bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amyloid pathology impairs experience-dependent inhibitory synaptic plasticity
Authors: Niraula Suraj , Yan Shirley ShiDu , Subramanian Jaichandar 
Published: May 2023

AbstractAlzheimer’s disease patients and mouse models exhibit aberrant neuronal activity and altered excitatory-to-inhibitory synaptic ratio. Using multicolor two-photon microscopy, we test how amyloid pathology alters the structural dynamics of excitatory and inhibitory synapses and their adaptation to altered visual experiencein vivoin the visual cortex. We show that the baseline dynamics of mature excitatory synapses and their adaptation to visual deprivation are not altered in amyloidosis. Likewise, the baseline dynamics of inhibitory synapses are not affected. In contrast, visual deprivation fails to induce inhibitory synapse loss in amyloidosis, a phenomenon observed in nonpathological conditions. Intriguingly, inhibitory synapse loss associated with visual deprivation in nonpathological mice is accompanied by the broadening of spontaneous but not visually evoked calcium transients. However, such broadening does not manifest in the context of amyloidosis. We also show that excitatory and inhibitory synapse loss is locally clustered under the nonpathological state. In contrast, a fraction of synapse loss is not locally clustered in amyloidosis, indicating an impairment in inhibitory synapse adaptation to changes in excitatory synaptic activity.
Neuro-Environmental Interactions: a time sensitive matter
Authors: Invernizzi Azzurra , Renzetti Stefano , Rechtman Elza , Ambrosi Claudia , Mascaro Lorella , Corbo Daniele , Gasparotti Roberto , Tang Cheuk Y. , Smith Donald R. , Lucchini Roberto G. , Wright Robert O. , Placidi Donatella , Horton Megan K. , Curtin Paul 
Published: May 2023

AbstractThe assessment of resting state (rs) neurophysiological dynamics relies on the control of sensory, perceptual, and behavioral environments to minimize variability and rule-out confounding sources of activation during testing conditions. Here, we investigated how temporally-distal environmental inputs, specifically metal exposures experienced up to several months prior to scanning, affect functional dynamics measured using rs functional magnetic resonance imaging (rs-fMRI). We implemented an interpretable XGBoost-Shapley Additive Explanation (SHAP) model that integrated information from multiple exposure biomarkers to predict rs dynamics in typically developing adolescents. In 124 participants (53% females, ages: 13-25 years) enrolled in the Public Health Impact of Metals Exposure (PHIME) study, we measured concentrations of six metals (manganese, lead, chromium, cupper, nickel and zinc) in biological matrices (saliva, hair, fingernails, toenails, blood and urine) and acquired rs-fMRI scans. Using graph theory metrics, we computed global efficiency (GE) in 111 brain areas (Harvard Oxford Atlas). We used a predictive model based on ensemble gradient boosting to predict GE from metal biomarkers, adjusting for age and biological sex. Model performance was evaluated by comparing predicted versus measured GE. SHAP scores were used to evaluate feature importance. Measured versus predicted rs dynamics from our model utilizing chemical exposures as inputs were significantly correlated (p< 0.001,r= 0.36). Lead, chromium, and copper contributed most to the prediction of GE metrics. Our results indicate that a significant component of rs dynamics, comprising approximately 13% of observed variability in GE, is driven by recent metal exposures. These findings emphasize the need to estimate and control for the influence of past and current chemical exposures in the assessment and analysis of rs functional connectivity.
Paired associated SARS-CoV-2 spike variable positions: a network analysis approach to emerging variants
Authors: Manoussopoulos Yiannis , Anastassopoulou Cleo , Ioannidis John P. A. , Tsakris Athanasios 
Published: May 2023

AbstractAmino acids in variable positions of proteins may be correlated, with potential structural and functional implications. Here, we apply exact tests of independence in R × C contingency tables to examine noise-free associations between variable positions of the SARS-CoV-2 spike protein, using as a paradigm sequences from Greece deposited in GISAID (N=6,683/1,078 full-length) for the period February 29, 2020 to April 26, 2021 that essentially covers the first three pandemic waves. We examine the fate and complexity of these associations by network analysis, using associated positions (exact p≤0.001 and Average Product Correction ≥2) as links and the corresponding positions as nodes . We found a temporal linear increase of positional differences and a gradual expansion of the number of position associations over time, represented by a temporally evolving intricate web, resulting in a non-random complex network of 69 nodes and 252 links. Overconnected nodes corresponded to the most adapted variant positions in the population, suggesting a direct relation between network degree and position functional importance. Modular analysis revealed 25k-cliques comprising three to 11 nodes. At differentk- clique resolutions, one to four communities were formed, capturing epistatic associations of circulating variants (Alpha, Beta, B.1.1.318), but also Delta, which dominated the evolutionary landscape later in the pandemic. Cliques of aminoacidic positional associations tended to occur in single sequences, enabling the recognition of epistatic positions in real-world virus populations. Our findings provide a novel way of understanding epistatic relationships in viral proteins with potential applications in the design of virus control procedures.ImportancePaired positional associations of adapted amino acids in virus proteins may provide new insights for understanding virus evolution and variant formation. We investigated potential intramolecular relationships between variable SARS-CoV-2 spike positions by exact tests of independence in R × C contingency tables, having applied Average Product Correction (APC) to eliminate background noise. Associated positions (exact p≤0.001 and APC≥2) formed a non- random, epistatic network of 25 cliques and 1-4 communities at different clique resolutions, revealing evolutionary ties between variable positions of circulating variants, and a predictive potential of previously unknown network positions. Cliques of different sizes represented theoretical combinations of changing residues in sequence space, allowing the identification of significant aminoacidic combinations in single sequences of real-world populations. Our analytic approach that links network structural aspects to mutational aminoacidic combinations in the spike sequence population offers a novel way to understand virus epidemiology and evolution.
Computational principles of adaptive multisensory combination in theDrosophilalarva
Authors: Wong Philip H. , Braun Andreas , Malagarriga Daniel , Moehlis Jeff , Moreno-Bote Rubén , Pouget Alexandre , Louis Matthieu 
Published: May 2023

AbstractMany sensory systems have evolved to optimally combine signals from multiple sensory modalities to improve perception. While theories have been proposed to explain how this process is accomplished through probabilistic inference using large neural populations in vertebrates, how animals with dramatically smaller nervous systems such as theDrosophila melanogasterlarva achieve multisensory combination remains elusive. Here, we systematically characterize larval navigation in different configurations of odor and temperature gradients with optogenetically-controlled noise. Using a data-driven agent-based model, we find that larvae adapt to the reliability of individual sensory signals, and in some cases minimize the variance of the combined signal. Besides firmly establishing that probabilistic inference directs natural orientation behaviors in theDrosophilalarva, our results indicate that the exact mechanism underlying the combination of sensory information may be modality-dependent. By underscoring that probabilistic inference is inherent to insect nervous systems, our work opens the way for studying its neural implementation.
Protein Engineering for Thermostability through Deep Evolution
Authors: Chu Huanyu , Tian Zhenyang , Hu Lingling , Zhang Hejian , Chang Hong , Bai Jie , Liu Dingyu , Cheng Jian , Jiang Huifeng 
Published: May 2023

AbstractProtein engineering for increased thermostability through iterative mutagenesis and high throughput screening is labor-intensive, expensive and inefficient. Here, we developed a deep evolution (DeepEvo) strategy to engineer protein thermostability through global sequence generation and selection using deep learning models. We firstly constructed a thermostability selector based on a protein language model to extract thermostability-related features in high-dimensional latent spaces of protein sequences with high temperature tolerance. Subsequently, we constructed a variant generator based on a generative adversarial network to create protein sequences containing the desirable function with more than 50% accuracy. Finally, the generator and selector were utilized to iteratively improve the performance of DeepEvo on the model protein glyceraldehyde-3-phosphate dehydrogenase (G3PDH), whereby 8 highly thermostable variants were obtained from only 30 generated sequences, demonstrating the high efficiency of DeepEvo for the engineering of protein thermostability.
Nanomolar range of FAM237B can activate receptor GPR83
Authors: Li Hao-Zheng , Wang Ya-Fen , Hu Wen-Feng , Liu Ya-Li , Xu Zeng-Guang , Guo Zhan-Yun 
Published: May 2023

AbstractThe orphan G protein-coupled receptor 83 (GPR83) is implicated in the regulation of energy metabolism and certain anxiety-related behaviors. Our recent study confirmed that family with sequence similarity 237 member A (FAM237A), also known as neurosecretory protein GL (NPGL), is an efficient agonist for GPR83, but did not support the proprotein convertase subtilisin/kexin type 1 inhibitor (PCSK1N, also known as proSAAS)-derived peptide PEN and the procholecystokinin-derived peptide proCCK56-63 as ligands of this receptor. FAM237B (also known as NPGM) is a paralog of FAM237A that was previously reported as a weak agonist for GPR83 with approximately 100-fold lower activity in an inositol 1-phosphate accumulation assay. In the present study, we prepared mature human FAM237B via an intein-fusion approach and measured its activity towards human GPR83 via a NanoLuc Binary Technology (NanoBiT)-based ligand□receptor binding assay and a NanoBiT-based β-arrestin recruitment assay. Mature FAM237B displayed moderately lower activity than its paralog FAM237A in these binding and activation assays, but could cause a significant activation effect at the nanomolar range (1□10 nM). Thus, FAM237B appears to be another endogenous agonist for receptor GPR83.
Resilient functioning is associated with altered structural brain network topology in adolescents exposed to childhood adversity
Authors: González-García Nadia , Buimer Elizabeth E.L. , Moreno-López Laura , Sallie Samantha N. , Váša František , Lim Sol , Romero-Garcia Rafael , Scheuplein Maximilian , Whitaker Kirstie , Jones Peter B. , Dolan Ray ,   NSPN consortium, Fonagy Peter , Goodyer Ian , Bullmore Ed , van Harmelen Anne-Laura 
Published: May 2023

AbstractChildhood adversity is one of the strongest predictors of adolescent mental illness. Therefore, it is critical that the mechanisms that aid resilient functioning in individuals exposed to childhood adversity are better understood. Here, we examined whether resilient functioning was related to structural brain network topology. We quantified resilient functioning at the individual level as psychosocial functioning adjusted for the severity of childhood adversity in a large sample of adolescents (N=2406, aged 14-24). Next, we examined nodal degree (the number of connections that brain regions have in a network) using brain-wide cortical thickness measures in a representative subset (N=275) using a sliding window approach. We found that higher resilient functioning was associated with lower nodal degree of multiple regions including the dorsolateral prefrontal cortex, the medial prefrontal cortex, and the posterior superior temporal sulcus (z> 1.645). During adolescence, decreases in nodal degree are thought to reflect a normative developmental process that is part of the extensive remodelling of structural brain network topology. Prior findings in this sample showed that decreased nodal degree was associated with age, as such our findings of negative associations between nodal degree and resilient functioning may therefore potentially resemble a more mature structural network configuration in individuals with higher resilient functioning.
Cross-modal feature based attention facilitates spatial transfer of perceptual learning in motion-domain figure-ground segregation
Authors: Fromm Catherine A. , Huxlin Krystel R. , Diaz Gabriel J. 
Published: May 2023

AbstractThis study tested the role of a cross-modal feature based attention (FBA) cue on perceptual learning and spatial transfer. The trained task was figure-ground segregation in the motion domain. The experiment involved a pre-test, ten days of training, and a post-test. Twelve visually intact participants were immersed in a virtual environment and tasked with identifying the location and motion direction of a peripheral 10◦aperture of semi-coherently moving dots embedded at randomized locations within whole-field random dot motion. The aperture contained both randomly moving dots and signal dots which had global leftward or rightward motion. To manipulate motion coherence, a 3-up-1-down staircase adjusted the direction range of the signal dots in response to segregation judgments. The dot stimulus was preceded by a 1s white-noise spatialized auditory cue emitted from the fixation point (neutral group), or from an emitter moving in the direction of signal dots at 80◦/s in a horizontal arc centered on the fixation point (FBA cue group). Visual feedback indicated the selected and true aperture locations, and correctness of the motion direction judgment. Analysis measured MD discrimination within the aperture as well as segregation ability, both measured in terms of direction range threshold (DRT). At trained locations, MD DRT improved similarly in FBA and neutral groups, and learning was retained when the pre-cue was removed (ΔDRT from pretest to posttest: 61±10◦(SD) FBA, 74±10◦neutral), and transferred to untrained locations (41±10◦FBA, 45±10◦neutral). DRT for localization also improved in both groups when pre-cues were removed (49±10◦FBA, 44±10◦neutral), but only the FBA group showed full transfer of learning to untrained locations in the segregation task (32±10◦FBA, 23±10◦neutral). In summary, transfer occurred for both motion direction and segregation tasks, but the segregation transfer required the presence of the cross-modal FBA cue during training.
Up-regulation of cholesterol synthesis pathways and limited neurodegeneration in a knock-inSod1mutant mouse model of ALS
Authors: Dominov Janice A. , Madigan Laura A. , Whitt Joshua P. , Rademacher Katerina L. , Webster Kristin M. , Zhang Hesheng , Banno Haruhiko , Tang Siqi , Zhang Yifan , Wightman Nicholas , Shychuck Emma M. , Page John , Weiss Alexandra , Kelly Karen , Kucukural Alper , Brodsky Michael H. , Jaworski Alexander , Fallon Justin R. , Lipscombe Diane , Brown Robert H. 
Published: May 2023

ABSTRACTAmyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder affecting brain and spinal cord motor neurons. Mutations in the copper/zinc superoxide dismutase gene (SOD1) are associated with ∼20% of inherited and 1-2% of sporadic ALS cases. Much has been learned from mice expressing transgenic copies of mutant SOD1, which typically involve high-level transgene expression, thereby differing from ALS patients expressing one mutant gene copy. To generate a model that more closely represents patient gene expression, we created a knock-in point mutation (G85R, a human ALS-causing mutation) in the endogenous mouseSod1gene, leading to mutant SOD1G85Rprotein expression. HeterozygousSod1G85Rmutant mice resemble wild type, whereas homozygous mutants have reduced body weight and lifespan, a mild neurodegenerative phenotype, and express very low mutant SOD1 protein levels with no detectable SOD1 activity. Homozygous mutants exhibit partial neuromuscular junction denervation at 3-4 months of age. Spinal cord motor neuron transcriptome analyses of homozygousSod1G85Rmice revealed up-regulation of cholesterol synthesis pathway genes compared to wild type. Transcriptome and phenotypic features of these mice are similar toSod1knock-out mice, suggesting theSod1G85Rphenotype is largely driven by loss of SOD1 function. By contrast, cholesterol synthesis genes are down-regulated in severely affected humanTgSOD1G93Atransgenic mice at 4 months. Our analyses implicate dysregulation of cholesterol or related lipid pathway genes in ALS pathogenesis. TheSod1G85Rknock-in mouse is a useful ALS model to examine the importance of SOD1 activity in control of cholesterol homeostasis and motor neuron survival.SIGNIFICANCE STATEMENTAmyotrophic lateral sclerosis is a devastating disease involving the progressive loss of motor neurons and motor function for which there is currently no cure. Understanding biological mechanisms leading to motor neuron death is critical for developing new treatments. Using a new knock-in mutant mouse model carrying aSod1mutation that causes ALS in patients, and in the mouse, causes a limited neurodegenerative phenotype similar toSod1loss-of-function, we show that cholesterol synthesis pathway genes are up-regulated in mutant motor neurons, whereas the same genes are down-regulated in transgenicSOD1mice with a severe phenotype. Our data implicate dysregulation of cholesterol or other related lipid genes in ALS pathogenesis and provide new insights that could contribute to strategies for disease intervention.
Distinct mechanisms for sebaceous gland self-renewal and regeneration provide durability in response to injury
Authors: Veniaminova Natalia A. , Jia Yunlong , Hartigan Adrien M. , Huyge Thomas J. , Tsai Shih-Ying , Grachtchouk Marina , Nakagawa Seitaro , Dlugosz Andrzej A. , Atwood Scott X. , Wong Sunny Y. 
Published: May 2023

SUMMARYSebaceous glands (SGs) release oils that protect our skin, but how these glands respond to injury has not been previously examined. Here, we report that SGs are largely self-renewed by dedicated stem cell pools during homeostasis. Using targeted single cell RNA-sequencing, we uncovered both direct and indirect paths by which these resident SG progenitors ordinarily differentiate into sebocytes, including transit through a PPARγ+Krt5+ transitional cell state. Upon skin injury, however, SG progenitors depart their niche, reepithelialize the wound, and are replaced by hair follicle-derived stem cells. Furthermore, following targeted genetic ablation of >99% of SGs from dorsal skin, these glands unexpectedly regenerate within weeks. This regenerative process is mediated by alternative stem cells originating from the hair follicle bulge, is dependent upon FGFR signaling, and can be accelerated by inducing hair growth. Altogether, our studies demonstrate that stem cell plasticity promotes SG durability following injury.
The infralimbic and prelimbic cortical areas bidirectionally regulate safety learning during normal and stress conditions
Authors: Felix-Ortiz Ada C. , Terrell Jaelyn M. , Gonzalez Carolina , Msengi Hope D. , Ramos Angelica R. , Boggan Miranda B. , Lopez-Pesina Savannah M. , Magalhães Gabrielle , Burgos-Robles Anthony 
Published: May 2023

AbstractSafety learning is a critical function for behavioral adaptation, environmental fitness, and mental health. Animal models have implicated the prelimbic (PL) and infralimbic (IL) subregions of the medial prefrontal cortex (mPFC) in safety learning. However, whether these regions differentially contribute to safety learning and how their contributions become affected by stress still remain poorly understood. In this study, we evaluated these issues using a novel semi-naturalistic mouse model for threat and safety learning. As mice navigated within a test arena, they learned that specific zones were associated with either noxious cold temperatures (“threat”) or pleasant warm temperatures (“safety”). Optogenetic-mediated inhibition revealed critical roles for the IL and PL regions for selectively controlling safety learning during these naturalistic conditions. This form of safety learning was also highly susceptible to stress pre-exposure, and while IL inhibition mimicked the deficits produced by stress, PL inhibition fully rescued safety learning in stress-exposed mice. Collectively, these findings indicate that IL and PL bidirectionally regulate safety learning during naturalistic situations, with the IL region promoting this function and the PL region suppressing it, especially after stress. A model of balanced IL and PL activity is proposed as a fundamental mechanism for controlling safety learning.Visual Abstract
Impairments in hippocampal oscillations accompany the loss of LTP induced by GIRK activity blockade
Authors: Contreras Ana , Djebari Souhail , Temprano-Carazo Sara , Múnera Alejandro , Gruart Agnès , Delgado-Garcia José M. , Jiménez-Díaz Lydia , Navarro-López Juan D. 
Published: May 2023

AbstractLearning and memory occurrence requires of hippocampal long-term synaptic plasticity and a precise neural activity orchestrated by brain network oscillations, both processes reciprocally influencing each other. As G-protein-gated inwardly rectifying potassium (GIRK) channels rule synaptic plasticity that supports hippocampal-dependent memory, here we assessed their unknown role in hippocampal oscillatory activity in relation to synaptic plasticity induction.In alert male mice, pharmacological GIRK modulation did not alter neural oscillations before long-term potentiation (LTP) induction. However, after an LTP generating protocol, bothgain- andloss-ofbasal GIRK activity transformed LTP into long-term depression, but only specific suppression of constitutive GIRK activity caused a disruption of network synchronization (δ, α, γbands), even leading to long-lasting ripples and fast ripples pathological oscillations.Together, our data showed that constitutive GIRK activity plays a key role in the tuning mechanism of hippocampal oscillatory activity during long-term synaptic plasticity processes that underlies hippocampal-dependent cognitive functions.
Structure-function analysis of the cyclic β-1,2-glucan synthase
Authors: Sedzicki Jaroslaw , Ni Dongchun , Lehmann Frank , Stahlberg Henning , Dehio Christoph 
Published: May 2023

AbstractThe synthesis of complex sugars is a key aspect of microbial biology. Cyclic β-1,2-glucan (CβG) is a circular polysaccharide critical for host interactions of many bacteria, including major pathogens of humans (Brucella) and plants (Agrobacterium). CβG is produced by the cyclic glucan synthase (Cgs), a massive multi-domain membrane protein. So far, its structure as well as the mechanisms underlining the synthesis have not been clarified. Here we use cryo-electron microscopy (cryo-EM) and functional approaches to study Cgs fromA. tumefaciens. We were able to determine the structure of this complex protein machinery and clarify key aspects of CβG synthesis. Our research opens new possibilities for combating pathogens that rely on polysaccharide virulence factors and can lead to new synthetic biology approaches for producing complex cyclic sugars.