Search Results (278)

Background and Objectives: Parkinson’s disease (PD) is a neurodegenerative disorder marked by bradykinesia, rigidity, and tremor. While deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) effectively alleviates motor symptoms, the potential of targeting the substantia nigra pars reticulata (SNr) is less understood. This study investigates the effects of mid-term DBS of the SNr on motor function and neuroplasticity in a 6-hydroxydopamine (6-OHDA) rat model of PD. Methods: Adult male Sprague-Dawley rats (280–300 g) were divided into healthy control (n = 10), PD (n = 9), sham-DBS (n = 7), and SNr-DBS (n = 7) groups. Bilateral striatal 6-OHDA lesions induced PD. High-frequency (130 Hz, 60 µs) SNr-DBS was delivered for 14 days. Locomotor activity (open-field), gait (footprint method), and motor coordination (rotarod) were assessed. Tyrosine hydroxylase (TH) expression in the SN and c-Fos and BDNF expression in the cerebellum, prefrontal cortex (PFC), and ventrolateral thalamus were analyzed histologically. Results: SNr-DBS significantly improved ambulation and horizontal activity compared to the PD group (p < 0.05). Gait analysis showed significant improvements in forelimb/hindlimb stride length and stance width, while rotarod performance indicated enhanced motor coordination (p < 0.05). Histology revealed increased TH expression in the SN and elevated c-Fos and BDNF levels in the cerebellum, PFC, and thalamus in the SNr-DBS group vs. PD rats (p < 0.05). Conclusions: Mid-term SNr-DBS produced significant functional gains in motor activity and coordination in a 6-OHDA PD model, together with molecular evidence of dopaminergic enhancement and neuroplastic activation. These translational findings suggest that targeting the SNr may offer a clinically relevant alternative for patients with PD, particularly for those who may not optimally respond to conventional STN or GPi stimulation. Full article

Background/Objectives: Fetal alcohol spectrum disorders (FASDs) occur in nearly 5% of children in the United States and have been associated with alterations in neurological functions, neuroanatomical changes, and behavioral deficits encompassing an individual’s lifetime. Alterations in myelination have been reported in both rodent models and humans. The cerebellum is a heavily myelinated brain region, and oligodendrocyte and myelination transcripts have been reported to be altered in the cerebellum following early-life ethanol (EtOH) exposure in a mouse model. In this study, we investigated cerebellar-recruited behaviors in adult female mice that were exposed to EtOH from postnatal day (P) 4 to P9. We investigated whether changes in oligodendrocyte lineage markers were present in adulthood. Methods: C57BL/6J offspring received a total of 5.0 g/kg/day of either ethanol (EtOH) or saline in two separate doses delivered subcutaneously two hours apart from P4 to P9. On P21, offspring were weaned and housed with same-sex littermates throughout the duration of the study. From P60 to P90, females underwent behavioral testing including an open field test (OFT), rotarod, and balance beam. Behavior naïve littermates were euthanized on P105, and cerebella were collected for qPCR to assess oligodendrocyte lineage transcripts. Results: We reported that, following EtOH exposure from P4 to P9, adult female mice had increased ambulatory behaviors in the OFT and subtle changes in behavior in the rotarod and balance beam compared to saline-exposed controls. Despite the behavioral changes observed in adulthood, we found that alterations in oligodendrocyte lineage transcripts present on P10 did not persist into adulthood. Conclusions: Subcutaneous injection of EtOH from P4 to P9 resulted in long-term consequences in locomotor and cerebellar-recruited behaviors in female mice. Full article

Sarcopenia and glucocorticoid-induced myopathy are significant forms of muscle atrophy that pose considerable public health challenges. In this regard, preventing muscle atrophy is crucial for enhancing quality of life and increasing life expectancy. In this study, we investigated the effect of recombinant human KAI1 (rhKAI1) on myogenic differentiation and its protective effect against dexamethasone-induced muscle atrophy. rhKAI1 enhanced myogenic differentiation in both murine C2C12 myoblasts and primary human endometrial stromal cells, as evidenced by upregulation of myogenic regulatory factors and increased myotube formation. These effects were accompanied by increased phosphorylation of Akt and AMPK. In a dexamethasone (Dex)-induced atrophy model, rhKAI1 increased myotube diameter, restored MyHC expression, and reduced the expression of the E3 ligase atrogin-1, accompanied by increased phosphorylation of Akt and AMPK. In addition, rhKAI1 administration improved Dex-induced functional impairment in mice, as reflected by increased grip strength and improved rotarod performance. Molecular analyses further showed that rhKAI1 modulated Dex-induced fiber-type-related gene expression by restoring MYH7 (type I) and reducing MYH4 (type IIb) expression. Collectively, our findings demonstrate that rhKAI1 promotes myogenic differentiation and alleviates several functional and molecular features associated with glucocorticoid-induced muscle deterioration. These results support the potential of rhKAI1 as a candidate molecule for further investigation in steroid-induced muscle dysfunction. Full article

Background: Tubular aggregate myopathy (TAM) is an autosomal dominant myopathy that results from gain-of-function mutations in the STIM1 and ORAI1 genes, which encode the two key proteins that coordinate store-operated Ca²⁺ entry in skeletal muscle and other cell types. Knock-in mice heterozygous for a glycine-to-serine point mutation in the ORAI1 pore (ORAI1^G100S/+ or GS mice) phenocopy several key aspects of TAM in humans with the analogous mutation including muscle weakness, exercise intolerance, elevated CK levels, hypocalcemia, and the presence of tubular aggregates. Methods: Since homozygous inheritance of the ORAI1-G100S mutation is embryonic lethal, we assessed the impact of homotypic ORAI1-G100S expression in skeletal muscle by crossing GS mice with constitutive, muscle-specific ORAI1 knock-in mice (cORAI1-KO). Results: Compound cORAI1-KO/GS mice exhibit only one active ORAI1 (GS) allele, and thus only express ORAI1-G100S monomers in skeletal muscle (‘homotypic’ GS mice). Homotypic GS mice exhibit an earlier onset and more severe muscle phenotype than age-matched heterotypic GS mice with both WT and GS alleles. Specifically, homotypic GS mice exhibit TAs at an earlier age, as well as significantly reduced in vivo muscle performance (grip strength, treadmill endurance, and rotarod endurance), maximal specific force production, and respiratory function, compared to those observed for both WT and heterotypic GS mice. Conclusions: These findings indicate that homotypic expression of the ORAI1-G100S mutation in skeletal muscle results in an earlier-onset and more severe muscle phenotype. Full article

Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily affects the motor neurons. T cell intracellular antigen 1 (TIA1) is a risk gene for ALS pathogenesis. To elucidate TIA1-mediated disease mechanisms, a mouse model recapitulating clinical and pathological features of ALS is needed. TIA1 mutations are rare in human ALS, and mutations are heterozygous, while this study uses a homozygous TIA1 mutant mouse model to amplify pathogenic effects for experimental tractability. Methods: To explore the mechanisms by which mutant TIA1 causes ALS neurodegeneration, we generated a TIA1 mutant mouse by introducing ALS-causing mutations into the endogenous animal via cytosine base editors. Next, behavioral experiments (open-field and rotarod tests) assessed motor function and analyzed pathologies using morphological assessments. Results: Our TIA1Δ mouse model phenocopies select pivotal features of ALS, including TAR DNA-binding protein 43 (TDP-43) accumulation, motor neuron loss, neuroinflammation in the lumbar spinal cord, and muscle atrophy. Notably, this homozygous mutation design with reduced TIA1 expression differs from human heterozygous TIA1 mutations. Conclusions: This work provides a foundation for understanding the TIA1-ALS relationship and for developing strategies to treat this intractable neurodegenerative disorder. Caution is warranted extrapolating findings to human ALS pathogenesis due to model design differences. Full article

Background/Objectives: Baichuan Baile (BCBL), a novel functional dietary formula, has been shown to exert antidepressant-like effects through modulation of the 5-HT system in our prior studies. Given the close neurobiological connections between depression and insomnia, along with its pharmacodynamic profile guided by TCM theory and nutritional assessments, BCBL is likely to possess beneficial effects against insomnia. However, this hypothesis and its underlying mechanisms require further validation. Methods: The chemical constituents of BCBL were analyzed by UPLC-Q-TOF-MS, and network pharmacology was applied to predict potential sleep-relevant targets and pathways. Subsequently, BCBL was evaluated for sedative-hypnotic effects using pentobarbital-induced hypnosis, locomotor activity, and polysomnography (EEG/EMG). Its therapeutic efficacy was further assessed in insomnia models induced by environmental stress, serotonin depletion, and rotarod-based sleep deprivation. The rotarod-induced chronic model was selected for mechanistic studies due to its sustained insomnia-like phenotype. Finally, key network-predicted targets were validated in this model through histopathology, Western blotting, and ELISA. Results: Pharmacological evaluation confirmed that BCBL significantly promoted sleep at both behavioral and EEG levels, confirming its sedative-hypnotic properties. BCBL mitigated environmental stress-triggered impairments in NREM sleep continuity and duration, and exerted protective effects against body weight loss and sleep disturbances in a serotonin depletion-induced insomnia model. In the rotarod sleep deprivation model, BCBL treatment increased spontaneous alternation rates and recognition indices, ameliorated hippocampal pathological alterations, and reduced hippocampal levels of HIF-1α, TNF-α, and IL-1β. Furthermore, BCBL elevated the p-GSK3β/GSK3β ratio and enhanced SIRT₁ expression in the hypothalamus. It also modulated the activity of key sleep–wake neurotransmitters/neuromodulators (serotonin, dopamine, adenosine, and glutamate) and key circadian rhythm regulators (BMAL₁, PER₂, and CLOCK) in this region. Conclusions: BCBL exhibits significant therapeutic efficacy against insomnia, indicating its potential as a dietary supplement for managing insomnia. Its mechanisms appear to involve anti-inflammatory effects, rebalancing of neurotransmitters/neuromodulators, and stabilization of circadian rhythm gene expression. Full article

Background. Cannabis and cannabinoids have been investigated for their potential therapeutic effects in Parkinson’s disease, but clinical research findings remain scant and inconsistent. This study provides a systematic overview of peer-reviewed meta-analyses assessing their impact on health outcomes in patients with Parkinson’s disease. Methods. A comprehensive search of PubMed, EMBASE, Web of Science, and Google Scholar (from database inception to April 2025) identified meta-analyses evaluating cannabis-based interventions in Parkinson’s disease. Eligible studies reported pooled estimates of effects on neurological symptoms. The most significant findings from the included studies were summarized and qualitatively analyzed. Results. After screening 975 research items, six meta-analyses of clinical and preclinical studies, primarily randomized controlled trials (RCTs), were included. One meta-analysis of five RCTs demonstrated that pure cannabidiol (CBD) or synthetic tetrahydrocannabinol (THC) significantly improved PD symptoms (SMD = −0.41, p = 0.004). Another meta-analysis combining two RCTs and two non-RCTs reported a significant improvement in the Unified Parkinson’s Disease Rating Scale (UPDRS) total score (MD = −4.19, p = 0.03). With regard to pain management, cannabinoids were found effective in one study. Preclinical meta-analyses in animal models showed notable motor improvements, including enhanced rotarod performance (MD = 31.63 s, p = 0.003) and reduced pole test completion times (MD = −1.51 s, p = 0.028). Conclusions. While meta-analyses of clinical studies suggest some benefits of specific cannabinoid formulations, findings are still uncertain. Preclinical data, however, demonstrate interesting motor improvements. Further well-designed RCTs are warranted to clarify the therapeutic role of cannabis in Parkinson’s disease management. Full article

Mutations in the Mitofusin 2 (MFN2) gene cause Charcot–Marie–Tooth type 2A (CMT2A). Neurotrophin 3 (NT-3) is an autocrine factor that supports Schwann cell survival and differentiation, axon regeneration and myelination, neuromuscular junction (NMJ) integrity, and mitochondrial function. In this study, we assessed the efficacy of NT-3 gene therapy using the AAVrh74 serotype in the Mfn2^+/− mouse model for CMT2A. Although haploinsufficiency is not reported in CMT2A patients, our model shows some features of CMT2A, including axonal atrophy, muscle atrophy, length-dependent axon loss, and abnormal mitochondria, in muscle in the enzyme histochemistry. Eight-month-old Mfn2^+/− mice received a 3 × 10¹¹ vector genome dose of AAVrh74.tMCK.NT-3 intramuscularly, and functional, electrophysiological, and histological outcomes were assessed six months post-treatment. NT-3 gene therapy in Mfn2^+/− mice significantly improved grip strength and rotarod performance, and ameliorated electrophysiological abnormalities and NMJ denervation in lumbrical muscles. Additionally, our therapeutic approach improved muscle histopathology with reductions in mitochondrial abnormalities and oxidative stress. NT-3 further remodeled carbohydrate metabolism in muscle. Our study indicated that AAV.NT-3 gene therapy has a disease-modifying effect in the Mfn2^+/− model of CMT2A, providing further support for the translational potential of this surrogate gene therapy approach to CMT2A patients. Full article

Peripheral nerve regeneration is most rapid during the early post-injury period but gradually slows over time, often limiting functional recovery. Electrical stimulation (ES) delivered via percutaneous needle electrodes has been shown to modulate the local neural microenvironment and promote axonal regeneration; however, the optimal temporal window and duration of stimulation remain unclear. This study aimed to evaluate the time-dependent effects of needle-based ES on peripheral nerve regeneration in a rat model of sciatic nerve transection, using a well-established silicone nerve conduit as a stable and reproducible non-biodegradable repair model. Female Sprague–Dawley rats underwent sciatic nerve transection and repair. Postoperatively (PO), animals were randomly assigned to control (C) needle insertion or needle-based ES groups, receiving stimulation for either 3 weeks (C-3W-PO and ES-3W-PO, respectively) or 7 weeks (C-7W-PO and ES-7W-PO, respectively). Functional recovery was evaluated using cold plate latency and rotarod performance tests. Electrophysiological assessments included measurements of nerve conduction velocity (NCV), compound muscle action potential amplitude, and muscle action potential (MAP) area. Histomorphometric analysis of regenerated nerve tissue quantified total nerve cross-sectional area, endoneurial space, axon number, and axon density. Retrograde labeling with fluoro-gold (FG) was used to quantify reinnervated motor neurons. Immunohistochemical analyses of calcitonin gene-related peptide (CGRP) and macrophage-associated markers were conducted to assess sensory neuropeptide expression and immune cell infiltration within the regenerated nerve. ES significantly improved both sensory and motor recovery in a duration-dependent manner. Behavioral data showed increased cold pain thresholds and improved motor coordination in ES groups, with the most pronounced functional gains observed in the ES-7W-PO group. Electrophysiological measures revealed higher NCV, amplitude, and MAP area in ES-treated animals, with the most pronounced improvements at 7 weeks. Morphologically, ES enhanced nerve regeneration, as evidenced by increased total and endoneurial areas, axonal counts, and axon density. FG-labeled neuron counts were significantly elevated in ES groups, indicating enhanced motor reinnervation. At 3 weeks, ES induced higher CGRP expression and macrophage density, suggesting transient activation of sensory-associated and pro-regenerative immune responses during the early post-injury phase. These findings demonstrate that ES accelerates peripheral nerve repair in rats and that sustained stimulation across the early regenerative window yields superior structural and functional outcomes. Full article

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by age-dependent degeneration of dopaminergic neurons in the substantia nigra, a process mediated by α-synuclein aggregation, mitochondrial dysfunction, and impaired proteostasis. While BAP31—an endoplasmic reticulum protein critical for protein trafficking and degradation—has been implicated in neuronal processes, its role in PD pathogenesis remains poorly understood. To investigate the impact of BAP31 deficiency on PD progression, we generated dopamine neuron-specific BAP31 conditional knockout with DAT-Cre (cKO) mice (Slc6a3cre-BAP31^fl/fl) and subjected them to MPTP-lesioned Parkinsonian models. Compared to BAP31^fl/fl controls, Slc6a3cre-BAP31^fl/fl mice exhibited exacerbated motor deficits following MPTP treatment, including impaired rotarod performance, reduced balance beam traversal time, and diminished climbing and voluntary motor capacity abilities. BAP31 conditional deletion showed no baseline phenotype, with deficits emerging only after MPTP. Our results indicate that these behavioral impairments correlated with neuropathological hallmarks: decreased NeuN neuronal counts, elevated GFAP astrogliosis, reduced tyrosine hydroxylase levels in the substantia nigra, and aggravated dopaminergic neurodegeneration. Mechanistically, BAP31 deficiency disrupted mitochondrial homeostasis by suppressing the PINK1–Parkin mitophagy pathway. Further analysis revealed that BAP31 regulates PINK1 transcription via the transcription factor Engrailed Homeobox 1. Collectively, our findings identify BAP31 as a neuroprotective modulator that mitigates PD-associated motor dysfunction by preserving mitochondrial stability, underscoring its therapeutic potential as a target for neurodegenerative disorders. Full article

Parkinson’s disease is the second most common neurodegenerative disease in the world. Natural products can offer a possible option of neuroprotective agents for preventing neurodegenerative diseases. D-Pinitol is a cyclic polyol with anxiolytic and antidepressant effects in acute assays. This work aimed to evaluate the effects of D-Pinitol (10, 50, and 100 mg/kg p.o.) in a chronic reserpine-induced depression model (19 days), using the forced swimming and tail suspension tests in female Balb/c mice, and the neuroprotective effects in an MPTP-induced Parkinsonism model (30 days) in male C57bL/6 mice, using behavioral tests such as wire grip, rotarod, catalepsy, and others. D-Pinitol showed low antidepressant-like effects in the reserpine-induced chronic depression model, compared to amitriptyline (25 mg/kg p.o.). D-Pinitol protected MPTP-treated mice from motor impairment with similar effects to those shown by L-Dopa (25 mg/kg p.o.) as evaluated in different behavioral tests. The inhibition of oxidative stress markers, increase in dopamine levels, and avoidance of apoptosis in neuronal cells were the mechanisms by which D-Pinitol protects MPTP-treated mice from motor impairment. Full article

Peripheral nerve injuries, particularly those involving the sciatic nerve, remain a major clinical challenge due to incomplete functional recovery and the limited translation of preclinical advances into effective therapies. This review synthesizes current evidence on the phase-specific evaluation of sciatic nerve regeneration in preclinical models, integrating behavioral, sensory, electrophysiological, and morphological approaches across the acute, subacute (Wallerian degeneration), early regenerative, and late regenerative phases. By mapping functional readouts onto the underlying biological events of each phase, we highlight how tools such as the Sciatic Functional Index, Beam Walk test, Rotarod test, nerve conduction studies, and nociceptive assays provide complementary and often non-interchangeable information about motor, sensory, and neuromuscular recovery. We further examine emerging therapeutic strategies, including intraoperative electrical stimulation, immunomodulation, platelet-rich plasma, bioengineered scaffolds, conductive and piezoelectric conduits, exosome-based hydrogels, tacrolimus delivery systems, and small molecules, emphasizing the importance of aligning their mechanisms of action with the dynamic microenvironment of peripheral nerve repair. Despite substantial advancements in experimental models, an analysis of publication trends and registries reveals a persistent translational gap, with remarkably few clinical trials relative to the high volume of preclinical studies. To illustrate how mechanistic insights can be complemented by molecular-level characterization, we also present a targeted computational analysis of alpha-lipoic acid (ALA,) including frontier orbital energies, physicochemical descriptors, and docking interactions with IL-6, TGF-β, and a growth-factor receptor—performed solely for this molecule due to its documented structural availability and relevance. By presenting an integrated, phase-specific framework for functional assessment and therapeutic evaluation, this review underscores the need for standardized, biologically aligned methodologies to improve the rigor, comparability, and clinical relevance of future studies in sciatic nerve regeneration. Full article

In this study, the neurorehabilitation potential of combined and isolated intermittent hypercapnia and hypoxia exposure was evaluated following photochemically induced cerebral thrombosis in rats. Particular attention was given to the roles of possible neuroplasticity mechanisms mediated by VEGF and BDNF, as well as the potential of hypercapnic–hypoxic interventions to synergistically amplify the therapeutic effects of pharmacological neuroprotectants during recovery. A total of 50 male Wistar rats were randomly assigned to five equal groups (n = 10 per group), each undergoing a course of respiratory interventions lasting 30 min per day for 15 sessions. The groups included (1) a normobaric hypoxia (PO₂ ≈ 90 mmHg) group, (2) a permissive hypercapnia (PCO₂ ≈ 50 mmHg) group, (3) a combined hypercapnic hypoxia (PO₂ ≈ 90 mmHg, PCO₂ ≈ 50 mmHg) group, (4) a control group, and (5) a sham-operated group. Following the rehabilitation protocol, animals exposed to hypercapnic hypoxia exhibited a two-fold reduction in stroke volume compared with controls, significant improvement in motor coordination (as assessed via the rotarod test), and marked upregulation of VEGF and BDNF expression within the ischemic brain region. Notably, only the HH group showed a decrease in serum neuron-specific enolase (NSE) levels. These findings indicate that hypercapnic hypoxia exerts a possible neurorehabilitative effect after focal ischemic injury, superior to that of isolated hypoxia or hypercapnia. Possible mechanisms underlying this outcome may involve activation of neurotrophic (BDNF) and angiogenic (VEGF) signaling pathways. Full article

Background/Objectives: Non-alcoholic steatohepatitis (NASH) is a progressive liver condition closely associated with gut microbial dysbiosis and hepatic metabolic abnormalities. Poria cocos polysaccharide (PCP), a bioactive component derived from the medicinal fungus Poria cocos, possesses hepatoprotective properties, yet the therapeutic mechanisms of PCP in NASH, particularly those involving microbial and metabolic regulation, remain incompletely elucidated. This study aimed to investigate the effects of PCP on improving NASH and explore its mechanisms related to prebiotic activity. Methods: Mice were induced to develop NASH using a Western diet, followed by PCP intervention for 12 weeks. Hepatic function, including liver enzymes and lipids, glucose metabolism, and liver histopathological changes, was assessed. Fatigue and neurobehavioral alterations were evaluated via rotarod, open field, and tail suspension tests. Hepatic pro-inflammatory cytokines were measured using RT-qPCR. Gut microbiota were analyzed through 16S RNA gene sequencing, and metabolites of liver tissue were analyzed through untargeted metabolomics. Results: PCP decreased blood glucose and hepatic lipid levels in NASH mice, alleviating liver inflammation, ballooning degeneration, and fibrosis. It also improved fatigue-like performance on rotarod test and reduced the hepatic expression of IL-6, IL-1β, TNF-α, and IL-18. Microbiota analysis revealed that PCP restored gut microbial diversity, promoted the growth of beneficial taxa such as Alistipes and Butyricoccaceae_UCG-009, and inhibited harmful bacteria, including Romboutsia ilealis. Liver metabolomics showed that PCP normalized key metabolites like taurocholate and regulated taurine and hypotaurine metabolism, which were correlated with reduced inflammation, fatigue-like performance, and fibrosis. Conclusions: PCP, as a promising edible agent, alleviates hepatic damage, metabolic disorders, and fatigue-like performance on rotarod test in NASH mice, probably by reshaping gut microbiota and modulating hepatic taurine and hypotaurine metabolism. Full article

Background: Despite life-saving newborn screening programs and a life-long galactose-restricted diet, many patients with classic galactosemia continue to develop long-term debilitating neurological deficits, speech dyspraxia, and primary ovarian insufficiency (POI). In an earlier study, we showed that administration of an experimental human GALT mRNA predominantly expressed in the liver of the GalT gene-trapped mouse model augmented the expression of hepatic GALT activity, which reduced build-up of galactose and its toxic metabolites not only in the liver but also in the peripheral tissues. Moreover, we showed that the administration of GALT mRNA in the mutant mice restored whole-body galactose oxidation (WBGO), which is a functional biomarker. Methods: In this pilot study, we extended our proof-of-concept efficacy studies to a disease-relevant phenotype: motor impairment. GalT-KO mice aged 3 and 6 weeks old administered biweekly intravenous injections of 100 µL GALT mRNA at a dose of 2 mg/kg for 2 months. Motor performance was assessed using rotarod testing and composite phenotype scoring, 3 and 9 weeks following the dosing regimen. Results: Preliminary results showed that a biweekly dosing at 2 mg/kg for 2 months improved the motor performance of the animals in rotarod and composite phenotype scoring tests in a short-term experiment. Conclusions: Despite being a small-scale study, our findings suggest that when treated early in life, the experimental GALT mRNA is effective in improving the motor-related phenotypes in GalT-KO mice using the specified dosing regimen. These findings highlight the potential of mRNA-based therapies for mitigating neurological symptoms in Classic galactosemia. Full article