bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optochemical profiling of NMDA receptor molecular diversity at synaptic and extrasynaptic sites
Authors: Sicard Antoine , Tian Meilin , Mostefai Zakaria , Shi Sophie , Cardoso Cécile , Zamith Joseph , McCort-Tranchepain Isabelle , Charrier Cécile , Paoletti Pierre , Mony Laetitia 
Published: October 2024

AbstractNeurotransmitter receptors are the linchpin of neuronal communication. These receptors often form large multimeric complexes that differ in their subunit composition, distribution and signaling properties. Studying individual subtypes in native tissues with subunit stoichiometry resolution remains challenging. This is the case of NMDA receptors (NMDARs), a class of glutamate-gated ion channels playing essential roles in brain development and plasticity. These receptors co-exist as multiple subtypes, with GluN1/GluN2A (GluN2A diheteromers), GluN1/GluN2B (GluN2B diheteromers) and GluN1/GluN2A/GluN2B (GluN2A/GluN2B triheteromers) receptors prevailing in the adult forebrain. Despite numerous investigations, the relative abundance and subcellular distribution of these subtypes remain contentious. Here, we designed a photochemical tool (Opto2B) enabling specific and reversible modulation of GluN2B diheteromers, while leaving other receptor subtypes unaffected (in particular GluN2A/GluN2B tri-heteromers). Using Opto2B, we established the differential contribution of GluN2B diheteromers to synaptic and extrasynaptic NMDAR pools during development. In particular, we show that in adult hippocampal CA1 pyramidal cells, GluN2A-receptors predominate in both pools, with no preferential contribution of GluN2B diheteromers to extrasynaptic currents. Our study clarifies decades of controversial research on extrasynaptic NMDARs and paves the way for interrogating NMDAR signaling diversity with unprecedented molecular and spatio-temporal resolution.Significance StatementPharmacological and genetic approaches, the gold standards for investigating receptor diversity, cannot easily distinguish between receptor populations containing one or more copies of the same subunit. For NMDARs, discriminating GluN2A/GluN2B triheteromers (containing one copy of GluN2A and one copy of GluN2B) from their diheteromeric counterparts (containing two copies of GluN2A or GluN2B) remains difficult. Here, we designed the first tool (Opto2B) allowing selective modulation of GluN2B diheteromers, leaving GluN2A/GluN2B triheteromers unaffected. Using Opto2B, we show that GluN2B diheteromers form a minor population in both synaptic and extrasynaptic compartments of the adult CA1 hippocampus, refuting the common belief of an enrichment of GluN2B diheteromers at extrasynaptic sites. This study should inform future drug discovery programs and studies on NMDAR molecular physiology.
Incorporating climatic extremes using the GEV distribution improves SDM range edge performance
Authors: Fonteyn Ward , Serra-Diaz Josep M. , Muys Bart , Van Meerbeek Koenraad 
Published: October 2024

AbstractAimThe changing frequency and intensity of climatic extremes due to climate change can have sudden and adverse impacts on the distribution of species. While species distribution modelling is a vital tool in ecological applications, current approaches fail to fully capture the distribution of climatic extremes, particularly of rare events with the most disruptive potential. Especially at the edges of species’ ranges, where conditions are already less favourable, predictions might be inaccurate when these extremes are not well represented.LocationEuropeTaxonTree speciesMethodsWe present a novel approach to integrate extreme events into species distribution models based on the generalised extreme value (GEV) distribution. This distribution, following from the extreme value theory has been established as a valuable tool in analysing climatic extremes, both in an ecological context and beyond. The approach relying on the GEV distribution is broadly applicable, readily transferable across species and relies on widely available data. We demonstrate the efficacy of our approach for 28 European tree species, illustrating its superior ability to fully capture the distribution of climatic extremes compared to state-of-the-art methods.ResultsWe found that incorporating parameters on climatic extremes derived from the GEV distribution increased model performance (AICmodel) and characterized range edges more accurately (AUCedge) compared to competing approaches. However, general AUC values were only marginally increased across the species and study period analysed. Overall, the GEV model predicted a narrower niche for the species included in this study.Main conclusionsIncorporating climatic extremes can impact spatial predictions of species distribution models, especially at range margins. We found that using the GEV distribution to characterise extreme variables in SDMs yields the best performance at these distribution edges. Given the importance of range edges for species conservation, a detailed inclusion of extremes in SDMs employed for those applications will help ensure robust conclusions.
Prefoldin 5 is a microtubule-associated protein that suppresses Tau-aggregation and neurotoxicity
Authors: Bisht Anjali , Pippadpally Srikanth , Majumder Snehasis , Gopi Athulya T , Das Abhijit , Sahi Chandan , Ramaswami Mani , Kumar Vimlesh 
Published: October 2024

AbstractTauopathies represent a major class of neurodegenerative disorders associated with intracellular aggregates of the microtubule-associated protein Tau. To identify molecular modulators of Tau toxicity, we used a genetic screen to identify protein chaperones whose RNAi-mediated knockdown could modulate hTauV337M-induced eye-ommatidial degeneration inDrosophila. This screen identified the Prefoldins Pfdn5 and Pfdn6 as strong modifiers of hTauV337Mcytotoxicity. Consistent with the known function of Pfdn as a cotranslational chaperone for tubulin,Pfdn5mutants showed substantially reduced levels of tubulin monomer. However, additional microtubule-related functions were indicated by the robust unexpected association of Pfdn5 with axonal microtubulesin vivo,as well as binding with stabilized microtubules in biochemical assays. Loss of Pfdn5 resulted in neuromuscular junctions (NMJ) defects similar to those previously described in hTau-expressing flies: namely, increased supernumerary boutons and fewer microtubule loops within mature presynaptic boutons. Significantly, synaptic phenotypes caused by hTauV337Moverexpression were also strongly enhanced in aPfdn5mutant background. Consistent with a role in modulating Tau toxicity, not only did loss ofPfdn5result in increased accumulations of Tau-aggregates in hTauV337Mexpressing neurons, but also neuronal overexpression of Prefoldin strikingly ameliorated age-dependent neurodegeneration and memory deficits induced by pathological hTau. Together, these and other observations described herein: (a) provide new insight into Prefoldin-microtubule interactions; (b) point to essential posttranslational roles for Pfdn5 in controlling Tau-toxicityin vivo; and (c) demonstrate that Pfdn5 overexpression is sufficient to restrict Tau-induced neurodegeneration.
Integrative profiling of condensation-prone RNAs during early development
Authors: Klobučar Tajda , Novljan Jona , Iosub Ira A. , Kokot Boštjan , Urbančič Iztok , Jones D. Marc , Chakrabarti Anob M. , Luscombe Nicholas M. , Ule Jernej , Modic Miha 
Published: October 2024

SummaryComplex RNA–protein networks play a pivotal role in the formation of many types of biomolecular condensates. How intrinsic RNA features contribute to condensate formation however remains unclear. Here, we integrate tailored transcriptomics assays to identify a distinct class of developmental condensation-prone RNAs termed ‘smOOPs’ (semi-extractable,orthogonalorganicphaseseparation-enriched RNAs). These transcripts are localised to larger intracellular foci, form denser RNA-RNA interaction subnetworks than expected and are heavily bound by RNA binding proteins (RBPs). Using an explainable deep learning framework, we reveal that smOOPs harbor characteristic sequence composition with lower sequence complexity, increased intramolecular folding and specific RBP binding patterns. Intriguingly, these RNAs encode proteins bearing extensive intrinsically disordered regions and are markedly predicted to be involved in biomolecular condensates, indicating an interplay between RNA- and protein-based features in phase separation. This work advances our understanding of condensation-prone RNAs and provides a versatile resource to further investigate RNA-driven condensation principles.
Cell shape noise strength regulates the rate of shape change during EMT-associated cell spreading
Authors: Pönisch Wolfram , Yanakieva Iskra , Salbreux Guillaume , Paluch Ewa K. 
Published: October 2024

ABSTRACTCellular shape is intimately linked to cell function and state, and transitions between cell states are tightly coupled to shape changes. Yet, shape has been largely overlooked in state transitions studies. Here, we combine morphometric analysis with theoretical modeling and molecular perturbations to interrogate cell shape dynamics during epithelial-to-mesenchymal transition (EMT). Using stochastic inference, we extract the morphogenetic landscape underlying EMT. We show that within this landscape, EMT-associated cell spreading reflects a transition between shape attractors. Strikingly, we observe a peak in cell shape noise strength concomitant with spreading, and show that higher shape noise accelerates transitions between shape attractors. Our morphometric analysis framework will be widely applicable to quantitative cell shape investigations in physiology and disease. Together, our results identify a key role for cellular stochasticity as a regulator of shape change rate, and highlight that shape dynamics yield rich phenotypic information that enhances our understanding of cellular states.
Reasoning by exclusion in food-caching Eurasian jays (Garrulus glandarius)
Authors: Hawkins Isobelle , Huemer Michael , Carey Susan , Clayton Nicola S. 
Published: October 2024

AbstractTwo related methods have been widely used to test animals’ capacity to reason by exclusion: Call’s (2004) 2-cups task, where subjects choose between two cups in which one reward was hidden and the empty cup is revealed; and Premack & Premack’s task (1994) where one reward goes in each of the two cups and one reward is removed. In both cases, success is identifying the cup with the reward. It has been suggested that among corvids, the demands associated with caching may foster exclusion abilities by reinforcing the experience of relevant contraries (e.g., empty vs. full), or by supporting domain general capacities that support caching and exclusion inferences. However, Shaw et al. (2013) found that Eurasian jays, proficient cachers, failed a version of Call’s 2-cups task. To further test the caching hypothesis, we amended the procedure using invisible displacement to hide rewards, removing aspects of Shaw et al.’s procedure that may have masked competence of Eurasian jays. We tested seven Eurasian jays, who showed spontaneous success on both Call’s 1-reward/show-empty (80% correct) and Premack and Premack’s 2-reward/remove-1 (85% correct). These results align with the hypothesis that corvids’ exclusion reasoning is related to caching behaviour.
Greater distal activation of the biceps femoris long head reflects proximodistal differences in motor unit action potential properties
Authors: Albarello José Carlos dos Santos , Cabral Hélio V. , Negro Francesco , de Oliveira Liliam Fernandes 
Published: October 2024

AbstractPurposeRecent research has explored region-specific responses within the biceps femoris long head. However, evidence on regional muscle activation remains controversial, primarily because information derived solely from surface electromyograms (sEMG) amplitude does not necessarily provide an accurate estimate of neural drive to the muscle. To address this limitation, this study investigated whether there are proximodistal differences in motor unit properties of the biceps femoris long head during isometric hip extension and knee flexion tasks.MethodsSeventeen resistance-trained males performed isometric knee flexion and hip extension tasks at 20% and 40% of maximal voluntary contraction. High-density sEMG were recorded from proximal and distal regions of the biceps femoris long head and decomposed into individual motor units. Central motor unit properties (mean discharge rate, discharge rate variability, recruitment and de-recruitment thresholds) and action potential properties (amplitude and conduction velocity) were analyzed. Bipolar sEMG amplitude was also calculated for each region to simulate traditional sEMG measurements.ResultsBipolar sEMG amplitude, motor unit action potential amplitude and conduction velocity were significantly greater in the distal region during both tasks. In contrast, no proximodistal differences were observed in central motor unit properties.ConclusionThese findings suggest that increased bipolar sEMG amplitude in the distal region of the biceps femoris long head is driven by motor unit action potential properties rather than differences in central modulation, likely influenced by intra-muscular variations in muscle mechanics and geometry. This emphasizes limitations of relying solely on sEMG amplitude to infer neural control strategies in the biceps femoris long head.
ATP-gated P2x7 receptor is a major channel type at type II auditory nerves and required for hearing sensitivity efferent controlling and noise protection
Authors: Liang Chun , Zhai Tian-Ying , Fang Shu , Chen Jin , Liu Li-Man , Yu Ning , Zhao Hong-Bo 
Published: October 2024

AbstractHearing sensitivity and noise protection are mediated and determined by negative feedback of the cochlear efferent system. Type II auditory nerves (ANs) innervate outer hair cells (OHCs) in the cochlea and provide an input to this efferent control. However, little is known about underlying channel information. Here, we report that ATP-gated P2x7 receptor had a predominant expression at type II ANs and the synaptic areas under inner hair cells and OHCs with lateral and medial olivocochlear efferent nerves. Knockout (KO) of P2x7 increased hearing sensitivity with enhanced acoustic startle response (ASR), auditory brainstem response (ABR), and cochlear microphonics (CM) by increasing OHC electromotility, an active cochlear amplifier in mammals. P2x7 KO also increased susceptibility to noise. Middle level noise exposure could impair active cochlear mechanics resulting in permanent hearing loss in P2x7 KO mice. These data demonstrate that P2x7 receptors have a critical role in type II AN function and the cochlear efferent system to control hearing sensitivity; deficiency of P2x7 receptors can impair the cochlear efferent suppression leading to hearing oversensitivity and susceptibility to noise.
Soluble TIM-3, likely produced by myeloid cells, predicts resistance to immune checkpoint inhibitors in metastatic clear cell renal cell carcinoma
Authors: Pourmir Ivan , Benhamouda Nadine , Tran Thi , Roux Hugo , Pineau Joséphine , Gey Alain , Munoz Andyara , Mabrouk Nesrine , Epaillard Nicolas , Verkarre Virginie , Vano Yann-Alexandre , Tartour Eric , Oudard Stéphane 
Published: October 2024

AbstractBackground and objectivesImmunotherapies targeting PD-1 and CTLA-4 are key components of the treatment of metastatic clear cell renal cell carcinoma (mccRCC). However, they have distinct safety profiles and resistance to treatment can occur. We assess soluble TIM-3 (sTIM-3) in the plasma of mccRCC patients as a potential theranostic biomarker, as well as its source and biological significance.MethodsWe analyzed the association of sTIM-3 with overall survival (OS), tumor response, and common clinical and biological factors across two mccRCC cohorts treated with anti-PD-1 (n = 27), anti- PD-1 or anti-PD-1 + anti-CTLA-4 (n = 124). The origin and role of sTIM-3 are studied on tumor and blood samples, using multiplex immunohistochemistry and flow cytometry as well as a syngeneic tumor model with antitumor vaccination. We also reanalyzed publicly available single-cell transcriptomic (scRNAseq) data and mass cytometry data.Key findings and limitationssTIM-3 is elevated in the plasma of patients with mccRCC and shows distinct associations with survival on anti-PD-1 vs anti-PD-1 + anti-CTLA-4. sTIM-3 is independent from other clinical and biological factors. Myeloid immune cells appear as the prominent source of sTIM-3, which may indicate their dysfunctional role in the antitumor immune response. Future investigations are warranted in patients treated with anti-PD-1 + antiangiogenic therapies. Further functional studies are needed to confirm its theranostic value and clarify its role in the immune response.Conclusions and clinical implicationssTIM-3 appears to be a promising biomarker for optimizing treatment strategies in ccRCC as well as a potential therapeutic target.
Diversification of Dentate Gyrus Granule Cell Subtypes is Regulated by Neuregulin1 Nuclear Back Signaling
Authors: Rajebhosale Prithviraj , Jiang Li , Ressa Haylee J. , Johnson Kory R. , Desai Niraj , Jone Alice , Role Lorna W. , Talmage David A. 
Published: October 2024

SummaryNeuronal heterogeneity is a defining feature of the developing mammalian brain, but the mechanisms regulating the diversification of closely related cell types remain elusive. In this study, we investigated the heterogeneity of dentate gyrus (DG) granule cells (GCs) and the influence of a psychosis associated V321L mutation in Neuregulin1 (Nrg1) on GC subtype composition. Using morpho-electric characterization, single-nucleus gene expression, and chromatin accessibility profiling, we identified distinct morphological and molecular features of typical GCs and a rare subtype known as semilunar granule cells (SGCs). The V321L mutation disrupts Nrg1 nuclear back-signaling, resulting in an overabundance of SGC-like cells. We discovered pseudotime gene expression trajectories suggesting the potential for GC-to-SGC transitions, supported by the accessibility of SGC-specific genes in other GCs. Intriguingly, we found an increase in SGC-marker expression over the adolescence to adulthood transition window in wild-type mice, coinciding with a decline in Nrg1 nuclear back-signaling capacity. This suggests that intact Nrg1 signaling suppresses SGC-like fate acquisition, and that its natural downregulation may underlie the emergence of SGC-like cells during postnatal development. Similarly, a pathological block of nuclear back signaling by the V321L mutation in Nrg1, may result in acquisition of the SGC-like fate due to loss of the repressive mechanisms maintained by intact nuclear back signaling. Our findings reveal a novel role for Nrg1 in maintaining DG cell-type composition and suggest that disrupted subtype regulation may contribute to disease-associated changes in DG GC morphology and function. Understanding these mechanisms provides new insights into mechanisms of cell-type diversity and its potential role in psychiatric pathology.
Synchrony dynamics underlie irregular neocortical spiking
Authors: Pattadkal Jagruti J. , O’Shea Ronan T , Hansel David , Taillefumier Thibaud , Brager Darrin , Priebe Nicholas J. 
Published: October 2024

AbstractCortical neurons are characterized by their variable spiking patterns. We challenge prevalent theories for the origin of spiking variability. We examine the specific hypothesis that cortical synchrony drives spiking variabilityin vivo. Using dynamic clamp, we demonstrate that intrinsic neuronal properties do not contribute substantially to spiking variability, but rather spiking variability emerges from weakly synchronous network drive. With large-scale electrophysiology we quantify the degree of synchrony and its time scale in cortical networksin vivo. We demonstrate that physiological levels of synchrony are sufficient to generate irregular responses foundin vivo. Further, this synchrony shifts over timescales ranging from 25 to 200 ms, depending on the presence of external sensory input. Such shifts occur when the network moves from spontaneous to driven modes, leading naturally to a decline in response variability as observed across cortical areas. Finally, while individual neurons exhibit reliable responses to physiological drive, different neurons respond in a distinct fashion according to their intrinsic properties, contributing to stable synchrony across the neural network.
SERPINB5-TGF-β signalling modulates desmoplakin membrane localization and ameliorates pemphigus vulgaris skin blistering
Authors: Rathod Maitreyi , Zimmermann Aude , Franz Henriette , Cunha Tomás , Didona Dario , Hertl Michael , Schmidt Enno , Spindler Volker 
Published: October 2024

AbstractImpairment of desmosomal cell-cell adhesion leads to several life-threatening diseases such as the autoimmune skin blistering disorder pemphigus vulgaris (PV). Disease management strategies that stabilize intercellular adhesion, in addition to the existing immunosuppression therapies, may result in improved clinical outcomes. Previous findings showed that the serine protease inhibitor SERPINB5 promotes intercellular adhesion by binding to and regulating the localization of the desmosomal adapter molecule desmoplakin (DSP) at the plasma membrane. We here show that SERPINB5 overexpression prevents PV-IgG-mediated loss of cell-cell adhesion and the loss of DSP from the cell membrane. We mechanistically demonstrate that SERPINB5 loss deregulates TGF-β signalling, a pathway known to destabilize DSP in keratinocytes. TGF-β signalling was also activated in skin biopsies of PV patients and keratinocytes treated with PV autoantibodies, suggesting a contribution to disease. Inhibition of TGF-β activation ameliorated PV-IgG-mediated loss of cell-cell adhesion, increased DSP membrane expression, and prevented PV-IgG-induced blister formation in a humanex-vivoskin model. Together, SERPINB5 modulates DSP and intercellular adhesion through the regulation of TGF-β signalling. Further, TGF-β signalling was identified as a potential target for pemphigus treatment.
Dynamic Multiday Seizure Cycles and Evolving Rhythms in a Tetanus Toxin Rat Model of Epilepsy
Authors: Zarei Eskikand Parvin , Cook Mark J. , Burkitt Anthony N. , Grayden David B. 
Published: October 2024

AbstractEpilepsy is characterized by recurrent, unpredictable seizures that impose significant challenges in daily management and treatment. One emerging area of interest is the identification of seizure cycles, including multiday patterns, which may offer insights into seizure prediction and treatment optimization. This study investigated multiday seizure cycles in a Tetanus Toxin (TT) rat model of epilepsy. Six TT-injected rats were observed over a 40-day period, with continuous EEG monitoring to record seizure events. Wavelet transform analysis revealed significant multiday cycles in seizure occurrences, with periods ranging from 4 to 7 days across different rats. Synchronization Index (SI) analysis demonstrated variable phase locking, with some rats showing strong synchronization of seizures with specific phases of the cycle. Importantly, the study revealed that these seizure cycles are dynamic and evolve over time, with some rats exhibiting shifts in cycle periods during the recording period. This suggests that the underlying neural mechanisms driving these cycles may change as the epileptic state progresses. The identification of stable and evolving multiday rhythms in seizure activity, independent of external factors, highlights a potential intrinsic biological basis for seizure timing. These findings offer promising avenues for improving seizure forecasting and designing personalized, timing-based therapeutic interventions in epilepsy. Future research should explore the underlying neural mechanisms and clinical applications of multiday seizure cycles.