bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of transcutaneous auricular vagus nerve stimulation on cardiovascular function in subarachnoid hemorrhage patients: a safety study
Authors: Tan Gansheng , Huguenard Anna L. , Donovan Kara M. , Demarest Phillip , Liu Xiaoxuan , Li Ziwei , Adamek Markus , Lavine Kory , Vellimana Ananth K. , Kummer Terrance T. , Osbun Joshua W. , Zipfel Gregory J. , Brunner Peter , Leuthardt Eric C. 
Published: April 2024

Structured AbstractIntroductionSubarachnoid hemorrhage (SAH) is characterized by intense central inflammation, leading to substantial post-hemorrhagic complications such as vasospasm and delayed cerebral ischemia. Given the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation (taVNS) and its ability to promote brain plasticity, taVNS has emerged as a promising therapeutic option for SAH patients. However, the effects of taVNS on cardiovascular dynamics in critically ill patients, like those with SAH, have not yet been investigated. Given the association between cardiac complications and elevated risk of poor clinical outcomes after SAH, it is essential to characterize the cardiovascular effects of taVNS to ensure this approach is safe in this fragile population. Therefore, we assessed the impact of both acute taVNS and repetitive taVNS on cardiovascular function in this study.MethodsIn this randomized clinical trial, 24 SAH patients were assigned to either a taVNS treatment or a Sham treatment group. During their stay in the intensive care unit, we monitored patient electrocardiogram (ECG) readings and vital signs. We compared long-term changes in heart rate, heart rate variability, QT interval, and blood pressure between the two groups. Additionally, we assessed the effects of acute taVNS by comparing cardiovascular metrics before, during, and after the intervention. We also explored acute cardiovascular biomarkers in patients exhibiting clinical improvement.ResultsWe found that repetitive taVNS did not significantly alter heart rate, QT interval, blood pressure, or intracranial pressure. However, taVNS increased overall heart rate variability and parasympathetic activity compared to the sham treatment. The increase in parasympathetic activity was most pronounced from 2–4 days after initial treatment (Cohen’s d = 0.50). Acutely, taVNS increased heart rate, blood pressure, and peripheral perfusion index without affecting the corrected QT interval, intracranial pressure, or heart rate variability. The acute post-treatment elevation in heart rate was more pronounced in patients who experienced a decrease of more than one point in their Modified Rankin Score at the time of discharge.ConclusionsOur study found that taVNS treatment did not induce adverse cardiovascular effects, such as bradycardia or QT prolongation, supporting its development as a safe immunomodulatory treatment approach for SAH patients. The observed acute increase in heart rate after taVNS treatment may serve as a biomarker for SAH patients who could derive greater benefit from this treatment.Trial registrationNCT04557618
Microbiome-based biomarkers to guide personalized microbiome-based therapies for Parkinson’s disease
Authors: Payami Haydeh , Sampson Timothy R , Murchison Charles F , Wallen Zachary D 
Published: April 2024

AbstractWe address an unmet challenge in Parkinson’s disease: the lack of biomarkers to identify the right patients for the right therapy, which is a main reason clinical trials for disease modifying treatments have all failed. The gut microbiome is a new target for treatment of Parkinson’s disease, with potential to halt disease progression. Our aim was to develop microbiome-based biomarkers to guide patient selection for microbiome-based clinical trials. We used microbial taxa that have been robustly associated with Parkinson’s disease across studies and at high significance as dysbiotic features of Parkinson’s disease. Using individual-level taxonomic relative abundance data, we classified patients according to their dysbiotic features, effectively defining microbiome-based subtypes of PD. We show that not all persons with Parkinson’s disease have a dysbiotic microbiome, and not all dysbiotic Parkinson’s disease microbiomes have the same features. Grounded in robust and reproducible data from differential abundance studies, we propose an intuitive and easily modifiable method to identify the optimal candidates for microbiome-based clinical trials, and subsequently, for treatments that are personalized for each individual’s dysbiotic features. We demonstrate the method for Parkinson’s disease. The concept, and the method, is generalizable for any disease with a microbiome component.
Multi-ancestry GWAS of diarrhea during acute SARS-CoV2 infection identifies multiple novel loci and contrasting etiological roles of irritable bowel syndrome subtypes
Authors: Chaudhary Ninad S. , Weldon Catherine H. , Nandakumar Priyanka , Shelton Janie F. ,   23andMe Research Team, Holmes Michael V. , Aslibekyan Stella 
Published: April 2024

ABSTRACTA substantial proportion of acute SARS-CoV2 infection cases exhibit gastrointestinal symptoms, yet the genetic determinants of these extrapulmonary manifestations are poorly understood. Using survey data from 239,866 individuals who tested positively for SARS-CoV2, we conducted a multi-ancestry GWAS of 80,289 cases of diarrhea occurring during acute COVID-19 infection (33.5%). Six loci (CYP7A1, LZFTL1- -CCR9, TEME182, NALCN, LFNG, GCKR) met genome-wide significance in a trans-ancestral analysis. The top significant GWAS hit mapped to theCYP7A1locus, which plays an etiologic role in bile acid metabolism and is in high LD (r2= 0.93) with theSDCBPgene, which was previously implicated in antigen processing and presentation in the COVID-19 context. Another association was observed with variants in theLZTFL1–CCR9region, which is a known locus for COVID-19 susceptibility and severity. PheWAS showed a shared association across three of the six SNPs with irritable bowel syndrome (IBS) and its subtypes. Mendelian randomization showed that genetic liability to IBS-diarrhea increased (OR=1.40,95%,CI[1.33-1.47]), and liability to IBS-constipation decreased (OR=0.86, 95%CI[0.79-0.94]) the relative odds of experiencing COVID-19+ diarrhea. Our genetic findings provide etiological insights into the extrapulmonary manifestations of acute SARS-CoV2 infection.
Identification of moderate effect size genes in autism spectrum disorder through a novel gene pairing approach
Authors: Caballero Madison , Satterstrom F Kyle , Buxbaum Joseph D. , Mahjani Behrang 
Published: April 2024

AbstractAutism Spectrum Disorder (ASD) arises from complex genetic and environmental factors, with inherited genetic variation playing a substantial role. This study introduces a novel approach to uncover moderate effect size (MES) genes in ASD, which individually do not meet the ASD liability threshold but collectively contribute when paired with specific other MES genes. Analyzing 10,795 families from the SPARK dataset, we identified 97 MES genes forming 50 significant gene pairs, demonstrating a substantial association with ASD when considered in tandem, but not individually. Our method leverages familial inheritance patterns and statistical analyses, refined by comparisons against control cohorts, to elucidate these gene pairs’ contribution to ASD liability. Furthermore, expression profile analyses of these genes in brain tissues underscore their relevance to ASD pathology. This study underscores the complexity of ASD’s genetic landscape, suggesting that gene combinations, beyond high impact single-gene mutations, significantly contribute to the disorder’s etiology and heterogeneity. Our findings pave the way for new avenues in understanding ASD’s genetic underpinnings and developing targeted therapeutic strategies.
ROS Mediated the Photodynamic Antibacterial ofVibrio vulnificusby a DNA-Targeted Molecular Rotor Probe
Authors: Yue Haiyun , Bian Qing , Li Xintong , Yu Chao , Chen Chao , Wang Kangnan , Cao Yuan 
Published: April 2024

AbstractVibrio vulnificus, a highly pathogenic Gram-negative bacterium, is capable of inducing sepsis, necrotizing fasciitis, and skin and soft tissue infections through contact with wounds. Currently, the majority ofV. vulnificusstrains have developed resistance to multiple drugs, highlighting the critical necessity for the development of novel therapeutics capable of effectively targeting and eradicating this bacterium. In recent years, material molecules have emerged as promising antimicrobial agents. This study introduces a novel molecular fluorescent probe, BDTP, which demonstrates a wide-ranging antimicrobial effect against both Gram-negative and Gram-positive bacteria while exhibiting minimal toxicity to normal mammalian cells. Of particular significance is BDTP’s ability to rapidly detect V. vulnificus, bind to bacterial DNA, and exhibit fluorescence monitoring behavior. Furthermore, BDTP displays enhanced photodynamic antibacterial activity when exposed to white light irradiation. Under a low dose of white light (15mW cm-2), the killing efficiency ofV. vulnificusirradiated with 4uM for 10 minutes was more than 99.8%. Moreover, it could significantly inhibit and eliminate the biofilm formed byV. vulnificus. It can induce the production of reactive oxygen species (ROS) inV. vulnificuscells, leading to bacterial cell damage. More importantly, BDTP significantly promoted the healing of infected wounds in an animal model ofV. vulnificusinfection. Therefore, BDTP shows great promise as a potent antibacterial agent againstV. vulnificusinfection.
Morphological, pathological and phylogenetic analyses identify a diverse group ofColletotrichumspp. causing leaf, pod, and flower diseases on the orphan legume African yam bean
Authors: Ogunsanya Olaide Mary , Adebisi Moruf Ayodele , Popoola Akinola Rasheed , Afolabi Clement Gboyega , Oyatomi Olaniyi , Colgan Richard , Armitage Andrew , Thompson Elinor , Abberton Michael , Ortega-Beltran Alejandro 
Published: April 2024

ABSTRACTAfrican yam bean (AYB;Sphenostylis stenocarpaHochst. Ex A. Rich.) is an underutilized legume indigenous to Africa. The crop has great potential as it can enhance food security and its chemical composition offers nutritional and medicinal opportunities. However, the low grain yield caused by fungal diseases, including pod blight and leaf tip dieback, deters farmers from large-scale cultivation. The causal agents of pod and leaf tip dieback on AYB are largely uncharacterized. To determine the prevalence of fungal diseases affecting leaves, pods, and flowers of AYB, a survey was conducted in 2018 and 2019 in major AYB-growing areas in Nigeria. Leaf tip dieback, flower bud rot, and pod blight were the most common symptoms. Morphological and molecular assays were conducted to identify the causal agents of the observed diseases. In all the samples examined, fungi from eight genera were isolated from leaves and pods showing disease symptoms. However, Koch’s postulates were fulfilled only for fungi belonging to theColletotrichumgenus. Fungi from the other seven genera did not produce disease symptoms in healthy AYB tissues. SeveralColletotrichumisolates were characterized by sequencing the ITS, glyceraldehyde-3-phosphate dehydrogenase, calmodulin, and ApMAT loci. A combined phylogenetic analysis revealed fourColletotrichumspecies:C. siamense,C. theobromicola,andC. fructicola, which were recovered from the diseased leaves, andC. truncatum, which was recovered from diseased pods and buds. Our results are useful to gear efforts to develop integrated management strategies to control diseases affecting AYB in Nigeria and other parts of Africa. The availability of such strategies may stimulate greater cultivation of AYB to contribute to diet diversification, which has been repeatedly advocated by a range of stakeholders to increase food security and the prosperity of smallholder farmers.
Machine learning recognises senescence in glioblastoma and discovers senescence-inducing compounds
Authors: Martin Lucy , Irving Anna , Suwanlikit Yossawat , Morrison Gillian , Elliott Richard J.R. , Carragher Neil , Pollard Steven , Chandra Tamir 
Published: April 2024

AbstractSenescence is a cell-intrinsic tumour suppressive response. A one-two-punch cancer treatment strategy aims to induce senescence in cancerous cells before removing them with a senolytic. It is important to accurately recognise senescent cells to investigate the feasibility of such a treatment strategy and identify compounds that induce senescence in cancer. We focus specifically on the terminal brain cancer glioblastoma, firstly identifying senescent glioblastoma cells with conventional stains, before training a machine learning model to distinguish senescent cells using only a DAPI nuclear stain. To demonstrate how our method can aid drug discovery, we apply our pipeline to existing glioblastoma high-throughput phenotypic drug screening imaging data to identify compounds that induce senescence in glioblastoma and verify these predictions experimentally.Author SummaryDamaged cells can enter a senescent cell state, in which they do not divide, but continue to interact with the environment around them. A novel potential cancer treatment strategy is to make tumor cells senescent, before removing senescent cancer cells with a targeted drug. To investigate this treatment strategy in the brain cancer glioblastoma, it is important to be able to accurately recognise senescent glioblastoma cells. As identifying senescent cells is challenging, we create a machine learning pipeline which can detect senescent glioblastoma cells in imaging data. We show that by applying our method to existing data we can discover compounds that induce senescence in glioblastoma. We verify our predictions by testing the compounds experimentally.
Seeding competent TDP-43 persists in human patient and mouse muscle
Authors: Lynch Eileen M. , Pittman Sara , Daw Jil , Ikenaga Chiseko , Chen Sheng , Dhavale Dhruva D. , Jackrel Meredith E. , Ayala Yuna M. , Kotzbauer Paul , Ly Cindy V. , Pestronk Alan , Lloyd Thomas E. , Weihl Conrad C. 
Published: April 2024

AbstractTAR DNA-binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous system of some neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy (IBM). TDP-43 aggregates from ALS and FTD brain lysates may serve as self-templating aggregate seedsin vitroandin vivo,supporting a prion-like spread from cell to cell. Whether a similar process occurs in IBM patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis and changes in TDP-43-related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with IBM, IMNM and ALS we found that TDP-43 seeding capacity was specific to IBM. Surprisingly, TDP-43 seeding capacity anti-correlated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.SummaryTDP-43 aggregate seeds persist in mouse and human skeletal muscle independent of large TDP-43 inclusions.
Molecular characterization of Rft1, an ER membrane protein associated with congenital disorder of glycosylation RFT1-CDG
Authors: Hirata Eri , Sakata Ken-taro , Dearden Grace I. , Noor Faria , Menon Indu , Chiduza George N. , Menon Anant K. 
Published: April 2024

ABSTRACTThe oligosaccharide needed for proteinN-glycosylation is assembled on a lipid carrier via a multi-step pathway. Synthesis is initiated on the cytoplasmic face of the endoplasmic reticulum (ER) and completed on the luminal side after transbilayer translocation of a heptasaccharide lipid intermediate. More than 30 Congenital Disorders of Glycosylation (CDGs) are associated with this pathway, including RFT1-CDG which results from defects in the membrane protein Rft1. Rft1 is essential for the viability of yeast and mammalian cells and was proposed as the transporter needed to flip the heptasaccharide lipid intermediate across the ER membrane. However, other studies indicated that Rft1 is not required for heptasaccharide lipid flipping in microsomes or unilamellar vesicles reconstituted with ER membrane proteins, nor is it required for the viability of at least one eukaryote. It is therefore not known what essential role Rft1 plays inN-glycosylation. Here, we present a molecular characterization of human Rft1, using yeast cells as a reporter system. We show that it is a multi-spanning membrane protein located in the ER, with its N and C-termini facing the cytoplasm. It is notN-glycosylated. The majority of RFT1-CDG mutations map to highly conserved regions of the protein. We identify key residues that are important for Rft1’s ability to supportN-glycosylation and cell viability. Our results provide a necessary platform for future work on this enigmatic protein.
Sexually dimorphic control of aggression by androgen signaling in a cichlid
Authors: Jackson Lillian R. , Alward Beau 
Published: April 2024

AbstractInnate social behaviors like aggression are modulated by sex steroid hormones such as androgens and estrogens. However, we know little about how the same hormone regulates similar behaviors in both sexes. We investigated the role of androgenic signaling in the regulation of aggression inAstatotilapia burtoni, a social fish in which males and females perform similar aggressive behaviors. We used ARα knockout (KO) animals for this study, which was recently shown to be required for male-typical aggression and mating. Surprisingly, ARα KO females did not show deficits in aggression. We also determined that females lacking the other AR, ARβ showed normal levels of aggression. Blocking both ARs pharmacologically confirmed that neither AR is necessary for aggression in females. However, ARα KO males showed clear deficits in attacks. Thus, inA. burtonithere appears to be a sexual dimorphism in the role of ARα in the control of aggression.
Quinoline-based compounds can inhibit diverse enzymes that act on DNA
Authors: Zhou Jujun , Chen Qin , Ren Ren , Yang Jie , Liu Bigang , Horton John R. , Chang Caleb , Li Chuxuan , Maksoud Leora , Yang Yifei , Rotili Dante , Zhang Xing , Blumenthal Robert M. , Chen Taiping , Gao Yang , Valente Sergio , Mai Antonello , Cheng Xiaodong 
Published: April 2024

AbstractDNA methylation, as exemplified by cytosine-C5 methylation in mammals and adenine-N6 methylation in bacteria, is a crucial epigenetic mechanism driving numerous vital biological processes. Developing non-nucleoside inhibitors to cause DNA hypomethylation is a high priority, in order to treat a variety of significant medical conditions without the toxicities associated with existing cytidine-based hypomethylating agents. In this study, we have characterized fifteen quinoline-based analogs. Notably, compounds with additions like a methylamine (9) or methylpiperazine (11) demonstrate similar low micromolar inhibitory potency against both human DNMT1 (which generates C5-methylcytosine) andClostridioides difficileCamA (which generates N6-methyladenine). Structurally, compounds9and11specifically intercalate into CamA-bound DNA via the minor groove, adjacent to the target adenine, leading to a substantial conformational shift that moves the catalytic domain away from the DNA. This study adds to the limited examples of DNA methyltransferases being inhibited by non-nucleotide compounds through DNA intercalation, following the discovery of dicyanopyridine-based inhibitors for DNMT1. Furthermore, our study shows that some of these quinoline-based analogs inhibit other enzymes that act on DNA, such as polymerases and base excision repair glycosylases. Finally, in cancer cells compound11elicits DNA damage response via p53 activation.Abstract FigureHighlightsSix of fifteen quinoline-based derivatives demonstrated comparable low micromolar inhibitory effects on human cytosine methyltransferase DNMT1, and the bacterial adenine methyltransferasesClostridioides difficileCamA andCaulobacter crescentusCcrM.Compounds9and11were found to intercalate into a DNA substrate bound by CamA.These quinoline-based derivatives also showed inhibitory activity against various base excision repair DNA glycosylases, and DNA and RNA polymerases.Compound11provokes DNA damage response via p53 activation in cancer cells.
Functional redundancy and formin-independent localization of tropomyosin isoforms in Saccharomyces cerevisiae
Authors: Dhar Anubhav , Bagyashree VT , Biswas Sudipta , Kumari Jayanti , Sridhara Amruta , Jeevan Subodh B , Shekhar Shashank , Palani Saravanan 
Published: April 2024

AbstractTropomyosin is an actin binding protein which protects actin filaments from cofilin-mediated disassembly. Distinct tropomyosin isoforms have long been hypothesized to differentially sort to subcellular actin networks and impart distinct functionalities. Nevertheless, a mechanistic understanding of the interplay between Tpm isoforms and their functional contributions to actin dynamics has been lacking. In this study, we present and charcaterize mNeonGreen-Tpm fusion proteins that exhibit good functionality in cells as a sole copy, surpassing limitations of existing probes and enabling real-time dynamic tracking of Tpm-actin filamentsin vivo. Using these functional Tpm fusion proteins, we find thatS. cerevisiaeTpm isoforms, Tpm1 and Tpm2, colocalize on actin cables and indiscriminately bind to actin filaments nucleated by either formin isoform-Bnr1 and Bni1in vivo, in contrast to the long-held paradigm of Tpm-formin pairing. We show that cellular Tpm levels regulate endocytosis by affecting balance between linear and branched actin networks in yeast cells. Finally, we discover that Tpm2 can protect and organize functional actin cables in absence of Tpm1. Overall, our work supports a concentration-dependent and formin isoform independent model of Tpm isoform binding to F-actin and demonstrates for the first time, the functional redundancy of the paralog Tpm2 in actin cable maintenance inS. cerevisiae.
Caspase cleavage of Influenza A virus M2 disrupts M2-LC3 interaction and regulates virion production
Authors: Figueras-Novoa Carmen , Akutsu Masato , Murata Daichi , Jiang Ming , Montaner Beatriz , Dubois Christelle , Shenoy Avinash , Beale Rupert 
Published: April 2024

AbstractInfluenza A virus (IAV) Matrix 2 (M2) protein is an ion channel, required for efficient viral entry and egress. M2 interacts with the small ubiquitin-like LC3 protein through a cytoplasmic C-terminal LC3 interacting region (LIR). Here, we report that M2 is cleaved by caspases, abolishing the M2-LC3 interaction. A crystal structure of the M2 LIR in complex with LC3 indicates the caspase cleavage tetrapeptide motif (82SAVD85) is an unstructured linear motif that does not overlap with the LIR. Furthermore, an IAV mutant expressing a permanently truncated M2, mimicking caspase cleavage, is impaired in M2 plasma membrane transport and produces a significantly attenuated virus. Our results reveal a dynamic regulation of the M2-LC3 interaction by caspases. This highlights the role of host proteases in regulating IAV exit, relating virion production with host cell state.