bluuebunny/crossref_metadata_2025_split huggingface dataset:
Excitatory and Inhibitory Effects of Saphenous Nerve Stimulation on Two Different Bladder Conditons: Underactivity and Overactivity
Authors: Li Chen , Zhou Zhonghan , Liao Limin , Li Xing 
Published: September 2024

ABSTRACTBackgroundThis study aimed at exploring the effects of saphenous nerve stimulation (SNS) on treating both overactive bladder (OAB) and underactive bladder (UAB).MethodIn 6 α-chloralose anesthetized cats, bipolar nerve cuff electrodes were implanted on the saphenous nerve and pudendal nerve. UAB was induced by pudendal nerve stimulation (PNS) at 5Hz, 2 threshold (T) and OAB was induced by infusion of 0.25% acetic acid (AA). Multiple cystometrograms (CMGs) were performed to investigate the effects of SNS on pathological bladder at 1Hz and 20Hz, respectively.ResultsApplication of PNS (5Hz, 2T) induced UAB by significantly increasing the bladder capacity (BC) to 156.3%±9.8% of control level, while combination of PNS and SNS (1Hz, 2T) applied during CMGs normalized the bladder underactivity by significantly reducing the BC to 93.6%±9.5% (P =0.026). Moreover, the BC was reduced to 64.1%±5.4% of control after infusion of AA, and SNS at 20Hz, 6T significantly increased the BC back to 93.4%±6.3% (P =0.005). No post-stimulation effect of SNS was detected at both 1Hz and 20Hz. However, there were no significant changes of contraction amplitude and duration during stimulation.ConclusionIn this study, we confirmed the frequency-dependence of SNS in regulating pathological bladder in cats. It provided experimental evidence for treating both OAB and UAB using SNS in clinic.
Improving the accuracy of pose prediction by incorporating symmetry-related molecules
Authors: Hima Sree , Remya Chandran , Dileep K.V. 
Published: September 2024

ABSTRACTAccurate prediction of biologically relevant binding poses is crucial for the success of computer-aided drug development. In this study, we describe a general strategy to enhance the precision of pose prediction in molecular docking by incorporating symmetry-related molecules (SRMs). Our objective was to demonstrate the significant impact of SRMs on the accuracy of pose prediction. To achieve this, we evaluated our method on high-quality protein-ligand complex structures, focusing on the presence and absence of SRMs during molecular docking studies. We have extracted the co-crystal ligands from the selected crystal structure and were redocked in presence and absence of SRM to assess their influence. Additionally, we calculated the free energy of the docked poses using the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) method, comparing the results in the presence and absence of SRMs. The findings revealed that redocking performed in the presence of SRMs significantly improved the prediction of biologically significant/crystallographically relevant poses. Consequently, our proposed strategy offers a robust method for enhancing pose prediction in current molecular docking programs, potentially leading to more effective and reliable drug development processes.
Spatial multi-omics reveal intratumoral humoral immunity niches associated with tertiary lymphoid structures in pancreatic cancer immunotherapy pathologic responders
Authors: Sidiropoulos Dimitrios N. , Shin Sarah M. , Wetzel Meredith , Girgis Alexander A. , Bergman Daniel , Danilova Ludmila , Perikala Susheel , Shu Daniel H. , Montagne Janelle M. , Deshpande Atul , Leatherman James , Dequiedt Lucie , Jacobs Victoria , Ogurtsova Aleksandra , Mo Guanglan , Yuan Xuan , Lvovs Dmitrijs , Stein-O’Brien Genevieve , Yarchoan Mark , Zhu Qingfeng , Harper Elizabeth I. , Weeraratna Ashani T. , Kiemen Ashley L. , Jaffee Elizabeth M. , Zheng Lei , Ho Won Jin , Anders Robert A. , Fertig Elana J. , Kagohara Luciane T. 
Published: September 2024

ABSTRACTPancreatic adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. We generated a spatial multi-omics atlas encompassing 26 PDAC tumors from patients treated with combination immunotherapies. Using machine learning-enabled H&E image classification models and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within TLS niches spanning across distinct morphologies and immunotherapies. Unsupervised learning generated a TLS-specific spatial gene expression signature that significantly associates with improved survival in PDAC patients. These analyses demonstrate TLS-associated intratumoral B cell maturation in pathological responders, confirmed with spatial proteomics and BCR profiling. Our study also identifies spatial features of pathologic immune responses, revealing TLS maturation colocalizing with IgG/IgA distribution and extracellular matrix remodeling.GRAPHICAL ABSTRACTHIGHLIGHTSIntegrated multi-modal spatial profiling of human PDAC tumors from neoadjuvant immunotherapy clinical trials reveal diverse spatial niches enriched in TLS.TLS maturity is influenced by tumor location and the cellular neighborhoods in which TLS immune cells are recruited.Unsupervised machine learning of genome-wide signatures on spatial transcriptomics data characterizes the TLS-enriched TME and associates TLS transcriptomes with survival outcomes in PDAC.Interactions of spatially variable gene expression patterns showed TLS maturation is coupled with immunoglobulin distribution and ECM remodeling in pathologic responders.Intratumoral plasma cell and immunoglobin gene expression spatial dynamics demonstrate trafficking of TLS-driven humoral immunity in the PDAC TME.SignificanceWe report a spatial multi-omics atlas of PDAC tumors from a series of immunotherapy neoadjuvant clinical trials. Intratumorally, pathologic responders exhibit mature TLS that propagate plasma cells into malignant niches. Our findings offer insights on the role of TLS-associated humoral immunity and stromal remodeling during immunotherapy treatment.
PhysiofUS : a tissue-motion based method for heart and breathing rate assessment in neurofunctional ultrasound imaging
Authors: Zucker Nicolas , Le Meur-Diebolt Samuel , Pereira Felipe Cybis , Baranger Jerome , Hurvitz Isabella , Demené Charlie , Osmanski Bruno , Ialy-Radio Nathalie , Biran Valérie , Baud Olivier , Pezet Sophie , Deffieux Thomas , Tanter Mickael 
Published: September 2024

AbstractRecent studies have shown growing evidence that brain function is closely synchronised with global physiological parameters. Heart rate is linked to various cognitive processes and previous research has also demonstrated a strong correlation between neuronal activity and breathing. These findings highlight the significance of monitoring these key physiological parameters during neuroimaging as they provide valuable insights into the overall brain function. Today, in neuroimaging, assessing these parameters required additional cumbersome devices or implanted electrodes.In this work, we performed ultrafast ultrasound imaging both in rodents and human neonates, and we extracted heart and breathing rates from local tissue motion assessed by raw ultrasound data processing. Such ‘PhysiofUS’ automatically select two specific and optimal brain regions with pulsatile tissue signals to monitor such parameters.We validated the correspondence of these periodic signals with heart and breathing rates assessed using gold-standard electrodes in various conditions in rodents. We also validated Physio-fUS imaging in a clinical environment using conventional ECG.We show the potential of fUS imaging as an integrative tool for simultaneously monitoring physiological parameters during neurofunctional imaging. Beyond the technological improvement, this innovation could enhance our understanding of the link between breathing, heart rate and neurovascular activity both anesthetised in preclinincal research and clinical functional ultrasound imaging.
MTALTCO1: a 259 amino-acid long mtDNA-encoded alternative protein that challenges conventional understandings of mitochondrial genomics
Authors: Robitaille Francis , Ben Hadj Aziz , Campbell Amy , Nadeau-Lachance Ludovic , Niaison Thierry , Choquette Thierry , Roucou Xavier , Angers Annie , Breton Sophie 
Published: September 2024

ABSTRACTMitochondrial-derived peptides significantly expand the coding potential of the human mitochondrial genome. Here, we report the discovery of MTALTCO1, a 259 amino-acid protein encoded by a mitochondrial alternative open reading frame found in the +3 reading frame of the cytochrome oxidase 1 gene (CO1). Using a custom antibody, we confirmed the mitochondrial expression of MTALTCO1 in human cell lines. Sequence analysis revealed high arginine content and an elevated isoelectric point that were not contingent on CO1’s amino acid sequence, suggesting selective pressures might be acting on this protein. MTALTCO1 displays extensive fusion-fission dynamics at the interspecies level, yet produces a full-length protein throughout human mitochondrial lineages. Our findings highlight the importance of identifying novel mitochondrial-derived peptides and proteins in expanding our understanding of the mitochondrial proteome.
Shift from visceral to subcutaneous fat inCyp17a1knockout rats prevent the progression of metabolic syndrome
Authors: Jeon Beom-Jin , Lee Jeong-Hwa , Kwon Dong-Hyeok , Kim Hee-Kyoung , Jang Goo 
Published: September 2024

ABSTRACTIn this study, we investigated the effects ofCyp17a1gene knockout (KO) on obesity and metabolic syndrome.Cyp17a1KO in rats using CRISPR-Cas9 resulted in sex dimorphism and obesity, and interestingly, idiopathic accumulation was found in subcutaneous adipose tissue. Surprisingly, an insulin tolerance test and oral glucose tolerance test did not show any issues with insulin sensitivity and secretion despite hyperglycemia. In addition,Cyp17a1KO rats showed normal plasma insulin and free fatty acid levels compared to wild-type rats, and blood biochemistry analysis revealed normal triglyceride, total cholesterol, high-density lipoprotein, and low-density lipoprotein levels.Cyp17a1KO adipose-tissue-derived stem cells from subcutaneous fat showed increased expression of KLF5, an early adipogenesis marker, which implies enhanced adipogenic potential in subcutaneous adipose tissue. When gene expression associated with lipid, glucose, and insulin metabolism as well as inflammation in adipose tissue was examined, a metabolic shift to subcutaneous adipose tissue was discovered in theCyp17a1KO group. In conclusion, in the Cyp17a1 KO rat models we generated for the first time, the phenotype promoted by obesity reflected health obesity hypothesis, but this did not result in metabolic syndrome due to enhanced metabolism in the subcutaneous fats.
Mechanistic model for epigenetic maintenance by methyl-CpG-binding domain proteins
Authors: Dai Liuhan , Johnson-Buck Alexander , Walter Nils G. 
Published: September 2024

AbstractDNA methylation is a fundamental element of epigenetic regulation that is governed by the MBD protein superfamily, a group of “readers” that share a highly conserved methyl-CpG-binding domain (MBD) and mediate chromatin remodeler recruitment, transcription regulation, and coordination of DNA and histone modification. Previous work has characterized the binding affinity and sequence selectivity of MBD-containing proteins toward palindromes of 5-methylcytosine (5mC) containing 5mCpG dinucleotides, often referred to as single symmetrically methylated CpG sites. However, little is known about how MBD binding is influenced by the prototypical local clustering of methylated CpG sites and the presence of DNA structural motifs encountered, e.g., during DNA replication and transcription. Here, we use Single-Molecule Kinetics through Equilibrium Poisson Sampling (SiMKEPS) to measure precise binding and dissociation rate constants of the MBD of human protein MBD1 to DNAs with varying patterns of multiple methylated CpG sites and diverse structural motifs. MBD binding is promoted by two major properties of its DNA substrates: 1) tandem (consecutive) symmetrically methylated CpG sites in double-stranded DNA and secondary structures in single-stranded DNA; and 2) DNA forks. Based on our findings, we propose a mechanistic model for how MBD proteins contribute to epigenetic boundary maintenance between transcriptionally silenced and active genome regions.
Enhancing NosZ Activity to Reduce N2O Emissions from Biological Wastewater Treatment Systems
Authors: Zhou Xueyang , Manna Bharat , Lyu Boyu , Singhal Naresh 
Published: September 2024

ABSTRACTNitrous oxide (N2O) emissions from wastewater treatment plants, with a warming potential 298 times that of CO2, pose a significant challenge to lowering their carbon footprint. Current mitigation strategies focus on limiting N2O formation during nitrification and denitrification but overlook microbial reduction mechanisms. This study examines the potential for enhancing nitrous oxide reductase (NosZ) activity to reduce N2O to N2. We hypothesize that strategic oxygen manipulation can enhance N2O destruction by continuous NosZ expression and enable NosZ activation in microorganisms with superior NosZ capabilities. We assess microbial community function and metabolic regulation using metagenomics and metaproteomics to clarify the effect of intermittent aeration regimes on N2O emission. Intermittent aeration with periodic anoxic exposure significantly reduced N2O emissions with 71% nitrogen removal by enhancing the metabolic activity ofHyphomicrobium. NosZ activity increased by 4- to 6.5-fold after system adaptation to oxygen modulations, compared to continuous oxic-anoxic cycling without the anoxic phase. The latter resulted in increased N2O emissions due to suppressed NosZ activity and higher N2O production fromMethylobacillus, which uses nitric oxide as an alternative electron acceptor. Our finding that strategic oxygen manipulation can energize N2O destruction lays the foundation for developing next-generation wastewater treatment technologies for mitigating N2O emissions.
The GeoTox Package: Open-source software for connecting spatiotemporal exposure to individual and population-level risk
Authors: Messier Kyle P , Reif David M , Marvel Skylar W 
Published: September 2024

AbstractBackgroundComprehensive environmental risk characterization, encompassing physical, chemical, social, ecological, and lifestyle stressors, necessitates innovative approaches to handle the escalating complexity. This is especially true when considering individual and population-level diversity, where the myriad combinations of real-world exposures magnify the combinatoric challenges. The GeoTox framework offers a tractable solution by integrating geospatial exposure data from source-to-outcome in a series of modular, interconnected steps.ResultsHere, we introduce theGeoToxopen-source R software package for characterizing the risk of perturbing molecular targets involved in adverse human health outcomes based on exposure to spatially-referenced stressor mixtures. We demonstrate its usage in building computational workflows that incorporate individual and population-level diversity. Our results demonstrate the applicability of GeoTox for individual and population-level risk assessment, highlighting its capacity to capture the complex interplay of environmental stressors on human health.ConclusionsTheGeoToxpackage represents a significant advancement in environmental risk characterization, providing modular software to facilitate the application and further development of the GeoTox framework for quantifying the relationship between environmental exposures and health outcomes. By integrating geospatial methods with cutting-edge exposure and toxicological frameworks,GeoToxoffers a robust tool for assessing individual and population-level risks from environmental stressors.GeoToxis freely available athttps://niehs.github.io/GeoTox/.
Socio-economic patterns of diet, obesity, and biomarkers for cardiovascular disease among Indian adolescents
Authors: Kalita Neelam , Griffin Susan , Mazumdar Sumit 
Published: September 2024

ABSTRACTBackgroundThe impact of socioeconomic (SES) factors, maternal education and household wealth on diet and consequently on a host of cardiovascular disease (CVD) biomarkers is rarely examined among Indian adolescents, who are in a critical development phase. This study examines the socio-economic patterning of dietary behaviour and its correlation with overweight/obesity and CVD biomarkers among Indian adolescents aged 10 to 19 years.MethodsWe use nationally representative data on dietary patterns and CVD biomarkers from the Comprehensive National Nutrition Dataset, a nationally representative survey of 35,830 adolescents conducted from 2016 to 2018. Dietary pattern is assessed using a summary indicator-Dietary Diversity Score based on 17 specific food groups. Overweight/obesity and the biomarkers, including the ratio of total cholesterol to high-density lipoprotein-cholesterol, serum triglycerides, hypertension, and pre-diabetic/diabetic, are analysed.ResultsAdolescents from higher SES have higher dietary diversity than those from lower SES. This socio-economic patterning is concentrated on higher daily consumption of certain foods such as fats and oil, sugar and jaggery and those high in fats, sugar, and salt (HFSS) comprising-junk food, fried food, sweets, and aerated drinks among those from high SES and urban areas. This, in turn, may explain the concentration of overweight/obesity in this cohort. The SES gradient in diet, overweight/obesity, and associated CVD biomarkers among Indian adolescents remains positive for the household wealth index (worse health for the more economically advantaged) and urban dwellers. However, it is starting to shift towards negative for maternal education, resulting in an inverted U shape (better health for the lowest and highest socially advantaged, worse health for those in the middle).ConclusionsThere is a clustering of overweight/obesity and CVD biomarkers among adolescents from urban and wealthier households that may be associated with increased consumption of HFSS in this cohort.
Morphometric variations of human mandible in Indian population: comparison between subjects having healthy and ankylosed temporomandibular joint
Authors: Chandra Girish , Ghosh Rajdeep , Kaur Kamalpreet , Roychoudhury Ajoy , Mukherjee Sudipto , Chawla Anoop , Mukherjee Kaushik 
Published: September 2024

AbstractThe temporomandibular joint (TMJ) helps to perform the functional activities of the oral cavity. Such activities often get affected by end-stage degenerative disorders such as TMJ ankylosis. Alloplastic reconstruction using TMJ implants helps to restore those activities. However, commercially available stock implants often suffer from fit discrepancies in Indian population. Therefore, this study is aimed to compare comparison between mandibular morphometry of subjects with healthy or normal TMJ joints (TMJN) and patients with TMJ ankylosis (TMJA) from the Indian population. Furthermore, the observed mandibular morphometry has also been compared with those of the other populations. In this study, the most useful anatomical parameters of mandible are measured from the CT-based reconstructed mandibles of 367 Indian subjects (199 healthy;168 ankylosis). Significant differences in ramus length (healthy males: 61.74±7.53 mm, ankylosis males: 46.81±10.35 mm; healthy females: 55.21±6.12 mm, ankylosis females: 41.77±8.57 mm) and condyle width (healthy males: 18.76±3.22 mm, ankylosis males: 22.67±5.56 mm; healthy females: 16.94±2.41 mm, ankylosis females: 21.31±4.65 mm) have been observed between mandibles of ankylosis and healthy subjects. Differences in ramus length (affected side: 43.87±9.51 mm; unaffected side: 55.34±7.12 mm) and condyle width (affected side: 23±4.68 mm; unaffected side: 17.99±2.81 mm) were also observed between affected and unaffected sides of mandibles for unilateral ankylosis patients. Ramus length in healthy subjects was found to be the most statistically significant parameter between mandibles of Indians and other populations.
Cell signaling facilitates apical constriction by basolaterally recruiting Arp2/3 via Rac and WAVE
Authors: Zhang Pu , Medwig-Kinney Taylor N. , Breiner Eleanor A. , Perez Jadyn M. , Song April N. , Goldstein Bob 
Published: September 2024

AbstractApical constriction is a critical cell shape change that bends tissues. How precisely-localized actomyosin regulators drive apical constriction remains poorly understood.C. elegansgastrulation provides a valuable model to address this question. The Arp2/3 complex is essential inC. elegansgastrulation. To understand how Arp2/3 is locally regulated, we imaged embryos with endogenously-tagged Arp2/3 and its nucleation-promoting factors (NPFs). The three NPFs – WAVE, WASP, and WASH – colocalized with Arp2/3 and controlled Arp2/3 localization at distinct subcellular locations. We exploited this finding to study distinct populations of Arp2/3 and found that only WAVE depletion caused penetrant gastrulation defects. WAVE localized basolaterally with Arp2/3 at cell-cell contacts, dependent on CED-10/Rac. Establishing ectopic cell contacts recruited WAVE and Arp2/3, identifying contact as a symmetry-breaking cue for localization of these proteins. These results suggest that cell-cell signaling via Rac activates WAVE and Arp2/3 basolaterally, and that basolateral Arp2/3 is important for apical constriction.
CLCC1 promotes membrane fusion during herpesvirus nuclear egress
Authors: Dai Bing , Polack Lucas , Sperl Adrian , Dame Haley , Huynh Tien , Deveney Chloe , Lee Chanyoung , Doench John G. , Heldwein Ekaterina E. 
Published: September 2024

ABSTRACT/SUMMARYHerpesviralesare an ancient viral order that infects species from mollusks to humans for life. During infection, these viruses translocate their large capsids from the nucleus to the cytoplasm independently from the canonical route through the nuclear pore. Instead, capsids dock at the inner nuclear membrane and bud into the perinuclear space. These perinuclear enveloped virions fuse with the outer nuclear membrane releasing the capsids into the cytoplasm for maturation into infectious virions. The budding stage is mediated by virally encoded proteins. But the mediator of the subsequent fusion stage is unknown. Here, using a whole-genome CRISPR screen with herpes simplex virus 1, we identified CLCC1 as an essential host factor for the fusion stage of nuclear egress. Loss of CLCC1 results in a defect in nuclear egress, accumulation of capsid-containing perinuclear vesicles, and a drop in viral titers. In uninfected cells, loss of CLCC1 causes a defect in nuclear pore complex insertion. Viral homologs of CLCC1 are present in herpesviruses that infect mollusks and fish. Our findings uncover an ancient cellular membrane fusion mechanism important for the fundamental cellular process of nuclear envelope morphogenesis that herpesviruses hijack for capsid transport.