Wei Li

Osteoarthritis (OA) is increasingly supported by evidence as a whole-joint disorder, in which chondrocyte injury drives whole-joint degeneration rather than merely accompanying cartilage breakdown. Under sustained mechanical, metabolic, and inflammatory stress, chondrocyte cytoprotective systems become progressively exhausted. These protective systems include the system Xc ⁻ /GSH/GPX4 axis and parallel anti-ferroptotic defenses, iron storage and export, mitochondrial quality control, and autophagy. This review focuses on the staged failure of these buffering systems during OA progression, from adaptation and compensation to threshold crossing, rather than presenting a catalogue of independent cell death pathways. Beyond this threshold, the predominant mode of chondrocyte death shifts from immunologically silent apoptosis to membrane-lytic inflammatory forms including ferroptosis, pyroptosis, and necroptosis, which are frequently co-activated within the same tissue. Two interrelated propositions are put forward. First, these cell death modalities share a limited set of upstream perturbations: accumulation of reactive oxygen species, NF-κB activation, dysregulated iron homeostasis, and mitochondrial dysfunction. Second, downstream cell death execution is determined by a small set of molecular switches. These switches include caspase-8 catalytic activity, ESCRT-III-dependent membrane repair capacity, and GPX4 abundance. CHMP5, a key component of membrane repair, is consistently depleted in OA cartilage. OA-specific evidence for these switches is now emerging, including ZBP1-dependent PANoptotic signalling in cartilage. Approximately one hundred regulators associated with regulated cell death (RCD) reported in OA joint tissue are catalogued and annotated by direction of change, tissue compartment, OA-specific experimental support, and druggability. A metabolic–epigenetic circuit is proposed to reinforce death-prone chondrocyte states. This circuit involves histone lactylation, m ⁶ A modification of GPX4 and ATG7, and α-ketoglutarate depletion. From this perspective, the limited efficacy of single-target therapies reflects the architecture of the shared network. Stage- and compartment-matched interventions represent a more tractable therapeutic strategy.

Peripheral hormonal dysfunction is associated with multiple neurological disorders, yet how astrocytes sense circulating stress‐related hormones to influence depression pathogenesis remains incompletely understood. Here, we showed that disruption of secretin receptor (SCTR) signaling in dorsal raphe nucleus (DRN) astrocytes promotes depression‐like behaviors. We identified AMPKα1 as a key downstream effector of astrocytic SCTR signaling and demonstrate its role in regulating astrocytic secretion of metallothionein‐1 (Mt1) and downstream megalin‐mediated AMPKα2 signaling in serotonergic neurons. We further identified the transcription factor Foxc2 as a downstream target of neuronal AMPKα2 that modulates depressive‐like behaviors through suppression of serotonergic activity and reduced neuronal excitability. Mechanistically, AMPKα2 regulates phosphorylation of the acetyltransferase KAT7, thereby modulating histone H4 acetylation and Foxc2 transcription. Together, these findings delineate an astrocyte–neuron signaling axis linking SCTR–AMPKα1 signaling in astrocytes to epigenetic regulation of Foxc2 by AMPKα2–KAT7/H4ac signaling in serotonergic neurons, providing fundamental insight into circuit‐level mechanisms underlying depression.

Objective: Temporal changes in spatiotemporal gait parameters and muscle activation may reflect progressive gait deterioration during prolonged walking in children with spastic cerebral palsy. Methods: A portable gait analysis system and surface electromyography were used to evaluate gait characteristics during a 3-minute walking protocol in 15 children with SCP and 15 age-matched healthy controls. Participants walked at a self-selected speed on a level surface. Spatiotemporal gait parameters, energy expenditure, and bilateral gastrocnemius and tibialis anterior muscle activation were assessed at predefined time points. Linear mixed-effects models were applied to examine group-by-time interactions while accounting for repeated measurements within participants. Results: Linear mixed-effects model analysis revealed significant Group × Time interactions for stance phase, swing phase, step length, lower-limb forward acceleration, foot clearance angle, and walking velocity (all P < 0.05), indicating divergent temporal trajectories between children with SCP and healthy controls. No significant Group × Time interactions were observed for single-step time, gait cycle duration, or cadence (all P > 0.05). For energy expenditure, a significant Group × Time interaction ( P = 0.047) indicated that the SCP group maintained elevated metabolic cost into the third minute while controls exhibited a declining trajectory. Similarly, significant Group × Time interactions were observed for bilateral gastrocnemius ( P = 0.002) and tibialis anterior ( P = 0.006) normalized root mean square amplitudes, reflecting a greater temporal decline in muscle activation in the SCP group from the second minute onward. Conclusion: Children with SCP may exhibit gradual changes in spatial-temporal gait parameters and muscle activation patterns during the later stages of a long walking task. These findings suggest that selected gait and EMG parameters in children with SCP begin to change after approximately 2 min of continuous walking, indicating a potential time window for closer monitoring or structured rest breaks during rehabilitation. Further studies incorporating direct fall-risk assessment and validated fatigue measures are warranted before definitive clinical recommendations can be made.

Disorders of consciousness (DoC) following severe brain injury remain difficult to treat, and effective non-invasive therapeutic options are still limited. Transcutaneous auricular vagus nerve stimulation (taVNS) has recently emerged as a promising neuromodulation approach in this field. In this narrative review, we synthesize recent evidence on taVNS for DoC across four domains: neurophysiological mechanisms, multimodal monitoring evidence, clinical efficacy, and stimulation parameter optimization with safety considerations. Current mechanistic models suggest that taVNS may influence consciousness through the auricular branch of the vagus nerve, engaging brainstem nuclei such as the nucleus tractus solitarius and locus coeruleus, and subsequently modulating thalamo-cortical and large-scale cortical networks; this remains a biologically plausible working model rather than a validated causal pathway. Preliminary clinical data suggest that patients in a minimally conscious state may respond more often than those with unresponsive wakefulness syndrome/vegetative state; however, this is a subgroup-level signal—the only sham-controlled randomized trial to date found no significant overall between-group difference—and the evidence remains limited by small samples, protocol heterogeneity, and short follow-up. Multimodal tools including electroencephalography, functional near-infrared spectroscopy, heart rate variability, and serum biomarkers may improve mechanistic understanding and responder stratification, but integrated evidence within the same patient cohorts remains scarce. Overall, taVNS appears to be a promising adjunctive intervention for DoC, but its routine clinical application remains provisional until ongoing multicenter randomized trials clarify efficacy, durability, optimal stimulation parameters, and responder profiles.

To investigate knee biomechanical characteristics and kinesiophobia levels across different body mass index (BMI) categories in patients following tibial plateau fracture surgery, and to examine the mediating role of kinesiophobia in the relationship between BMI and knee biomechanical outcomes. A cross-sectional controlled study was conducted. Sixty postoperative tibial plateau fracture patients were stratified into Group A (obese, BMI ≥ 28 kg/m²), Group B (overweight, BMI 24.0-27.9 kg/m²), and Group C (normal weight, BMI 18.5-23.9 kg/m²), with 20 patients per group, alongside 20 healthy controls (Group D). Kinesiophobia and knee function were assessed using the Tampa Scale for Kinesiophobia-17 (TSK-17) and the Lysholm Knee Scoring Scale, respectively. A three-dimensional motion capture system synchronized with a force platform was used to collect spatiotemporal gait parameters and knee kinematic and kinetic data. Between- and within-group bilateral limb differences were analyzed, and correlation analysis, multiple linear regression, and bootstrap mediation analysis were performed to examine the mediating effect of kinesiophobia. Between-group comparisons revealed that Lysholm scores progressively decreased (Group A: 73.80 ± 4.74; Group B: 77.95 ± 2.86; Group C: 81.65 ± 3.63), whereas TSK-17 scores progressively increased (Group A: 57.00 ± 3.88; Group B: 51.40 ± 3.44; Group C: 46.70 ± 4.66) with increasing BMI (P < 0.01). On the affected side, cadence (Group A: 60.90 ± 12.56; Group D: 105.90 ± 4.61 steps/min), gait velocity (Group A: 0.58 ± 0.19; Group D: 1.08 ± 0.06 m/s), and sagittal plane range of motion (Group A: 47.46° ± 9.46°; Group D: 67.23° ± 2.82°) progressively decreased, whereas sagittal plane moments progressively increased (Group A: 680.35 ± 130.98; Group D: 225.13 ± 85.78 N·m) across BMI groups (P < 0.01). Within-group comparisons demonstrated that sagittal plane range of motion on the affected side was significantly smaller than that on the unaffected side, and that joint moments were significantly greater on the affected side across all three patient groups (P < 0.05); however, no significant bilateral differences were observed in the control group. Mediation analysis indicated that kinesiophobia partially mediated the relationship between BMI and gait velocity on the unaffected side (indirect effect = - 0.01; 95% CI [- 0.03, - 0.00]) as well as between BMI and sagittal plane moments on the affected side (indirect effect = 7.45; 95% CI [0.43, 18.56]), with mediation proportions of 48.4% and 27.5%, respectively. Patients with postoperative tibial plateau fractures and higher BMI exhibited significantly worse knee function, greater kinesiophobia, and compromised biomechanical characteristics, including slower gait, reduced sagittal plane range of motion, and elevated knee joint moments. Kinesiophobia partially mediated the adverse effects of elevated BMI on gait velocity and sagittal plane moments. Clinical rehabilitation programs should incorporate BMI-stratified individualized interventions integrating weight management with targeted psychological support to reduce kinesiophobia. Chinese Clinical Trial Registry ChiCTR2500101020. Registered on 18/04/2025.

Background: Functional recovery following tibial plateau fracture surgery exhibits substantial heterogeneity, with 30-40% of patients demonstrating persistent functional limitations. However, the impact of reduced functional scores on walking capacity and the underlying neuromuscular mechanisms remain unclear, limiting the development of individualized rehabilitation protocols. This study aimed to characterize gait patterns and neuromuscular control strategies across different functional outcome levels through multimodal assessment, providing objective evidence for precision rehabilitation.Methods: This cross-sectional study enrolled 64 patients at 12 months post-surgery, stratified by KOOS-ADL scores into higher (≥80, n=32) and lower (≤70, n=32) functional outcome groups. Participants completed normal walking, dual-task walking, and balance-challenged walking while three-dimensional motion capture, fNIRS, and sEMG data were synchronously acquired.Results: During normal walking, no significant between-group differences were observed in spatiotemporal parameters, but the lower functional outcome group exhibited sensorimotor cortex hypoactivation (S6-D5, S6-D11, p<0.01) and reduced affected-side ankle muscle co-contraction (TA-GL: d=1.23, p<0.001). During dual-task walking, affected-side ankle power demonstrated superior discriminative capacity (1.06 vs. 3.07 W/kg, p<0.001, r=0.572), with reduced unaffected-side thigh muscle co-contraction (RF-Ham: d=0.74, p=0.004). During balance-challenged walking, knee coronal plane ROM asymmetry reached maximum differentiation (32.74% vs. 7.29%, d=2.54, p<0.001), accompanied by bilateral DLPFC deactivation (S8-D8, S9-D9, p<0.001), bilateral co-contraction deficits (affected-side RF-Ham: d=0.89, p=0.001), and positive correlation between DLPFC activation and unaffected-side muscle coordination (r=0.478, p<0.001).Conclusions: Patients with lower functional scores exhibit knee coronal plane control impairment, ankle power insufficiency, sensorimotor cortex hypoactivation, DLPFC exhaustion, and reduced antagonist muscle co-contraction. Task-challenge paradigms effectively unmask latent deficits. Compensatory strategies manifest as enhanced unaffected-side thigh muscle coordination regulated by prefrontal cognitive control. These findings support a "bone-brain-muscle coordination" framework for precision rehabilitation.

The comorbidity of mood disorders (MDs), represented by depression and anxiety, with chronic somatic diseases (CDs), particularly cardiometabolic conditions, poses a significant global public health challenge, markedly increasing the risk of adverse prognoses and all‐cause mortality. Epidemiological studies indicate that ~36% of patients with multimorbidity exhibit psychosomatic comorbidity, with higher risk populations concentrated among females, older adults, and socioeconomically disadvantaged individuals. This review systematically analyzes the epidemiological distribution patterns of MD–CD comorbidity, with the strongest emphasis on cardiometabolic diseases—diabetes, metabolic syndrome (MetS), obesity, hypertension (HTA), and cardiovascular disease (CVD)—for which the mechanistic data are most developed, while also addressing osteoarthritis, psoriasis, inflammatory bowel disease (IBD), cancer, and neurological disorders. By integrating molecular mechanisms with clinical evidence, we highlight core pathological pathways and critically evaluate the strength of evidence supporting each: hypothalamic–pituitary–adrenal (HPA) axis dysfunction and insulin resistance (IR), substantiated by clinical data and Mendelian randomization; NLRP3 inflammasome‐mediated neuroinflammation as a transdiagnostic inflammatory node; gut–brain axis dysregulation involving bile acid–GLP‐1 signaling and gut‐derived metabolites such as trimethylamine N‐oxide (TMAO); and the kynurenine pathway (KP) as a branched metabolite axis with organ‐specific consequences. Sex‐specific mechanisms, particularly estrogen‐regulated neuroendocrine and metabolic pathways, are identified as consistent biological modifiers of this comorbidity. A bidirectional vicious cycle underpins MD–CD comorbidity: metabolic abnormalities exacerbate limbic system dysfunction via HPA‐axis hyperactivity, neuroinflammatory cascades, and disrupted gut–brain signaling, while MDs aggravate metabolic dysregulation through neuroendocrine disturbances and reduced treatment adherence.

Functional recovery after cardiac events is heterogeneous, with up to 40% of patients showing limited improvement despite standardized rehabilitation. Curr