bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel biomechanical indicator for impaired ankle dorsiflexion function during walking in individuals with chronic stroke
Authors: Srivastava Shraddha , Kindred John H , Seamon Bryant A. , Charalambous Charalambos C. , Boan Andrea D. , Kautz Steven A. , Bowden Mark G 
Published: April 2023

AbstractAnkle dorsiflexion function during swing phase of the gait cycle contributes to foot clearance and plays an important role in walking ability post-stroke. Commonly used biomechanical measures such as foot clearance and ankle joint excursion have limited ability to accurately evaluate dorsiflexor function in stroke gait. We retrospectively evaluated ankle angular velocity and ankle angular acceleration as direct measures for swing phase dorsiflexor function in post-stroke gait of 61 chronic stroke survivors. Our linear regression models revealed that peak ankle angular velocity (AAVP), peak ankle angular acceleration (AAAP), peak dorsiflexion angle (DFAP) and peak foot clearance (FCLP) during swing had a significant relationship (p < 0.05) with impaired dorsiflexion function. AAAPand DFAPaccounted for the most variance of dorsiflexion function. Additionally, AAVP, AAAP, FCLPduring swing, correlated significantly with all clinical outcome measures of walking ability. DFAPduring swing had a positive correlation only with FMA-LE. Post-hoc William’st-tests, used to compare the magnitude of difference between two non-independent correlations, revealed that the correlation between all clinical measures and DFAPwere significantly weaker than with AAVPand AAAP. We also found that correlation between FMA-LE and FCLPwas weaker than with AAVPand AAAP. We found an excellent test-retest reliability for both AAVP(ICC = 0.968) and AAAP(ICC = 0.947). These results suggest that DFAPmay only be associated with non-task specific isolated dorsiflexion movement, but not during walking. FCLPis associated with dorsiflexion function and walking ability measures but not as strongly as AAVPand AAAPpossibly because FCLPis influenced by contribution from hip and knee joint movements during walking. Therefore, we believe that AAVPand AAAPboth can be used as reliable measures of impaired dorsiflexion function in post-stroke gait.
Semantic Representation of Neural Circuit Knowledge inCaenorhabditis elegans
Authors: Prakash Sharan J. , Van Auken Kimberly M. , Hill David P. , Sternberg Paul W. 
Published: April 2023

AbstractIn modern biology, new knowledge is generated quickly, making it challenging for researchers to efficiently acquire and synthesise new information from the large volume of primary publications. To address this problem, computational approaches that generate machine-readable representations of scientific findings in the form of knowledge graphs have been developed. These representations can integrate different types of experimental data from multiple papers and biological knowledge bases in a unifying data model, providing a complementary method to manual review for interacting with published knowledge. The Gene Ontology Consortium (GOC) has created a semantic modelling framework that extends individual functional gene annotations to structured descriptions of causal networks representing biological processes (Gene Ontology Causal Activity Modelling, or GO-CAM). In this study, we explored whether the GO-CAM framework could represent knowledge of the causal relationships between environmental inputs, neural circuits and behavior in the model nematodeC. elegans(C. elegansNeural Circuit Causal Activity Modelling (CeN- CAM)). We found that, given extensions to several relevant ontologies, a wide variety of author statements from the literature about the neural circuit basis of egg-laying and carbon dioxide (CO2) avoidance behaviors could be faithfully represented withCeN-CAM. Through this process, we were able to generate generic data models for several categories of experimental results. We also discuss how semantic modelling may be used to functionally annotate theC. elegansconnectome. Thus, Gene Ontology-based semantic modelling has the potential to support various machine-readable representations of neurobiological knowledge.Graphical Abstract
Anin vitroassay to investigate venom neurotoxin activity on muscle-type nicotinic acetylcholine receptor activation and for the discovery of toxin-inhibitory molecules
Authors: Patel Rohit N , Clare Rachel H , Ledsgaard Line , Nys Mieke , Kool Jeroen , Laustsen Andreas H , Ulens Chris , Casewell Nicholas R 
Published: April 2023

AbstractSnakebite envenoming is a neglected tropical disease that causes over 100,000 deaths annually. Envenomings result in variable pathologies, but systemic neurotoxicity is among the most serious and is currently only treated with difficult to access and variably efficacious commercial antivenoms. Venom-induced neurotoxicity is often caused by α-neurotoxins antagonising the muscle-type nicotinic acetylcholine receptor (nAChR), a ligand-gated ion channel. Discovery of therapeutics targeting α-neurotoxins is hampered by relying on binding assays that do not reveal restoration of receptor activity or more costly and/or lower throughput electrophysiology-based approaches. Here, we report the validation of a screening assay for nAChR activation using immortalised TE671 cells expressing the γ-subunit containing muscle-type nAChR and a fluorescent dye that reports changes in cell membrane potential. Assay validation using traditional nAChR agonists and antagonists, which either activate or block ion fluxes, was consistent with previous studies. We then characterised antagonism of the nAChR by a variety of elapid snake venoms that cause muscle paralysis in snakebite victims, before defining the toxin-inhibiting activities of commercial antivenoms, and new types of snakebite therapeutic candidates, namely monoclonal antibodies, decoy receptors, and small molecules. Our findings show robust evidence of assay uniformity across 96-well plates and highlight the amenability of this approach for the future discovery of new snakebite therapeutics via screening campaigns. The described assay therefore represents a useful first-step approach for identifying α-neurotoxins and their inhibitors in the context of snakebite envenoming, and it should provide wider value for studying modulators of nAChR activity from other sources.
Radio-Immune Response Modelling for Spatially Fractionated Radiotherapy
Authors: Cho Young-Bin , Yoon Nara , Suh John H. , Jacob Scott G. 
Published: April 2023

AbstractRadiation-induced cell death is a complex process influenced by physical, chemical and biological phenomena. Strong dose gradient may intensify the complexity and reportedly creates significantly more cell death known as bystander effect. Although consensus on the nature and the mechanism of the bystander effect were not yet made, the immune process presumably plays an important role in many aspects of the radiotherapy including the bystander effect. Immune response of host body and immune suppression of tumor cells are modelled with four compartments in this study; viable tumor cells, T cell lymphocytes, immune triggering cells, and doomed cells. The growth of tumor was analyzed in two distinctive modes of tumor status (immune limited and immune escape) and its bifurcation condition. Tumors in the immune limited mode can grow only up to a finite size, named as terminal tumor volume analytically calculated from the model. The dynamics of the tumor growth in the immune escape mode is much more complex than the tumors in the immune limited mode especially when the status of tumor is close to the bifurcation condition. Radiation can kill tumor cells not only by radiation damage but also by boosting immune reaction. The model demonstrated that the highly heterogeneous dose distribution in spatially fractionated radiotherapy (SFRT) can make a drastic difference in tumor cell killing compared to the homogeneous dose distribution. SFRT can not only enhance but also moderate the cell killing depending on the immune response triggered by many factors such as dose prescription parameters, tumor volume at the time of treatment and tumor characteristics. The model was applied to the lifted data of 67NR tumors on mice and a sarcoma patient treated multiple times over 1200 days for the treatment of tumor recurrence as a demonstration.
PersonalizedClostridioides difficileengraftment risk prediction and probiotic therapy assessment in the human gut
Authors: Carr Alex , Baliga Nitin S. , Diener Christian , Gibbons Sean M. 
Published: April 2023

AbstractClostridioides difficilecolonizes up to 30-40% of community-dwelling adults without causing disease.C. difficileinfections (CDIs) are the leading cause of antibiotic-associated diarrhea in the U.S. and typically develop in individuals following disruption of the gut microbiota due to antibiotic or chemotherapy treatments. Further treatment of CDI with antibiotics is not always effective and can lead to antibiotic resistance and recurrent infections (rCDI). The most effective treatment for rCDI is the reestablishment of an intact microbiota via fecal microbiota transplants (FMTs). However, the success of FMTs has been difficult to generalize because the microbial interactions that prevent engraftment and facilitate the successful clearance ofC. difficileare still only partially understood. Here we show how microbial community-scale metabolic models (MCMMs) accurately predicted known instances ofC. difficilecolonization susceptibility or resistancein vitroandin vivo. MCMMs provide detailed mechanistic insights into the ecological interactions that governC. difficileengraftment, like cross-feeding or competition involving metabolites like succinate, trehalose, and ornithine, which differ from person to person. Indeed, three distinctC. difficilemetabolic niches emerge from our MCMMs, two associated with positive growth rates and one that represents non-growth, which are consistently observed across 15,204 individuals from five independent cohorts. Finally, we show how MCMMs can predict personalized engraftment andC. difficilegrowth suppression for a probiotic cocktail (VE303) designed to replace FMTs for the treatment rCDI. Overall, this powerful modeling approach predicts personalizedC. difficileengraftment risk and can be leveraged to assess probiotic treatment efficacy. MCMMs could be extended to understand the mechanistic underpinnings of personalized engraftment of other opportunistic bacterial pathogens, beneficial probiotic organisms, or more complex microbial consortia.
BCAT1 regulates glioblastoma cell plasticity and contributes to immunosuppression
Authors: Boskovic Pavle , Wilke Nathalie , Lichter Peter , Francois Liliana , Radlwimmer Bernhard 
Published: April 2023

AbstractGlioblastoma is the most common malignant brain tumor in adults. Cellular plasticity and the poorly differentiated features result in a fast relapse of the tumors following treatment. Moreover, the immunosuppressive microenvironment proved to be a major obstacle to immunotherapeutic approaches. Branched-chain amino acid transaminase 1 (BCAT1) is a metabolic enzyme that converts branched-chain amino acids into branched-chain keto acids, depleting cellular α-ketoglutarate and producing glutamate. BCAT1 is expressed in and drives the growth of glioblastoma and other cancers. Here we show that low-BCAT1 expression correlates with differentiated glioblastoma subtypes and its knockout (KO) results in a differentiated phenotype in human and mouse glioblastoma cells. Consistent with these observations, Bcat1-KO mouse glioblastoma cells were highly susceptible to serum-induced differentiationin vitro. The transition to a differentiated cell state was linked to the increased activity of TET demethylases and the hypomethylation and activation of neuronal differentiation genes. Orthotopic tumor injection into immunocompetent mice demonstrated that the brain microenvironment is sufficient to induce differentiation of Bcat1-KO tumorsin vivo. In addition, the knockout of Bcat1 attenuated immunosuppression, allowing for an extensive infiltration of CD8+cytotoxic T-cells and complete abrogation of tumor growth. Additional analysis in immunodeficient hosts revealed that both Bcat1-KO-induced differentiation and immunomodulation contribute to the long-term suppression of tumor growth. In summary, our study demonstrates that BCAT1 promotes glioblastoma growth by blocking tumor cell differentiation and sustaining an immunosuppressive microenvironment. These findings suggest novel modes limiting glioblastoma phenotypic plasticity and therapeutic failure through targeting BCAT1.Importance of the studyHigh expression of BCAT1 occurs in many tumor entities and is related to aggressiveness, proliferation and invasion of tumor cells. In this study, we show that its expression is crucial for the continuous growth of glioblastoma cells by preventing their differentiation. Furthermore, we show that the expression of BCAT1 modulates the tumor immune microenvironment, suppressing the CD8 T-cell response. BCAT1 knockout causes glioblastoma cell differentiation and a persistent CD8 T-cell response, which is sufficient to abrogate tumor growth and prolong survival inin vivoimmunocompetent and immunodeficient models, respectively. Our findings consolidate BCAT1 as a major player in glioblastoma and highlight its importance as a potential future target of research in this and other tumor entities.Key PointsBCAT1 expression maintains poorly differentiated features of glioblastoma cells and provides resistance to differentiation.Expression of BCAT1 in glioblastoma cells contributes to the immunosuppressive features of the tumor.
The Genome-wide Signature of Short-term Temporal Selection
Authors: Lynch Michael , Wei Wen , Ye Zhiqiang , Pfrender Michael 
Published: April 2023

AbstractDespite evolutionary biology’s obsession with natural selection, few studies have evaluated multi-generational series of patterns of selection on a genome-wide scale in natural populations. Here, we report on a nine-year population-genomic survey of the microcrustaceanDaphnia pulex.The genome-sequences of > 800 isolates provide insights into patterns of selection that cannot be obtained from long-term molecular-evolution studies, including the pervasiveness of near quasi-neutrality across the genome (mean net selection coefficients near zero, but with significant temporal variance about the mean, and little evidence of positive covariance of selection across time intervals), the preponderance of weak negative selection operating on minor alleles, and a genome-wide distribution of numerous small linkage islands of observable selection influencing levels of nucleotide diversity. These results suggest that fluctuating selection is a major determinant of standing levels of variation in natural populations, challenge the conventional paradigm for interpreting patterns of nucleotide diversity and divergence, and motivate the need for the development of new theoretical expressions for the interpretation of population-genomic data.SignificanceExcept for mono/oligogenic traits known in advance to be under strong selection, there is little information on genome-wide patterns of temporal dynamics of allele-frequency changes in well-defined and unmanipulated natural populations. A multi-year survey of a population of the microcrustaceanDaphnia pulexprovides insight into these matters. Genome-wide analysis of > 800 genetic isolates demonstrates that temporal variation in selection intensity is a major determinant of levels of nucleotide polymorphism and divergence. Most nucleotide sites experience fluctuating selection with mean selection coefficients near zero, with little covariance in the strength of selection across time intervals, and with selection distributed across large numbers of genomic islands of linked sites. These results raise challenges for the conventional interpretation of measures of nucleotide diversity and divergence as indicators of effective population sizes and intensities of positive/negative selection.
Cortical parvalbumin neurons are responsible for homeostatic sleep rebound through CaMKII activation
Authors: Kon Kazuhiro , Ode Koji L. , Mano Tomoyuki , Fujishima Hiroshi , Tone Daisuke , Shimizu Chika , Shiono Shinnosuke , Yada Saori , Garçon Junko Yoshida , Kaneko Mari , Shinohara Yuta , Takahashi Riina R. , Yamada Rikuhiro G. , Shi Shoi , Sumiyama Kenta , Kiyonari Hiroshi , Susaki Etsuo A. , Ueda Hiroki R. 
Published: April 2023

AbstractThe homeostatic regulation of sleep is characterized by rebound sleep after prolonged wakefulness, but the molecular and cellular mechanisms underlying this regulation are still unknown. We show here that CaMKII-dependent activity control of parvalbumin (PV)-expressing cortical neurons is involved in sleep homeostasis regulation. Prolonged wakefulness enhances cortical PV-neuron activity. Chemogenetic suppression or activation of cortical PV neurons inhibits or induces rebound sleep, implying that rebound sleep is dependent on increased activity of cortical PV neurons. Furthermore, we discovered that CaMKII kinase activity boosts the activity of cortical PV neurons, and that kinase activity is important for homeostatic sleep rebound. We propose that CaMKII-dependent PV-neuron activity represents negative feedback inhibition of cortical neural excitability, which serves as the distributive cortical circuits for sleep homeostatic regulation.
Differentiation of Large Extracellular Vesicles in Oral Fluid: Combined Protocol of Small Force Centrifugation and Pattern Analysis
Authors: Kawano Takamasa , Okamura Kohji , Shinchi Hiroki , Ueda Koji , Takeshi Nomura , Shiba Kiyotaka 
Published: April 2023

AbstractExtracellular vesicles (EVs) in biofluids are highly heterogeneous entities in terms of their origins and physicochemical properties. Considering the application of EVs in diagnostic and therapeutic fields, it is of extreme importance to establish differentiating methods by which focused EV subclasses are operationally defined. Several differentiation protocols have been proposed; however, they have mainly focused on smaller types of EVs, and the heterogeneous nature of large EVs has not yet been fully explored. In this report, to classify large EVs into subgroups based on their physicochemical properties, we have developed a protocol, named EV differentiation by sedimentation patterns (ESP), in which entities in the crude large EV fraction are first moved through a density gradient of iodixanol with small centrifugation forces, and then the migration patterns of molecules through the gradients are analyzed using a non-hierarchical data clustering algorithm. Based on this method, proteins in the large EV fractions of oral fluids clustered into three groups: proteins shared with small EV cargos and enriched in immuno-related proteins (Group 1), proteins involved in energy metabolism and protein synthesis (Group 2), and proteins required for vesicle trafficking (Group 3). These observations indicate that the physiochemical properties of EVs, which are defined through low-speed gradient centrifugation, are well associated with their functions within cells. This protocol enables the detailed subclassification of EV populations that are difficult to differentiate using conventional separation methods.
The outer membrane and peptidoglycan layer form a single mechanical device balancing turgor
Authors: Deghelt Michaël , Cho Seung-Hyun , Govers Sander K. , Janssens Arne , Dachsbeck Alix , Remaut Han K. , Collet Jean-François 
Published: April 2023

ABSTRACTBacteria are subject to a substantial concentration differential of osmolytes between the interior and exterior of the cell, which results in cytoplasmic turgor pressure. Failure to mechanically balance turgor pressure causes cells to burst. Here, we show that in Gram-negative bacteria, the outer membrane and peptidoglycan layer function together to resist turgor: when attached to each other, these two layers form a robust mechanical unit that allows pressure build-up in the periplasmic compartment, which in turn balances cytoplasmic turgor across the inner membrane, preventing cell death. Thus, the peptidoglycan layer is necessary but not sufficient to maintain turgor, which challenges the general view that protecting cells from bursting is the specific task of the peptidoglycan cell wall.ONE-SENTENCE SUMMARYThe peptidoglycan and outer membrane are interconnected layers that cooperate to balance cytoplasmic turgor.
To deliberate, remember; to anticipate, forget: Cognitive deliberation profiles underpinning active forgetting-dependent everyday-like memory performance in young and aged mice
Authors: Stevens Christopher , Al Abed Shaam , Sellami Azza , Ducourneau Eva , Lacroix Cathy , Bouchet Mathilde , Roudier Faustine , Marsicano Giovanni , Marighetto Aline 
Published: April 2023

AbstractRecalling a specific past episode that will enable us to decide which action is suited to a given present situation is a core element of everyday life. A wealth of research has demonstrated that such selective remembering is dependent upon a capacity to inhibit or provisionally ‘forget’ related yet inappropriate memory episodes which could orient behavior in unwilled directions. Everyday-like memory (EdM) refers to this type of common organizational mnemonic capacity, known to deteriorate significantly with age, putatively as a result of decline in the cognitive capacity for selective inhibition or ‘active forgetting’. Moreover, this memory retrieval-concomitant active forgetting comes at the cost of genuine amnesic weakening of the inhibited episodes, a phenomenon referred to as retrieval-induced forgetting (RIF). In the present study, we introduce a novel characterization of our previously validated mouse model of EdM in terms of the existing active forgetting and RIF literature. We also introduce novel behavioral analyses of the deliberation processes elicited by EdM challenge and use detailed multi-factorial explorations to reveal how these processes are impacted by age, temporal retention demand, difficulty of EdM challenge, and anticipation of trial outcome. Our observations indicate that deliberation requires remembering while accurate anticipation—in which a critical age-related deficit is also observed—requires active forgetting. Our results represent a significant advance towards unifying our understanding of the neurocognitive processes underpinning everyday-like memory, RIF, mnemonic deliberation, anticipatory function, and how they all are impacted by the physiological ageing process. In parallel, we present preliminary results using a transgenic mouse model which point to a fundamental role for the endocannabinoid system (eCS) in active forgetting and EdM, thereby demonstrating that deeper investigation of previously characterized age-related decline of the eCS should be a pre-clinical priority with a view to developing treatments for age-related decline of EdM function.
Per-pixel unmixing of spectrally overlapping fluorophores using intra-exposure excitation modulation
Authors: Valenta Hana , Bierbuesse Franziska , Vitale Raffaele , Ruckebusch Cyril , Vandenberg Wim , Dedecker Peter 
Published: April 2023

AbstractMultilabel fluorescence imaging is essential for the visualization of complex systems, though a major challenge is the limited width of the usable spectral window. Here, we present a new method, exNEEMO, that enables per-pixel quantification of spectrally-overlapping fluorophores based on their light-induced dynamics, in a way that is compatible with a very broad range of timescales over which these dynamics may occur. Our approach makes use of intra-exposure modulation of the excitation light to distinguish the different emitters given their reference responses to this modulation. We use approach to simultaneously image four green photochromic fluorescent proteins at the full spatial resolution of the imaging.Graphical abstract