bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chromatin priming elements direct tissue-specific gene activity prior to hematopoietic specification
Authors: Maytum Alexander , Edginton-White Benjamin , Keane Peter , Cockerill Peter N , Cazier Jean-Baptiste , Bonifer Constanze 
Published: September 2023

AbstractTissue-specific gene regulation during development involves the interplay between transcription factors and epigenetic regulators binding to enhancer and promoter elements. The pattern of active enhancers defines the cellular differentiation state. However, developmental gene activation involves a previous step called chromatin priming which is not fully understood. We recently developed a genome-wide functional assay that allowed us to functionally identify enhancer elements integrated in chromatin regulating each of five stages spanning the in vitro differentiation of embryonic stem cells to blood. We also measured global chromatin accessibility, histone modifications and transcription factor binding. The integration of these data identified and characterised cis-regulatory elements which become activated prior to the onset of gene expression, some of which are primed in a signalling-dependent fashion. Deletion of such a priming element leads to a delay in the upregulation of its associated gene in development. Our work uncovers the details of a complex network of regulatory interactions with the dynamics of early chromatin opening being at the heart of dynamic tissue-specific gene expression control.Summary blurbIn this manuscript, we exploited a new dataset of functionally characterised enhancer elements active at five stages of differentiation from mouse embryonic stem cells to blood to determine the developmental stages at which these elements are being activated. We show that many enhancer elements are activated at the level of chromatin prior to the activation of their associated genes (priming), which can be associated with signalling events. Elimination of priming elements within a gene locus leads to a delay in cellular development.
Omix: A Multi-Omics Integration Pipeline
Authors: Schneegans Eléonore , Fancy Nurun , Thomas Michael , Willumsen Nanet , Matthews Paul M , Jackson Johanna 
Published: September 2023

AbstractSummaryTheOmixpipeline offers an integration and analysis framework for multiomics intended to preprocess, analyse, and visualise multimodal data flexibly to address various research questions. From biomarker discovery and patient stratification to the investigation of complex biological processes,Omixempowers researchers to derive valuable insights from omics data. Using Alzheimer’s Disease (AD) bulk proteomics and transcriptomics datasets generated from two distinct regions derived from post-mortem brains, we demonstrate the utility ofOmixin generating an integrated pseudo-temporal multi-omics profile of AD.Availability and ImplementationOmixis implemented as a software package in R. The code for theOmixpackage is available athttps://github.com/eleonoreschneeg/Omix. Reference documentation and online tutorials are available athttps://eleonore-schneeg.github.io/Omix. All code is open-source and available under the GNU General Public License v3.0 (GPL-3).Contacteleonore.schneegans17@imperial.ac.uk,johanna.jackson@imperial.ac.uk
Epidemiological modeling of SARS-CoV-2 in white-tailed deer (Odocoileus virginianus) reveals conditions for introduction and widespread transmission
Authors: Rosenblatt Elias , Cook Jonathan D. , DiRenzo Graziella V. , Grant Evan H.C. , Arce Fernando , Pepin Kim M. , Rudolph F. Javiera , Runge Michael C. , Shriner Susan , Walsh Daniel P. , Mosher Brittany A. 
Published: September 2023

AbstractEmerging infectious diseases with zoonotic potential often have complex socioecological dynamics and limited ecological data, requiring integration of epidemiological modeling with surveillance. Although our understanding of SARS-CoV-2 has advanced considerably since its detection in late 2019, the factors influencing its introduction and transmission in wildlife hosts, particularly white-tailed deer (Odocoileus virginianus), remain poorly understood. We use a Susceptible-Infected-Recovered-Susceptible epidemiological model to investigate the spillover risk and transmission dynamics of SARS-CoV-2 in wild and captive white-tailed deer populations across various simulated scenarios. We found that captive scenarios pose a higher risk of SARS-CoV-2 introduction from humans into deer herds and subsequent transmission among deer, compared to wild herds. However, even in wild herds, the transmission risk is often substantial enough to sustain infections. Furthermore, we demonstrate that the strength of introduction from humans influences outbreak characteristics only to a certain extent. Transmission among deer was frequently sufficient for widespread outbreaks in deer populations, regardless of the initial level of introduction. We also explore the potential for fence line interactions between captive and wild deer to elevate outbreak metrics in wild herds that have the lowest risk of introduction and sustained transmission. Our results indicate that SARS-CoV-2 could be introduced and maintained in deer herds across a range of circumstances based on testing a range of introduction and transmission risks in various captive and wild scenarios. Our approach and findings will aid One Health strategies that mitigate persistent SARS-CoV-2 outbreaks in white-tailed deer populations and potential spillback to humans.
The antigenic landscape of human influenza N2 neuraminidases from 2009 until 2017
Authors: Catani João Paulo Portela , Smet Anouk , Ysenbaert Tine , Vuylsteke Marnik , Bottu Guy , Mathys Janick , Botzki Alexander , Cortes-Garcia Guadalupe , Strugnell Tod , Gomila Raul , Hamberger John , Catalan John , Ustyugova Irina V. , Farrell Timothy , Stegalkina Svetlana , Ray Satyajit , LaRue Lauren , Saelens Xavier , Vogel Thorsten U. 
Published: September 2023

AbstractHuman H3N2 influenza viruses are subject to rapid antigenic evolution which translates into frequent updates of the composition of seasonal influenza vaccines. Despite these updates, the effectiveness of influenza vaccines against H3N2-associated disease is suboptimal. Seasonal influenza vaccines primarily induce hemagglutinin-specific antibody responses. However, antibodies directed against influenza neuraminidase (NA) also contribute to protection. Here, we analyzed the antigenic diversity of a panel of N2 NAs derived from human H3N2 viruses that circulated between 2009 and 2017. The antigenic breadth of these NAs was determined based on the NA inhibition (NAI) of a broad panel of ferret and mouse immune sera that were raised by infection and recombinant N2 NA immunization. This assessment allowed us to distinguish at least 4 antigenic groups in the N2 NAs derived from human H3N2 viruses that circulated between 2009 and 2017. Computational analysis further revealed that the amino acid residues in N2 NA that have a major impact on susceptibility to NAI by immune sera are in proximity of the catalytic site. Finally, a machine learning method was developed that allowed to accurately predict the impact of mutations that are present in our N2 NA panel on NAI. These findings have important implications for the renewed interest to develop improved influenza vaccines based on the inclusion of a protective NA antigen formulation.
Human inborn errors of long-chain fatty acid oxidation show impaired inflammatory responses to TLR4-ligand LPS
Authors: Mosegaard Signe , Twayana Krishna S. , Denis Simone W. , Kroon Jeffrey , Schomakers Bauke V. , van Weeghel Michel , Houtkooper Riekelt H. , Olsen Rikke K. J. , Holm Christian K. 
Published: September 2023

ABSTRACTStimulation of mammalian cells with inflammatory inducers such as lipopolysaccharide (LPS) leads to alterations in the activity of central cellular metabolic pathways. Interestingly, these metabolic changes seem to be important for the subsequent release of pro-inflammatory cytokines. This has become particularly clear for enzymes of the tricarboxylic acid (TCA) cycle such as succinate dehydrogenase (SDH). LPS leads to inhibition of SDH activity and accumulation of succinate to enhance the LPS-induced formation of IL-1β. If enzymes involved in beta-oxidation of fatty acids are important for sufficient responses to LPS is currently not clear.Using cells from various patients with inborn fatty acid oxidation disorders, we report that disease-causing deleterious variants of Electron Transfer Flavoprotein Dehydrogenase (ETFDH) and of Very Long Chain Acyl-CoA Dehydrogenase (ACADVL), both cause insufficient responses to stimulation with LPS. The insufficiencies included reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro-inflammatory cytokines such as IL-6. The insufficient responses to LPS were reproduced in cells from normal healthy controls by targeted loss-of-function of eitherETFDHorACADVL,supporting that the deleteriousETFDHandACADVLvariants cause the attenuated responses to LPS.ETFDHandACADVLencode two distinct enzymes both involved in fatty acid beta-oxidation, and patients with these deficiencies cannot sufficiently metabolize long-chain fatty acids. With this report, we therefore provide genetic evidence from two genetically distinct but phenotypically similar human metabolic diseases, that genes important for beta-oxidation of long-chain fatty acids are also important for inflammatory responses to LPS.
Nested neural circuits generate distinct acoustic signals during Drosophila courtship
Authors: Lillvis Joshua L. , Wang Kaiyu , Shiozaki Hiroshi M. , Xu Min , Stern David L. , Dickson Barry J. 
Published: September 2023

SummaryMany motor control systems generate multiple movements using a common set of muscles. How are premotor circuits able to flexibly generate diverse movement patterns? Here, we characterize the neuronal circuits that drive the distinct courtship songs ofDrosophila melanogaster. Male flies vibrate their wings towards females to produce two different song modes – pulse and sine song – which signal species identity and male quality. Using cell-type specific genetic reagents and the connectome, we provide a cellular and synaptic map of the circuits in the male ventral nerve cord that generate these songs and examine how activating or inhibiting each cell type within these circuits affects the song. Our data reveal that the song circuit is organized into two nested feed-forward pathways, with extensive reciprocal and feed-back connections. The larger network produces pulse song, the more complex and ancestral song form. A subset of this network produces sine song, the simpler and more recent form. Such nested organization may be a common feature of motor control circuits in which evolution has layered increasing flexibility on to a basic movement pattern.
Five-year Efficacy and Safety of TiNO-Coated Stents Versus Drug-Eluting Stents in Acute Coronary Syndrome. A meta-analysis
Authors: Daoud Frederic C. , Catargi Bogdan , Karjalainen Pasi P. , Gerbaud Edouard 
Published: September 2023

Abstract(1) Background: Percutaneous Coronary Interventions (PCI) in patients with acute coronary syndrome (ACS) are performed with titanium-nitride-oxide-coated stents (TiNOS) or drug-eluting stents (DES). This prospective systematic literature review (SLR) of prospective, randomized, controlled trials (RCTs) showed TiNOS is non-inferior to DES in major adverse cardiac events (MACE) rates and presents a lower risk of recurrent myocardial infarction (MI) at 1-year follow-up. (2) Methods: The previously described SLR and meta-analysis protocol, per PRISMA, Cochrane methods, and GRADE, applied here to 5-year follow-up outcomes. (3) Results: Three RCTs were eligible, comprising 1,620 patients with TiNOS vs. 1,123 with DES. The pooled risk ratios (RRs) and 95% confidence intervals were: MACE 0.82 [0.68, 0.99], MI 0.58 [0.44, 0.78], cardiac death (CD) 0.46 [0.28, 0.76], ischemia-driven target lesion re-vascularization (TLR) 1.03 [0.79, 1.33], probable or definite stent thrombosis (ST) 0.32 [0.21, 0.59], and all-cause mortality (TD) 0.84 [0.63, 1.12]. Evidence certainty was high in MACE, CD, MI, and ST. Certainty was moderate in TLR and TD. (4) Conclusions: TiNOS in ACS at 5-year follow-up appears safer than DES and equally efficacious. Stratified pooled outcomes by clinical presentation would facilitate clinical validity benchmarking and generalization to target populations.
DIAGNOSTIC ACCURACY OF ARTIFICIAL INTELLIGENCE FOR ANALYSIS OF 1.3 MILLION MEDICAL IMAGING STUDIES: THE MOSCOW EXPERIMENT ON COMPUTER VISION TECHNOLOGIES
Authors: Morozov Sergey , Vladzymyrskyy Anton , Ledikhova Natalia , Andreychenko Anna , Arzamasov Kirill , Omelyanskaya Olga , Reshetnikov Roman , Gelezhe Pavel , Blokhin Ivan , Turavilova Elena , Kozhikhina Daria , Anikina Daria , Bondarchuk Dmitry 
Published: September 2023

AbstractObjectiveto assess the diagnostic accuracy of services based on computer vision technologies at the integration and operation stages in Moscow’s Unified Radiological Information Service (URIS).Methodsthis is a multicenter diagnostic study of artificial intelligence (AI) services with retrospective and prospective stages. The minimum acceptable criteria levels for the index test were established, justifying the intended clinical application of the investigated index test. The Experiment was based on the infrastructure of the URIS and United Medical Information and Analytical System (UMIAS) of Moscow. Basic functional and diagnostic requirements for the artificial intelligence services and methods for monitoring technological and diagnostic quality were developed. Diagnostic accuracy metrics were calculated and compared.Resultsbased on the results of the retrospective study, we can conclude that AI services have good result reproducibility on local test sets. The highest and at the same time most balanced metrics were obtained for AI services processing CT scans. All AI services demonstrated a pronounced decrease in diagnostic accuracy in the prospective study. The results indicated a need for further refinement of AI services with additional training on the Moscow population datasets.Conclusionsthe diagnostic accuracy and reproducibility of AI services on the reference data are sufficient, however, they are insufficient on the data in routine clinical practice. The AI services that participated in the experiment require a technological improvement, additional training on Moscow population datasets, technical and clinical trials to get a status of a medical device.
Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19
Authors: Padi Sathish K.R. , Vos Margaret R. , Godek Rachel J. , Fuller James R. , Kruse Thomas , Hein Jamin B. , Nilsson Jakob , Kelker Matthew S. , Page Rebecca , Peti Wolfgang 
Published: September 2023

AbstractProgression through the cell cycle is controlled by regulated and abrupt changes in phosphorylation.1Mitotic entry is initiated by increased phosphorylation of mitotic proteins, a process driven by kinases,2while mitotic exit is achieved by counteracting dephosphorylation, a process driven by phosphatases, especially PP2A:B55.3While the role of kinases in mitotic entry is well-established, recent data have shown that mitosis is only successfully initiated when the counterbalancing phosphatases are also inhibited.4For PP2A:B55, inhibition is achieved by the two intrinsically disordered proteins (IDPs), ARPP19 (phosphorylation-dependent)6,7and FAM122A5(inhibition is phosphorylation-independent). Despite their critical roles in mitosis, the mechanisms by which they achieve PP2A:B55 inhibition is unknown. Here, we report the cryo-electron microscopy structures of PP2A:B55 bound to phosphorylated ARPP19 and FAM122A. Consistent with our complementary NMR spectroscopy studies both IDPs bind PP2A:B55, but do so in highly distinct manners, unexpectedly leveraging multiple distinct binding sites on B55. Our extensive structural, biophysical and biochemical data explain how substrates and inhibitors are recruited to PP2A:B55 and provides a molecular roadmap for the development of therapeutic interventions for PP2A:B55 related diseases.
A synthetic biology approach to transgene expression
Authors: Leftwich Philip T. , Purcell Jessica C. , Anderson Michelle A.E. , Fragkoudis Rennos , Basu Sanjay , Lycett Gareth , Alphey Luke 
Published: September 2023

AbstractThe ability to control gene expression is pivotal in genetic engineering and synthetic biology. However, in most non-model and pest insect species, empirical evidence for predictable modulation of gene expression levels is lacking. This knowledge gap is critical for genetic control systems, particularly in mosquitoes, where transgenic methods offer novel routes for pest control. Commonly, the choice of RNA polymerase II promoter (Pol II) is the primary method for controlling gene expression, but the options are limited.To address this, we developed a systematic approach to characterize modifications in translation initiation sequences (TIS) and 3’ untranslated regions (UTR) of transgenes, enabling the creation of a toolbox for gene expression modulation in mosquitoes and potentially other insects. The approach demonstrated highly predictable gene expression changes across various cell lines and promoter sequences, representing a significant advancement in mosquito synthetic biology gene expression. tools.Abstract Figure
New structural features of the APC/C from high-resolution cryo-EM structures of apo-APC/C and APC/CCDH1:EMI1complexes
Authors: Höfler Anna , Yu Jun , Yang Jing , Zhang Ziguo , Chang Leifu , McLaughlin Stephen H. , Grime Geoffrey W. , Garman Elspeth F. , Boland Andreas , Barford David 
Published: September 2023

AbstractThe multi-subunit anaphase-promoting complex/cyclosome (APC/C) is a master regulator of cell division. It controls progression through the cell cycle by timely marking mitotic cyclins and other cell cycle regulatory proteins for degradation. The APC/C itself is regulated by the sequential action of its coactivator subunits CDC20 and CDH1, post-translational modifications, and its inhibitory binding partners EMI1 and the mitotic checkpoint complex (MCC). In this study, we took advantage of the latest developments in cryo-electron microscopy (cryo-EM) to determine the structures of human APC/CCDH1:EMI1and apo-APC/C at 2.9 Å and 3.2 Å resolution, respectively, providing novel insights into the regulation of APC/C activity. The high-resolution maps allowed the unambiguous assignment of a previously unassigned α-helix to the N-terminus of CDH1 (CDH1α1) in the APC/CCDH1:EMI1ternary complex. We also identified a novel zinc-binding module in APC2 that confers structural stability to APC2, and we confirmed the presence of zinc ions experimentally. Finally, due to the higher resolution and well defined density of these maps, we were able to build, aided by AlphaFold predictions, several intrinsically disordered regions in different APC/C subunits that likely play a role in proper APC/C assembly and regulation of its activity.
Holistic integration of omics data reveals the drivers that shape the ecology of microbial meat spoilage scenarios
Authors: Poirier Simon , Coeuret Gwendoline , Champomier-Vergès Marie-Christine , Desmonts Marie-Hélène , Werner Dalal , Feurer Carole , Frémaux Bastien , Guillou Sandrine , Martin Luong Ngoc-Du , Rué Olivier , Loux Valentin , Zagorec Monique , Chaillou Stéphane 
Published: September 2023

AbstractThe use of omics data for monitoring the microbial flow of fresh meat products along a production line and the development of spoilage prediction tools from these data is a promising but challenging task. In this context, we produced a large multivariate dataset (over 600 samples) obtained on the production lines of two similar types of fresh meat products (poultry and raw pork sausages).We describe a full analysis of this dataset in order to decipher how the spoilage microbial ecology of these two similar products may be shaped differently depending on production parameter characteristics.Our strategy involved a holistic approach to integrate unsupervised and supervised statistical methods on multivariate data (OTU-based microbial diversity; metabolomic data of volatile organic compounds; sensory measurements; growth parameters), and a specific selection of potential uncontrolled (initial microbiota composition) or controlled (packaging type; lactate concentration) drivers.Our results demonstrate that the initial microbiota, which is shown to be very different between poultry and pork sausages, has a major impact on the spoilage scenarios and on the effect that a downstream parameter such as packaging type has on the overall evolution of the microbial community. Depending on the process, we also show that specific actions on the pork meat (such as deboning and defatting) elicit specific food spoilers such asDellaglioa algida,which becomes dominant during storage. Finally, ecological network reconstruction allowed us to map six different metabolic pathways involved in the production of volatile organic compounds involved in spoilage. We were able connect them to the different bacterial actors and to the influence of packaging type in an overall view. For instance, our results demonstrate a new role ofVibrionaceaein isopropanol production, and ofLatilactobacillus fuchuensisandLactococcus pisciumin methanethiol/disylphide production. We also highlight a possible commensal behavior betweenLeuconostoc carnosumandLatilactobacillus curvatusaround 2,3-butanediol metabolism.We conclude that our holistic approach combined with large-scale multi-omic data was a powerful strategy to prioritize the role of production parameters, already known in the literature, that shape the evolution and/or the implementation of different meat spoilage scenarios.
An architectural role ofoskarmRNA in granule assembly
Authors: Bose Mainak , Rankovic Branislava , Mahamid Julia , Ephrussi Anne 
Published: September 2023

AbstractRibonucleoprotein (RNP) granules are membraneless condensates that organize the intracellular space by compartmentalization of specific RNAs and proteins1. Studies have shown that RNA tunes the phase behavior of RNA binding proteins (RBPs)2–4, but the role of intermolecular RNA-RNA interactions in assembly of RNP granulesin vivoremains less explored5–7. Here, we determine the role of a sequence-specific RNA-RNA kissing-loop interaction in assembly of mesoscaleoskarRNP granules in the femaleDrosophilagermline. A two-nucleotide mutation that disrupts kissing-loop-mediatedoskarmRNA dimerization impairs condensate formationin vitro,oskargranule assembly in the developing oocyte - leading to defective posterior localization of the RNA, and abrogation ofoskar-associated processing bodies (P-bodies) upon nutritional stress. This specifictransRNA-RNA interaction acts synergistically with the scaffold RBP, Bruno8, in driving condensate assembly. Our study highlights the architectural contribution of an mRNA and its specific secondary structure and tertiary interactions in formation of an RNP granule essential for embryonic development.