bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomics-informed Neuropsychiatric Care for Neurodevelopmental Disorders: Results from A Multidisciplinary Clinic
Authors: Besterman Aaron D. , Adams David J. , Wong Nicole R. , Schneider Benjamin N. , Mehta Sunil , DiStefano Charlotte , Wilson Rujuta B. , Martinez-Agosto Julian A. , Jeste Shafali S. 
Published: May 2024

ABSTRACTBackgroundPatients with neurodevelopmental disorders (NDDs) have high rates of neuropsychiatric comorbidities that can be highly impairing and treatment refractory. Genomic medicine may help guide care, as pathogenic variants are identified in up to 50% of patients with NDDs. We evaluate the impact of a genomics-informed, multidisciplinary, neuropsychiatric specialty clinic on the diagnosis and management of patients with NDDs.MethodsWe performed a retrospective study of 316 patients from the UCLA Care and Research in Neurogenetics Clinic, a genomics-informed multidisciplinary clinic composed of psychiatry, neurology, medical genetics, psychology, and social work.ResultsWe observed high rates of psychiatric and medical comorbidity. Among the 246 patients that underwent genetic testing, 41.8% had a pathogenic or likely pathogenic (P/LP) variant. Patients had 62 different genetic diagnoses, with 12 diagnoses shared by two or more patients, including Duplication 15q syndrome (9.18%), Tuberous Sclerosis Complex (3.48%), and Angelman syndrome (1.27%), while 50 diagnoses were found in only single patients. Genetic diagnosis resulted in direct changes to clinical management in all patients with a P/LP variant, including high rates of cascade testing (30.6%), family counseling (22.2%), medication changes (13.9%), clinical trial referral (2.8%), medical surveillance (30.6%), and specialty referrals (69.4%).ConclusionsA genomics-informed model can provide significant clinical benefits to patients with NDDs, directly impacting management across multiple domains for most diagnosed patients. As precision treatments for NDDs advance, establishing a genetic diagnosis will be critical for proper management. With the growing number of rare neurogenetic disorders, clinician training should emphasize core principles of genomic medicine over individual syndromes.
Sex differences in change-of-mind neuroeconomic decision-making is modulated by LINC00473 in medial prefrontal cortex
Authors: Cuttoli Romain Durand-de , Issler Orna , Yakubov Benjamin , Jahan Nusrat , Abid Aisha , Kasparov Susanna , Granizo Kastalia , Ahmed Sanjana , Russo Scott J. , Nestler Eric J. , Sweis Brian M. 
Published: May 2024

AbstractChanging one’s mind is a complex cognitive phenomenon involving a continuous re-appraisal of the trade-off between past costs and future value. Recent work modeling this behavior across species has established associations between aspects of this choice process and their contributions to altered decision-making in psychopathology. Here, we investigated the actions in medial prefrontal cortex (mPFC) neurons of long intergenic non-coding RNA, LINC00473, known to induce stress resilience in a striking sex-dependent manner, but whose role in cognitive function is unknown. We characterized complex decision-making behavior in male and female mice longitudinally in our neuroeconomic foraging paradigm, Restaurant Row, following virus-mediated LINC00473 expression in mPFC neurons. On this task, mice foraged for their primary source of food among varying costs (delays) and subjective value (flavors) while on a limited time-budget during which decisions to accept and wait for rewards were separated into discrete stages of primary commitments and secondary re-evaluations. We discovered important differences in decision-making behavior between female and male mice. LINC00473 expression selectively influenced multiple features of re-evaluative choices, without affecting primary decisions, in female mice only. These behavioral effects included changing how mice (i) cached the value of the passage of time and (ii) weighed their history of economically disadvantageous choices. Both processes were uniquely linked to change-of-mind decisions and underlie the computational bases of distinct aspects of counterfactual thinking. These findings reveal a key bridge between a molecular driver of stress resilience and psychological mechanisms underlying sex-specific decision-making proclivities.
Functional Resilience of the Neural Visual Recognition System Post-Pediatric Occipitotemporal Resection
Authors: Granovetter Michael C. , Maallo Anne Margarette S. , Ling Shouyu , Robert Sophia , Freud Erez , Patterson Christina , Behrmann Marlene 
Published: May 2024

AbstractIn the typically developing (TD) brain, neural representations for visual stimulus categories (e.g., faces, objects, and words) emerge in bilateral occipitotemporal cortex (OTC), albeit with weighted asymmetry; in parallel, recognition behavior continues to be refined. A fundamental question is whether two hemispheres are necessary or redundant for the emergence of neural representations and recognition behavior typically distributed across both hemispheres. The rare population of patients undergoing unilateral OTC resection in childhood offers a unique opportunity to evaluate whether neural computations for visual stimulus individuation suffice for recognition with only a single developing OTC. Here, using functional magnetic resonance imaging, we mapped category selectivity (CS) and neural representations for individual stimulus exemplars using repetition suppression (RS) in the non-resected hemisphere of pediatric OTC resection patients (n= 9) and control patients with resection outside of OTC (n= 12), as well as in both hemispheres of TD controls (n= 21). There were no univariate group differences in the magnitude of CS or RS or any multivariate differences (per representational similarity analysis) in neural activation to faces, objects, or words across groups. Notwithstanding their comparable neural profiles, accuracy of OTC resection patients on face and object recognition, but not word recognition, was statistically inferior to that of controls. The comparable neural signature of the OTC resection patients’ preserved hemisphere and the other two groups highlights the resilience of the system following damage to the contralateral homologue. Critically, however, a single OTC does not suffice for normal behavior, and, thereby, implicates the necessity for two hemispheres.
Cell-surface receptor-mediated regulation of synaptic organelle distribution controls dendritic spine maturation
Authors: Verpoort Ben , Amado Luísa , Vandensteen Jeroen , Leysen Elke , Dascenco Dan , Vandenbempt Joris , Lemmens Irma , Wauman Joris , Vennekens Kristel , Escamilla-Ayala Abril , Nogueira Freitas Ana Cristina , Voets Thomas , Munck Sebastian , Tavernier Jan , de Wit Joris 
Published: May 2024

AbstractThe spine apparatus (SA), an endoplasmic reticulum-related organelle present in a subset of mature dendritic spines, plays a key role in postsynaptic development and has been implicated in various neurological disorders. However, the molecular mechanisms that dictate SA localization at selected synapses remain elusive. Here, we identify a postsynaptic signaling complex comprising the GPCR-like receptor GPR158 and a largely uncharacterized phospholipase C (PLC), PLCXD2, that controls SA abundance. Sparse genetic manipulationsin vivodemonstrate that in the absence of GPR158, unrestrained PLCXD2 activity impedes postsynaptic SA incorporation and hampers dendritic spine maturation. Finally, we show that extracellular heparan sulfate proteoglycan (HSPG) binding modulates the GPR158-PLCXD2 interaction. Together, our findings reveal how a postsynaptic receptor signaling complex regulates the local lipid microenvironment to control SA abundance required for the proper maturation of dendritic spines.
autoMEA: Machine learning-based burst detection for multi-electrode array datasets
Authors: Hernandes Vinicius , Heuvelmans Anouk M. , Gualtieri Valentina , Meijer Dimphna H. , van Woerden Geeske M. , Greplova Eliska 
Published: May 2024

AbstractNeuronal activity in the highly organized networks of the central nervous system is the vital basis for various functional processes, such as perception, motor control, and cognition. Understanding interneuronal connectivity and how activity is regulated in the neuronal circuits is crucial for interpreting how the brain works. Multi-electrode arrays (MEAs) are particularly useful for studying the dynamics of neuronal network activity and their development as they allow for real-time, high-throughput measurements of neural activity. At present, the key challenge in the utilization of MEA data is the sheer complexity of the measured datasets. Available software offers semi-automated analysis for a fixed set of parameters that allow for the definition of spikes and bursts. However, this analysis remains time-consuming, user-biased, and limited by pre-defined parameters. Here, we present autoMEA, software for machine learning-based automated burst detection in MEA datasets. We exemplify autoMEA efficacy on neuronal network activity of primary hippocampal neurons from wild-type mice monitored using 24-well multiwell MEA plates. To validate and benchmark the software, we showcase its application using wild-type neuronal networks and two different neuronal networks modeling neurodevelopmental disorders to assess network phenotype detection. Detection of network characteristics typically reported in literature, such as synchronicity and rhythmicity, could be accurately detected compared to manual analysis using the autoMEA software. Additionally, autoMEA could detect reverberations, a more complex burst dynamic present in hippocampal cultures. Furthermore, autoMEA burst detection was sufficiently sensitive to detect changes in the synchronicity and rhythmicity of networks modeling neurodevelopmental disorders as well as detecting changes in their burst dynamics. Thus, we show that autoMEA reliably analyses neural networks measured with the multi-well MEA setup with the precision and accuracy compared to that of a human expert.
Unraveling the complexity of rat object vision requires a full convolutional network - and beyond
Authors: Muratore Paolo , Alemi Alireza , Zoccolan Davide 
Published: May 2024

AbstractDespite their prominence as model systems to dissect visual cortical circuitry, it remains unclear whether rodents are capable of truly advanced processing of visual information. Here, we considered several psychophysical studies of rat object vision, and we used a deep convolutional neural network (CNN) to measure the computational complexity required to account for the patterns of rat performances reported in these studies, as well as for the animals’ perceptual strategies. We found that at least half of the CNN depth was required to match the modulation of rat classification accuracy in tasks where objects underwent variations of size, position and orientation. However, the full network was needed to equal the tolerance of rat perception to more severe image manipulations, such as partial occlusion and reduction of objects to their outlines. Finally, rats displayed a perceptual strategy that was way more invariant than that of the CNN, as they more consistently relied on the same set of diagnostic features across object transformations. Overall, these results reveal an unexpected level of sophistication of rat object vision, while reinforcing the intuition that, despite their proficiency in solving challenging image classification tasks, CNNs learn solutions that only marginally match those of biological visual systems.
Coxsackievirus group B3 regulates ASS1-mediated metabolic reprogramming and promotes macrophage inflammatory polarization in viral myocarditis
Authors: Liu Qiong , Shang Yinpan , Tao Ziwei , Li Xuan , Shen Lu , Zhang Hanchi , Liu Zhili , Rao Zhirong , Yu Xiaomin , Cao Yanli , Zeng Lingbing , Huang Xiaotian 
Published: May 2024

ABSTRACTCoxsackievirus group B3 (CVB3) belongs to the genusEnterovirusesof the familyPicornaviridaeand is the main pathogen underlying viral myocarditis (VMC). No specific therapeutic is available for this condition. Argininosuccinate synthase 1 (ASS1) is a key enzyme in the urea cycle that converts citrulline and aspartic acid to argininosuccinate. Here, we found that CVB3 and its capsid protein VP2 inhibit the autophagic degradation of ASS1 and that CVB3 consumes citrulline to upregulate ASS1, triggers urea cycle metabolic reprogramming, then activates macrophages to develop pro-inflammatory polarization, thereby promoting the occurrence and development of VMC. Conversely, citrulline supplementation to prevent depletion can downregulate ASS1, rescue macrophage polarization, and alleviate the pathogenicity of VMC. These findings provide a new perspective on the occurrence and development of VMC, revealing ASS1 as a potential new target for the treatment of this disease.IMPORTANCEViral myocarditis (VMC) is a common and potentially life-threatening myocardial inflammatory disease, most commonly caused by CVB3 infection. So far, the pathogenesis of VMC caused by CVB3 is mainly focused on two aspects: one is the direct myocardial injury caused by a large number of viral replication in the early stage of infection, and the other is the local immune cell infiltration and inflammatory damage of the myocardium in the adaptive immune response stage. There are few studies on the early innate immunity of CVB3 infection in myocardial tissue, but the appearance of macrophages in the early stage of CVB3 infection suggests that they can play a regulatory role as early innate immune response cells in myocardial tissue. Here, we discovered a possible new mechanism of VMC caused by CVB3, revealed new drug targets for anti-CVB3 and discovered the therapeutic potential of citrulline for VMC.
Generating gnotobiotic bivalves: a new method on Manila clam (Ruditapes philippinarum)
Authors: Gallo Marialaura , Quagliariello Andrea , Rovere Giulia Dalla , Maietti Federica , Cardazzo Barbara , Peruzza Luca , Bargelloni Luca , Martino Maria Elena 
Published: May 2024

AbstractThe microbiome, which encompasses microbial communities associated with animal hosts, exerts a profound impact on host physiology and ecosystem dynamics. The application of advanced sequencing technologies has enabled researchers to investigate the composition of microbiomes across a range of hosts and environments. While correlating microbial composition with health outcomes has been a priority, interpreting such data requires caution to avoid overemphasizing the roles of microbes. Understanding microbial influence demands mechanistic insights, which are often elucidated through gnotobiology. Despite their limitations in representing animal diversity, model organisms offer the advantage of reproducibility and experimental tractability. However, the marine realm, especially bivalves, which are crucial for ecosystem functioning and aquaculture, lacks gnotobiotic models. In this study, we present a method for generating microbiome-depleted and gnotobiotic clams (Ruditapes philippinarum), one of the most widely farmed molluscs in the world and a sentinel organism for climate change. This model expands gnotobiotic research into marine invertebrates, thereby enabling investigations into the impact of microbes on such key animal species.
Electroacupuncture regulates microglia activation through the STING/NF-κB pathway to reduce pain in bone cancer pain model
Authors: Liang Ying , Liu Wenhao , Shen Zhiyi , Yan Xu , He Yihan , Xu Nenggui 
Published: May 2024

AbstractCancer pain is a global public health problem. The mechanism of cancer pain is complex, and opioid analgesics, which are widely used clinically, have obvious addiction and side effects, which seriously affect patients’life functions and may aggravate their anxiety, depression and other negative emotions. Acupuncture has a history of thousands of years in China, and acupuncture analgesia has been confirmed by many studies. This study investigated whether electroacupuncture can alleviate abnormal pain in bone cancer pain (BCP) mouse models and its possible central mechanism. A bone cancer pain model was established by injecting Lewis lung cancer cells into the left femoral cavity of adult male mice. Mechanical paw withdrawal threshold was tested baseline before surgery and 1, 4, 7, 10, 14 and 21 days after surgery. On day 21, behaviours related to depression emotions were tested. After the behaviours, the femurs were removed to observe pathological changes, the neck was broken and brain tissue was collected from the basal lateral amygdala (BLA) area for subsequent Western Blot and ELISA experiments were performed to verify the expression of (stimulator of interferon genes, STING) STING/NF-κB pathway proteins and the expression of inflammatory factors. Immunofluorescence of Ionized calcium-binding adapter molecule-1 (Iba-1) and STING in the basal lateral amygdala (BLA) brain region was also performed. The results show that electroacupuncture can increase the pain threshold of the bone cancer pain model and alleviate the depressive-like emotional phenotype. Electroacupuncture inhibited the expression of STING/NF-κB pathway proteins, activation of microglia and release of inflammatory factors in the basal lateral amygdala (BLA) area. Therefore, this study shows that electroacupuncture may relieve bone cancer pain by regulating microglial activation and inflammatory factor release through the STING/NF-κB pathway.
Modelling the gut microbiota of children with malnutrition:in vitromodels reveal differences in fermentability of widely consumed carbohydrates
Authors: Ahn-Jarvis Jennifer , Corbin Kendall , Harris Suzanne , Rey-Troncoso Perla , Olupot-Olupot Peter , Calder Nuala , Walsh Kevin , Maitland Kathryn , Frost Gary , Warren Frederick J. 
Published: May 2024

AbstractThere is increasing evidence in children suffering from Severe Acute Malnutrition (SAM) that there is disruption of the gut microbiome and low gut microbiota diversity, which may be contributing factors to poor outcomes during nutritional treatment and recovery. The gut microbiome of children with SAM has been demonstrated to have a lower production of beneficial short chain fatty acids, which may contribute to impaired gut barrier function. Recently, several microbiota-directed therapies have been tested in clinical trials in children with SAM. Among them we hypothesized that feeds containing fermentable carbohydrates from various sources (legumes, chicory, milk oligosaccharides) would be fermented to produce beneficial microbial metabolites by the microbiota of children with SAM. In this study we used anin vitromodel system inoculated with stool from children with SAM to investigate the fermentability of four substrates; inulin (a chicory-derived fructan), two milk powders (one supplemented with a human milk oligosaccharide) and a chickpea enriched feed. We demonstrated that while the milk powders and chickpea feed were fermented to produce short chain fatty acids, inulin was only fermented to a very limited degree. Through 16S rRNA sequencing we demonstrated that the samples inoculated with inulin had low microbial diversity and linked this to the limited ability to metabolise inulin. Through revealing the fermentability of different complementary feeds, the findings of this study will be of use for the design of future therapeutic feeds for treatment of SAM.ImportanceMalnutrition is a major contributor to childhood mortality globally and is a major public health problem primarily affecting Lower- and Middle-Income Countries. Despite the development of nutritional recovery therapies, for those with the severe and complicated form of malnutrition (SAM), mortality and relapse rates remain high. Emerging evidence suggests a role for the gut microbiome in these poor outcomes, which is known to be significantly altered in children in SAM, compared to healthy age matched controls. To aid in recovery from SAM, nutritional interventions should be designed to support the gut microbiome, using a range of ingredients targeted for colonic fermentation. It is important to understand the fermentation capacity of the gut microbiome of children with SAM, to design future nutritional interventions. In this work, we demonstrate that inulin, a widely used chicory-derived prebiotic, is not a suitable fermentation substrate for the gut microbiome of SAM children, while legume-based formulations and milk oligosaccharides result in increased production of beneficial metabolites.
Function and contribution of two putativeEnterococcus faecalisglycosaminoglycan degrading enzymes to bacteremia and catheter-associated urinary tract infection
Authors: Johnson Alexandra O. , Shipman Braden M. , Hunt Benjamin C. , Learman Brian S. , Brauer Aimee L. , Zhou Serena P. , Blair Rachael Hageman , De Nisco Nicole J. , Armbruster Chelsie E. 
Published: May 2024

AbstractEnterococcus faecalisis a common cause of healthcare acquired bloodstream infections and catheter associated urinary tract infections (CAUTI) in both adults and children. Treatment ofE. faecalisinfection is frequently complicated by multi-drug resistance. Based on protein homology,E. faecalisencodes two putative hyaluronidases, EF3023 (HylA) and EF0818 (HylB). In other Gram-positive pathogens, hyaluronidases have been shown to contribute to tissue damage and immune evasion, but function inE. faecalishas yet to be explored. Here, we show that bothhylAandhylBcontribute toE. faecalispathogenesis. In a CAUTI model, ΔhylAexhibited defects in bladder colonization and dissemination to the bloodstream, and ΔhylBexhibited a defect in kidney colonization. Furthermore, a ΔhylAΔhylBdouble mutant exhibited a severe colonization defect in a model of bacteremia while the single mutants colonized to a similar level as the wild-type strain, suggesting potential functional redundancy within the bloodstream. We next examined enzymatic activity, and demonstrate that HylB is capable of digesting both HA and CSin vitrowhile HylA exhibits only a very modest activity against heparin. Importantly, HA degradation by HylB provided a modest increase in cell density during stationary phase and also contributed to dampening of LPS-mediated NF-Bκ activation. Overall, these data demonstrate that glycosaminoglycan degradation is important forE. faecalispathogenesis in the urinary tract and during bloodstream infection.