bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantifying the Impact of Co-Housing on Murine Aging Studies
Authors: Luciano Alison , Churchill Gary A. 
Published: August 2024

AbstractAnalysis of preclinical lifespan studies often assume that outcome data from co-housed animals are indepen-dent. In practice, treatments, such as controlled feeding or putative life-extending compounds, are applied to whole housing units, and as a result the outcomes are potentially correlated within housing units. We consider intra-class (here, intra-cage) correlation in three published and two unpublished lifespan studies of aged mice encompassing more than 20 thousand observations. We show that the independence assumption underlying common analytic techniques does not hold in these data, particularly for traits associated with frailty. We describe and demonstrate various analytical tools available to accommodate this study design and highlight a limitation of standard variance components models (i.e., linear mixed models) which are the usual statisti-cal tool for handling correlated errors. Through simulations, we examine the statistical biases resulting from intra-cage correlations with similar magnitudes as observed in these case studies and discuss implications for power and reproducibility.
Challenges and lessons learned from preliminary modeling of with-in herd transmission of highly pathogenic avian influenza H5N1in dairy cattle
Authors: Bellotti Brinkley Raynor , DeWitt Michael E. , Wenner Jennifer J. , Lombard Jason E. , McCluskey Brian J. , Kortessis Nicholas 
Published: August 2024

AbstractThe emergence of highly pathogenic avian influenza A H5N1in dairy cattle raises many questions related to animal health and changes to the risk of an epidemic in humans. We synthesized information currently published to fit a compartment model of H5N1transmission within a dairy herd. An accompanying web application allows users to run simulations for specific outbreak scenarios. We estimatedR0near 1.2 with a short duration of infectiousness and fast time course of an epidemic within a farm, which we discuss in the context of possible on-farm control strategies. The web application allows users to simulate consequences of an epidemic using herd-specific information, a tool we propose will help inform stakeholders about potential consequences of uncontrolled H5N1spread. Our modeling work has identified several key information gaps that would strengthen our understanding and control of this emerging infectious disease.
Predicting mutation-disease associations through protein interactions via deep learning
Authors: Li Xue , Cao Ben , Wang Jianmin , Meng Xiangyu , Wang Shuang , Huang Yu , Petretto Enrico , Song Tao 
Published: August 2024

ABSTRACTDisease is one of the primary factors affecting life activities, with complex etiologies often influenced by gene expression and mutation. Currently, wet-lab experiments have analyzed the mechanisms of mutations, but these are usually limited by the costs of wet experiments and constraints in sample types and scales. Therefore, this paper constructs a real-world mutation-induced disease dataset and proposes Capsule networks and Graph topology networks with multi-head attention (CGM) to predict the mutation-disease associations. CGM can accurately predict protein mutation-disease associations, and in order to further elucidate the pathogenicity of protein mutations, we also verified that protein mutations lead to protein structural alterations by Swiss-model, which suggests that mutation-induced conformational changes may be an important pathogenic factor. Limited by the size of the mutated protein dataset, we also performed experiments on benchmark and imbalanced datasets, where CGM mined 22 unknown protein interaction pairs from the benchmark dataset, better illustrating the potential of CGM in predicting mutation-disease associations. In summary, this paper curates a real dataset and proposes CGM to predict the protein mutations-disease associations, providing a novel tool for further understanding of biomolecular pathways and disease mechanisms.
Synaptic cell adhesion moleculeCdh6identifies a class of sensory neurons with novel functions in colonic motility
Authors: Gomez-Frittelli Julieta , Devienne Gabrielle , Travis Lee , Kyloh Melinda A. , Duan Xin , Hibberd Tim J. , Spencer Nick J. , Huguenard John R. , Kaltschmidt Julia A. 
Published: August 2024

AbstractIntrinsic sensory neurons are an essential part of the enteric nervous system (ENS) and play a crucial role in gastrointestinal tract motility and digestion. Neuronal subtypes in the ENS have been distinguished by their electrophysiological properties, morphology, and expression of characteristic markers, notably neurotransmitters and neuropeptides. Here we investigated synaptic cell adhesion molecules as novel cell type markers in the ENS. Our work identifies two Type II classic cadherins,Cdh6andCdh8,specific to sensory neurons in the mouse colon. We show thatCdh6+neurons demonstrate all other distinguishing classifications of enteric sensory neurons including marker expression ofCalcbandNmu, Dogiel type II morphology and AH-type electrophysiology andIHcurrent. Optogenetic activation ofCdh6+sensory neurons in distal colon evokes retrograde colonic motor complexes (CMCs), while pharmacologic blockade of rhythmicity-associated currentIHdisrupts the spontaneous generation of CMCs. These findings provide the first demonstration of selective activation of a single neurochemical and functional class of enteric neurons, and demonstrate a functional and critical role for sensory neurons in the generation of CMCs.One-Sentence SummaryIntrinsic sensory neurons of the enteric nervous system in the mouse distal colon exclusively express synaptic cell adhesion moleculesCdh6andCdh8,evoke retrograde colonic motor complexes (CMCs) when stimulated, and possess rhythmicity-associatedIHcurrent, involved in producing spontaneous CMCs.
RiboSnake – a user-friendly, robust, reproducible, multipurpose and documentation-extensive pipeline for 16S rRNA gene microbiome analysis
Authors: Dörr Ann-Kathrin , Welling Josefa , Dörr Adrian , Gosch Jule , Möhlen Hannah , Schmithausen Ricarda , Kehrmann Jan , Meyer Folker , Kraiselburd Ivana 
Published: August 2024

AbstractBackgroundNext-generation sequencing for assaying microbial communities has become a standard technique in recent years. However, the initial investment required into in-silico analytics is still quite significant, especially for facilities not focused on bioinformatics. With the rapid decline in costs and growing adoption of sequencing-based methods in a number of fields, validated, fully automated, reproducible and yet flexible pipelines will play a greater role in various scientific fields in the future.ResultsWe present RiboSnake, a validated, automated, reproducible QIIME2-based analysis pipeline implemented in Snakemake for the computational analysis of16S rRNAgene amplicon sequencing data. The pipeline comes with pre-packaged validated parameter sets, optimized for different sample types. The sets range from complex environmental samples to patient data. The configuration packages can be easily adapted and shared, requiring minimal user input.ConclusionRiboSnake is a new alternative for researchers employing16S rRNAgene amplicon sequencing and looking for a customizable and yet user-friendly pipeline for microbiome analysis with in-vitro validated settings. The complete analysis generated with a fully automated pipeline based on validated parameter sets for different sample types is a significant improvement to existing methods. The workflow repository can be found on GitHub (https://github.com/IKIM-Essen/RiboSnake).
Processivity of the monomeric KLP-6 kinesin and a Brownian ratchet model with symmetric potentials
Authors: Kita Tomoki , Sasaki Kazuo , Niwa Shinsuke 
Published: August 2024

ABSTRACTMost kinesin molecular motors dimerize to move processively and efficiently along microtubules; however, some can maintain processivity even in a monomeric state. Previous studies have suggested that asymmetric potentials between the motor domain and microtubules underlie this motility. In this study, we demonstrate that the kinesin-3 family motor protein KLP-6 can move along microtubules as a monomer upon release of autoinhibition. This motility can be explained by a change in length between the head and tail, rather than by asymmetric potentials. Using mass photometry and single-molecule assays, we confirmed that activated full-length KLP-6 is monomeric both in solution and on microtubules. KLP-6 possesses a microtubule-binding tail domain, and its motor domain does not exhibit biased movement, indicating that the tail domain is crucial for the processive movement of monomeric KLP-6. We developed a mathematical model to explain the unidirectional movement of monomeric KLP-6. Our model concludes that a slight conformational change driven by neck-linker docking in the motor domain enables the monomeric kinesin to move unidirectionally if a second microtubule-binding domain exists.SIGNIFICANCEKinesin molecular motors are designed to move efficiently using two heads. Studying these biological molecular motors provides valuable insights into the mechanisms that generate unidirectional movements amidst intense thermal fluctuations. This study reveals that the monomeric kinesin-3 KLP-6 can move along microtubules through interactions with its tail domain. The proposed Brownian ratchet model explains this movement by considering a change in stalk length caused by neck-linker docking rather than asymmetric potentials. This model suggests that a slight conformational change can achieve robust processive movement of kinesin. These findings have significant implications for understanding Brownian ratchet motors and designing rational artificial molecular motors.
VC2regulates baseline vicine content in faba bean
Authors: Ugwuanyi Samson , Makhoul Manar , Golicz Agnieszka A. , Obermeier Christian , Snowdon Rod J. 
Published: August 2024

AbstractFaba bean (Vicia faba) is a valuable legume crop desired globally for its high nutritional composition. However, the seed vicine and convicine (v-c) content reduces the nutritional quality of faba bean protein and can induce favism in individuals with glucose-6-phosphate dehydrogenase deficiency. Recently,VC1gene, encoding a bi-functional riboflavin protein, was reported to be responsible for initiating the biosynthetic pathway inV. faba. In low v-c cultivars, a 2 bp insertion in this gene results in a loss of function, but the mutation only partially eliminates v-c biosynthesis, indicating the involvement of other genes. Here, we demonstrate that a novelV. fabariboflavin gene,VC2, is responsible for the residual v-c contents in faba bean.VC2shares nearly identical functional domains withVC1and has GTP cyclohydrolase II activity, catalyzing the conversion of GTP into an intermediate molecule in the biosynthetic pathway. Gene expression analysis reveals thatVC2contributes a minor effect to the trait, accounting for approximately 5-10% of total riboflavin gene transcripts which significantly correlates with the baseline contents in low v-c cultivars. Our results illustrate that cultivars carrying the 2 bp inactivating insertion inVC1still have residual v-c levels due toVC2activity. Furthermore, we find thatVC1has multiple alleles and exhibits copy number variations, complicating molecular marker development. Conversely, single nucleotide polymorphisms withinVC2provide a reliable alternative for marker-assisted selection in faba bean breeding. In conclusion, our study elucidates the complex genetic regulation of v-c biosynthesis and provides valuable insights to facilitate its elimination in faba bean.
Diabetic liver-enriched secretory dipeptidyl peptidase 4 (DPP4) fuels gut inflammation via attenuation of autophagy
Authors: Athar Mohammad , Bhadury Ratulananda , Gogoi Chayanika , Mishra Pooja , Kumari Prity , Yadav Manisha , Maras Jaswinder Singh , Ghorpade Devram S. 
Published: August 2024

AbstractThe recurrent pathological inflammation of the gut is a major concern in diabetic patients. With the failure of anti-inflammatory or diabetic drugs to limit relapse of colon inflammation demands the unearthing of mechanistic details underlying higher incidences of colitis in diabetic patients. Here we report the enrichment of DPP4 in the livers and blood samples of diabetic humans and mice models of diabesity that is in parallel to the development of colitis. Overexpression of DPP4 exacerbates or hepatic silencing of DPP4 impairs experimental colitis induced by DSS and STM. Mechanistically, we identified liver DPP4 attenuates gut-autophagic response to trigger enteric cell apoptosis, reduced mucin secretion, and compromised gut barrier leading to high infiltration of immune cells secreting inflammatory cytokines establishing pathological gut inflammation. Thus, liver-DPP4-mediated gut autophagy inhibition is a key pathway in diabesitic colitis.
p-IgGen: A Paired Antibody Generative Language Model
Authors: Turnbull Oliver M. , Oglic Dino , Croasdale-Wood Rebecca , Deane Charlotte M. 
Published: August 2024

SummaryA key challenge in antibody drug discovery is designing novel sequences that are free from developability issues - such as aggregation, polyspecificity, poor expression, or low solubility. Here, we present p-IgGen, a protein language model for paired heavylight chain antibody generation. The model generates diverse, antibody-like sequences with pairing properties found in natural antibodies. We also create a finetuned version of p-IgGen that biases the model to generate antibodies with 3D biophysical properties that fall within distributions seen in clinical-stage therapeutic antibodies.
Microglia initially seed and later reshape amyloid plaques in Alzheimer’s disease
Authors: Baligács Nóra , Albertini Giulia , Borrie Sarah C. , Serneels Lutgarde , Pridans Clare , Balusu Sriram , De Strooper Bart 
Published: August 2024

AbstractWe demonstrate the dual role of microglia in Alzheimer’s disease (AD), initially harmful, by seeding amyloid plaques, and protective in later stages by compacting amyloid plaques. Early microglial depletion using pharmacological or genetic blockage of CSF1R reduces plaque load and associated neuritic dystrophy, while human microglia transplantation restores plaque formation, confirming their seeding role. TransplantedTREM2R47H/R47Hmicroglia exacerbate plaque pathology, highlighting microglia as key initiators of the amyloid pathology cascade.
Sexual receptivity increases in synchrony with the ovulatory cycle in female medaka
Authors: Tomihara Soma , Shimomai Rinko , Nakajo Mikoto , Oka Yoshitaka , Umatani Chie 
Published: August 2024

AbstractSuccessful reproduction requires coordinated regulation of gonadal function and sexual behavior. However, the mechanisms of such a regulation remain elusive. Here, we used a teleost medaka to find out possible involvement of ovulation in the control of female sexual behaviors by analyzing the sexual behaviors of the female gene-knockout medaka that do not ovulate and found that ovulation is essential for the facilitation of female sexual receptivity. Behavioral recordings and anatomical examinations showed that the sexual behavior of medaka occurs only after the ovulation. Furthermore, progesterone administration partially reinstated the sexual receptivity of the anovulatory knockout females. Taken together with the result that progesterone receptor is expressed in the brain regions that are considered strong candidate for regulation of sexual behavior, we propose that female sexual receptivity is facilitated in synchrony with the ovulatory cycle via progesterone receptor signaling in specific brain regions that occurs around the timing of ovulation.
Integrin blocking peptide reverses immunosuppression in experimental gliomas and improves anti-PD-1 therapy outcome
Authors: Ellert-Miklaszewska Aleksandra , Pilanc-Kudlek Paulina , Poleszak Katarzyna , Roura Adria-Jaume , Cyranowski Salwador , Ghosh Mitrajit , Baluszek Szymon , Pasierbinska Maria , Gielniewski Bartłomiej , Swatler Julian , Hovorova Yuliana , Wojnicki Kamil , Kaminska Bozena 
Published: August 2024

ABSTRACTImmune checkpoint inhibitors (ICI) presented clinical benefits in many cancer patients but invariably fail in glioblastoma (GBM), the most common and deadly primary brain tumor. Lack of ICI efficacy in GBM is attributed to the accumulation of immunosuppressive myeloid cells that create the “cold” tumor microenvironment (TME) impeding infiltration and activation of effector T cells. We developed a designer RGD peptide that hindered glioma-instigated, integrin-mediated pro-tumoral reprogramming of myeloid cells and blocked microglia-dependent invasion of human and mouse glioma cells in co-culturesin vitro. Intratumorally-delivered RGD alone did not reduce glioma growth in syngeneic mice but prevented the emergence of immunosuppressive myeloid cells and led to peritumoral blood vessels normalization. Furthermore, combining RGD with immunotherapy using PD-1 blockade reduced tumor growth, led to upsurge of proliferating, interferon-ɣ producing CD8+T cells and depleted regulatory T cells. Transcriptomic profiles of myeloid cells were altered by the combined treatment, consistently with the restored “hot” inflammatory TME and boosted immunotherapy responses. RGD modified the phenotypes of myeloid cells in human gliomas in nude mice. Thus, combining the integrin blockade with ICI reinvigorates antitumor immunity and paves the way to improve immunotherapy outcomes in GBM.
Improved vectors for retron-mediated CRISPR-Cas9 genome editing inSaccharomyces cerevisiae
Authors: Stuecker Tara N. , Hood Stephanie E. , Pineda Julio Molina , Lenaduwe Sonali , Winter Joshua , Sadhu Meru J. , Lewis Jeffrey A. 
Published: August 2024

AbstractIn vivosite-directed mutagenesis is a powerful genetic tool for testing the effects of specific alleles in their normal genomic context. While the budding yeastSaccharomyces cerevisiaepossesses classical tools for site-directed mutagenesis, more efficient recent CRISPR-based approaches use Cas ‘cutting’ combined with homologous recombination of a ‘repair’ template that introduces the desired edit. However, current approaches are limited for fully prototrophic yeast strains, and rely on relatively low efficiency cloning of short gRNAs. We were thus motivated to simplify the process by combining the gRNA and its cognate repair template incison a single oligonucleotide. Moreover, we wished to take advantage of a new approach that uses anE. coliretron (EcRT) to amplify repair templates as multi-copy single-stranded (ms)DNAin vivo, which are more efficient templates for homologous recombination. To this end, we have created a set of plasmids that express Cas9-EcRT, allowing for co-transformation with the gRNA-repair template plasmid in a single step. Our suite of plasmids contains different antibiotic (Nat, Hyg, Kan) or auxotrophic (HIS3, URA3) selectable markers, allowing for editing of fully prototrophic wild yeast strains. In addition to classic galactose induction, we generated a β-estradiol-inducible version of each plasmid to facilitate editing in yeast strains that grow poorly on galactose. The plasmid-based system results in >95% editing efficiencies for point mutations and >50% efficiencies for markerless deletions, in a minimum number of steps and time. We provide a detailed step-by-step guide for how to use this system.
Genomic data reveal a north-south split and introgression history of blood fluke (Schistosoma haematobium) populations from across Africa
Authors: Platt Roy N , Enabulele Egie E. , Adeyemi Ehizogie , Agbugui Marian O , Ajakaye Oluwaremilekun G , Amaechi Ebube C , Ejikeugwu Chika E , Igbeneghu Christopher , Njom Victor S , Dlamini Precious , Arya Grace A. , Diaz Robbie , Rabone Muriel , Allan Fiona , Webster Bonnie , Emery Aidan , Rollinson David , Anderson Timothy J.C. 
Published: August 2024

AbstractThe human parasitic fluke,Schistosoma haematobiumhybridizes with the livestock parasiteS. bovisin the laboratory, but the frequency of hybridization in nature is unclear. We analyzed 34.6 million single nucleotide variants in 162 samples from 18 African countries, revealing a sharp genetic discontinuity between northern and southernS. haematobium. We found no evidence for recent hybridization. Instead the data reveal admixture events that occurred 257-879 generations ago in northernS. haematobiumpopulations. Fifteen introgressedS. bovisgenes are approaching fixation in northernS. haematobiumwith four genes potentially driving adaptation. We identified 19 regions that were resistant to introgression; these were enriched on the sex chromosomes. These results (i) suggest strong barriers to gene flow between these species, (ii) indicate that hybridization may be less common than currently envisaged, but (iii) reveal profound genomic consequences of rare interspecific hybridization between schistosomes of medical and veterinary importance.
Neolithic introgression ofIL23R-related protection against chronic inflammatory bowel diseases in modern Europeans
Authors: Krause-Kyora Ben , da Silva Nicolas Antonio , Kaplan Elif , Kolbe Daniel ,   Archaeological Civilization Disease Consortium (ACDC), Wohlers Inken , Busch Hauke , Ellinghaus David , Caliebe Amke , Sezgin Efe , Nebel Almut , Schreiber Stefan 
Published: August 2024

SummaryBackgroundThe hypomorphic variant rs11209026-A in theIL23Rgene provides significant protection against immune-related diseases in Europeans, notably inflammatory bowel disease (IBD). Today, the A-allele occurs with an average frequency of 5% in Europe.MethodsThis study comprised 251 ancient genomes from Europe spanning over 14,000 years. In these samples, the investigation focused on admixture informed analyses and selection scans of rs11209026-A and its haplotypes.Findingsrs11209026-A was found at high frequencies in Anatolian Farmers (AF, 18%) where it was likely under weak positive selection. AF later introduced the allele into the ancient European gene-pool. Subsequent admixture caused its frequency to decrease and formed the current southwest-to-northeast allele frequency cline in Europe. The geographic distribution of rs11209026-A may influence the gradient in IBD incidence rates that are highest in northern and eastern Europe.InterpretationGiven the dramatic changes from hunting and gathering to agriculture during the Neolithic, AF might have been exposed to selective pressures from a pro-inflammatory lifestyle and diet. Therefore, the protective A-allele may have increased survival by reducing intestinal inflammation and microbiome dysbiosis. The adaptively evolved function of the variant likely contributes to the high efficacy and low side-effects of modern IL-23 neutralization therapies for chronic inflammatory diseases. This study highlights how evolutionary informed research can provide promising targets for new therapeutic strategies.FundingDeutsche Forschungsgemeinschaft (DFG German Research Foundation) under Germany’s Excellence Strategy – EXC 2167 390884018 and EXC 2150 390870439.