bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancing patient representation learning from electronic health records through predicted family relations
Authors: Huang Xiayuan , Arora Jatin , Erzurumluoglu Abdullah Mesut , Lam Daniel ,   Boehringer Ingelheim – Global Computational Biology and Digital Sciences, Zhao Hongyu , Ding Zhihao , Wang Zuoheng , de Jong Johann 
Published: March 2024

AbstractArtificial intelligence and machine learning are powerful tools in analyzing electronic health records (EHRs) for healthcare research. Despite the recognized importance of family health history, in healthcare research individual patients are often treated as independent samples, overlooking family relations. To address this gap, we present ALIGATEHR, which models predicted family relations in a graph attention network and integrates this information with a medical ontology representation. Taking disease risk prediction as a use case, we demonstrate that explicitly modeling family relations significantly improves predictions across the disease spectrum. We then show how ALIGATEHR’s attention mechanism, which links patients’ disease risk to their relatives’ clinical profiles, successfully captures genetic aspects of diseases using only EHR diagnosis data. Finally, we use ALIGATHER to successfully distinguish the two main inflammatory bowel disease subtypes (Crohn’s disease and ulcerative colitis), illustrating its great potential for improving patient representation learning for predictive and descriptive modeling of EHRs.
PICK1 links KIBRA and AMPA receptors in coiled-coil-driven supramolecular complexes
Authors: Shao Xin , Volk Lenora 
Published: March 2024

AbstractThe human memory-associated protein KIBRA regulates synaptic plasticity and trafficking of AMPA-type glutamate receptors, and is implicated in multiple neuropsychiatric and cognitive disorders. How KIBRA forms complexes with and regulates AMPA receptors remains unclear. Here, we show that KIBRA does not interact directly with the AMPA receptor subunit GluA2, but that PICK1, a key regulator of AMPA receptor trafficking, can serve as a bridge between KIBRA and GluA2. We identified structural determinants of KIBRA-PICK1-AMPAR complexes by investigating interactions and cellular expression patterns of different combinations of KIBRA and PICK1 domain mutants. We find that the PICK1 BAR domain, a coiled-coil structure, is sufficient for interaction with KIBRA, whereas mutation of the BAR domain disrupts KIBRA-PICK1-GluA2 complex formation. In addition, KIBRA recruits PICK1 into large supramolecular complexes, a process which requires KIBRA coiled-coil domains. These findings reveal molecular mechanisms by which KIBRA can organize key synaptic signaling complexes.
The gut contractile organoid: a novel model for studying the gut motility regulated by coordinating signals between interstitial cells of Cajal and smooth muscles
Authors: Yagasaki Rei , Nakamura Ryo , Shikaya Yuuki , Tadokoro Ryosuke , Hao Ruolin , Wang Zhe , Eiraku Mototsugu , Inaba Masafumi , Takahashi Yoshiko 
Published: March 2024

AbstractThe gut undergoes peristaltic movements regulated by intricate cellular interactions. However, they have poorly been explored due to a lack of model system. We here developed a novel contractile organoid that is derived from the muscle layer of chicken embryonic hindgut. The organoid contained smooth muscle cells (SMCs) and interstitial cells of Cajal (ICCs; pacemaker) with few enteric neurons, and underwent periodic contractions. The organoid formed by self-organization with morphological arrangements of ICCs (internal) and SMCs (peripheral), allowing identification of these cells in live. GCaMP-Ca2+imaging analyses revealed that Ca2+transients between ICC- ICC, SMC-SMC or SMC-ICC were markedly coordinated. Pharmacological studies further showed that gap junctions play a role in ICC-to-SMC signaling, and also possible feedback from SMC’s contraction to ICC’s pace-making activities. In addition, two organoids with different rhythm became synchronized when mediated by SMCs, unveiling a novel contribution of SMCs to ICC’s pace-making. The gut contractile organoid developed in this study offers a useful model to understand the mechanisms underlying the rhythm coordination between/among ICCs and SMCs during gut peristaltic movements.
Spatial Dynamics of the Developing Human Heart
Authors: Lázár Enikő , Mauron Raphaël , Andrusivová Žaneta , Foyer Julia , He Mengxiao , Larsson Ludvig , Shakari Nick , Salas Sergio Marco , Avenel Christophe , Sariyar Sanem , Hansen Jan N. , Vicari Marco , Czarnewski Paulo , Braun Emelie , Li Xiaofei , Bergmann Olaf , Sylvén Christer , Lundberg Emma , Linnarsson Sten , Nilsson Mats , Sundström Erik , Adameyko Igor , Lundeberg Joakim 
Published: March 2024

ABSTRACTHeart development relies on a topologically defined interplay between a diverse array of cardiac cells. We finely curated spatial and single-cell measurements with subcellular imaging-based transcriptomics validation to explore spatial dynamics during early human cardiogenesis. Analyzing almost 80,000 individual cells and 70,000 spatially barcoded tissue regions between the 5.5thand 14thpostconceptional weeks, we identified 31 coarse- and 72 fine-grained cell states and mapped them to highly resolved cardiac cellular niches. We provide novel insight into the development of the cardiac pacemaker-conduction system, heart valves, and atrial septum, and decipher heterogeneity of the hitherto elusive cardiac fibroblast population. Furthermore, we describe the formation of cardiac autonomic innervation and present the first spatial account of chromaffin cells in the fetal human heart. We support independent exploration of our datasets by an open-access, spatially centric interactive viewer. In summary, our study delineates the cellular and molecular landscape of the developing heart’s architecture, offering links to genetic causes of heart disease.
Anti-fungal recombinant psoriasin effectively inhibits Candida albicans growth on denture base
Authors: Lifshits Lucia Adriana , Brohnshtein Edward , Attias May , Breuer Yoav , Cohen Adi , Gabay Matan , Sova Marina , Weinberg Evgeny , Zenziper Eran , Bar Daniel Z. , Sterer Nir , Gal Maayan 
Published: March 2024

AbstractOral candidiasis leading to denture stomatitis is a fungal infection resulting from unregulated growth and adhesion mainly ofCandida albicansonto acrylic denture base. Once the biofilm is formed, it is immune resistant and mainstay treatments involve toxic chemical antifungal agents or mechanical cleaning techniques, both offer limited efficacy. Consequently, there is an urgent need for more effective and safer therapeutic approaches. While biological modalities are expanding in general medicine, the exploration of protein-based therapeutics in dental medicine remains limited. This research evaluates the inhibitory effect of recombinantly expressed psoriasin on the growth ofCandida albicanson polymethyl methacrylate denture bases. Psoriasin, also known as S100-A7, has shown promise in treating microbial skin infections, and its natural presence in saliva makes it a promising candidate for treating oral microbial infections. Our findings indicate that psoriasin exhibits a strong, dose-dependent inhibition ofCandida albicansgrowth. Further, we incubated a polymethyl methacrylate denture base within the psoriasin solution. Notably, immersing the denture base in the solution completely eradicated fungal growth. Our research utilizes natural antifungal proteins within biomedical devices like denture bases, suggesting psoriasin as a safe alternative to chemical antifungals in dental medicine.
Chemical modification of hyaluronan oligosaccharides differentially modulates hyaluronan- hyaladherin interactions
Authors: Dodd Rebecca J. , Blundell Charles D. , Sattelle Benedict M. , Enghild Jan J. , Milner Caroline M. , Day Anthony J. 
Published: March 2024

AbstractThe glycosaminoglycan hyaluronan (HA) is a ubiquitous, non-sulphated polysaccharide with diverse biological roles mediated through its interactions with HA-binding proteins (HABPs). Most HABPs belong to the Link module superfamily, including the major HA receptor, CD44, and secreted protein TSG-6, which catalyzes the covalent transfer of Heavy Chains (HC) from inter-a-inhibitor (IaI) onto HA. The structures of the HA-binding domains (HABD) of CD44 (HABD_CD44) and TSG-6 (Link_TSG6) have been determined and their interactions with HA extensively characterized. The mechanisms of binding are different, with Link_TSG6 interacting with HA primarily via ionic and CH−π interactions, whereas HABD_CD44 binds solely via hydrogen bonds and van der Waals forces. Here we exploit these differences to generate HA oligosaccharides, chemically modified at their reducing ends, that bind specifically and differentially to these target HABPs. Hexasaccharides (HA6AN) modified with 2- or 3-aminobenzoic acid or 2-amino-4-methoxybenzoic acid (HA6-2AA, HA6-3AA, HA6-2A4MBA, respectively) had increased affinities for Link_TSG6 compared to unmodified HA6AN. These modifications did not increase the affinity for CD44_HABD. A model of HA6-2AA (derived from the solution dynamic 3D structure of HA4-2AA) was docked into the Link_TSG6 structure, providing evidence that the 2AA-carboxyl forms a salt bridge with Arginine-81. These modeling results informed a 2ndseries of chemical modifications for HA oligosaccharides, which again showed differential binding to the two proteins. Several modifications to HA4and HA6were found to convert the oligosaccharide into substrates for HC-transfer, whereas unmodified HA4and HA6are not. This study has generated valuable research tools to further understand HA biology.
Contrast-enhanced ultrasound imaging detects anatomical and functional changes in rat cervical spine microvasculature with normal aging
Authors: Harmon Jennifer N. , Chandran Preeja , Chandrasekaran Abarajithan , Hyde Jeffrey E. , Hernandez Gustavo J. , Reed May J. , Bruce Matthew F. , Khaing Zin Z. 
Published: March 2024

AbstractNormal aging is associated with significant deleterious cerebrovascular changes; these have been implicated in disease pathogenesis and increased susceptibility to ischemic injury. While these changes are well documented in the brain, few studies have been conducted in the spinal cord. Here, we utilize specialized contrast-enhanced ultrasound (CEUS) imaging to investigate age-related changes in cervical spinal vascular anatomy and hemodynamics in male Fisher 344 rats, a common strain in aging research. Aged rats (24-26 mo., N=6) exhibited significant tortuosity in the anterior spinal artery and elevated vascular resistance compared to adults (4-6 mo., N=6; tortuosity index 2.20±0.15 vs 4.74±0.45, p<0.05). Baseline blood volume was lower in both larger vessels and the microcirculation in the aged cohort, specifically in white matter (4.44e14±1.37e13 vs 3.66e14±2.64e13 CEUS bolus AUC, p<0.05). To elucidate functional differences, animals were exposed to a hypoxia challenge; whereas adult rats exhibited significant functional hyperemia in both gray and white matter (GM: 1.13±0.10-fold change from normoxia, p<0.05; WM: 1.16±0.13, p<0.05), aged rats showed no response. Immunohistochemistry revealed reduced pericyte coverage and activated microglia behavior in aged rats, which may partially explain the lack of vascular response. This study provides the firstin vivodescription of age-related hemodynamic differences in the cervical spinal cord.
Characterisation ofSkoliomonasgen. nov., a haloalkaliphilic anaerobe related to barthelonids (Metamonada)
Authors: Eglit Yana , Williams Shelby K. , Roger Andrew J. , Simpson Alastair G.B. 
Published: March 2024

AbstractMetamonads are a large and exclusively anaerobic clade of protists. Additionally, metamonads are one of the three clades with a proposed ‘excavate’ ancestral cell morphology, characterised by a conspicuous ventral groove often accompanied by a posterior flagellum with a vane. Here, we characterise four isolates of an anaerobic bacterivorous flagellate from hypersaline and alkaline soda lake environments, which represents a novel clade. Small subunit ribosomal RNA (SSU rRNA) gene phylogenies support recent phylogenomic analyses in placing this clade as the sister group toBarthelonaspp., a lineage that is itself sister to or deeply branching within Fornicata (Metamonada). The cells have a distinctive morphology comprised of a hunchbacked cell body with a narrow twisting ventral groove ending in a large opening to a conspicuous cytopharynx curving up the dorsal side of the cell. The right margin of the groove is defined by a thin ‘lip’ that twists slightly to the left towards the posterior. The posterior of the cell ends in a spike up to half a cell body long. The posterior flagellum bears a wide ventral-facing vane. One isolate forms cysts with a complex wall and a single plug. The narrow ventral groove and elongate cytopharynx are shared with barthelonids. We describe one isolate asSkoliomonas litria, gen. et sp. nov. Further investigation of mitochondrial-related organelles (MRO) inSkoliomonasspp. and detailed ultrastructural studies would be important to understanding the evolution of adaptation to anaerobic conditions in Metamonads—especially fornicates—as well as the evolution of the ‘excavate’ groove.
Trends in using intraoperative parathyroid monitoring during parathyroidectomy: Protocol and rationale for a cross-sectional survey study of North American surgeons
Authors: Staibano Phillip , McKechnie Tyler , Thabane Alex , Xie Michael , Zhang Han , Gupta Michael K. , Au Michael , Pasternak Jesse D. , Parpia Sameer , (Ted) Young JEM , Bhandari Mohit 
Published: March 2024

ABSTRACTIntroductionHyperparathyroidism is a common endocrine disorder that can be secondary to a single or multiple abnormal parathyroid glands and can occur in the context of chronic kidney disease (CKD). There are three types of hyperparathyroidism, and all are definitively managed via surgical extirpation of abnormal parathyroid gland tissue. Intraoperative parathyroid hormone (IOPTH) monitoring was introduced over three decades ago and has been shown to improve clinical outcomes in patients with primary hyperparathyroidism (PHPT). As the incidence of PHPT rises due to improving screening globally and the incidence of CKD rises, it will be important to optimize adoption and standardization of IOPTH within endocrine surgery centers around the world. We will perform a cross-sectional survey study of surgeon rationale, operational details, and barriers associated with IOPTH adoption across North America.Methods and analysisWe will utilize a convenience sampling technique to distribute an online survey to head and neck surgeons and endocrine surgeons across North America. This survey will be distributed via email to three North American professional societies (i.e., Canadian Society for Otolaryngologists–Head and Neck Surgeons, American Head and Neck Society, and American Association of Endocrine Surgeons). The survey will consist of 30 multiple choice questions that are divided into three concepts: (1) participant demographics and training details, (2) details of surgical adjuncts during parathyroidectomy, and (3) barriers to adoption of IOPTH. Descriptive analyses and multiple logistic regression models will be used to evaluate the impact of demographic, institutional, and training variables on the use of IOPTH monitoring and barriers to IOPTH adoption.DiscussionThis study will explore IOPTH monitoring for guiding parathyroid surgeries in secondary and tertiary hyperparathyroidism. An ability to capture surgeon practices regarding IOPTH monitoring will inform trials aimed to help optimize IOPTH in challenging populations.Ethics and disseminationEthics approval was obtained by the Hamilton Integrated Research Ethics Board (2024-17173-GRA). We do not expect any survey respondents to experience any harms because of participating in this study. We plan to present the results of this study at national and international conferences, and we will publish these findings in peer-reviewed surgical journals. We plan to use these study findings to advocate for adoption of IOPTH technologies and inform future studies and trials.
Dissociable roles of the mPFC-to-VTA Pathway in the control of iImpulsive Action and Risk-Related Decision-Making in Roman High- And Low-Avoidance Rats
Authors: Urueña-Méndez Ginna , Arrondeau Chloé , Marchessaux Florian , Goutaudier Raphaël , Ginovart Nathalie 
Published: March 2024

AbstractImpulsivity is a multidimensional trait associated with various psychiatric disorders including drug abuse. Impulsivity facets, such as impulsive action and risk-related decision-making (RDM), have been associated with reduced frontocortical activity and alterations in dopamine function in the ventral tegmental area (VTA). However, despite direct projections from the medial prefrontal cortex (mPFC) to the VTA, the specific role of the mPFC-to-VTA pathway in the control of impulsive behaviors remains unexplored. Here, we used Positron Emission Tomography with [18F]-Fluorodeoxyglucose to evaluate brain metabolic activity in Roman High-(RHA) and Low-avoidance (RLA) rats, which exhibit innate differences in impulsivity. Notably, we used a viral-based intersectional chemogenetic strategy to isolate, for the first time, the role of the mPFC-to-VTA pathway in controlling impulsive behaviors. We selectively activated the mPFC-to-VTA pathway in RHAs and inhibited it in RLAs, and assessed the effects on impulsive action and RDM in the rat gambling task. Our results showed that RHA rats displayed higher impulsive action, less optimal decision-making, and lower cortical activity than RLA rats at baseline. Chemogenetic activation of the mPFC-to-VTA pathway reduced impulsive action in RHAs, whereas chemogenetic inhibition had the opposite effect in RLAs. However, these manipulations did not affect RDM. Thus, by specifically and bidirectionally targeting the mPFC-to-VTA pathway in a phenotype-dependent way, we were able to revert innate patterns of impulsive action, but not RDM. Our findings suggest a dissociable role of the mPFC-to-VTA pathway in impulsive action and RDM, highlighting its potential as a target for investigating impulsivity-related disorders.
GDFold2: a fast and parallelizable protein folding environment with freely defined objective functions
Authors: Mi Tianyu , Xiao Nan , Gong Haipeng 
Published: March 2024

AbstractAn important step of mainstream protein structure prediction is to model the 3D protein structure based on the predicted 2D inter-residue geometric information. This folding step has been integrated into a unified neural network to allow end-to-end training in state-of-the-art methods like AlphaFold2, but is separately implemented using the Rosetta folding environment in some traditional methods like trRosetta. Despite the inferiority in prediction accuracy, the conventional approach allows for the sampling of various protein conformations compatible with the predicted geometric constraints, partially capturing the dynamic information. Here, we propose GDFold2, a novel protein folding environment, to address the limitations of Rosetta. On the one hand, GDFold2 is highly computationally efficient, capable of accomplishing multiple folding processes in parallel within the time scale of minutes for generic proteins. On the other hand, GDFold2 supports freely defined objective functions to fulfill diversified optimization requirements. Moreover, we propose a quality assessment (QA) model to provide reliable prediction on the quality of protein structures folded by GDFold2, thus substantially simplifying the selection of structural models. GDFold2 and the QA model could be combined to investigate the transition path between protein conformational states, and the online server is available athttps://structpred.life.tsinghua.edu.cn/server_gdfold2.html.
CircRNA-Pro: A Novel Toolkit for High-Precision Detection of Differentially Expressed Circular RNAs and Translatable Circular RNAs
Authors: Song Wei , Yu Liqun , Ye Tianrui , Zhang Honglei , Wang Yan , Yang Yang , Shen Dawei , Piao Weilan , Jin Hua 
Published: March 2024

AbstractWith the increasing discovery of circular RNAs (circRNAs) and their critical roles in gene regulation and disease progression, there is a growing need for more accurate and efficient tools for circRNAs research. In response, we have developed an integrated software suite specifically for circRNAs. This all-in-one tool specializes in detecting differentially expressed circRNAs, including those with the potential to be translated into proteins, and allows for comparing against relevant databases, thereby enabling comprehensive circRNA profiling and annotation. To enhance the accuracy in detecting differentially expressed circRNAs, we incorporated three different software algorithms and cross-validated their results through mutual verification. Additionally, this toolkit improves the effectiveness in identifying translatable circRNAs by optimizing Ribo-seq alignment and verifying against public circRNA databases. The performance of circRNA-pro has been evaluated through its application to public RNA-seq and Ribo-seq datasets on breast cancer and SARS-CoV-2 infected cells, and the results obtained have been validated against previous literature and databases. Overall, our integrated toolkit provides a reliable workflow for circRNA research, facilitating insights into their diverse roles across life sciences.
The Structure of the Lujo Virus Spike Complex
Authors: Eilon-Ashkenazy Maayan , Cohen-Dvashi Hadas , Borni Sarah , Shaked Ron , Calinsky Rivka , Levy Yaakov , Diskin Ron 
Published: March 2024

AbstractLujo virus is a human pathogen that emerged as the etiology agent of a deadly viral disease in Africa. While it is a member of theArenaviridae, it is a distinct virus that does not classify with the classical ‘Old World’ or ‘New World’ groups of viruses in this family. It further utilizes neuropilin-2 (NRP2) as an entry receptor, a property that is not shared by other arenaviruses. So far, structural information is limited to the receptor binding domain of LUJV, and the overall organization of the trimeric complex, as well as the way NRP2 is recognized in the context of the complete viral spike, were unknown. Here, we present the cryo-EM structure of the complete, native, membrane-embedded spike complex of LUJV. We found that NRP2 is bound at the apex of the spike in a way that allows each trimer to engage with a single NRP2. Also, the complete receptor binding site is quaternary, depending on interactions contributed by neighboring protomers. Recognition of NRP2 involves an overlooked arginine-methionine interaction, which we have now characterized. This LUJV’s spike structure, which is the second determined structure of a complete arenaviral spike, points to similarities and differences in the structures of these viral spikes, informing vaccine design and allowing us to be better prepared to combat future outbreaks of this virus.
De novoGenome Sequencing and Annotation of a Thermophilic Cyanobacterium using the Oxford Nanopore Technologies Sequencing Platform
Authors: Woortman Dirk V. , Kandawa-Schulz Martha , Mehlmer Norbert , Brück Thomas B. 
Published: March 2024

AbstractIn this project the MinION DNA sequencing platform was tested and introduced. It was proven that Next-Generation Sequencing (NGS) is not restricted to core facilities, but can be implemented in a standard laboratory setting. This makes the MinION suitable for decentralized strain screening, development and quality monitoring applications in the biotechnology industry. Over the course of the MinION early Access Program, the device was used to sequence a novel extremophile cyanobacteria candidate isolated from a hot spring at Klein Barmen, Namibia. Thede novoassembly of the microorganism genome resulted in one bacterial chromosome without gaps. Further analysis showed, that significant variation/heterogeneity between related genomes is present. This underlines the novel character of the sequenced genome.