搜索结果：Molecular and cellular neurosciences

The intricate cellular architecture and dynamic molecular interplay in the nervous system have long challenged mechanistic studies of neurological diseases. Conventional approaches often miss the transient, low-affinity, or spatially confined interactions that underlie neural homeostasis and pathogenesis. Proximity labeling (PL) technologies overcome this limitation by enabling in situ capture of these elusive molecular events within living systems. Through spatially restricted biotinylation, PL methods, including engineered biotin ligases (e.g., TurboID), peroxidases (e.g., APEX2), and emerging photocatalytic platforms, allow high-resolution mapping of proteomes and interactomes within defined subcellular compartments, cell types, and cell-cell interfaces. In this review, we systematically outline the principles of PL and its transformative applications in constructing molecular atlases of the nervous system. We highlight how these tools are revolutionizing our understanding of brain function by elucidating pathophysiological mechanisms in Alzheimer's disease, Parkinson's disease and other neurological disorders. Furthermore, we discuss how PL accelerates the translation of basic research into clinical practice by facilitating the discovery of mechanistic biomarkers and druggable targets. Finally, we address current challenges and future directions, including integration with multi-omics and single-cell methodologies, and conclude that PL can advance precision neurology by bridging molecular neurobiology with therapeutic innovation.

Disruption of the intestinal barrier facilitates microbial translocation to the liver and contributes to chronic liver disease. We aimed to study the role of the fecal proteome in disease progression in patients with alcohol-associated hepatitis. We used fecal proteomics data from a multicenter cohort of patients with alcohol-associated hepatitis (n = 80), alcohol use disorder (n = 20), and controls (n = 19) (InTeam), and a cathepsin B activity assay in an independent multicenter cohort of patients with alcohol-associated hepatitis (n = 80), alcohol use disorder (n = 20), and controls (n = 18) (AlcHepNet). Mice lacking cathepsin B in myeloid cells and transgenic mice overexpressing occludin in intestinal epithelial cells, were subjected to the chronic-plus-binge ethanol feeding model (NIAAA). Fecal proteomics and activity analysis revealed that the protease cathepsin B progressively increased with alcohol use disorder and alcohol-associated hepatitis compared to controls, and is associated with higher short-term mortality in patients with alcohol-associated hepatitis. Cathepsin B is predominantly expressed in intestinal macrophages and is upregulated by ethanol. Cathepsin B deficiency in myeloid cells or oral treatment with the gut-restricted cathepsin B inhibitor CA074 stabilized the gut barrier by preserving the tight junction protein occludin, lowered serum lipopolysaccharide levels, and attenuated ethanol-induced steatohepatitis. Transgenic overexpression of occludin in intestinal epithelial cells sufficed to reduce steatohepatitis and blunted the effects of CA074 in ethanol-fed mice. Cathepsin B proteolytically cleaves occludin in enzymatic assays, and its inhibition prevented occludin degradation and barrier disruption in intestinal organoids and epithelial monolayers. Molecular modeling and peptide profiling reveal specific cathepsin B-induced cleavage sites in the extracellular region of occludin. Intestinal cathepsin B is an essential mediator of gut barrier dysfunction and a potential therapeutic target in alcohol-associated liver disease. Intestinal barrier disruption facilitates microbial translocation to the liver, contributing to the progression of alcohol-associated liver disease; however, the molecular mechanisms driving barrier dysfunction remain incompletely understood. Our study identifies the protease cathepsin B as a key contributor to alcohol-associated liver disease progression by degrading the extracellular region of the tight junction protein occludin in the intestine, thereby leading to barrier disruption. This work advances the field by establishing causality, uncovering the molecular target, and proposing cathepsin B as a promising therapeutic target in alcohol-associated hepatitis - a condition for which liver transplantation remains the only effective treatment in a limited subset of patients.

Exercise may be a potential disease-modifying therapy to improve physiological function in people living with dementia (PWD), though further evidence is required. The purpose of this randomized controlled trial (RCT) was to investigate whether a modified Otago Exercise Program (OEP) would improve markers of metabolic aging, cellular aging, and epigenetics relative to usual care alone in PWD. In this 6-month, parallel-group, assessor-blinded RCT (NCT05488951), 42 PWD (mean age 82.1 ± 8.1 years; mean MoCA score 10.0 ± 5.9; 35.7% female) were randomly allocated 1:1 to exercise (n = 21) or usual care (n = 21). The exercise group performed 30 min of physical therapist-supervised strength and balance exercises followed by 30 min of walking, 3×/week for six months, alongside usual care. The usual care group continued routine healthcare and social activities. Primary outcomes were changes in fasted blood biomarkers: kynurenine (metabolic aging), leukocyte telomere length (cellular aging), and global DNA methylation (epigenetics), assessed at baseline and 6 months. The intention-to-treat analysis included all 42 participants, and the per-protocol analysis included only those in the exercise group who completed ≥2×/week exercise (n = 9/21) and all usual care participants (n = 21). Intention-to-treat and per-protocol analyses revealed no statistically significant between-group differences in any biomarker. However, telomere length increased in the usual care group (7.90 ± 0.90 to 8.70 ± 0.90 kb), while there was no change in the exercise group (8.00 ± 0.90 to 7.90 ± 0.90 kb) from baseline to 6 months. While statistically significant group differences were not observed, our trial demonstrates the feasibility of biomarker collection in PWD and reveals trends-particularly in telomere length-that warrant investigation in larger, adequately powered trials.

Sleep is a vital physiological process essential for maintaining neural homeostasis, cognitive function, behavior, and health. Sleep deprivation (SD) is an increasing public health concern, largely driven by modern lifestyles and occupational demands. Research shows that SD induces oxidative stress and neuroinflammation, leading to structural changes in neurons, particularly in hippocampus, a brain region critical for learning and memory. Long-term SD has been associated with an increased risk of neurodegenerative disorders, metabolic disorders, and cardiovascular diseases. Therefore, understanding the type and extent of sleep loss and its impact on neural and overall health is essential for managing individuals affected by SD. In this review, we summarize the current literature on SD-induced changes in the brain, focusing on: (i) methods used to induce SD, (ii) SD-induced oxidative stress and neuroinflammatory alterations in the brain, (iii) effects of SD on dendritic arborization in hippocampal neurons, (iv) neuronal loss in hippocampus and other brain region, (v) impact of SD on spatial memory and behavior, and (vi) the efficacy of sleep recovery in reversing SD-induced changes. The literature shows that both acute and chronic sleep deprivation (CSD) increased oxidative stress, decreased dendritic arborization, increased neuronal loss, induced anxiety, and impaired spatial memory. While sleep recovery mitigates the damage caused by SD, full reversal depends on type of SD and duration of recovery, especially the CSD induced damage is not fully reversed. Overall, the evidence underscores the importance of understanding the nature of sleep loss and its neural impacts for developing effective strategies to manage SD.

Neuroplasticity refers to the ability of the brain to modify synaptic connections and reorganize neural circuits, underpinning cognitive function, emotional regulation, and recovery from injury. Recent advances have redefined adult neuroplasticity as more dynamic and therapeutically accessible than previously thought, spurring investigation into pharmacological interventions that can augment these adaptive processes. This review dissects current evidence for drug strategies targeting synaptic modulators (NMDA, AMPA, and GABA receptors), neuropeptide systems (including BDNF, oxytocin, vasopressin), and psychedelic compounds (psilocybin, LSD, ketamine), integrating insights from cellular, preclinical, and clinical studies. We detail how these agents modulate molecular pathways governing synaptic transmission, dendritic remodeling, and gene expression linked to neuronal growth and resilience. Highlighted findings include the rapid-acting antidepressant effects of NMDA antagonists, the structural and functional reorganization induced by classic psychedelics via 5-HT2A receptor activation, and the neurorestorative roles of neuropeptides in synaptic and network adaptation. Alongside these advances, we critically address safety, ethical considerations, and the risk of maladaptive plasticity, underscoring the importance of dosing, patient selection, and controlled therapeutic environments. Non-hallucinogenic neuroplastogens and combinatorial approaches that are still emerging offer new avenues to fine-tune plasticity with an improved safety profile. The collective evidence positions neuroplasticity-targeting pharmacology as a promising and complex frontier for the treatment of neuropsychiatric and neurodegenerative disorders in adulthood.

Alzheimer's disease (AD), a prevalent neurodegenerative disorder characterized by cognitive impairment and neuronal degeneration, is increasingly recognized as being driven not only by the traditional amyloid-beta and tau pathologies but also by persistent neuroinflammation and systemic immune dysregulation. Emerging evidence implicates microglia senescence and gut microbiota dysbiosis is critical contributors to the neuroinflammatory landscape. Senescent microglia marked by reduced phagocytic ability and a pro-inflammatory secretory profile, are unable to clear pathogenic stimuli, thereby intensifying neuronal damage. Simultaneously, gut dysbiosis, characterized by a reduction in beneficial bacteria and an increase in endotoxin-producing species, elevates systemic inflammation and compromises the intestinal and blood brain barrier. Microbial metabolites, such as short-chain fatty acids (SCFAs) and lipopolysaccharides (LPS), affect microglial activation through the gut-brain axis, primarily via the TLR4/NF-κB and NLRP3 inflammasome pathways, thus promoting microglial senescence and exacerbating AD pathology. Therapeutic approaches that target these interacting pathways are rejuvenation of microglia with senolytics and stimulation of TREM2; regulation of gut microbiota with probiotics, prebiotics, lifestyle modification, dietary intervention; and fecal microbiota transplantation. Precision medicine approaches incorporating microbiome profiling and immunogenetic analysis will enhance these treatments. This review combines mechanistic insight into microglial aging and gut-brain interaction, emphasizes their synergistic role in AD pathogenesis, and delineates integrated therapeutic strategies. Dissection of the gut-microglia axis can reveal novel targets for early intervention to counteract neuroinflammation, improve cognitive function, and slow disease progression in AD.

Ultrafine particles (UFPs), an integral component of air pollution generated through dynamic processes, possess high surface reactivity and heterogeneous chemistry that drives toxicity. UFPs toxicity is associated with oxidative stress and inflammation at the olfactory-brain interface, which are also common in age-related diseases of the brain. However, how UFPs composition shapes time-resolved cellular injury and adaptation in aged individuals remains unclear. Cells of the olfactory mucosa (OM), which directly interface with inhaled air and provide access to the brain, offer a relevant model to assess these effects. This study investigates source-specific and time-dependent effects of UFPs on primary human OM cells, focusing on the interplay between particle composition, exposure duration, and age-related susceptibility to UFPs. OM cells from aged female donors were exposed invitro to well-characterized UFPs collected from a megacity (Nanjing, China) and a Nordic urban area (Kuopio, Finland). Transcriptional responses were profiled at 4, 12, 24, and 72 h, alongside assays for cytotoxicity, DNA damage, and cell-cycle dynamics. Interaction modeling identified 2614 genes with divergent temporal trajectories between sources. Nanjing metals and polycyclic aromatic hydrocarbons rich UFPs produced sustained oxidative stress, DNA damage, early G0/G1 checkpoint activation, and a senescence-linked transcriptional program (p53/p21 axis). While Kuopio mineral-/biomass- influenced UFPs elicited a milder viability loss, S/G2 enrichment, and a compensatory proliferative transcriptomic signature after 12 h exposure. Overall, UFP-induced toxicity in OM cells is both source- and time-dependent. UFPs chemical properties dictated the pace and nature of cellular response and adaptation at the olfactory interface in OM cells derived from aged individuals, underscoring the need for composition-aware air-pollution risk assessment in aging populations.

Pathological aggregation of α-synuclein is a key event in the development of synucleinopathies, such as Parkinson's disease and Lewy body dementia. Currently, no effective disease-modifying therapy is available, necessitating the search for new therapeutic agents. One promising strategy involves the use of low-molecular-weight compounds capable of inhibiting the formation of toxic protein aggregates. This study evaluates the anti-aggregation properties of EC3222x, a conjugate of pharmacophoric fragments of amantadine and a fluorinated derivative of tetrahydro-γ-carboline. α-Synucleinopathy was modeled in the SH-SY5Y neuroblastoma cell line by transfection with a plasmid vector encoding the mutant human α-synuclein A53T protein. EC3222x at a concentration of 1 µM reduced the number of cells with α-synuclein A53T aggregates. Its efficacy was comparable to that of SynuClean-D and Buntanetap, known inhibitors of α-synuclein aggregation. Treatment with EC3222x reduced both the level of diffusely distributed intracellular α-synuclein and the formation of mature fibrillar aggregates and large aggresomes. Importantly, EC3222x did not affect the accumulation of another aggregation-prone protein, TDP-43, in a similar cellular model, indicating its specificity for α-synuclein. These findings suggest that EC3222x may represent a promising candidate for the development of therapeutic agents targeting synucleinopathies.

ULK1 (Atg1) initiates macroautophagy and mitophagy, which support neuronal growth and survival, yet how this pathway is disrupted in aging and Alzheimer's disease (AD) remains unclear. Here we report reduced ULK1 in serum and cerebrospinal fluid during aging in cognitively unimpaired participants from the COGNORM study (n = 75) and in patients with AD from the NorCog Memory Clinic Cohort (n = 316). In AD mice, ULK1 overexpression stimulates autophagic flux, reduces AD pathology and delays cognitive decline alongside increased phagocytic degradation of amyloid-β, reduced tauopathy and improved mitochondrial quality. Mechanistically, ULK1 upregulation increases autophagy and PINK1-, FUNDC1- and AMBRA1-associated mitophagy; higher autophagy and mitophagy increase cellular NAD+, which in turn deacetylates acetylated-Tau174 via the NAD+-SIRT1 axis, leading to reduced tauopathy. Using in vitro tau seeding assays and a Caenorhabditis elegans tau model, we validate the efficacy of ULK1 activators in inhibiting tauopathy. We propose that age-related decline in ULK1 leads to autophagy and mitophagy impairment and increases the progression of AD and identify ULK1 as a potential therapeutic target.

Peripheral nerve injuries (PNIs) are a significant health concern, affecting millions of individuals and result in debilitating sensory and motor deficits, as well as severe neuropathic pain. Treatment of PNIs depend on severity and gap length, with small gaps repaired by sutures and larger ones requiring autologous nerve grafting, the gold standard for bridging defects. However, autologous grafting also has significant limitations, including low recovery rates and complications such as neuroma formation. Tissue engineering and regenerative medicine offer promising alternatives but lack effective treatments directly enhancing nerve regeneration. Our previous research explored the potential of repurposing non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen and indomethacin, to promote peripheral nerve regeneration (PNR). These drugs demonstrated enhanced axonal growth and calcium signaling, suggesting a dual role in promoting neuronal recovery. The present study aimed to identify the underlying mechanism of this drug-mediated axonal growth. We hypothesized that ibuprofen and indomethacin function as peroxisome proliferator-activated receptor gamma (PPARγ) agonists, inhibiting RhoA activation and thus facilitating axonal growth. To test this, we performed immunostaining, Western blotting, and calcium imaging on dorsal root ganglion (DRG) explants treated with these drugs, both with and without PPARγ antagonists. We also investigated whether cyclooxygenase (COX) inhibition, the primary pain-relieving mechanism of NSAIDs, contributes to axonal growth. Our findings indicate that ibuprofen and indomethacin promote axonal growth through PPARγ activation, independent of COX inhibition, suggesting that targeting the PPARγ pathway could be a novel therapeutic strategy for enhancing nerve regeneration and improving outcomes for patients with PNIs.

Cerebral ischemia (CI) triggers a cascade of cellular communication disruptions, with chemokines serving as key mediators of neuroinflammation and blood-brain barrier (BBB) dysfunction. This review outlines current knowledge on the specific functions of chemokines and their receptors in CI development, emphasizing their potential as therapeutic targets. It details the mechanisms of chemokine release, including the role of extracellular vesicles (EVs) from various glial and neuronal cells, and examines how post-translational modifications (PTMs) influence chemokine and receptor activity. The review also explores signaling pathways such as NF-κB, p38 MAPK, PI3K/AKT, and RhoA/ROCK, which are central to chemokine responses. A significant focus is on the bidirectional communication between neurons and glia, highlighting dynamic shifts in chemokine signaling from acute injury to chronic repair. By targeting this network-using receptor antagonists and modulating chemokine release-we aim to discover new therapeutic strategies. This comprehensive framework enhances understanding of the spatiotemporal and molecular intricacies of chemokine signaling in CI, guiding the development of precise interventions to support neuroprotection and functional recovery.

Autism spectrum disorder (ASD) involves impaired synaptic plasticity tightly coupled to local mRNA translation. Cytoplasmic polyadenylation element-binding proteins 3 and 4 (CPEB3 and CPEB4) are post-transcriptional regulators of neuronal mRNA translation that may contribute to ASD-related molecular alterations. In this theoretical-computational study, we develop a weighted functional impact model that integrates transcriptomic expression with intrinsic molecular constraints of CPEB3 and CPEB4 to estimate regional and cell type-specific vulnerability in ASD. Coarse-grained molecular dynamics (MD) simulations were quantitatively analyzed to assess aggregation, diffusion, and cluster stability under cell type-specific cytoplasmic conditions, with statistical uncertainty explicitly evaluated. The anterior cingulate cortex and thalamus emerged as primary vulnerability sites. Despite higher CPEB4 expression-mainly in glial cells-our weighted functional impact model predicted greater theoretical susceptibility linked to CPEB3 dysfunction, particularly in inhibitory and excitatory neurons. MD simulations revealed that CPEB3 forms transient diffusion-permissive aggregates, whereas CPEB4 tends to assemble into more stable condensates. These complementary behaviors suggest differential but interdependent regulation of neuronal and glial functions. Importantly, the proposed framework provides experimentally testable predictions on how protein-protein interactions, microexon loss, and cytoplasmic crowding influence translational control in ASD. This integrative approach provides a quantitative and biologically grounded framework to investigate how post-transcriptional regulators contribute to ASD-relevant molecular vulnerability.

Alzheimer's disease (AD) is the leading cause of dementia and a significant unmet medical challenge, pathologically characterized by amyloid β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction, and chronic neuroinflammation. Although Aβ has long been a central therapeutic target, clinical translation has historically been hindered by late-stage intervention, inadequate blood-brain barrier (BBB) penetration, and the molecular heterogeneity of AD. Recent advances with Aβ-targeted monoclonal antibodies, particularly lecanemab and donanemab, have provided the first clinical evidence of disease modification, demonstrating robust amyloid clearance and measurable slowing of cognitive decline in early-stage AD. These results validate the Aβ hypothesis but also highlight persistent barriers, including amyloid-related imaging abnormalities (ARIA), questions about the durability of benefit, challenges in patient stratification, and the high economic burden of biologics. To overcome these limitations, next-generation strategies are emerging that extend beyond single-pathway targeting toward multimodal and precision-based frameworks. Innovative approaches include tau-directed therapies to prevent the propagation of neurofibrillary tangles, immunomodulatory strategies to enhance microglial clearance of aggregated proteins, and neuroprotective interventions to counteract oxidative and inflammatory stress. Concurrently, nanotechnology-based drug delivery systems are being engineered to efficiently traverse the BBB and deliver multifunctional payloads, while artificial intelligence (AI)- driven discovery platforms are accelerating target identification, biomarker integration, and patient stratification. Future perspectives emphasize the importance of preclinical-stage intervention, long-term efficacy trials, and the adoption of personalised treatment paradigms that integrate genomic, biomarker, and digital profiling to optimise outcomes. Collectively, these advances signal a paradigm shift in AD therapeutics, positioning Aβ-targeted therapies as a foundation while paving the way for combination strategies that more effectively address the disease's multifactorial nature.

Voltage-gated potassium channel KCNQ1 (Kv7.1) plays a critical role in electrical excitability in the heart, gut, and brain. Together with the auxiliary subunit KCNE1, KCNQ1 generates a slow delayed rectifier current (IKs) that is essential for cardiac repolarization. Mutations and dysregulation of this channel are found in channelopathies leading to sudden death, long-QT syndrome, atrial fibrillation, epilepsy, deafness, diabetes, and neuropsychiatric disorders. Although KCNQ1 and related potassium channels are promising therapeutic targets, there are few potent, selective, and therapeutically safe inhibitors and activators available for these proteins. A virtual screening of 36,374 compounds was conducted against KCNQ1, followed by in silico analyses that identified eight potential ligand candidates for experimental evaluation using human KCNQ1 coexpressed with KCNE1 in Xenopus laevis oocytes. Electrophysiological recordings showed that the benzodiazepine-based ligand Zinc13732787 was a potent inhibitor of the channel complex, without affecting KCNQ2/KCNQ3. Based on virtual screening and molecular docking, the 1-(3-chlorophenyl)-urea substituent on the benzodiazepine core is important for selective inhibition of KCNQ1/KCNE1, as further supported by structure-activity relationship and stereochemical exploration of Zinc13732787. Furthermore, low concentrations of Zinc13732787 reduced neurite outgrowth in human neuronal stem cells (NSCs), mirroring the phenotype observed in homozygous KCNQ1-knockout cells. Importantly, Zinc13732787 did not affect NSC proliferation, nor did it induce cytotoxicity. In homozygous KCNQ1-knockout NSCs, compound Zinc13732787 had no effect on neurite outgrowth, indicating high target specificity. These findings suggest that this compound is a valuable tool for investigating the physiological and pathological roles of KCNQ1 across various tissues. Additionally, it could be used as a precursor for novel antiarrhythmic agents as well as for epilepsy and neuropsychiatric conditions.

The molecular mechanisms of Merkel cell polyomavirus (MCPyV)-negative MCC (VN-MCC) initiation remain poorly understood. Although hsa-miR-34a-5p dysregulation has been reported in MCC, its role in VN-MCC is unknown. We aimed to investigate the functional role of hsa-miR-34a-5p on the malignant phenotype of VN-MCC and elucidate the potential underlying mechanisms. Hsa-miR-34a-5p expression was investigated in MCC cell lines (n = 5) and tissues (n = 34), and in fibroblast/epithelial cell lines (n = 2). Functional experiments evaluated the effect of hsa-miR-34a-5p on VN-MCC MCC13 phenotype. Gene expression profiling, enrichment analyses and protein-protein interaction network of hsa-miR-34a-5p target genes (n = 84) were conducted in these cells to identify relevant targets/pathways. The impact of hsa-miR-34a-5p on VN-MCC spheroid volume/growth was investigated. Hsa-miR-34a-5p was significantly downregulated in VN-MCC cells and tissues compared to MCPyV-positive counterparts, as well as to fibroblast/epithelial cells. Mechanistically, ectopic hsa-miR-34a-5p expression in MCC13 cells significantly inhibited proliferation, colony formation, and migration abilities, while promoted apoptosis. Hsa-miR-34a-5p silencing in epithelial HaCaT cells increased colony formation and partially enhanced migration. Ectopic hsa-miR-34a-5p expression in MCC13 cells negatively regulated key target genes and pathways involved in both G1/S transition of the cell cycle (CDK4, CDK6, CCNE2) and epithelial-to-mesenchymal transition (MET, NOTCH1, JAG1, along with Snail protein), leading to anti-proliferative and anti-migratory effects. Ectopic hsa-miR-34a-5p expression strongly inhibited MCC13 spheroid formation, whereas miRNA inhibition yielded the opposite effect in HaCaT spheroids from intermediate through later time points. We provide the first functional evidence of the pleiotropic tumor suppressor role of hsa-miR-34a-5p in VN-MCC.

This study investigates the role of extracellular vesicles (EVs) in predicting melanoma patients' responses to anti-PD1 immunotherapy. Nine patients with advanced melanoma provided blood samples at three stages: before treatment, before the second dose, and either at disease progression or nine months later. EVs were isolated from serum and analyzed using mass-spectrometry proteomics, followed by network and enrichment analyses. Six out of nine patients progressed despite treatment. Before therapy, responders exhibited higher levels of adaptive immune and cell adhesion proteins, while proteins related to UV radiation response were deplected. An eight-protein signature and cellular adhesion markers correlated with longer progression-free survival. After treatment, non-responders had EV proteins enriched in proteasome activity and metabolic pathways, especially glycolysis. Finally, dynamic changes in EV protein over time showed decreased coagulation proteins, along with an increase in MHC proteins in patients with progressive disease. Overall, EV protein profiles differed between responders and non-responders both before and during therapy. These findings suggest that EVs could provide predictive biomarkers and insights into resistance mechanisms, potentially guiding more effective melanoma treatment strategies.

Surface adhesion is critical to the survival of pathogenic bacteria both in natural niches and during infections, often via forming matrix-embedded communities called biofilms. Vibrio cholerae, the causal agent of pandemic cholera, is capable of forming biofilms adhering to both biotic and abiotic surfaces and the biofilm lifestyle has been implicated in promoting the survival of V. cholerae both in the natural reservoir and during host colonization. Previously, a 57-amino acid loop in the biofilm-specific adhesin Bap1 (Bap1-57aa) has been identified as a key contributor to the adhesion of V. cholerae biofilms to various surfaces including lipid membranes. However, the mechanism underlying its interaction with lipids, as well as its secondary structures, remain unresolved. Here, we combined biophysical, computational, and genetic approaches to elucidate the molecular mechanism of how this adhesive peptide interacts with lipids and lipid-coated surfaces. We found that a central aromatic-rich motif anchors the peptide to lipid bilayers while peripheral pseudo repeats enhance binding through avidity. Surprisingly, the core motif undergoes a lipid-induced conformational transition into a β-hairpin, enabling robust membrane insertion. We confirmed these findings both in vitro and in the biofilm context. Moreover, we demonstrated that the adhesive peptide can adhere to model host surfaces and is sensitive to membrane curvature. Finally, we show that the biofilm-derived peptide is found in several other Vibrio species, and its sequence is well-conserved. Our results provide molecular insight into biofilm adhesion and may lead to new strategies for targeted biofilm removal, as well as the design of bioinspired underwater adhesives.

Chronic stress is a major risk factor for psychiatric and neurological disorders, operating through interconnected molecular cascades that link neuroendocrine dysfunction to synaptic pathology. This review mechanistically examines how stress-induced hypothalamic-pituitary-adrenal (HPA) axis hyperactivation sustains glucocorticoid release, driving microglial activation and astrocytic reactivity toward pro-inflammatory phenotypes characterized by immunometabolic reprogramming. Key inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and quinolinic acid (QUIN) derived from the upregulated kynurenine pathway (KP)- impair glutamate homeostasis by compromising astrocytic reuptake and promoting excitotoxic extrasynaptic N-methyl-d-aspartate receptor (NMDAR) signaling. These pathological alterations disrupt synaptic plasticity through modified NMDAR subunit composition, impaired long-term potentiation (LTP), and complement cascade-mediated synaptic pruning, establishing a self-perpetuating cycle of vulnerability particularly within the hippocampus and prefrontal cortex. Consequently, by elucidating these interconnected pathways reveals promising therapeutic targets, including microglial phenotype modulators, NMDAR-specific interventions, and integrated pharmacological and non-pharmacological strategies aimed at restoring synaptic homeostasis and circuit function. Ultimately, this review maps these biological pathways to outline protective interventions against the physical damage of chronic stress, offering a roadmap for new treatments to restore healthy neural connections and brain function.

In the retina, rod and cone photoreceptors relay information to bipolar cells at glutamatergic synapses. At dendritic tips of ON-type bipolar cells, which depolarize in response to light, the metabotropic glutamate receptor mGluR6 is required for neurotransmitter detection. mGluR6 also has a critical interaction with the presynaptic cell adhesion molecule ELFN1, and N-linked glycosylation of mGluR6 is required for this interaction. In the retina and in heterologous cells, mGluR6 undergoes conventional secretory trafficking with complex glycosylation acquired in the Golgi. However, the mechanisms regulating mGluR6 secretory trafficking are poorly understood. Like other class C GPCRs, mGluR6 has a large extracellular domain, which includes a bi-lobed ligand binding domain. We show that a series of small deletions in the upper lobe of the ligand-binding domain led to exclusive use of unconventional secretion and plasma membrane insertion of immature core-glycosylated protein in heterologous cells. Deletion of larger regions partially restored Golgi trafficking and complex glycosylation. The mutants with large deletions also exhibited dramatically increased plasma membrane localization, which was not recapitulated in the panel of mutants with small deletions. A large deletion did not prevent constitutive internalization, suggesting the increase in plasma membrane protein is due to forward trafficking flux. The results indicate an important role of the upper lobe of the ligand binding domain in regulating mGluR6 secretory trafficking, and suggest that disruption of the structure of this domain leads to unconventional trafficking. These findings are consistent with an intraluminal interaction regulating mGluR6 sorting within the endoplasmic reticulum.