bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temperature Sensitive Glutamate Gating of AMPA-subtype iGluRs
Authors: Kumar Mondal Anish , Carrillo Elisa , Jayaraman Vasanthi , Twomey Edward C. 
Published: September 2024

SummaryIonotropic glutamate receptors (iGluRs) are tetrameric ligand-gated ion channels that mediate the majority of excitatory neurotransmission1. iGluRs are gated by glutamate, where upon glutamate binding, they open their ion channels to enable cation influx into post-synaptic neurons, initiating signal transduction2. The structural mechanism of iGluR gating by glutamate has been extensively studied in the context of positive allosteric modulators (PAMs)3–15. A fundamental question has remained – are the PAM activated states of iGluRs representative of glutamate gating in the absence of PAMs? Here, using the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype iGluR (AMPAR) we show that glutamate gating is unique from gating in the presence of PAMs. We demonstrate that glutamate gating is temperature sensitive, and through temperature-resolved cryo-electron microscopy (cryo-EM), capture all major glutamate gating states. Physiological temperatures augment channel activation and conductance. Activation by glutamate initiates ion channel opening that involves all ion channel helices hinging away from the pores axis in a motif that is conserved across all iGluRs. Desensitization occurs when the local dimer pairs decouple and enables closure of the ion channel below through restoring the channel hinges and refolding the channel gate. Our findings define how glutamate gates iGluRs, provide foundations for therapeutic design, and point to iGluR gating being temperature sensitive.
Membrane-assisted Aβ40 aggregation pathways
Authors: Muhammedkutty Fidha Nazreen Kunnath , Zhou Huan-Xiang 
Published: September 2024

AbstractAlzheimer’s disease (AD) is caused by the assembly of amyloid-beta (Aβ) peptides into oligomers and fibrils. Endogenous Aβ aggregation may be assisted by cell membranes, which can accelerate the nucleation step enormously, but knowledge of membrane-assisted aggregation is still very limited. Here we used extensive MD simulations to structurally and energetically characterize key intermediates along the membrane-assisted aggregation pathways of Aβ40. Reinforcing experimental observations, the simulations reveal unique roles of GM1 ganglioside and cholesterol in stabilizing membrane-embedded β-sheets and of Y10 and K28 in the ordered release of a small oligomeric seed into solution. The same seed leads to either an open-shaped or R-shaped fibril, with significant stabilization provided by inter- or intra-subunit interfaces between a straight β- sheet (residues Q15-D23) and a bent β-sheet (residues A30-V36). This work presents the first comprehensive picture of membrane-assisted aggregation of Aβ40, with broad implications for developing AD therapies and rationalizing disease-specific polymorphisms of amyloidogenic proteins.
Distinct evolution at TCRα and TCRβ loci in the genusMus
Authors: Peters Moritz , Soltys Volker , Su Dingwen , Chan Yingguang Frank 
Published: September 2024

AbstractT cells recognize an immense spectrum of pathogens to initiate immune responses by means of a large repertoire of T cell receptors (TCRs) that arise from somatic rearrangements ofvariable,diversityandjoininggene segments at the TCR loci. These gene segments have emerged from a limited number of ancestral genes through a series of gene duplication events, resulting in a greatly variable number of such genes across different species. Apart from the complete V(D)J gene annotations in the human and mouse reference assemblies, little is known about the structure of TCR loci in other species.Here, we performed a comprehensive comparison of the TCRα and TCRβ gene segment clusters in mice and three of its closely related sister species. We show that the TCRαvariablegene cluster is frequently rearranged, leading to deletions and sequence inversions in this region. The resulting complexity of TCR loci severely complicates the assembly of these loci and the annotation of gene segments. By jointly utilizing genomic and transcriptomic data, we show that inMus musculus castaneusthe variable gene cluster at the α locus has undergone a recent major locus contraction, leading to the loss of 74variablegene segments. Additionally, we validated the expression of functional variable genes, including atypical ones with inverted orientation relative to other such segments. Disentangling the fine-scale structure of TCR loci in different species can provide valuable insights in the evolution and diversity of TCR repertoires.
Wildlife provisioning selects for higher pathogen virulence in hosts with incomplete immunity
Authors: Walsman Jason Cosens , Fleming-Davies Arietta E , Hall Richard , Hawley Dana 
Published: September 2024

AbstractAnthropogenic food provisioning provides massive inputs of food to wildlife, with profound ecological and evolutionary consequences. By altering wildlife condition, density, and behavior, provisioning can influence transmission of infectious diseases and thus may impose strong selection pressure on wildlife pathogens. But surprisingly, we lack theory on the eco-evolutionary consequences of provisioning for host-pathogen dynamics. Here we develop a mathematical model of the eco-evolutionary dynamics of a wildlife pathogen under provisioning, motivated byMycoplasma gallisepticum, a bacterial pathogen that emerged, spread, and changed its virulence in provisioned house finches. We model how provisioning influences the evolution of pathogen virulence, defined here as mortality associated with infection. Consistent with past empirical work, house finches recover from infection and acquire incomplete immunity; this incomplete immunity is stronger if their initial infection was with a more virulent pathogen strain. We find that, even though provisioning improves body condition, it should still select for higher virulence, and thus may actually lead to declines in host populations. These negative effects arise because provisioning magnifies the impact of incomplete immunity, selecting for higher virulence and driving host populations down. Our results highlight that food provisioning can select for more virulent pathogens, with potentially far-reaching implications for conservation.
Feature-specific divisive normalization improves natural image encoding for depth perception
Authors: Ni Long , Burge Johannes 
Published: September 2024

AbstractVision science and visual neuroscience seek to understand how stimulus and sensor properties limit the precision with which behaviorally-relevant latent variables are encoded and decoded. In the primate visual system, binocular disparity—the canonical cue for stereo-depth perception—is initially encoded by a set of binocular receptive fields with a range of spatial frequency preferences. Here, with a stereo-image database having ground-truth disparity information at each pixel, we examine how response normalization and receptive field properties determine the fidelity with which binocular disparity is encoded in natural scenes. We quantify encoding fidelity by computing the Fisher information carried by the normalized receptive field responses. Several findings emerge from an analysis of the response statistics. First, broadband (or feature-unspecific) normalization yields Laplace-distributed receptive field responses, and narrowband (or feature-specific) normalization yields Gaussian-distributed receptive field responses. Second, the Fisher information in narrowband-normalized responses is larger than in broadband-normalized responses by a scale factor that grows with population size. Third, the most useful spatial frequency decreases with stimulus size and the range of spatial frequencies that is useful for encoding a given disparity decreases with disparity magnitude, consistent with neurophysiological findings. Fourth, the predicted patterns of psychophysical performance, and absolute detection threshold, match human performance with natural and artificial stimuli. The current computational efforts establish a new functional role for response normalization, and bring us closer to understanding the principles that should govern the design of neural systems that support perception in natural scenes.
NetMedPy: A Python package for Large-Scale Network Medicine Screening
Authors: Aldana Andrés , Sebek Michael , Ispirova Gordana , Dorantes-Gilardi Rodrigo , Barabási Albert-László , Loscalzo Joseph , Menichetti Giulia 
Published: September 2024

AbstractSummaryNetwork medicine leverages the quantification of information flow within sub-cellular networks to elucidate disease etiology and comorbidity, as well as to predict drug efficacy and identify potential therapeutic targets. However, current Network Medicine toolsets often lack computationally efficient data processing pipelines that support diverse scoring functions, network distance metrics, and null models. These limitations hamper their application in large-scale molecular screening, hypothesis testing, and ensemble modeling. To address these challenges, we introduce NetMedPy, a highly efficient and versatile computational package designed for comprehensive Network Medicine analyses.AvailabilityNetMedPy is an open-source Python package under an MIT license. Source code, documentation, and installation instructions can be downloaded fromhttps://github.com/menicgiulia/NetMedPyandhttps://pypi.org/project/NetMedPy. The package can run on any standard desktop computer or computing cluster.
Allosteric modulation of proton binding confers Cl-activation and glutamate selectivity to vesicular glutamate transporters
Authors: Borghans Bart , Kortzak Daniel , Longo Piersilvio , Machtens Jan-Philipp , Fahlke Christoph 
Published: September 2024

AbstractVesicular glutamate transporters (VGLUTs) fill synaptic vesicles with glutamate and remove luminal Cl-via an additional anion channel mode. Both of these transport functions are stimulated by luminal acidification, luminal-positive membrane potential, and luminal Cl-. We studied VGLUT1 transporter/channel activation using a combination of heterologous expression, cellular electrophysiology, fast solution exchange, and mathematical modeling. Cl-channel gating can be described with a kinetic scheme that includes two protonation sites and distinct opening, closing, and Cl--binding rates for each protonation state. Cl-binding promotes channel opening by modifying the pKavalues of the protonation sites and rates of pore opening and closure. VGLUT1 transports glutamate and aspartate at distinct stoichiometries: H+-glutamate exchange at 1:1 stoichiometry and aspartate uniport. Neurotransmitter transport with variable stoichiometry can be described with an alternating access model that assumes that transporters without substrate translocate in the doubly protonated state to the inward-facing conformation and return with the bound amino acid substrate as either singly or doubly protonated. Glutamate, but not aspartate, promotes the release of one proton from inward-facing VGLUT1, resulting in preferential H+-coupled glutamate exchange. Cl-stimulates glutamate transport by making the glutamate-binding site accessible to cytoplasmic glutamate and by facilitating transitions to the inward-facing conformation after outward substrate release. We conclude that allosteric modification of transporter protonation by Cl-is crucial for both VGLUT1 transport functions.
Rhopilema nomadicain the Mediterranean: molecular evidence for migration and ecological hypothesis regarding its proliferation
Authors: Kuplik Zafrir , Dror Hila , Tamar Karin , Sutton Alan , Lusana James , Lugendo Blandina , Angel Dror 
Published: September 2024

AbstractSince it was first observed in Israel in the 1970s, the ‘nomad jellyfish’Rhopilema nomadicahas established a reputation as one of the worst invasive species in the Mediterranean Sea. It was assumed to originate in the Red Sea, or in the Indo-Pacific region, but in the absence of additional reports of live specimens outside the Mediterranean, its origins remained a mystery. Here, via molecular analysis, we present the first verified results of the existence ofR. nomadicain the Western Indian Ocean. Moreover, using additional evidence fromCassiopea andromedaandR. nomadica, we propose that the construction of the Aswan High Dam may have led to the proliferation ofR. nomadicain the Levantine Basin.
Exploring cellular changes in ruptured human quadriceps tendons at single-cell resolution
Authors: Mimpen Jolet Y. , Baldwin Mathew J. , Paul Claudia , Ramos-Mucci Lorenzo , Kurjan Alina , Cohen Carla J. , Sharma Shreeya , Chevalier Florquin Marie S.N. , Hulley Philippa A. , McMaster John , Titchener Andrew , Martin Alexander , Costa Matthew L. , Gwilym Stephen E. , Cribbs Adam P. , Snelling Sarah J.B. 
Published: September 2024

AbstractTendon ruptures in humans have regularly been studied during the chronic phase of injury. However, the early response to injury remains less investigated. Quadriceps tendons, which require prompt surgical treatment, offer a model to investigate this early response. Therefore, this study aimed to explore the early cellular changes in ruptured compared to healthy human quadriceps tendons. Quadriceps tendon samples were collected from patients undergoing tibial shaft fracture repair (healthy) or tendon repair surgery for complete rupture (collected 7-8 days post-injury). Nuclei were isolated for single-nucleus RNA sequencing, and comprehensive transcriptomic analysis was conducted to profile cellular changes. The transcriptomes of 12,808 nuclei were profiled, including 7,268 nuclei from healthy and 5,540 nuclei from ruptured quadriceps tendons, revealing 12 major cell types and several cell subtypes and states. Rupture samples showed increased expression of genes related to extracellular matrix organisation and cell cycle signalling, and a decrease in expression of genes in lipid metabolism pathways. These changes were driven predominantly by gene expression changes in the fibroblast, vascular endothelial cells (VECs), mural cell, and macrophage populations: fibroblasts shift to an activated phenotype upon rupture and there is an increase in proportion of capillary and dividing VECs, suggesting an angiogenic response. A diverse immune environment was observed, with a shift from homeostatic to activated macrophages following rupture. Cell-cell interactions increased in rupture, both in their number and diversity, and primarily involving fibroblast and endothelial cell populations. Collectively, this transcriptomic analysis suggests that fibroblasts and endothelial cells are key orchestrators of the early injury response within ruptured quadriceps tendon.
Multiscale topological analysis of kinetoplast DNA via high-resolution AFM
Authors: Diggines Bradley , Whittle Sylvia , Yadav Indresh , Holmes Elizabeth P. , Rollins Daniel E. , Catley Thomas E. , Doyle Patrick S. , Pyne Alice L.B. 
Published: September 2024

AbstractKinetoplast DNA is a complex nanoscale network, naturally assembled from thousands of interconnected DNA circles within the mitochondrion of certain parasites. Despite the relevance of this molecule to parasitology and the recent discovery of tuneable mechanics, its topology remains highly contested. Here we present a multiscale analysis into the structure of kDNA using a combination of high-resolution atomic force microscopy and custom-designed image analysis protocols. By capturing a notably large set of high-resolution images, we are able to look beyond individual kDNA variations and quantify population properties throughout several length scales. Within the sample, geometric fluctuations of area and mean curvature are observed, corresponding with previous in-vitro measurements. These translate to localised variations in density, with a sample-wide decrease in DNA density from the outer rim of the molecule to the centre and an increase in pore size. Nodes were investigated in a single molecule study, and their estimated connectivity significantly exceeded mean valence, with a high dependence on their position in the network. While node separation was approximately half the minicircle circumference, it followed a strong bimodal distribution, suggesting more complex underlying behaviour. Finally, upon selective digestion of the network, breakdown of the fibril-cap heterogeneity was observed, with molecules expanding less upon immobilisation on the mica surface. Additionally, selective digestion was seen in localised areas of the network, increasing pore size disproportionately. Overall, the combination of high-resolution AFM and single molecule image analysis provides a promising method to the continued investigation of complex nanoscale structures. These findings support the ongoing characterisation of kDNA topology to aid understanding of its biological and mechanical phenomena.
Integrating promiscuous enzyme activities in protein-constrained models pinpoints the role of underground metabolism in robustness of metabolic phenotypes
Authors: de Moura Ferreira Maurício Alexander , Menezes de Almeida Eduardo Luís , Batista da Silveira Wendel , Nikoloski Zoran 
Published: September 2024

AbstractThe integration of enzyme parameters in constraint-based models have significantly improved the prediction of physiological and molecular traits, including enzyme resource usage and distribution. However, current approaches largely neglect the set of promiscuous enzyme activities that jointly comprise the so-called underground metabolism. To allow enzyme-constrained study of underground metabolism, we developed the CORAL Toolbox. This toolbox reworks enzyme usage into subpools for each reaction catalysed by a promiscuous enzyme, increasing the resolution of modelled enzyme resource allocation. Applying CORAL with an enzyme-constrained genome-scale metabolic model ofEscherichia coli, we found that underground metabolism resulted in larger flexibility in metabolic fluxes and enzyme usage. Knocking out the main activity of a promiscuous enzyme led to small enzyme redistribution to the side activities. Further, knocking out pairs of main activities showed that non-promiscuous enzymes exhibited larger effect on growth. In addition, we demonstrated these findings are robust with respect to the parameterization of the models with catalytic rates from different prediction tools. Together, our results from modelling underground metabolism in enzyme-constrained models indicated that promiscuous enzyme activities are vital to maintain robust metabolic function and growth.
The T-type voltage-gated Ca2+channel CaV3.1 as a candidate receptor forPasteurella multocidatoxin and contributes to the disruption of respiratory epithelial barrier induced by the toxin
Authors: Bi Haixin , Wang Fei , Lin Lin , Zhang Dajun , Chen Menghan , Shang Yuyao , Hua Lin , Chen Huanchun , Wu Bin , Peng Zhong 
Published: September 2024

AbstractPasteurella multocidatoxin (PMT) is an exotoxin produced by several members of the zoonotic respiratory pathogenP. multocida. The role of PMT in disrupting the mammalian respiratory barrier remains to be elucidated. In this study, we discovered that inoculation of recombinantly expressed PMT increased the permeability of the respiratory epithelial barrier in mouse and respiratory cell models. This was evidenced by a decreased expression of tight junctions (ZO-1, occludin) and adherens junctions (β-catenin, E-cadherin), as well as enhanced cytoskeletal rearrangement. In mechanism, we demonstrated that PMT inoculation induced cytoplasmic Ca2+inflow, leading to an imbalance of cellular Ca2+homeostasis and endoplasmic reticulum stress. This process further stimulated the RhoA/ROCK signaling, promoting cytoskeletal rearrangement and reducing the expression of tight junctions and adherens junctions. Notably, the T-type voltage-gated Ca2+channel CaV3.1 was found to participate in PMT-induced cytoplasmic Ca2+inflow. Knocking out CaV3.1 significantly reduced the cytotoxicity induced by PMT on swine respiratory epithelial cells and mitigated cytoplasmic Ca2+inflow stimulated by PMT. Further analysis identified Ser (aa92), Glu (aa155), Tyr (aa167), and Leu (aa448) as crucial sites utilized by PMT to interact with CaV3.1. These findings suggest CaV3.1 serves as an important host receptor of PMT and contributes to PMT-induced respiratory epithelial barrier disruption.ImportancePMT is a significant toxin produced by the zoonotic respiratory pathogenP. multocida, yet little is known about its pathogenesis beyond causing progressive atrophic rhinitis in pigs. In our study, we have discovered that PMT has the capacity to disrupt the integrity of the mammalian respiratory epithelial barrier. This disruption involves an imbalance in cellular Ca2+homeostasis, endoplasmic reticulum stress, and activation of the RhoA/ROCK signaling pathway induced by PMT. Importantly, we have identified CaV3.1 as a pivotal receptor that plays a crucial role in the pathogenic effects of PMT. Our findings highlight the potential of CaV3.1 as a target for intervention strategies aimed at combating the detrimental effects of PMT.
Resting State Cortical Network and Subcortical Hyperconnectivity in Youth With Generalized Anxiety Disorder in the ABCD Study
Authors: Sievertsen Sam A. , Zhu Jinhan , Fang Angela , Forsyth Jennifer K. 
Published: September 2024

AbstractIntroductionGeneralized anxiety disorder (GAD) frequently emerges during childhood or adolescence, yet, few studies have examined functional connectivity differences in youth GAD. Functional MRI studies of adult GAD have implicated multiple brain regions; however, frequent examination of individual brain seed regions and/or networks has limited a holistic view of GAD-associated differences. The current study therefore used resting-state fMRI data from the Adolescent Brain Cognitive Development study to investigate connectivity in youth with GAD across multiple cortical networks and subcortical regions implicated in adult GAD, considering diagnosis changes across two assessment periods.MethodsWithin- and between-network connectivity in 164 GAD youth and 3158 healthy controls for 6 cortical networks and 6 subcortical regions was assessed using linear mixed effect models. Changes in GAD-associated connectivity between baseline and 2-year follow-up were then compared for subjects with: continuous GAD, GAD at baseline and not follow-up (GAD-remitters), GAD at follow-up and not baseline (GAD-converters), and controls. Associations between GAD-associated connectivity metrics and Child Behavior Checklist (CBCL) symptom severity were assessed using mixed effects models.ResultsGAD youth showed greater within-ventral attention network (VAN) connectivity, and hyperconnectivity between the amygdala and cingulo-opercular network, and between striatal regions and the cingulo-opercular, default mode, and salience networks (FDR p<0.05). Within-VAN connectivity decreased for GAD-remitters between baseline and follow-up. Connectivity was not associated with symptom severity.DiscussionResults indicate that GAD in childhood and adolescence is associated with altered subcortical to cortical network connectivity affecting multiple networks, and that within-VAN hyperconnectivity, in particular, is associated with clinically-significant GAD symptoms.