bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whole-genome sequencing of half-a-million UK Biobank participants
Authors: Li Shuwei , Carss Keren J , Halldorsson Bjarni V , Cortes Adrian ,   UK Biobank Whole-Genome Sequencing Consortium
Published: December 2023

Summary ParagraphWhole-genome sequencing (WGS) provides a comprehensive view of the genome, enabling detection of coding and non-coding genetic variation, and surveying complex regions which are difficult to genotype. Here, we report on whole-genome sequencing of 490,640 UK Biobank participants, building on previous genotyping1and whole-exome sequencing (WES) efforts2,3. This advance deepens our understanding of how genetics influences disease biology and further enhances the value of this open resource for the study of human biology and health. Coupling this dataset with rich phenotypic data, we surveyed within- and cross-ancestry genomic associations with health-related phenotypes and identified novel genetic and clinical insights. While most genome-wide significant associations with disease traits were primarily observed in Europeans, we also identified strong or novel signals in individuals of African and Asian ancestries. Deeper capture of exonic variation in both coding and UTR sequences, strengthened and surfaced novel insights relative to WES analyses. This landmark dataset, representing the largest collection of WGS and available to the UK Biobank research community, will enable advances into our understanding of the human genome, and facilitate the discovery of new diagnostics, therapeutics with higher efficacy and improved safety profile, and enable precision medicine strategies with the potential to improve global health.Abstract FigureGraphic summary.Framework of the WGS UKB study. This figure captures the flow of this manuscript. We start with the collection of patient samples by UK Biobank and followed by the strategy taken to perform WGS. We continue with quality control performed on GraphTyper and DRAGEN datasets, followed by variant calling of SNPs, in/dels, and structural variants (SV). Thereafter we defined the phenotypes (binary and quantitative) associated with SV, SNPs and at the gene level (rare variant analysis) and conclude with the definition of five ancestry groups and collective association effect as a cross-ancestry meta-analysis.
Haloperidol inhibits inflammasome activation via LAMTOR1 and reduces the risk of arthritides
Authors: Ambati Vidya L. , Yerramothu Praveen , Konduri Ranjith , Nguyen Joseph , Gelfand Bradley D. , Taylor E. Will , Werner Brian C. , Wang Shao-bin 
Published: December 2023

ABSTRACTGout is the most prevalent form of inflammatory arthritis in the world. Although multiple treatments exist, many patients are poorly responsive. Here we report, using a health insurance database analysis, that use of the anti-psychotic haloperidol is associated with a reduced risk of incident gout. Haloperidol inhibits ASC speck formation, caspase-1 activation, and release of IL-1β and IL-6, suggesting that it inhibits NLRP3 inflammasome activation and downstream cytokine responses. We also identified LAMTOR1 as a novel binding partner for haloperidol and demonstrate that haloperidol inhibits the aggregation of LAMTOR1 and NLRP3. Since NLRP3 inflammasome activation has been implicated in gout, these data provide a foundation for exploring haloperidol as a potential therapy.
Mycorrhizal fungi modulate tree diversity effects on nutrient dynamics
Authors: Bönisch Elisabeth , Blagodatskaya Evgenia , Dirzo Rodolfo , Ferlian Olga , Fichtner Andreas , Huang Yuanyuan , Leonard Samuel J. , Maestre Fernando T. , von Oheimb Goddert , Ray Tama , Eisenhauer Nico 
Published: December 2023

SummarySpecies-specific differences in nutrient acquisition strategies allow for complementary use of resources among plants in mixtures, which may be further shaped by mycorrhizal associations. However, empirical evidence of these relationships is scarce, particularly for tree communities.We investigated the impact of tree species richness and mycorrhizal types, arbuscular mycorrhizal fungi (AM) and ectomycorrhizal fungi (EM), on the above- and belowground carbon (C), nitrogen (N), and phosphorus (P) dynamics.Soil and microbial biomass elemental pools did not strongly respond to tree species richness or mycorrhizal type. Tree species richness increased foliage C and P pools depending on mycorrhizal type. Additive partitioning analyses showed that net biodiversity effects for C, N, P pools in EM tree communities, and N pools in AM tree communities, were driven by selection effects, while mixtures of both mycorrhizal types were influenced by complementarity effects. Furthermore, tree species richness enhanced soil nitrate uptake over two years but had no impact on ammonium and phosphate levels.Our results indicate that positive effects of tree diversity on aboveground nutrient storage are mediated by complementary mycorrhizal strategies. Given the prevalence of anthropogenic impacts on tree species richness globally, these results may have important implications for reforestation of multifunctional forests.
Unravelling neuronal and glial differences in ceramide composition, synthesis, and sensitivity to toxicity
Authors: McInnis John J. , Sood Disha , Guo Lilu , Dufault Michael R. , Garcia Mariana , Passaro Rachel , Gao Grace , Zhang Bailin , Dodge James C. 
Published: December 2023

AbstractCeramides are lipids that play vital roles in complex lipid synthesis, membrane function, and cell signaling. Disrupted ceramide homeostasis is implicated in cell-death and several neurologic diseases. Ceramides are often analyzed in tissue, but this approach fails to resolve cell-type differences in ceramide homeostasis that are likely essential to understanding cell and non-cell autonomous contributions to neurodegeneration. We show that human iPSC-derived neurons and glia differ in their rate of ceramide synthesis, ceramide isoform composition, and responses to altered ceramide levels. RNA-sequencing of cells treated to increase or decrease ceramides revealed connections to inflammation, ER stress, and apoptosis. Moreover, introducing labeled sphinganine showed that glia readily synthesize ceramide de novo and that neurons are relatively more sensitive to ceramide toxicity. Our findings provide a framework for understanding neurologic diseases with sphingolipid alternations and insights in to designing therapeutics that target ceramide for treating them.
A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma
Authors: Weiner Amber K. , Radaoui Alexander B. , Tsang Matthew , Martinez Daniel , Sidoli Simone , Conkrite Karina L. , Delaidelli Alberto , Modi Apexa , Rokita Jo Lynne , Patel Khushbu , Lane Maria V. , Zhang Bo , Zhong Chuwei , Ennis Brian , Miller Daniel P. , Brown Miguel A. , Rathi Komal S. , Raman Pichai , Pogoriler Jennifer , Bhatti Tricia , Pawel Bruce , Glisovic-Aplenc Tina , Teicher Beverly , Erickson Stephen W. , Earley Eric J. , Bosse Kristopher R. , Sorensen Poul H. , Krytska Kateryna , Mosse Yael P. , Havenith Karin E. , Zammarchi Francesca , van Berkel Patrick H. , Smith Malcolm A. , Garcia Benjamin A. , Maris John M. , Diskin Sharon J. 
Published: December 2023

SummaryCancer immunotherapies have produced remarkable results in B-cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor specimens along with normal tissues to identify biologically relevant cell surface proteins that can serve as immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer of the developing nervous system. We apply this approach to human-derived cell lines (N=9) and cell/patient-derived xenograft (N=12) models of neuroblastoma. Plasma membrane-enriched mass spectrometry identified 1,461 cell surface proteins in cell lines and 1,401 in xenograft models, respectively. Additional proteogenomic analyses revealed 60 high-confidence candidate immunotherapeutic targets and we prioritized Delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlated with the presence of a super-enhancer spanning the DLK1 locus. Robust cell surface expression of DLK1 was validated by immunofluorescence, flow cytometry, and immunohistochemistry. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells resulted in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), showed potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Moreover, DLK1 is highly expressed in several adult cancer types, including adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PCPG), hepatoblastoma, and small cell lung cancer (SCLC), suggesting potential clinical benefit beyond neuroblastoma. Taken together, our study demonstrates the utility of comprehensive cancer surfaceome characterization and credentials DLK1 as an immunotherapeutic target.HighlightsPlasma membrane enriched proteomics defines surfaceome of neuroblastomaMulti-omic data integration prioritizes DLK1 as a candidate immunotherapeutic target in neuroblastoma and other cancersDLK1 expression is driven by a super-enhancerDLK1silencing in neuroblastoma cells results in cellular differentiationADCT-701, a DLK1-targeting antibody-drug conjugate, shows potent and specific cytotoxicity in DLK1-expressing neuroblastoma preclinical models
Comparative phosphoproteome analysis of primary and metastatic uveal melanoma cell lines
Authors: Glinkina K. , Prieto R. Gonzalez , Teunisse A.F.A.S. , Gelmi M.C. , Jager M.J. , Vertegaal A.C.O. , Jochemsen A.G. 
Published: December 2023

AbstractUveal melanoma (UM) is an ocular tumor that often develops asymptomatically. Statistically, every second patient eventually develops metastases that drastically worsen the prognosis by several months of overall survival. While isolated liver perfusion with melphalan and more recently immunotherapy (Tebentafusp) are the few treatment options available for metastatic UM patients, their application is complex or expensive. There is an urgent need to understand drug response and identify potential avenues for therapy. Hence, we focused on uncovering altered phosphorylation signaling events in metastatic UM using proteomics as an approach to identify potential drug targets.We analyzed the phosphoproteomes of the primary UM cell line Mel270 and two cell lines OMM2.3 and OMM2.5, derived from metastatic lesions of the same patient. We found 177 phosphosites to be altered significantly between primary and metastatic cell lines. Pathway analysis of up-regulated phosphosites in metastatic lines suggests that Rho signaling and mitotic cell cycle to be significantly altered uncovering potential routes of signaling for metastasis. Clinical data from LUMC and TCGA datasets uncoveredMARK3expression (which links to Rho signaling) correlation with chromosome 3 status, a prognostic marker in UM, suggesting that MARK3 kinase might be involved in metastatic UM signaling.
NRPS genes provide antifungal activity to newBacillusandPaenibacillusstrains and change their expression in the presence of phytopathogens in a strain-specific manner
Authors: Vasilchenko N.G. , Kulikov M.P. , Prazdnova E.V. , Gorovtsov A.V. , Usatov A.V. , Chistyakov V.A. 
Published: December 2023

AbstractFusarium diseases pose a significant threat to agricultural crops. In agricultural practice, various chemical fungicides, typically triazole-based, are often used to control fusariosis. However, this practice contributes to the development of resistant strains among the pathogenic fungi. A potential alternative to chemical fungicide treatments involves utilizing biopreparations derived from natural antagonists ofFusarium.BacillusandPaenibacillusbacteria, isolated from farmland soils have shown notable antagonistic activity against phytopathogenicFusariumfungi. Genetic analysis via PCR has indicated the presence of nonribosomal peptide synthase genes in the isolated bacterial strains, with the absence of chitinase activity suggesting that the antifungal effect primarily stems from nonribosomal synthesized peptides. Furthermore, the expression of these genes is heightened in the presence of fungi during co-culturing, although the magnitude of this effect appears to be specific to each strain and dependent on the pathogen in question. Field trials have demonstrated the efficacy of a biocontrol preparation made from studiedBacillusandPaenibacillusstrains. These results suggest promising prospects for the development of pathogen-targeted treatments.
Democratizing biomedical simulation through automated model discovery and a universal material subroutine
Authors: Peirlinck Mathias , Linka Kevin , Hurtado Juan A. , Holzapfel Gerhard A. , Kuhl Ellen 
Published: December 2023

AbstractPersonalized computational simulations have emerged as a vital tool to understand the biomechanical factors of a disease, predict disease progression, and design personalized intervention. Material modeling is critical for realistic biomedical simulations, and poor model selection can have life-threatening consequences for the patient. However, selecting the best model requires a profound domain knowledge and is limited to a few highly specialized experts in the field. Here we explore the feasibility of eliminating user involvement and automate the process of material modeling in finite element analyses. We leverage recent developments in constitutive neural networks, machine learning, and artificial intelligence to discover the best constitutive model from thousands of possible combinations of a few functional building blocks. We integrate all discoverable models into the finite element workflow by creating a universal material subroutine that contains more than 60,000 models, made up of 16 individual terms. We prototype this workflow using biaxial extension tests from healthy human arteries as input and stress and stretch profiles across the human aortic arch as output. Our results suggest that constitutive neural networks can robustly discover various flavors of arterial models from data, feed these models directly into a finite element simulation, and predict stress and strain profiles that compare favorably to the classical Holzapfel model. Replacing dozens of individual material subroutines by a single universal material subroutine–populated directly via automated model discovery–will make finite element simulations more user-friendly, more robust, and less vulnerable to human error. Democratizing finite element simulation by automating model selection could induce a paradigm shift in physics-based modeling, broaden access to simulation technologies, and empower individuals with varying levels of expertise and diverse backgrounds to actively participate in scientific discovery and push the boundaries of biomedical simulation.
Method for Identifying Proteomic Biomarkers of Health
Authors: Zlobina Ksenia , Gopinath Ashwin , Thubagere Anu 
Published: December 2023

ABSTRACTClassification of proteomic samples from sick and non-sick individuals is important for developing high-quality diagnostics of diseases. Creating a shortlist of proteins useful for diagnostics is challenging. In this manuscript a simple algorithm of creating a multidimensional biomarker of health based on scanning proteomics data is provided. The algorithm is applied to several existing publicly available datasets and demonstrates a 9-protein indicator of atopic dermatitis, and 6-protein indicator of heart failure.
Knockdown ofNeuroD2leads to seizure-like behaviour, brain neuronal hyperactivity and a leaky blood-brain barrier in aXenopus laevistadpole model of DEE75
Authors: Banerjee S. , Szyszka P. , Beck C.W. 
Published: December 2023

AbstractDevelopmental and Epileptic Encephalopathies (DEE) are a genetically diverse group of severe, early onset seizure disorders. DEE are normally identified clinically in the first six months of life by the presence of frequent, difficult to control seizures and accompanying stalling or regression of development. DEE75 results fromde novomutations of theNEUROD2gene that result in loss of activity of the encoded transcription factor, and the seizure phenotype was shown to be recapitulated inXenopus tropicalistadpoles. We used CRISPR/Cas9 to make a DEE75 model inXenopus laevis, to further investigate the developmental aetiology.NeuroD2.SCRISPR/Cas9 edited tadpoles were more active, swam faster on average, and had more unprovoked escape responses (C-starts) than their sibling controls. Live imaging of Ca2+signalling revealed prolongued, strong signals sweeping through the brain, indicative of neuronal hyperactivity. While the resulting tadpole brain appeared grossly normal, the blood-brain barrier was found to be leakier than that of controls. Additionally, the TGFβ antagonist Losartan was shown to have a short-term protective effect, reducing neuronal hyperactivity and reducing permeability of the blood- brain barrier. Severity of the behavioral phenotype correlated with increased with editing efficiency. Our results support a haploinsufficiency model of DEE75 resulting from reduced NeuroD2 activity during vertebrate brain development, and indicate that a leaky blood- brain barrier contributes to epileptogenesis.
Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain
Authors: Hopp Sarah C. , Rogers Juliet Garcia , Smith Sabrina , Campos Gabriela , Miller Henry , Barannikov Savannah , Kuri Eduardo Gutierrez , Wang Hu , Han Xianlin , Bieniek Kevin F. , Weintraub Susan T. , Palavicini Juan Pablo 
Published: December 2023

AbstractPhospholipase C gamma-2 (PLCγ2) catalyzes the hydrolysis of the membrane phosphatidylinositol-4,5-bisphosphate (PIP2) to form diacylglycerol (DAG) and inositol trisphosphate (IP3), which subsequently feed into numerous downstream signaling pathways. PLCG2 polymorphisms are associated with both reduced and increased risk of Alzheimer’s disease (AD) and with longevity. In the brain, PLCG2 is highly expressed in microglia, where it is proposed to regulate phagocytosis, secretion of cytokines/chemokines, cell survival and proliferation. We analyzed the brains of three-month-old PLCγ2 knockout (KO), heterozygous (HET), and wild-type (WT) mice using multiomics approaches, including shotgun lipidomics, proteomics, and gene expression profiling, and immunofluorescence. Lipidomic analyses revealed sex-specific losses of total cerebrum PIP2and decreasing trends of DAG content in KOs. In addition, PLCγ2 depletion led to significant losses of myelin-specific lipids and decreasing trends of myelin-enriched lipids. Consistent with our lipidomics results, RNA profiling revealed sex-specific changes in the expression levels of several myelin-related genes. Further, consistent with the available literature, gene expression profiling revealed subtle changes on microglia phenotype in mature adult KOs under baseline conditions, suggestive of reduced microglia reactivity. Immunohistochemistry confirmed subtle differences in density of microglia and oligodendrocytes in KOs. Exploratory proteomic pathway analyses revealed changes in KO and HET females compared to WTs, with over-abundant proteins pointing to mTOR signaling, and under-abundant proteins to oligodendrocytes. Overall, our data indicate that loss of PLCγ2 has subtle effects on brain homeostasis that may underlie enhanced vulnerability to AD pathology and aging via novel mechanisms in addition to regulation of microglia function.Significance StatementThePLCG2gene contains a number of rare variants linked with increased and decreased risk for Alzheimer’s disease and longevity, but little is known about the role of PLCγ2 in normal brain function. The results described herein are significant because they describe the effects of knockout of PLCγ2 on brain cell types, thus mimicking the loss of function Alzheimer’s disease risk mutation. Our data describe novel effects of PLCγ2 deficiency on myelin homeostasis and mTOR signaling that have not been previously described that may underlie its association with Alzheimer’s disease pathogenesis and longevity.
Fungal pleural infection due toMicroascus graciliswith pulmonary aspergillosis after COVID-19 pneumonia
Authors: Hu Zhi-Min , Mao Li-Na , Deng Ti-Ying , Su Bin-Tao , Yang Yi , Dong Bi-Lin , Xu Qing , Yang Shuo 
Published: December 2023

AbstractBackgroundScopulariopsis/Microascusis a rare but devastating pathogen due to its intrinsic resistance to nearly all available antifungal agents.Microascus gracilis, an ascomycetous mould in the orderMicroascales, familyMicroascaceae, has recently emerged as a significant invasive pathogen causing opportunistic infections.Objectives and MethodsWe present a case of pleural infection caused byM. graciliswith pulmonary aspergillosis in an immunocompromised man after COVID-19 pneumonia. To further understand the characteristics of the pathogen isolated from the patient, we identified the strain through mycological characteristics, matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MALDI-TOF MS) and internal transcribed spacer (ITS)-based sequencing, and performedin vitrodrug susceptibility testing against common antifungal agents. Moreover, we assessed lymphocyte subsets and programmed cell death protein 1 (PD-1) expression in peripheral blood and pleural effusion to monitor the efficacy of therapy with thymosin-α-1 and intravenous immunoglobulin.ResultsFilamentous fungi isolated from pleural fluid were identified asM. gracilisbased on classical morphology, mass spectrometry and molecular biology methods. The susceptibility resultsin vitrorevealed that multiple antifungal agents were inactive against the strain. Adjuvant immunomodulatory treatment successfully increased the levels of CD3+ T and CD4+ T cells while decreasing the levels of CD3+PD-1+ and CD4+PD-1+ T cells in both peripheral blood and pleural effusion.ConclusionsThe immunocompromised host with opportunisticM. gracilisinfection, rapid and accurate recognition through direct microscopic testing with calcofluor white and MOLDI-TOF MS, is the key to achieving a definite diagnosis, and a combination of antifungal therapy with immunomodulatory therapy is vital for improving survival.
Epidermal turnover in the planarianSchmidtea mediterraneainvolves basal cell extrusion and intestinal digestion
Authors: Lee Jun-Ru , Boothe Tobias , Mauksch Clemens , Rink Jochen C. 
Published: December 2023

SummaryPlanarian flatworms undergo continuous internal turnover, wherein old cells are replaced by the division progeny of adult pluripotent stem cells known as neoblasts. How dynamic cell turnover is executed at the organismal scale remains an intriguing question in planarians and biological systems in general. While previous studies have predominantly focused on neoblast proliferation, little is known about the processes that mediate cell loss during tissue homeostasis. Here, we use the planarian epidermis as a model to study the mechanisms of cell removal inSchmidtea mediterranea. We established a covalent dye-labeling assay and image analysis pipeline to quantify the cell turnover rate in the planarian epidermis. Our findings indicate that the ventral epidermis is highly dynamic, with a half-life of the constituent cells of approximately 4.5 days. Using live-imaging and pulse-chase assays, we find that epidermal cells undergo internalization via basal extrusion, followed by a migration towards the intestine and ultimately digestion by intestinal phagocytes. Overall, our studies reveal an intricate homeostatic cell clearance process that may reduce the metabolic costs of high turnover tissues in planarians.