bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of serum uric acid with male sexual hormones and erectile dysfunction: a bidirectional 2-sample Mendelian randomization analysis
Authors: Chen Hui , Feng Wei-Dong , Feng Jun-Long , Zhao Cong , Gao Zi-Xiang , Wang Bin 
Published: August 2024

Abstract

Background
Observational studies indicated that serum uric acid (SUA) was associated with male sexual hormones and erectile dysfunction (ED). However, their relationship was still heterogeneous.

Aim
This study conducted 2-sample univariate mendelian randomization (UVMR) and multivariate mendelian randomization (MVMR) to explore the causal relationship between SUA and sexual hormones as well as ED.

Methods
Genetic variants associated with SUA were derived from the UK Biobank database (N = 437 354). Outcomes from the IEU Open GWAS and summary data sets were sexual hormones (sex hormone–binding globulin [SHBG], testosterone, estradiol [E2], follicle-stimulating hormone, luteinizing hormone) and ED, with 3301 to 625 650 participants. UVMR analysis primarily utilized the inverse variance weighted method, complemented by MVMR analysis. Thorough sensitivity analyses were carried out to ensure the reliability of results. Moreover, mediation analysis was conducted to estimate the mediated effect between SUA and outcomes.

Outcomes
The primary outcomes included results of UVMR and MVMR analysis and mediation analysis, along with sensitivity analyses involving the Cochran Q test, the MR Egger intercept test, leave-1-out analysis, and the MR-PRESSO method (mendelian randomization pleiotropy residual sum and outlier).

Results
UVMR analysis revealed that an elevated SUA level could decrease levels of SHBG (β = –0.10, P = 1.70 × 10–7) and testosterone (β = –0.10, P = 5.94 × 10–3) and had a positive causal effect on ED (odds ratio, 1.10; P = .018). According to reverse mendelian randomization results, increased levels of SHBG (β = –0.06, P = 4.82 × 10–4) and E2 (β = –0.04, P = .037) could also reduce SUA levels. As shown by MVMR analysis, SUA had a negative effect on SHBG and testosterone levels (P &lt; .05), while the significant causal relationship between SUA and ED disappeared. Furthermore, SHBG mediated 98.1% of the effect of SUA on testosterone levels. Results of other mendelian randomization analyses were not statistically significant. No pleiotropy was found by sensitivity analysis in this study.

Clinical Implications
Given the causal relationship between SUA and sexual hormones, we must focus on SUA and E2 levels in men, especially patients with hypogonadism and ED.

Strengths and Limitations
This study evaluated the causal effect of SUA on male sexual hormones and ED genetically for the first time, clarifying the common biases in observational studies and confirming the negative relationship between SUA and testosterone level. Limitations include a population based on European ancestry, some crossover of the samples, and unobserved confounding factors.

Conclusion
Genetic studies provide evidence for the causal relationship between SUA and male sexual hormones (SHBG, testosterone, E2), while the relationship between SUA and ED should be further evaluated.
First Complete Genome Sequence of Nigrospora osmanthi: A Fundamental Resource for Studying the Plant Pathogenic Fungus
Authors: Huang Hui , Kong Jiajia , Lin Jingyu , Zhang Xiao , Xu Guoyong , Ding Weiwen , Jin Rui , Wang Wei , Chen Jianming , Lin Zhenyue 
Published: August 2024

Nigrospora osmanthi strain Z1 is a potential bioherbicide for the biological control of water lettuce, one of the most common invasive weeds. Here, the first high-quality genome assembly of N. osmanthi was obtained by a combination of PacBio and Illumina sequencing technologies. Twelve contigs representing the nuclear genome and one mitochondrial DNA were generated, with a total length of 45.94 Mb, an N50 equal to 6.99 Mb, and a GC content of 57.91%; 9 of the 12 nuclear contigs represented chromosomes from telomere to telomere characterized by telomeric-like repeats. A total of 11,051 genes were predicted using a combination of gene prediction tools, including 336 noncoding RNAs, 1,298 genes encoding secretory proteins, 1,735 genes encoding carbohydrate-active enzymes, 1,955 fungal virulence factors, and 50 putative secondary metabolite gene clusters. This complete genome sequence can serve as a valuable resource for future comparative genomic studies of the fungus Nigrospora for effective application in the biocontrol of invasive species and the discovery of fungal secondary metabolites. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Insomnia score: predictive ability of insomnia, high-diagnostic and prognostic value for cancer
Authors: Xiao Dan , Lan Yixin , Zhang Haohan , Li Siyu , Zhou Chuandong 
Published: August 2024

AbstractObjectiveThis study utilized bioinformatics methods to investigate the association between insomnia and cancer.MethodsWe identified key insomnia-related genes and constructed an insomnia score (riskScore = ∑ Expressiongene* Coefficient) based on an insomnia dataset using differential analysis, Weighted Gene Co-expression Network Analysis (WGCNA), and Least Absolute Shrinkage and Selection Operator (LASSO) regression. The predictive ability of the insomnia score was validated in the insomnia dataset using Receiver Operating Characteristic (ROC) analysis. Finally, the diagnostic and prognostic value of the insomnia score was assessed in a pan-cancer cohort.ResultsDifferential analysis, WGCNA, and LASSO screening of the insomnia dataset yielded three key insomnia-related genes (PTMA, NLRP8, and CCBE1). An insomnia score was then constructed using the formula: riskScore = -0.8039667 * ExpressionPTMA+ - 3.1975230 * ExpressionNLRP8+ -0.4957560 * ExpressionCCBE1. The ROC analysis demonstrated that the insomnia score has excellent predictive ability for insomnia. Furthermore, pan-cancer analysis illustrated the diagnostic and prognostic value of the insomnia score across various cancers.ConclusionWe successfully constructed an insomnia score and demonstrated its diagnostic and prognostic value in multiple cancers.
Phosphoryl group wires stabilize pathological tau fibrils as revealed by multiple quantum spin counting NMR
Authors: Potnuru Lokeswara Rao , DuBose Austin , Nowotarski Mesopotamia S. , Vigers Michael , Zhang Boqin , Han Chung-Ta , Han Songi 
Published: August 2024

AbstractHyperphosphorylation of the protein tau is one of the biomarkers of neurodegenerative diseases in the category of tauopathies. However, the molecular level, mechanistic, role of this common post- translational modification (PTM) in enhancing or reducing the aggregation propensity of tau is unclear, especially considering that combinatorial phosphorylation of multiple sites can have complex, non-additive, effects on tau protein aggregation. Since tau proteins stack in register and parallel to elongate into pathological fibrils, phosphoryl groups from adjacent tau strands with 4.8 Å separation must find an energetically favorable spatial arrangement. At first glance, this appears to be an unfavorable configuration due to the proximity of negative charges between phosphate groups from adjacent neighboring tau fibrils. However, this study tests a counterhypothesis that phosphoryl groups within the fibril core-forming segments favorably assemble into highly ordered, hydrogen-bonded, one-dimensionally extended wires under biologically relevant conditions. We selected two phosphorylation sites associated with neurodegeneration, serine 305 (S305p) and tyrosine 310 (Y310p), on a model tau peptide jR2R3-P301L (tau295-313) spanning the R2/R3 splice junction of tau, that readily aggregate into a fibril with characteristics of a seed-competent mini prion. Using multiple quantum spin counting (MQ-SC) by31P solid-state NMR of phosphorylated jR2R3-P301L tau peptide fibrils, enhanced by dynamic nuclear polarization, we find that at least six phosphorous spins must neatly arrange in 1D within fibrils or in 2D within a protofibril to yield the experimentally observed MQ-coherence orders of four. We found that S305pstabilizes the tau fibrils and leads to more seeding-competent fibrils compared to jR2R3 P301L or Y310p. This study introduces a new concept that phosphorylation of residues within a core forming tau segment can mechanically facilitate fibril registry and stability due a hitherto unrecognized role of phosphoryl groups to form highly ordered, extended, 1D wires that stabilize pathological tau fibrils.Graphical Abstract
C9orf72repeat expansion-carrying iPSC-microglia from FTD patients show increased phagocytic activity concomitantly with decreased number of autophagosomal-lysosomal vesicles
Authors: Rostalski Hannah , Hietanen Tomi , Hoffmann Dorit , Heikkinen Sami , Huber Nadine , Dhingra Ashutosh , Rodriguez-Nieto Salvador , Kuulasmaa Teemu , Ohtonen Sohvi , Jäntti Henna , Pekkala Viivi , Leskelä Stina , Mäkinen Petra , Katisko Kasper , Hartikainen Päivi , Lehtonen Šárka , Solje Eino , Koistinaho Jari , Malm Tarja , Portaankorva Anne M. , Natunen Teemu , Martiskainen Henna , Takalo Mari , Hiltunen Mikko , Haapasalo Annakaisa 
Published: August 2024

AbstractC9orf72hexanucleotide repeat expansion (HRE) is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The role of microglia in theseC9orf72HRE-associated diseases is understudied. To elucidate effects ofC9orf72HRE on microglia, we have characterized human induced pluripotent stem cell-derived microglia (iMG) from behavioral variant frontotemporal dementia (bvFTD) patients carrying theC9orf72HRE.C9orf72HRE iMG were compared to iMG from healthy controls and sporadic bvFTD patients. The phenotypes of iMG were analyzed using bulk RNA sequencing, biochemical and immunofluorescence analyses, and live cell imaging.C9orf72HRE-carrying iMG showed nuclear RNA foci and poly-GP dipeptide repeat proteins but no decreased C9orf72 mRNA or protein expression. TDP-43 pathology was absent from all bvFTD iMG. As compared to healthy control iMG, quantitative immunofluorescence analyses indicated that all bvFTD iMG had reduced number, size, and intensity of LAMP2-A-positive vesicles.C9orf72HRE-carrying iMG additionally showed decreased number, size, and intensity of p62/SQSTM1-positive vesicles. These changes were accompanied by increased phagocytic activity of theC9orf72HRE-carrying iMG. Serum starvation increased phagocytic activity also in the iMG of sporadic bvFTD patients. RNA sequencing revealed that iMG ofC9orf72HRE-carrying bvFTD patients as compared to the iMG of sporadic bvFTD patients showed differential gene expression in pathways related to RNA and protein regulation and mitochondrial metabolism. Our data suggest potential alterations in the autophagosomal/lysosomal pathways in bvFTD patient iMG, which are further reinforced by theC9orf72HRE and functionally manifest as increased phagocytic activity.
Comparison of Fixed Single Cell RNA-seq Methods to Enable Transcriptome Profiling of Neutrophils in Clinical Samples
Authors: Hatje Klas , Schneider Kim , Danilin Sabrina , Koechl Fabian , Giroud Nicolas , Juglair Laurent , Marbach Daniel , Knuckles Philip , Bergauer Tobias , Metruccio Matteo , Garrido Alba , Zhang Jitao David , Sultan Marc , Bell Emma 
Published: August 2024

SummaryMonitoring neutrophil gene expression is a powerful tool for understanding disease mechanisms, developing new diagnostics, therapies and optimizing clinical trials. Neutrophils are sensitive to the processing, storage and transportation steps that are involved in clinical sample analysis. This study is the first to evaluate the capabilities of technologies from 10X Genomics, PARSE Biosciences, and HIVE (Honeycomb Biotechnologies) to generate high-quality RNA data from human blood-derived neutrophils. Our comparative analysis shows that all methods produced high quality data, importantly capturing the transcriptomes of neutrophils. 10X FLEX cell populations in particular showed a close concordance with the flow cytometry data. Here, we establish a reliable single-cell RNA sequencing workflow for neutrophils in clinical trials: we offer guidelines on sample collection to preserve RNA quality and demonstrate how each method performs in capturing sensitive cell populations in clinical practice.
Identifying a gene signature of metastatic potential by linking pre-metastatic state to ultimate metastatic fate
Authors: Handler Jesse S , Li Zijie , Dveirin Rachel K , Fang Weixiang , Goodarzi Hani , Fertig Elana J , Kalhor Reza 
Published: August 2024

AbstractIdentifying the key molecular pathways that enable metastasis by analyzing the eventual metastatic tumor is challenging because the state of the founder subclone likely changes following metastatic colonization. To address this challenge, we labeled primary mouse pancreatic ductal adenocarcinoma (PDAC) subclones with DNA barcodes to characterize their pre-metastatic state using ATAC-seq and RNA-seq and determine their relativein vivometastatic potential prospectively. We identified a gene signature separating metastasis-high and metastasis-low subclones orthogonal to the normal-to-PDAC and classical-to-basal axes. The metastasis-high subclones feature activation of IL-1 pathway genes and high NF-κB and Zeb/Snail family activity and the metastasis-low subclones feature activation of neuroendocrine, motility, and Wnt pathway genes and high CDX2 and HOXA13 activity. In a functional screen, we validated novel mediators of PDAC metastasis in the IL-1 pathway, including the NF-κB targetsFosandIl23a, and beyond the IL-1 pathway includingMyo1bandTmem40. We scored human PDAC tumors for our signature of metastatic potential from mouse and found that metastases have higher scores than primary tumors. Moreover, primary tumors with higher scores are associated with worse prognosis. We also found that our metastatic potential signature is enriched in other human carcinomas, suggesting that it is conserved across epithelial malignancies. This work establishes a strategy for linking cancer cell state to future behavior, reveals novel functional regulators of PDAC metastasis, and establishes a method for scoring human carcinomas based on metastatic potential.
A nanobody-based proximity ligation assay detects constitutive and stimulus-regulated native Arc/Arg3.1 oligomers in hippocampal neuronal dendrites
Authors: Baldinotti Rodolfo , Pauzin Francois P. , Fevang Hauk , Ishizuka Yuta , Bramham Clive R. 
Published: August 2024

AbstractActivity-regulated cytoskeleton-associated (Arc), the product of an immediate early gene, plays critical roles in synaptic plasticity and memory. Evidence suggests that Arc function is determined by its oligomeric state, however, methods for localization of native Arc oligomers are lacking. Here, we developed a nanobody-based proximity ligation assay (PLA) for detection, localization, and quantification of Arc-Arc complexes in primary rat hippocampal neuronal cultures. We used nanobodies with single, structurally defined epitopes in the bilobar Arc capsid domain. Nanobody H11 binds inside the N-lobe ligand pocket, while nanobody C11 binds to the C-lobe surface. For each nanobody, ALFA- and FLAG-epitope tags created a platform for antibody binding and PLA. Surprisingly, PLA puncta in neuronal dendrites revealed widespread constitutive Arc-Arc complexes. Treatment of cultures with tetrodotoxin or cycloheximide had no effect, suggesting stable complexes that are independent of recent neuronal activity and protein synthesis. To assess detection of oligomers, cultures were exposed to a cell-penetrating peptide inhibitor of the Arc oligomerization motif (OligoOFF). Arc-Arc complexes detected by H11 PLA were inhibited by OligoOff but not by control peptide. Notably, Arc complexes detected by C11 were unaffected by OligoOFF. Furthermore, we evaluated Arc complex formation after chemical stimuli that increase Arc synthesis. Brain-derived neurotrophic factor increased Arc-Arc signal detected by C11, but not H11. Conversely, dihydroxyphenylglycine (DHPG) treatment selectively enhanced H11 PLA signals. In sum, nanobody-based PLA reveals constitutive and stimulus-regulated Arc oligomers in hippocampal neuronal dendrites. A model is proposed based on detection of Arc dimer by C11 and higher-order oligomer by H11 nanobody.
Inhibition of glycolysis in tuberculosis-mediated metabolic rewiring reduces HIV-1 spread across macrophages
Authors: Vahlas Zoï , Faivre Natacha , Monard Sarah C. , Hertel Quentin , Maio Mariano , Barros Joaquina , Lucas Alexandre , Manh Thien-Phong Vu , Ben Neji Myriam , Corti Marcelo , Poincloux Renaud , Blanchet Fabien , Raynaud-Messina Brigitte , Letisse Fabien , Neyrolles Olivier , Lugo-Villarino Geanncarlo , Balboa Luciana , Vérollet Christel 
Published: August 2024

ABSTRACTTuberculosis (TB) is a significant aggravating factor in individuals living with human immunodeficiency virus type 1 (HIV-1), the causative agent for acquired immunodeficiency syndrome (AIDS). BothMycobacterium tuberculosis(Mtb), the bacterium responsible for TB, and HIV-1 target macrophages. Understanding how Mtb subverts these cells may facilitate the identification of new druggable targets. Here, we explored how TB can induce macrophages to form tunneling nanotubes (TNT), promoting HIV-1 spread. We found that TB triggers metabolic rewiring of macrophages, increasing their glycolytic ATP production. Using pharmacological inhibitors and glucose deprivation, we discovered that disrupting aerobic glycolysis significantly reduces HIV-1 exacerbation in these macrophages. Glycolysis is essential for tunneling nanotubes (TNT) formation, which facilitates viral transfer and cell-to-cell fusion and induces the expression of the sialoadhesin Siglec-1, enhancing both HIV-1 binding and TNT stabilization. Glycolysis did not exacerbate HIV-1 infection when TNT formation was pharmacologically prevented, indicating that higher metabolic activity is not sufficient per se to make macrophages more susceptible to HIV-1. Overall, these data might facilitate the development of targeted therapies aimed at inhibiting glycolytic activity in TB-induced immunomodulatory macrophages to ultimately halt HIV-1 dissemination in co-infected patients.
Hedgehog signaling controls cytotoxic T cell migration in the tumour microenvironment
Authors: Kapeni Chrysa , O’Brien Louise , Sabirova Dilyara , Cast Oliver , Carbonaro Valentina , Clark-Leonard Stephen , Beke Flavio , McDonald Sarah , Fife Kate , de la Roche Maike 
Published: August 2024

ABSTRACTCytotoxic T lymphocytes effectively eliminate cancer cells. Their abundance in the tumour microenvironment is one of the strongest pan-cancer predictors of clinical response. Here, we show that Hedgehog (Hh) signaling regulates T cell migration into tumours.Using conditional knockout mouse models of central Hh signaling componentsIhh,SmoandGli1in CD8 T cells, we show thatSmodeletion greatly impairs the anti-tumour responsein vivodue to diminished CD8 T cell migration into the tumour microenvironment. The migration defect is mediated exclusively by Smo, both inin vivocancer models andin vitromigration assays. This effect is independent of the canonical Hh pathway and relies on the GPCR function of Smo to regulate the migration of murine and human CD8 T cells via RhoA.Hh signaling is critical during embryonic development and adult stem cell homeostasis, but is also amplified in multiple cancer types. Hh inhibitors targeting SMO have been clinically-approved and shown efficacy in the treatment of Hh-driven basal cell carcinoma and medulloblastoma but have failed in clinical trials in other solid cancers with upregulated Hh signaling. We demonstrate that SMO inhibitors specifically decrease CD8 T cell migration into the tumour microenvironment, both in murine cancer models and resected BCCs from patients treated with the SMO inhibitor vismodegib, providing the first mechanistic explanation as to why Hh inhibitors have failed in solid cancers.Our data establishes a novel link between Hh inhibitionin vivoand the anti-tumour immune response and reveals a fundamental mechanism controlling T cell migration. The work provides the basis for improved Hh targeting approaches in the clinic and new entry points into enhancing migration in T cell therapies.
Conservative taxonomy and quality assessment of giant virus genomes with GVClass
Authors: Pitot Thomas M , Brůna Tomàš , Schulz Frederik 
Published: August 2024

AbstractBackgroundLarge double-stranded DNA viruses of the phylum Nucleocytoviricota (Giant viruses; GVs) include the largest known viruses, both in terms of capsid and genome size and are associated with a wide range of eukaryotic hosts. The ones able to infect protists and algae have been shown to be the dominant orders of GVs in the environmental samples. These viruses encode for genes that may have significantly impacted biogeochemical cycling and host genome evolution. While GVs are frequently found in environmental sequence data, their large and complex genomes, composed of genes acquired from various cellular lineages, pose challenges for their identification and taxonomic classification.ResultsWe present GVClass, a tool that identifies giant viruses in sequence data and provides taxonomic assignments, and estimates for genome completeness and contamination. GVClass performs gene calling optimized for giant viruses and utilizes a conservative approach based on consensus single protein phylogenies for robust taxonomic assignments. The genes used for classification represent highly conserved giant virus orthologous groups and low copy number cellular and viral panorthologs. In our benchmarking, GVClass demonstrated high quality and accurate taxonomic assignment of giant virus sequences. GVClass showed high to very high precision, with over 90% of tested instances correctly predicted at the genus level and near-perfect prediction (>99%) at higher taxonomic ranks (family, order, class).ConclusionIn the light of rapidly increasing amounts of sequence data and associated metagenome-assembled genomes, GVClass provides a conservative approach to identify, classify and quality-check giant virus genomes, which with other methods often remained unassigned or misclassified using other methods. GVClass has already been used through viral meta-analysis and to benchmark the viral sequences detection pipeline geNomad. The standalone version is freely available and it has been integrated in the Integrated Microbial Genomes / Virus database (IMG/VR), offering the opportunity to upload user data for giant virus classification.