bluuebunny/crossref_metadata_2025_split huggingface dataset:
The STRIPAK complex is required for radial sorting and laminin receptor expression in Schwann cells
Authors: Weaver Michael R. , Shkoruta Dominika , Pellegatta Marta , Berti Caterina , Palmisano Marilena , Ferguson Scott , Hurley Edward , French Julianne , Patel Shreya , Belin Sophie , Selbach Matthias , Paul Florian Ernst , Sim Fraser , Poitelon Yannick , Feltri M. Laura 
Published: October 2024

ABSTRACTDuring peripheral nervous system development, Schwann cells undergo Rac1-dependent cytoskeletal reorganization as they insert cytoplasmic extensions into axon bundles to radially sort, ensheath, and myelinate individual axons. However, our understanding of the direct effectors targeted by Rac1 is limited. Here, we demonstrate that striatin-3 and MOB4 are novel Rac1 interactors. We show that, similar to Rac1-null Schwann cells, Schwann cell specific ablation of striatin-3 causes defects in lamellipodia formation. In addition, conditional Schwann cell knockout of multiple striatin proteins presents a severe delay in radial sorting. Finally, we demonstrate here that deletion of Rac1 or striatin-1/3 in Schwann cells causes defects in Hippo pathway regulation, phosphorylation of the Hippo pathway effectors YAP and TAZ, and expression of genes co-regulated by YAP and TAZ, such as extracellular matrix receptors. In summary, our results indicate that striatin-3 is a novel Rac1 interactor, show that striatin proteins are required for peripheral nervous system development, and reveal a role for Rac1 in regulation of the Hippo pathway in Schwann cells.
A synthetic platform for multiplex screening of cell-cell communication between soil fungi
Authors: Schiesaro Giovanni , Jönsson Mathias , Tenente Ricardo , Sørensen Mathies B. , Wäneskog Marcus , Undabarrena Agustina , Deichmann Marcus , Hoch-Schneider Emma E. , Kandasamy Vijayalakshmi , Frimurer Thomas M. , Clemmensen Line , Jensen Michael K. , Jensen Emil D. 
Published: October 2024

AbstractFungi are essential members across ecosystems yet also pose significant risks to crops and human health. To thrive in microbial consortia, a fungal organism must integrate the perception of both inter- and intra-species signals. Here we present a Yeast Mating Platform (YeMaP) to decipher cell-cell communication based on fungal G protein-coupled receptors (GPCRs) and pheromone peptides. We use YeMaP to investigate the influence of abiotic factors on cell-cell communication in multiplex and for high-throughput screening of pheromone sequences to identify peptides with improved potency or antagonism action. Additionally, we demonstrate that the plant pathogenFusarium oxysporumGPCR-pheromone interaction is robust across abiotic conditions, and that it can be disrupted by pheromone supplementation to promote the communication of non-pathogenic fungal GPCRs in consortia. Taken together, YeMaP is a useful tool for deciphering the complexity of fungal GPCR-based cell-cell communication and for guiding the design of future crop pest- and disease-management programs.
Genome-wide antibiotic-CRISPRi profiling identifies LiaR activation as a strategy to resensitize fluoroquinolone-resistantStreptococcus pneumoniae
Authors: Sewgoolam Bevika , Jim Kin Ki , de Bakker Vincent , Bock Florian P. , Gibson Paddy , Veening Jan-Willem 
Published: October 2024

AbstractStreptococcus pneumoniaeis a human pathogen that has become increasingly resistant to the synthetic fluoroquinolone antibiotics that target bacterial topoisomerases. To identify pathways that are essential under fluoroquinolone stress and thus might represent novel targets to revitalize the use of this class of antibiotics, we performed genome-wide CRISPRi-seq screens to determine antibiotic-gene essentiality signatures. As expected, genes involved in DNA recombination and repair become more important under fluoroquinolone-induced DNA damage, such asrecA, recJ, recF, recO, rexABandruvAB.Surprisingly, we also found that specific downregulation of the gene encoding the histidine kinaseliaScaused fluoroquinolone hypersensitivity. LiaS is part of the LiaFSR (VraTSR) three-component regulatory system involved in cell envelope homeostasis. We show that LiaS keeps the response regulator LiaR inactive, and that deletion ofliaScauses hyperphosphorylation of LiaR and subsequent upregulation of the LiaR regulon. RNA-seq was used to refine the LiaR regulon, highlighting the role of the heat-shock response and the pleiotropic regulator SpxA2 in fluoroquinolone sensitivity. Activating the LiaR-regulon by the cell envelope-targeting antibiotic bacitracin synergized with ciprofloxacin and levofloxacin. This synergistic antibiotic combination restored sensitivity in fluoroquinolone-resistant strainsin vitro. Importantly, bacitracin/levofloxacin combination therapy was also effectivein vivoand improved the treatment of fluoroquinolone-resistantS. pneumoniaeinfection in a zebrafish meningitis model. Together, the approaches and findings presented here provides a starting point for identification and validation of potent combination therapies that could be used in the clinic to treat antibiotic-resistant pneumococcal infections.
Short-term plasticity of EI balance at single neurons can detect pattern transitions
Authors: Asopa Aditya , Bhalla Upinder Singh 
Published: October 2024

AbstractSensory input and internal context converge onto the hippocampus as spatio-temporal patterns of activity. Transitions in these input patterns are frequently salient, yet the CA1 pyramidal neurons operate under conditions of divisive normalisation of summed patterned input by excitatory-inhibitory (EI) balance which suppresses most responses. We characterized the role of short-term potentiation (STP) in mediating change detection in the mouse hippocampus CA3-CA1 network using optogenetic patterned stimuli in CA3 while recording from CA1 pyramidal neurons. We parameterized STP and its effect on summation, and developed a multiscale model of network projections onto hundreds of E and I boutons each including stochastic signaling to mediate STP on the postsynaptic neuron. We show that STP modulates EI summation across patterns, and predicted and confirmed that single neurons can detect transitions in input patterns responses. Using the model we show that in feedforward networks, STP coupled with moderate sparsity of input due to input pattern sparsity and connections, strengthens rapid pattern change detection by single neurons.
Transport-Related Effects on Intrinsic and Synaptic Properties of Human Cortical Neurons: A Comparative Study
Authors: Qi Guanxiao , Yang Danqing , Bak Aniella , Hucko Werner , Delev Daniel , Hamou Hussam , Feldmeyer Dirk , Koch Henner 
Published: October 2024

AbstractTransporting human brain tissue from the operating theater to an off-site laboratory may affect sample integrity for electrophysiological studies. This study investigated how a 30-40 minute transport influenced the intrinsic, synaptic, and morphological properties of human cortical neurons. Electrophysiological recordings were performed on Layer 2/3 (L2/3 pyramidal cells and fast-spiking (FS) interneurons from human cortical slices (n = 200 neurons from 32 surgeries), comparing on-site recordings at RWTH Aachen University Hospital and off-site at Research Centre Juelich. Action potential firing patterns remained largely preserved across both recording sites, but several differences were observed. Off-site recorded pyramidal cells showed a slightly depolarized resting membrane potential and a significantly lower rheobase current. In off-site recorded FS interneurons, we found a narrower action potential half-width and an increased amplitude, suggesting altered ion channel kinetics and/or neuromodulatory environment. Additionally, a significant reduction in large rhythmic depolarizations (LRDs) and the amplitudes of excitatory postsynaptic potentials (EPSPs) in off-site recorded FS interneurons indicated an impaired synaptic efficacy. The dendritic spine densities in apical oblique and apical tuft dendrites of off-site recorded pyramidal cells were also reduced. These findings emphasize the need for optimized transport conditions to preserve synaptic integrity, network properties, and neuronal morphology. Standardized protocols are crucial for ensuring reliable and reproducible results in studies of human cortical microcircuits.Significance StatementThis study demonstrates that transporting live human brain tissue for neuronal recordings significantly impacts the intrinsic, synaptic, and network properties of cortical neurons. By comparing on-site and off-site recordings, we found that even a brief transportation (30-40 minutes) induces increased neuronal excitability, reduced synaptic efficacy, and diminished network events such as LRDs. These alterations are likely due to the mechanical stress and washout of critical neuromodulators, which compromise tissue integrity and neuronal function. The findings underscore the necessity for optimizing transport protocols to preserve synaptic and network integrity, ensuring reliable and reproducible results in human brain research. Ultimately, this work advances our understanding of cortical microcircuitry and informs best practices for handling human brain tissue in experimental settings.
A mammalian inferior colliculus model for sound source separation using interaural time differences
Authors: Leibold Christian , Groß Sebastian 
Published: October 2024

AbstractThe inferior colliculus (IC) hosts many neurons tuned to interaural time differences (ITDs) at low frequencies. ITD tuning, however, is already observed and generated in the superior olivary complex. Here, we argue that combining ITD sensitive inputs from medial superior olive (MSO) and low-frequency lateral superior olive (LSO) requires a temporally well adjusted delay of commissural fibers from LSO to IC, given the fast synaptic kinetics of IC neurons. We present a normative model of the midbrain auditory circuitry that finds an optimal commissural delay of 0.3 cycles and optimal synaptic strengths by maximizing the firing rate of IC neurons for a given ITD. The model suggests that, by varying the relative synaptic weight of MSO and LSO input, individual neurons are optimized to transmit information for any sound source in complex auditory scenes. ITD tuning of IC neurons results as a side effect and follows the statistics known from experimental recordings.
Distinct representations of economic variables across regions and projections of the frontal cortex
Authors: Majumdar Antara , Ashcroft Caitlin , Fritsche Matthias , Zatka-Haas Peter , Walker Niamh , Bijoch Lukasz , Mistry Leah , Rominto Anita M. , Duckworth-Essilfie Tolu , Swann Jake , Molnar Zoltan , Packer Adam M. , Butt Simon J. B. , Lak Armin 
Published: October 2024

SummaryEconomic decision-making requires evaluating information about available options, such as their expected value and economic risk. Previous studies have shown that frontal cortical neurons encode these variables, but how this encoding is structured across different frontal regions and projection pathways remains unclear. We developed a decision-making task for head-fixed mice in which we varied the expected value and risk associated with reward-predicting stimuli. Using large-scale electrophysiology and projection-specific optotagging across multiple frontal regions, we identified distinct spatial gradients for these variables, with stronger expected value coding in dorsal regions and stronger risk coding in medial regions. We then demonstrated that this encoding further depends on the neuronal projections: frontal neurons projecting to the dorsomedial striatum and claustrum differentially encoded economic variables. Our findings illustrate that frontal cortical representation of economic variables is jointly determined by spatial organization and downstream connectivity of neurons, revealing a structured, multi-scale code for economic variables.
Sex and Region-Specific Disruption of Autophagy and Mitophagy in Alzheimer’s Disease: Linking Cellular Dysfunction to Cognitive Decline
Authors: Adlimoghaddam Aida , Fayazbakhsh Fariba , Mohammadi Mohsen , Babaei Zeinab , Behrooz Amir Barzegar , Tabasi Farhad , Guan Teng , Beheshti Iman , Aghaei Mahmoud , Klionsky Daniel J , Albensi Benedict C. , Ghavami Saeid 
Published: October 2024

AbstractMacroautophagy and mitophagy are critical processes in Alzheimer’s disease (AD), yet their links to behavioral outcomes, particularly sex-specific differences, are not fully understood. This study investigates autophagy (LC3B-II, SQSTM1) and mitophagy (BNIP3L, BNIP3, BCL2L13) markers in the cortex and hippocampus of male and female 3xTg-AD mice, using western blotting, transmission electron microscopy (TEM), and behavioral tests (novel object recognition and novel object placement).Significant sex-specific differences emerged: female 3xTg-AD mice exhibited autophagosome accumulation due to impaired degradation in the cortex, while males showed fewer autophagosomes, especially in the hippocampus, without significant degradation changes. TEM analyses demonstrated variations in mitochondrial and mitophagosome numbers correlated with memory outcomes. Females had enhanced mitophagy, with higher BNIP3L and BCL2L13 levels, whereas males showed elevated BNIP3 dimers. Cognitive deficits in females correlated with mitochondrial dysfunction in the cortex, while in males, higher LC3B-II levels associated positively with cognitive performance, suggesting protective autophagy effects.Using machine learning, we predicted mitophagosome and mitochondrial numbers based on behavioral data, pioneering a predictive approach to cellular outcomes in AD. These findings underscore the importance of sex-specific regulation of autophagy and mitophagy in AD and support personalized therapeutic approaches targeting these pathways. Integrating machine learning emphasizes its potential to advance neurodegenerative research.Abstract FigureGraphical AbstractSex-specific differences in autophagy and mitophagy regulation in Alzheimer’s disease (AD) are highlighted. Female 3xTg-AD mice show autophagosome accumulation and cognitive deficits, while males exhibit variations in mitophagy markers and behavior.
Abstract rule generalization for composing novel meaning recruits the frontoparietal control network
Authors: Zheng Xiaochen Y. , Garvert Mona M. , den Ouden Hanneke E. M. , Horstman Lisa I. , Richter David , Cools Roshan 
Published: October 2024

AbstractThe ability to generalize previously learned knowledge to novel situations is crucial for adaptive behavior, representing a form of cognitive flexibility that is particularly relevant in language. Humans excel at combining linguistic building blocks to infer the meanings of novel compositional words, such as “un-reject-able-ish”. How do we accomplish this? While recent research on compositional generalization in relational memory, action planning and vision strongly implicates a medial prefrontal-hippocampal network (Baram et al., 2021; Barron et al., 2020; Schwartenbeck et al., 2023), it remains unclear whether the same network supports compositional inference in language. To this end, we trained participants on an artificial language in which the meanings of compositional words could be derived from known stems and unknown affixes, using abstract affixation rules (e.g., “good-kla” which means “bad”, where “-kla” reverses the meaning of the stem word “good”). According to these rules, word meaning depended on the sequential relation between the stem and the affix (i.e., pre- vs. post-stem). During fMRI, participants performed a semantic priming task, with novel compositional words as either sequential order congruent (e.g., “white-kla”) or incongruent primes (e.g., “kla-white”), and synonyms of the composed meaning as targets (“black”). Our results show that the compositional process engages a broad temporoparietal network, including the hippocampus, while the composed meanings are represented in left-lateralized language areas. Notably, newly composed meanings were decodable already at the time of the prime. Finally, we found that the composition process recruits abstract structure rule representations in a lateral frontoparietal network, rather than the predicted medial frontotemporal network, perhaps because abstract rules in language are more readily formatted as production rules rather than as relational map structures.
Impacts ofperRon oxygen sensitivity, gene expression, and murine infection inClostridioides difficile630Δerm
Authors: Gregory Anna L. , Bussan Hailey E. , Topf Madeline A. , Hryckowian Andrew J. 
Published: October 2024

AbstractClostridioides difficileinfection (CDI), characterized by colitis and diarrhea, afflicts approximately half a million people in the United States every year, burdening both individuals and the healthcare system.C. difficile630Δermis an erythromycin-sensitive variant of the clinical isolateC. difficile630 and is commonly used in theC. difficileresearch community due to its genetic tractability. 630Δermpossesses a point mutation inperR, an autoregulated transcriptional repressor that regulates oxidative stress resistance genes. This point mutation results in a constitutively de-repressed PerR operon in 630Δerm. To address the impacts ofperRon phenotypes relevant for oxygen tolerance and relevant to a murine model of CDI, we corrected the point mutant to restore PerR function in 630Δerm(herein, 630Δerm perRWT). We demonstrate that there is no difference in growth between 630Δermand a 630Δerm perRWTunder anaerobic conditions or when exposed to concentrations of O2that mimic those found near the surface of the colonic epithelium. However, 630Δerm perRWTis more sensitive to ambient oxygen than 630Δerm, which coincides with alterations in expression of a variety ofperR-dependent andperR-independent genes. Finally, we show that 630Δermand 630Δerm perRWTdo not differ in their ability to infect and cause disease in a well-established murine model of CDI. Together, these data support the hypothesis that theperRmutation in 630Δermarose as a result of exposure to ambient oxygen and that theperRmutation in 630Δermis unlikely to impact CDI-relevant phenotypes in laboratory studies.ImportanceClostridioides difficileis a diarrheal pathogen and a major public health concern. To improve humans’ understanding ofC. difficile, a variety ofC. difficileisolates are used in research, includingC. difficile630Δerm. 630Δermis a derivative of the clinical isolate 630 and is commonly studied because it is genetically manipulable. Previous work showed that a mutation inperRin 630Δermresults in a dysregulated oxidative stress response, but no work has been done to characterizeperR-dependent effects on the transcriptome or to determine impacts ofperRduring infection. Here, we identify transcriptomic differences between 630Δerm and630Δerm perRWTexposed to ambient oxygen and demonstrate that there is no strain-based difference in burdens in murineC. difficileinfection.
Spatiotemporal map of the developing human reproductive tract at single-cell resolution
Authors: Lorenzi Valentina , Mazzeo Cecilia Icoresi , Yayon Nadav , Ruiz-Morales Elias R. , Sancho-Serra Carmen , Wong Frederick C.K. , Marečková Magda , Tuck Liz , Roberts Kenny , Li Tong , Jacques Marc-Antoine , He Xiaoling , Barker Roger , Crespo Berta , Cakir Batuhan , Murray Simon , Prete Martin , Gu Yong , Kelava Iva , Garcia Alonso Luz , Marioni John C , Tormo Roser Vento 
Published: October 2024

AbstractThe human reproductive tract plays an essential role in species perpetuation. Its development involves complex processes of sex specification, tissue patterning and morphogenesis, which, if disrupted, can cause lifelong health issues, including infertility. Here, we generated an extensive single-cell and spatial multi-omic atlas of the human reproductive tract during prenatal development, which allowed us to answer questions that smaller-scale, organ-focused experiments could not address before. We identified potential regulators of sexual dimorphism in reproductive organs, pinpointing novel genes involved in urethral canalisation of the penis, with relevance to hypospadias. By combining histological features with gene expression data, we defined the transcription factors and cell signalling events required for the regionalisation of the Müllerian and Wolffian ducts. This led to a refinement of how theHOXcode is established in the distinct reproductive organs, including increased expression of thoracicHOXgenes in the rostral mesenchyme of the fallopian tube and epididymis. Our study further revealed that the epithelial regionalisation of the fallopian tube and epididymis required for sperm maturation in adulthood is established early in development. In contrast, later events in gestation or postnatally are necessary for the regionalisation of the uterocervical canal epithelium. By mapping sex-specific reproductive tract regionalisation and differentiation at the cellular level, our study offers valuable insights into the causes and potential treatments of reproductive disorders.
The persistent effects of predator odor stressor enhance interoceptive sensitivity to alcohol through GABAAreceptor adaptations in the prelimbic cortex in male, but not female rats
Authors: Tyler Ryan E. , Bluitt Maya N. , Van Voorhies Kalynn J. , Liu Wen , Magee Sarah N. , Pitrolo Elisabeth R. , Cordero Victoria L. , Ornelas Laura C. , Krieman Caroline G. , Bender Brooke N. , Mosera Alejandro M. , Besheer Joyce 
Published: October 2024

ABSTRACTBackgroundTraumatic stress is associated with high rates of problematic alcohol use, but how the persistent effects of trauma impact sensitivity to alcohol remain unknown. This study examined the persistent effects of traumatic stress exposure on sensitivity to alcohol and underlying neurobiological mechanisms in rats.MethodsMale (N=98) and female (N=98) Long-Evans rats were exposed to the predator odor TMT, and two weeks later, molecular, neuronal, and behavioral sensitivity to alcohol were assessed. Next, rats were trained to discriminate alcohol from water (male N=70; female N=56), and the impact of TMT on interoceptive sensitivity to alcohol and the alcohol-like effects of systemic GABAAreceptor activation were evaluated. Lastly, functional involvement of GABAAand NMDA receptors in the prelimbic cortex (PrL) and the anterior insular cortex (aIC) was investigated.ResultsTMT exposure sex-dependently altered PrLGabra1, and elevated aICGrin2bandGrin2cin males. TMT increased PrL c-Fos in males, which was attenuated by alcohol administration. Alcohol-induced locomotor and startle response effects were attenuated in the TMT group in both sexes. TMT exposure potentiated interoceptive sensitivity to alcohol in males but not in females, and this effect was driven by GABAAreceptors in the PrL. Greater stress reactivity during TMT exposure was associated with higher interoceptive sensitivity to alcohol, and alcohol exposure history was linked to a heightened stress response to TMT in males.ConclusionsTraumatic stress increased interoceptive sensitivity to alcohol in males, but not females, through PrL GABAAreceptor adaptations, potentially enhancing the stimulatory, and by extension the rewarding, effects of alcohol.