bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypertensive disorders of pregnancy and risk of cardiovascular disease: A Mendelian Randomisation study in the UK Biobank
Authors: Tschiderer Lena , van der Schouw Yvonne T , Burgess Stephen , Bloemenkamp Kitty WM , Seekircher Lisa , Willeit Peter , Onland-Moret N Charlotte , Peters Sanne AE 
Published: March 2023

AbstractBackgroundObservational studies show that hypertensive disorders of pregnancy (HDPs) are related to unfavourable maternal cardiovascular disease (CVD) risk profiles later in life. We investigated whether genetic liability to pre-eclampsia/eclampsia and gestational hypertension is associated with CVD risk factors and occurrence of CVD events.MethodsWe obtained genetic associations with HDPs from a genome-wide association study and used individual-participant-data of women and men from the UK Biobank to obtain genetic associations with CVD risk factors and CVD events (defined as myocardial infarction or stroke). The rationale for including men and nulligravidae was to study genetic liability to HDPs and CVD risk without experiencing the underlying phenotype. We applied Mendelian Randomisation analysis using inverse variance weighted regression in our primary analysis.ResultsWe included 264,160 women (mean age 56.4 [SD 8.0]) and 223,043 men (mean age 56.7 [8.2]) with available genetic data. Genetically proxied pre-eclampsia/eclampsia was related to higher risk of CVD with odds ratios of 1.20 (1.01, 1.43) and 1.29 (1.08, 1.53) in women and men, respectively. For genetically proxied gestational hypertension, odds ratios for CVD were 1.22 (1.10, 1.36) and 1.28 (1.16, 1.42) in women and men, respectively. Furthermore, genetically proxied HDPs were associated with higher levels of systolic and diastolic blood pressure and younger age at hypertension diagnosis in both women and men.ConclusionsGenetic liability to HDPs including pre-eclampsia/eclampsia and gestational hypertension is associated with higher CVD risk, implying biological mechanisms relating to these disorders are causally related to CVD risk in both women and men.
Antimicrobial peptides modulate lung injury by altering the intestinal microbiota
Authors: Abdelgawad Ahmed , Nicola Teodora , Martin Isaac , Halloran Brian A. , Tanaka Kosuke , Adegboye Comfort Y. , Jain Pankaj , Ren Changchun , Lal Charitharth V. , Ambalavanan Namasivayam , O’Connell Amy E. , Jilling Tamás , Willis Kent A. 
Published: March 2023

SUMMARYMammalian mucosal barriers secrete antimicrobial peptides (AMPs) as critical host-derived regulators of the microbiota. However, mechanisms that support homeostasis of the microbiota in response to inflammatory stimuli such as supraphysiologic oxygen remain unclear. Here, we show that neonatal mice breathing supraphysiologic oxygen or direct exposure of intestinal organoids to supraphysiologic oxygen suppress the intestinal expression of AMPs and alters the composition of the intestinal microbiota. Oral supplementation of the prototypical AMP lysozyme to hyperoxia exposed neonatal mice reduced hyperoxia-induced alterations in their microbiota and was associated with decreased lung injury. Our results identify a gut-lung axis driven by intestinal AMP expression and mediated by the intestinal microbiota that is linked to lung injury. Together, these data support that intestinal AMPs modulate lung injury and repair.Graphical AbstractIn BriefUsing a combination of murine models and organoids, Abdelgawad and Nicola et al. find that suppression of antimicrobial peptide release by the neonatal intestine in response to supra-physiological oxygen influences the progression of lung injury likely via modulation of the ileal microbiota.HighlightsSupraphysiologic oxygen exposure alters intestinal antimicrobial peptides (AMPs).Intestinal AMP expression has an inverse relationship with the severity of lung injury.AMP-driven alterations in the intestinal microbiota form a gut-lung axis that modulates lung injury.AMPs may mediate a gut-lung axis that modulates lung injury.
Structure-Based Neural Network Protein-Carbohydrate Interaction Predictions at the Residue Level
Authors: Canner Samuel W. , Shanker Sudhanshu , Gray Jeffrey J. 
Published: March 2023

AbstractCarbohydrates dynamically and transiently interact with proteins for cell-cell recognition, cellular differentiation, immune response, and many other cellular processes. Despite the molecular importance of these interactions, there are currently few reliable computational tools to predict potential carbohydrate binding sites on any given protein. Here, we present two deep learning models named CArbohydrate-Protein interaction Site IdentiFier (CAPSIF) that predict carbohydrate binding sites on proteins: (1) a 3D-UNet voxel-based neural network model (CAPSIF:V) and (2) an equivariant graph neural network model (CAPSIF:G). While both models outperform previous surrogate methods used for carbohydrate binding site prediction, CAPSIF:V performs better than CAPSIF:G, achieving test Dice scores of 0.597 and 0.543 and test set Matthews correlation coefficients (MCCs) of 0.599 and 0.538, respectively. We further tested CAPSIF:V on AlphaFold2-predicted protein structures. CAPSIF:V performed equivalently on both experimentally determined structures and AlphaFold2 predicted structures. Finally, we demonstrate how CAPSIF models can be used in conjunction with local glycan-docking protocols, such as GlycanDock, to predict bound protein-carbohydrate structures.
A novel sustained release therapy of combined VEGF and TNF-α inhibitors leads to pan-ocular protection for months after severe ocular trauma
Authors: Zhou Chengxin , Lei Fengyang , Hui Pui-Chuen , Wolkow Natalie , Dohlman Claes H. , Vavvas Demetrios G. , Chodosh James , Paschalis Eleftherios I. 
Published: March 2023

AbstractPurposeTo develop a clinically feasible and practical therapy for multi-ocular protection following ocular injury by using a thermosensitive drug delivery system (DDS) for sustained delivery of TNF-α and VEGF inhibitors to the eye.MethodsA thermosensitive, biodegradable hydrogel DDS (PLGA-PEG-PLGA triblock polymer) loaded with 0.7mg of adalimumab and 1.4 mg of aflibercept was injected subconjunctivally in Dutch-belted pigmented rabbits after corneal alkali injury. The polymer was tuned to transition from liquid to gel upon contact with body temperature without need of a catalyst. Control rabbits received 2mg of IgG loaded DDS or 1.4mg aflibercept loaded DDS. Animals were followed for 3 months and assessed for tolerability and prevention of corneal neovascularization (NV), improvement of corneal re-epithelialization, inhibition of retinal ganglion cell (RGC) and optic nerve axon loss, and inhibition of immune cell infiltration into the cornea. Drug release kinetics was assessedin vivousing aqueous humor protein analysis.ResultsA single subconjunctival administration of dual anti-TNFα/anti-VEGF DDS achieved sustained 3-month delivery of antibodies to the anterior chamber, iris, ciliary body, and retina. Administration after corneal alkali burn suppressed CD45+immune cell infiltration into the cornea, completely inhibited cornea NV for 3 months, accelerated corneal re-epithelialization and wound healing, and prevented RGC and optic nerve axon loss at 3 months. In contrast, anti-VEGF alone or IgG DDS treatment led to persistent corneal epithelial defect, increased infiltration of CD45+immune cells into the cornea, and significant loss of RGCs and optic nerve axons at 3 months. Aqueous humor protein analysis showed first-order release kinetics without adverse effects at the injection site.ConclusionSustained concomitant inhibition of TNF-α and VEGF using a biodegradable, slow-release thermosensitive DDS provides significant ocular protection and prevents corneal neovascularization and irreversible damage to retina and optic nerve after corneal alkali injury. This therapeutic approach has the potential to dramatically improve the outcomes of severe ocular injuries in patients.
Mitochondrial genome evolution in the Diprionidae: Major gene rearrangement in the basal Hymenoptera
Authors: Li Min , Niu Gengyun , Xu Min , Dai Mengxuan , Jiang Xinghong , Ma Yong , Meng Guanliang , Wei Meicai 
Published: March 2023

AbstractIn comparison to other non-parasitic basal lineages, Apocrita have consistently demonstrated a greatly accelerated rate of gene rearrangement. A number of mechanisms or correlates have been proposed for this observation, such as oxidative stress tolerated by exposure to the host immune system might lead to a high proportion of rearranged mt-genomes. Our studies reveal that gene rearrangements involving the protein-coding gene are present in the basal Hymenoptera lineage based on enriched sampling. We speculate the processes of diversification of rearrangements in the vicinity ofnad2involved tRNAs and NCRs by producing the chronogram of Diprionids. Furthermore, we investigated the relationship between rearranged genes and their nucleotide sequences. In conclusion, we demonstrate the great potential of gene order and associated sequence features as phylogenetic markers in the study of Hymenoptera evolution, offering a new perspective on studying organisms that undergo frequent gene rearrangements.
Mistakes in the re-analysis of lipidomic data obtained from a human model of resolving inflammation lead to erroneous conclusions
Authors: Dalli Jesmond 
Published: March 2023

AbstractRecent years have seen an increased interest in the biology of specialized pro-resolving lipid mediators (SPM) with many investigators evaluating both their endogenous production as well as their biological and pharmacological properties. This increased interest has led to a rapid evolution in our understanding of both the biological and pharmacological activities of these mediators with their endogenous formation and biological activities being documented in a wide range of species that spans the evolutionary tree including fish, planaria and humans. Despite this plethora of evidence in a recent article Homer and colleagues claim that the reanalysis of a published dataset - partly originating from our laboratory - demonstrates that these molecules are absent in human blister exudates, contrary to the evidence published earlier. Based on their observations these Authors conclude that SPM are not relevant to human resolution biology. In this manuscript a reanalysed the dataset using unbiased methodologies and criteria that align with those recently proposed by the UK Consortium on Metabolic Phenotyping was performed together with the re-analysis of the dataset using criteria described by Homer and colleagues. Results from this re-analysis confirmed presence of SPM in human blister exudates and that the methodologies employed for quantitation of these molecules are robust. We also discuss how the results obtained in the article published by Homer and colleagues present several points of concern including the use of employ an arbitrary cut-off value to assign the noise for all the transitions used that does not take into consideration the fluctuation of the signal in each transition and therefore is not truly representative of the background signal. The use of different transitions to those employed in the original analyses and misreporting of findings based on the criteria employed. In conclusion the evidence presented herein demonstrates that correct application of rigorous criteria accepted by the community is essential in ensuring accurate identification of mediators and avoid blatant mistakes which can impact on the scientific development of the field.
Exposure to the persistent organic pollutant 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) disrupts development of the zebrafish inner ear
Authors: Cintrón-Rivera Layra G. , Oulette Gabrielle , Prakki Aishwarya , Burns Nicole M. , Patel Ratna , Cyr Rachel , Plavicki Jessica 
Published: March 2023

AbstractDioxins are a class of highly toxic and persistent environmental pollutants that have been shown through epidemiological and laboratory-based studies to act as developmental teratogens. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent dioxin congener, has a high affinity for the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor. TCDD-induced AHR activation during development impairs nervous system, cardiac, and craniofacial development. Despite the robust phenotypes previously reported, the characterization of developmental malformations and our understanding of the molecular targets mediating TCDD-induced developmental toxicity remains limited. In zebrafish, TCDD-induced craniofacial malformations are produced, in part, by the downregulation ofSRY-box transcription factor 9b(sox9b), a member of the SoxE gene family.sox9b, along with fellow SoxE gene family memberssox9aandsox10, have important functions in the development of the otic placode, the otic vesicle, and, ultimately, the inner ear. Given thatsox9bin a known target of TCDD and that transcriptional interactions exist among SoxE genes, we asked whether TCDD exposure impaired the development of the zebrafish auditory system, specifically the otic vesicle, which gives rise to the sensory components of the inner ear. Using immunohistochemistry,in vivoconfocal imaging, and time-lapse microscopy, we assessed the impact of TCDD exposure on zebrafish otic vesicle development. We found exposure resulted in structural deficits, including incomplete pillar fusion and altered pillar topography, leading to defective semicircular canal development. The observed structural deficits were accompanied by reduced collagen type II expression in the ear. Together, our findings reveal the otic vesicle as a novel target of TCDD-induced toxicity, suggest that the function of multiple SoxE genes may be affected by TCDD exposure, and provide insight into how environmental contaminants contribute to congenital malformations.HighlightsThe zebrafish ear is necessary to detect changes in motion, sound, and gravity.Embryos exposed to TCDD lack structural components of the developing ear.TCDD exposure impairs formation of the fusion plate and alters pillar topography.The semicircular canals of the ear are required to detect changes in movement.Following TCDD exposure embryos fail to establish semicircular canals.
PhAT: A flexible open-source GUI-driven toolkit for photometry analysis
Authors: Murphy Kathleen Z. , Haile Eyobel , McTigue Anna , Pierce Anne F. , Donaldson Zoe R. 
Published: March 2023

ABSTRACTPhotometry approaches detect sensor-mediated changes in fluorescence as a proxy for rapid molecular changes within the brain. As a flexible technique with a relatively low cost to implement, photometry is rapidly being incorporated into neuroscience laboratories. While multiple data acquisition systems for photometry now exist, robust analytical pipelines for the resulting data remain limited. Here we present thePhotometryAnalysisToolkit (PhAT) - a free open source analysis pipeline that provides options for signal normalization, incorporation of multiple data streams to align photometry data with behavior and other events, calculation of event-related changes in fluorescence, and comparison of similarity across fluorescent traces. A graphical user interface (GUI) enables use of this software without prior coding knowledge. In addition to providing foundational analytical tools, PhAT is designed to readily incorporate community-driven development of new modules for more bespoke analyses, and data can be easily exported to enable subsequent statistical testing and/or code-based analyses. In addition, we provide recommendations regarding technical aspects of photometry experiments including sensor selection and validation, reference signal considerations, and best practices for experimental design and data collection. We hope that the distribution of this software and protocol will lower the barrier to entry for new photometry users and improve the quality of collected data, increasing transparency and reproducibility in photometry analyses.Basic Protocol 1: Software Environment InstallationBasic Protocol 2: GUI-driven Fiber Photometry AnalysisBasic Protocol 3: Adding Modules
Single molecule MATAC-seq reveals key determinants of DNA replication origin efficiency
Authors: Chanou Anna , Weiβ Matthias , Holler Karoline , Straub Tobias , Krietsch Jana , Sanchi Andrea , Ummethum Henning , Lee Clare S. K. , Kruse Elisabeth , Trauner Manuel , Werner Marcel , Lalonde Maxime , Lopes Massimo , Scialdone Antonio , Hamperl Stephan 
Published: March 2023

Summary:Stochastic origin activation gives rise to significant cell-to-cell variability in the pattern of genome replication. The molecular basis for heterogeneity in efficiency and timing of individual origins is a long-standing question. Here, we developedMethylationAccessibility ofTArgetedChromatin domain Sequencing (MATAC-Seq) to determine single-molecule chromatin accessibility of specific genomic loci after targeted purification in their native chromatin context. Applying MATAC-Seq to selected early-efficient (EE) and late-inefficient (LI) budding yeast replication origins revealed large heterogeneity of chromatin states. Disruption of INO80 or ISW2 chromatin remodeling complexes leads to changes at individual nucleosomal positions that correlate with changes in their replication efficiency. We found a chromatin state with an optimal 100-115bp nucleosome-free region in combination with surrounding well-positioned nucleosomes and open +2 linker region is a strong predictor for efficient origin activation. Thus, MATAC-Seq identifies the large spectrum of alternative chromatin states that co-exist on a given locus previously masked in population-based experiments and provides a mechanistic basis for origin activation heterogeneity during DNA replication of eukaryotic cells. Consequently, our single-molecule assay for chromatin accessibility will be ideal to define single-molecule heterogeneity across many fundamental biological processes such as transcription, replication, or DNA repairin vitroandex vivo.
Congruent downy mildew-associated microbiomes reduce plant disease and function as transferable resistobiomes
Authors: Goossens P. , Spooren J. , Baremans K.C.M. , Andel A. , Lapin D. , Echobardo N. , Pieterse C.M.J. , Van den Ackerveken G. , Berendsen R.L. 
Published: March 2023

SummaryRoot-associated microbiota can protect plants against severe disease outbreaks. In the model-plantArabidopsis thaliana, leaf infection with the obligate downy mildew pathogenHyaloperonospora arabidopsidis(Hpa) results in a shift in the root exudation profile, therewith promoting the growth of a selective root microbiome that induces a systemic resistance againstHpain the above-ground plant parts. Here we show that, additionally, a conserved subcommunity of the recruited soil microbiota becomes part of a pathogen-associated microbiome in the phyllosphere that is vertically transmitted with the spores of the pathogen to consecutively infected host plants. This subcommunity ofHpa-associated microbiota (HAM) limits pathogen infection and is therefore coined a “resistobiome”. The HAM resistobiome consists of a small number of bacterial species and was first found in our routinely maintained laboratory cultures of independentHpastrains. When co-inoculated withHpaspores, the HAM rapidly dominates the phyllosphere of infected plants, negatively impactingHpaspore formation. Remarkably, isogenic bacterial isolates of the abundantly-present HAM species were also found in strictly separatedHpacultures across Europe, and even in early published genomes of this obligate biotroph. Our results highlight that pathogen-infected plants can recruit protective microbiota via their roots to the shoots where they become part of a pathogen-associated resistobiome that helps the plant to fight pathogen infection. Understanding the mechanisms by which pathogen-associated resistobiomes are formed will enable the development of microbiome-assisted crop varieties that rely less on chemical crop protection.
Generalising the HCP multimodal cortical parcellation to UK Biobank
Authors: Williams Logan Z. J. , Glasser Matthew F. , Alfaro-Almagro Fidel , Dahan Simon , Fawaz Abdulah , Coalson Timothy S. , Fitzgibbon Sean P. , Suliman Mohamed A. , Van Essen David C. , Smith Stephen M. , Edwards A. David , Robinson Emma C. 
Published: March 2023

AbstractThe Human Connectome Project Multimodal Parcellation (HCP_MMP1.0) provides a robustin vivomap of the cerebral cortex, which demonstrates variability in structure and function that cannot be captured through diffeomorphic image registration alone. The HCP successfully employed a fully-connected neural network architecture to capture this variation, however it is unclear whether this approach generalises to other datasets with less rich imaging protocols. In this paper we propose and validate a novel geometric deep learning framework for generating individualised HCP_MMP1.0 parcellations in UK Biobank (UKB), an extremely rich resource that has led to numerous breakthroughs in neuroscience. To address substantial differences in image acquisition (for example, 6 minutes of resting-state fMRI per subject for UKB vs. 60 minutes per subject for HCP), we introduce a multi-step learning procedure including pretraining with a convolutional autoencoder. Compared to a fully-connected baseline, our proposed framework improved average detection rate across all areas by 10.4% (99.1% vs 88.7%), and detection of the worst performing area by 51.0% (80.9% vs. 29.9%). Importantly, this was not a result of the framework predicting one consistent parcellation across subjects, as visual inspection indicated that our method was sensitive to atypical cortical topographies. Code and trained models will be made available athttps://www.github.com.
What is hidden in the darkness? Deep-learning assisted large-scale protein family curation uncovers novel protein families and folds
Authors: Durairaj Janani , Waterhouse Andrew M. , Mets Toomas , Brodiazhenko Tetiana , Abdullah Minhal , Studer Gabriel , Akdel Mehmet , Andreeva Antonina , Bateman Alex , Tenson Tanel , Hauryliuk Vasili , Schwede Torsten , Pereira Joana 
Published: March 2023

AbstractDriven by the development and upscaling of fast genome sequencing and assembly pipelines, the number of protein-coding sequences deposited in public protein sequence databases is increasing exponentially. Recently, the dramatic success of deep learning-based approaches applied to protein structure prediction has done the same for protein structures. We are now entering a new era in protein sequence and structure annotation, with hundreds of millions of predicted protein structures made available through the AlphaFold database. These models cover most of the catalogued natural proteins, including those difficult to annotate for function or putative biological role based on standard, homology-based approaches. In this work, we quantified how much of such “dark matter” of the natural protein universe was structurally illuminated by AlphaFold2 and modelled this diversity as an interactive sequence similarity network that can be navigated athttps://uniprot3d.org/atlas/AFDB90v4. In the process, we discovered multiple novel protein families by searching for novelties from sequence, structure, and semantic perspectives. We added a number of them to Pfam, and experimentally demonstrate that one of these belongs to a novel superfamily of translation-targeting toxin-antitoxin systems, TumE-TumA. This work highlights the role of large-scale, evolution-driven protein comparison efforts in combination with structural similarities, genomic context conservation, and deep-learning based function prediction tools for the identification of novel protein families, aiding not only annotation and classification efforts but also the curation and prioritisation of target proteins for experimental characterisation.