bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential composition of lymphocyte subpopulations and activation between the hypertensive Bph/2 and normotensive Bpn/3 mouse strains
Authors: Dattmore Devon , McDonald Paiton , Chowdhury Afrin , Awali Saamera , Boss Allison P. , Jin Yining , Sather Lisa , Lauver D. Adam , Rockwell Cheryl E. 
Published: October 2024

AbstractNumerous studies point to a role for the immune system in various animal models of hypertension. However, little is known about the immune system of Bph/2 mice, a spontaneously hypertensive strain. To address this, we conducted a comprehensive comparison of immune cell composition and response to polyclonal T cell activation in hypertensive Bph/2 mice and normotensive Bpn/3 control mice. We quantified immune cell populations by flow cytometry from spleen and inguinal, brachial and mesenteric lymph nodes. While composition of myeloid immune cell types was largely comparable between strains, we observed differences in B and T cell subpopulations. Specifically, we found an increased percentage of IgM+ IgDLoand IgM+ IgD-B cells in Bph/2 mice, suggesting greater baseline B cell activation. In addition, we observed a decreased percentage of CD4 effector memory T cells and CD8 central memory T cells. The diminished proportion of memory T cells in Bph/2 mice correlated with decreased proliferation and cytokine response of splenic T cells to polyclonal T cell activation. In splenic T cells from Bph/2 mice 24 h after activation we observed a pronounced decrease in the majority of T cell cytokines. At 120 h after activation, the Th1 and Th17 cytokine responses of splenic T cells from Bph/2 mice were decreased, but other T cell cytokines were largely comparable. Overall, the data suggest a decreased percentage of memory T cells in Bph/2 mice that correlates with markedly diminished proliferation and a reduced cytokine response to polyclonal activation.
Brainstem neurons coordinate the bladder and urethra sphincter for urination
Authors: Li Xing , Li Xianping , Li Jun , Qin Han , Liang Shanshan , Li Jun , Jian Tingliang , Wang Xia , Yin Lingxuan , Yuan Chunhui , Liao Xiang , Jia Hongbo , Chen Xiaowei , Yao Jiwei 
Published: October 2024

AbstractUrination, a vital and conserved process of emptying urine from the urinary bladder in mammals, requires precise coordination between the bladder and external urethra sphincter (EUS) that is tightly controlled by a complex neural network. However, the specific subpopulation of neurons that accounts for such coordination remains unidentified, limiting the development of target-specific therapies for certain urination disorders, e.g. detrusor-sphincter dyssynergia. Here, we find that cells expressing estrogen receptor 1 (ESR1+) in the pontine micturition center (PMC) initiate voiding when activated and suspend ongoing voiding when suppressed, each at 100% reliability, respectively. Transection of either the pelvic or the pudendal nerve does not impair PMCESR1+control of the downstream target through the other nerve at all. Anatomically, PMCESR1+cells possess two subpopulations projecting to either the pelvic or pudendal nerve and a third, dual-projecting subpopulation, locking in the coordination of bladder contraction and sphincter relaxation in a rigid temporal order. We identify a cell type in the brainstem that controls the bladder-urethra coordination for urination.
Tbc1d15 knockdownin vivoalleviates α-synuclein-induced neurotoxicity by promoting autophagy
Authors: Siddiqi F. H. , Raval N. R. , Palner M. , Nielsen J. E. , Pocock R. , Rubinsztein D. C. , Ejlerskov P. 
Published: October 2024

AbstractParkinson’s disease is a neurodegenerative disease, which is associated with accumulation of α-synuclein protein aggregates and Lewy Body formation. These neurotoxic inclusions are especially harmful for dopamine-producing neurons in the substantia nigra of the brain. The cellular degradation system autophagy can reduce neurotoxicity caused by accumulated α-synuclein, by targeting it for degradation. Previously, we demonstrated that human TBC1D15 inhibits autophagyin vitro, resulting in accumulation of neurotoxic protein aggregates. Conversely, lowering the TBC1D15 expression promotes autophagy and degradation of α-synuclein and huntingtin proteins in various cell models. Here we show that knockdown of murine Tbc1d15in vivoactivates autophagy, reduces α-synuclein-mediated neurotoxicity, and improves motor performance. Thus, targeting Tbc1d15 expression may be a therapeutic avenue for neurodegenerative diseases.
ProteusAI: An Open-Source and User-Friendly Platform for Machine Learning-Guided Protein Design and Engineering
Authors: Funk Jonathan , Machado Laura , Bradley Samuel A. , Napiorkowska Marta , Gallegos-Dextre Rodrigo , Pashkova Liubov , Madsen Niklas G. , Webel Henry , Phaneuf Patrick V. , Jenkins Timothy P. , Acevedo-Rocha Carlos G. 
Published: October 2024

AbstractProtein design and engineering are crucial for advancements in biotechnology, medicine, and sustainability. Machine learning (ML) models are used to design or enhance protein properties such as stability, catalytic activity, and selectivity. However, many existing ML tools require specialized expertise or lack open-source availability, limiting broader use and further development. To address this, we developed ProteusAI, a user-friendly and open-source ML platform to streamline protein engineering and design tasks. ProteusAI offers modules to support researchers in various stages of the design-build-test-learn (DBTL) cycle, including protein discovery, structure-based design, zero-shot predictions, and ML-guided directed evolution (MLDE). Our benchmarking results demonstrate ProteusAI’s efficiency in improving proteins and enyzmes within a few DBTL-cycle iterations. ProteusAI democratizes access to ML-guided protein engineering and is freely available for academic and commercial use. Future work aims to expand and integrate novel methods in computational protein and enzyme design to further develop ProteusAI.
Environmental polysulfides promote protein disulfide bond formation of microorganisms growing under anaerobic condition
Authors: Xin Yuping , Wang Qingda , Yang Jianming , Wu Xiaohua , Xia Yongzhen , Xun Luying , Liu Huaiwei 
Published: October 2024

ABSTRACTPolysulfides are rich in anaerobic and microbial metabolism active environments. Anaerobic survival of microorganisms requires the formation of protein disulfide bond (DSB). The relation between environmental polysulfides and anaerobic DSB formation has not been studied so far. Herein, we discovered that environmental polysulfides can efficiently mediate protein DSB formation of microorganisms under anaerobic condition. We used polysulfides to treat proteins including roGFP2, Trx1, and DsbA under anaerobic condition and found that all three proteins formed intramolecular DSBin vitro. The growth ofE. coliΔdsbBwas reduced and the amount of its intracellular protein DSB was decreased under anaerobic condition. However, treating the mutant strain with polysulfides recovered the growth and reversed DSB decrease. TreatingE. coliΔdsbAwith polysulfides promoted DSB formation of its periplasmic roGFP2 and recovered its growth under anaerobic condition. In addition, treatingSchizosaccharomyces pombewith polysulfides led to increase of the intracellular protein DSB content. Thus, our study reveals that environmental polysulfides can promote DSB formation independent of the enzymatic DSB mediating system and oxygen. In this aspect, environmental polysulfides are beneficial for the survival of microorganisms in anaerobic habitats.IMPORTANCEHow polysulfides benefit adaption of microorganisms to anaerobic environments are unclear. Our study reveals that environmental polysulfides efficiently facilitate protein DSB formation under anaerobic condition. Polysulfides contain zero valent sulfur atoms (S0), which can be transferred to the thiol group of cysteine residue. This S0atom gets two electrons from two cysteine residues and becomes reduced H2S, leaving two cysteine residues in disulfide bond form. Anaerobic growth of microorganisms was benefited from the formation of DSB. This finding paves the way for a deeper understanding of the intricate relationship between polysulfides and microorganisms in environmental contexts.
Investigation of cell metabolism dysfunction in autism spectrum disorders using genome-scale metabolic network analysis of neuronal development
Authors: Pourmajidian Moohebat , Marashi Sayed-Amir 
Published: October 2024

AbstractAutism Spectrum Disorders (ASDs) are a group of highly heterogeneous neurodevelopmental conditions characterized by impairments in social interactions and repetitive behaviors. In spite of extensive efforts, known genetic mutations can hardly explain the ASD cases, which signifies the highly heterogeneous nature of ASDs and calls for shifting to a more holistic approach for understanding the mechanism of these disorders. Several studies have reported that a wide range of metabolic markers is present in blood, urine and brain samples of ASD patients. In this study, using transcriptome data of neurons derived from ASD and control individuals, we reconstructed neuron-specific metabolic network models for two neurodevelopmental time points representing late neural progenitor stage and mature neurons. We simulate gene inactivation in these networks to investigate the altered metabolic fluxes and biological pathways in ASD metabolism. We further examine these networks using reporter metabolite analysis to identify those metabolites around which significant gene expression changes occur. Briefly, our model was successful in predicting previously reported metabolites and pathways implicated in ASD metabolism, including oxidative phosphorylation and fatty acid oxidation, and points to a new finding concerning alterations in the less studied pathways like keratan sulfate degradation pathway and N/O-glycosylation in ASD. Finally, by employing the robust metabolic transformation algorithm (rMTA) we set to find potential drug targets that can reverse the ASD metabolic state into a healthy one. Interestingly, our model found phosphatidic phosphatase enzyme, as well as phosphatidylethaolamine and phosphatidylserine transfer proteins as targets that could recover the healthy metabolic state.
Decreased hippocampal neurite density in middle-aged/aging adults following prenatal exposure to higher levels of maternal inflammation
Authors: Mohyee Raana A. , Elliott Blake L. , Pike Madeline R. , Smith Emma , Kring Ann M. , Olson Ingrid R. , Breen Elizabeth C. , Cohn Barbara A. , Cirillo Piera M. , Krigbaum Nickilou Y. , Olino Thomas M. , D’Esposito Mark , Cogan Ashby B. , Patwardan Bhakti P. , Ellman Lauren M. 
Published: October 2024

AbstractIn animal models, exposure to heightened maternal inflammation in utero is associated with altered offspring hippocampal development, including reduced dendritic arborization and density. However, the effects of prenatal maternal inflammation (PNMI) on offspring hippocampal microstructure in humans remains unclear. Here, we examined the relationship between exposure to PNMI and neurite density in the hippocampus and its subfields among offspring during late middle age. Participants included 72 mother-offspring dyads from the Child Health and Development Studies (CHDS) cohort. Data for four inflammatory biomarkers (IL-6, IL-8, IL-1 receptor antagonist [IL-1RA], and soluble TNF receptor-II [sTNF-RII]) were available from first and second trimester maternal sera. Neurite density in the offspring hippocampus and its subfields was estimated using microstructural modeling of offsprings’ diffusion-weighted Magnetic Resonance Imaging data (mean age of offspring at imaging = 59 years; 51% male). We estimated the relationship between each biomarker and region-of-interest’s neurite density. Higher first trimester maternal IL-1RA and IL-6 levels were associated with lower offspring hippocampal neurite density. These relationships were specific to the CA3, CA4, dentate gyrus, and subiculum subfields. In addition, higher second trimester IL-6 was associated with lower subiculum neurite density. Our findings reveal that exposure to heightened prenatal levels of maternal inflammation is linked to altered offspring hippocampal microstructure in late middle age, which could have implications for memory decreases during this period and may be relevant for understanding risk of aging-related cognitive changes.Significance StatementThe contribution of prenatal maternal inflammation (PNMI) to offspring brain microstructure in later life is well established in animal models, but poorly understood in humans. Our study discovered long-lasting impacts of elevated PNMI during early-mid gestation on the structural integrity of the hippocampus in offspring during late middle age. Our findings underscore the potential role of developmental programming in aging-related neurological and cognitive decline, as the observed degradation in hippocampal microstructure is present over half a century following exposure.
TYK2 inhibition enhances Treg differentiation and function while preventing Th1 and Th17 differentiation
Authors: Tuomela Karoliina , Garcia Rosa V. , Boardman Dominic A. , Tavakoli Pedram , Ancheta-Schmit Maria , Sham Ho Pan , Cheng Lihong , Struthers Mary , Bressler Brian , Vallance Bruce A. , Zhao Qihong , Levings Megan K. 
Published: October 2024

ABSTRACTJanus kinase (JAK) inhibitors are widely use to inhibit inflammatory cytokine signalling in autoimmune and inflammatory diseases but their effect on regulatory T cells (Tregs) is poorly characterized. We investigated the effect of JAK inhibition on human Treg differentiation, phenotype, and function using a JAK inhibitor, upadacitinib, in comparison to BMS-986202, a selective Tyrosine kinase 2 (TYK2) inhibitor. Both upadacitinib and BMS-986202 blocked the differentiation of naïve CD4+T cells into Th1 and Th17 cells, but only BMS-986202 spared IL-2 signalling and Treg differentiation. BMS-986202 also increased Treg suppressive function and stability under Th1- and Th17-polarizing conditions, whereas upadacitinib significantly impaired the phenotype and viability ofex vivoTregs. Analysis of lamina propria mononuclear cells from patients with inflammatory bowel disease revealed that, under Th17 polarizing conditions, BMS-986202 redirected CD4+T cells towards a Treg phenotype. The Treg-sparing and enhancing properties of TYK2 inhibition suggest that TYK2 inhibitors are a promising pharmacological approach for tolerance induction.eTOC SUMMARYTuomela et al. report that TYK2 inhibition does not affect human Treg induction from naïve CD4+T cells, promotes Treg differentiation in lamina propria-derived T cells, and increases blood-derived Treg stability/function. In contrast, JAK inhibition strongly impairs Treg function.
Stable primary brain cell cultures from zebrafish reveal hyperproliferation of non-neuronal cells fromscn1labmutants
Authors: Lorenzo Odierna G. , Stednitz Sarah , Pruitt April , Arnold Joshua , Hoffman Ellen J. , Scott Ethan K. 
Published: October 2024

AbstractZebrafish are a popular model system for studying the genetic and neural underpinnings of perception and behavior, both in wild-type animals and in the context of disease modelling. Cultured primary neurons provide a key complementary tool for such studies, but existing protocols for culturing embryonic zebrafish primary neurons are limited by short cell survival and low neuronal purity. In this study, we set out to establish a protocol to produce long lived, pure neuronal cultures from zebrafish that could be used to study the mechanistic contributions of genes to neuronal networks. We then used these primary cultures to characterize cell proliferation and differentiation in primary neurons derived fromscn1labmutant embryos, which lack a sodium channel relevant to Dravet syndrome and autism. Using our optimized protocol, we generated cultures that proliferate, diversify, and form stable networks of neurons surviving for months. These stable cultures allowed us to perform genetic experiments, in this case revealing dramatic differences in the cellular composition of cultures derived fromscn1labmutant embryos versus their wild type siblings. Specifically, we find that loss ofscn1labpromotes hyperproliferation of non-neuronal cells in mixed cultures of brain cells. In pure neuronal cultures, we find alterations in neurotransmitter subtypes consistent with known effects ofscn1labloss of function. Validating the utility of this approach, we then identify a corresponding hyperproliferation phenotype in livescn1labmutant embryos, shedding light on potential mechanisms that may be relevant for Dravet syndrome.Significance statementMost existing embryonic zebrafish primary neuron culture protocols describe growing mixed cell types for restricted durations. Here, we report generation of zebrafish mixed type or pure neuronal cultures that are viable for over 100 days. We apply these cultures to gain new insight intoscn1lab, a zebrafish orthologue of the Dravet Syndrome-associated sodium channel geneSCN1A. We report that loss ofscn1labresults in hyperproliferation of non-neuronal cells, revealing an underappreciated mechanism by which mutations inSCN1Aimpact the structure and function of neuronal networks. Ourin vitrocultures thus faithfully recapitulatein vivoneurobiology and provide a powerful platform to interrogate brain function in health and disease.
Students’ perspectives on communication skills’ course learning modes in two medical schools in Zambia: An interview-based descriptive study
Authors: Ezeala Mercy Ijeoma Okwudili , Volk John 
Published: October 2024

AbstractIntroductionThis study sought the views of undergraduate medical students on the effectiveness of their modes of instruction in communication skills knowledge and skills acquisition and transfer. Understanding the teaching-learning experiences from the students’ viewpoint could influence communication skills course facilitators to adopt instructional modes and learning experiences that enhance competency development in communication skills. It could also emphasize the need for curriculum developers to review the medical school curriculum, specifying student-centered and active learning pedagogical practices.MethodsThe descriptive study involved an in-depth semi-structured interview of eight undergraduate medical students from two medical schools in Zambia, who participated in communication skills training, selected through a purposive nonprobability sampling. The study mostly appropriated Tracy’s phronetic iterative analysis during its thematic analysis of the textual data collected between April and May 2022.ResultsThe participants affirmed the importance of communication skills to their medical training but, decried the dominance of lecture-based delivery, limited interactive sessions, untimely and inadequate feedback from teachers and peers, inefficacy of teaching communication skills as theory, and limited understanding and distraction from online delivery as factors that hindered communication skills teaching-learning.ConclusionAlthough the students expressed communication skills as pivotal to their training and medical practice, their experiences of learning the skills through non-experiential and traditional lecture-based methods did not facilitate the motivation required for mastery and competency, suggesting that facilitators and curriculum planners should reevaluate the teaching-learning modes and process.
The multivariate genetic architecture of psychiatric and insulin resistance multimorbidity
Authors: Mota Nina Roth , Fanelli Giuseppe , Erdogan Izel , Klein Marieke , Sprooten Emma , Fóthi Ábel , Ruisch I. Hyun , Poelmans Geert , Alam Kazi Asraful , Haavik Jan , Wimberley Theresa , Arenella Martina , Serretti Alessandro , Fabbri Chiara , Franke Barbara , Bralten Janita 
Published: October 2024

AbstractPsychiatric disorders frequently co-occur with insulin resistance (IR)-related conditions, including obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MetS). Although pairwise genetic correlations have been observed, the shared genetics underlying this multimorbidity remains underexplored. Here, we investigate the joint genetic architecture of psychiatric-IR multimorbidity, explore tissue-specific gene expression associations, and identify potential underlying biological mechanisms and repurposable drugs. We applied genomic structural equation modeling (SEM) to genome-wide association study (GWAS) data (N=9,725–933,970) from five psychiatric disorders (attention-deficit/hyperactivity disorder, anorexia nervosa, major depressive disorder, obsessive-compulsive disorder, and schizophrenia) and three IR-related conditions (MetS, obesity, T2DM). Factor analyses revealed a 2-factor solution, where one of the factors was composed by all psychiatric disorders (excluding schizophrenia) and IR-related conditions (the Psych-IR factor), representing the shared genetics of these psychiatric and IR-conditions. This factor showed genetic correlations with the inferior temporal, lateral occipital, and total cortical brain surface areas. A multivariate GWAS of the Psych-IR factor identified 150 risk loci and 366 associated genes (128 novel). The significant gene-set associations included the insulin binding and the Notch signaling pathways, while the gene-property tissue expression implicated the cerebellum, brain cortex, and pituitary gland, particularly involving the brain during prenatal development stages. Transcriptome-wide SEM (T-SEM) assessed tissue-specific gene expression associations and identified 499 genes (191 novel), including MHC-related genes. Drug repurposing analysis using PharmOmics suggested six potential candidates, including memantine and rosiglitazone. Associated genes derived from the Psych-IR factor multivariate GWAS and T-SEM results were combined for enrichment analyses, which highlighted the involvement of the chr16p11.2 region, BDNF signaling, and lipid metabolism. The identified Psych-IR factor offers novel insights into the shared genetic and biological mechanisms underlying psychiatric-IR multimorbidity, providing a foundation for future research on precision medicine and prevention approaches.