bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-Wide Association Testing for Haemorrhagic Bowel Syndrome in a Swiss Large White Pig Population
Authors: Mehrotra Arnav , Leonard Alexander S. , Drögemüller Cord , Grahofer Alexander , Khayatzadeh Negar , Hofer Andreas , Neuenschwander Stefan , Pausch Hubert 
Published: April 2024

ABSTRACTBackgroundThe porcine haemorrhagic bowel syndrome (HBS) is a multifactorial disease causing fatal gastrointestinal disturbances and sudden death in fattening pigs. HBS is the leading cause of deaths during fattening in Swiss pigs, with unclear etiology. Environmental and management factors are associated with HBS incidence, but recent findings also suggest a potential genetic predisposition. Pigs sired by a Swiss Large White (SLW) line appear more prone to HBS. Here we conduct genome-wide association studies (GWAS) for HBS between cases and controls to investigate potential genetic factors for the disease in Swiss fattening pigs.ResultsOur study included 1,036 HBS cases and 4,080 controls with available microarray genotypes or whole-genome sequencing data. Variant positions were determined according to the current porcine reference assembly (Sscrofa11.1) or a HiFi-based SLW haplotype assembly which we constructed using trio-binning. GWAS for HBS were conducted using 12.49 to 15.46 million biallelic variants in three mapping cohorts consisting of purebred animals from SLW sire and dam lines, or crosses between these two parental lines. The statistical model applied for the GWAS accounted for animal relatedness, population structure, and an imbalanced case/control ratio. No sequence variants significantly associated with HBS were identified, regardless of the cohort analysed and the reference sequence considered.ConclusionsThe lack of genetic associations despite a relatively large sample size suggests that susceptibility to HBS in the studied SLW population is not due to large effect variants but may be influenced by numerous small effect genetic variants, in addition to environmental and management factors.
Migration of endocrine and metabolism disrupting chemicals from plastic food packaging
Authors: Stevens Sarah , Bartosova Zdenka , Völker Johannes , Wagner Martin 
Published: April 2024

ABSTRACTPlastics constitute a vast array of substances, with over 16 000 known plastic chemicals, including intentionally and non-intentionally added substances. Toxicity and thousands of chemicals are extractable from plastics; however, the extent to which toxicity and chemicals migrate from everyday plastic products remains poorly understood. This study aims to characterize the endocrine and metabolism disrupting activity, as well as chemical composition of migrates from plastic food contact articles (FCAs) from four countries as significant sources of human exposure. Additionally, strategies for prioritization of chemicals were explored. Fourteen plastic FCAs covering seven polymer types with high global market shares were migrated into water and a water-ethanol mixture as food simulants according to European regulations. The migrates were analyzed using reporter gene assays for nuclear receptors relevant to human health and non-target chemical analysis to characterize the chemical composition of the migrates. All FCA migrates interfered with at least two nuclear receptors, predominantly targeting pregnane X receptor. Moreover, peroxisome proliferator receptor gamma was broadly activated by the migrates, though mostly with lower potencies, while estrogenic and antiandrogenic activities were more selectively induced by specific FCAs. Fewer chemicals and less toxicity migrated into water compared to the water-ethanol mixture. The latter exhibited similar toxicity and number of chemicals as methanol extracts of the same FCAs. Novel strategies were employed to address the chemical complexity of FCAs and narrow down the list of potential active chemicals. By comparing the composition of multiple leachates of one sample and using stepwise partial least squares regressions, we successfully reduced the chemical complexity, pinpointed potential endocrine disruptors such as triphenyl phosphate and prioritized chemicals for further identification efforts. This study demonstrates the migration of endocrine and metabolism disrupting chemicals from plastic FCAs into food simulants, rendering a migration of these compounds into food and beverages probable.
Mirror-assisted light-sheet microscopy: a simple upgrade to enable bi-directional sample excitation
Authors: Zylbertal Asaph , Bianco Isaac H. 
Published: April 2024

AbstractSignificanceLight-sheet microscopy is a powerful imaging technique that achieves optical sectioning via selective illumination of individual sample planes. However, when the sample contains opaque or scattering tissue, the incident light-sheet may not be able to uniformly excite the entire sample. For example, in the context of larval zebrafish whole-brain imaging, occlusion by the eyes prevents access to a significant portion of the brain during common implementations using unidirectional illumination.AimWe introduce mirror-assisted light-sheet microscopy (mLSM), a simple inexpensive method that can be implemented on existing digitally scanned light-sheet setups by adding a single optical element – a mirrored micro-prism. The prism is placed near the sample to generate a second excitation path for accessing previously obstructed regions.ApproachScanning the laser beam onto the mirror generates a second, reflected illumination path that circumvents the occlusion. Online tuning of the scanning and laser power waveforms enables near uniform sample excitation with dual illumination.ResultsmLSM produces cellular-resolution images of zebrafish brain regions inaccessible to unidirectional illumination. Imaging quality in regions illuminated by the direct or reflected sheet is adjustable by translating the excitation objective. The prism does not interfere with visually guided behaviour.ConclusionsmLSM presents an easy to implement, cost-effective way to upgrade an existing light-sheet system to obtain more imaging data from a biological sample.
DNA isolation in bark beetles: reliability of extraction methods and application in downstream molecular procedures
Authors: Stazione Leonel , Lantschner Victoria , Corley Juan , Soliani Carolina 
Published: April 2024

AbstractMolecular tools are increasingly used in entomology for several applications such as taxonomy, genetics, ecology and evolution. For these studies, DNA extraction from individual insects is a crucial step, since the yield and quality vary depending on the methods used. Finding an ideal balance between quality and yield is particularly difficult to reach and several constraints must be considered upon selecting the final protocol. Bark beetles (Coleoptera: Curculionidae, Scolytinae) are a diverse group of forest insects for which molecular studies at the individual level are important, given that many species are invasive and may become pests. However, DNA extraction in bark beetles is not easy, given their small size and complex molecules of diverse nature conforming their exoskeleton and present in their digestive tract. Here, we carried out a comparative analysis of DNA extraction performance in five bark beetle species:Hylurgus ligniperda, Hylastes ater, Orthotomicus erosus, Orthotomicus laricisandCyrtogenius luteus. By assessing the efficiency of two different protocols, our aim was to establish the best species-specific method for population-level studies. Our results showed that a method’s whole performance mainly depends on the species considered and translates into DNA quantity and quality variance. We also noted that the traditional method showed better PCR efficiency for the smallest species whereas the commercial kit performed better for the larger beetles. Our comparative analysis provides evidence that no single method for DNA isolation is best, and that each particular species requires optimization.
Meta-transcriptomic analysis of companion animal infectomes reveals their diversity and potential roles in animal and human disease
Authors: Wu Wei-Chen , Pan Yuan-Fei , Zhou Wu-Di , Liao Yu-Qi , Peng Min-Wu , Luo Geng-Yan , Xin Gen-Yang , Peng Ya-Ni , An Tongqing , Li Bo , Luo Huanle , Barrs Vanessa R. , Beatty Julia A. , Holmes Edward C. , Zhao Wenjing , Shu Yuelong 
Published: April 2024

AbstractCompanion animals such as cats and dogs harbor diverse microbial communities that can potentially impact human health due to close and frequent contact. To better characterize their total infectomes and assess zoonotic risks, we performed meta-transcriptomic profiling on 239 samples from cats and dogs collected across China, comparing the similarities and differences between animal species (cats or dogs), sampling sites (rectal or oropharyngeal), and health status (healthy or diseased). We identified 24 viral species, 270 bacterial genera, and two fungal genera, including many known pathogens such ascanine parvovirus,Clostridium difficile, andCandida albicans,as well as opportunistic pathogens such ascanine vesivirus. Microbial compositions differed mainly according to sampling site (i.e., rectal and oropharyngeal swabs), and less so between host species and health status. Notably, we detected 27 potential zoonotic pathogens, such asalphacoronavirus 1, among all sampling sites, hosts, and health status, underscoring substantial zoonotic risks requiring surveillance. Overall, our meta-transcriptomic analysis reveals a landscape of actively transcribing microorganisms in major companion animals, including key pathogens, those with the potential for cross-species transmission, and possible zoonotic threats.
Menopausal hormone therapy and the female brain: leveraging neuroimaging and prescription registry data from the UK Biobank cohort
Authors: Barth Claudia , Galea Liisa A.M. , Jacobs Emily G. , Lee Bonnie H. , Westlye Lars T. , de Lange Ann-Marie G. 
Published: April 2024

AbstractBackground and ObjectivesMenopausal hormone therapy (MHT) is generally thought to be neuroprotective, yet results have been inconsistent. Here, we present a comprehensive study of MHT use and brain characteristics in middle-to older aged females from the UK Biobank, assessing detailed MHT data, APOE ε4 genotype, and tissue-specific gray (GM) and white matter (WM) brain age gap (BAG), as well as hippocampal and white matter hyperintensity (WMH) volumes.MethodsA total of 19,846 females with magnetic resonance imaging data were included (current-users = 1,153, 60.1 ± 6.8 years; past-users = 6,681, 67.5 ± 6.2 years; never-users = 12,012, mean age 61.6 ± 7.1 years). For a sub-sample (n = 538), MHT prescription data was extracted from primary care records. Brain measures were derived from T1-, T2- and diffusion-weighted images. We fitted regression models to test for associations between the brain measures and MHT variables including user status, age at initiation, dosage and duration, formulation, route of administration, and type (i.e., bioidentical vs synthetic), as well as active ingredient (e.g., estradiol hemihydrate). We further tested for differences in brain measures among MHT users with and without a history of hysterectomy ± bilateral oophorectomy and examined associations by APOE ε4 status.ResultsWe found significantly higher GM and WM BAG (i.e., older brain age relative to chronological age) as well as smaller left and right hippocampus volumes in current MHT users, not past users, compared to never-users. Effects were modest, with the largest effect size indicating a group difference of 0.77 years (∼9 months) for GM BAG. Among MHT users, we found no significant associations between age at MHT initiation and brain measures. Longer duration of use and older age at last use post menopause was associated with higher GM and WM BAG, larger WMH volume, and smaller left and right hippocampal volumes. MHT users with a history of hysterectomy ± bilateral oophorectomy showedlowerGM BAG relative to MHT users without such history. Although we found smaller hippocampus volumes in carriers of two APOE ε4 alleles compared to non-carriers, we found no interactions with MHT variables. In the sub-sample with prescription data, we found no significant associations between detailed MHT variables and brain measures after adjusting for multiple comparisons.DiscussionOur results indicate that population-level associations between MHT use, and female brain health might vary depending on duration of use and past surgical history. Future research is crucial to establish causality, dissect interactions between menopause-related neurological changes and MHT use, and determine individual-level implications to advance precision medicine in female health care.
Prescription Trends of Initial Antihypertensive Medications among Treatment-Naïve Individuals in South Korea: A Retrospective Analysis
Authors: Joo Hajung , Chae Seung Eun , Eom Yeong Rok , Je Nam Kyung 
Published: April 2024

AbstractIntroductionManaging hypertension effectively is crucial for preventing cardiovascular complications. This study investigates the prescribing trends of initial antihypertensive treatments in South Korea, focusing on the shift towards combination therapies, especially fixed-dose combinations, as recommended by current guidelines.MethodsWe retrospectively analyzed data from 59,950 treatment-naïve hypertension patients without significant comorbidities from the National Patient Sample of the Health Insurance Review and Assessment Service, spanning 2009 to 2020. The study examined the prevalence of monotherapy versus combination therapy and the preferred classes of antihypertensive drugs.ResultsAmong the cohort, 55.7% received monotherapy, and 44.3% were initiated on combination therapy. There was a notable increase in the prescription of fixed-dose combinations from 73.8% in 2009 to 93.8% in 2020. ARBs and CCBs were the predominant choices, with a preference for ARBs over ACE inhibitors, possibly due to the lower risk of side effects such as cough. The trend towards fixed-dose combinations aligns with guidelines advocating for improved patient adherence and efficacy.ConclusionsThe evolving prescription trends in South Korea towards combination therapy, particularly fixed-dose combinations, reflect a commitment to aligning with international hypertension management guidelines. This adaptation underscores the importance of evidence-based practice in enhancing hypertension care.
Dynamic self-association of archaeal tubulin-like protein CetZ1 drivesHaloferax volcaniimorphogenesis
Authors: de Silva Roshali T. , Shinde Vinaya , Brown Hannah J. , Liao Yan , Duggin Iain G. 
Published: April 2024

AbstractTubulin superfamily (TSF) proteins include the well-known eukaryotic tubulin and bacterial FtsZ families, and lesser-known archaeal CetZ family. In eukaryotes and bacteria, GTP-dependent polymerization and self-association of tubulin and FtsZ protofilaments are integral to the formation of cytoskeletal structures with essential roles in cell division, growth, and morphology. Archaeal CetZs are implicated in the control of cell shape and motility through unknown mechanisms. Here, we reveal a sequence of subcellular localization patterns of CetZ1, the prototypical member of the CetZ family, during stages ofHaloferax volcaniirod cell development, in which it plays an essential role. Like tubulin and FtsZ, we found that CetZ1 formed GTP-dependent polymers in vitro, which appear to associate laterally as irregular polymer bundles. Mutations targeting regions predicted to mediate self-association and dynamic turnover of CetZ1, including the longitudinal (GTPase T7 and T4 loops) and lateral assembly interfaces, perturbed or altered rod shape development and subcellular assembly and dynamics, and caused corresponding effects on polymerization in vitro. Remarkably, a conspicuous amphipathic protrusion in the large microtubule (M-) loop, a characteristic of the CetZ1 subfamily, also strongly influenced function and assembly. Our findings reveal the importance of dynamic CetZ1 self-association in cellular morphogenesis involving multiple regions of the TSF fold, including tubulin- and FtsZ-like structural characteristics and CetZ1-specific features. Furthermore, they support a mechanism involving CetZ1 dynamic guidance of cell envelope-associated structures that reshape the cell during morphogenesis.
Microdroplet screening rapidly profiles a biocatalyst to enable its AI-assisted engineering
Authors: Gantz Maximilian , Mathis Simon V. , Nintzel Friederike E. H. , Zurek Paul J. , Knaus Tanja , Patel Elie , Boros Daniel , Weberling Friedrich-Maximilian , Kenneth Matthew R. A. , Klein Oskar J. , Medcalf Elliot J. , Moss Jacob , Herger Michael , Kaminski Tomasz S. , Mutti Francesco G. , Lio Pietro , Hollfelder Florian 
Published: April 2024

AbstractEngineering enzyme biocatalysts for higher efficiency is key to enabling sustainable, ‘green’ production processes for the chemical and pharmaceutical industry. This challenge can be tackled from two angles: by directed evolution, based on labor-intensive experimental testing of enzyme variant libraries, or by computational methods, where sequence-function data are used to predict biocatalyst improvements. Here, we combine both approaches into a two-week workflow, where ultra-high throughput screening of a library of imine reductases (IREDs) in microfluidic devices provides not only selected ‘hits’, but also long-read sequence data linked to fitness scores of >17 thousand enzyme variants. We demonstrate engineering of an IRED for chiral amine synthesis by mapping functional information in one go, ready to be used for interpretation and extrapolation by protein engineers with the help of machine learning (ML). We calculate position-dependent mutability and combinability scores of mutations and comprehensively illuminate a complex interplay of mutations driven by synergistic, often positively epistatic effects. Interpreted by easy-to-use regression and tree-based ML algorithms designed to suit the evaluation of random whole-gene mutagenesis data, 3-fold improved ‘hits’ obtained from experimental screening are extrapolated further to give up to 23-fold improvements in catalytic rate after testing only a handful of designed mutants. Our campaign is paradigmatic for future enzyme engineering that will rely on access to large sequence-function maps as profiles of the way a biocatalyst responds to mutation. These maps will chart the way to improved function by exploiting the synergy of rapid experimental screening combined with ML evaluation and extrapolation.
Maturation-informed synthetic Magnetic Resonance Images of the Developing Human Fetal Brain
Authors: Lajous Hélène , Boeuf Fló Andrés le , Gordaliza Pedro M. , Esteban Oscar , Marqués Ferran , Dunet Vincent , Koob Mériam , Cuadra Meritxell Bach 
Published: April 2024

ABSTRACTMagnetic resonance imaging is a powerful modality to investigate abnormal developmental patternsin utero. However, since it is not the first-line diagnostic tool in this sensitive population, data remain scarce and heterogeneous between scanners and centers. In addressing the data scarcity issue while generating data representative of real fetal brain MRI, we proposedFaBiAN, a ‘Fetal Brain magnetic resonance Acquisition Numerical phantom. Here, we present a novel synthetic dataset of 594 two-dimensional, low-resolution series of T2-weighted images corresponding to 78 developing human fetal brains between 20.0 and 34.8 weeks of gestational age. Data are generated with substantive improvements from the originalFaBiANto account for local heterogeneities within white matter tissues throughout maturation. These synthetic-yet-highly-realistic images cover both healthy and pathological development trajectories simulated with standard clinical settings and anatomically informed by the Fetal Tissue Annotations (FeTA) dataset. Two independent radiologists qualitatively assessed the realism of the simulated images. We also quantitatively demonstrate the simulated data’s increased fidelity to real data compared to the previousFaBiANversion. The reuse potential of the proposed dataset was also evaluated in the context of automated fetal brain tissue segmentation. Besides, our dataset that combines images generated from various clinical scenarios has been made publicly available to support the continuous endeavor of the community to develop advanced post-processing methods aswell as cutting-edge artificial intelligence models.
Histones are exosome membrane proteins regulated by cell stress
Authors: Singh Birendra , Sundbom Marcus Fredriksson , Muthukrishnan Uma , Natarajan Balasubramanian , Stransky Stephanie , Görgens André , Nordin Joel Z. , Wiklander Oscar P. B. , Sandblad Linda , Sidoli Simone , Andaloussi Samir EL , Haney Michael , Gilthorpe Jonathan D. 
Published: April 2024

ABSTRACTHistones are conserved nuclear proteins that function as part of the nucleosome in the regulation of chromatin structure and gene expression. Interestingly, extracellular histones populate biofluids from healthy individuals and when elevated may contribute to various acute and chronic diseases. It is generally assumed that most extracellular histones exist as nucleosomes, as components of extracellular chromatin. We analysed cell culture models under normal and stressed conditions to identify pathways of histone secretion. We report that core and linker histones localize to extracellular vesicles (EVs) and are secreted via the multivesicular body/exosome pathway. Upregulation of histone EV secretion occurs in response to cellular stress, with enhanced vesicle secretion and a shift towards a population of smaller EVs. Most histones were membrane associated with the outer surface of EVs. Degradation of EV-DNA did not impact significantly on EV-histone association. Individual histones or histone octamers bound strongly to liposomes and EVs, but nucleosomes did not, showing histones do not require DNA for EV binding. EV histones colocalized most frequently with the tetraspanin CD63 but using genetic or pharmacological intervention, we found that all known pathways of exosome biogenesis acted positively on histone secretion. Inhibition of autophagy and lysosomal degradation had a strong positive effect on EV histone release. Unexpectedly, EV-associated histones lacked the extensive post-translational modification of their nuclear counterparts, suggesting loss of PTMs may be involved in their trafficking or secretion. Our data does not support a significant role for EV-histones existing as nucleosomes. We show for the first time that histones are secreted from cells as membrane proteins via EVs/exosomes. This fundamental discovery provides support for further investigation of the biological activity of exosome associated histones and their role in disease.
Topological confinement by a membrane anchor suppresses phase separation into protein aggregates: implications for prion diseases
Authors: Gogte Kalpshree , Kriegler Simon , Bader Verian , Kamps Janine , Grover Prerna , Winter Roland , Winklhofer Konstanze F. , Tatzelt Jörg 
Published: April 2024

ABSTRACTProtein misfolding and aggregation are a hallmark of various neurodegenerative disorders. However, the underlying mechanisms driving protein misfolding in the cellular context are incompletely understood. Here we show that the restriction of conformational degrees of freedom by a membrane anchor stabilizes the native protein conformation and suppresses liquid-liquid phase separation and protein aggregation. Inherited prion diseases in humans and neurodegeneration in transgenic mice are linked to the expression of anchorless prion protein (PrP), suggesting that the C-terminal glycosylphosphatidylinositol (GPI) anchor of native PrP impedes spontaneous formation of neurotoxic and infectious PrP species. Combining novelin vitroandin vivoapproaches, we show that anchoring to membranes prevents spontaneous aggregation of PrP. Upon release from the membrane, PrP undergoes a rapid conformational transition to detergent-insoluble aggregates. Our study supports an essential role of the GPI anchor in preventing spontaneous misfolding of PrPC.