bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of OT-elicited reductions of body weight gain and adiposity in male diet-induced obese rats
Authors: Edwards Melise M. , Nguyen Ha K. , Dodson Andrew D. , Herbertson Adam J. , Honeycutt Mackenzie K. , Slattery Jared D. , Rambousek June R. , Tsui Edison , Wolden-Hanson Tami , Wietecha Tomasz A. , Graham James L. , Tapia Geronimo P. , Sikkema Carl L. , O’Brien Kevin D. , Mundinger Thomas O. , Peskind Elaine R. , Ryu Vitaly , Havel Peter J. , Khan Arshad M. , Taborsky Gerald J. , Blevins James E. 
Published: September 2024

AbstractRecent studies indicate that central administration of oxytocin (OT) reduces body weight (BW) in high fat diet-induced obese (DIO) rodents by reducing energy intake and increasing energy expenditure (EE). Previous studies in our lab have shown that administration of OT into the fourth ventricle (4V; hindbrain) elicits weight loss and stimulates interscapular brown adipose tissue temperature (TIBAT) in DIO rats. We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of IBAT contributes to its ability to activate BAT and reduce BW in DIO rats. To test this, we determined the effect of disrupting SNS activation of IBAT on OT-elicited stimulation of TIBATand reduction of BW in DIO rats. We first confirmed that bilateral surgical SNS denervation to IBAT was successful based on having achieved ≥ 60% reduction in IBAT norepinephrine (NE) content from DIO rats. NE content was selectively reduced in IBAT by 94.7 ± 2.7, 96.8 ± 1.8 and 85.9 ± 6.1% (P<0.05) at 1, 6 and 7-weeks post-denervation, respectively, and was unchanged in liver or inguinal white adipose tissue. We then measured the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (1, 5 µg) to stimulate TIBATin DIO rats. We found that the high dose of 4V OT (5 µg) stimulated TIBATsimilarly between sham and denervated rats (P=NS) and that the effects of 4V OT to stimulate TIBATdid not require beta-3 adrenergic receptor signaling. We subsequently measured the effect of bilateral surgical denervation of IBAT on the effect of chronic 4V OT (16 nmol/day) or vehicle infusion to reduce BW, adiposity, and energy intake in DIO rats. Chronic 4V OT reduced BW gain by –7.2 ± 9.6 g and –14.1 ± 8.8 g in sham and denervated rats (P<0.05 vs vehicle treatment), respectively, and this effect was similar between groups (P=NS). These effects were associated with reductions in adiposity and energy intake (P<0.05). Collectively, these findings support the hypothesis that sympathetic innervation of IBAT is not required for central OT to increase BAT thermogenesis and reduce BW gain and adiposity in male DIO rats.
Gene identification for ocular congenital cranial motor neuron disorders using human sequencing, zebrafish screening, and protein binding microarrays
Authors: Jurgens Julie A. , Ruiz Paola M. Matos , King Jessica , Foster Emma E. , Berube Lindsay , Chan Wai-Man , Barry Brenda J. , Jeong Raehoon , Rothman Elisabeth , Whitman Mary C. , MacKinnon Sarah , Rivera-Quiles Cristina , Pratt Brandon M. , Easterbrooks Teresa , Mensching Fiona M. , Di Gioia Silvio Alessandro , Pais Lynn , England Eleina M. , de Berardinis Teresa , Magli Adriano , Koc Feray , Asakawa Kazuhide , Kawakami Koichi , O’Donnell-Luria Anne , Hunter David G. , Robson Caroline D. , Bulyk Martha L. , Engle Elizabeth C. 
Published: September 2024

AbstractPurposeTo functionally evaluate novel human sequence-derived candidate genes and variants for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs).MethodsThrough exome and genome sequencing of a genetically unsolved human oCCDD cohort, we previously identified variants in 80 strong candidate genes. Here, we further prioritized a subset of these (43 human genes, 57 zebrafish genes) using a G0 CRISPR/Cas9-based knockout assay in zebrafish and generated F2 germline mutants for seventeen. We tested the functionality of variants of uncertain significance in known and novel candidate transcription factor-encoding genes through protein binding microarrays.ResultsWe first demonstrated the feasibility of the G0 screen by targeting known oCCDD genesphox2aandmafba. 70-90% of gene-targeted G0 zebrafish embryos recapitulated germline homozygous null-equivalent phenotypes. Using this approach, we then identified three novel candidate oCCDD genes (SEMA3F,OLIG2,andFRMD4B) with putative contributions to human and zebrafish cranial motor development. In addition, protein binding microarrays demonstrated reduced or abolished DNA binding of human variants of uncertain significance in known and novel sequence-derived transcription factorsPHOX2A(p.(Trp137Cys)),MAFB(p.(Glu223Lys)), andOLIG2(p.(Arg156Leu)).ConclusionsThis study nominates three strong novel candidate oCCDD genes (SEMA3F,OLIG2,andFRMD4B) and supports the functionality and putative pathogenicity of transcription factor candidate variantsPHOX2Ap.(Trp137Cys),MAFBp.(Glu223Lys), andOLIG2p.(Arg156Leu). Our findings support that G0 loss-of-function screening in zebrafish can be coupled with human sequence analysis and protein binding microarrays to aid in prioritizing oCCDD candidate genes/variants.
A modulator of cognitive function: Cerebellum modifies human cortical network dynamics via integration
Authors: Bansal Kanika , Cattaneo Zaira , Oldrati Viola , Ferrari Chiara , Grossman Emily D. , Garcia Javier O. 
Published: September 2024

AbstractThe cerebellum, with distinctive architecture and extensive cortical connections, has long been associated with motor control; however, evidence suggests its role extends beyond motor functions, playing a crucial role in cognitive processes. Despite these insights, how cerebellar computations modulate cortical networks remains elusive. Here, we evaluate dynamic network reconfigurations in the cerebral cortex connectivity following noninvasive inhibitory repetitive transcranial magnetic stimulation (rTMS) targeting the right cerebellum. Using dynamic community detection, we uncover the dynamic network properties by which cerebellar stimulation spreads through the cortex, inspecting the evolution of modular network structures prior to and after cerebellar stimulation. Our results indicate that: (1)flexibility, or the likelihood of network nodes to change module allegiances, increases post stimulation; (2) dynamic patterns in which module allegiances emerge and evolve are individualistic and do not follow a single functional prototype; and (3) cerebellar nodes play the role of integrators for distinct network modules. These results suggest that the cerebellum plays a pivotal role in modulating distributed cortical activity, seamlessly integrating and segregating information beyond motor control. This integrative capacity may underlie the cerebellum’s contributions to high-level cognitive functions and, more broadly, to the foundation of human intelligence.
Hypoxic stress dysregulates functions of glioma-associated myeloid cells through epigenomic and transcriptional programs
Authors: Dzwigonska Monika , Rosa Patrycja , Kaza Beata , Lipiec Szymon , Cyranowski Salwador , Ellert-Miklaszewska Aleksandra , Kominek Agata , Obrebski Tomasz , Malik Anna R. , Piwocka Katarzyna , Mieczkowski Jakub , Kaminska Bozena , Leszczynska Katarzyna B. 
Published: September 2024

ABSTRACTHypoxia rapidly alters gene expression to allow cellular adaptation to challenging conditions and support tumour growth. Hypoxia also affects the chromatin structure by modifications of histones and DNA methylation. Glioblastoma (GBM) is an aggressive, deadly primary brain tumour for which there is no effective treatment. The tumour microenvironment of GBM is highly heterogeneous, with infiltration of glioma-associated microglia and macrophages (GAMs) and the presence of necrotic, hypoxic regions which significantly impair effectiveness of therapies. The mechanisms through which hypoxia alters the tumour microenvironment and regulates functions of infiltrating immune cells remain poorly understood.Here, we show that hypoxia modulates the expression of myeloid markers in distinct ways: upregulates the expression of monocytic markerLgals3and downregulates the microglial markersP2ry12andTmem119in microglial and monocytic GAMsin vitroandin vivo. Underlying genome-wide hypoxia-dependent transcriptomic changes in microglial cells were identified using microglia-glioma co-cultures and validated in human and mouse GBM single- cell transcriptomics datasets. Numerous GAM subtype markers are dysregulated in response to hypoxic stress due to associated changes in chromatin accessibility, as determined using ATACseq. While hypoxia alone drives a decrease of the overall chromatin accessibility at gene promoters, the exposure to glioma cells under hypoxic conditions leads to both increases and decreases of chromatin accessibility at promoter regions in microglial cells. Hypoxia downregulates the chromatin accessibility at the regions enriched in motifs for transcription factors known as master regulators of microglial cell identity and function, includingSPI1orIRF8. Overall, our results highlight the importance of hypoxic stress as a strong intratumoral regulator of myeloid cell functions, which adds a new dimension to the characterisation of particular GAM subpopulations.
Protonation effects in protein-ligand complexes - a case study of endothiapepsin and pepstatin A with computational and experimental methods
Authors: Vatheuer Helge , Palomino-Hernández Oscar , Müller Janis , Galonska Phillip , Glinca Serghei , Czodrowski Paul 
Published: September 2024

1AbstractProtonation states serve as an essential molecular recognition motif for biological processes. Their correct consideration is key to successful drug design campaigns, since chemoinformatic tools usually deal with default protonation states of ligands and proteins and miss atypical protonation states. The protonation pattern for the Endothiapepsin/PepstatinA (EP/pepA) complex is investigated using different dry lab and wet lab techniques. ITC experiments revealed an uptake of more than one mole of protons upon pepA binding to EP. Since these experiments were performed at physiological conditions (and not at pH=4 at which a large variety of crystal structures is available), a novel crystal structure at pH=7.6 was determined. This crystal structure showed that only modest structural changes occur upon increasing the pH value. This lead to computational studies to reveal the exact location of the protonation event. Both computational studies could reveal a significant pKa shift resulting in non-default protonation state and that the catalytic dyad is responsible for the uptake of protons. This study shows that assessing protonation states for two separate systems (protein and ligand) might result in the incorrect assignment of protonation states and hence incorrect calculation of binding energy.
Cross-Sectional Analysis of the Association Between Abnormal Immune Responses in the Pathogenesis of Postpartum Cardiomyopathy in Ethiopian Women: A Hospital-based Study at Saint Paul Hospital
Authors: Paulos Azarreia , Mulu Leul , Metiku Kalab 
Published: September 2024

1.0AbstractBackgroundPostpartum cardiomyopathy (PPCM) is a condition that is characterized by the weakening of heart muscles which is known as left ventricular dysfunction and occurs during the later stages of pregnancy or during the early stages of postpartum.ObjectiveTo evaluate the role of abnormal immune responses and risk factors such as advanced age, high parity, and presence of gestational diabetes in the pathogenesis of PPCM in Ethiopia.MethodA cross-sectional hospital-based study was conducted at Saint Paul Millennium Medical College (SPMCC) between January 2021 and January 2023. All female pregnant patients who were attending the Maternal Care Fetal Unit, Antenatal Unit, and High-Risk Unit at SPMMC were included in this study. However, among those patients, those mothers younger than 20 years old and older than 40 years old were excluded from the study. The total sample size collected from this facility was 250 patients.ResultsOxidative stress and inflammation were primarily correlated with pre-eclampsia and gestational diabetes. These risk factors were particularly prevalent within patients diagnosed with PPCM, 52.8% and 40% respectively. Prolactin Cleavage and Microvascular Dysfunction was associated with higher BMI and advanced age. With a general increasing trend observed in PPCM incidence and advancing age. As well as a high prevalence rate of PPCM in patients with Obesity Class I (at 33.0%). Another notable risk factor was high parity ( 45.0% with 4+ prior pregnancies). The most common symptom presented was dyspnea at 35.0%. The mortality rate was 14% whilst recurrence and the fully recovered ratio were at 13.1% and 34.0%, respectively.ConclusionResults aligned with those conducted in other African countries (e.g. Zambia and South Africa) however mitigating high mortality as well as low full recovery rate will need to be done by earlier diagnosis, effective treatment, and intervention mechanisms. A different study design will need to be conducted (over a longer time period) to support and make findings more holistic.
Prediction of the ectasia screening index from raw Casia2 volume data for keratoconus identification by using convolutional neural networks
Authors: Mirsalehi Maziar , Fassbind Benjamin , Streich Andreas , Langenbucher Achim 
Published: September 2024

AbstractPurposePrediction of Ectasia Screening Index (ESI), an estimator provided by the Casia2 for identifying keratoconus, from raw Optical Coherence Tomography (OCT) data with Convolutional Neural Networks (CNN).MethodsThree CNN architectures (ResNet18, DenseNet121 and EfficientNetB0) were employed to predict the ESI. Mean Absolute Error (MAE) was used as the performance metric for predicting the ESI by the adapted CNN models on the test set. Scans with an ESI value higher than a certain threshold were classified asKeratoconus, while the remaining scans were classified asNot Keratoconus. The models’ performance was evaluated using metrics such as accuracy, sensitivity, specificity, Positive Predictive Value (PPV) and F1 score on data collected from patients examined at the eye clinic of the Homburg University Hospital. The raw data from the Casia2 device, in 3dv format, was converted into 16 images per examination of one eye. For the training, validation and testing phases, 3689, 1050 and 1078 scans (3dv files) were selected, respectively.ResultsIn the prediction of the ESI, the MAE values for the adapted ResNet18, DenseNet121 and EfficientNetB0, rounded to two decimal places, were 7.15, 6.64 and 5.86, respectively. In the classification task, the three networks yielded an accuracy of 94.80%, 95.27% and 95.83%, respectively; a sensitivity of 92.07%, 94.64% and 94.17%, respectively; a specificity of 96.61%, 95.69% and 96.92%, respectively; a PPV of 94.72%, 93.55% and 95.28%, respectively; and a F1 score of 93.38%, 94.09% and 94.72%, respectively.ConclusionsOur results show that the prediction of keratokonus based on the ESI values estimated from raw data outperforms previous approaches using processed data. Adapted EfficientNetB0 outperformed both the other adapted models and those in state-of-the-art studies, with the highest accuracy and F1 score.
A GWAS of ACE Inhibitor-Induced Angioedema in a South African Population
Authors: Mugo Jacquiline W. , Day Cascia , Choudhury Ananyo , Deetlefs Maria , Freercks Robert , Geraty Sian , Panieri Angelica , Cotchbos Christian , Ribeiro Melissa , Engelbrecht Adelein , Micklesfield Lisa K. , Ramsay Michèle , Pedretti Sarah , Peter Jonny 
Published: September 2024

AbstractBackgroundAngiotensin-converting enzyme inhibitor-induced angioedema (AE-ACEI) is a life-threatening adverse event and, globally, the commonest cause of emergency presentations with angioedema. Several large genome-wide association studies (GWAS) have found genomic associations with AE-ACEI. However, despite African Americans having a 5-fold increased risk of AE-ACEI, there are no published GWAS from Africa. The aim of this study was to conduct a case-control GWAS of AE-ACEI in a South African population and perform a meta-analysis with an African American and European American population.MethodsThe GWAS included 202 South African adults with a history of AE-ACEI and 513 controls without angioedema following angiotensin-converting enzyme inhibitor (ACEI) treatment for at least 2 years. A meta-analysis was conducted with GWAS summary statistics from an African American and European American cohort (from Vanderbilt/Marshfield with 174 cases and 489 controls).ResultsNo SNPs attained genome-wide significance. However, 26 SNPs in the post-imputation standard GWAS of the South African cohort and 37 SNPs in the meta-analysis were associated to AE-ACEI with suggestive threshold(p-value<5.0×10−06). Some of these SNPs were found to be located close to the genesPRKCQandRIMS1,previously linked with drug-induced angioedema, and also close to theCSMD1gene linked to ACEI cough, providing replication at the gene level, but with novel lead SNPs.ConclusionsOur results highlight the importance of African populations to detect novel variants in replication studies. Further increased sampling across the continent and matched functional work are needed to confirm the importance of genetic variation in understanding the biology of AE-ACEI.
BRUCE liver-deficiency potentiates MASLD/MASH in PTEN liver-deficient background by impairment of mitochondrial metabolism in hepatocytes and activation of STAT3 signaling in hepatic stellate cells
Authors: Che Lixiao , Stevenson Camille K. , Plas David R. , Wang Jiang , Du Chunying 
Published: September 2024

AbstractMetabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common liver disease, affecting up to 25% of people worldwide, featuring excessive fat accumulation in hepatocytes. Its advanced form, metabolic dysfunction-associated steatohepatitis (MASH), is a serious disease with hepatic inflammation and fibrosis, increasing the need for liver transplants. However, the pathogenic mechanism of MASLD and MASH is not fully understood. We reported that BRUCE (BIRC6)is a liver cancer suppressor and is downregulated in MASLD/MASH patient liver specimens, though the functional role of BRUCE in MASLD/MASH remains to be elucidated. To this end, we generated liver-specific double KO (DKO) mice of BRUCE and PTEN, a major tumor suppressor and MASLD/MASH suppressor. By comparing liver histopathology among 2-3-month-old mice, there were no signs of MASLD or MASH in BRUCE liver-KO mice and only onset of steatosis in PTEN liver-KO mice. Interestingly, DKO mice had developed robust hepatic steatosis with inflammation and fibrosis. Further analysis of mitochondrial function with primary hepatocytes found moderate reduction of mitochondrial respiration, ATP production and fatty acid oxidation in BRUCE KO and the greatest reduction in DKO hepatocytes. Moreover, aberrant activation of pro-fibrotic STAT3 signaling was found in hepatic stellate cells (HSCs) in DKO mice which was prevented by administered STAT3-specific inhibitor (TTI-101). Collectively, the data demonstrates by maintaining mitochondrial metabolism BRUCE works in concert with PTEN to suppress the pro-fibrogenic STAT3 activation in HSCs and consequentially prevent MASLD/MASH. The findings highlight BRUCE being a new co-suppressor of MASLD/MASH.
Exploring American Elderberry Compounds for Antioxidant, Antiviral, and Antibacterial Properties Through High-Throughput Screening Assays Combined with Untargeted Metabolomics
Authors: Dwikarina Amanda , Bayati Mohamed , Efrat Novianus , Roy Anuradha , Lei Zhentian , Ho Khanh-Van , Sumner Lloyd , Greenlief Michael , L.Thomas Andrew , Applequist Wendy , Townesmith Andrew , Lin Chung-Ho 
Published: September 2024

AbstractAmerican elderberry (Sambucus nigrasubsp.canadensis) is a rapidly emerging new perennial crop for Missouri, recognized for its high level of bioactive compounds with significant health benefits, including antibacterial, antiviral, and antioxidant properties. A high-throughput screening assay combined with untargeted metabolomics analysis was utilized on American elderberry juice from 21 genotypes to explore and characterize these bioactive compounds. Our metabolomics study has identified 32 putative bioactive compounds in the American Elderberry juices. An array of high-throughput screening bioassays was conducted to evaluate 1) total antioxidant capacity, 2) activation of antioxidant response elements (ARE), 3) antiviral activity, and 4) antibacterial activity of the putatively identified compounds. Our results revealed that 14 of the 32 American elderberry compounds exhibited strong antioxidant activity. Four compounds (isorhamnetin 3-O-glucoside, kaempferol, quercetin, and naringenin) activated ARE activity and were found to be non-cytotoxic to cells. Notably, six of the 32 compounds demonstrated significant antiviral activity in anin vitroTZM-bl assay against two strains of HIV-1 virus, CXCR4-dependent NL4-3 virus and CCR5-dependent BaL virus. Luteolin showed the most potent anti-HIV activity against the NL4-3 virus (IC50= 1.49 µM), followed by isorhamnetin (IC50= 1.67 µM). The most potent anti-HIV compound against the BaL virus was myricetin (IC50= 1.14 µM), followed by luteolin (IC50= 4.38 µM). Additionally, six compounds were found to have antibacterial activity against gram-positive bacteriaS. aureus, with cyanidin 3-O-rutinoside having the most potent antibacterial activity in vitro (IC50= 2.9 µM), followed by cyanidin 3-O-glucoside (IC50= 3.7 µM). These findings support and validate the potential health benefits of compounds found in American elderberry juices and highlight their potential for use in dietary supplements as well as innovative applications in health and medicine.
ARHGEF3 Regulates Hair Follicle Morphogenesis
Authors: Kalyanakrishnan Krithika , Beaudin Amy , Jetté Alexandra , Ghezelbash Sarah , Hotea Diana Ioana , Chen Jie , Lefrançois Philippe , Laurin Mélanie 
Published: September 2024

ABSTRACTDuring embryogenesis, cells arrange into precise patterns that enable tissues and organs to develop specialized functions. Despite its critical importance, the molecular choreography behind these collective cellular behaviors remains elusive, posing a major challenge in developmental biology and limiting advances in regenerative medicine. By using the mouse hair follicle as a mini-organ system to study the formation of bud-like structures during embryonic development, our work uncovers a crucial role for the Rho GTPase regulator ARHGEF3 in hair follicle morphogenesis. We demonstrate thatArhgef3expression is upregulated at the onset of hair follicle placode formation. InArhgef3knockout animals, we observed defects in placode compaction, leading to impaired hair follicle downgrowth. Through cell culture models, we show that ARHGEF3 promotes F-actin accumulation at the cell cortex and P-cadherin enrichment at cell-cell junctions. Collectively, our study identifies ARHGEF3 as a new regulator of cell shape rearrangements during hair placode morphogenesis, warranting further exploration of its role in other epithelial appendages that arise from similar developmental processes.