bluuebunny/crossref_metadata_2025_split huggingface dataset:
Common and Rare Variants Associated with Cardiometabolic Traits across 98,622 Whole-Genome Sequences in theAll of UsResearch Program
Authors: Wang Xin , Ryu Justine , Kim Jihoon , Ramirez Andrea , Mayo Kelsey R. ,   All of Us Research Program, Condon Henry , Vaitinadin Nataraja Sarma , Ohno-Machado Lucila , Talavera Greg A. , Ellinor Patrick T. , Lubitz Steven A. , Choi Seung Hoan 
Published: November 2022

AbstractAll of Usis a biorepository aiming to advance biomedical research by providing various types of data in diverse human populations. Here we present a demonstration project validating the program’s genomic data in 98,622 participants. We sought to replicate known genetic associations for three diseases (atrial fibrillation [AF], coronary artery disease, type 2 diabetes [T2D]) and two quantitative traits (height and low-density lipoprotein [LDL]) by conducting common and rare variant analyses. We identified one known risk locus for AF, five loci for T2D, 143 loci for height, and nine loci for LDL. In gene-based burden tests for rare loss-of-function variants, we replicated associations betweenTTNand AF,GIGYF1and T2D,ADAMTS17, ACAN, NPR2and height,APOB, LDLR, PCSK9and LDL. Our results are consistent with previous literature, indicating that theAll of Usprogram is a reliable resource for advancing the understanding of complex diseases in diverse human populations.
miR-210 expression is strongly hypoxia-induced in anaplastic thyroid cancer cell lines and is associated with extracellular vesicles & Argonaute-2
Authors: Powell Bonita H. , Turchinovich Andrey , Wang Yongchun , Gololobova Olesia , Buschmann Dominik , Zeiger Martha A. , Umbricht Christopher B. , Witwer Kenneth W. 
Published: November 2022

ABSTRACTHypoxia, or low oxygen tension, is frequently found in highly proliferative solid tumors such as anaplastic thyroid carcinoma (ATC) and is believed to promote resistance to chemotherapy and radiation. Identifying hypoxic cells for targeted therapy may thus be an effective approach to treating aggressive cancers. Here, we explore the potential of the well-known hypoxia-responsive microRNA (miRNA) miR-210-3p as a cellular and extracellular biological marker of hypoxia. We compare miRNA expression across several ATC and papillary thyroid cancer (PTC) cell lines. In the ATC cell line SW1736, miR-210-3p expression levels indicate hypoxia during exposure to low oxygen conditions (2% O2). Furthermore, when released by SW1736 cells into the extracellular space, miR-210-3p is associated with RNA carriers such as extracellular vesicles (EVs) and Argonaute-2 (AGO2), making it a potential extracellular marker for hypoxia.
Plasticity in centromere organization: Holocentromeres can consist of merely a few megabase-sized satellite arrays
Authors: Kuo Yi-Tzu , Câmara Amanda Souza , Schubert Veit , Neumann Pavel , Macas Jiří , Melzer Michael , Chen Jianyong , Fuchs Jörg , Abel Simone , Klocke Evelyn , Huettel Bruno , Himmelbach Axel , Demidov Dmitri , Dunemann Frank , Mascher Martin , Ishii Takayoshi , Marques André , Houben Andreas 
Published: November 2022

AbstractThe centromere is the chromosome region where the microtubules attach during cell division. In contrast to monocentric chromosomes with one centromere location, holocentric species usually distribute hundreds of centromere units along the entire chromatid. We assembled the chromosome-scale reference genome and analyzed the holocentromere and (epi)genome organization of the lilioidChionographis japonica.Remarkably, each of its holocentric chromatids consists of only 7 to 11 evenly-spaced megabase-sized centromere-specific histone H3-positive units. These units contain satellite arrays of 23 and 28 bp-long monomers capable of forming palindromic structures. Like monocentric species,C. japonicaforms distinctly clustered centromeres in chromocenters at interphase. Additionally, the large-scale eu- and heterochromatin arrangement differs betweenC. japonicaand other known holocentric species. Using polymer simulations, we modeled the formation of prometaphase line-like holocentromeres from interphase centromere clusters. Our findings broaden the knowledge about the diversity of centromere organization, showing that holocentricity is not restricted to species with numerous and small centromere units.
Machine learning analysis of the T cell receptor repertoire identifies sequence features that predict self-reactivity
Authors: Textor Johannes , Buytenhuijs Franka , Rogers Dakota , Gauthier Ève Mallet , Sultan Shabaz , Wortel Inge M. N. , Kalies Kathrin , Fähnrich Anke , Pagel René , Melichar Heather J. , Westermann Jürgen , Mandl Judith N. 
Published: November 2022

SummaryThe T cell receptor (TCR) determines the specificity and affinity for both foreign and self-peptides presented by MHC. It is established that self-pMHC reactivity impacts T cell function, but it has been challenging to identify TCR sequence features that predict T cell fate. To discern patterns distinguishing TCRs from naïve CD4+T cells with low versus high self-pMHC reactivity, we used data from 42 mice to train a machine learning (ML) algorithm that predicts self-reactivity directly from TCRβ sequences. This approach revealed that n-nucleotide additions and acidic amino acids weaken self-reactivity. We tested our ML predictions of TCRβ sequence self-reactivity using retrogenic mice. Extrapolating our analyses to independent datasets, we found high predicted self-reactivity for regulatory CD4+T cells and low predicted self-reactivity for T cells responding to chronic infection. Our analyses suggest a potential trade-off between repertoire diversity and self-reactivity intrinsic to the architecture of a TCR repertoire.
ExposomeX: Integrative Exposomic Platform Expediates Discovery of “Exposure-Biology-Disease” Nexus
Authors: Wang Bin , Lan Changxin , Zhang Guohuan , Ren Mengyuan , Feng Yanqiu , Gao Ning , Lin Weinan , Jiangtulu Bahabake , Liu Zhijian , Shao Xuqiang , Su Shu , Wang Yuting , Wang Han , Zhao Fanrong , Peng Bo , Ji Xiaotong , Chen Xiaojia , Nian Min , Fang Mingliang 
Published: November 2022

ABSTRACTExposome has become the hotspot of next-generation health studies. To date, there is no available effective platform to standardize the analysis of exposomic data. In this study, we aim to propose one new framework of exposomic analysis and build up one novel integrated platform “ExposomeX” to expediate the discovery of the “Exposure-Biology-Disease” nexus. We have developed 13 standardized modules to accomplish six major functions including statistical learning (E-STAT), exposome database search (E-DB), mass spectrometry data processing (E-MS), meta-analysis (E-META), biological link via pathway integration and protein-protein interaction (E-BIO) and data visualization (E-VIZ). Using ExposomeX, we can effectively analyze the multiple-dimensional exposomics data and investigate the “Exposure-Biology-Disease” nexus by exploring mediation and interaction effects, understanding statistical and biological mechanisms, strengthening prediction performance, and automatically conducting meta-analysis based on well-established literature databases. The performance of ExposomeX has been well validated by re-analyzing two previous multi-omics studies. Additionally, ExposomeX can efficiently help discover new associations, as well as relevant in-depth biological pathways via protein-protein interaction and gene ontology network analysis. In sum, we have proposed a novel framework for standardized exposomic analysis, which can be accessed using both R and online interactive platform (http://www.exposomex.cn/).
A new Paleogene fossil and a new dataset for waterfowl (Aves: Anseriformes) clarify phylogeny, ecological evolution, and avian evolution at the K-Pg Boundary
Authors: Musser Grace , Clarke Julia A. 
Published: November 2022

AbstractDespite making up one of the most ecologically diverse groups of living birds, comprising soaring, diving and giant flightless taxa, the evolutionary relationships and ecological evolution of Anseriformes (waterfowl) remain unresolved. Although Anseriformes have a comparatively rich, global Cretaceous and Paleogene fossil record, morphological datasets for this group that include extinct taxa report conflicting relationships for all known extinct taxa. Correct placement of extinct taxa is necessary to understand whether ancestral anseriform feeding ecology was more terrestrial or one of a set of diverse aquatic ecologies and to better understand avian evolution around the K-T boundary. Here, we present a new morphological dataset for Anseriformes that includes more extant and extinct taxa than any previous anseriform-focused dataset and describe a new anseriform species from the early Eocene Green River Formation of North America. The new taxon has a mediolaterally narrow bill which is not known in any previously described anseriform fossils other than portions of the pseudotoothed Pelagornithidae. The matrix created to assess the placement of this taxon comprises 41 taxa and 719 discrete morphological characters describing skeletal morphology, musculature, syringeal morphology, ecology, and behavior. We additionally combine the morphological dataset with published sequences using Bayesian methods and perform ancestral state reconstruction for ecological and behavioral characters. We recover the new Eocene taxon as a stem anseranatid across all analyses, and find that the new taxon represents a novel ecology within known Anseriformes and the Green River taxa. Results indicate that Anseriformes were likely ancestrally aquatic herbivores with rhamphothecal lamellae and provide insight into avian evolution during and following the K-Pg mass extinction.
A three-dimensional, discrete-continuum model of blood pressure in microvascular networks
Authors: Sweeney Paul W. , Walsh Claire , Walker-Samuel Simon , Shipley Rebecca J. 
Published: November 2022

AbstractWe present a 3D discrete-continuum model to simulate blood pressure in large microvascular tissues in the absence of known capillary network architecture. Our hybrid approach combines a 1D Poiseuille flow description for large, discrete arteriolar and venular networks coupled to a continuum-based Darcy model, point sources of flux, for transport in the capillary bed. We evaluate our hybrid approach using a vascular network imaged from the mouse brain medulla/pons using multi-fluorescence high-resolution episcopic microscopy (MF-HREM). We use the fully-resolved vascular network to predict the hydraulic conductivity of the capillary network and generate a fully-discrete pressure solution to benchmark against. Our results demonstrate that the discrete-continuum methodology is a computationally feasible and effective tool for predicting blood pressure in real-world microvascular tissues when capillary microvessels are poorly defined.
BLEND: A Fast, Memory-Efficient, and Accurate Mechanism to Find Fuzzy Seed Matches in Genome Analysis
Authors: Firtina Can , Park Jisung , Alser Mohammed , Kim Jeremie S. , Cali Damla Senol , Shahroodi Taha , Ghiasi Nika Mansouri , Singh Gagandeep , Kanellopoulos Konstantinos , Alkan Can , Mutlu Onur 
Published: November 2022

Generating the hash values of short subsequences, called seeds, enables quickly identifying similarities between genomic sequences by matching seeds with a single lookup of their hash values. However, these hash values can be used only for finding exact-matching seeds as the conventional hashing methods assign distinct hash values for different seeds, including highly similar seeds. Finding only exact-matching seeds causes either 1) increasing the use of the costly sequence alignment or 2) limited sensitivity.We introduceBLEND,the first efficient and accurate mechanism that can identifybothexact-matching and highly similar seeds with a single lookup of their hash values, called fuzzy seed matches. BLEND 1) utilizes a technique called SimHash, that can generate the same hash value for similar sets, and 2) provides the proper mechanisms for using seeds as sets with the SimHash technique to find fuzzy seed matches efficiently.We show the benefits of BLEND when used in read overlapping and read mapping. For read overlapping, BLEND is faster by2.4×−83.9×(on average19.3×),has a lower memory footprint by0.9×−14.1 ×(on average3.8×),and finds higher quality overlaps leading to accuratede novoassemblies than the state-of-the-art tool, minimap2. For read mapping, BLEND is fasterby0.8×−4.1×(on average1.7×)than minimap2. Source code is available athttps://github.com/CMU-SAFARI/BLEND.
Deep-learning-assisted Sort-Seq enables high-throughput profiling of gene expression characteristics with high precision
Authors: Feng Huibao , Li Fan , Wang Tianmin , Xing Xin-hui , Zeng An-ping , Zhang Chong 
Published: November 2022

ABSTRACTAs an essential physiological process, gene expression determines the function of each cell. However, owing to the complex nondeterministic and nonlinear nature of gene expression, the steady-state intracellular protein abundance of a clonal population forms a distribution. The characteristics of this distribution, including expression strength and noise, are closely related to cellular behavior. Therefore, quantitative description of these characteristics is an important goal in biology. This task, however, has so far relied on arrayed methods, which are time-consuming and labor-intensive. To address this issue, we propose a deep-learning-assisted Sort-Seq approach (dSort-Seq) in this work, enabling high-throughput profiling of expression properties with high precision. We demonstrated the validity of dSort-Seq for large-scale assaying of the dose–response relationships of biosensors. In addition, we comprehensively investigated the contribution of transcription and translation to noise production inE. coli, from which we discovered that the expression noise is strongly coupled with the mean expression level instead of translation strength, even in the case of weak transcription. We also discovered that the transcriptional interference caused by overlapping RpoD-binding sites contributes to noise production, which suggested the existence of a simple and feasible noise control strategy inE. coli. Overall, dSort-Seq is able to efficiently determine the strength-noise landscape, which has promising applications in studies related to gene expression.
Evaluating spatially variable gene detection methods for spatial transcriptomics data
Authors: Chen Carissa , Kim Hani Jieun , Yang Pengyi 
Published: November 2022

AbstractThe identification of genes that vary across spatial domains in tissues and cells is an essential step for spatial transcriptomics data analysis. Given the critical role it serves for downstream data interpretations, various methods for detecting spatially variable genes (SVGs) have been proposed. The availability of multiple methods for detecting SVGs bears questions such as whether different methods select a similar set of SVGs, how reliable is the reported statistical significance from each method, how accurate and robust is each method in terms of SVG detection, and how well the selected SVGs perform in downstream applications such as clustering of spatial domains. Besides these, practical considerations such as computational time and memory usage are also crucial for deciding which method to use. In this study, we address the above questions by systematically evaluating a panel of popular SVG detection methods on a large collection of spatial transcriptomics datasets, covering various tissue types, biotechnologies, and spatial resolutions. Our results shed light on the performance of each method from multiple aspects and highlight the discrepancy among different methods especially on calling statistically significant SVGs across datasets. Taken together, our work provides useful considerations for choosing methods for identifying SVGs and serves as a key reference for the future development of such methods.
Dopamine neurons that informDrosophilaolfactory memory have distinct, acute functions driving attraction and aversion
Authors: Mohammad Farhan , Mai Yishan , Ho Joses , Zhang Xianyuan , Ott Stanislav , Stewart James Charles , Claridge-Chang Adam 
Published: November 2022

AbstractThe brain must guide immediate responses to beneficial and harmful stimuli while simultaneously writing memories for future reference. While both immediate actions and reinforcement learning are instructed by dopamine, how dopaminergic systems maintain coherence between these two reward functions is unknown. Through optogenetic activation experiments, we showed that the dopamine neurons that inform olfactory memory inDrosophilahave a distinct, parallel function driving attraction and aversion (valence). Sensory neurons required for olfactory memory were dispensable to dopaminergic valence. A broadly projecting set of dopaminergic cells had valence that was dependent on dopamine, glutamate, and octopamine. Similarly, a more restricted dopaminergic cluster with attractive valence was reliant on dopamine and glutamate; flies avoided opto-inhibition of this narrow subset, indicating the role of this cluster in controlling ongoing behavior. Dopamine valence was distinct from output-neuron opto-valence in locomotor pattern, strength, and polarity. Overall our data suggest that dopamine’s acute effect on valence provides a mechanism by which a dopaminergic system can coherently write memories to influence future responses while guiding immediate attraction and aversion.
Genetic ablation of a female specific Apetala 2 transcription factor blocks oocyst shedding inCryptosporidium parvum
Authors: Tandel Jayesh , Walzer Katelyn A. , Byerly Jessica H. , Pinkston Brittain , Beiting Daniel P. , Striepen Boris 
Published: November 2022

The apicomplexan parasiteCryptosporidiumis a leading global cause of diarrheal disease, and the infection poses a particularly grave threat to young children and those with weakened immune function. Infection occurs by ingestion of meiotic spores called oocysts, and transmission relies on fecal shedding of new oocysts. The entire lifecycle thus occurs in a single host and features asexual as well as sexual forms of replication. Here we identify and locus tag two Apetala 2-type (AP2) transcription factors and demonstrate that they are exclusively expressed in male and female gametes, respectively. To enable functional studies of essential genes inC. parvumwe develop and validate a small molecule inducible gene excision system, which we apply to the female factor AP2-F to achieve conditional gene knock out. Analyzing this mutant, we find the factor to be dispensable for asexual growth and early female fate determination in vitro, but to be required for oocyst shedding in infected animals in vivo.Transcriptional analyses conducted in the presence or absence of AP2-F revealed that the factor controls the transcription of genes encoding crystalloid body proteins, which are exclusively expressed in female gametes. InC. parvum, the organelle is restricted to sporozoites, and its loss in other apicomplexan parasites leads to blocked transmission. Overall, our development of conditional gene ablation inC. parvumprovides a robust method for genetic analysis in this parasite that enabled us to identify AP2-F as an essential regulator of transcription required for oocyst shedding and transmission.
A systematic review of gene editing clinical trials
Authors: Eshka Sahar Fallah Akbarpoor , Bahador Mina , Gordan Mohammad Mahdi , Karbasi Sara , Tabar Zahra Mahmoudi , Basiri Mohsen 
Published: November 2022

AbstractGene editing technologies such as zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), and clustered regularly interspaced short palindromic repeats (CRISPR) have revolutionized genetic engineering and now are being used in clinical gene therapy. We systematically reviewed gene editing clinical trials fromClinicalTrials.govusing a searching strategy that included all different gene editing technologies, followed by two rounds of independent assessment based on the inclusion and exclusion criteria, data extraction, and review of the background publications. 76 trials met our inclusion criteria including 30 studies on genetically engineered T-cell therapies for cancer, 19 studies on virus infections, and 26 studies on monogenic diseases. We have also analyzed the proportions to which different gene editing and gene delivery methods are used. We observed a growing trend of registered CRISPR-based trials indicating a raising interest in developing new therapeutic methods based on this technology. Overall, our study showed that there are promising phase-I and -II trials testing the safety and feasibility of gene editing in different clinical settings.
User feedback on the NHS Test & Trace Service during COVID-19: the use of machine learning to analyse free-text data from 37,914 UK adults
Authors: Bondaronek P , Papakonstantinou T , Stefanidou C , Chadborn T 
Published: November 2022

AbstractObjectivesThe UK government’s approach to the pandemic relies on a test, trace and isolate strategy, mainly implemented via the digital NHS Test & Trace Service. Feedback on user experience is central to the successful development of public-facing services. As the situation dynamically changes and data accumulate, interpretation of feedback by humans becomes time-consuming and unreliable. The specific objectives were to 1) evaluate a human-in-the-loop machine learning technique based on structural topic modelling in terms of its serviceability in the analysis of vast volumes of free-text data, 2) generate actionable themes that can be used to increase user satisfaction of the Service.MethodsWe evaluated an unsupervised Topic Modelling approach, testing models with 5-40 topics and differing covariates. Two human coders conducted thematic analysis to interpret the topics. We identified a Structural Topic Model with 25 topics and metadata as covariates as the most appropriate for acquiring insights.ResultsResults from analysis of feedback by 37,914 users from May 2020 to March 2021 highlighted issues with the Service falling within three major themes: multiple contacts and incompatible contact method and incompatible contact method, confusion around isolation dates and tracing delays, complex and rigid system.ConclusionsStructural Topic Modelling coupled with thematic analysis was found to be an effective technique to rapidly acquire user insights. Topic modelling can be a quick and cost-effective method to provide high quality, actionable insights from free-text feedback to optimize public health services.