bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of the p75NTR during adolescent alcohol exposure prevents cholinergic neuronal atrophy and associated acetylcholine activity and behavioral dysfunction
Authors: Kipp Brian T. , Lisa M. Savage 
Published: April 2024

AbstractBinge alcohol consumption during adolescence produces lasting deficits in learning and memory, while also increasing the susceptibility to substance use disorders. The adolescent intermittent ethanol (AIE) rodent model mimics human adolescent binge drinking and has identified the Nucleus Basalis Magnocellularis (NbM) as a key site of pathology. The NbM is a critical regulator of prefrontal cortical (PFC) cholinergic function and attention. The cholinergic phenotype is controlled pro/mature neurotrophin receptor activation. We sought to determine if p75NTR activity contributes to the loss of cholinergic phenotype in AIE by using a p75NTR modulator (LM11A-31) to inhibit prodegenerative signaling during ethanol exposure. Male and female rats underwent 5g/kg ethanol (AIE) or water (CON) exposure following 2-day-on 2-day-off cycles from PND 25-57. A subset of these groups also received a protective dose of LM11A-31 (50mg/kg) during adolescence. Rats were trained on a sustained attention task (SAT) while recording activity with a fluorescent acetylcholine indicator (AChGRAB 3.0). AIE produced learning deficits on the SAT, which were spared with LM11A-31. In addition, mPFC ACh activity was blunted by AIE, which LM11A-31 corrected. Investigation of NbM ChAT+ and TrkA+ neuronal expression found that AIE led to a reduction of ChAT+TrkA+ neurons, which again LM11A-31 protected. Taken together these findings demonstrate the p75NTR activity during AIE treatment is a key regulator of cholinergic degeneration.
Quantitative Image Analysis of Tissue Properties: A MATLAB Tool for Measuring Morphology and Co-localization in 2D Images
Authors: Landau Shira , Shor Erez , Radisic Milica , Levenberg Shulamit 
Published: April 2024

AbstractIn recent years, the structural analysis of tissue elements has gained significant importance in biomedical research. Advancements in imaging technologies have created a pressing need to quantify tissue and cell properties accurately. This paper introduces a MATLAB-based analytical tool designed to measure a spectrum of properties from 2D images of tissues and cells. Our software efficiently computes parameters such as eccentricity, orientation, density, co-localization, size, and perimeter. The algorithm’s precision in evaluating these characteristics has broad implications for enhancing the understanding of various biological processes and diseases. The code’s flexibility allows for application across different tissue types and experimental conditions, providing researchers with a robust method for quantitative analysis. This advancement in computational image analysis represents a pivotal step towards more detailed and objective assessment in tissue engineering and cellular biology.
Functional Bias of Contractile Control in Mouse Resistance Arteries
Authors: Haghbin Nadia , Richter David M. , Kharche Sanjay , Kim Michelle S.M. , Welsh Donald G. 
Published: April 2024

AbstractBackgroundConstrictor agonists set vascular tone through two coupling processes, one tied to (electromechanical), the other independent (pharmacomechanical) of membrane potential (VM). This arrangement raises an intriguing query: are they variably recruited such that each agonist elicits a range of vasomotor signatures, functionally biased towards one mechanism or the other? This query underlies this study and our examination of agonist-induced arterial constriction.MethodsMouse mesenteric arteries were exposed to a classic Gq/11(phenylephrine) or Gq/11/G12/13(U46619) coupled receptor agonist, and responses monitored in the absence and presence of L-type Ca2+channel/protein kinase inhibitors. Contractile work was supplemented with measures of protein phosphorylation, VM, and cytosolic Ca2+; conceptual insights were enhanced with computational modeling.ResultsEach constrictor elicited a response curve that was attenuated and rightward shifted by nifedipine, findings aligned with functional bias; electromechanical coupling preceded pharmacomechanical, the latter’s importance rising with agonist concentration. Ensuing contractile and phosphorylation (CPI-17 & MYPT1 (T-855 & T-697)) measures revealed phenylephrine-induced pharmacomechanical coupling was tied to protein kinase C (PKC), while U46619 was tied to both PKC and Rho-kinase. A switch to pharmacomechanical coupling dominance occurred when agonist superfusion was replaced with discrete application to a small portion of artery. This switch was predicted by electromechanical modeling and supported by direct measures of VMand cytosolic Ca2+.ConclusionsOur work illustrates that constrictor agonists elicit functionally biased responses and that arteries toggle among contractile mechanisms, dependent on receptor signal bias, structural/electrical properties, and how agents are applied. We discuss how hemodynamic control is intimately tied to functional bias in both health and disease states, including but not limited to arterial vasospasm.HighlightsAgonist-induced constrictor responses exhibit a “functional bias” toward electromechanical or pharmacomechanical coupling dependent on agent concentration and mode of application.Electromechanical coupling typically but not exclusively precedes pharmacomechanical, the latter rising to prominence with agent concentration. Pharmacomechanical coupling is mediated through receptor pathways linked to PKC and Rho-kinase, regulatory proteins that target the catalytic and targeting subunit of MLCP.Functional bias is malleable and thus each agonist elicits a range of vasomotor signatures, each presumptively important in controlling blood flow delivery in space and time.
Effects of Exercise Frequency on Aortic Calcification in Hyperlipidemic Mice
Authors: Safvati Nora , Kalanski Sophia , Hon Andy , Pradhan Stuti , Lu Mimi , Demer Linda L. , Tintut Yin 
Published: April 2024

AbstractCardiovascular disease risk is associated with coronary artery calcification and is mitigated by regular exercise. However, the optimal regimen (activity level and frequency) for benefitting cardiovascular health is not clear. The surface area of calcium deposits, in addition to the quantity of calcium mineral, is a key factor in the risk of plaque rupture in humans due to compliance mismatch of edges with surrounding distensible tissue resulting in debonding. We previously found that aortic PET tracer uptake, a marker of mineral surface area, was reduced in hyperlipidemic (Apoe-/-) mice that underwent treadmill exercise, especially those in the low-speed (12.5 meters/min) regimen. To test the optimal exercise frequency on cardiovascular health, hyperlipidemic mice with baseline aortic calcification were subjected to none, 3- or 5-day/week treadmill regimen (12.5 meters/min for 30 min/day) for 5 weeks. MicroPET/microCT imaging and echocardiography were performed before and after the 5-week study. Results show that aortic calcification significantly progressed in all 3 groups, and18F-NaF uptake increased in the control and 3-day groups, but not in the 5-day group. As for cardiac function, left ventricular (LV) systolic function was not affected but LV mass and wall thickness decreased in the 5-day group, suggesting cardiac remodeling. Skeletal bone density assessed at lumbar vertebrae shows that bone density decreased in all 3 groups. These findings suggest that, in mice with underlying calcific atherosclerosis, low-speed exercise and a frequency of 5 days/week is optimal for benefitting cardiovascular health.
Divergent lineage trajectories and genetic landscapes in human gastric intestinal metaplasia organoids associated with early neoplastic progression
Authors: Yue Sarah SK , Tong Yin , Siu Hoi Cheong , Ho Siu Lun , Law Simon YK , Tsui Wai Yin , Chan Dessy , Huang Yuanhua , Chan Annie SY , Yun Shui Wa , Hui Ho Sang , Chan April S , Yuen Siu Tsan , Clevers Hans , Leung Suet Yi , Yan Helen HN 
Published: April 2024

ABSTRACTObjectiveGastric intestinal metaplasia (IM) is a pre-cancerous stage spanning a morphological spectrum that is poorly represented by human cell line models. We aim to establish and characterize human IM cell models to better understand IM progression along the cancer spectrum.DesignA large human gastric IM organoid (IMO) cohort (n=28) was established, along with normal gastric organoids (n=42) for comparison, and comprehensive multi-omics profiling and functional characterization were performed.ResultsSingle-cell transcriptomes revealed IMO cells spanning a spectrum from hybrid gastric/intestinal to advanced intestinal differentiation, and unveiled lineage trajectories that connected different cycling and quiescent stem and progenitors, highlighting their differences in gastric to IM transition. The hybrid IMO cells showed impaired differentiation potential, high lineage plasticity beyond gastric or intestinal fates, and reactivation of a fetal gene program.Cell populations in gastric IM and cancer tissues were found to be highly similar to those derived from IMOs and exhibited fetal signature. Genomically, IMOs showed an elevated mutation burden, frequent chromosome 20 gain, and epigenetic de-regulation of many intestinal and gastric genes. Functionally, IMOs downregulatedFGFR2and became independent of FGF10 for survival. Several IMOs exhibited a cell-matrix adhesion independent (CMi) subpopulation that displayed chromosome 20 gain but lacked key cancer driver mutations, which could represent the earliest neoplastic precursor of IM-induced gastric cancer.ConclusionsOverall, our IM organoid biobank captured the heterogeneous nature of IM, revealing mechanistic insights on IM pathogenesis and its neoplastic progression, offering an ideal platform for studying early gastric neoplastic transformation and chemoprevention.
Preregistered analytic plan: the gut microbiome and acute kidney injury in sepsis
Authors: Winner Katherine M. , Chanderraj Rishi , He Ying , Nuppnau Mark , Woods Robert J. , Heung Michael , Schaub Jennifer A. , Sjoding Michael W. , Dickson Robert P. 
Published: April 2024

AbstractOverviewWe here share a pre-registered analytic plan for a matched case-control study nested in a retrospective cohort of hospitalized patients with suspected sepsis. We will compare gut microbiota (measured near the time of admission) among patients with sepsis who do and do not develop sepsis-induced acute kidney injury.RationaleSepsis afflicts nearly 50 million people annually, and sepsis-induced acute kidney injury (AKI) is a frequent complication that contributes to morbidity, mortality, and increased healthcare costs. Despite the clinical significance of AKI in sepsis, we still do not understand why some patients with sepsis develop AKI while others do not. The gut microbiome has been implicated in other clinical features and sequelae of sepsis, but to date has not been studied in sepsis-induced AKI.ObjectiveTo determine whether gut microbiota predict AKI in patients with suspected sepsis.HypothesisWe hypothesize that among patients with suspected sepsis, gut bacterial density and identity (at the time of admission) predict the onset and severity of AKI.Study designWe will perform a matched case-control study nested in an observational cohort. The cohort includes patients admitted to the University of Michigan in 2016-2020 with suspected sepsis. We will divide patients into cohorts that did and did not develop AKI. We will derive matched cohorts based on relevant clinical covariates. We will characterize their gut microbiota using 16S rRNA gene amplicon sequencing of rectal swabs obtained within 24 hours of AKI onset. We will compare admission gut microbiota across these matched cohorts to test our primary hypothesis.
Generalizability of Clinical Prediction Models in Mental Health - Real-World Validation of Machine Learning Models for Depressive Symptom Prediction
Authors: Richter Maike , Emden Daniel , Leenings Ramona , Winter Nils R. , Mikolajczyk Rafael , Massag Janka , Zwiky Esther , Borgers Tiana , Redlich Ronny , Koutsouleris Nikolaos , Falguera Renata , Thanarajah Sharmili Edwin , Padberg Frank , Reinhard Matthias A. , Back Mitja D. , Morina Nexhmedin , Buhlmann Ulrike , Kircher Tilo , Dannlowski Udo ,   2107 consortium,   PRONIA consortium,   MBB consortium, Hahn Tim , Opel Nils 
Published: April 2024

AbstractMental health research faces the challenge of developing machine learning models for clinical decision support. Concerns about the generalizability of such models to real-world populations due to sampling effects and disparities in available data sources are rising. We examined whether harmonized, structured collection of clinical data and stringent measures against overfitting can facilitate the generalization of machine learning models for predicting depressive symptoms across diverse real-world inpatient and outpatient samples. Despite systematic differences between samples, a sparse machine learning model trained on clinical information exhibited strong generalization across diverse real-world samples. These findings highlight the crucial role of standardized routine data collection, grounded in unified ontologies, in the development of generalizable machine learning models in mental health.One-Sentence SummaryGeneralization of sparse machine learning models trained on clinical data is possible for depressive symptom prediction.
Fc proteoforms of ACPA IgG discriminate autoimmune responses in plasma and synovial fluid of rheumatoid arthritis patients and associate with disease activity
Authors: Blöchl Constantin , Stork Eva Maria , Scherer Hans Ulrich , Toes Rene E. M. , Wuhrer Manfred , Domínguez-Vega Elena 
Published: April 2024

AbstractAutoantibodies and their post-translational modifications (PTMs) are insightful markers of autoimmune diseases providing diagnostic and prognostic clues, thereby informing clinical decisions. However, current autoantibody analyses focus mostly on IgG1 glycosylation representing only a subpopulation of the actual IgG proteome. Here, by taking rheumatoid arthritis (RA) as prototypic autoimmune disease, we sought to circumvent these shortcomings and illuminate the importance of (auto)antibody proteoforms employing a novel comprehensive mass spectrometry (MS)-based analytical workflow. Profiling of anti-citrullinated protein antibodies (ACPA) IgG and total IgG in paired samples of plasma and synovial fluid revealed a clear distinction of autoantibodies from total IgG and between biofluids. This discrimination relied on comprehensive subclass-specific PTM profiles including previously neglected features such as IgG3 CH3 domain glycosylation, allotype ratios, and non-glycosylated IgG. Intriguingly, specific proteoforms were found to correlate with markers of inflammation and disease accentuating the need of such approaches in clinical investigations and calling for further mechanistic studies to comprehend the role of autoantibody proteoforms in defining autoimmune responses.
General mechanisms for a top-down origin of the predator-prey power law
Authors: Mazzarisi Onofrio , Barbier Matthieu , Smerlak Matteo 
Published: April 2024

AbstractThe ratio of predator-to-prey biomass density is not constant along ecological gradients: denser ecosystems tend to have fewer predators per prey, following a scaling relation known as the “predator-prey power law”. The origin of this surprisingly general pattern, particularly its connection with environmental factors and predator-prey dynamics, is unknown. Here, we explore some ways that a sublinear predator-prey scaling could emerge from density-dependent interactions among predators and between predators and prey (which we call a top-down origin), rather than among prey (bottom-up origin) as proposed in Hattonet al. (2015). We combine two complementary theoretical approaches. First, we use phenomenological differential equations to explore the role of environmental parameters and dynamical properties in controlling the predator-prey ratio. Second, we simulate an agent-based model with tunable predator self-regulation to investigate the emergence of predator-prey scaling from plausible microscopic rules. While we cannot rule out alternative explanations, our results show that density-dependent mechanisms relative to predation and intraspecific predator interactions, including prey saturation, predator interference, and predator self-regulation, offer potential explanations for the predator-prey power law.
Missense mutation in the activation segment of the kinase CK2 models Okur Chung neurodevelopmental disorder and alters the hippocampal glutamatergic synapse
Authors: Cruz-Gamero Jose M. , Ballardin Demetra , Lecis Barbara , Zhang Chun-Lei , Cobret Laetitia , Gast Alexander , Morisset-Lopez Severine , Piskorowski Rebecca , Langui Dominique , Jose Joachim , Chevreux Guillaume , Rebholz Heike 
Published: April 2024

AbstractExome sequencing has enabled the identification of causative genes of monogenic forms of autism, amongst them, in 2016, CSNK2A1, the gene encoding the catalytic subunit of the kinase CK2, linking this kinase to Okur-Chung Neurodevelopmental Syndrome (OCNDS), a newly described neurodevelopmental condition with many symptoms resembling those of autism spectrum disorder.Thus far, no preclinical model of this condition exists. Here we describe a knockin mouse model that harbors the K198R mutation in the activation segment of the kinase. This region is a mutational hotspot, representing one-third of patients. These mice exhibit behavioral phenotypes that mirror patient symptoms. Homozygous knock-in (KI) mice die mid-gestation while heterozygous KI mice are born at half of the expected mendelian ratio and are smaller in weight and size than wildtype littermates. Heterozygous KI mice showed alterations in cognition and memory-assessing paradigms, enhanced stereotypies, altered circadian activity patterns, and nesting behavior. Phosphoproteome analysis from brain tissue revealed alterations in the phosphorylation status of major pre- and postsynaptic proteins of heterozygous KI mice. In congruence, we detect reduced synaptic maturation in hippocampal neurons and attenuated long-term potentiation in the hippocampus of KI mice. Taken together, K198R KI mice exhibit significant face validity, presenting ASD-relevant phenotypes, synaptic deficits and alterations in synaptic plasticity, all of which strongly validate this line as a mouse model of OCNDS.
TOTEM: A web TOol for Tissue-EnrichMent analysis on gene lists
Authors: Coleto-Alcudia Veredas , Lozano-Elena Fidel , Vera Gonzalo , Betegón Isabel , Gupta Aditi , Efroni Idan , Caño-Delgado Ana I. 
Published: April 2024

SummaryAnalysis of spatiotemporal patterns of gene expression is crucial to decode biological systems responses. High-throughput sequencing allows in-depth transcriptome analyses and experimental designs, providing valuable reference expression atlases. Specifically, testing overrepresentations of tissue-specific genes based on these atlases can provide valuable insights; however, such an approach is not accessible to inexperienced users. Here, we introduce TOTEM (TOol forTissue-EnrichMent), a web tool designed to calculate enrichment values per tissue by identifying tissue-specific genes from an organ/organism of interest given a user gene list. Results are visually represented, and user’s gene classified. The utility of TOTEM is manifest when using integrated single cell expression atlases, enabling the study of complicated tissues, with the maximum possible resolution. Its effectiveness is validated by the study of BRL3 role in stress specifically from the vascular tissues. Finally, TOTEM’s modular design allows for continual integration of new experiments. TOTEM can be freely accessed at:https://totemwebtool.com.
Mutation of theP. falciparumflavokinase confers resistance to roseoflavin and 8-aminoriboflavin
Authors: Hemasa Ayman , Spry Christina , Mack Matthias , Saliba Kevin J. 
Published: April 2024

AbstractWe previously found that two riboflavin analogues, roseoflavin and 8-aminoriboflavin, inhibit malaria parasite proliferation by targeting riboflavin utilisation. To determine the mechanism of action of roseoflavin inP. falciparum, we generated roseoflavin-resistant parasites byin vitroevolution over 27 weeks. The roseoflavin-resistant parasites were found to be four times more resistant to roseoflavin and cross-resistant to 8-aminoriboflavin. Resistant parasites were subjected to whole genome sequencing and a missense mutation (T2015A), leading to an amino acid exchange (L672H), was detected in the gene coding for a putative flavokinase (PfFK), the enzyme responsible for converting riboflavin (vitamin B2) into the cofactor flavin mononucleotide (FMN). To confirm that the L672H mutation is responsible for the observed phenotype, we generated parasites with the missense mutation incorporated into thePfFK geneviaa single-crossover recombination. The IC50values for roseoflavin (RoF) and 8-aminoriboflavin against the RoF-resistant parasites created throughin vitroevolution were indistinguishable from the IC50values for parasites in which the missense mutation was specifically introduced into the nativePfFK. To investigate this mutation, we generated two parasite lines episomally-expressing GFP-tagged versions of either the wild type or mutant forms of flavokinase. We found thatPfFK-GFP localises to the parasite cytosol and that immunopurifiedPfFK-GFP was active and phosphorylated riboflavin into flavin mononucleotide. The L672H mutation caused a reduction of the binding affinity, especially for the substrate RoF, which explains the resistance phenotype. The mutantPfFK is no longer capable of phosphorylating 8-aminoriboflavin, but its antiplasmodial activity against resistant parasites can still be antagonised by increasing the extracellular concentration of riboflavin, consistent with the compound also inhibiting parasite growth through competitive inhibition ofPfFK. Our findings, therefore are consistent with roseoflavin and 8-aminoriboflavin inhibiting parasite growth by inhibiting FMN production, in addition to the generation of toxic flavin cofactor analogues.