bluuebunny/crossref_metadata_2025_split huggingface dataset:
IGHV allele similarity clustering improves genotype inference from adaptive immune receptor repertoire sequencing data
Authors: Peres Ayelet , Lees William D. , Rodriguez Oscar L. , Lee Noah Y. , Polak Pazit , Hope Ronen , Kedmi Meirav , Collins Andrew M. , Ohlin Mats , Kleinstein Steven H. , Watson Corey T , Yaari Gur 
Published: December 2022

AbstractIn adaptive immune receptor repertoire analysis, determining the germline variable (V) allele associated with each T- and B-cell receptor sequence is a crucial step. This process is highly impacted by allele annotations. Aligning sequences, assigning them to specific germline alleles, and inferring individual genotypes are challenging when the repertoire is highly mutated, or sequence reads do not cover the whole V region.Here, we propose an alternative naming scheme for the V alleles as well as a novel method to infer individual genotypes. We demonstrate the strength of the two by comparing their outcomes to other genotype inference methods and validated the genotype approach with independent genomic long read data.The naming scheme is compatible with current annotation tools and pipelines. Analysis results can be converted from the proposed naming scheme to the nomenclature determined by the International Union of Immunological Societies (IUIS). Both the naming scheme and the genotype procedure are implemented in a freely available R package (PIgLET). To allow researchers to explore further the approach on real data and to adapt it for their future uses, we also created an interactive website (https://yaarilab.github.io/IGHV_reference_book).
Quantitative analysis of morphogenesis and growth dynamics in an obligate intracellular bacterium
Authors: Figueroa-Cuilan Wanda M. , Irazoki Oihane , Feeley Marissa , Smith Erika , Nguyen Trung , Cava Felipe , Goley Erin D. 
Published: December 2022

ABSTRACTObligate intracellular bacteria of the order Rickettsiales include numerous arthropod-borne human pathogens. However, our understanding of the basic biology ofRickettsiaspecies is limited by technical challenges imposed by their obligate intracellular lifestyle. To overcome this roadblock, we developed quantitative methods to assess the cell wall composition, intracellular growth, and morphology ofRickettsia parkeri, a human pathogen in the Spotted Fever Group of theRickettsiagenus. Analysis of the cell wall composition ofR. parkerirevealed unique features including a high M3 monomer fraction and absence of LD-crosslinks. Using a novel fluorescence microscopy approach, we quantified the cell morphology ofR. parkeriin live host cells and found that bacterial morphology is maintained stably during exponential growth in two different epithelial cell lines. To assess population growth kinetics in a high-throughput and high-resolution manner, we developed an imaging-based growth assay and applied this to determine the growth rate of up to 24 infected cultures at a time. We also sought to gain insight into the cell cycle regulation ofR. parkeri. To this end, we developed methods to quantify the fraction of the population preparing to divide as well as those undergoing active constriction. These approaches permitted a quantitative analysis of cell cycle status across a population ofR. parkeri.Finally, as a proof of concept, we applied the above tools to quantitatively determine how MreB, a bacterial actin homolog, contributes to the growth and morphogenesis ofR. parkeri. Inhibition of MreB with the small molecule MP265 led to cell rounding and slowed growth, suggesting that MreB is required for the growth and shape maintenance ofR. parkeri. Collectively, we developed a toolkit of high-throughput, quantitative tools to understand intracellular growth and morphogenesis ofR. parkerithat is translatable to other obligate intracellular bacteria.AUTHOR SUMMARYThe obligate intracellular lifestyle of members of the bacterial order Rickettsiales, which includes important human pathogens, has hindered our progress in understanding their biology. Here we developed and applied high-throughput, quantitative tools to analyze essential features of rickettsial cell biology such as morphology and growth in living host cells. By applying these tools in a proof of concept, we showed that the bacterial actin homolog, MreB is required for the regulation of rod shape and intracytoplasmic growth.
Dysregulation of murine long non-coding single cell transcriptome in non-alcoholic steatohepatitis and liver fibrosis
Authors: Karri Kritika , Waxman David J. 
Published: December 2022

SummaryLncRNAs are typified by low expression, nuclear enrichment, high tissue-specificity and functional diversity, but the vast majority are uncharacterized. Here, we develop a catalog of 48,000 mouse liver-expressed lncRNAs and use to elucidate lncRNA dysregulation in high fat diet-induced non-alcoholic steatohepatitis and carbon tetrachloride-induced liver fibrosis by single cell RNA-seq. LncRNA zonation patterns across the liver lobule were discovered in five cell populations. Perturbations in lncRNA expression were common in disease-associated cell types, including non-alcoholic steatohepatitis-associated macrophages, a hallmark of fatty liver disease progression, and collagen-producing myofibroblasts, key to liver fibrosis. Gene regulatory network analysis linked individual lncRNAs to biological pathways and network centrality metrics identified network-essential, disease-associated regulatory lncRNAs. Regulatory lncRNAs with network-predicted target gene promoters enriched for triplex-based lncRNA binding were also identified. These findings elucidate hepatic lncRNA cell-type specificities, spatial zonation patterns, linked biological networks and dysregulation in disease progression. A subset of the disease-associated lncRNAs have human orthologs and are promising candidates for biomarkers and therapeutic targets.
The interplay between adsorption and aggregation of von Willebrand factor chains in shear flows
Authors: Amaya-Espinosa Helman , Alexander-Katz Alfredo , Aponte-Santamaría Camilo 
Published: December 2022

AbstractVon Willebrand factor (VWF) is a giant extracellular glycoprotein that carries out a key adhesive function during primary hemostasis. Upon vascular injury and triggered by the shear of flowing blood, VWF establishes specific interactions with several molecular partners in order to anchor platelets to collagen on the exposed sub-endothelial surface. VWF also interacts with itself to form aggregates that, adsorbed on the surface, provide more anchor sites for the platelets. However, the interplay between elongation and subsequent exposure of cryptic binding sites, self-association, and adsorption on the surface, remained unclear for VWF. In particular, the role of shear flow in these three processes is not well understood. In this study, we address these questions by using Brownian dynamics simulations at a coarse-grained level of resolution. We considered a system consisting of multiple VWF-like self-interacting chains that also interact with a surface under a shear flow. By a systematic analysis, we reveal that chain-chain and chain-surface interactions coexist non-trivially to modulate the spontaneous adsorption of VWF and the posterior immobilization of secondary tethered chains. Accordingly, these interactions tune VWF’s extension and its propensity to form shear-assisted functional adsorbed aggregates. Our data highlights the collective behavior VWF self-interacting chains have when bound to the surface, distinct from that of isolated or flowing chains. Furthermore, we show that the extension and the exposure to solvent have a similar dependence on shear flow, at a VWF-monomer level of resolution. Overall, our results highlight the complex interplay that exists between adsorption, cohesion, and shear forces and its relevance for the adhesive hemostatic function of VWF.
Synanthropic flora in the vicinity of the mediaeval Castle Kolno, Stare Kolnie near Brzeg, southwestern Poland
Authors: Kosina Romuald , Marek Lech 
Published: December 2022

AbstractThe mediaeval castle Kolno situated near the village Stare Kolnie served as a custom house at the confluence of two rivers, Budkowiczanka and Stobrawa. Numerous diaspores of plants were obtained from the archaeological excavations, from the layers of the 14th-15th centuries A.D. The excavations were located near the former access road, where increased human activity has affected the composition of the fossil macroremains of plants. Two species of cabbage cultivated in small fields near the castle were recognised. Diaspores of weeds and ruderal plants were deposited at the site. The most frequent were:Solanum nigrum, Setaria pumila, Chenopodium album, Rumex acetosella, Polygonum lapathifoliumandUrtica dioica. The botanical set of fossil diaspores was composed of plant species associated with anthropogenic habitats and showing the dispersion dynamics in various micro-niches within them.
Dissociation of direct and peripheral transcranial magnetic stimulation effects in nonhuman primates
Authors: Perera Nipun D , Alekseichuk Ivan , Shirinpour Sina , Wischnewski Miles , Linn Gary , Masiello Kurt , Butler Brent , Russ Brian E , Schroeder Charles E , Falchier Arnaud , Opitz Alexander 
Published: December 2022

ABSTRACTTranscranial magnetic stimulation (TMS) is a non-invasive brain stimulation method that is rapidly growing in popularity for studying causal brain-behavior relationships. However, its dose-dependent direct neural mechanisms, i.e., due to electric field or connectivity, and peripheral sensory co-stimulation effects remain debated. Understanding how TMS stimulation parameters affect brain responses is vital for the rational design of TMS protocols. Studying these mechanisms in humans is challenging due to the limited spatiotemporal resolution of available non-invasive neuroimaging methods. Here, we leverage invasive recordings of local field potentials in non-human primates to study TMS mesoscale responses. We demonstrate that early TMS-evoked potentials show a sigmoidal dose-response with stimulation intensity. We further show that stimulation responses are spatially specific. We employ several control conditions to dissociate direct neural responses from auditory and somatosensory co-activation. These results provide crucial evidence regarding TMS neural effects at the brain circuit level. Our findings are highly relevant for interpreting human TMS studies and biomarker developments for TMS target engagement in clinical applications.
Development and evaluation of a scalable alternative to chart review for phenotype case adjudication using standardized structured data from electronic health records
Authors: Ostropolets Anna , Hripcsak George , Husain Syed A , Richter Lauren , Spotnitz Matthew , Elhussein Ahmed , Ryan Patrick B 
Published: December 2022

ABSTRACTObjectiveChart review as the current gold standard for phenotype evaluation cannot support observational research at scale. It is expensive, time-consuming, and variable. We aimed to evaluate the ability of structured data to support efficient patient status ascertainment and develop a standardized and scalable alternative to chart review.MethodsWe developed Knowledge-Enhanced Electronic Patient Profile Review system (KEEPER) that extracts a patient’s structured data elements relevant to a given phenotype and presents them in a standardized fashion that follows clinical reasoning principles. We evaluated its performance compared to manual chart review for four conditions (diabetes type I, acute appendicitis, end stage renal disease and chronic obstructive lung disease) using randomized two-period, two-sequence crossover design. Inter-method agreement, inter-rater agreement, accuracy, and review duration were measured.ResultsAscertaining patient status with KEEPER was twice as fast compared to manual chart review. 88.1% of the patients were classified concordantly using full chart and KEEPER, but agreement varied depending on the condition. Pairs of clinicians agreed in classification of patient status in 91.2% of the cases when using KEEPER compared to 76.3% when using full chart. Patient classification aligned with the gold standard in 88.1% and 86.9% of the cases respectively.ConclusionThis proof-of-concept study demonstrated that structured data can be used for efficient patient ascertainment if are limited to only relevant subset and organized according to the clinical reasoning principles. A system that implements these principles can achieve similar accuracy and higher inter-rater reliability compared to chart review at a fraction of time.
Tryptophan metabolism, gut microbiota, and carotid artery plaque in women with and without HIV infection
Authors: Luo Kai , Wang Zheng , Peters Brandilyn A , Hanna David B , Wang Tao , Sollecito Christopher C , Grassi Evan , Wiek Fanua , Peter Lauren St , Usyk Mykhaylo , Post Wendy S , Landay Alan L , Hodis Howard N , Weber Kathleen M , French Audrey , Golub Elizabeth T , Lazar Jason , Gustafson Deborah , Sharma Anjali , Anastos Kathryn , Clish Clary B , Knight Rob , Kaplan Robert C , Burk Robert D , Qi Qibin 
Published: December 2022

AbstractBackgroundThe perturbation of tryptophan (TRP)-kynurenine (KYN) metabolism has been linked with HIV infection and cardiovascular disease (CVD), but the interrelationship among TRP metabolites, gut microbiota, and atherosclerosis has not yet been fully understood in the context of HIV infection.MethodsWe included 361 women (241 HIV+, 120 HIV-) with carotid artery plaque assessments from the Women’s Interagency HIV Study, measured ten plasma TRP metabolites and profiled fecal gut microbiome. TRP metabolites related gut microbial features were selected through the Analysis of Compositions of Microbiomes with Bias Correction method. The associations of TRP metabolites and related microbial features with plaque were examined using multivariable logistic regression.ResultsWhile plasma kynurenic acid (KYNA) (odds ratio [OR]=1.93[1.12, 3.32] per one SD increase,P=0.02) and KYNA/TRP (OR=1.83[1.08, 3.09],P=0.02) were positively associated with plaque, indole-3-propionate (IPA) (OR=0.62 [0.40, 0.98],P=0.03) and IPA/KYNA (OR=0.51[0.33, 0.80],P<0.01) were inversely associated with plaque. Five gut bacterial genera and many affiliated species were positively associated with IPA (FDR-q<0.25), includingRoseburia sp.,Eubacterium sp.,Lachnospira sp., andCoprobacter sp.; but no bacterial genera were found to be associated with KYNA. Furthermore, an IPA-associated-bacteria score was inversely associated with plaque (OR=0.47[0.28, 0.79],P<0.01). But no significant effect modification by HIV serostatus was observed in these associations.ConclusionsIn a cohort of women living with and without HIV infection, plasma IPA levels and related gut bacteria were inversely associated with carotid artery plaque, suggesting a potential beneficial role of IPA and its gut bacterial producers in atherosclerosis and CVD.
Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors
Authors: Iyer Sudarshan R. , Nusser Kevin , Jones Kristen , Shinde Pushkar , Beach Catherine Z. , Keddy Clare , Aguero Erin , Force Jeremy , Shinde Ujwal , Davare Monika A. 
Published: December 2022

AbstractChromosomal rearrangements ofROS1generate ROS1 tyrosine kinase fusion proteins that are established oncogenes predicting effectiveness of tyrosine kinase inhibitors (TKI) treatment. The cancer genome reveals nonsynonymous missense mutations inROS1,however, their oncogenic potential remains unknown. We nominated thirty-four tumor-associated missense mutations in ROS1 kinase domain for functional interrogation. Immunoblotting revealed diverse impact of the mutations on the kinase, ranging from loss of function to significant increase in catalytic activity. Notably, Asn and Gly substitutions at the Asp-2113 position in ROS1 kinase domain were TKI- sensitive hyper-activating mutations, and transformative oncogenes in independent cell models. Molecular modeling revealed drastic alterations in the activation loop of ROS1D2113Ncompared to wildtype kinase. Proteomics studies showed that ROS1D2113Nincreases phosphorylation of known effectors akin to ROS1 fusions, and upregulates pathways not previously linked to ROS1, including mTORC2, JNK1/2, AP-1, TGFB1 and CCN1/2.In vivo, ROS1D2113Ndrove tumor formation that was sensitive to inhibition by crizotinib and lorlatinib. Taken together, these data show that select point mutations within ROS1 RTK are oncogenic, and maybe therapeutically targetable with FDA-approved TKI.
SCIP: a self-paced, community-based summer coding program creates community and increases coding confidence, lessons learned from the pandemic
Authors: Reyes Rochelle-Jan , Pham Olivia , Fergusson Ryan , Ceberio Niquo , Clark Candace , Cohen C Sarah , Fuse Megumi , Pennings Pleuni 
Published: December 2022

AbstractIn 2020, many students lost summer opportunities due to the COVID-19 pandemic. We wanted to offer students an opportunity to learn computational skills and be part of a community while they were stuck at home. Because the pandemic was very isolating, it was important to support students to learn and build community online. We used lessons learned from literature and our own experience to design, run and test an online program for students called the Science Coding Immersion Program (SCIP). In our program, students worked in small teams for 8 hours a week spread over the week, with one participant as the team leader and Zoom host. Teams worked on an online R or Python class at their own pace with support on Slack from the organizing team. For motivation and career advice, we hosted a weekly webinar with guest speakers. We used pre- and post-program surveys to determine how different aspects of the program impacted students. We were able to recruit a large and diverse group of participants who were happy with the program, found community in their team, and improved their coding confidence. We hope that our work will inspire others to start their own version of SCIP.
In situ genetically targeted chemical assembly of polymers on living neuronal membranes
Authors: Zhang Anqi , Loh Kang Yong , Kadur Chandan S. , Michalek Lukas , Dou Jiayi , Ramakrishnan Charu , Bao Zhenan , Deisseroth Karl 
Published: December 2022

AbstractMulticellular biological systems, most notably living neural networks, exhibit highly complex physical organization properties that pose challenges for building cell-specific and biocompatible interfaces. We developed a novel approach to genetically program cells to chemically assemble artificial structures that modify the electrical properties of neuronsin situ, opening up the possibility of minimally-invasive cell-specific interfaces with neural circuits in living animals. However, the efficiency and biocompatibility of this approach were challenged by limited membrane targeting of the constructed material. Here, we report a method with significantly improved molecular construct properties, which expresses highly localized enzymes targeted to the plasma membrane of primary neurons with minimal intracellular retention. Polymers synthesizedin situby this approach form dense clusters on the targeted cell membrane, and neurons remain viable after polymerization. This platform can be readily extended to incorporate a broad range of materials onto the surface membranes of specific cells within complex tissues, using chemistry that may further enable the next generation of interfaces with living biological systems.
Genetically-encoded photosensitizers enable light-controlled polymerization on living neuronal membranes
Authors: Zhang Anqi , Kadur Chandan S. , Ramakrishnan Charu , Bao Zhenan , Deisseroth Karl 
Published: December 2022

AbstractThe ability to record, stimulate, and modify brains of living animals would unlock numerous research opportunities and create potential clinical interventions, but it is difficult to interface with a living neural network without damaging it. We previously reported a novel approach to building neural interfaces, namely: genetically programming cells to build artificial structures to modify the electrical properties of neuronsin situ, which opens up the possibility of modifying neural circuits in living animals without surgery. However, the spatiotemporal resolution, efficiency, and biocompatibility of this approach were still limited and lacked selectivity on cell membrane. Here, we demonstrate an approach using genetically-targeted photosensitizers to instruct living cells to synthesize functional materials directly on the plasma membrane under the control of light. Polymers synthesized by this approach were selectively deposited on the membrane of targeted live neurons. This platform can be readily extended to incorporate a broad range of light-controlled reactions onto specific cells, which may enable researchers to grow seamless, dynamic interfaces directly in living animals.
Refinement of AlphaFold-Multimer structures with single sequence input
Authors: Oda Toshiyuki 
Published: December 2022

AbstractAlphaFold2, introduced by DeepMind in CASP14, demonstrated outstanding performance in predicting protein monomer structures. It could model more than 90% of targets with high accuracy, and so the next step would surely be multimer predictions, since many proteins do not act by themselves but with their binding partners. After the publication of AlphaFold2, DeepMind published AlphaFold-Multimer, which showed excellent performance in predicting multimeric structures. However, its accuracy still has room for improvement compared to that of monomer predictions by AlphaFold2. In this paper, we introduce a fine-tuned version of AlphaFold-Multimer, named AFM-Refine-G, which uses structures predicted by AlphaFold-Multimer as inputs and produces refined structures without the help of multiple sequence alignments or templates. The performance of AFM-Refine-G was assessed using four datasets: Ghani_et_al_Benchmark2 and Yin_et_al_Hard using AlphaFold-Multimer version 2.2 outputs, and CASP15_multimer and Yin_and_Pierce_af23 using AlphaFold-Multimer version 2.3 outputs. Of 1925 predicted structures, 203 had DockQ improvement > 0.05 after refinement, demonstrating that our model is useful for the refinement of multimer structures. However, considering the per target success rate, the overall improvement was modest, suggesting that the original AlphaFold-Multimer network had already learned a biophysical energy function independent of MSAs or templates, as proposed by Roney and Ovchinnikov (Roney and Ovchinnikov, 2022). Furthermore, both the default AlphaFold-Multimer and our refinement model showed lower performance for immune-related targets compared to general targets, indicating that room for improvement remains.AvailabilityThe inference scripts are available fromhttps://github.com/t-oda-ic/afm_refinerunder the Apache License, Version 2.0. The network parameters are available fromhttps://figshare.com/articles/online_resource/afm_refine_g_20230110_zip/21856407under the license CC BY 4.0.