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Stimulating brain areas connected to the hippocampus may improve memory function in humans.

Excessive alcohol consumption poses significant health risks and is closely associated with oxidative damage. The KEAP1-NRF2-ARE signaling pathway serves as the primary antioxidant system. However, current small molecule inhibitors are all covalently bound to KEAP1, meaning that once bound, they are not easily dissociated, while continuous inhibition of KEAP1 exhibits severe side effects. In this study, BLI, CETSA, Pull-down, Co-IP, and HDX-MS assay analysis were conducted to detect the KEAP1 binding behavior of natural product, capsaicin (CAP), both in vitro and in cells. The ethanol-induced acute gastric mucosal damage rat model was also established to evaluate the therapeutic effect of CAP. Our findings demonstrated that CAP mitigated mitochondrial damage, facilitated the nuclear translocation of NRF2, leading to the up-regulation of downstream antioxidant response elements, HMOX1, TXN, GSS, and NQO1 in GES-1 cells. Furthermore, CAP directly bind to KEAP1 and inhibit the interaction between KEAP1 and NRF2. In the KEAP1-knockout 293T cells, CAP failed to activate NRF2 expression. We identified that CAP non-covalently bound to the Kelch domain and allosterically regulated three specific regions of KEAP1: L342-L355, D394-G423, and N482-N495. To improve drug solubility and delivery efficiency, we developed IR-Dye800 modified albumin-coated CAP nanoparticles. The nanoparticles significantly reduced the gastric mucosal inflammation and activated NRF2 downstream genes in vivo. Our hypothesis was further verified our hypothesis in Nrf2-knockout mice. This study provides new insights that CAP is a safe and novel NRF2 agonist by allosterically regulating KEAP1, which may contribute to the development of lead drugs for oxidative stress-related illness, e.g., aging, cancer, neurodegenerative, and cardiovascular diseases.

Calcium-sensitive fluorescent indicators enable monitoring of spiking activity in large neuronal populations in animal models. Despite the plethora of algorithms developed over the past decades, accurate spike-time inference methods for spike rates exceeding 20 Hz are lacking. More importantly, little attention has been devoted to the quantification of statistical uncertainties in spike time estimation, which is essential for assigning confidence levels to inferred spike patterns. To address these challenges, we introduce (1) a statistical model that accounts for bursting neuronal activity and baseline fluorescence modulation and (2) apply a Monte Carlo strategy (particle Gibbs with ancestor sampling) to estimate the joint posterior distribution of spike times and model parameters. Our method is competitive with state-of-the-art supervised and unsupervised algorithms, as evaluated on the CASCADE benchmark datasets. Analysis of fluorescence transients recorded with the ultrafast genetically encoded calcium indicator GCaMP8f demonstrates that our method can resolve interspike intervals as short as 5 ms. Overall, our study describes a Bayesian inference method for detecting neuronal spiking patterns and quantifying their uncertainty. The use of particle Gibbs samplers enables unbiased estimates of spike times and all model parameters, providing a flexible statistical framework for testing more specific models of calcium indicators.

Hsp70s are essential molecular chaperones that are increasingly recognized to be regulated by post-translational modifications. Here, we show that phosphorylation of a conserved threonine (T495), previously shown to be exploited by a Legionella pneumophila kinase to inhibit Hsp70, occurs endogenously in human cells in response to DNA damage, particularly when base excision repair is overburdened. This modification is cell cycle dependent, and in yeast, phosphomimetic or phosphonull Hsp70 variants disrupt G1/S progression under normal and DNA-damaging conditions. Biochemically, the phosphomimetic T495E mutation locks Hsp70 in an open-like conformation without blocking substrate engagement. Together, our results reveal a conserved mechanism by which dynamic Hsp70 phosphorylation regulates the G1/S transition and delays cell cycle progression during DNA damage, highlighting how pathogen-derived insights can uncover fundamental cell biology principles.

Visual motion information is essential to guiding the movements of many animals. The establishment of direction-selective signals, a hallmark of motion detection, is considered a core neural computation and has been characterized extensively in primates, mice, and fruit flies. In flies, the circuits that produce direction-selective signals rely on feedforward visual pathways that connect peripheral visual inputs to the dendrites of the ON and OFF-direction-selective cells. Here, we describe a novel role for feedback inhibition in motion computation. Two GABAergic neurons, C2 and C3, connect to neurons upstream of the direction-selective T4 and T5 cells, and blocking C2 and C3 affects direction selectivity in T4/T5. In the ON pathway, this is likely achieved by C2-mediated suppression of responses in the major T4 input neuron Mi1. Together, C2 and C3 suppress responses to non-preferred stimuli in both T4 and T5. At the behavioral level, feedback inhibition temporally sharpens responses to ON-moving stimuli, enhancing the fly's ability to discriminate visual stimuli that occur in quick succession. GABAergic inhibitory feedback neurons thus constitute an essential component within the circuitry that computes visual motion.

Respiratory organs must balance their primary function of gas exchange with the constant threat of inhaled pathogens. In the Drosophila tracheal system, gas exchange occurs at the tracheal terminal cells (TTCs), the functional equivalents of mammalian alveoli. While bacterial infection triggers a robust innate immune response throughout the broader airway epithelium, we reveal that TTCs are uniquely exempt from this reaction. Mechanistically, TTCs lack expression of the membrane-associated peptidoglycan recognition receptor PGRP-LC. This absence protects these highly susceptible cells from immune deficiency (Imd) pathway activation and subsequent JNK-mediated cell death, establishing TTCs as a distinct, immune-privileged niche. Ectopic immune activation via targeted PGRP-LCx overexpression in TTCs caused a severe reduction in branching, cellular damage, and ultimately cell death, phenotypes that were fully rescued by the depletion of AP-1 or foxo. Because both structural plasticity (in response to nutritional cues and hypoxia) and innate immune responses strictly require the transcription factor FoxO, we demonstrate that potent immune signaling is fundamentally incompatible with dynamic TTC remodeling. Ultimately, the immune-privileged status of TTCs represents an essential evolutionary trade-off, restricting local inflammation to preserve foxo-dependent structural plasticity and vital respiratory function.

Organisms have evolved protective strategies that are geared toward limiting cellular damage and enhancing organismal survival in the face of environmental stresses, but how these protective mechanisms are coordinated remains unclear. Here, we define a requirement for neural activity in mobilizing the antioxidant defenses of the nematode Caenorhabditis elegans both during chronic oxidative stress and prior to its onset. We show that acetylcholine-deficient mutants are particularly vulnerable to chronic oxidative stress. We find that extended oxidative stress mobilizes a broad transcriptional response which is strongly dependent on both cholinergic signaling and activation of the muscarinic G-protein acetylcholine-coupled receptor (mAChR) GAR-3. Gene enrichment analysis revealed a lack of upregulation of proteasomal proteolysis machinery in both cholinergic-deficient and gar-3 mAChR mutants, suggesting that muscarinic activation is critical for stress-responsive upregulation of protein degradation pathways. Further, we find that GAR-3 overexpression in cholinergic motor neurons prolongs survival during chronic oxidative stress. Our studies demonstrate neuronal modulation of antioxidant defenses through cholinergic activation of G protein-coupled receptor signaling pathways, defining new potential links between cholinergic signaling, oxidative damage, and neurodegenerative disease.

Altered sensory perception is a hallmark of autism and shapes how individuals engage with their environment, with tactile perception playing a critical role in daily functioning and for social interactions. While sensory alterations are thought to contribute to cognitive differences in autism, the impact of cognition on sensory perception remains unclear. Here, we investigated how cognitive processes modulate tactile perception in the Fmr1-KO genetic mouse model of autism through a translational perceptual decision-making task. Our results revealed salience-dependent cognitive alterations that influenced sensory performance. During training, Fmr1-/y male mice distinguishing between a high- and a low-salience stimulus exhibited an increased choice consistency bias in low-salience trials. When tested across a continuum of intermediate stimulus intensities, these mice demonstrated enhanced tactile discrimination of low-salience stimuli but reduced discrimination facilitation for stimuli crossing category boundaries. These effects were accompanied by diminished integration of sensory history and were dissociable from the attention deficits that emerged under high cognitive load. Together, our findings reveal that tactile perceptual alterations reflect context-dependent weighting and integration of sensory information during decision-making rather than uniform sensory deficits or enhancements, supporting a shift beyond traditional sensory-cognitive dichotomies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection poses a major threat to public health, and understanding the mechanism of viral replication and virion release would help identify therapeutic targets and effective drugs for combating the virus. Herein, we identified E3 ubiquitin protein ligase Itchy homolog (ITCH) as a central regulator of SARS-CoV-2 at multiple steps and processes. ITCH enhances the ubiquitination of viral envelope and membrane proteins and mutual interactions of structural proteins, thereby aiding in virion assembly. ITCH-mediated ubiquitination also enhances the interaction of viral proteins to the autophagosome receptor p62, promoting their autophagosome-dependent secretion. Additionally, ITCH disrupts the trafficking of the protease furin and the maturation of cathepsin L, thereby suppressing their activities in cleaving and destabilizing the viral spike protein. Furthermore, ITCH exhibits robust activation during the SARS-CoV-2 replication stage, and SARS-CoV-2 replication is significantly decreased by genetic or pharmacological inhibition of ITCH. These findings provide new insights into the mechanisms of the SARS-CoV-2 life cycle and identify a potential target for developing treatments for the virus-related diseases.

Bacteria precisely regulate the place and timing of their cell division. One of the best-understood systems for division site selection is the Min system in Escherichia coli. In E. coli, the Min system displays remarkable pole-to-pole oscillation, creating a time-averaged minimum at the cell's geometric center, which marks the future division site. Interestingly, the Gram-positive model species Bacillus subtilis also encodes homologous proteins: the cell division inhibitor MinC and the Walker-ATPase MinD. However, B. subtilis lacks the activating protein MinE, which is essential for Min dynamics in E. coli. We have shown before that the B. subtilis Min system is highly dynamic and quickly relocalizes to active sites of division. This raised questions about how Min protein dynamics are regulated on a molecular level in B. subtilis. Here, we show with a combination of in vitro experiments and in vivo single-molecule imaging that the ATPase activity of B. subtilis MinD is activated by membrane binding. Additionally, both monomeric and dimeric MinD bind to the membrane, and binding of ATP to MinD is a prerequisite for fast membrane detachment. Single-molecule localization microscopy data confirm membrane binding of monomeric MinD variants. However, only wild-type MinD enriches at cell poles and sites of ongoing division, likely due to interaction with MinJ. Monomeric MinD variants and locked dimers remain distributed along the membrane and lack the characteristic pattern formation. Single-molecule tracking data further support that MinD has a freely diffusive population, which is increased in the monomeric variants and a membrane-binding defective mutant. Thus, MinD dynamics in B. subtilis under the tested conditions do not require any unknown protein component and can be fully explained by MinD's binding and unbinding kinetics with the membrane. The spatial organization of MinD relies on the short-lived temporal residence of MinD dimers at the membrane.

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Perception relies on the neural representation of sensory stimuli. Primary sensory cortical representations have been extensively studied, but how sensory information propagates to memory-related multisensory areas has not been well described. We studied this question in the olfactory cortico-hippocampal pathway in mice. We recorded single units in the anterior olfactory nucleus (AON), the anterior piriform cortex (aPCx), the lateral entorhinal cortex (LEC), the hippocampal CA1 subfield, and the subiculum (SUB) while animals performed a non-associative learning paradigm involving novel and familiar stimuli. In the AON, neurons were broadly tuned to different chemicals, and their responses were strongly modulated by experience. From the AON to hippocampal structures, the selectivity of neurons for specific odorants increased, concurrent with the development of population-level odor representations, which became independent of novelty and familiarity. While both stimulus identity and experience were thus reflected in all regions, their neural representations progressively separated. Our findings provide a potential mechanism for how sensory representations are transformed to support stimulus identification and implicit memories.

The Faroe Islands are home to descendants of a North Atlantic founder population with a unique history shaped by both migration and periods of relative isolation. Here, we investigate the genetic diversity, population structure, and demographic history of the islands by analyzing whole genome sequencing data from 40 participants in the Faroe Genome Project. This represents the first whole genome sequencing panel of this size from the Faroe Islands. We observed numerous putatively functional private alleles, including stop gain variants and high impact missense variants in the cohort. Faroese individuals had a higher proportion of their genomes contained in long runs of homozygosity than other European groups, including Finnish, suggesting a more recent or stronger bottleneck in the Faroese population. Signals of positive selection were identified at loci containing genes that play roles in vitamin D and dietary fat absorption and DNA repair, while increased diversity on lactase persistence haplotypes was observed. Fine-scale analysis of haplotype structure in present-day and ancient European genomes revealed genetic affinities with ancient Iron Age individuals from the North and West of Europe, providing evidence for potential contributions to the Faroese gene pool from Celtic and Viking populations as well as information about the temporal order in which these events happened. This study highlights the impact of evolutionary processes, such as ancient admixture, founder events, and positive selection, on the present-day genetic architecture of North Atlantic founder populations like the Faroe Islands. Our DNA contains a wealth of information about our ancestors. By examining the DNA of present-day populations, researchers can infer aspects of their history, including migration patterns, interactions with other groups, changes in population size, and adaptation to local environments. When a small group of “founders” settles a new location, they carry only a subset of the larger population’s genetic diversity. As a result, their descendants often exhibit reduced genetic diversity and elevated frequencies of certain genetic variants, some of which may influence health, disease, or adaptation. The Faroe Islands, a remote North Atlantic archipelago, were settled around the 9th century CE, primarily by people from Scandinavia and the British Isles. Today’s population of approximately 54,000 Faroese descends from this relatively small founding group. This distinctive demographic history – characterized by mixed ancestry, geographic isolation, and a limited number of founders – is likely reflected in the genomes of present-day Faroese individuals. To investigate the genetic diversity, ancestry, and evolutionary history of the Faroese population, Hamid et al. conducted whole-genome sequencing on 40 individuals selected to represent the geographic diversity of the islands. Previous studies of the Faroese population were limited either to small sample sizes (fewer than 10 individuals) or to specific regions of the genome, leaving substantial gaps in our understanding of the population’s full genetic landscape. The Faroe Islands also have elevated rates of several diseases, including inflammatory bowel disease and type 2 diabetes, compared with other European populations. Understanding the unique genetic architecture and demographic history of the Faroese population may therefore provide important insight into the genetic basis of these health disparities. The analyses revealed that Faroese individuals carry numerous rare and potentially disease-associated genetic variants that are absent from mainland European populations, including variants predicted to disrupt gene function. Compared with other European groups –including Finns, another well-known founder population – Faroese genomes contain longer runs of homozygosity (long, identical DNA segments), reflecting extensive segments of identical DNA inherited from common ancestors. This pattern suggests a stronger or more recent population bottleneck in the Faroese population. Hamid et al. also identified signatures of natural selection in genes involved in vitamin D metabolism and dietary fat absorption (SLC10A1), as well as DNA repair (POLQ), which may reflect adaptation to the Faroese environment and traditional diet. Comparisons with ancient European genomes indicated that the Faroese derive approximately equal ancestry from Iron Age “West European” (Celtic-related) and “North European” (Viking-related) populations. Importantly, the data suggest that this genetic mixing likely occurred before the settlement of the islands rather than afterwards. These findings have direct relevance for the Faroese population because they identify genetic variants enriched in the islands that may contribute to conditions such as glycogen storage disease, ankylosing spondylitis, and other disorders. In the future, this knowledge could help inform disease prevention strategies and clinical care in the Faroe Islands. However, the study of Hamid et al. represents only a pilot phase. A greater ongoing effort, the FarGen project, aims to integrate genomic data with detailed health records to better understand the relationship between genetics and disease in the Faroese population. More broadly, the Faroe Islands provide an important model for studying how historical isolation and founder effects shape genetic diversity and disease risk in human populations worldwide.

The mammalian circadian clock is governed by a feedback loop in which the transcription activator CLOCK:BMAL1 induces expression of its inhibitors, PERs and CRYs, which form a complex with CK1δ, the main circadian kinase. However, the spatiotemporal dynamics of this feedback loop and the precise role of CK1δ remain incompletely understood. Using an inducible overexpression system, we show that nuclear availability of CK1δ is limited by both rapid nuclear degradation and active export of unassembled kinase, while cytoplasmic kinase is readily available for association with PERs. We demonstrate that CK1δ-mediated phosphorylation may disrupt PER2-CRY1 interaction, thereby resulting in cytoplasmic PER2 dimers containing substoichiometric amounts of CRY1. Analysis of endogenous PER2 localization in the context of an intact circadian clock reveals that PER2 accumulates in the cytoplasm late in the circadian cycle. Based on these findings, we propose that cytoplasmic accumulation of PER:CRY:CK1δ complexes contributes to the clearance of nuclear PER2, while the CK1δ-dependent release of CRY1 into the nucleus may sustain CLOCK:BMAL1 repression on DNA, supporting the transition from the early to the late repressive phase.

Ewing sarcoma is the second most common bone cancer in children and young adults. In 85% of patients, a translocation between chromosomes 11 and 22 results in a potent fusion oncoprotein, EWSR1::FLI1. EWSR1::FLI1 is the only genetic alteration in an otherwise unaltered genome of Ewing sarcoma tumors. The EWSR1 portion of the protein is an intrinsically disordered domain involved in transcriptional regulation by EWSR1::FLI1. The FLI portion of the fusion contains a DNA binding domain shown to bind core GGAA motifs and GGAA repeats. A small alpha-helix in the DNA binding domain of FLI1, DBD-α4 helix, is critical for the transcription function of EWSR1::FLI1. In this study, we aimed to understand the mechanism by which the DBD-α4 helix promotes transcription and therefore oncogenic transformation. We utilized a multi-omics approach to assess chromatin organization, active chromatin marks, genome binding, and gene expression in cells expressing EWSR1::FLI1 constructs with and without the DBD-α4 helix. Our studies revealed DBD-α4 helix is crucial for cooperative binding of EWSR1::FLI1 at GGAA microsatellites. This binding underlies many aspects of genome regulation by EWSR1::FLI1, such as formation of topologically associated domains (TADs), chromatin loops, enhancers, and productive transcription hubs.

Widespread antibiotic usage has resulted in the rapid evolution of drug-resistant bacterial pathogens. Resolving how pathogens respond to antibiotics under different contexts is critical for understanding disease emergence. It remains unclear how interactions between hosts and antibiotics impact pathogen evolution. Here, we evolved Staphylococcus aureus, a major bacterial pathogen, varying exposure to host and antibiotics to tease apart the contributions of these selective pressures on pathogen adaptation. After 12 passages, S. aureus evolving in Caenorhabditis elegans nematodes exposed to a sub-minimum inhibitory antibiotic concentration became highly virulent, regardless of whether the ancestral pathogen was methicillin-resistant (MRSA) or methicillin-sensitive (MSSA). Host and antibiotic selected for reduced drug susceptibility in MSSA while increasing MRSA total growth outside hosts. We identified mutations in genes involved in regulatory networks linking virulence and metabolism, suggesting that rapid adaptation to infect hosts may have pleiotropic effects. Mutations that arose in these genes were also enriched in clinical isolates associated with systemic infections in humans. Despite evolving in similar environments, MRSA and MSSA populations-differing only in the presence of an intact accessory gene-proceeded on divergent evolutionary paths, with MSSA populations exhibiting more similarities across replicates. Our results underscore the importance of the host context as a driver of virulence and antibiotic resistance.

The ability of newborns to distinguish between different voices helps them to establish verbal memories from a very early age.

Chromosomes must efficiently and properly interact with the mitotic spindle during prometaphase for correct segregation in anaphase. Chromosomes at the nuclear periphery or behind the spindle poles interact less efficiently with the mitotic spindle, increasing the risk of missegregation. The mechanisms that mitigate such risks in unperturbed cells are unknown. An actomyosin network (PANEM) forms around the nucleus during prophase. While the myosin-II-dependent PANEM contraction immediately after nuclear envelope breakdown (NEBD) facilitates chromosome interaction with the mitotic spindle, the mechanism by which it does so remains unclear. Here, using human cell lines, we show that immediately after NEBD, PANEM contraction directly pushes chromosomes at the nuclear periphery or behind spindle poles toward the center of cells. Detailed tracking of kinetochore movements following light-induced activation of a myosin II inhibitor reveals that this inward movement of chromosomes facilitates kinetochores' initial interaction with spindle microtubules. It also promotes the onset of kinetochores' congression toward the spindle mid-plane, but not congression itself once it starts. Thus, PANEM contraction ensures high-fidelity chromosome segregation by relocating chromosomes from unfavorable locations. Since some chromosomally unstable cancer cells fail to establish PANEM during early mitosis, the absence of PANEM may contribute to numerical chromosomal instability in these cells.

Tyrosine kinase 2 (TYK2) is a genetically defined target for autoimmune disease, with first-generation inhibitors showing clinical success in some but not all associated indications. A deeper understanding of TYK2 structure-function relationships, protein-ligand interactions, and the impact of human variants could inform next-generation therapeutics. Here, we applied deep mutational scanning (DMS) to assess >23,000 amino acid substitutions across two TYK2 functions: interferon alpha (IFN-α) signaling and protein abundance. This enabled high-resolution structure-function mapping and the identification of novel allosteric sites. By coupling DMS with inhibitor treatment, we uncovered variants that modulate compound potency. We also show that human variants - both common and rare - that are protective against autoimmune phenotypes reduce TYK2 protein abundance. Together, these findings demonstrate that DMS can prospectively reveal novel druggable sites, clarify structure-activity relationships (SAR), and highlight TYK2 degradation as a potential therapeutic strategy in autoimmunity.