Locomotor Impairment Research Articles

Patients with multiple sclerosis and low disability display cautious rotational behavior during gait initiation.

Multiple sclerosis induces locomotor impairments. The objective was to characterize the effects of Multiple Sclerosis on whole-body angular momentum control during gait initiation. Fifteen patients with Multiple Sclerosis with Expanded Disability status scale of 2.5 and 16 healthy participants were instructed to perform gait initiation. Spatiotemporal parameters, whole-body angular momentum, net external moment about the body's center of mass and its components were calculated by using a 3D motion capture system and two force plates. Patients with Multiple Sclerosis had a significantly smaller whole-body angular momentum range during the double support phase of gait initiation in the transversal plane (p=0.011), and smaller net external moment at the transition between the initial double support phase and the execution phase in the sagittal plane (p=0.013). In the transversal plane, patients with Multiple Sclerosis had a smaller net external moment during the double support phase (p=0.024) and between the double support phase and the execution phase (p<0.001). Despite preserved spatiotemporal parameters during gait initiation, patients with Multiple Sclerosis with low disability had reduced net external moments in the transversal and sagittal planes during the critical transitional period of this functional task, which appeared as a compensatory modality to preserve global postural stability. This finding highlights the cautious rotational behaviors in these planes to prevent the risk of falling and preserve dynamic stability. Whole-body angular momentum and net external moment are relevant parameters for functional and disease progression follow-up of the disease.

Biomechanical aspects of gait impairments after stroke: an analytical review

Restoring gait and balance functions after stroke constitutes a major problem in modern neurology. Post-stroke static and locomotor impairments are the most common disabling consequences that are critical for patients’ quality of life and basic functional independence. This analytical review attempts to comprehensively examine and assess the biomechanical aspects affecting the gait in patients with post-stroke static and locomotor impairments. The review outlines the multifaceted nature of such impairments, including muscle weakness, changes in neuromotor coordination, proprioception and stability, as well as compensatory mechanisms developing in patients. A particular focus is on biomechanical parameters, including kinematics and kinetics of movements, to provide a deeper understanding of the nature of impairments in order to develop more effective treatment strategies. The analysis highlights the importance of a personalized rehabilitation approach to be based on specific impairments of each patient. This review is intended to enhance the understanding of the biomechanical aspects of gait impairments for further research and development of innovative approaches in rehabilitation. The data presented are of great importance for the development and elaboration of personalized medical rehabilitation plans for post-stroke patients and may contribute to improving their functional independence and quality of life.

Deep brain stimulation of the anterior cingulate cortex reduces opioid addiction in preclinical studies

Substance Use Disorder (SUD) is a medical condition where an individual compulsively misuses drugs or alcohol despite knowing the negative consequences. The anterior cingulate cortex (ACC) has been implicated in various types of SUDs, including nicotine, heroin, and alcohol use disorders. Our research aimed to investigate the effects of deep brain stimulation (DBS) in the ACC as a potential therapeutic approach for morphine use disorder. Additionally, we measured c-Fos protein expression as an indicator of neural activity in the nucleus accumbens (NAc) and prefrontal cortex (PFC). Our findings indicate that high-frequency (130 Hz) DBS at different amperages, 150 µA and 200 µA in the ACC during the acquisition phase of morphine conditioned place preference (CPP) inhibited the rewarding properties of morphine. Furthermore, DBS at these intensities during the extinction phase facilitated the extinction and mitigated the reinstatement of morphine CPP triggered by drug priming. Morphine conditioning was associated with impaired novel object conditioning (NOR) and locomotor activity. While DBS in the acquisition and extinction phases at both intensities restored NOR memory, only DBS at 200 µA recovered locomotor activity in the open field test. Treatment with DBS at 200 µA decreased c-Fos protein expression in the NAc and PFC (compared to morphine-only group). In conclusion, our data indicate an intensity-dependent effect of ACC DBS on the acquisition, extinction, and reinstatement of morphine-induced CPP in rats. These findings suggest that ACC DBS could be a potential intervention for the treatment of morphine use disorder.

Trehalose Ameliorates Zebrafish Emotional and Social Deficits Caused by CLN8 Dysfunction.

CLN8 and other neuronal ceroid lipofuscinoses (NCLs) often lead to cognitive decline, emotional disturbances, and social deficits, worsening with disease progression. Disrupted lysosomal pH, impaired autophagy, and defective dendritic arborization contribute to these symptoms. Using a cln8-/- zebrafish model, we identified significant impairments in locomotion, anxiety, and aggression, along with subtle deficits in social interactions, positioning zebrafish as a useful model for therapeutic studies in NCL. Our findings show that trehalose, an autophagy enhancer, ameliorates anxiety, and modestly improves social behavior and predator avoidance in mutant zebrafish. This finding aligns animal models with clinical reports suggestive of behavioral improvements in NCL patients. Trehalose holds promise as a therapeutic agent for CLN8, warranting further research into its neuroprotective mechanisms and clinical applications.

MODULATION OF MORPHINE ANTINOCICEPTIVE AND REWARDING EFFECT BY MIRTAZAPINE IN AN ANIMAL MODEL OF OSTEOARTHRITIC PAIN

People with chronic pain mitigate their suffering by the action of opioids. Adverse reactions aside, opioids are not exempt from potential complications like addiction and abuse, which have posed a global public health problem lately. Finding new therapeutic strategies to improve analgesia and to reduce opioid side effects has become a priority. In this regard, the association of different adjuvant therapies has been postulated. Despite preclinical and clinical evidence supporting the use of antidepressants as analgesics, it is not clear whether they could help reduce the risk of addiction in combination with opioids. To further explore this idea a model of chronic osteoarthritis pain was employed, and a combination of mirtazapine and morphine was used in a chronic regimen in male and female rats. The effects on the development of tactile allodynia, movement-evoked pain, reward, analgesic tolerance, naloxone-induced withdrawal symptoms, impaired locomotor activity and anxiety were evaluated under a 25-day experimental protocol. Additionally, protein expression of μ-opioid receptors and clusterin (related with substance abuse) was evaluated in plasma and in brain structures of the reward system. Chronic morphine caused analgesic tolerance, reward and naloxone-induced withdrawal symptoms. The combination reduced the analgesic tolerance and prevented the development of withdrawal symptoms but showed sex-based differences regarding reward. Increased levels of clusterin in plasma were observed in females treated with morphine, but not with combined therapy. The combination of mirtazapine and morphine could be a promising strategy to improve the management of long-term opioid treatment and its risk of abuse, especially in females.

Leflunomide exerts neuroprotective effects in an MPTP‑treated mouse model of Parkinsonism.

Neuroinflammation and the immune response are recognized as significant mechanisms contributing to the progression and pathophysiology of Parkinson's disease (PD). Consequently, extensive research is being conducted on drugs targeting inflammation and immune response. Leflunomide, known for its anti‑inflammatory and immunomodulatory properties, is currently used as a disease‑modifying agent for the treatment of rheumatoid arthritis. The objective of this study was to investigate the effect of leflunomide on PD. The PD model was established by administering 18 mg/kg of 1‑methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine (MPTP) intraperitoneally for 5 consecutive days. Leflunomide was administered intraperitoneally at doses of 1, 5, and 10 mg/kg for 14 days. Motor and behavioral deficits were assessed using the rotarod test, locomotor activity assessment, hanging wire test, and pole test. MPTP administration impaired motor function and locomotor activity, and caused muscle weakness and bradykinesia. Leflunomide at a dose of 10 mg/kg mitigated the severity of motor deficits and muscle weakness. Furthermore, leflunomide at a dose of 10 mg/kg suppressed the MPTP‑induced elevation of interleukin‑2, interleukin‑6, and tumor necrosis factor‑alpha levels in the brain tissue. Similarly, leflunomide attenuated the increased expression of nuclear factor kappa B and inducible nitric oxide synthase caused by MPTP treatment. Moreover, leflunomide at a dose of 10 mg/kg preserved neuronal integrity and prevented the loss of tyrosine hydroxylase expression induced by MPTP administration. Based on our findings, leflunomide exhibited a beneficial effect on the MPTP‑induced PD model, potentially through modulation of anti‑inflammatory mechanisms.

Neuronal nitric oxide synthase activation by tadalafil protects neurological impairments in a zebrafish larva model of hyperammonemia.

Hyperammonaemia (HA) is a metabolic disorder characterized by increased ammonia levels in the blood and is associated with severe neurological impairments. Some previous findings have shown the involvement of the nitric oxide pathway in HA-induced neurological impairments. The current study explored the impact of tadalafil on neurological impairments induced by HA in a zebrafish larval model due to its reported indirect interactions with the nitric oxide pathway. HA was induced in zebrafish larvae by ammonium acetate exposure from 2 to 9 days post fertilization (dpf). Locomotor and cognitive functions were analysed following the treatment. The levels of gamma-aminobutyric acid (GABA), glutamate, and dopamine were measured in the larval head. The expression of genes associated with apoptosis (baxa and bcl2a), selected neurotransmitter receptors and bdnf was analysed. The protein levels of CREB and nNOS were also quantified. Tadalafil incubation reversed the HA-associated locomotor and cognitive impairments in larvae. The treatment attenuated GABA, dopamine, and glutamate levels. An upregulation in the expression of grin1a, gria2b, drd1b, drd2b, bdnf, and bcl2a, and downregulation of gabrz, gabrd, gabrg2 and baxa was observed following tadalafil treatment. The protein expression showed increased nNOS, p-CREB(Ser133), and decreased p-nNOS(Ser847) levels in the larvae incubated with tadalafil. The study concluded that tadalafil mitigates HA-induced neurological impairments by activating neuronal nitric oxide synthase. The study highlighted the possible application of tadalafil in the symptomatic management of neurological impairments in HA provided its efficacy and safety are further ensured in higher mammals.

Outstretched wing is controlled by intestinal enteroblasts-derived unpaired 2 cytokine signaling in Drosophila.

The outstretched wing phenotype in Drosophila melanogaster can be induced by various genetic mutations and environmental perturbations, yet the role of gut-derived signals in coordinating wing development remains largely unexplored. In this study, we demonstrate that Upd2, secreted from the gut to the wing discs, plays a crucial role in regulating the outstretched wing phenotype. The intestinal precursor cell driver esg-Gal4 exhibits low levels of leaky expression, even in the presence of Gal80ts at room temperature (25°C). This leaky expression of TDP-43, Notch, and Yki in intestinal precursor cells leads to a held-out wing phenotype, shortened lifespan, and impaired locomotor function. Although esg-Gal4 is expressed in imaginal discs, overexpression of TDP-43, Notch, or Yki using the wing-specific driver does not result in the outstretched wing. Furthermore, our data indicate that genetic alterations associated with the spread-out wing phenotype originate in enteroblasts (EBs) during early development. RNA sequencing analysis with guts from third instar larvae revealed that the JAK-STAT pathway ligand Upd2 is among the most significantly downregulated transcripts. Notably, ectopic expression of Upd2 in EBs partially rescued the abnormal held-out wing phenotype induced by TDP-43, Notch, and Yki overexpression. Together, our findings identify gut-derived Upd2 cytokine signaling as a key mediator of the outstretched wing phenotype, providing evidence for gut-to-wing communication axis during Drosophila development.

Доступність адміністративного судочинства: проблеми подолання дискримінації

Abstract. The article is devoted to the study of the problems of accessibility of administrative proceedings through the lens of overcoming the problems of discrimination. The principle of access to the court is key in ensuring the right to justice in the modern social and legal reality, provided for by numerous international and national norms of the constitutional and industry levels, therefore the change of certain guarantees of the judicial process causes threats to the accessibility of the judicial process. It was established that new opportunities in the field of electronic justice create a problem of discriminatory access to administrative proceedings. Guarantees of human and citizen rights and freedoms, implementation of the principle of equality and non-discrimination remain the key paradigm of modern society, legal system and practice. The position is motivated that the latest virtual capabilities should be adapted to years-tested and internationally recognized world standards. The article points out the duality of the nature of administrative proceedings, which consists in the fact that courts can act in a double role: on the one hand, they are institutional state bodies that are obliged to create fair guarantees of protection against discrimination, and on the other hand, they themselves can complicate access to justice for certain groups of people or an individual due to his protected characteristics, thus the person affected by a discriminatory situation receives secondary victimization, which additionally has a destructive effect on the legal reality and the state of law and order and trust in the authorities. A separate analysis is devoted to the problem of proper access and non-discrimination of persons with disabilities and persons with limited mobility. It is proposed to expand the list of protected features in Article 8 of the Civil Code of Ukraine in accordance with the legislative policy of preventing and combating discrimination in Ukraine, and to supplement Clause 9 of the Regulations on the Procedure for the Operation of Individual Subsystems (Modules) of the Unified Judicial Information and Telecommunication System with additional guarantees for users with impaired vision, hearing, locomotor apparatus, speech and intellectual development, as well as with various combinations of disorders. Keywords: electronic justice; administrative justice; rule of law; discrimination; persons with disabilities; protected signs.

The relationship between changes in inflammation and locomotor function in sensory phenotypes of central neuropathic pain after spinal cord injury.

Central neuropathic pain (CNP) commonly develops in patients after spinal cord injury (SCI), causing debilitating symptoms and sensory abnormalities to mechanical and thermal stimuli. The biological variability of pain phenotypes in individuals has limited the number of positive outcomes. Thus, it is necessary to investigate the physiological processes contributing to sensory changes that develop over time. To investigate the physiological processes contributing to neuropathic pain sensory changes and locomotor impairments with sensory phenotypes that develop over time. Using the tail flick and von Frey tests, we performed hierarchical clustering to determine the subpopulation of rats that developed thermal and mechanical sensory abnormalities. To measure inflammation as a potential mediator of CNP phenotypes, we used flow cytometry and immunohistochemistry. Finally, to assess the secondary effects on locomotor recovery, up to 8 weeks after injury, we used the CatWalk test to assess multiple parameters of gait. The von Frey test showed a subpopulation of SCI rats that were hyposensitive to mechanical stimuli from 6 to 8 weeks after injury. The tail flick test showed a subpopulation of SCI rats that were hypersensitive to thermal stimuli at 1 week and 3 to 8 weeks after injury. Although there were no differences in inflammatory cells between subpopulations, we did see significant changes in locomotor recovery between rats with and without sensory abnormalities. The myeloid cell population at large is not affected by mechanical or thermal phenotypes of pain in this model; however, locomotor recovery is impaired depending on the pain phenotype present. Further investigation into acute inflammatory cells may be insightful for predicting the development of pain phenotypes.

Neurotoxic effects of citronellol induced by the conversion of kynurenine to 3-hydroxykynurenine.

Citronellol is widely utilized in consumer products, including cosmetics, fragrances, and household items. However, despite being considered a relatively safe chemical, the health effects and toxicity mechanisms associated with exposure to high concentrations of citronellol, based on product content, remain inadequately understood. Here, we aimed to analyze the neurological effects of citronellol in zebrafish larvae using behavioral and histological analyses and elucidate the mechanisms underlying its neurotoxicity in vivo. Exposure to citronellol (2, 4 and 8 mg/L) in zebrafish larvae induced a range of neurotoxic effects, including locomotor impairments, anxiety-like behaviors, oxidative stress, an inflammatory response, and apoptosis in the brain. Additionally, citronellol exposure compromised the blood-brain barrier (BBB) integrity, permitting the infiltration of inflammatory cell into the brain. Neurotoxic effects were further sustained by increased kynurenine (KYN) metabolism to the neurotoxic metabolite 3-hydroxykynurenine (3-HK), accompanied by altered neurosteroid levels, including reduced progesterone and allopregnanolone, and elevated cortisol. Similar metabolic dysregulation was observed in mouse models following oral administration (345, 690 and 3450 mg/kg) and in human brain organoids exposed to citronellol (1, 10 and 100 μM), suggesting conserved mechanisms across species. Notably, experiments using zebrafish, mice and brain-chip systems confirmed that citronellol crosses the BBB and accumulates in the brain. Overall, we identified a novel neurotoxic pathway involving the KYN to 3-HK metabolic pathway, oxidative stress, and neuroinflammation, underscoring the potential risks of prolonged citronellol exposure.

Integration of In-vivo screening, molecular docking, and molecular dynamics simulations for studying the antiepileptic potential of newly synthesized 5-naphthalen-1-yl-5,10-dihydro-1H-pyrimido[4,5-b]quinoline-2,4-diones in optimized reaction conditions by utilizing l-proline as green catalyst

In a green, one-pot approach, several 5-naphthalen-1-yl-5,10-dihydro-1H-pyrimidoi-[4,5-b]-iquinoline-2,4-dionesi (4a-k) were synthesized via a three-component reaction comprising substituted anilines, naphthaldehyde, and barbituric acids. The reaction conditions were optimized by testing different catalysts (PTSA, CF3COOH, and l-proline) and different solvents. Most of the tested reaction conditions influenced the synthetic reaction. l-proline was more effective with water as a solvent in synthesizing the targeted compounds with high yields. All the synthesized compounds underwent antiepileptic screening using in vivo and in silico methods. In vivo, screening has been performed following the maximal electroshock seizure (MES), and subcutaneous pentylenetetrazole (scPTZ) animal screening methods. The antidepressant screening of the most potent antiepileptic compounds has been tested through a locomotor impairment test (using an actophotometer). The in silico molecular docking and simulation studies were determined by utilizing AutoDock 4.2 version and Groomacs. Among all, compounds 4b, 4d, 4e, and 4j have demonstrated significant antiepileptic activity with effective antidepressant properties. In silico studies (calculation of ADME parameters, molecular docking, and MD simulation) established that targeted molecules have good ADME parameters (good for oral use), the possible mechanism involved interactions primarily with GABAA receptors while interactions with other receptors like VGSCs and NMDA also took place.

Elocalcitol mitigates high-fat diet-induced microglial senescence via miR-146a modulation

BackgroundMicroRNAs (miRNAs) play crucial roles in regulating inflammation and cellular senescence. Among them, miR-146a has emerged as a key modulator of inflammation, but its role in obesity-induced senescence remains unexplored. This study investigates the involvement of miR-146a in high-fat diet (HFD)-induced hypothalamic senescence and in protective effects of elocalcitol (Elo), a non-hypercalcemic, fluorinated vitamin D analog on HFD-induced senescence.ResultsWild-type (WT) HFD-fed mice exhibited increased body weight, impaired locomotor activity, and cognitive decline compared to low-fat diet (LFD) controls. In the brain, HFD induced senescence markers (p16, p21), β-galactosidase activity (β-gal) of microglia, and increased expression of senescence associated secretory phenotype (SASP) cytokines (Il1b, Il18, Tnf, Il6) in activated hypothalamic microglia. In the liver, increased p21 and SASP cytokines were detected, although p16 and β-gal levels remained unchanged. Importantly, miR-146a expression was significantly downregulated in the hypothalamus following HFD exposure in WT mice, while miR-146a knockout (Mir146a-/-) mice subjected to HFD showed augmented hypothalamic senescence characterized by higher levels of p16, p21, and β-gal + microglial cells as compared to WT mice. The SASP profile remained similar between Mir146a-/- HFD and WT HFD mice. Among miR-146a target genes, smad4 was upregulated the hypothalamus of HFD-fed mice, with a more pronounced increase in the hypothalamus of HFD-fed Mir146a-/- mice. Further, treatment with Elo upregulated miR-146a expression in both the hypothalamus and the liver, lowered body weight and improved cognitive function, while reducing senescence markers and SASP cytokines in WT HFD mice. These effects were absent in Mir146a-/- HFD mice when treated with Elo, indicating the dependence of Elo’s therapeutic efficacy on miR-146a.ConclusionElocalcitol prevents development of senescence in microglia via modulation of miR-146a expression, while miR-146a provides protection against HFD-induced cellular senescence in the hypothalamus most probably via inhibition of TGF/Smad4 pathway. These findings highlight Elo and miR-146a as promising therapeutic candidates for ameliorating obesity-related neuroinflammation and senescence.

Protective effect of a novel furan hybrid chalcone against bisphenol A-induced craniofacial developmental toxicity in zebrafish embryos

Bisphenol A (BPA), a pervasive endocrine disruptor, is known to cause significant developmental toxicity, particularly affecting craniofacial structures through oxidative stress and apoptosis. A novel furan hybrid chalcone derivative, 3-(2-hydroxy-5-nitrophenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one (DK04), specifically with a hydroxyl group for its antioxidant properties and a nitro group for enhanced electron-withdrawing ability, was evaluated for its potential to mitigate these toxic effects. Zebrafish embryos were exposed to BPA and co-treated with various concentrations of DK04. Our results demonstrated that DK04 significantly reduced reactive oxygen species (ROS) generation and lipid peroxidation, increased antioxidant enzyme activities (SOD and CAT), and restored the balance between pro-apoptotic (p53) and anti-apoptotic (bcl2) genes. Furthermore, DK04 treatment improved bone mineralization and chondrogenesis by reversing BPA-induced disruptions in osteogenic markers (runx2, sox9a, bmp6, and mmp13a). The locomotion impairments observed in BPA-exposed embryos were also ameliorated by DK04, indicating its potential neuroprotective effects. These findings suggest that DK04 offers a multifaceted approach to counteract BPA toxicity, making it a promising candidate for therapeutic intervention. This research underscores the importance of developing prophylactic compounds to safeguard health against environmental toxicants like BPA. Future studies should focus on long-term safety and efficacy in mammalian models and explore synergistic effects with other protective agents to broaden the applications of DK04 and contribute to public health benefits.

Dose-Dependent Cognitive Decline, Anxiety, and Locomotor Impairments Induced by Doxorubicin: Evidence from an Animal Model.

Cognitive impairment and anxiety are common side effects of chemotherapy, particularly with the use of doxorubicin (DOX), known as "chemobrain". This study aimed to examine the dose-dependent effects of DOX on cognitive decline, anxiety, and locomotor activity in healthy female Wistar rats. The rats were divided into groups receiving low (2 mg/kg), intermediate (4 mg/kg), and high (5 mg/kg) doses of DOX for four weeks, alongside a control group. Behavioral tests, including open field, elevated plus maze, and Y-maze tests, assessed anxiety, locomotion, and cognitive performance, while brain tissue analysis evaluated neuroinflammation using markers such as GFAP and Iba-1. The results showed that all doses of DOX induced anxiety-like behavior, reduced locomotion, and caused neuroinflammation in the hippocampus, with more severe effects at higher doses. Notably, high-dose DOX also caused short-term memory deficits. These findings highlight the dose-dependent nature of DOX's impact on behavior and cognition, suggesting that DOX plays a key role in the development of cognitive symptoms during chemotherapy. Further research is needed to understand the mechanisms behind these effects and to explore potential interventions.

Hyperbaric Oxygen Therapy Ameliorates Olanzapine-Induced Hypolocomotion in a Rat Model.

Olanzapine (OLZ) is a commonly prescribed drug for the treatment of schizophrenia and related disorders. However, OLZ use is associated with several adverse effects, including decreased locomotor activity and increased body weight. While the majority of studies have directed their focus towards managing the metabolic side effects of OLZ, there has been limited attention given to the effects on locomotor activity. This study aimed to investigate the potential therapeutic effect of hyperbaric oxygen therapy (HBOT) in alleviating OLZ-induced locomotor impairment in female Sprague Dawley rats. Subjects were divided into four groups: control rats (CR), HBOT, OLZ, and HBOT + OLZ. In addition to behavioral effects, we also evaluated the total antioxidant capacity (TAC) of rats' brain tissue to demonstrate the maintenance of OLZ effectiveness in improving antioxidant status during the intervention using a rotarod device to measure locomotor activity and coordination. Results showed that HBOT effectively counteracted the hypolocomotion produced after OLZ administration. Moreover, HBOT did not result in a decrease in TAC in brain tissue, which is linked to OLZ treatment effectiveness. Therefore, our results suggest that HBOT may represent a promising non-pharmacological approach to improving locomotor and motor coordination impairments associated with OLZ treatment.

Axon demyelination and degeneration in a zebrafish spastizin model of hereditary spastic paraplegia.

Hereditary spastic paraplegias (HSPs) are a diverse set of neurological disorders characterized by progressive spasticity and weakness in the lower limbs caused by damage to the axons of the corticospinal tract. More than 88 genetic mutations have been associated with HSP, yet the mechanisms underlying these disorders are not well understood. We replicated the pathophysiology of one form of HSP known as spastic paraplegia 15 (SPG15) in zebrafish. This disorder is caused in humans by mutations in the ZFYVE26 gene, which codes for a protein called SPASTIZIN. We show that, in zebrafish, the significant reduction of Spastizin caused degeneration of large motor neurons. Motor neuron degeneration is associated with axon demyelination in the spinal cord and impaired locomotion in the spastizin mutants. Our findings reveal that the reduction in Spastizin compromises axonal integrity and affects the myelin sheath, ultimately recapitulating the pathophysiology of HSPs.

Intrinsic capacity loss rates and protective factors among individuals aged 80 years and older in Chinese nursing homes: A latent class analysis

Prior to this cross-sectional study, the intrinsic capacity (IC) loss rates and protective factors in nursing homes for individuals aged 80 and older remained unexplored. Analysing 434 participants, this study found 86.9 % of individuals experienced the loss of at least one IC domain, with detailed losses in locomotion, vision, vitality, hearing, psychological, and cognitive capacities at rates of 83.2 %, 52.8 %, 50.9 %, 46.5 %, 44.9 %, and 44.0 %, respectively. Following latent class analysis (LCA), five distinct IC impairment patterns were noted, with locomotor impairment emerging as a central component across most classes. IC protective factors for persons aged 80 years and older included financial stability, being male or younger within the cohort, junior high school or higher education, being married, no smoking history, manageable comorbidity levels, minimal medication use, good sleep, and not using assistive devices. Based on these five classes, this study provides a potential practical framework alongside recommendations for IC care strategies in the oldest-old, emphasising the importance of locomotor function in maintaining the overall IC.

χ-Conotoxins are an Evolutionary Innovation of Mollusk-Hunting Cone Snails as a Counter-Adaptation to Prey Defense.

Mollusk-hunting (molluscivorous) cone snails belong to a monophyletic group in Conus, a genus of venomous marine snails. The molluscivorous lineage evolved from ancestral worm-hunting (vermivorous) snails ∼18 Ma. To enable the shift to a molluscivorous lifestyle, molluscivorous cone snails must solve biological problems encountered when hunting other gastropods, namely: (i) preventing prey escape and (ii) overcoming the formidable defense of the prey in the form of the molluscan shell, a problem unique to molluscivorous Conus. Here, we show that χ-conotoxins, peptides exclusively expressed in the venoms of molluscivorous Conus, provide solutions to the above problems. Injecting χ-conotoxins into the gastropod mollusk Aplysia californica results in impaired locomotion and uncoordinated hyperactivity. Impaired locomotion impedes escape, and a hyperactive snail will likely emerge from its shell, negating the protection the shell provides. Thus, χ-conotoxins are an evolutionary innovation that accompanied the emergence of molluscivory in Conus and provide solutions to problems posed by hunting other snails.

Abnormal outer and inner retina in a mouse model of Huntington's disease with age.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor dysfunction and cognitive decline. While retinal abnormalities have been documented in some HD patients and animal models, the nature of these abnormalities-specifically whether they originate in the inner or outer retina-remains unclear, particularly regarding their progression with age. This study investigates the retinal structure and function in HD transgenic mice (R6/1) compared to C57BL/6 J control mice at 2, 4, and 6 months of age, encompassing both pre-symptomatic and symptomatic stages of HD. Pathological assessments of the striatum and evaluations of motor function confirmed significant HD-related alterations in R6/1 mice at 6 months. Visual function was subsequently analyzed, accompanied by immunofluorescent staining of retinal and optic nerve tissues over time. Our findings revealed that R6/1 mice exhibited pronounced HD symptoms at 6 months, characterized by neuronal loss in the striatum and impaired locomotor abilities. Functionally, visual acuity declined at 6 months, while retinal light responses began to deteriorate by 4 months. Structurally, R6/1 mice demonstrated a global reduction in cone opsin expression as early as 2 months, with a decrease in rhodopsin levels at 4 months, alongside a thinner retinal structure compared to controls. Notably, rod bipolar cell populations were decreased at 6 months, exhibiting shorter dendritic branches and reduced synaptic connections with photoreceptors in the outer retina. Additionally, ganglion cell numbers in the inner retina decreased at 6 months, accompanied by aberrant neural fibers in the optic nerve. Microglial activation was evident at 4 months, while astrocytic activation was observed at 6 months. Aggregates of mutant huntingtin (mHTT) were first detected in the ganglion cell layer and optic nerve at 2 months, subsequently disseminating throughout all retinal layers with advancing age. These results indicate that retinal pathology in R6/1 mice manifests earlier in the outer retina than in the inner retina, which does not align with the progression of mHTT aggregation. Consequently, the R6/1 mouse retina may serve as a more effective model for elucidating the mechanisms underlying HD and evaluating potential therapeutic strategies, rather than functioning as an early diagnostic tool for the disease.