Exoskeletons have been considered for mitigating ergonomic risks of work-related musculoskeletal disorders (WMSDs), but they are not consistently utilized in initial deployments as workers in some facilities have not voluntarily used them. In this study, we investigated the impact of a passive shoulder exoskeleton on a drilling-fastening task with participants (n = 13) from a manufacturing training facility who have a little or no experience in using an exoskeleton. The direct measures of joint angles (shoulder and torso) and user perceptions of discomfort were analyzed. Inertial Measurement Units (IMUs) were used to estimate the shoulder and torso posture, with the orientations mapped to the Rapid Upper Limb Assessment (RULA) risk regions to support posture interpretation. Key actions (e.g., drilling and countersinking) were characterized within the work to understand how well a passive upper-body exoskeleton aligned with the task. Exoskeleton presence decreased the observed torso flexion for a subset of tasks, indicating decreased injury risk from the perspective of the torso, but limitations in selected postures. Exoskeleton presence did not have a large influence on the shoulder elevation, suggesting workers could perform the necessary tasks with the exoskeleton. However, the exoskeleton did not support a consistent positive influence on user perceptions. Importantly, participant postures show that the passive exoskeleton did not align with the dynamic shoulder movement for these tasks and created times when workers moved against the exoskeleton. These findings help explain potential barriers to exoskeleton acceptance reported in past studies. Factors such as limited postural adaptability, no linked decrease in perceived discomfort, and misalignment between exoskeleton support and the dynamic movements required by specific tasks may contribute to workers' reluctance to adopt exoskeletons. There are opportunities to extend shoulder exoskeletons to be more aligned with the nature of work, such as adding controllers to adjust the exoskeleton support to align with the user's actions.

Huntington's Disease is a neurodegenerative disorder that progresses over time and can be passed down from parent to child. In uncontrolled motor activities, behavioural problems come into play, as well as progressive mental decline. The CAG triplet in the HTT gene found on chromosome 4 undergoes changes, leading to the production of a mutant protein called huntingtin, which consists of a bigger-than-normal polyglutamine tract that then undergoes misfolding and produces toxic oligomers and fibrillar deposits that can cause dysfunction in normal cell functioning and therefore in nerve cells as well. Although early research linked the pathophysiology of Huntington's disease primarily to mHTT aggregation, more recent research indicates broad protein-protein interaction networks that affect several cellular pathways. Systems biology approaches using tools such as STRING, BioGRID, and Cytoscape have provided evidence of interconnected networks that promote proteostasis, mitochondrial dynamics, energy metabolism, neuroinflammation, synaptic transmission, and transcriptional and epigenetic regulation. Important protein hubs, including HSP70, DRP1, NLRP3, and TFEB, act as central controls that bind those pathways. mHTT-mediated defect in the function of the ubiquitin-proteasome system promotes mitochondrial oxidative stress, which triggers the NLRP3 inflammasome, leading to synaptic dysfunction and specific loss of striatal medium spiny neurons. Investigations using various experimental techniques, which involve R6/2 and YAC128 mouse models, neurons derived from human iPS cells, and multi-omics studies, reveal that faulty neuroplasticity develops before the formation of visible protein aggregates. As for therapeutics targeting central components of neuronal networks, they have all demonstrated certain neuroprotective effects.

Parkinson's disease (PD) is characterised by progressive dopaminergic neurodegeneration and alpha-synuclein (α-syn) aggregation, with levodopa remaining the gold-standard symptomatic therapy despite its inability to halt disease progression or prevent levodopa-induced dyskinesia (LID). Caenorhabditis elegans has emerged as a highly tractable model for mechanistic PD research owing to its conserved dopaminergic pathways, optical transparency, rapid lifecycle, and suitability for high-throughput pharmacological screening. This review critically examines the pharmacological effects of levodopa in C. elegans PD models across locomotor behaviour, α-syn aggregation, lifespan, and dyskinesia-related phenotypes, while comparing these findings with phytochemicals evaluated in analogous experimental systems. Levodopa consistently restored dopamine-dependent locomotor deficits but failed to substantially reduce α-syn aggregation or extend lifespan, recapitulating the clinical dissociation between symptomatic motor rescue and persistent neurodegeneration. In contrast, phytochemicals, including Frondoside A, hydroxytyrosol/Hidrox®, Neurogrit Gold, Mucuna pruriens extract, quercetin, and quercetin nanoemulsions, demonstrated broader mechanistic profiles involving antioxidant responses, mitophagy, proteostasis, and dopaminergic neuroprotection. The available evidence suggests that phytochemicals are best regarded not as replacements for levodopa but as candidate adjuncts that, in preclinical worm models, appear to act on upstream pathological processes; whether this translates into genuine complementarity in vivo remains a hypothesis requiring direct testing. The central argument advanced here is methodological rather than pharmacological: C. elegans is currently the only PD model in which symptomatic motor rescue and α-synuclein pathology can be quantified simultaneously in the same living animal, and this dissociation provides a measurable framework for defining what an adjunctive compound would need to achieve. On this basis, levodopa is proposed as a mandatory positive control for future C. elegans phytochemical screening. Critical translational limitations-including the absence of a blood-brain barrier in C. elegans, phytochemical bioavailability constraints, and uncertainty regarding the relationship between aggregate reduction and true neuroprotection-are also discussed.

The abnormal expansion of repetitive DNA sequences falls within the spectrum of neurological conditions driven by dual pathogenic pathways of RNA toxicity and protein toxicity. Within this spectrum, hexanucleotide repeat disorders (HRDs) represent a rare but important subgroup: C9orf72-amyotrophic lateral sclerosis/frontotemporal dementia (C9orf72-ALS/FTD), X-linked dystonia-parkinsonism (XDP) and spinocerebellar ataxia type 36 (SCA36), unified by the presence of expanded intronic repeats capable of forming non-canonical nucleic acid structures. Despite this shared repeat architecture, they differ in critical molecular and genetic respects: C9orf72-ALS/FTD is hallmarked by TDP-43 aggregation and prominent proteinopathy; SCA36 lacks TDP-43 pathology entirely; and XDP uniquely harbors a SINE-VNTR-Alu (SVA) retrotransposon insertion within the expanded locus and follows an X-linked recessive inheritance pattern. Among these, C9orf72-ALS/FTD is relatively well characterized, with established pathogenic mechanisms including G-quadruplex (G4) formation, dipeptide repeat (DPR) protein toxicity, RNA foci formation, and downstream cellular disruptions. The molecular mechanism underlying SCA36 and XDP remains comparatively less characterized. Given the mechanistic overlap with ALS/FTD, downstream disruptions such as RNA toxicity, mitochondrial dysfunction, impaired DNA repair and proteasomal dysfunction could similarly result from these core molecular processes. However, direct experimental evidence supporting these mechanisms in SCA36 and XDP remains limited. This review compares established, emerging and hypothetical mechanisms across HRDs to distinguish shared pathogenic pathways from disease-specific molecular features. Through horizontal comparison, this review identifies opportunities and limitations for translating ALS/FTD therapeutics to XDP and SCA36, establishing a unified analytical framework for mechanistic research and clinical intervention in rare repeat expansion disorders.

Treadmill exercise improves motor and dopaminergic phenotypes in toxin-based Parkinson's disease models, but the contribution of monocarboxylate transport remains uncertain. This small-scale, hypothesis-generating exploratory study tested whether systemic AR-C155858, an MCT1/MCT2 inhibitor used in experimental systems, altered lactate kinetics and recovery-related outcomes in MPTP-treated mice during identical treadmill exercise. Its purpose was to detect a coordinated phenotype that could justify subsequent confirmatory mechanistic testing. The two-group design was not intended to estimate the independent effect of exercise, the effect of AR-C155858 without exercise, or a drug-by-exercise interaction. Male C57BL/6J mice received MPTP (20 mg/kg/day, intraperitoneally, 5 days) and, after 3 days, completed 4 weeks of forced treadmill exercise (16 m/min, 40 min/day, 5 days/week, 5° incline). Mice received vehicle (Ex-Veh) or AR-C155858 (Ex-AR; 10 mg/kg intraperitoneally, 30 min before exercise). Blood lactate was measured in weeks 1 and 4; motor behavior was assessed before MPTP, after MPTP, and after the intervention; endpoint striatal TH, Iba1, GFAP, and dopamine metabolites were measured. AR-C155858 was associated with higher 30-min post-exercise lactate and smaller recovery amplitude, but not altered lactate peak increment or AUC. Ex-AR mice showed smaller changes in open-field distance, pole-test turning, stride length, and fore-hind overlap, together with lower endpoint striatal TH and dopamine and higher Iba1. GFAP and DOPAC did not differ significantly; HVA was not tested because multiple values were below quantification. In male MPTP-treated mice under a common treadmill condition, systemic AR-C155858 was associated with delayed peripheral lactate decline and less favorable motor and endpoint striatal outcomes. Because MCT1/MCT2 expression, localization, and target engagement were not measured, the findings do not establish a brain- or cell-specific MCT mechanism. These findings generate testable hypotheses for a subsequent, larger factorial mechanistic study. Animal-level open-field data, a baseline-adjusted sensitivity analysis, and executable analysis code are supplied as Supplementary materials.

Parkinsonian tremor can remain disabling despite optimized medical therapy, impairing writing, drinking, feeding, and other activities of daily living. Gamma Knife radiosurgical (GKRS) thalamotomy is an incisionless surgical option for tremor patients who require chronic anticoagulation or have other major comorbidities for more invasive alternatives. We retrospectively evaluated the outcomes of 42 Gamma Knife thalamotomy procedures performed for medically refractory Parkinsonian tremor during the 1996 - 2020 interval. Outcomes parameters included clinical benefit, initial tremor relief, recurrence, motor functional improvement, and complications. Functional outcomes were assessed using Fahn-Tolosa-Marín (FTM) subscore composed of tremor, writing, drawing, and drinking domains. The median age at treatment was 76.5 years (IQR, 72.0-81.8), and median final follow-up was 14.0 months (IQR, 8.0-28.2). Clinical benefit occurred in 37 of 42 patients (88.1%), with a median time to onset of benefit of 4.0 months (IQR, 3.0-6.0). Tremor arrest occurred in 14 of 40 evaluable patients (35.0%), and complete arrest occurred in 10 of 40 (25.0%). The median total tremor-related FTM subscore improved from 12 before treatment to 4 after treatment, corresponding to a median relative improvement of 54.2% (p < 0.001). Temporary adverse effects occurred in 5 patients (11.9%). No definite tremor recurrence was documented. GKRS thalamotomy provides meaningful clinical benefit and significant tremor-related functional improvement with a low complication rate in selected patients with medically refractory Parkinsonian tremor. It remains a valuable incisionless surgical option for tremor-dominant Parkinson's disease when medical or more invasive therapies are unsuitable.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the pathological accumulation of Lewy bodies composed predominantly of aggregated α-synuclein (αSyn). Despite decades of progress in genetics and neuropathology, the mechanisms driving disease initiation and progression remain incompletely understood, and no disease-modifying therapy has yet demonstrated conclusive efficacy. Neuroinflammation and metabolic dysfunction have emerged as two central and mechanistically intertwined pillars of PD pathogenesis. We propose an integrative model in which these processes function not merely in parallel, but as mutually reinforcing components of a self-amplifying pathological circuit, while acknowledging that this model remains to be fully validated and that alternative causal architectures are possible. This review systematically addresses the mechanistic coupling between neuroinflammation and metabolic dysregulation in PD, covering: (1) the molecular basis of innate immune activation via DAMPs, pattern recognition receptors, and inflammasome signaling; (2) microglial metabolic reprogramming and the NLRP3/NF-κB inflammatory axis; (3) αSyn-driven innate and adaptive immune responses; (4) mitochondrial dysfunction and oxidative stress as bidirectional amplifiers; (5) the gut-brain axis as a conduit for peripheral immunometabolic disruption; (6) the AMPK/mTOR/HIF-1α molecular network integrating metabolism and inflammation; (7) sphingolipid metabolism and the GBA-lysosomal axis; and (8) translational evidence from animal models and randomized controlled trials. A concise section integrates key fluid biomarkers as clinical surrogates of the underlying mechanisms.

Parkinson's disease (PD) is increasingly recognized as a multisystem disorder in which gastrointestinal dysfunction and gut microbial alterations may contribute to disease pathophysiology. Although most microbiome research in PD has focused on bacteria, growing evidence suggests that the gut ecosystem should be considered more broadly to include fungi, viruses, metabolites, and proteins.