bluuebunny/crossref_metadata_2025_split huggingface dataset:
MAGqual: A standalone pipeline to assess the quality of metagenome-assembled genomes
Authors: Cansdale Annabel , Chong James P.J. 
Published: December 2023

AbstractMetagenomics, the whole genome sequencing of microbial communities, has provided insight into complex ecosystems. It has facilitated the discovery of novel microorganisms, explained community interactions, and found applications in various fields. Advances in high-throughput and third-generation sequencing technologies have further fuelled its popularity. Nevertheless, managing the vast data produced and addressing variable dataset quality remain ongoing challenges. Another challenge arises from the number of assembly and binning strategies used across studies. Comparing datasets and analysis tools is complex as it requires a measure of metagenome quality. The inherent limitations of metagenomic sequencing, which often involves sequencing complex communities means community members are challenging to interrogate with traditional culturing methods leading to many lacking reference sequences.The MIMAG standards (Bowerset al., 2017) aim to provide a method to assess metagenome quality for comparison but have not been widely adopted. To bridge this gap, the MAGqual pipeline outlined here offers an accessible way to evaluate metagenome quality and generate metadata on a large scale. MAGqual is built in Snakemake to ensure readability and scalability and its open-source nature promotes accessibility, community development, and ease of updates. Here, we introduce the pipeline MAGqual (metagenome-assembled genome qualifier) and demonstrate its effectiveness at determining metagenomic dataset quality when compared to the MIMAG standards. MAGqual is built in Snakemake, R, and Python and is available under the MIT License on GitHub athttps://github.com/ac1513/MAGqual.
Melanoma innervation is associated with cancer progression in a zebrafish xenograft model
Authors: Lorenzini Francesca , Marines Johanna , Friec Julien Le , Do Khoa Nam , Nieto Maria Angela , Sanchez-Laorden Berta , Mione Maria Caterina , Fontenille Laura , Kissa Karima 
Published: December 2023

AbstractThe peripheral nervous system has a key role in regulating tumour biology in different types of cancer. Here, by modelling aggressive melanoma in larval zebrafish xenografts, we highlight the dynamics of tumour innervation in the tumour microenvironment (TME). Axonogenesis and dendritogenesis are detected in the motoneurons surrounding the melanoma niche and neurogenesis is observed in the nearby population of the enteric nervous system. We also demonstrate the crucial role of catecholamines in promoting melanoma progression, supportingin vivocancer cell dissemination and invasion. Thiszebrafishmodel will allow to uncover neural markers associated with melanoma progression to help in the design of innovative anti-neurogenic therapies targeting specifically the neuronal signals that regulate melanoma progression.Graphical abstractHighlightsTransplantation of human melanoma cells in 3 dpf zebrafish swim bladder allows the development of aggressive melanoma, which cells invade the surrounding organs and migrate over distant locations.The presence of melanoma cells in the larval zebrafish induces morphological changes in the motoneurons inside the tumour niche, including increased axon length and dendritic arborization.The invasion of melanoma cells in the larval intestine promotes neurogenesis of enteric neurons.Transplanted melanoma cells display direct contact with enteric neurons in the intestinal region and migrate along axons to escape from the primary cancer mass, as a mechanism similar to vessel co-option during metastatic dissemination.Catecholamines promote melanoma cell migration and invasion in the zebrafish, modelling melanoma progression.
chronODE: A framework to integrate time-series multi-omics data based on ordinary differential equations combined with machine learning
Authors: Borsari Beatrice , Frank Mor , Wattenberg Eve S. , Xu Ke , Liu Susanna X. , Yu Xuezhu , Gerstein Mark 
Published: December 2023

AbstractMost functional genomic studies are conducted in steady-state conditions, therefore providing a description of molecular processes at a particular moment of cell differentiation or organismal development. Longitudinal studies can offer a deeper understanding of the kinetics underlying epigenetic events and their contribution to defining cell-type-specific transcriptional programs. Here we developchronODE, a mathematical framework based on ordinary differential equations that uniformly models the kinetics of temporal changes in gene expression and chromatin features.chronODEemploys biologically interpretable parameters that capture tissue-specific kinetics of genes and regulatory elements. We further integrate this framework with a neural-network architecture that can link and predict changes across different data modalities by solving multivariate time-series regressions. Next, we apply this framework to investigate region-specific kinetics of epigenome rewiring in the developing mouse brain, and we demonstrate that changes in chromatin accessibility within regulatory elements can accurately predict changes in the expression of putative target genes over the same time period. Finally, by integrating single-cell ATAC-seq data generated during the same time course, we show that regulatory elements characterized by fast activation kinetics in bulk measurements are active in early-appearing cell types, such as radial glial and other neural progenitors, whereas elements characterized by slow activation kinetics are specific to more differentiated cell types that emerge at later stages of brain development.
Characterization of bovine vaginal microbiota and its relationship with host fertility, health, and production
Authors: Brulin L , Ducrocq S , Even G , Sanchez MP , Martel S , Merlin S , Audebert C , Croiseau P , Estellé J 
Published: December 2023

AbstractBackgroundBecause of its potential influence on the host’s phenotype, increasing attention is paid to organ-specific microbiota in several animal species, including cattle. However, ecosystems other than those related to the digestive tract remain largely understudied. In particular, little is known about the vaginal microbiota of ruminants despite the importance of the reproductive functions of cows in a livestock context, where fertility disorders represent one of the primary reasons for culling.ResultsIn the present study, we aimed at better characterizing the vaginal microbiota of dairy cows through 16S rRNA sequencing, using a large cohort of Holstein cows from Northern France. Our results allowed to define a core microbiota of the dairy cows’ vagina, and highlighted that 90% of the sequences belonged to the Firmicutes, the Proteobacteria, and the Bacteroidetes phyla. The core microbiota was composed of four phyla, 16 families, 14 genera and only one amplicon sequence variant (ASV), supporting the idea of the high diversity of vaginal microbiota within the studied population. This variability was partly explained by various environmental factors such as the herd, the sampling season, the lactation rank and the lactation stage. In addition, we investigated potential associations between the diversity and the composition of the vaginal microbiota and several health-, performance-, and fertility-related phenotypes. Our analyses highlighted significant associations between the α and β- diversities and several traits including the first insemination outcome, the productive longevity, and the culling. Besides, relevant phenotypes were correlated with the abundance of several genera, some of which, such asLeptotrichia,Streptobacillus,Methylobacterium-Methylorubrum, orNegativibacillus, were linked to multiple traits.ConclusionConsidering the large number of samples, which were collected in commercial farms, and the diversity of the phenotypes considered, this study represents a first step towards a better understanding of the close relationship between the vaginal and the dairy cow’s phenotypes.
Biosynthesis of Strained Amino Acids Through a PLP-Dependent Enzyme via Cryptic Halogenation
Authors: Sosa Max B. , Leeman Jacob T. , Washington Lorenzo J. , Scheller Henrik V. , Chang Michelle C. Y. 
Published: December 2023

AbstractAmino acids (AAs) are modular and modifiable building blocks which nature uses to synthesize both macromolecules, such as proteins, and small molecule natural products, such as alkaloids and non-ribosomal peptides (NRPs). While the 20 main proteinogenic AAs display relatively limited side-chain diversity, a wide range of non-canonical amino acids (ncAAs) exist that are not used by the ribosome for protein synthesis but contain a broad array of structural features and functional groups not found in proteinogenic AAs. In this communication, we report the discovery of the biosynthetic pathway for a new ncAA, pazamine, which contains a cyclopropane ring formed in two steps. In the first step, a chlorine is added onto the C4position of lysine by a radical halogenase PazA. The cyclopropane ring is then formed in the next step by a pyridoxal-5’-phosphate-dependent enzyme, PazB, via an SN2-like attack onto C4to eliminate chloride. Genetic studies of this pathway in the native host,Pseudomonas azotoformans, show that pazamine and its succinylated derivative, pazamide, potentially inhibit ethylene biosynthesis in growing plants based on alterations in the root phenotype ofArabidopsis thalianaseedlings. We further show that PazB can be utilized to make an alternative cyclobutane-containing AA. These discoveries may lead to advances in biocatalytic production of specialty chemicals and agricultural biotechnology.
Pigs are highly susceptible to but do not transmit mink-derived highly pathogenic avian influenza virus H5N1 clade 2.3.4.4b
Authors: Kwon Taeyong , Trujillo Jessie D. , Carossino Mariano , Lyoo Eu Lim , McDowell Chester D. , Cool Konner , Matias-Ferreyra Franco S. , Jeevan Trushar , Morozov Igor , Gaudreault Natasha N. , Balasuriya Udeni B.R. , Webby Richard J. , Osterrieder Nikolaus , Richt Juergen A. 
Published: December 2023

AbstractRapid evolution of highly pathogenic avian influenza viruses (HPAIVs) is driven by antigenic drift but also by reassortment, which might result in robust replication in and transmission to mammals. Recently, spillover of clade 2.3.4.4b HPAIV to mammals including humans, and their transmission between mammal species has been reported. This study aimed to evaluate the pathogenicity and transmissibility of a mink-derived clade 2.3.4.4b H5N1 HPAIV isolate from Spain in pigs. Experimental infection caused moderate to severe interstitial pneumonia with necrotizing bronchiolitis with high titers of virus present in the lower respiratory tract of principal-infected pigs and 100% seroconversion. Principal-infected pigs shed limited amount of virus through the nasal and oral cavities, and importantly, there was no transmission to contact sentinel pigs. Notably, critical mammalian-like mutations such as PB2-E627K and HA-Q222L emerged at low frequencies in clinical samples and tissues derived from principal-infected pigs. It is concluded that pigs are highly susceptible to infection with the mink-derived clade 2.3.4.4b H5N1 HPAIV and provide a favorable environment for HPAI viruses to acquire mammalian-like adaptations. This work is critical for further risk assessment on the ability of the newly emerging H5N1 clade 2.3.4.4b HPAIVs to cross the species barriers into mammals.
ATOM-1: A Foundation Model for RNA Structure and Function Built on Chemical Mapping Data
Authors: Boyd Nicholas , Anderson Brandon M. , Townshend Brent , Chow Ryan , Stephens Connor J. , Rangan Ramya , Kaplan Matias , Corley Meredith , Tambe Akshay , Ido Yuzu , Yukich Jake , Tcheau Tabitha , Abdeldayem Ayah , Ferns Gabriel , Patel Harsh , Barman Shaon , Schleck April , Sanborn Adrian L. , Eismann Stephan , Townshend Raphael J. L. 
Published: December 2023

AbstractRNA-based medicines and RNA-targeting drugs are emerging as promising new approaches for treating disease. Optimizing these therapeutics by naive experimental screening is a time-consuming and expensive process, while rational design requires an accurate understanding of the structure and function of RNA. To address this design challenge, we present ATOM-1, the first RNA foundation model trained on chemical mapping data, enabled by data collection strategies purposely developed for machine learning training. Using small probe neural networks on top of ATOM-1 embeddings, we demonstrate that this model has developed rich internal representations of RNA. Trained on limited amounts of additional data, these small networks achieve state-of-the-art accuracy on key RNA prediction tasks, suggesting that this approach can enable the design of therapies across the RNA landscape.
Long-range action of an HDAC inhibitor treats chronic pain in a spared nerve injury rat model
Authors: Centeno Maria Virginia , Alam Md. Suhail , Haldar Kasturi , Apkarian Apkar Vania 
Published: December 2023

AbstractHistone deacetylase inhibitors (HDACi) that modulate epigenetic regulation and are approved for treating rare cancers have, in disease models, also been shown to mitigate neurological conditions, including chronic pain. They are of interest as non-opioid treatments, but achieving long-term efficacy with limited dosing has remained elusive. Here we utilize a triple combination formulation (TCF) comprised of a pan-HDACi vorinostat (Vo at its FDA-approved daily dose of 50mg/Kg), the caging agent 2-hydroxypropyl-β-cyclodextrin (HPBCD) and polyethylene glycol (PEG) known to boost plasma and brain exposure and efficacy of Vo in mice and rats, of various ages, spared nerve injury (SNI) model of chronic neuropathic pain. Administration of the TCF (but not HPBCD and PEG) decreased mechanical allodynia for 4 weeks without antagonizing weight, anxiety, or mobility. This was achieved at less than 1% of the total dose of Vo approved for 4 weeks of tumor treatment and associated with decreased levels of major inflammatory markers and microglia in ipsilateral (but not contralateral) spinal cord regions. A single TCF injection was sufficient for 3-4 weeks of efficacy: this was mirrored in repeat injections, specific for the injured paw and not seen on sham treatment. Pharmacodynamics in an SNI mouse model suggested pain relief was sustained for days to weeks after Vo elimination. Doubling Vo in a single TCF injection proved effectiveness was limited to male rats, where the response amplitude tripled and remained effective for > 2 months, an efficacy that outperforms all currently available chronic pain pharmacotherapies. Together, these data suggest that through pharmacological modulation of Vo, the TCF enables single-dose effectiveness with extended action, reduces long-term HDACi dosage, and presents excellent potential to develop as a non-opioid treatment option for chronic pain.
Amyloid-motif-dependent tau self-assembly is modulated by isoform sequence context
Authors: Bali Sofia , Singh Ruhar , Wydorski Pawel M. , Van Nuland Nico E. , Wosztyl Aleksandra , Perez Valerie A. , Chen Dailu , Chen Jie , Rizo Josep , Joachimiak Lukasz A. 
Published: December 2023

AbstractThe microtubule-associated protein tau is implicated in neurodegenerative diseases characterized by amyloid formation. Mutations associated with frontotemporal dementia increase tau aggregation propensity and disrupt its endogenous microtubule-binding activity. However, the structural relationship between aggregation propensity and biological activity remains unclear. We employed a multi-disciplinary approach, including computational modeling, NMR, cross-linking mass spectrometry, and cell models to engineer tau sequences that modulate its structural ensemble. Our findings show that substitutions near the conserved ‘PGGG’ β-turn motif informed by tau isoform context reduce tau aggregation in vitro and cells and can even counteract aggregation induced by turn destabilizing disease-associated proline-to-serine mutations. Engineered tau sequences maintain microtubule binding and explain why 3R isoforms exhibit reduced pathogenesis compared to 4R. We propose a simple mechanism to reduce the formation of pathogenic species while preserving biological function, thus offering insights for therapeutic strategies aimed at reducing tau protein misfolding in neurodegenerative diseases.Abstract Figure
Multivalent DNA-encoded lectins on phage enable detecting compositional glycocalyx differences
Authors: Lima Guilherme Meira , Chenarboo Zeinab Jame , Sojitra Mirat , Sarkar Susmita , Carpenter Eric J. , Yang Claire Yi-Ling , Schmidt Edward , Lai Justine , Atrazhev Alexey , Yazdan Danial , Peng Chuanhao , Volker Elizabeth Anne , Ho Ray , Monteiro Gisele , Lai Raymond , Mahal Lara K. , Macauley Matthew S. , Derda Ratmir 
Published: December 2023

AbstractSelective detection of disease-associated changes in the cellular glycocalyx is a foundation of modern targeted therapies. Detecting minor changes in the density and identity of glycans on the cell surface is a technological challenge exacerbated by lack of 1:1 correspondence between cellular DNA/RNA and glycan structures on cell surface. We demonstrate that multivalent displays of up to 300 lectins on DNA-barcoded M13 phage on a liquid lectin array (LiLA), detects subtle differences in composition and density of glycans on cellsex vivoand in immune cells or organs in animals. For example, constructs displaying 73 copies of diCBM40 lectin per 700×5 nm virion (φ-CBM73) exhibit non-linear ON/OFF-like recognition of sialoglycans on the surface of normal and cancer cells. In contrast, a high-valency φ-CBM290 display, or soluble diCBM40, exhibit canonical progressive scaling in binding with increased epitope density; these constructs cannot amplify the subtle differences detected by φ-CBM73. Similarly, multivalent displays of diCBM40 and Siglec-7 detect differences in the glycocalyx between stem-like and non-stem populations in cancer cells that are not detected with soluble lectins. Multivalent display of lectins on M13 scaffold with protected DNA inside the phage offer non-destructive detection of minor differences in glycocalyx in cellsin vitroandin vivonot feasible to currently available technologies.
Interplay between m6A modification and overall transcripts quantity: Impacts on mRNA composition in plant stress granules
Authors: Kubiak Dawid Jakub , Szczesniak Michal Wojciech , Ostrowska Karolina , Bielewicz Dawid , Bhat Susheel Sagar , Niedojadlo Katarzyna , Szweykowska-Kulinska Zofia , Jarmolowski Artur , Fray Rupert George , Niedojadlo Janusz 
Published: December 2023

AbstractStress granules (SGs) are cytoplasmic structures that emerge in response to unfavorable environmental conditions. They contain a rich pool of RNA, including non-translated mRNA. The mechanisms governing transcripts accumulation in SGs is only partially understood. Despite the recognized role of m6A in plant transcriptome regulation, its impact on SGs’ composition and assembly remains elusive. We examined the formation of SGs, the presence of m6A, and the transcription-level-dependent localization of selected mRNAs within these granules during hypoxia in the roots ofLupinus angustifoliusandArabidopsis thaliana. In lupine, SGs exhibit a distinctive bi-zonal structure, comprising of a ring and a central area with differences in ultrastructure and composition. Following the transcriptome analysis, mRNAs were selected for examination of their localization in SGs and m6A levels. Transcripts from genes responsive to hypoxia (ADH1 and HUP7) exhibited significant lower levels of m6A compared to housekeeping genes but only ADH1 was not present in SGs. HUP7 mRNA with low quantity of m6A, is present both in the SGs and cytoplasm probably due to extremely high expression level. It was also shown that the amount of m6A in SGs was higher than in the cytoplasm only in the first hours of hypoxia and then decreased. In mutants of A. thaliana with reduced level of m6A, formation and quantity of SGs were studied. In this line, ECT2 was not observed and poly(A) RNA levels were slightly reduced in SGs. Additionally the number of SGs was lower than that of the wild type. In summary, our findings demonstrate the limited impact of m6A modification on SGs assembly. However the interplay between m6A modification and the overall transcript quantity in the cytoplasm plays a regulatory role in mRNA partitioning into SGs.
Cyanobacterial sigma factor controls biofilm-promoting genes through intra- and intercellular pathways
Authors: Suban Shiran , Yemini Sapir , Shor Anna , Ben-Asher Hiba Waldman , Yaron Orly , Lampert Sarit , Sendersky Eleonora , Golden Susan S , Schwarz Rakefet 
Published: December 2023

AbstractCyanobacteria frequently constitute integral components of microbial communities known as phototrophic biofilms. These assemblages are not only widespread in various environmental contexts but also hold significant industrial relevance. Nevertheless, the governing elements responsible for cyanobacterial biofilm development have remained elusive. This study, which employs the model cyanobacteriumSynechococcus elongatusPCC 7942, demonstrates that the RNA polymerase sigma factor SigF1, but not its paralog SigF2, is required for a biofilm-suppression mechanism that operates in this organism. Comprehensive transcriptome analyses identified distinct regulons under the control of each of these sigma factors. Additional data indicate that SigF1 regulates biofilm through its involvement in transcriptional induction of genes that include those for the primary pilus subunit:sigF1inactivation both prevents pilus assembly and abrogates secretion of a biofilm inhibitor. Consequently, expression is significantly upregulated for theebfG-operon that encodes matrix components and the genes that encode their corresponding secretion system. Thus, this study uncovers a basic regulatory component of cyanobacterial communal behavior. Elevated expression of biofilm-promoting genes in asigF1mutant supports an additional layer of regulation by SigF1 that operates via an intracellular mechanism.
Closure of the γ-tubulin ring complex by CDK5RAP2 activates microtubule nucleation
Authors: Xu Yixin , Muñoz-Hernández Hugo , Krutyhołowa Rościsław , Marxer Florina , Cetin Ferdane , Wieczorek Michal 
Published: December 2023

SummaryMicrotubule nucleation in cells is templated by the γ-tubulin ring complex (γ-TuRC), a 2.3 MDa multiprotein assembly concentrated at microtubule organizing centers (MTOCs). Current γ-TuRC structures exhibit an open conformation that deviates from the geometry of α/β-tubulin in the microtubule, potentially explaining their low in vitro microtubule-nucleating activity. Several proteins have been proposed to activate the γ-TuRC, but the mechanisms underlying activation are not known. Here, we isolated the porcine γ-TuRC using CDK5RAP2’s centrosomin motif 1 (CM1) and determined its structure with cryo-electron microscopy. 3D heterogeneity analysis revealed an unexpected conformation of the γ-TuRC, in which five protein modules containing MZT2, GCP2, and CDK5RAP2 decorate the outer face of the holocomplex. These decorations drive a long-range constriction of the γ-tubulin ring, bringing the GCP2/GCP3-rich core of the complex in close agreement with the architecture of a microtubule. A purified CDK5RAP2 fragment stimulated the microtubule nucleating-activity of the porcine γ-TuRC as well as a reconstituted, CM1-free human complex in single molecule assays. Our results show that CDK5RAP2 activates the γ-TuRC by promoting γ-tubulin ring closure, providing a structural mechanism for the regulation of microtubule nucleation by CM1 motif proteins in mammals and revealing conformational transitions in γ-tubulin that prime it for templating microtubule nucleation at MTOCs.