bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early- but not late-adolescent Western diet consumption programs for long-lasting memory impairments in male but not female rats
Authors: Hayes Anna M. R. , Kao Alicia E. , Ahuja Arun , Subramanian Keshav S. , Klug Molly E. , Rea Jessica J. , Nourbash Anna C. , Tsan Linda , Kanoski Scott E. 
Published: October 2023

AbstractEarly life Western diet (WD) consumption leads to impaired memory function, particularly for processes mediated by the hippocampus. However, the precise critical developmental window(s) during which WD exposure negatively impacts hippocampal function are unknown. Here, we exposed male and female rats to a WD model involving free access to a variety of high-fat and/or high-sugar food and drink items during either the early-adolescent period (postnatal days [PN] 26-41; WD-EA) or late-adolescent period (PN 41-56; WD-LA). Control (CTL) rats were given healthy standard chow throughout both periods. To evaluate long-lasting memory capacity well beyond the early life WD exposure periods, we performed behavioral assessments after both a short (4 weeks for WD-EA, 2 weeks for WD-LA) and long (12 weeks for WD-EA, 10 weeks for WD-LA) period of healthy diet intervention. Results revealed no differences in body weight or body composition between diet groups, regardless of sex. Following the shorter period of healthy diet intervention, both male and female WD-EA and WD-LA rats showed deficits in hippocampal-dependent memory compared to CTL rats. Following the longer healthy diet intervention period, memory impairments persisted in male WD-EA but not WD-LA rats. In contrast, in female rats the longer healthy diet intervention reversed the initial memory impairments in both WD-EA and WD-LA rats. Collectively, these findings reveal that early-adolescence is a critical period of long-lasting hippocampal vulnerability to dietary insults in male but not female rats, thus highlighting developmental- and sex-specific effects mediating the relationship between the early life nutritional environment and long-term cognitive health.
Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson’s-like gut pathology
Authors: Mackie PM , Koshy J , Bhogade M , Hammoor T , Hachmeister W , Lloyd GM , Paterno G , Bolen M , Tansey MG , Giasson BI , Khoshbouei H 
Published: October 2023

SummaryDeposition of misfolded α-synuclein (αsyn) in the enteric nervous system (ENS) is found in multiple neurodegenerative diseases. It is hypothesized that ENS synucleinopathy contributes to both the pathogenesis and non-motor morbidity in Parkinson’s Disease (PD), but the cellular and molecular mechanisms that shape enteric histopathology and dysfunction are poorly understood. Here, we demonstrate that ENS-resident macrophages, which play a critical role in maintaining ENS homeostasis, initially respond to enteric neuronal αsyn pathology by upregulating machinery for complement-mediated engulfment. Pharmacologic depletion of ENS-macrophages or genetic deletion of C1q enhanced enteric neuropathology. Conversely, C1q deletion ameliorated gut dysfunction, indicating that complement partially mediates αsyn-induced gut dysfunction. Internalization of αsyn led to increased endo-lysosomal stress that resulted in macrophage exhaustion and temporally correlated with the progression of ENS pathology. These novel findings highlight the importance of enteric neuron-macrophage interactions in removing toxic protein aggregates that putatively shape the earliest stages of PD in the periphery.
Enabling brain-wide mapping of layer-specific functional connectivity at 3T via layer-dependent fMRI with draining-vein suppression
Authors: Chang Wei-Tang , Lin Weili , Giovanello Kelly S. 
Published: October 2023

ABSTRACTLayer-dependent functional magnetic resonance imaging (fMRI) is a promising yet challenging approach for investigating layer-specific functional connectivity (FC). Achieving a brain-wide mapping of layer-specific FC requires several technical advancements, including sub-millimeter spatial resolution, sufficient temporal resolution, functional sensitivity, global brain coverage, and high spatial specificity. Although gradient echo (GE)–based echo planar imaging (EPI) is commonly used for rapid fMRI acquisition, it faces significant challenges due to the draining-vein contamination. In this study, we addressed these limitations by integrating velocity-nulling (VN) gradients into a GE-BOLD fMRI sequence to suppress vascular signals from the vessels with fast-flowing velocity. The extravascular contamination from pial veins was mitigated using a GE-EPI sequence at 3T rather than 7T, combined with phase regression methods. Additionally, we incorporated advanced techniques, including simultaneous multi-slice (SMS) acceleration and NOise Reduction with DIstribution Corrected principal component analysis (NORDIC PCA) denoising, to improve temporal resolution, spatial coverage, and signal sensitivity. This resulted in a VN fMRI sequence with 0.9-mm isotropic spatial resolution, a repetition time (TR) of 4 seconds, and brain-wide coverage. The VN gradient strength was determined based on results from a button-pressing task. Using resting-state data, we validated layer-specific FC through seed-based analyses, identifying distinct connectivity patterns in the superficial and deep layers of the primary motor cortex (M1), with significant inter-layer differences. Further analyses with a seed in the primary sensory cortex (S1) demonstrated the reliability of the method. Brain-wide layer-dependent FC analyses yielded results consistent with prior literature, reinforcing the efficacy of VN fMRI in resolving layer-specific functional connectivity. Given the widespread availability of 3T scanners, this technical advancement has the potential for significant impact across multiple domains of neuroscience research.
Environmental change drives multi-generational shifts in the gut microbiome that mirror changing animal fitness
Authors: Williams Candace L. , Williams Claire E. , King Shauna N. D. , Shier Debra M. 
Published: October 2023

AbstractGut microbiomes can dramatically affect host health and fitness and can also be highly dynamic in response to changing environmental conditions. This intricate interplay between gut microbiota, environmental pressures, and host health necessitates accounting for all these variables when predicting the response of animals to a changing environment. These predictions are of broad concern but are highly relevant to conservation biology, and more specifically to populations transitioning from the wild to human care for the purposes ofex situbreeding programs. Captivity can dramatically alter both host-associated microbial communities and host health, but the dynamics of how the host and microbiome transition between the wild and captive state—within and across generations—are not well described. Here, we evaluate the microbiome and host fitness metrics for Pacific pocket mice (Perognathus longimembris pacificus) during the establishment of anex situconservation breeding program to characterize how pocket mice and their microbiomes respond to the environmental pressures of captivity across five generations. We found that the microbiome assumes a novel, stable conformation after two to three generations in captivity and that the patterns observed in the transitioning microbiota mirror the patterns of transitioning hosts’ weight and reproductive metrics. Moreover, we identify several microbial taxa which are correlated with successful reproduction. Our results provide insight not only into the effects of captivity but can be broadly applicable for understanding the effects of environmental change on organisms and their gut microbiota, which we propose may require multiple generations to reach an alternative stable state.
Nationally endorsed learning objectives to improve course design in introductory biology
Authors: Hennessey Kelly M , Freeman Scott 
Published: October 2023

AbstractIntroductory biology for majors is one of the most consequential courses in STEM, with annual enrollments of several hundred thousand students in the United States alone. To support increased student success and meet current and projected needs for qualified STEM professionals, it will be crucial to redesign majors biology by using explicit learning objectives (LOs) that can be aligned with assessments and active learning exercises. When a course is designed in this way, students have opportunities for the practice and support they need to learn, and instructors can collect the evidence they need to evaluate whether students have mastered key concepts and skills. Following an iterative process of review, revision, and evaluation, which included input from over 800 biology instructors around the country, we produced a nationally endorsed set of lesson-level LOs for a year-long introductory biology for major’s course. These LOs are granular enough to support individual class sessions and provide instructors with a framework for course design that is directly connected to the broad themes inVision and Changeand the general statements in the BioCore and BioSkills Guides. Instructors can implement backward course design by aligning these community endorsed LOs with daily and weekly learning activities and with formative and summative assessments.
NeoHeadHunter: an algorithm for the detection, ranking and probabilistic classification of neoepitope candidates
Authors: Zhao Xiaofei 
Published: October 2023

AbstractBackgroundThe manufacturing of personalized cancer vaccine requires the accurate identification of neoepitopes, abnormal peptides presented by cancer cells and recognized by the host immune system of the cancer patient.ResultsWe designed and developed NeoHeadHunter, a computational algorithm and pipeline to detect and rank neoepitope candidates. Unlike other algorithms, NeoHeadHunter can estimate the probability that each predicted neoepitope candidate is true positive. To evaluate NeoHeadHunter, we used the Tumor neoantigEn SeLection Alliance (TESLA) data-set derived from the sequencing of nine patients and characterized by 44 experimentally validated positive neoepitopes, a data-set derived from the sequencing of three cancer patients and characterized by eight experimentally validated positive neoepitopes and a manually curated data-set consisting of 64 experimentally validated positive neoepitopes. Our evaluation shows that NeoHeadHunter performs the best compared with other algorithms for both detecting and ranking neoepitope candidates and that NeoHeadHunter can accurately predict such probabilities.ConclusionsNeoHeadHunter can increase the effectiveness of personalized cancer vaccine by sensitively detect, accurately rank and probabilistically classify neoepitope candidates. NeoHeadHunter is released under the APACHE-II license athttps://github.com/XuegongLab/neoheadhunterfor academic use.
Semi-automated seizure detection using interpretable machine learning models
Authors: Antonoudiou Pantelis , Basu Trina , Maguire Jamie 
Published: October 2023

AbstractNumerous methods have been proposed for seizure detection automation, yet the tools to harness these methods and apply them in practice are limited. Here we compare four interpretable and widely-used machine learning models (decision tree, gaussian naïve bayes, passive aggressive classifier, stochastic gradient descent classifier) on an extensive electrographic seizure dataset collected from chronically epileptic mice. We find that the gaussian naïve bayes model achieved the highest precision and f1 score, while also detecting all seizures in our dataset and only requires a small amount of data to train the model and achieve good performance. We use this model to create an open-source python application SeizyML that couples model performance with manual curation allowing for efficient and accurate detection of electrographic seizures.Author SummarySeizure detection based on electrographic recordings is critical for epilepsy diagnosis and research. However, the current gold standard for seizure detection is manual curation, which is biased, costly, incredibly laborious, and requires extensive training and expertise, prohibiting advances in epilepsy diagnosis and research. Here we demonstrate that fast, simple, and interpretable machine learning (ML) models are sufficient to detect all seizures in an extensive dataset collected from a well-established mouse model of epilepsy. Importantly, we created an open-source python application, SeizyML, that integrates the most precise model tested here with human curation of the detected events. This semi-automated approach greatly enhances efficiency and precision of seizure detection while also being transparent. We believe that the adoption of semi-automated and transparent technologies is indispensable for understanding ML model predictions, improving their reliability, and fostering trust between ML models and neurodiagnostic professionals.
Involvement of TRPV4 in temperature-dependent perspiration in mice
Authors: Kashio Makiko , Derouiche Sandra , Yoshimoto Reiko U. , Sano Kenji , Lei Jing , Kido Mizuho A. , Tominaga Makoto 
Published: October 2023

ABSTRACTReports indicate that an interaction between TRPV4 and anoctamin 1 could be widely involved in water efflux of exocrine glands, suggesting that the interaction could play a role in perspiration. In secretory cells of sweat glands present in mouse foot pads, TRPV4 clearly colocalized with cytokeratin 8, anoctamin 1 (ANO1) and aquaporin-5 (AQP5). Mouse sweat glands showed TRPV4-dependent cytosolic Ca2+increases that was inhibited by menthol. Acetylcholine-stimulated sweating in foot pads was temperature-dependent in wild-type, but not in TRPV4-deficient mice, and was inhibited by menthol both in wild-type and TRPM8KO mice. The basal sweating without acetylcholine stimulation was inhibited by an ANO1 inhibitor. Sweating could be important for maintaining friction forces in mouse foot pads, and this possibility is supported by the finding that wild-type mice climbed up a slippery slope more easily than TRPV4-deleted mice. Furthermore, TRPV4 expression was significantly higher in controls and normohidrotic skin from patients with AIGA (acquired idiopathic generalized anhidrosis) compared to anhidrotic skin from patients with AIGA. Collectively, TRPV4 is likely involved in temperature-dependent perspiration via interactions with ANO1, and TRPV4 itself or the TRPV4/ANO 1 complex would be targets to develop agents that regulate perspiration.
Metabolic similarity and the predictability of microbial community assembly
Authors: Vila Jean C.C. , Goldford Joshua , Estrela Sylvie , Bajic Djordje , Sanchez-Gorostiaga Alicia , Damian-Serrano Alejandro , Lu Nanxi , Marsland Robert , Rebolleda-Gomez Maria , Mehta Pankaj , Sanchez Alvaro 
Published: October 2023

AbstractWhen microbial communities form, their composition is shaped by selective pressures imposed by the environment. Can we predict which communities will assemble under different environmental conditions? Here, we hypothesize that quantitative similarities in metabolic traits across metabolically similar environments lead to predictable similarities in community composition. To that end, we measured the growth rate and by-product profile of a library of proteobacterial strains in a large number of single nutrient environments. We found that growth rates and secretion profiles were positively correlated across environments when the supplied substrate was metabolically similar. By analyzing hundreds of in-vitro communities experimentally assembled in an array of different synthetic environments, we then show that metabolically similar substrates select for taxonomically similar communities. These findings lead us to propose and then validate a comparative approach for quantitatively predicting the effects of novel substrates on the composition of complex microbial consortia.
Development of a genome scale metabolic model for the lager hybrid yeastS. pastorianusto understand evolution of metabolic pathways in industrial settings
Authors: Timouma Soukaina , Balarezo-Cisneros Laura Natalia , Schwartz Jean-Marc , Delneri Daniela 
Published: October 2023

ABSTRACTIn silicotools such as genome-scale metabolic models (GSMM) have shown to be powerful for metabolic engineering of microorganisms. Here, we created the iSP_1513 GSMM for the aneuploid hybridS. pastorianusCBS1513 to allow top-down computational approaches to predict the evolution of metabolic pathways and to aid strain optimisation and media engineering in production processes. The iSP_1513 comprises 4062 reactions, 1808 alleles and 2747 metabolites, and takes into account the functional redundancy in the gene-protein-reaction rule caused by the presence of orthologous genes. Moreover, a universal algorithm to constrain GSMM reactions using transcriptome data was developed as a python library and enabled the integration of temperature as parameter. Essentiality datasets, growth data on various carbohydrates and volatile metabolites secretion were used to validate the model. Overall, the iSP_1513 GSMM represent an important step towards understanding the metabolic capabilities, evolutionary trajectories and adaptation potential ofS. pastorianusin different industrial settings.
Transcriptomic network analysis of brain and bone reveals shared molecular mechanisms underlying Alzheimer’s Disease and related dementias (ADRD) and Osteoporosis
Authors: Nagarajan Archana , Laird Jason , Ugochukwu Obiadada , Reppe Sjur , Gautvik Kaare , Ross Ryan D. , Bennett David A. , Rosen Clifford , Kiel Douglas P. , Higginbotham Lenora A. , Seyfried Nicholas , Lary Christine W. 
Published: October 2023

AbstractAlzheimer’s disease and related dementias (ADRD) and Osteoporosis (OP) are two prevalent diseases of aging with numerous epidemiological associations, but the underlying molecular mechanisms contributing to this association are unknown. We used WGCNA (weighted gene co-expression network analysis) to develop transcriptomic networks in bone and brain tissue using two different studies to discover common molecular mechanisms. We used RNA-sequencing data from the dorsolateral prefrontal cortex tissue of autopsied brains in 629 participants from ROSMAP (Religious Orders Study and the Memory and Aging Project), including a subset of 298 meeting criteria for inclusion in five ADRD categories and the full set in a secondary analysis, and RNA array data from transiliac bone in 84 participants from the Oslo study of postmenopausal women. After developing each network, we analyzed associations between modules (groups of co-expressed genes) with multiple bone and neurological traits, examined overlap in modules between networks, and performed pathway enrichment analysis to discover conserved mechanisms. We discovered three modules in ROSMAP that showed significant associations with ADRD and bone related traits and four modules in Oslo that showed significant associations with multiple bone outcomes. We found significant module overlap between the two networks, most notably among those modules linked to canonical Wnt signaling and skeletal tissue homeostasis and development. These results were preserved with a network from the full ROSMAP cohort (n=629), which included a broader spectrum of participants. Our results require validation in experimental studies but show support for Wnt signaling as an important driver of pathology in OP and ADRD. We additionally show a strong link between Dementia with Lewy bodies and bone outcomes. These results have translational significance in the development of novel treatments and biomarkers for both ADRD and OP.
Intermittent Nicotine Access is as Effective as Continuous Access in Promoting Nicotine Seeking and Taking in Rats
Authors: Algallal Hajer E , Jacquemet Vincent , Samaha Anne-Noël 
Published: October 2023

AbstractNicotine is a principal psychoactive agent in tobacco, contributing to tobacco’s addictive potential. Preclinical studies on the effects of voluntary nicotine intake typically use self-administration procedures that provide continuous nicotine access during each self-administration session. However, many smokers consume cigarettes intermittently rather than continuously throughout each day. For drugs including cocaine and opioids, research in laboratory rats shows that intermittent intake can be more effective than continuous intake in producing patterns of drug use relevant to addiction. We asked, therefore, how intermittent versus continuous nicotine self-administration influences nicotine seeking and taking behaviours. Female and male rats had continuous (i.e., Long Access; LgA, 6 h/day) or intermittent (IntA; 12 min ON, 60 min OFF, for 6 h/day) access to intravenous nicotine (15 µg/kg/infusion), for 12 daily sessions. We then assessed intake, responding for nicotine under a progressive ratio schedule of drug reinforcement and cue- and nicotine-induced reinstatement of drug seeking. We also estimated nicotine pharmacokinetic parameters during LgA and IntA self-administration. Overall, LgA rats took twice more nicotine than did IntA rats, yielding more sustained increases in estimated brain concentrations of the drug. However, the two groups showed similar motivation to seek and take nicotine, as measured using reinstatement and progressive ratio procedures, respectively. Thus, intermittent nicotine use is just as effective as continuous use in producing addiction-relevant behaviours, despite significantly less nicotine exposure. This has implications for modeling nicotine self-administration patterns in human smokers and resulting effects on brain and behaviour.
Targeted genome editing restores auditory function in adult mice with progressive hearing loss caused by a human microRNA mutation
Authors: Zhu Wenliang , Du Wan , Rameshbabu Arun Prabhu , Armstrong Ariel Miura , Silver Stewart , Kim Yehree , Wei Wei , Shu Yilai , Liu Xuezhong , Lewis Morag A , Steel Karen P. , Chen Zheng-Yi 
Published: October 2023

AbstractMutations inmicroRNA-96(MIR96) cause dominant delayed onset hearing loss DFNA50 without treatment. Genome editing has shown efficacy in hearing recovery by intervention in neonatal mice, yet editing in the adult inner ear is necessary for clinical applications. Here, we developed an editing therapy for a C>A point mutation in the seed region of theMir96gene,Mir9614C>Aassociated with hearing loss by screening gRNAs for genome editors and optimizing Cas9 and sgRNA scaffold for efficient and specific mutation editing in vitro. By AAV delivery in pre-symptomatic (3-week-old) and symptomatic (6-week-old) adultMir9614C>Amutant mice, hair cell on-target editing significantly improved hearing long-term, with an efficacy inversely correlated with injection age. We achieved transient Cas9 expression without the evidence of AAV genomic integration to significantly reduce the safety concerns associated with editing. We developed an AAV-sgmiR96-master system capable of targeting all known humanMIR96mutations. As mouse and humanMIR96sequences share 100% homology, our approach and sgRNA selection for efficient and specific hair cell editing for long-term hearing recovery lays the foundation for future treatment of DFNA50 caused byMIR96mutations.