Recent advances in single-cell RNA sequencing (scRNA-seq) have transformed neuroscience research by enabling the identification of genes, cell types, and molecular pathways involved in brain development and function. However, scRNA-seq lacks spatial information regarding the anatomic location of gene expression. Emerging spatial genomics technologies, including MERFISH, CosMx, Stereo-seq, and Visium Spatial Gene Expression overcome this limitation by enabling transcriptomic and epigenomic profiling within intact tissue architecture. Integration of spatial genomics with scRNA-seq has revolutionized genomics and biomedical research by allowing gene expression to be mapped in situ at cellular and even subcellular resolution. These advances have facilitated the construction of brain spatial genomics atlases in several species, including mouse, human, non-human primate, and zebrafish. Spatial genomics technologies are particularly valuable for defining cellular heterogeneity across brain regions and characterizing the spatial organization of neuronal circuits when integrated with single-cell sequencing approaches. These reference atlases provide powerful resources for investigating brain development, function and disease, and for identifying region-specific molecular signatures associated with neurological disorders. Here, we review currently available brain spatial genomics atlases and the spatial genomics technologies used to generate these reference resources.

Alzheimer's disease (AD) progressively impairs cognitive function and quality of life (QoL). Patients frequently experience anxiety, which may accelerate cognitive decline. This study aimed to investigate the effects of narrative nursing combined with cognitive behavioral rehabilitation on cognitive function and anxiety in AD patients. In this randomized controlled trial, 172 AD patients were assigned to a control group (conventional care, n = 86) or an observation group (additional 6-month narrative nursing and cognitive behavioral rehabilitation, n = 86). Outcomes were assessed at baseline and after the 6-month intervention using validated Chinese versions of the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Generalised Anxiety Disorder-7 (GAD-7), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), and Quality of Life in Alzheimer's Disease (QoL-AD) scales. Baseline characteristics, including age (mean: 68.5 10.2 years), sex distribution (57.6% men), body mass index (22.95 3.44 kg/m 2 ), disease duration (5.32 0.79 years), and baseline cognitive scores (MMSE: 19.25 2.88; MoCA: 17.00 2.55), did not differ significantly between groups. After 6 months of intervention, the observation group demonstrated greater improvement in cognitive function (MMSE: F = 4.461, p = 0.039; MoCA: F = 5.441, p = 0.040), anxiety (GAD-7: F = 14.937, p 0.001), ADL (ADCS-ADL: F = 11.967, p 0.001), and QoL (QoL-AD: F = 7.307, p 0.001) than the control group. Adherence was high (92%), with no significant group differences. Missed sessions were primarily attributable to acute illness, transportation difficulties, or family commitments. Medication regimens (cholinesterase inhibitors, memantine, and antidepressants) remained stable between groups, with no significant interaction with the intervention. Narrative nursing combined with cognitive behavioral rehabilitation can effectively increase cognitive function, reduce anxiety, and improve the ADL and QoL of patients with AD. ISRCTN10742199.

Noninvasive brain stimulation may alleviate social media addiction, but its efficacy requires accurate individual targeting and real-time brain monitoring. The neural mechanisms underlying the effects of social media use (SMU) remain unclear, limiting the development of interventions. Understanding how different levels of SMU modulate brain activity could guide personalized neuromodulation strategies. This study investigated a cohort of young adults using a multistage design, with concurrent electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) to examine the effects of SMU on brain activity. It aimed to characterize static and dynamic neural changes at baseline and after a standardized SMU task in individuals with different daily SMU durations. Participants were all male and were divided into a heavy social media users (HSMU) group and a light social media users (LSMU) group based on self-reported daily SMU duration. All participants underwent baseline fMRI scanning, followed by an EEG-fMRI session immediately after a 2-hour controlled SMU task. Analyses were performed on the static and dynamic amplitudes of low-frequency fluctuations (sALFF and dALFF), static and dynamic functional connectivity (sFC and dFC), and EEG microstates. At baseline, compared with the LSMU group, the HSMU group showed lower dALFF variability in the middle frontal gyrus. After the immediate-effect task, the LSMU group exhibited increased sALFF in the temporal lobe and decreased sALFF in the middle and superior frontal gyri. The HSMU group showed increased sALFF in the middle temporal gyrus and decreased sALFF in the inferior temporal gyrus, superior parietal gyrus, and prefrontal cortex. Regarding dALFF variability, the LSMU group showed a decrease in the superior medial frontal gyrus, whereas the HSMU group showed a decrease in the middle frontal gyrus and an increase in the calcarine cortex. sFC analysis revealed increased connectivity across nearly all networks in the LSMU group. Conversely, the HSMU group showed reduced sFC between the visual and default mode networks. The HSMU group showed significantly shorter duration of microstate A, shorter duration and lower coverage of microstate C, and longer duration and higher coverage of microstate D. This study is the first to characterize the distinct neural patterns associated with different levels of daily SMU, using both EEG and fMRI to assess sALFF and dALFF alterations, widespread functional connectivity changes, and EEG microstate reorganizations. These findings demonstrate the unique value of multimodal assessment in identifying potential neural targets for personalized neuromodulation in social media addiction. Future studies should explore whether modulating these identified neural markers can effectively alleviate addictive behaviors and improve clinical outcomes across diverse populations.

Rare diseases individually affect few patients but collectively impose a substantial global health burden. Many have a genetic origin, yet the cellular contexts in which disease genes exert their effects often remain unclear. Direct molecular investigation of disease-relevant tissues is often infeasible owing to small patient populations and frequent congenital or pediatric onset, limiting access to patient-derived samples. Here we investigate whether existing healthy human single-cell atlases can help identify candidate cellular contexts associated with rare disease phenotypes. Specifically, we test the hypothesis that cells expressing more genes linked to a phenotype than expected from their overall transcriptional activity may represent contexts particularly susceptible to disruption. Applied to more than 1300 phenotypes across multiple tissues, the analysis shows partial concordance with literature-derived phenotype-cell type relationships, with predictive performance reaching AUC 0.71 depending on the dataset. These findings suggest that transcriptional patterns captured in healthy single-cell atlases may contain informative signals about disease-relevant cellular contexts when the relevant cell populations are represented. At the same time, the results highlight the limitations of current reference resources and the need for continued efforts to improve single-cell atlases, phenotype-tissue mappings, and benchmarking datasets linking rare disease phenotypes to cellular contexts.

Neocortical expansion is a key innovation of crown primates, although fossil evidence for how the neocortex has evolved remains elusive. We studied neocortical evolution using virtual brain endocasts from extant and Eocene-Miocene fossil primates. We found that neocortex size increased in parallel across crown primate clades, with rapid increases in tarsiers and anthropoids. Although the frontal lobe is commonly described as having expanded disproportionately in primates, we show that it evolved gradually, following a common pattern for allometric scaling. By contrast, nonfrontal neocortical regions underwent rapid increases relative to brain size in haplorhines. Neocortical expansion occurred in concert with increases in optic foramen area, suggesting that visual sensory inputs are functionally tied to modular evolution of the primate neocortex.

Young-onset stroke represents a growing public health concern, yet data from the United Arab Emirates (UAE) remain limited. This study aimed to examine the risk factors and clinical outcomes associated with young-onset stroke in the UAE. A retrospective chart review was conducted on 419 patients aged below 50 years who were admitted at Al Qassimi Hospital, Sharjah, UAE, with a diagnosis of stroke between 2016 and 2022. Data on demographics, comorbidities, stroke subtype, management, and outcomes were collected and analyzed using Python-based statistical libraries. The study population comprised predominantly of male individuals (78.28%), with most patients originating from South Asia (63.96%) and the Middle East and North Africa region (19.33%). Ischemic stroke was the most common subtype (50.12%), followed by intracerebral hemorrhage (27.21%) and non-traumatic subarachnoid hemorrhage (22.67%). Hypertension (45.45%) and diabetes mellitus (24.42%) were the most prevalent comorbidities. Only 0.24% of patients underwent mechanical thrombectomy, and 9.41% received intravenous thrombolysis. The overall mortality rate was 12.68%, with coronary artery disease significantly associated with death (p 0.001). South Asian patients were 2.19 times more likely to have large-artery atherosclerosis compared to non-South Asians (95% CI: 1.11-4.30, p = 0.02). Young-onset stroke in the UAE is characterized by a high burden of modifiable cardiovascular risk factors, particularly hypertension and diabetes mellitus. Targeted preventive strategies and region-specific research are essential to reduce disease burden and improve patient outcomes.

Cervical cancer remains a leading cause of cancer related mortality in women worldwide. Cisplatin (CP) is a cornerstone chemotherapeutic agent; however, its clinical utility is constrained by dose-limiting toxicity and the emergence of drug resistance, necessitating novel combinatorial strategies. This study investigated the therapeutic potential of combining CP with Aloe vera extract (AVE) against HeLa cervical cancer cells and the normal human skin fibroblast cell line CCD-1072Sk. Cytotoxicity assays performed using the xCELLigence Real-Time Cell Analysis (RTCA) system determined IC 50 values of 18.45 M for CP and 18.88 g/mL for AVE in HeLa cells, compared with 53.31 M and 19.09 g/mL, respectively, in CCD-1072Sk cells. The CP + AVE combination exhibited markedly enhanced antiproliferative activity in HeLa cells compared with CP alone, while CCD-1072Sk cells exhibited continued but decelerated proliferation, suggesting a differential cellular response. Seahorse metabolic analysis revealed that AVE, both alone and in combination with CP, markedly increased mitochondrial oxygen consumption rate (OCR) and ATP-linked respiration in HeLa cells, indicating induction of sustained bioenergetic stress beyond the cells' adaptive capacity. Transcriptomic profiling of HeLa cells identified 453 differentially expressed genes (DEGs) upon combination treatment, with significant downregulation of oxidative phosphorylation (OXPHOS) components, mitochondrial electron transport chain subunits, and the fatty acid metabolism gene CPT1B, collectively indicating a severe disruption of cellular energy metabolism. DepMap database analysis confirmed that downregulated targets including CPT1B and CHN2 are functionally important for HeLa cell survival. Collectively, these data suggest that AVE drives HeLa cells into a hypermetabolic state that overloads mitochondrial capacity; in combination with CP, this converging bioenergetic stress produces enhanced cytotoxicity descriptively consistent with an additive interaction (a term used here in its dose-response sense, as no formal combination-index or Bliss/Loewe synergy analysis was performed) at the IC 50 doses employed. This study highlights the potential of AVE as a metabolically active combinatorial agent capable of potentiating CP efficacy by targeting cancer cell energy metabolism, and provides a mechanistic basis for further investigation.

Post-stroke urinary retention is common and clinically relevant. Repetitive transcranial magnetic stimulation (rTMS) may modulate supraspinal micturition circuits, but evidence in retention is limited. We retrospectively studied 103 patients with post-stroke urinary retention: 52 received 4 weeks of contralesional M1 low-frequency rTMS plus rehabilitation, and 51 rehabilitation alone. Outcomes included post-void residual volume (PVR) and neurophysiological measures, while the urinary function score was analyzed as an exploratory symptom measure. Most baseline characteristics were similar between groups. Compared with controls, the rTMS group showed greater reductions in PVR (- 30 vs. - 10 ml at week 2; -64 vs. - 17 ml at week 4, p 0.001), exploratory improvements in urinary function scores (- 6.1 vs. - 2.1, p 0.001), shorter reflex latency (- 14.4 vs. - 5.0 ms, p 0.001), and higher EMG amplitude (+ 23.4 vs. + 2.5 V, p 0.001). In this retrospective cohort, low-frequency rTMS was associated with improved bladder emptying and neurophysiological changes in post-stroke urinary retention.

During winter, grapevine (Vitis vinifera) bud dormancy and cold hardiness are regulated by complex interactions between chilling accumulation and warm temperature cues. However, the molecular mechanisms underlying physiological transitions during winter remain poorly understood. In this study, we performed time-series RNA-seq on "Cabernet Sauvignon" dormant buds with varying chilling accumulation, followed by warm temperature exposure under a controlled forcing condition. Using weighted gene co-expression network analysis, empirical modeling, and a novel calculation of molecular warm temperature response rate, we identified gene expression patterns responsive to warm temperature exposure alone, chilling alone, and their interaction. Genes responsive to warm temperature exposure under forcing conditions showed rapid, chilling-independent activation and were primarily associated with metabolism, environmental sensing, and auxin signaling. Chilling-responsive genes were enriched for functions of chromatin remodeling and heat shock protein pathways, which may indicate progressive cellular reprogramming under field conditions. Interaction-responsive genes, including those involved in ABA/auxin metabolism and cell wall modification, may function in both dormancy progression and deacclimation. These findings provide a transcriptomic framework suggesting how chilling and temperature synergistically regulate dormancy transitions in grapevine, thereby enhancing the understanding of temperature sensing and response and the chilling-mediated dormancy progression underlying grapevine dormant season physiology.

Peripheral nerve injury (PNI) is a common component of combat extremity trauma, frequently associated with residual disability. Large animal models are critical for the study of PNI because of their anatomical and physiological similarities to human nerves. This study describes reproducible surgical techniques for creating PNI models in Yucatan pigs using the median and sciatic nerves. For median and ulnar nerve exposure, pigs were positioned in the right lateral recumbent with the left forelimb retracted off the field. A transverse incision was made at the axillary crease, exposing the superficial pectoral muscle and its distal fascia insertion. This was subsequently incised, exposing the median and ulnar nerves. The nerves were isolated from surrounding tissues, extending from the brachial plexus to the elbow. For sciatic nerve exposure, pigs were positioned in the left lateral recumbent, and an incision was made connecting the lateral femoral epicondyle and the greater trochanter. The fascia lata and biceps femoris were incised and bluntly dissected off the femur posteriorly, exposing the sciatic nerve. All nerve injuries were created using a #10 scalpel with the intent of minimizing pressure during transection and creating perpendicular cut faces for appropriate neurorrhaphy. Both the median and sciatic nerves were used for single-cut injuries, although the median nerve was used to create segmental defects between 2-5cm which were reconstructed using an ipsilateral ulnar nerve autograft. These techniques were applied successfully to 36 experimental animals without modifications to the landmarks or intervals. All nerve injuries created were amenable to immediate re-approximation with primary neurorrhaphy, or autograft reconstruction in the case of segmental defects. There were no instances of infection or wound dehiscence, and all animals were able to ambulate. Multiple study surgeons were trained using these approaches and injury methods, including surgeons without prior nerve surgery experience. Mean operative time from skin incision to nerve repair was under one hour for single-cut defects (mean 49.75 16.38 minutes) and under 90 minutes for segmental defects (mean 76.26 21.17 minutes). This work expands existing porcine PNI literature by describing reproducible surgical techniques for forelimb nerve injury and supplementing prior work focused predominantly on hindlimb models using the sciatic and common peroneal nerves. These techniques provide a structured framework for large-animal PNI experimentation and may reduce technical variability during early model development.

Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder worldwide, affecting millions of individuals and imposing substantial socioeconomic burdens. While traditional research has focused on amyloid- (A ) plaques and neurofibrillary tangles as primary pathological hallmarks, mounting evidence implicates neuroinflammation as a critical third pillar in AD pathogenesis. This review critically evaluates current understanding of neuroinflammatory mechanisms in AD, examining the complex interplay between cellular mediators, molecular pathways and environmental triggers across a temporal disease-stage framework. We explore the dual and stage-dependent roles of microglia and astrocytes, expand discussion of blood-brain barrier (BBB) dysfunction and peripheral immune infiltration as underappreciated pathogenic contributors, and integrate emerging evidence linking neuroinflammation specifically to tau pathology and its stereotyped propagation through the brain. Diagnostic biomarkers, including translocator protein-positron emission tomography (TSPO-PET) and plasma glial fibrillary acidic protein (GFAP), are evaluated with explicit attention to clinical utility, technical limitations, and their relationship to established AD biomarkers. Therapeutic strategies are critically assessed with careful distinction between preclinical proof-of-concept data and available clinical evidence, and key translational challenges are highlighted throughout. The review emphasizes the need for stage-appropriate intervention windows, patient stratification by neuroinflammatory endotype, and biologically rational combination strategies. Understanding neuroinflammation's temporal and spatial dynamics offers promising but as yet insufficiently realized avenues for early intervention and disease modification in AD.

Migraine is a common neurological disorder and a non-traditional risk factor for ischaemic stroke. Its relationship with specific stroke subtypes and post-stroke outcomes remains unclear. We evaluated the association between migraine (with and without aura), stroke aetiology, functional outcomes, and cardiovascular risk profiles in young patients with ischaemic stroke or TIA. Patients aged 55 years enrolled in the STROKE-CARD long-term follow-up study underwent structured face-to-face headache interviews by headache specialists using ICHD-3 criteria. A predefined protocol collected demographic, clinical, neuroimaging, aetiological, and cardiovascular risk data. Among 289 young stroke patients (median age 48.0 [41-52] years; 36.3% women), 92 (31.8%) had a history of migraine (51.1% with aura). Migraine was more common in women, associated with younger age at stroke onset and more frequent headache at stroke onset, but not with traditional vascular risk factors. PFO was more prevalent in patients with migraine with aura (68.9% vs. 36.9% no migraine, p 0.001). No significant differences were observed in stroke territory or stroke pattern. Stroke severity (NIHSS) and functional outcome (mRS) at discharge were more favourable in migraineurs (p 0.001). In multivariable analysis, migraine without aura was independently associated with good functional outcome (OR 7.21, 95% CI 1.93-26.93, p = 0.003). In young adults with ischaemic stroke, migraine-particularly with aura-was associated with younger age at stroke onset and a higher prevalence of PFO, while traditional vascular risk factors and stroke characteristics were similar across groups. Despite comparable stroke patterns, patients with migraine experienced more favourable short-term outcomes. Post-Stroke Disease Management-Stroke Card: NCT02156778; Stroke Card Long-term Follow-Up NCT04205006.

People with HIV (PWH) require lifelong antiretroviral therapy (ART) to maintain viral suppression, yet integrated HIV DNA persists in long-lived cellular reservoirs in blood and tissues. Most integrated proviruses are defective, meaning they contain deletions, hypermutation, packaging-signal defects, splice defects, or other defects that prevent production of replication-competent viruses. However, these genomes are not necessarily biologically inert as many remain capable of transcription and, in some cases, translation of viral proteins. Recent evidence has demonstrated that the brain is a stable reservoir of both intact and defective HIV despite viral suppression with ART. Whilst intact replication capable proviruses are known to induce cell activation and pathology, recent studies suggest that defective proviruses with large internal deletions and hypermutation can remain transcriptionally, and in some cases, translationally active and have now been linked with persistent immune activation during ART. Therefore, transcriptionally active defective proviral DNA may be a contributor to underlying neuropathogenesis in ART-suppressed PWH. Defective HIV proviruses make up the majority of the proviral reservoir across blood and tissue compartments. Although they are replication-incompetent, many remain transcriptionally and translationally competent and may contribute to chronic inflammation, antigen persistence, and neuropathology in ART-suppressed PWH.

To obtain rewards, animals must select actions while facing threats, often under competing appetitive and defensive drives and with uncertainty about harm. While neural circuits controlling isolated threats or rewards are well characterized, it remains unclear which specific cortical and subcortical nodes are causally necessary to organize behavior during motivational conflict. Here, we used the step-down avoidance-mediated conflict (SDAmC) task in adult male rats, which quantifies avoidance, risk assessment, and reward approach within the same session. We performed pharmacological inactivation across eight candidate structures implicated in valence and action selection: prelimbic (PL) and infralimbic (IL) cortices, lateral orbitofrontal cortex (lOFC), anterior (aIC) and posterior (pIC) insular cortices, lateral habenula (LHb), basolateral amygdala (BLA), and nucleus accumbens (NAc). Inactivation revealed a precise anatomical dissociation within this network. Silencing PL or pIC facilitated approach behavior during conflict, but with dissociable effects on risk assessment. In contrast, BLA inactivation induced a broader behavioral disinhibition evident even in non-conflict conditions, whereas NAc inactivation disrupted the temporal organization of approach, yielding a fragmented behavioral phenotype. Notably, inactivation of IL, lOFC, aIC, and LHb did not alter conflict resolution in this paradigm. Together, these findings identify a selective cortico-limbic network in which PL and pIC are necessary for limiting approach under conflict, BLA contributes to avoidance expression across motivational states, and NAc contributes to approach-related behavioral organization under conflict, constraining the set of brain regions that are necessary to organize behavior when reward seeking competes with threat.

Hearing loss is a common sensory disorder with few treatment options, mainly due to the blood-labyrinth barrier and lack of effective targeted delivery systems. Small molecules such as LLY283 and RG108 protect hair cells (HCs), but clinical use is limited by poor cellular uptake, off-target toxicity, and inefficient cochlear delivery. We developed a ferritin (Fn)-based nanocage (LR@Fn) to co-deliver RG108 and LLY283 via local injection through the round window membrane. Fn offers natural HC targeting, a hollow cavity, and good biocompatibility. Drugs were loaded using a pH-triggered strategy while maintaining structural and colloidal stability. In neonatal cisplatin and adult noise-induced hearing loss models, LR@Fn reduced HCs loss, synaptic damage, and apoptosis more effectively than dexamethasone. LR@Fn treatment activated the Wnt/ -catenin pathway, which may contribute to the observed protective effect. LR@Fn is a biocompatible ferritin-based platform for targeted inner-ear therapy, showing potential for multiple forms of hearing loss.

Anti-synthetase syndrome (ASS) associated interstitial lung disease (ILD) usually responds to immunosuppressive therapy, but recurrence is common. We report a 58-year-old man with ASS-ILD who developed recurrent ILD within one year after bilateral lung transplantation (LTx). Despite triple immunosuppression (glucocorticoids, tacrolimus, mycophenolate mofetil), systemic inflammation persisted. This case represents an in vivo model of ASS-ILD recurrence, warranting further investigation into underlying mechanisms and novel therapeutic strategies. Peripheral blood mononuclear cells (PBMCs) were collected at 56 and 84 weeks post-transplant for single-cell RNA sequencing (scRNA-seq), while lung tissue was analyzed via spatial transcriptomics. Control data came from five na ve ASS-ILD patients and two clinically stable connective tissue disease associated ILD (CTD-ILD) patients post-LTx. Differential gene expression and pathway enrichment analyses were performed to identify therapeutic targets. Exploratory PBMC scRNA-seq analysis suggested enrichment of interferon-, interleukin- and JAK-STAT-related signaling programs in circulating monocytes and neutrophils. Based on this immune activation profile, a multidrug treatment adjustment was implemented, including short-term glucocorticoid augmentation, replacement of mycophenolate mofetil with Janus kinase inhibitor tofacitinib, and replacement of tacrolimus with cyclosporine A. Following treatment adjustment, systemic inflammatory markers declined and interstitial lesions in both lungs were markedly alleviated on imaging. Subsequent spatial transcriptomic analysis of lung tissue revealed persistent interferon-related signaling and identified pro-fibrotic transcriptional programs in alveolar macrophages and transitional type II alveolar cells. Functional enrichment suggested a potential association between systemic inflammatory activation and localized fibrotic remodeling within the lung microenvironment. This case illustrates the potential utility of scRNA-seq and spatial transcriptomics for characterizing immune-related transcriptional programs in recurrent ASS-ILD after LTx. Transcriptomic profiling informed therapeutic decision-making in this complex clinical setting, and clinical improvement was observed following treatment adjustment. These findings generate exploratory insights into potential therapeutic targets in recurrent ASS-ILD.

The application of transsynaptic viruses has transformed neural circuit analysis, enabling increasingly precise mapping of neuronal connectivity. These approaches can be broadly divided into polysynaptic and monosynaptic strategies. Polysynaptic retrograde tracers based on pseudorabies virus, including the classically selected Bartha strain and genetically engineered retrograde variants have provided important insights into multisynaptic circuit organization in rodents. For polysynaptic anterograde tracing, herpes simplex virus strain H129 and its derivatives have been used to map output pathways, with later genetic modifications improving detectability and experimental control. Over the past few years, growing attention has shifted toward monosynaptic tracing based on engineered rabies virus platforms used in combination with adeno-associated virus helper systems, which enable genetically restricted spread to direct presynaptic partners. Viral tracing is increasingly integrated with functional approaches, including calcium and voltage imaging, optogenetics, chemogenetics, and recombinase-based genetic strategies, thereby extending circuit analysis from anatomical mapping to causal interrogation of the function of defined neuronal populations. Looking forward, improved control of polysynaptic spread, together with large transgene capacity, suitability for tracing hierarchical circuit architecture, and the ability to incorporate functional readouts, is expected to revive interest in multisynaptic tracing.

Enlarged perivascular spaces (EPVSs) in the basal ganglia (BG-EPVS) are an important marker of cerebral small vessel disease (cSVD), and EPVS in the centrum semiovale (CSO-EPVS) are part of the diagnostic criteria for cerebral amyloid angiopathy. We aimed to investigate associations of EPVS with reduced estimated glomerular filtration rate (eGFR) and glomerular hyperfiltration (higher than normal eGFR), which have scarcely been studied previously. In this cross-sectional study, we used pooled individual patient data from the Microbleeds International Collaborative Network which includes patients with ischemic stroke or transient ischemic attack. We investigated associations of impaired kidney function, defined as an eGFR of 30-60 or 30 mL/minute/1.73 m 2 , and glomerular hyperfiltration, defined as eGFR above the age-adjusted and sex-adjusted 95th centile, with BG-EPVS and CSO-EPVS severity. EPVS were rated according to a validated 5-point ordinal scale, and combined cSVD burden was rated using a validated 5-point ordinal scale with 1 point assigned for the presence of each of the following: severe white matter hyperintensities, 1 cerebral microbleed, 1 lacune, and BG-EPVS 11. Normal glomerular filtration was defined as eGFR 60 without hyperfiltration. We used multivariable ordinal logistic regression models to estimate risk of increased EPVS and cSVD burden severity adjusted for age, sex, and comorbidities. Seven thousand two hundred fifty-four patients (mean age 71 13 years, 43% female) were included in the analysis, 357 with glomerular hyperfiltration, 1,692 with eGFR 30-60, and 256 with eGFR 30. Compared with normal glomerular filtration, hyperfiltration was independently associated with BG-EPVS (adjusted odds ratio [aOR] 1.38, 95% CI 1.11-1.70, p 0.001) and CSO-EPVS (aOR 1.34, 95% CI 1.08-1.64, p = 0.011). Associations of eGFR 30-60 and eGFR 30 with EPVS were not statistically significant. Compared with normal glomerular filtration, eGFR 30 (aOR 1.27, 95% CI 1.03-1.57) was independently associated with increased cSVD burden, but eGFR 30-60 (aOR 1.06, 95% CI 0.95-1.20) and hyperfiltration (aOR 1.15, 95% CI 0.98-1.34) were not. Glomerular hyperfiltration was independently associated with EPVS severity, in both the basal ganglia and centrum semiovale. eGFR 30 was independently associated with total cSVD burden. A key limitation was a lack of repeated eGFR measurements.

The primary mechanism and subcellular localisation of -synuclein toxicity in Parkinson's disease pathogenesis remain unknown. We spatially and temporally resolved proteomic and transcriptomic changes in human iPSC-derived dopaminergic neurons with increasing burden of pathological -synuclein. We found that misfolded -synuclein proteoforms, signified by the formation of nanoscale intraneuronal puncta, are associated with impaired translocon function at the endoplasmic reticulum (ER). We show that -synuclein interacts with Sec61A in iPSC-derived dopaminergic neurons and in post-mortem brain tissue from patients with Parkinson's disease. This interaction interferes with the co-translational translocation of ER-processed proteins including the vacuolar-type ATPase V0a1 subunit, glucocerebrosidase, and Cathepsin B, causing defective organelle function such as reduced lysosomal acidification, leading to increased extracellular vesicle release of -synuclein. Defective ER-translocation was associated with increased ribosomal UFMylation and proteasomal recruitment but not activation of the unfolded protein response. Reduction of pathological -synuclein by either CRISPRi to decrease -synuclein expression or pharmacological activation of proteasomal degradation with repurposed drugs mitigates the ER defect. Our study offers a unifying mechanistic link between -synuclein pathology and dysregulation of diverse organelle-associated proteins that are both Sec61A translocon substrates and genetic modifiers of Parkinson's disease risk. Our data also provide a therapeutic rationale for proteasomal activation in early Parkinson's disease.

Long-term high-salt diets (HSD) are known to impair cognitive function, whereas the effects of low-salt diets (LSD) remain less well characterized. Here, we systematically compared the long-term effects of LSD and HSD on cognitive function and alterations along the gut-metabolite-brain axis under the same humanized microbiota background. We found that both long-term LSD and HSD induced cognitive impairment in humanized control (HC) mice, but were associated with distinct biological patterns. Both LSD and HSD impaired working and recognition memory and reduced hippocampal synaptic proteins. They also altered gut microbiota composition and decreased propionate and butyrate levels. Notably, HSD were additionally associated with increased pro-inflammatory microbial taxa, elevated circulating inflammatory cytokines, and broad lipid metabolic alterations. In contrast, cognitive impairment under LSD occurred in the absence of detectable systemic inflammation and was more specifically associated with reduced microbial metabolic output, including further decreases in acetate and isobutyrate. Our findings suggest that excessive salt restriction is not biologically equivalent to normal intake and may represent a distinct biological risk pattern for cognitive impairment, highlighting the importance of balanced dietary salt intake.

Poststroke cognitive impairment (PSCI) is a common and disabling complication after stroke; however, early screening remains challenging due to limited access to neuropsychological testing and the high cost of neuroimaging. Portable, tablet-based eye-tracking technology may offer a scalable, low-cost solution for early PSCI detection. This study aimed to evaluate the clinical utility of a tablet-based, AI-driven eye-tracking system for early screening of PSCI at 3 months after acute ischemic stroke. We sought to quantify oculomotor-cognitive associations and develop a practical nomogram for individualized risk prediction. We prospectively enrolled 142 hospitalized patients with acute cerebral infarction between May 2023 and October 2024, of whom 122 completed the 3-month follow-up and were included in the final analysis, along with 20 healthy community-dwelling controls. All patients underwent tablet-based eye tracking (visual paired comparison and antisaccade tasks) during the acute phase, as well as baseline and 3-month neuropsychological assessments. PSCI was defined using validated cutoffs. Multivariable logistic regression was used to identify independent predictors, and a nomogram was constructed. Internal validation was performed using bootstrap resampling (1000 samples). At 3 months, out of 122 patients, 47 (38.5%) met PSCI criteria. Compared with patients with non-PSCI (n=75), patients with PSCI showed significantly prolonged correct saccade latency (median 322.96, IQR 209.45-445.59 ms vs 194.55, IQR 141.50-299.75 ms; Z=-4.03, P .001), increased uncorrected error rate (median 30.00%, IQR 15.00%-42.00% vs 5.00%, IQR 0.00%-28.00%; Z=-4.24, P .001), and reduced novelty preference ratio (median 1.44, IQR 0.97-1.70 vs 2.12, IQR 1.27-4.56; Z=-3.44, P=.001). Multivariable analysis identified 4 independent predictors of 3-month PSCI: older age (odds ratio [OR] 1.067 per year, 95% CI 1.009-1.129; P=.02), lower education level (OR 0.841 per year, 95% CI 0.708-0.999; P=.049), higher NIHSS (National Institutes of Health Stroke Scale) scores (OR 1.557 per point, 95% CI 1.075-2.256; P=.02), and prolonged correct saccade latency (OR 1.004 per ms, 95% CI 1.000-1.007; P=.04). A nomogram incorporating these 4 factors achieved good discriminative performance (area under the receiver operating characteristic curve 0.86, 95% CI 0.793-0.927) with satisfactory calibration. Age, education, admission NIHSS, and correct saccade latency were identified as possible independent predictors of 3-month PSCI in this cohort. The tablet-based eye-tracking system, when combined with clinical variables, may represent a feasible approach for early PSCI screening. A nomogram based on these variables demonstrated high accuracy and potential clinical utility for early PSCI identification. This approach may facilitate early identification of high-risk patients and enable timely, personalized interventions in resource-limited settings.

What did our ancestors eat? Current understanding of diet in human evolution is predicated on abundant animal foods and mastery of fire, both unlikely for early hominins. Using multiple lines of evidence, including the metabolic requirements of an enlarging brain and reproduction, we model macronutrient distribution across 4 million years of evolution. Before cooking made starch easily digestible, the sugars in fruit and honey provided glucose, the brain's preferred fuel. Modeling suggests that sugars provided 25% of dietary energy, fulfilling obligatory glucose demand. Pounding and cooking released glucose specifically, not merely energy. The evolution of a bigger brain is therefore a story of carbohydrate foods as much as animal foods: from sweet sugars to cooked starch, from chewing to processing, and from wadging to advanced nutrient extraction.

Understanding how the brain processes bodily signals requires mapping the circuits that transform interoceptive information into coordinated responses. Visceral signals converge in the nucleus of the solitary tract (NTS), which coordinates appetite, breathing, cardiovascular reflexes, and digestion. The NTS contains many intermingled subpopulations of neurons, and deciphering their functions requires understanding their connections. Here, we used cell-type-specific tracing to test whether molecularly distinct NTS neurons exhibit unique connectivity patterns. First, we found that Lmx1b-expressing excitatory neurons provide output to a broad array of NTS target regions in both the brainstem and forebrain, while inhibitory neurons in this region project predominantly within the brainstem. Next, we found that several genetically defined excitatory subpopulations-catecholaminergic (Th), neuropeptidergic (Cck, Npff, or Pdyn), and aldosterone-sensitive (Hsd11b2)-exhibit unique output patterns across multiple targets. As examples, the ventrolateral medulla receives moderate Th, Cck, and Pdyn, light Npff, and no Hsd11b2 input. The outer rim of the external lateral parabrachial subnucleus receives concentrated Th, Cck, and Npff input, contrasting a more uniform Pdyn input and a lack of Hsd11b2 input. The subcommissural bed nucleus of the stria terminalis receives broad Th, light Cck, sparse Pdyn, and virtually no Npff input, contrasting the focal Hsd11b2 input to its fusiform subnucleus. These divergent patterns demonstrate that molecular identity predicts connectivity and define the organizational logic by which interoceptive signals are transformed into coordinated autonomic and behavioral responses.

Accurate annotation of cell types in single-cell transcriptome sequencing (scRNA-seq) data is critical for understanding cellular identities. The transcriptional regulatory networks (TRNs), which map the regulatory relationships between transcription factors (TFs) and their target genes (TGs), capture the molecular dependencies underlying transcriptional programs. However, most existing cell type annotation methods do not fully exploit this regulatory information. Therefore, we introduce ScanNet, a Single cell annotation method informed by transcriptional regulation Network, to integrate prior knowledge of TRN into data of gene expression and capture the cell-type-specific characteristics underlying TRN mechanism. TRN can be naturally represented as heterogeneous graphs consisting of two regulatory elements, TFs and TGs connected by directed edges, thereby encoding the regulatory dependencies that shape transcriptional programs and ultimately determine cellular identity. To leverage this structure, ScanNet introduces an iterative heterogeneous graph convolutional framework that learns both local and global cellular embeddings through a dual-channel encoder. The Regulation-level Encoder applies iterative heterogeneous graph convolution to capture local TF-TG regulatory interactions within TRN, while the Expression-level Encoder learns global cellular transcriptional states. By integrating the multiple-view representations, ScanNet can accurately annotate cell types. Comprehensive evaluations across eight scRNA-seq datasets spanning different species, sample scales, and sequencing platforms demonstrate that ScanNet consistently outperforms ten state-of-the-art cell type annotation methods. By embedding prior TRN structures into a heterogeneous graph, ScanNet also achieves robust performance in cross-platform cell type annotation and in identifying novel cell types under constrained structural information. Moreover, the ScanNet framework can be flexibly transferred to single-cell ATAC-seq (scATAC-seq) data by mapping chromatin accessibility to gene level, where it achieves superior performance compared to existing annotation tools. Overall, ScanNet is a scalable, transferable, and mechanistically informed framework for accurate cell type annotation across diverse single-cell data modalities.

Impaired glymphatic function has been associated with shorter survival in glioblastoma. However, the relationship between glymphatic dysfunction and survival has not yet been evaluated in the context of established prognostic factors, including extent of resection, adjuvant therapy, MGMT promoter methylation status, and clinical performance status. Single-center retrospective study including patients undergoing surgery for unifocal glioblastoma IDHwt CNS WHO grade 4 (GBM), with preoperative DTI studies in comparison to healthy controls (HC). Glymphatic impairment was assessed using diffusion tensor imaging analysis along the perivascular space (DTI-ALPS), which is an accepted surrogate marker for glymphatic function. This study follows the STROBE guidelines for cohort studies. We included 47 patients with GBM and 50 HC. The hemispherically averaged ALPS index was lower in GBM patients (1.15 vs. 1.27, p = 0.01). There were no differences between contralateral ALPS and HC (1.22 vs. 1.27, p = 0.29). Ipsilateral ALPS was lower compared to HC (1.05 vs. 1.27, p 0.001) and to the contralateral hemisphere (1.1 vs. 1.22, p = 0.01). Univariable Cox regression showed no association between overall survival and ALPS parameters (ipsilateral HR 2.25 95% CI 0.49-10.31 p = 0.3, contralateral HR 2.96 95% CI 0.57-15.32 p = 0.2). In multivariate analysis significant associations were found for female and extent of resection but not for MGMT status, age, ipsi- or contralateral ALPS indices. In patients with GBM, glymphatic function might be impaired as expressed by decreased ALPS index in the ipsilateral hemisphere. Ipsi- or contralateral ALPS index reduction did not predict overall survival independent of known predictors. Because DTI-ALPS has inherent limitations, further investigation of glymphatic dysfunction using different methods in glioblastoma is warranted.

Alzheimer's disease (AD) features A -driven neuroinflammation and synaptic dysfunction that converge on cognitive decline, underscoring the potential value of multi-target interventions. Aurantio-obtusin (AO), a bioactive anthraquinone from Cassia obtusifolia L., exhibits reported anti-inflammatory and antioxidant activities; however, whether AO counteracts A -associated behavioral impairment through coordinated modulation of inflammatory and synaptic alterations remains unclear. Here, we investigated whether AO alleviates A -induced cognitive deficits and examined synapse- and inflammation-related molecular correlates. Male C57BL/6 mice received intracerebroventricular A to establish an acute AD-like model and were treated with AO (10 mg/kg/day, oral gavage) for consecutive weeks. The results showed that AO improved spatial learning and memory in the Morris water maze, recognition memory in the novel object recognition test, and working memory in the Y-maze, without affecting spontaneous locomotor activity. Furthermore, AO alleviated synaptic dysfunction by restoring synaptophysin expression and upregulating GAD65, and mitigated neuroinflammation by elevating anti-inflammatory factors (IL-4, IL-10, ARG1) and reducing TNF- . In vitro experiments confirmed that AO was non-cytotoxic to N2A APP cells across 0-80 M, mildly downregulated BACE1 expression, and suppressed the A -induced upregulation of pro-inflammatory mediators (IL-6, iNOS) in BV2 microglial cells. Overall, AO attenuated A 1-42 -driven behavioral impairment in parallel with improvements in synapse-associated markers and inflammatory readouts. These findings support further evaluation of AO as a natural compound associated with modulation of A -related neuroinflammatory and synapse-associated alterations.

Rapid identification of trauma-induced brain activity is critical for mitigating posttraumatic stress disorder (PTSD), especially in military personnel exposed to high-stress environments. This work proposes a novel framework that integrates reservoir computing (RC) with deep learning to classify individuals with PTSD and healthy controls based on EEG data. RC, particularly echo state networks (ESN), efficiently processes temporal data by projecting inputs into a high-dimensional space, making it ideal for complex datasets. To further enhance accuracy, we incorporate long short-term memory (LSTM) and attention-based models for focused feature learning and error correction. EEG-derived features were extracted and used to train three deep learning architectures: dense neural networks (DNNs), LSTM, and attention-based models. Results show that DNN achieved the highest classification accuracy at 92.16%, while LSTM and attention models yielded 84.31% and 74.51%, respectively. These findings demonstrate the potential of the RC-deep learning hybrid framework for both EEG signal prediction and PTSD classification. Future work will focus on real-time implementation in wearable neural technologies for continuous monitoring and early diagnosis of PTSD in high-stress environments.

Although powered orthotic devices are becoming more available and increasingly recognized by the medical community, several factors still prevent them from being widely adopted. These orthoses typically use a simple controller, often termed a "bang-bang" controller, which actuates a motor if the muscle's electromyography (EMG) signal is above a set threshold. A proportional controller that could actuate the elbow mechanism based on the EMG signal magnitude would enable a better human-machine connection. The real challenge for designing a proportional controller lies in the heterogeneity of the types of injury and surgeries used in this patient population, as well as the extent of recovery post-surgery. Neural networks effectively model nonlinear relationships in control system design. Recently, a novel powered myoelectric elbow orthosis (PMEO) was developed and tested on patients with a brachial plexus injury (BPI) that used a bang-bang controller. The report evaluated the possibility of using a proportional controller using a neural network-powered regression (NNR) for this exoskeleton. Data from 31 participants with a BPI were collected after receiving IRB approval. A custom apparatus was designed to measure elbow flexion torque and EMG, while participants were instructed to match their torque to a predefined target (10%-40% of MVC). A 2-layered NNR (2 hidden nodes) with a Tanh activation and 5 cross-validation folds was used to find a relationship between the properties of the EMG (moving average, root mean square, variance, standard deviation, and slope) and the elbow torque for individual participants. The collected data were divided into a training set (70%) and a test set (30%). The root mean squared error (RMSE) for the test set was calculated for each NNR model, along with the training time and prediction speed. A standard computer (Intel Core i5-10500 with 16 GB RAM) was used to train the models. The trained models required 82 seconds (range: 3-332 seconds) to train on 8.2e4 (range: 7.7e4-8.9e4) samples. The test dataset consisted of 3.5e4 (range: 3.3e4-3.8e4) samples. The median test RMSE was 0.39 Nm (range: 0.1-3.09 Nm). The NNR took 7 milliseconds (range: 6-10 milliseconds) to predict the test dataset; 35% and 16% of the models had an R2 0.5 and 0.7, respectively. A low-powered office computer was sufficient to train an NNR with training time short enough to be completed in an orthotist's office within a typical appointment time. These data verify that the process can be field deployable.

Lewy body diseases (LBDs) are heterogeneous, and this variability is already evident in the prodromal phase. Several frameworks propose that prodromal heterogeneity reflects distinct phenotypic and biological subtypes, supported by differences in clinical profiles, imaging, and -synuclein biomarkers. We provide a detailed clinical characterization of two enriched prodromal cohorts: isolated REM Sleep Behavior Disorder (iRBD) and Hyposmia with Dopamine Transporter Deficit. This cross-sectional study included 360 participants with iRBD, 1101 with hyposmia and abnormal dopamine transporter imaging and 283 healthy controls from the Parkinson's Progression Markers Initiative. Using the earliest assessments available, we compared the Montreal Cognitive Assessment (MoCA), Scales for Outcomes in Parkinson's Disease Autonomic Dysfunction (SCOPA-AUT) and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I-III. Group differences were assessed using age and sex-adjusted permutation testing. Secondary descriptive analysis identified the individual items contributing most to between-group differences. Both prodromal cohorts had significantly worse scores than healthy controls in all assessments. Compared with hyposmia, iRBD was associated with higher SCOPA-AUT and MDS-UPDRS Part I scores, driven mainly by constipation and urinary symptoms. In prodromal Lewy body disease, iRBD is associated with a statistically significant excess of autonomic symptom burden compared with hyposmia with dopamine transporter deficit, with the largest item-level differences in urinary and constipation measures.

Parkinson's disease (PD) is a multisystemic disorder that manifests through motor and non-motor symptoms. Motor dysfunction results from the degeneration of dopamine-producing neurons in the substantia nigra pars compacta. Increasing evidence suggests that synapse dysfunction precedes neuronal loss by years. Still, early synaptic alterations in PD remain poorly understood. Here, we integrate literature meta-analysis and multi-omics with biochemical, imaging, and electrophysiological measurements in Lrrk2 mouse models and human iPSC-derived neurons lacking LRRK2. We demonstrate that brain-derived neurotrophic factor (BDNF) activates LRRK2 in differentiated SH-SY5Y cells and primary mouse neurons, reshaping the LRRK2 interactome toward a network of actin cytoskeleton-related proteins. Gene-ontology analyses of both literature-curated LRRK2 interactors and phospho-proteome from striatal tissues with elevated LRRK2 activity highlight synapse-actin remodeling as major affected pathways. We further observed that loss of LRRK2 impairs BDNF signaling and alters postsynaptic density architecture. Young Lrrk2 knockout mice display structural alterations in dendritic protrusions, a phenotype that normalizes with age. In human iPSC-derived neurons, LRRK2 knockout affects maturation and BDNF-dependent regulation of spontaneous synaptic activity. Taken together, our study discloses a critical role of LRRK2 in BDNF-dependent synaptic modulation and identifies the synaptic actin cytoskeleton as a convergent site of LRRK2-associated pathophysiological processes in PD.

Skeletal muscle loss is associated with cognitive decline, but whether neuroimaging-derived muscle characteristics predict incident dementia remains unclear. We evaluated associations of deep learning-derived temporalis muscle (TM) cross-sectional area (CSA) and radiomic texture features from baseline T1-weighted magnetic resonance imaging (MRI) with incident dementia in dementia-free participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 750) and the Atherosclerosis Risk in Communities (ARIC) study (n = 532). TM was segmented using a convolutional neural network trained in ADNI and externally validated in ARIC. Radiomic features were reduced using least absolute shrinkage and selection operator-penalized Cox models to generate a composite score. Multivariable Cox regression adjusted for demographics, apolipoprotein E 4, baseline cognition, body mass index, and physical performance. Higher TM radiomic scores were associated with increased dementia risk in ADNI (hazard ratio per SD, 1.32) and ARIC (1.64). Smaller TM CSA predicted dementia in ADNI but not ARIC. TM texture patterns from routine brain MRI are associated with dementia risk, supporting TM phenotyping as a scalable marker of systemic biological vulnerability.

Pudendal neuralgia (PN) severely impacts quality of life, particularly sitting. Uncertainty exists whether catheter-based sacral nerve block with daily intermittent bolus (SNB) or pudendal nerve block (PNB) is more effective. This trial compared their efficacy over 6 months. A prospective, randomized, double-blinded trial in China enrolled 90 PN patients. Patients were randomized to CT-guided catheter-based PNB near the pudendal nerve or SNB through the third posterior sacral foramen. In both groups, the catheter remained in place for 7 days, and 10 mL of 0.2% ropivacaine was administered once daily as an intermittent bolus, with compound betamethasone administered on Day 7. Primary outcome was pain intensity (VAS) over 6 months; secondary outcomes included patient-reported global outcomes and maximum sitting time at 6 months. The SNB group had significantly lower VAS scores at 1 month (2.98 1.47 vs. 3.72 1.08, p = 0.04), 3 months (3.36 1.14 vs. 4.17 1.19, p = 0.02), and 6 months (3.85 1.04 vs. 4.95 1.08, p 0.0001). Significantly more SNB patients reported excellent/good outcomes at 1 month (83.88% vs. 63.40%, p = 0.04) and 6 months (75.61% vs. 37.50%, p = 0.002). Maximum sitting time at 6 months was longer with SNB (68.56 21.61 vs. 37.65 16.25 min, p 0.0001). No severe complications occurred. SNB provided superior and sustained pain relief, functional improvement, and patient satisfaction compared to PNB over 6 months in PN patients. Broader sacral root (S2-4) coverage by SNB may enhance efficacy by targeting pudendal neuropathy and central sensitization. SNB may be considered as an intermediate minimally invasive option for selected refractory PN patients in experienced centers, pending larger safety and feasibility studies. This first RCT directly comparing catheter-based nerve blocks for pudendal neuralgia demonstrates that sacral nerve block (SNB targeting S2-4) provides significantly superior and sustained pain relief, functional gains (doubled sitting tolerance), and patient satisfaction over pudendal nerve block (PNB) at 6 months. Its broader root coverage likely addresses central sensitization alongside neuropathy. Catheter-based sacral nerve block with daily intermittent bolus may represent an intermediate minimally invasive option for selected patients with refractory PN in experienced centers capable of structured catheter monitoring. Because this trial was not powered to estimate rare infectious complications and required a 7-day inpatient protocol, larger multicenter studies are needed to define safety, feasibility, cost-effectiveness, and the potential for outpatient adaptation.

Recent advances in cancer neuroscience have established the nervous system as an active regulator of tumor initiation and progression, emphasizing the complex bidirectional crosstalk between neural networks and oncology. In order to deconstruct the relationship between primary central nervous system malignancies and brain metastasis, this review systematically studies the specific mechanisms of neuron tumor synaptic communication, paracrine signaling, and neuroimmune interactions. Innovatively, autophagy is considered as a regulatory bridge connecting neuronal activity and tumor behavior. When functioning in neurons, autophagic flux determines synaptic plasticity and regulates neurotransmitter turnover. Inside tumor cells, autophagy may lead to uncontrolled proliferation and help evade immune surveillance. Integrating these molecular observations establishes the neuro-autophagy-tumor axis, and interconnected nodes in this axis provide emerging therapeutic strategies that target neural signaling and autophagy. These insights highlight the importance of incorporating neurobiological context into cancer research and position autophagy as a promising target for disrupting neural regulation in cancer therapy.

There are no community-based surveys for the development or assessment of public policies with an ecobiopsychosocial approach for autistic children. This article reports the development of an instrument assessing characteristics of Chilean autistic children, in order to understand how autism manifests in different environments. This study consisted of two stages: Firstly, after a comprehensive literature review, an instrument was designed by health and education professionals alongside autistic individuals and primary caregivers. Secondly, content validation was performed using the Content Validity Index, through the calculation of the Lawshe Content Validity Ratio. Sixty questions were validated, distributed across six subscales: "General Health Profile" obtained a Content Validity of 0.94; The subscales "Sex and Gender," "Autism Diagnosis and Concomitant Pathologies," "Family Income and the Impact of Autism on Socioeconomic Status," "Diet of the Autistic Person," and "Therapies and Schooling" obtained Content Validity Indexes of 0.89; 0.98; 1.0; 0.96; and 1.0, respectively. The Content Validity Index for the full instrument was 0.96. The survey presented demonstrated initial evidence of content validity and may serve as a basis for future psychometric validation. It allows for the assessment of this population in various life aspects, and offers great potential for creating public care policies regarding this community. As this study represents an initial content validation phase, future research should assess construct validity, criterion-related validity, reliability, and cross-cultural applicability.

Alcohol-related liver disease (ALD) is a major cause of liver-related morbidity and mortality worldwide, yet the associations linking alcohol-induced gut microbial alterations to metabolic remodeling and hepatocyte dysfunction remain incompletely understood. Here, we applied an integrative multi-omics strategy combining untargeted fecal metabolomics, shotgun metagenomics, mouse liver bulk RNA sequencing, and reanalysis of publicly available human hepatic single-cell and bulk transcriptomic datasets to characterize alcohol exposure-associated gut-liver immunometabolic features. In a mouse model of acute ethanol-induced liver injury, fecal metabolomic and metagenomic profiling revealed marked alterations in microbial functional potential and fecal metabolic composition, identifying six convergent metabolic pathways across fecal multi-omics layers, including nucleotide metabolism, the pentose phosphate pathway, histidine metabolism, glycerophospholipid metabolism, glycine/serine/threonine metabolism, and the phosphotransferase system. Reanalysis of human ALD single-cell transcriptomes showed hepatocyte-enriched activity patterns for several corresponding pathways, suggesting potential pathway-level associations between fecal metabolic alterations and hepatic transcriptional responses. Integrative transcriptomic analysis further identified a ten-gene hepatocyte-associated signature, comprising LRG1, ORM1, ORM2, TAT, HP, FGB, FGG, ITIH3, NNMT, and AGT, which was associated with pathway activity and showed consistent upregulation across acute ethanol-induced liver injury and human ALD/AH transcriptomic datasets. In an external human cohort, this signature stratified patients into exploratory molecular subgroups with distinct metabolic pathway activities and clinical outcome distributions. Collectively, these findings provide a hypothesis-generating multi-omics framework for investigating alcohol-related liver injury and support further validation in chronic ethanol exposure models and functional studies.

Late-onset unexplained epilepsy (LOUE) represents a substantial proportion of epilepsies with onset after 50 years and often manifests as temporal lobe epilepsy (LO-TLE). Although a link with Alzheimer disease (AD) has been suggested, only a subset of LO-TLE shows AD-related biomarkers, indicating biological heterogeneity. This study aims to characterize the cognitive and CSF phenotype of LO-TLE and compare it with healthy controls (HCs) and patients with mild cognitive impairment due to AD (MCI-AD). This Italian cross-sectional cohort study included LO-TLE patients with normal CSF -amyloid (A ) biomarkers, MCI-AD, and age-matched and sex-matched HC. Participants underwent structural MRI, neuropsychological assessment, and CSF biomarkers assay, including neurofilament light chain (NfL) and the phosphorylated-to-total tau ratio (p/t-tau). Cortical thickness and subcortical volumes were quantified from structural MRI. Cognitive performance was summarized using principal component analyses. Group differences in imaging, cognition, and CSF biomarkers were assessed, and associations between CSF markers and cognition were examined within groups. The study included 18 LO-TLE, 24 MCI-AD, and 17 HC. LO-TLE showed preserved cortical thickness and subcortical volumes comparable with HC, whereas MCI-AD exhibited widespread cortical thinning and medial temporal atrophy. Despite normal imaging, LO-TLE showed lower performance compared with HC in episodic memory ( t (53) = -7.79, p FDR 0.001), short-term memory ( t (53) = -2.94, p FDR = 0.007), language ( t (53) = 4.12, p FDR 0.001), and executive functions ( t (53) = -3.76, p FDR 0.001), while attention was preserved. Global cognitive performance further distinguished LO-TLE from MCI-AD, with the former group performing better ( t (53) = 4.21, p FDR 0.001). LO-TLE CSF profiles were characterized by low NfL levels and a p/t-tau ratio below the proposed cutoff of 0.17, whereas MCI-AD showed pathologic A and tau alterations, elevated NfL, and p/t-tau ratio above 0.17. In LO-TLE, a higher p/t-tau ratio was associated with better performance on global cognition ( rs = 0.585, p FDR = 0.032) and short-term memory ( rs = 0.588, p FDR = 0.032), whereas no associations emerged in MCI-AD. LO-TLE with normal CSF AD biomarkers is characterized by distinct cognitive and biological features compared with MCI-AD, suggesting a disease process independent of AD. The low p/t-tau ratio may reflect alternative pathophysiologic mechanisms and warrants further investigation in larger longitudinal studies to clarify the underlying pathology and clinical trajectories.

Pancreatic acinar cell carcinoma (ACC) is a rare and aggressive malignancy whose molecular basis remains poorly understood. N6-methyladenosine (m A) RNA modification, mediated particularly through methyltransferase 3 (METTL3), has emerged as a critical regulator in various cancers. Here, we investigated the role of METTL3-mediated RNA methylation in ACC development and progression. We used transgenic mouse models overexpressing Mettl3 and SV40 large T antigen under the pancreatic elastase I promoter. Comprehensive analyses included m A-methylated RNA immunoprecipitation sequencing (MeRIP-seq), single-cell RNA sequencing (scRNA-seq), functional studies using the METTL3 inhibitor STM2457, and S-adenosylmethionine (SAM)-binding domain deletion mutants to assess functional requirements. Mettl3 overexpression significantly accelerated ACC development and increased tumor aggressiveness. The SAM-binding domain was essential for tumor formation, as deletion mutants failed to promote carcinogenesis. MeRIP-seq revealed preferential methylation of cell cycle and DNA replication genes in Mettl3-overexpressing tumors. scRNA-seq analysis demonstrated enhanced malignancy signatures, including epithelial-to-mesenchymal transition and transforming growth factor- signaling. METTL3 also promoted PRSS1-mediated signaling from ACC cells to inflammatory cancer-associated fibroblasts, creating a feed-forward loop involving IGF1 that amplifies tumor growth. Conditional Mettl3 deletion induced rapid tumor apoptosis. Pharmacological inhibition with STM2457 similarly triggered caspase-3/7-dependent apoptosis in pancreatic tumors. METTL3-mediated RNA methylation drives ACC pathogenesis through tumor-intrinsic cell cycle regulation and tumor-extrinsic stromal interactions. These findings establish METTL3 as a promising therapeutic target and provide mechanistic insights supporting the clinical development of METTL3 inhibitors for ACC treatment.

Maladaptive self-beliefs are a core symptom of major depressive disorder. These beliefs are perpetuated by a negatively biased integration of self-related feedback. Understanding the neurocomputational mechanisms of biased belief updating may help to counteract maladaptive beliefs and the maintenance of depression. The present study uses a belief-updating task and functional neuroimaging to examine the neurocomputational mechanisms associated with self-related feedback processing in individuals with major depression (n = 35) and matched healthy controls (n = 32). We hypothesized that increased symptom burden in depression is associated with negatively biased self-belief updating and altered hemodynamic responses to social feedback. Our findings show that, in the clinical sample, the incorporation of unexpected positive feedback was reduced with greater symptom burden, and that insula reactivity was generally elevated to unexpected negative feedback. The interplay of increased hemodynamic responsiveness to negative feedback and the reduced learning from positive feedback provide new insights into cognitive distortions in depression and may explain the persistence of maladaptive self-beliefs and, thus, the maintenance of depression.

To evaluate the clinical impact of the DHACA method on the development of social skills in children with Autism Spectrum Disorder (ASD). This longitudinal quantitative intervention study conducted with 23 children with ASD, aged 3 to 6 years, who were nonverbal or minimally verbal. Individual intervention sessions using the DHACA method were held weekly for 20 weeks. Social skills were assessed before and after the intervention using the ACOTEA-R protocol. Data were statistically analyzed using the Wilcoxon test. There was a significant improvement (p 0.05) in ten of the sixteen skills assessed, including "responds to name," "eye contact," "shared attention," and "symbolic play." Other skills, such as "responds to 'no'" and "takes turns," showed a tendency toward clinical improvement, although not statistically significant. Only three skills did not show relevant progress. The DHACA method proved effective in promoting social skills in children with ASD, contributing to greater autonomy and social participation. The results reinforce its clinical potential as a therapeutic resource in both educational and healthcare settings. avaliar o impacto cl nico do m todo DHACA no desenvolvimento de habilidades sociais em crian as com TEA. Estudo de interven o, longitudinal e quantitativo, realizado com 23 crian as com TEA, entre 3 e 6 anos, n o-verbais ou minimamente verbais. As sess es individuais de interven o com o DHACA ocorreram semanalmente durante 20 semanas. A avalia o das habilidades sociais foi realizada antes e ap s a interven o, por meio do protocolo ACOTEA-R. Os dados foram analisados estatisticamente com o teste de Wilcoxon. Houve melhora significativa (p 0,05) em dez das 16 habilidades avaliadas, incluindo responde pelo nome , contato visual , aten o compartilhada e brincar simb lico . Outras habilidades, como responde ao n o e respeita turnos , apresentaram tend ncia de melhora cl nica, ainda que sem signific ncia estat stica. Apenas tr s habilidades n o demonstraram evolu o relevante. Os achados indicam melhorias nas habilidades sociais de crian as com TEA associadas ao uso do m todo DHACA , contribuindo para maior autonomia e participa o social. Os resultados refor am seu potencial cl nico como recurso terap utico em contextos educacionais e de sa de.

Efficient navigation requires prioritizing information from behaviorally relevant locations. In rats, such selective sampling may arise from theta-paced sweeps in grid and place cell populations, which scan nearby space in a left-right alternating pattern coordinated by parasubicular direction signals. This alternation promotes uniform spatial coverage during exploration, but whether sweeps can be flexibly tuned to moment-to-moment demands remains unknown. Using large-scale Neuropixels recordings in freely behaving rats, we show that sweeps and direction signals are rapidly and dynamically modulated: They track moving targets during pursuit, precede orienting responses during immobility, and reverse during backward locomotion-all without prior spatial learning of goal locations. Comparable modulation occurs during rapid eye movement (REM) sleep. Together, these findings identify sweeps as a flexible, attention-like mechanism for selectively sampling allocentric cognitive maps.

Serotonin (5-HT) depletion is a critical driver of migraine pathophysiology, yet its precise impact on trigeminal ganglion (TG) neurons remains unclear. This study investigates how 5-HT depletion shapes the "intrinsic neuronal susceptibility" of the first-order TG neurons by analyzing the electrophysiological properties of small-to-medium (SM) and large (L)-sized TG neurons in a rat model using patch-clamp recordings. Our findings reveal that 5-HT depletion significantly heightens the intrinsic susceptibility of TG neurons, with the electrophysiological disparities between SM and L-sized neurons acting as aggravating factors that intensify peripheral sensitization. Although this study focuses on intrinsic neuronal properties, our findings raise the possibility that 5-HT depletion may indirectly influence the functional balance between pro- and anti-nociceptive 5-HT receptor subtypes within the trigeminovascular system, a hypothesis that warrants further investigation. Functionally, this increased neuronal excitability may predispose TG neurons to heightened responsiveness, potentially contributing to hyperalgesia and altered somatosensory processing. By elucidating the role of serotonin in maintaining sensory homeostasis, this study provides critical insights into migraine pathogenesis and highlights the potential for targeted serotonergic therapies to mitigate excessive trigeminovascular activation.

Intravenous thrombolysis (IVT) is an established therapy for acute ischemic stroke when administered within 4.5 hours of symptom onset. However, many patients present beyond this window or with unknown onset, and recent randomized clinical trials (RCTs) have evaluated whether imaging-selected patients may benefit from thrombolysis in the extended window. To evaluate the functional and safety outcomes associated with IVT administered 4.5 hours or more after stroke onset. PubMed, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from database inception through March 3, 2026. RCTs enrolling adults with acute ischemic stroke treated with IVT 4.5 hours or more after symptom onset were included. Trials comparing thrombolysis with placebo or standard medical care and reporting functional or safety outcomes were eligible. Data were extracted independently by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Risk ratios (RRs) and mean differences with 95% CIs were pooled using random-effects models. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Primary outcomes were excellent functional outcome (modified Rankin scale scores of 0-1 at 90 days), good functional outcome (modified Rankin scale scores of 0-2 at 90 days), all-cause 90-day mortality, and symptomatic intracerebral hemorrhage (ICH). Fourteen RCTs including 4174 patients (2102 in the thrombolysis group and 2072 in the control group) were analyzed, 9 of which were published within the past 5 years. IVT was associated with a higher likelihood of excellent functional outcome (RR, 1.22; 95% CI, 1.14-1.31) and good functional outcome (RR, 1.12; 95% CI, 1.06-1.18) at 90 days. Mortality did not differ between groups (RR, 1.13; 95% CI, 0.93-1.38), but thrombolysis was associated with an increased the risk of symptomatic ICH (RR, 2.44; 95% CI, 1.45-4.09). Absolute treatment effects corresponded to a number needed to treat of 12 to 16 for an additional favorable outcome and a number needed to harm of 62 for symptomatic ICH. In this systematic review and meta-analysis of 14 RCTs, IVT administered beyond 4.5 hours after stroke onset was associated with improved functional outcomes despite an increased risk of symptomatic ICH, supporting extension of thrombolytic therapy beyond the conventional treatment window in appropriately imaging-selected patients.

The utilization of plant protein in aquafeeds to reduce dependence on fishmeal has become an important strategy for improving the sustainability of marine aquaculture. This study investigated the effects of low-fishmeal plant protein diets on growth performance and gut-liver molecular responses in large yellow croaker. A total of 2,048 fish were fed two diets for 206 days: a commercial-like control diet containing 280 g/kg fishmeal (C group) and a low-fishmeal diet containing 100 g/kg fishmeal with increased inclusion of plant protein sources (P group). Growth trials indicated that fish in the C group had significantly higher weight gain rate and specific growth rate than those in the P group (p 0.001). Transcriptomic analysis identified 546 and 724 differentially expressed genes (DEGs) in the hindgut and liver, respectively. Hindgut DEGs were mainly enriched in pathways associated with lipid metabolism, immune responses, and signal transduction, whereas liver DEGs were primarily involved in lipid metabolism, immune regulation, and apoptosis. Several pathways, including fat digestion and absorption, complement and coagulation cascades, taurine and hypotaurine metabolism, antigen processing and presentation, and cytokine-cytokine receptor interaction, were enriched in both tissues, suggesting coordinated gut-liver regulation. Representative genes involved in lipid metabolism and immune regulation, including apob, scarb1, c3, b2m, and ccr9, exhibited tissue-specific and coordinated expression changes. PPI network analysis further identified c3, scarb1, vwf, and apob as key regulatory nodes potentially involved in coordinated metabolic and immune adaptation. Collectively, these findings provide new insights into the molecular mechanisms underlying gut-liver adaptation to plant-based diets in marine fish.

This study was conducted to determine whether early dietary supplementation with an intermediate vitamin D metabolite could improve metabolic efficiency and liver function in rainbow trout. Over a 20-week feeding trial from first feeding, rainbow trout were fed either a control diet containing vitamin D 3 alone or a diet additionally supplemented with 80 g/kg 25-OH-D 3 . Plasma analysis confirmed that 25-OH-D 3 was efficiently absorbed, with detectable levels of 25-OH-D 3 and its epimer, indicating enhanced vitamin D status. While growth was similar between the experimental groups, fish receiving 25-OH-D 3 exhibited a significantly improved feed efficiency, indicating a better nutrient utilization. Whole-body composition analysis revealed higher protein and ash content and reduced lipid levels, consistent with transcriptomic evidence of modulated cholesterol and bile acid metabolism. Transcriptome profiling revealed 1301 differentially expressed genes in the liver, with strong modulation of pathways related to vitamin D metabolism, lipid handling, bile acid recycling, and ferroptosis. Additional signatures suggested improved nutrient partitioning and metabolic efficiency, potentially mediated by transcriptional and post-transcriptional mechanisms, including mRNA splicing. Consistent with its role on genome regulation via the vitamin D receptor, the data support the role of an active vitamin D system as a key potent modulator of efficient hepatic metabolism and function supporting improved feed utilization and long-term health outcomes in aquaculture.

Real-time cortical and cardiac electrophysiology provides direct insight into brain and heart function, revealing early signs of neurological or circulatory instability, supporting medics with rapid triage, continuous monitoring, and intervention during transport, evacuation, or battlefield operations. However, their deployment remains limited by motion and vibration artifacts that degrade signal integrity in dynamic field settings. This study examines the feasibility of auricular (in-ear) electrode configurations for improved signal robustness compared with scalp and wrist sites under both sustained vibration and dynamic acceleration within custom-built electrodes on matched electronics. Simultaneous recordings were obtained from the auricular canal (electroencephalogram [EEG] and electrocardiogram [ECG]), temple (F7 EEG), and wrist (ECG) in n = 5 participants across 3 motion conditions: engine off (parked), engine on (parked), and city driving ( 30 mph). Signal quality was assessed via waveform morphology, frequency-domain signal-to-noise ratio (SNR), coherence, and root mean square error (RMSE) relative to inertial measurement unit (IMU) data. Across 5 participants, auricular channels showed reduced 60 Hz interference ( -8 dB) and slightly higher SNR (median increase of 2 dB during driving) compared with scalp and wrist sites. This trend may reflect mechanical and electromagnetic shielding because of the enclosure of the canal. Under motion conditions, coherence and RMSE suggest weaker coupling between IMU motion and auricular signals compared with on-body sites ( 0.03 higher RMSE and 0.05 10-3 lower coherence). Auricular recordings indicate feasible signal integrity under vehicular motion, compared to conventional scalp and wrist placements. These preliminary results indicate suitability for neurocardiac monitoring.

Complex networks often exhibit emergent behaviors, where simple dyadic interactions yield collective dynamics that cannot be explained by examining the system's units individually or in pairs. Understanding how redundant and synergistic interaction emerges from elementary connectivity patterns is important in characterizing the behavior of physical, biological, and engineering systems. In this study, the information-theoretic framework of Partial Information Decomposition (PID) is employed to investigate how pairs of signals measured at the nodes of large network systems contribute individually and jointly to determine the overall state of the network. The analyzed systems are networks of numerically simulated R ssler oscillators and physical single-transistor electronic chaotic oscillators, reproducing purely pairwise and symmetric links in biological neuronal cultures, and cortical electroencephalographic networks assessed in humans. In the two settings, PID was extensively applied to decompose the information brought by pairs of signals to the overall state of the system, which was assessed respectively as the dynamic regime (from asynchronous chaos to synchronization) and the subject condition (open vs closed eyes). Our approach highlights the coexistence of redundant and synergistic interplays in determining the effect of the pairwise dynamics on the system's state. Specifically, we demonstrate how, in a highly synchronized system, where units act following overlapped redundant behaviors, their joint consideration helps determine the system's state though their synergistic interactions. Our findings reveal the emergence of non-trivial behaviors in networked systems based on pairwise connections and straightforward neural states, highlighting the need for using appropriate analytical tools to capture complex phenomena.

CVT-301 (Inbrija) has demonstrated its effectiveness in treating OFF periods in people with Parkinson's disease (PwP). However, its effect on non-motor symptoms (NMS) and quality of life has not been researched yet. Our aim was to analyze the change observed in health-related quality of life (HRQoL) and, as a secondary exploratory analysis, NMS associated with OFF episodes in PwP treated with CVT-301. INLEVO-LIFE PD (an open-label study of the effect of INhaled LEVOdopa on quality of LIFE and non-motor symptoms in Parkinson's Disease) is a prospective open-label study conducted in five centers in Spain. The change from baseline (V0) to the end of the observational period (12 2 weeks) (V12w) in the 39-item Parkinson's Disease Quality of Life Questionnaire (PDQ-39) total score was the primary efficacy measure. Forty PD patients (age 62.3 9.2 years; 55% males) were included between March/2024 and November/2025. At 12 weeks, 34 patients were using CVT-301 and completed the follow-up (85%). The PDQ39 total score decreased from 43.6 24.2 at V0 to 31.4 20.6 at V12w (p 0.0001). A significant decrease was observed in the mean score of 4 domains of the PDQ39. NMS burden was reduced at v12w from the OFF state to 30, 60, and 90 min after using CVT-301 (p 0.0001). Mean daily OFF time decreased by 1.6 1.9 h (p 0.0001). Adverse events related to CVT-301 were reported in 35% of the patients. HRQoL and NMS associated with OFF episodes improved in PwP after 12 weeks using CVT-301.

Urination, a vital and conserved process of emptying urine from the urinary bladder in mammals, requires precise coordination between the bladder and external urethral sphincter (EUS) that is tightly controlled by a complex neural network. However, the specific subpopulation of neurons that accounts for such coordination remains unidentified, limiting the development of target-specific therapies for certain urination disorders, for example, detrusor-sphincter dyssynergia. Here, we find that cells expressing estrogen receptor 1 (ESR1 + ) in the pontine micturition center (PMC) initiate voiding when activated and suspend ongoing voiding when suppressed, each at 100% reliability. Transection of the pelvic nerve does not impair PMC ESR1+ neurons' control of the EUS via the pudendal nerve, whereas transection of the pudendal nerve does not impair their control of the bladder via the pelvic nerve. Anatomically, PMC ESR1+ neurons consist of three distinct spinal-projection-based subpopulations: one targeting the sacral parasympathetic nucleus, one innervating the dorsal gray commissure, and a third that projects to both regions, thereby enforcing the coordination of bladder contraction and sphincter relaxation in a rigid temporal sequence. Thus, we identify a cell type in the brainstem that controls the bladder-urethra coordination for urination.

Multiple sclerosis (MS) can present with neurological and psychiatric symptoms that may overlap with those of schizophrenia, making differentiation difficult particularly because their typical onset ages are similar. We present the case of a woman in her 50s who developed persecutory delusions and a subjective sense of being under surveillance in Year X-31 and was diagnosed with schizophrenia. Despite the long-term antipsychotic treatment, the patient's symptoms persisted and worsened. In Year X-1, brain magnetic resonance imaging revealed multiple white matter lesions, and then cerebrospinal fluid analysis revealed oligoclonal bands, leading to a diagnosis of MS. Treatment with ofatumumab was initiated. Owing to persistent psychiatric symptoms, clozapine was administered, which showed partial effectiveness. This case highlights the clinical overlap between schizophrenia and MS and suggests that comorbid MS pathology may be clinically relevant in the context of treatment resistance and cognitive impairment. Similarities in symptoms and disease course raise the possibility that a subset of patients with schizophrenia may share pathophysiological features with MS. In addition, postmortem studies, including our previous and current observations, provide hypothesis-generating support for partially overlapping MS-like changes in some patients with schizophrenia. Clinicians should consider the possibility of comorbid MS in patients with treatment-resistant schizophrenia, particularly when atypical clinical or neurological features are present.

Heart failure (HF) is increasingly recognized as a systemic disorder that extends beyond the heart and affects neurovascular tissues, including the retina. However, the mechanisms by which circulating factors from HF trigger retinal neuroinflammation remain unclear. HF was induced in adult mice by transverse aortic constriction (TAC). Retinal structure and function were evaluated using optical coherence tomography (OCT) and electroretinography (ERG). Parabiosis and plasma transfer experiments were performed to assess the role of circulating factors. Endothelial senescence, microglial activation, and inflammatory signaling were analyzed using immunofluorescence, qPCR, and molecular assays. The functional relevance of TGF 2 and microglia was tested using anti-TGF 2 antibody administration and microglial depletion with PLX5622 treatment. TAC mice exhibited pronounced retinal thinning, diminished electroretinography (ERG) amplitudes, and reduced vascular density. Exposure of healthy mice to HF plasma reproduced these abnormalities, indicating that circulating mediators drive retinal injuries. TGF 2 levels were markedly elevated in the plasma of both patients with HF and TAC mice. Mechanistically, TGF 2 activated the pSMAD2/EP300 pathway in retinal endothelial cells, promoting H3K9 acetylation, P21 induction, and endothelial cell senescence. Senescent endothelial cells release proinflammatory factors that activate retinal microglia, leading to hypertrophic morphology, enhanced synaptic phagocytosis, and upregulation of cytokines such as IL1 , TNF , and IL6. Neutralization of TGF 2 or microglial depletion markedly reduced inflammation, preserved the retinal architecture, and restored visual function. Elevated TGF 2 levels in heart failure drive retinal endothelial epigenetic senescence, which secondarily activates microglia and induces neuroinflammation. Endothelial-specific disruption of TGF 2 signaling is sufficient to protect the retina independently of primary cardiac recovery. Targeting the TGF 2-endothelial-microglia axis may represent a promising therapeutic strategy for preventing retinal neurovascular degeneration associated with systemic cardiac disease.

Following spinal cord injury (SCI), activated microglia sustain neuroinflammation and drive secondary tissue damage, and this limits functional recovery. Myeloid differentiation primary response 88 (MyD88) is a central adaptor of innate immune signaling, but whether and how microglial MyD88 regulates state transition after SCI remains unclear. This study aims to explore the impact of microglial MyD88 signaling on microglial state trajectories and tissue repair after SCI and to develop a microglia-targeted delivery strategy for therapeutic modulation. A forceps-mediated SCI mouse model was established, and bulk and single-cell RNA sequencing were used to profile the temporal activation of microglial MyD88 signaling in the spinal cord. Pharmacological MyD88 inhibition (ST2825) and inducible microglia-specific MyD88 conditional knockout mice ( Tmem119 CreERT2 ; Myd88 fl/fl ) were used to assess neuroinflammation, tissue remodeling and downstream signaling. Functional recovery was evaluated by behavioral testing, bidirectional axonal tracing and electrophysiology. For translational validation, microglia membrane-coated, peptide-modified biomimetic nanoparticles (ST2825 DSPE@MG) were engineered to enhance microglia targeting and therapeutic efficacy. Transcriptomic analyses revealed rapid and sustained activation of MyD88 signaling preferentially in microglia after SCI. ST2825 suppressed pro-inflammatory outputs in vitro and in vivo while preserving trophic mediators. Microglia-specific MyD88 deletion reprogrammed injury-activated microglia from a pro-inflammatory state to a repair-associated phenotype, reducing neuronal damage, preserving axons and improving locomotor recovery. TGF- receptor blockade with LY2109761 abolished the protective effects of MyD88 deficiency. Additionally, ST2825 DSPE@MG nanoparticles exhibited microglia-targeted uptake and conferred superior therapeutic efficacy. Our data establish MyD88 as a critical regulator of microglial reprogramming after SCI and highlight its potential as a therapeutic target for spinal cord repair.

The functional responses of antigen (Ag) specific T cells are complex, clonotype-specific, context-dependent, and incompletely captured by dominant analytic approaches. Here we present T Cell Antigenic Recognition Sequencing (TAR-seq), a two-part process that uses single-cell RNA + T cell receptor sequencing (scRNA/TCR-seq) to provide a precise and comprehensive characterization of the differentiation state and functional response of T cells specific to a given antigen, ex vivo and in vivo . Many approaches use stimulation and activation-induced markers to identify Ag-specific T cells. We extend this by adding an scRNA/TCR-seq readout to identify the responding TCRs for each subject. We performed rigorous validation using tetramer-sorted T cells and developed a reusable probabilistic model to differentiate TCR-stimulated cells from bystander activation. These TCRs provide molecular barcodes to identify Ag-specific cells from unsorted scRNA/TCR-seq data, irrespective of stimulation, enabling a comprehensive view of their activity. We applied this method to a cohort of SIV-vaccinated rhesus macaques (RMs). We performed SIV-infected cell recognition assays to identify the SIV-specific TCRs for each RM. We used these TCRs to subset SIV-specific cells and perform precise contrasts. Despite identical vaccination, we identified clone- and subject-level variability in their cytotoxic differentiation and cytokine production after incubation with SIV-infected targets. Per clonotype, the percentage of cells that responded after antigen exposure varied widely. Finally, we used TCRs as barcodes to precisely map the in vivo activity of CD8+ T cells 48-120H after SIV challenge. Precise TCR-based identification separated Ag-specific and bystander effects, measuring tissue-specific responses of SIV-specific T cells within 48 hours of infection. Together, our data validate a powerful method to comprehensively understand T cell activity, with relevance to infectious disease, cancer, and autoimmunity, across species.

Epilepsy is one of the most common neurological disorders worldwide, affecting around 1% of the population. The epilepsies represent a diverse group of conditions, ranging from acquired forms resulting from neurological insults to common multifactorial epilepsies and rare, often monogenic epilepsies caused by highly penetrant genetic variants. The genetic epilepsies demonstrate frequent comorbidity with a range of neurodevelopmental and psychiatric disorders, and epileptic seizures are also a common feature of neurodevelopmental disorders such as Fragile X syndrome and Rett syndrome. Astrocytes, the most numerous glial cells in the central nervous system, have emerged as crucial players in the pathophysiology of acquired epilepsies. Whilst the contribution of astrocytes to acquired epilepsy has been widely reviewed, astrocyte dysfunction in rare genetic epilepsies or neurodevelopmental disorders has been neglected, despite the fact that the genes implicated are expressed in astrocytes, albeit to a lesser extent than in neurons. Additionally, affected individuals with rare genetic epilepsies are more likely to exhibit drug-resistant seizures, highlighting the need to identify novel therapeutic targets. In this paper, we review the existing literature on astrocyte dysfunction in genetic epilepsy syndromes and neurodevelopmental disorders with seizures. We have identified several key studies that highlight alterations in crucial astrocyte functions including calcium signaling and ion homeostasis. Our review highlights the need for further research to establish the contribution of astrocyte dysfunction to neuronal health and seizure activity in rare genetic epilepsies.