bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying distinct neural features between the initial and corrective phases of precise reaching using AutoLFADS
Authors: Lee Wei-Hsien , Karpowicz Brianna M , Pandarinath Chethan , Rouse Adam G. 
Published: July 2023

AbstractMany initial movements require subsequent corrective movements, but how motor cortex transitions to make corrections and how similar the encoding is to initial movements is unclear. In our study, we explored how the brain’s motor cortex signals both initial and corrective movements during a precision reaching task. We recorded a large population of neurons from two male rhesus macaques across multiple sessions to examine the neural firing rates during not only initial movements but also subsequent corrective movements. AutoLFADS, an auto-encoder-based deep-learning model, was applied to provide a clearer picture of neurons’ activity on individual corrective movements across sessions. Decoding of reach velocity generalized poorly from initial to corrective submovements. Unlike initial movements, it was challenging to predict the velocity of corrective movements using traditional linear methods in a single, global neural space. We identified several locations in the neural space where corrective submovements originated after the initial reaches, signifying firing rates different than the baseline before initial movements. To improve corrective movement decoding, we demonstrate that a state-dependent decoder incorporating the population firing rates at the initiation of correction improved performance, highlighting the diverse neural features of corrective movements. In summary, we show neural differences between initial and corrective submovements and how the neural activity encodes specific combinations of velocity and position. These findings are inconsistent with assumptions that neural correlations with kinematic features are global and independent, emphasizing that traditional methods often fall short in describing these diverse neural processes for online corrective movements.Significance StatementWe analyzed submovement neural population dynamics during precision reaching. Using an auto- encoder-based deep-learning model, AutoLFADS, we examined neural activity on a single-trial basis. Our study shows distinct neural dynamics between initial and corrective submovements. We demonstrate the existence of unique neural features within each submovement class that encode complex combinations of position and reach direction. Our study also highlights the benefit of state-specific decoding strategies, which consider the neural firing rates at the onset of any given submovement, when decoding complex motor tasks such as corrective submovements.
IgG sialylation occurs via the FcRn-mediated recycling pathway in endothelial cells
Authors: Glendenning Leandre M. , Reynero Kalob M. , Kukan Emily N. , Long Megan D. , Cobb Brian A. 
Published: July 2023

AbstractIgG is a key mediator of immune responses throughout the human body, and the structure of the conserved glycan on the Fc region has been identified as a key inflammatory switch regulating its downstream effects. In particular, the absence of terminal sialic acid has been shown to increase the affinity of IgG for activating Fc receptors, cascading the inflammatory response in a variety of diseases and conditions. Previously, we have shown that IgG sialylation is mediated by B cell-extrinsic processes. Here, we show that the FcRn-mediated recycling pathway within endothelial cells is a critical modulator of IgG sialylation. Building a deeper understanding of how IgG sialylation is regulated will drive the development of novel therapeutics which dynamically tune IgG functionalityin vivo.One-Sentence SummaryEndothelial cells remodel IgG glycans within the FcRn-mediated recycling pathway.
Readiness of nociceptor cell bodies to generate spontaneous activity results from background activity of diverse ion channels and high input resistance
Authors: Tian Jinbin , Bavencoffe Alexis G. , Zhu Michael X. , Walters Edgar T. 
Published: July 2023

AbstractNociceptor cell bodies generate “spontaneous” discharge that can promote ongoing pain in persistent pain conditions. Little is known about the underlying mechanisms. Recordings from nociceptor cell bodies (somata) dissociated from rodent and human dorsal root ganglia (DRGs) have shown that prior pain in vivo is associated with low-frequency discharge controlled by irregular depolarizing spontaneous fluctuations of membrane potential (DSFs), likely produced by transient inward currents across the somal input resistance. Here we show that DSFs are associated with high somal input resistance over a wide range of membrane potentials, including depolarized levels where DSFs approach action potential (AP) threshold. Input resistance and both the amplitude and frequency of DSFs were increased in neurons exhibiting spontaneous activity. Ion substitution experiments indicated that the depolarizing phase of DSFs is generated by spontaneous opening of channels permeable to Na+and/or Ca2+, and that Ca2+-permeable channels are especially important for larger DSFs. Partial reduction of the amplitude and/or frequency of DSFs by perfusion of pharmacological inhibitors indicated small but significant contributions from Nav1.7, Nav1.8, TRPV1, TRPA1, TRPM4, and N-type Ca2+channels. Less specific blockers suggested a contribution from NALCN channels, and global knockout suggested a role for Nav1.9. The combination of high somal input resistance plus background activity of diverse ion channels permeable to Na+and/or Ca2+produces DSFs that are poised to reach AP threshold if resting membrane potential (RMP) depolarizes, AP threshold decreases, and/or DSFs become enhanced -- all of which have been reported under painful neuropathic and inflammatory conditions.
A Rationally Designed Antimicrobial Peptide from Structural and Functional Insight ofClostridium difficileTranslation Initiation Factor 1
Authors: Alanis Elvira , Aguilar Faith , Banaei Niaz , Dean Frank B. , Alanis Miguel , Bullard James M. , Zhang Yonghong 
Published: July 2023

ABSTRACTA significant increase of hospital-acquired bacterial infections during the COVID-19 pandemic has become an urgent medical problem.Clostridioides difficileis an urgent antibiotic-resistant bacterial pathogen and a leading causative agent of nosocomial infections. The increasing recurrence ofC. difficileinfection and antibiotic resistance inC. difficilehas led to an unmet need for discovery of new compounds distinctly different from present antimicrobials, while antimicrobial peptides as promising alternatives to conventional antibiotics have attracted growing interest recently. Protein synthesis is an essential metabolic process in all bacteria and a validated antibiotic target. Initiation factor 1 fromC. difficile(Cd-IF1) is the smallest of the three initiation factors that acts to establish the 30S initiation complex to initiate translation during protein biosynthesis. Here we report the solution NMR structure of Cd-IF1 which adopts a typical β-barrel fold and consists of a five-stranded β-sheet and one short α-helix arranged in the sequential order β1-β2-β3-α1-β4-β5. The interaction of Cd-IF1 with the 30S ribosomal subunit was studied by NMR titration for the construction of a structural model of Cd-IF1 binding with the 30S subunit. The short α-helix in IF1 was found to be critical for IF1 ribosomal binding. A peptide derived from this α-helix was tested and displayed a high ability to inhibit the growth ofC. difficileand other bacterial strains. These results provide a clue for rational design of new antimicrobials.
The CB1 Negative Allosteric Modulator PSNCBAM-1 Reduces Ethanol Self-Administration via a Nonspecific Hypophagic Effect
Authors: Buechler Harley M. , Sumi Mousumi , Madhuranthakam Indu Mithra , Donegan Christa , DiGiorgio Frank , Acosta Alisha A , Uribe Sarah , Rahman Mohammad A , Sorbello Alison , Fischer Bradford D. , Keck Thomas M. 
Published: July 2023

ABSTRACTAlcohol use disorder (AUD) affects more than 15 million people in the United States. Current pharmacotherapeutic treatments for AUD are only modestly effective, necessitating the identification of new targets for medications development. The cannabinoid receptor type 1 (CB1) has been a target of interest for the development of medications for substance use disorders and other compulsive disorders. However, CB1 antagonists/inverse agonists (e.g., rimonabant) have severe side effects that limit their clinical utility, including anxiety, depression, and suicide. Recent development of CB1 negative allosteric modulators (NAMs), including PSNCBAM-1, may provide an alternative mechanism of attenuating CB1 signaling with reduced side effects. PSNCBAM-1 has not yet been evaluated for effects in models of AUD. In this study, we investigated the effects of the CB1 NAM, PSNCBAM-1, in rodent models of AUD using adult male mice. PSNCBAM-1 dose-dependently attenuated oral ethanol self-administration (8% w/v ethanol in water), significantly reducing ethanol rewards at a dose of 30 mg/kg, but not at 10 or 18 mg/kg. PSNCBAM-1 also dose-dependently attenuated palatable food self-administration (diluted vanilla Ensure), significantly reducing food rewards at 18 and 30 mg/kg PSNCBAM-1. PSNCBAM-1 did not affect conditioned place preference for 2 g/kg ethanol. These results suggest PSNCBAM-1 reduces ethanol-taking behavior via a nonspecific hypophagic effect and does not reduce the rewarding effects of ethanol.
Loss of NR2E3 disrupts rod photoreceptor cell maturation causing a fate switch late in human retinal development
Authors: Mullin Nathaniel K. , Bohrer Laura R. , Voigt Andrew P. , Lozano Lola P. , Wright Allison , Mullins Robert F. , Stone Edwin M. , Tucker Budd A. 
Published: July 2023

ABSTRACTWhile dysfunction and death of light-detecting photoreceptor cells underlie most inherited retinal dystrophies, knowledge of the species-specific details of human rod and cone photoreceptor cell development remains limited. Here, we generate retinal organoids using induced pluripotent stem cells (iPSC) derived from a patient with genetic photoreceptor disease due to mutations inNR2E3, an isogenic control, and an unrelated control. Organoids were sampled using single-cell RNA sequencing across the developmental window encompassing photoreceptor specification, emergence, and maturation, up to 260 days ofin vitrodifferentiation. Using single-cell transcriptomics data, we reconstruct the rod photoreceptor developmental lineage and identify a branchpoint in development unique to the disease state that gives rise to a divergent rod photoreceptor cell population. We show that the rod-specific transcription factor NR2E3 is required for the proper expression of genes involved in phototransduction, including expression of the light-sensitive protein rhodopsin, which is absent in divergent rods. NR2E3-null rods additionally misexpress several cone-specific phototransduction genes at both the transcript and protein level. Using joint multimodal single-cell sequencing on late-stage retinal organoids, we further identify specific putative regulatory sites where rod-specific factors act to steer rod and cone photoreceptor cell development. Importantly, these findings are strikingly different than those observed in rodent models of disease. Together, these data provide a roadmap of human photoreceptor development and leverage patient iPSCs to define the specific roles of rod transcription factors in photoreceptor cell emergence and maturation.
Identification of State Markers in Anorexia Nervosa: Replication and Extension of Inflammation Associated Biomarkers Using Multiplex Profiling in Anorexia Nervosa and Atypical Anorexia Nervosa
Authors: Breithaupt Lauren , Holsen Laura M. , Ji Chunni , Hu Jie , Petterway Felicia , Rosa-Caldwell Megan , Nilsson Ida A.K. , Thomas Jennifer J. , Williams Kyle A. , Boutin Regine , Slattery Meghan , Bulik Cynthia M. , Arnold Steven E. , Lawson Elizabeth A. , Misra Madhusmita , Eddy Kamryn T. 
Published: July 2023

AbstractProteomics provides an opportunity for detection and monitoring of anorexia nervosa (AN) and its related variant, atypical-AN (atyp-AN). However, research to date has been limited by the small number of proteins explored, exclusive focus on adults with AN, and lack of replication across studies. This study performed Olink Proseek Multiplex profiling of 92 proteins involved in inflammation among females with AN and atyp-AN (N = 64), all<90% of expected body weight, and age-matched healthy controls (HC; N=44). After correction for multiple testing, nine proteins differed significantly in the AN/atyp-AN group relative to HC group (lowerlevels: CXCL1, HGF, IL-18R1, TNFSF14, TRANCE;higherlevels: CCL23, Flt3L, LIF-R, MMP-1). The expression levels of three proteins (lowerIL-18R1, TRANCE;higherLIF-R) were uniquely disrupted in females with AN. No unique expression levels emerged for atyp-AN. Across the whole sample, twenty-one proteins correlated positively with BMI (ADA, AXIN1, CD5, CD244, CD40, CD6, CXCL1, FGF-21, HGF, IL-10RB, IL-12B, IL18, IL-18R1, IL6, LAP TGF-beta-1, SIRT2, STAMBP, TNFRSF9, TNFSF14, TRAIL, TRANCE) and six (CCL11, CCL23, FGF-19, IL8, LIF-R, OPG) were negatively correlated with BMI. Overall, our results replicate the prior study demonstrating a dysregulated inflammatory status in AN, and extend these results to atyp-AN (AN/atyp-AN all<90% of expected body weight). Of the 27 proteins correlated with BMI, 18 were replicated from a prior study using similar methods, highlighting the promise of inflammatory protein expression levels as biomarkers of disease monitoring. Additional studies of individuals across the entire weight spectrum are needed to understand the role of inflammation in atyp-AN.
Germline Mutations Associated with Triple Negative Breast Cancer in US Hispanic and Guatemalan Women using Hospital and Community-Based Recruitment Strategies
Authors: Paredes Jesica Godinez , Rodriguez Isabel , Ren Megan , Orozco Anali , Ortiz Jeremy , Albanez Anaseidy , Jones Catherine , Nahleh Zeina , Barreda Lilian , Garland Lisa , Gonzalez Edmundo Torres , Wu Dongjing , Luo Wen , Liu Jia , Argueta Victor , Orozco Roberto , Gharzouzi Eduardo , Dean Michael 
Published: July 2023

AbstractPurposeIdentify optimum strategies to recruit Latin American and Hispanic women into genetic studies of breast cancer. We evaluated hospital and community-based recruitment strategies.MethodsWe used targeted gene sequencing to identify mutations in DNA from unselected Hispanic breast cancer cases from community and hospital-based recruitment in the US and Guatemala.ResultsWe recruited 287 Hispanic US women, 38 (13%) from community-based and 249 (87%) from hospital-based strategies. In addition, we ascertained 801 Guatemalan women using hospital-based recruitment. In our experience, a hospital-based approach was more efficient than community-based recruitment. In this study, we sequenced 103 US and 137 Guatemalan women and found 11 and 10 pathogenic variants, respectively. The most frequently mutated genes wereBRCA1, BRCA2, CHEK2, andATM. In addition, an analysis of 287 US Hispanic patients with pathology reports showed a significantly higher percentage of triple-negative disease in patients with pathogenic mutations (41% vs. 15%). Finally, an analysis of mammography usage in 801 Guatemalan patients found reduced screening in women with a lower socioeconomic status (P<0.001).ConclusionsGuatemalan and US Hispanic women have rates of hereditary breast cancer mutations similar to other populations and are more likely to have early age at diagnosis, a family history, and a more aggressive disease. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients to reduce breast cancer mortality in Hispanic women.
Identification Cure Hub Genes of Chromophobe Cell Renal Carcinoma : A study based on Weighted Gene Co-expression Network Analysis (WGCNA) and the Cure Defective Models
Authors: Ahmadian Maryam , Molavi Zahra , Baghestani Ahmad Reza , Maboudi Ali Akbar 
Published: July 2023

ABSTRACTRenal cell carcinoma (RCC) is a prevalent and aggressive tumor of the urinary system with limited treatment success and poor patient outcomes. However, some patients exhibit long-term symptom relief and are considered ’cured’ after successful treatment. This study explores the genetic and pathway mechanisms underlying RCC cure for the first time, utilizing a survival model called the 3-parameter defective Gompertz cure model.The study methodology involved two main steps: Firstly, employing Weighted Gene Co-expression Network Analysis (WGCNA) for gene network analysis, which identified six key modules associated with different aspects of cancer progression and survival. Hub genes, pivotal in cellular interactions, were pinpointed through network analysis. Secondly, the 3-parameter defective Gompertz model was utilized to identify therapeutic genes linked to successful treatment outcomes (CSRGs) in RCC. These genes were then compared with genes associated with patient survival (SRGs) using a cox model.The study found ten hub genes commonly identified by both the defective 3-parameter Gompertz and Cox models, with six genes (NCAPG, TTK, DLGAP5, TOP2A, BUB1B, and BUB1) showing strong predictive values. Moreover, six hub genes (TTK, KIF20A, DLGAP5, BUB1, AURKB, and CDC45) were highlighted by the defective Gompertz model as significantly impacting cure when expressed at high levels. Targeting these hub genes may hold promise for improving RCC treatment outcomes and prognosis prediction.Overall, this study provides valuable insights into the molecular mechanisms of RCC and underscores the potential of the defective 3-parameter Gompertz model in guiding targeted therapeutic approaches.
Polymerized type I collagen down-regulates STAT-1 phosphorylation through engagement to LAIR-1 in M1-macrophages avoiding long COVID
Authors: Olivares-Martínez Elizabeth , Hernández-Ramírez Diego Francisco , Núñez-Álvarez Carlos Alberto , Chapa-Ibarguengoitia Mónica , Méndez-Flores Silvia , Ranero Ángel Priego- , Azamar-Llamas Daniel , Olvera-Prado Héctor , Rivas-Redonda Kenia Ilian , Ochoa-Hein Eric , López-Mosqueda Luis Gerardo , Rojas-Castañeda Estefano , Urbina-Terán Said , Septién-Stute Luis , Hernández-Gilsoul Thierry , Aguilar-León Diana , Torres-Villalobos Gonzalo , Furuzawa-Carballeda Janette 
Published: July 2023

AbstractBackgroundThe polymerized type I collagen (PTIC) is a γ-irradiated mixture of pepsinized porcine type I collagen and polyvinylpyrrolidone (PVP). It has immunomodulatory properties. However, the receptor and signaling pathway through which it exerts its therapeutic effects has not yet been identified.AimTo evaluate LAIR-1 as a potential receptor for PTIC and the signaling pathway evoked by ligand-receptor binding.MethodsLAIR-1 binding assay was performed by incubating various concentrations of recombinant human LAIR-1 with native type I collagen or PTIC. Macrophages M1- derived from THP-1 cells were cultured with 2-10% PTIC for 24 h. Cell lysates from THP- 1, monocytes-like cells (MLCs), M1, M1+IFN-γ, M1+LPS, and 2 or 10% PTIC treated M1 were analyzed by western blot for the transcription factors NF-κB (p65), p38, STAT-1, and pSTAT-1. Cytokines, Th1 cells, and M1/M2 macrophages were analyzed by luminometry and flow cytometry from blood samples of symptomatic COVID-19 outpatients on treatment with intramuscular administration of PTIC.ResultsPTIC binds LAIR-1 with a similar affinity to native collagen. This binding decreases STAT-1 signaling IFN-γ-induced and IL-1β expression in M1 macrophages by down-regulating STAT-1 phosphorylation. Moreover, intramuscular PTIC treatment of symptomatic COVID-19 outpatients decreased at statistically significant levels the percentage of M1 macrophages and cytokines (IP-10, MIF, eotaxin, IL-8, IL-1RA, and M- CSF) associated with STAT-1 transcription factor and increased M2 macrophages and Th1 cells. The downregulation of inflammatory mediators was related to better oxygen saturation and decreased dyspnea, chest pain, cough, and chronic fatigue syndrome in the acute phase of infection and the long term.ConclusionPTIC is an agonist of LAIR-1 and down-regulates STAT-1 phosphorylation. PTIC could be relevant for treating STAT-1-mediated inflammatory diseases, including COVID-19 and long COVID
CHAPERONg: A tool for automated GROMACS-based molecular dynamics simulations and trajectory analyses
Authors: Yekeen Abeeb Abiodun , Durojaye Olanrewaju Ayodeji , Idris Mukhtar Oluwaseun , Muritala Hamdalat Folake , Arise Rotimi Olusanya 
Published: July 2023

AbstractMolecular dynamics (MD) simulation is a powerful computational tool used in biomolecular studies to investigate the dynamics, energetics, and interactions of a wide range of biological systems at the atomic level. GROMACS is a widely used free and open-source biomolecular MD simulation software recognized for its efficiency, accuracy, and extensive range of simulation options. However, the complexity of setting up, running, and analyzing MD simulations for diverse systems often poses a significant challenge, requiring considerable time, effort, and expertise. Here, we introduce CHAPERONg, a tool that automates the GROMACS MD simulation pipelines for protein and protein-ligand systems. CHAPERONgalso integrates seamlessly with GROMACS modules and third-party tools to provide comprehensive analyses of MD simulation trajectories, offering up to 20 post-simulation processing and trajectory analyses. It also streamlines and automates established pipelines for conducting and analyzing biased MD simulations via the steered MD-umbrella sampling workflow. Thus, CHAPERONgmakes MD simulations more accessible to beginner GROMACS users whilst empowering experts to focus on data interpretation and other less programmable aspects of MD simulation workflows.
A Spatiotemporal Proteomic Map of Human Adipogenesis
Authors: Klingelhuber Felix , Frendo-Cumbo Scott , Omar-Hmeadi Muhmmad , Taylor Austin J. , Kakimoto Pamela , Couchet Morgane , Ribicic Sara , Wabitsch Martin , Messias Ana C. , Iuso Arcangela , Müller Timo D. , Rydén Mikael , Mejhert Niklas , Krahmer Natalie 
Published: July 2023

SUMMARYWhite adipocytes function as the major energy reservoir in humans by storing substantial amounts of triglycerides and their dysfunction is associated with metabolic disorders. However, the mechanisms underlying cellular specialization during adipogenesis remain unknown. Here, using a high-sensitivity-high throughput workflow, we generated a spatiotemporal proteomic atlas of human adipogenesis encompassing information for ~8.000 proteins. Our systematic approach gives insights into cellular remodeling and the spatial reorganization of metabolic pathways to optimize cells for lipid accumulation and highlights the coordinated regulation of protein localization and abundance during adipogenesis. More specifically, we identified a compartment-specific regulation of protein levels and localization changes of metabolic enzymes to reprogram branched chain amino acid and one-carbon metabolism to provide building blocks and reduction equivalents for lipid synthesis. Additionally, we identified C19orf12 as a differentiation induced and adipocyte-specific lipid droplet (LD) protein, which interacts with the translocase of the outer membrane (TOM) complex of LD associated mitochondria and regulates adipocyte lipid storage. Overall, our study provides a comprehensive resource for understanding human adipogenesis and for future discoveries in the field.KEY POINTSHuman adipogenesis induces distinct temporal changes in protein abundance20% of all detected proteins change organellar localization during adipogenesisBCAA and one-carbon metabolism enzyme levels and localizations are coordinately regulated to promote adipogenesisC19orf12 is an adipocyte specific LD protein and regulator of lipid storage