AD-affected and AD-unaffected subjects, indicating their potential modulatory roles. Our Cox regression analysis showed that minor alleles of four inter-chromosomal and ten intra-chromosomal polymorphisms exerted significant modulating effects on the ε2- and ε4-associated AD risks, respectively, and identified ε2-independent (rs2884183 polymorphism, 11q22.3) and ε4-independent (rs483082 polymorphism, 19q13.32) associations with AD. Our functional analysis highlighted ε2- and/or ε4-linked processes affecting the lipid and lipoprotein metabolism, and cell junction organization which may contribute to AD pathogenesis. These findings provide insights into the ε2- and ε4-associated mechanisms of AD pathogenesis, underlying their incomplete penetrance.
Data-driven dissection of the fever effect in autism spectrum disorder
Authors: Muller Efrat , Shalev Ido , Bachmat Eitan , Eran Alal 
Published: June 2022

ABSTRACTSome individuals with autism spectrum disorder (ASD) demonstrate marked behavioral improvements during febrile episodes, in what is perhaps the only present-day means of modulating the core ASD phenotype. Understanding the nature of this so-calledfever effectis therefore essential for leveraging this natural temporary relief of symptoms to a sustained efficacious intervention. Towards this goal, we used machine learning to analyze the rich clinical data of the Simons Simplex Collection, in which 1 out of every 6 children with ASD was reported to improve during febrile episodes, across multiple ASD domains. Reported behavioral improvements during febrile episodes were associated with maternal infection in pregnancy (OR = 1.7, 95% CI = [1.42, 2.03], P = 4.24×10−4) and gastrointestinal (GI) dysfunction (OR=1.46, 95% CI = [1.15, 1.81], P = 1.94×10−3). Family members of children reported to improve when febrile have an increased prevalence of autoimmune disorders (OR=1.43, 95% CI = [1.23, 1.67], P = 3.0×10−6), language disorders (OR=1.63, 95% CI = [1.29, 2.04], P = 2.5×10−5), and neuropsychiatric disorders (OR=1.59, 95% CI = [1.34, 1.89], P < 1×10−6). Since both GI abnormalities and maternal immune activation have been linked to ASD via proinflammatory cytokines, these results might suggest a possible involvement of immune dysregulation in the fever effect, consistent with findings in mouse models. This work advances our understanding of the fever-responsive ASD subtype and motivates future studies to directly test the link between proinflammatory cytokines and behavioral modifications in individuals with ASD.Lay summarySome individuals with ASD demonstrate marked behavioral improvements when they have a fever. However, the magnitude, scope, nature, and underlying neurobiological basis of the so-called fever effect remain unknown. This large-scale biomedical data analysis found that children with ASD reported to improve when febrile tend to be those with worse gastrointestinal symptoms and whose mothers reported an infection during pregnancy. These and other findings point to the involvement of proinflammatory cytokines in this phenomenon.
An S1 subunit vaccine and combination adjuvant (COVAC-1) elicits robust protection against SARS-CoV-2 challenge in African green monkeys
Authors: Garnett Lauren , Tran Kaylie N , Chan Mable , Tierney Kevin , Schiffman Zachary , Audet Jonathan , Lew Jocelyne M. , Meilleur Courtney , Chan Michael , Manguiat Kathy , Tailor Nikesh , Vendramelli Robert , Deschambault Yvon , Beaudoin-Bussières Guillaume , Bourassa Catherine , Richard Jonathan , Finzi Andrés , Higgins Rick , Littlel-van den Hurk Sylvia van Drunen , Gerdts Volker , Strong James E , Falzarano Darryl 
Published: June 2022

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent responsible for the ongoing global pandemic. With over 500 million cases and more than 6 million deaths reported globally, the need for access to effective vaccines is clear. An ideal SARS-CoV-2 vaccine will prevent pathology in the lungs and prevent virus replication in the upper respiratory tract, thus reducing transmission. Here, we assessed the efficacy of an adjuvanted SARS-CoV-2 S1 subunit vaccine, called COVAC-1, in an African green monkey (AGM) model. AGMs immunized and boosted with COVAC-1 were protected from SARS-CoV-2 challenge compared to unvaccinated controls based on reduced pathology and reduced viral RNA levels and infectious virus in the respiratory tract. Both neutralizing antibodies and antibodies capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) were observed in vaccinated animals prior to the challenge. COVAC-1 induced effective protection, including in the upper respiratory tract, thus supporting further development and utility for determining the mechanism that confers this protection.AUTHOR SUMMARYVaccines that can prevent the onward transmission of SARS-CoV-2 and prevent disease are highly desirable. Whether this can be accomplished without mucosal immunization by a parenterally administered subunit vaccine is not well established. Here we demonstrate that following two vaccinations, a protein subunit vaccine containing the S1 portion of the SARS-CoV-2 spike glycoprotein and the novel adjuvant TriAdj significantly reduces the amount of virus in the lungs and also mediates rapid clearance of the virus from the upper respiratory tract. Further support of the effectiveness of COVAC-1 was the observation of reduced pathology in the lungs and viral RNA being largely absent from tissues, blood, and rectal swabs. Thus COVAC-1 appears promising at mediating protection in both the upper and lower respiratory tract and may be capable of reducing subsequent transmission of SARS-CoV-2. Further investigation into the mechanism of protection in the upper respiratory tract and the initial immune response that supports this would be warranted.
PhaseTypeR: phase-type distributions in R with reward transformations and a view towards population genetics
Authors: Rivas-González Iker , Nørvang Andersen Lars , Hobolth Asger 
Published: June 2022

AbstractPhase-type distributions are a general class of models that are traditionally used in actuarial sciences and queuing theory, and more recently in population genetics. A phase-type distributed random variable is the time to absorption in a discrete or continuous time Markov chain on a finite state space with an absorbing state. The R package PhaseTypeR contains all the key functions—mean, (co)variance, probability density function, cumulative distribution function, quantile function, random sampling and reward transformations—for both continuous (PH) and discrete (DPH) phase-type distributions. Additionally, we have also implemented the multivariate continuous case (MPH) and the multivariate discrete case (MDPH). We illustrate the usage of PhaseTypeR in simple examples from population genetics (e.g. the time until the most recent common ancestor or the total number of mutations in an alignment of homologous DNA sequences), and we demonstrate the power of PhaseTypeR in more involved applications from population genetics, such as the coalescent with recombination and the structured coalescent. The multivariate distributions and ability to reward-transform are particularly important in population genetics, and a unique feature of PhaseTypeR.
The MeshCODE to scale – Visualising synaptic binary information
Authors: Barnett Samuel F H , Goult Benjamin T 
Published: June 2022

AbstractThe Mercator projection map of the world provides a useful, but distorted, view of the relative scale of countries. Current cellular models suffer from a similar distortion. Here, we undertook an in-depth structural analysis of the molecular dimensions in the cell’s computational machinery, the MeshCODE, that is assembled from a meshwork of binary switches in the scaffolding proteins talin and vinculin. Talin contains a series of force-dependent binary switches and each domain switching state introduces quantised step-changes in talin length on a micrometre scale. The average dendritic spine is 1 µm in diameter so this analysis identifies a plausible Gearbox-like mechanism for dynamic regulation of synaptic function, whereby the positioning of enzymes and substrates relative to each other, mechanically-encoded by the MeshCODE switch patterns, might control synaptic transmission. Based on biophysical rules and experimentally derived distances, this analysis yields a novel perspective on biological digital information.
Hybrid Autoencoder with Orthogonal Latent Space for Robust Population Structure Inference
Authors: Yuan Meng , Hoskens Hanne , Goovaerts Seppe , Herrick Noah , Shriver Mark D. , Walsh Susan , Claes Peter 
Published: June 2022

AbstractBackgroundAnalysis of population structure and genomic ancestry remains an important topic in human genetics and bioinformatics. Commonly used methods require high-quality genotype data to ensure accurate inference. However, in practice, laboratory artifacts and outliers are often present in the data. Moreover, existing methods are typically affected by the presence of related individuals in the dataset.ResultsIn this work, we propose a novel hybrid method, called SAE-IBS, which combines the strengths of traditional matrix decomposition-based (e.g., principal component analysis) and more recent neural network-based (e.g., autoencoders) solutions. I.e., it yields an orthogonal latent space enhancing dimensionality selection while learning non-linear transformations. The proposed approach achieves higher accuracy than existing methods for projecting poor quality target samples (genotyping errors and missing data) onto a reference ancestry space and generates a robust ancestry space in the presence of relatedness.ConclusionWe introduce a new approach and an accompanying open-source program for robust ancestry inference in the presence of missing data, genotyping errors, and relatedness. The obtained ancestry space allows for non-linear projections and exhibits orthogonality with clearly separable population groups.
De novodesign of site-specific protein interactions with learned surface fingerprints
Authors: Gainza Pablo , Wehrle Sarah , Van Hall-Beauvais Alexandra , Marchand Anthony , Scheck Andreas , Harteveld Zander , Buckley Stephen , Ni Dongchun , Tan Shuguang , Sverrisson Freyr , Goverde Casper , Turelli Priscilla , Raclot Charlène , Teslenko Alexandra , Pacesa Martin , Rosset Stéphane , Georgeon Sandrine , Marsden Jane , Petruzzella Aaron , Liu Kefang , Xu Zepeng , Chai Yan , Han Pu , Gao George F. , Oricchio Elisa , Fierz Beat , Trono Didier , Stahlberg Henning , Bronstein Michael , Correia Bruno E. 
Published: June 2022

AbstractPhysical interactions between proteins are essential for most biological processes governing life. However, the molecular determinants of such interactions have been challenging to understand, even as genomic, proteomic, and structural data grows. This knowledge gap has been a major obstacle for the comprehensive understanding of cellular protein-protein interaction (PPI) networks and for thede novodesign of protein binders that are crucial for synthetic biology and translational applications. We exploit a geometric deep learning framework operating on protein surfaces that generates fingerprints to describe geometric and chemical features critical to drive PPIs. We hypothesized these fingerprints capture the key aspects of molecular recognition that represent a new paradigm in the computational design of novel protein interactions. As a proof-of-principle, we computationally designed severalde novoprotein binders to engage four protein targets: SARS-CoV-2 spike, PD-1, PD-L1, and CTLA-4. Several designs were experimentally optimized while others were purely generatedin silico, reaching nanomolar affinity with structural and mutational characterization showing highly accurate predictions. Overall, our surface-centric approach captures the physical and chemical determinants of molecular recognition, enabling a novel approach for thede novodesign of protein interactions and, more broadly, of artificial proteins with function.
The complex roles of genomic DNA modifications of bacteriophage T4 in resistance to nuclease-based defense systems of E. coli
Authors: Wang Shuangshuang , Sun Erchao , Liu Yuepeng , Yin Baoqi , Zhang Xueqi , Li Mengling , Huang Qi , Tan Chen , Qian Ping , Rao Venigalla B. , Tao Pan 
Published: June 2022

ABSTRACTThe interplay between defense and counter-defense systems of bacteria and phages is a major driver of evolution of both organisms, leading to their greatest genetic diversity. Bacterial restriction-modification (R-M) and CRISPR-Cas are two well-known defense systems that target phage DNAs through their nuclease activities, whereas phages have developed counter-defense systems through covalent modifications of their genomes. Recent studies have revealed many novel nuclease-containing antiphage systems, which leads to the question of what’s the role of phage genome modifications in countering these systems. Here, we scanned Escherichia coli genome sequences available in the NCBI databases and found abundant nuclease-containing defense systems, indicating that phage genomic DNA could be a major target for E. coli to restrict infection. From a collection of 816 E. coli strains, we cloned and validated 14 systems. Particularly, Gabija and type III Druantia systems have broad antiphage activities. Using wild-type phage T4 and its mutants, T4 (hmC) and T4 (C), which contain glucosyl-5-hydroxymethylcytosines, 5-hydroxymethylcytosines, and unmodified cytosines in the genomic DNA respectively, we revealed the complex roles of genomic modification of phage T4 in countering the nuclease-containing defense systems other than simply blocking the degradation of genomic DNA by nuclease.
Optimizing Cryo-FIB Lamellas for sub-5Å in situ Structural Biology
Authors: Khavnekar Sagar , Vrbovská Veronika , Zaoralová Magda , Kelley Ron , Beck Florian , Klumpe Sven , Kotecha Abhay , Plitzko Jürgen , Erdmann Philipp S. 
Published: June 2022

AbstractWe here present a method based on metallic platinum sputtering that can substantially enhance the quality of subtomogram averages from lamellas and thereby reduce the number of particles needed for high-resolution subtomogram averaging. We provide evidence for the physical background of this improvement and demonstrate its usefulness by producing sub-5Å ribosome averages from yeast.