Functional Deficits Research Articles

MCU expression in hippocampal CA2 neurons modulates dendritic mitochondrial morphology and synaptic plasticity

Neuronal mitochondria are diverse across cell types and subcellular compartments in order to meet unique energy demands. While mitochondria are essential for synaptic transmission and synaptic plasticity, the mechanisms regulating mitochondria to support normal synapse function are incompletely understood. The mitochondrial calcium uniporter (MCU) is proposed to couple neuronal activity to mitochondrial ATP production, which would allow neurons to rapidly adapt to changing energy demands. MCU is uniquely enriched in hippocampal CA2 distal dendrites compared to proximal dendrites, however, the functional significance of this layer-specific enrichment is not clear. Synapses onto CA2 distal dendrites readily express plasticity, unlike the plasticity-resistant synapses onto CA2 proximal dendrites, but the mechanisms underlying these different plasticity profiles are unknown. Using a CA2-specific MCU knockout (cKO) mouse, we found that MCU deletion impairs plasticity at distal dendrite synapses. However, mitochondria were more fragmented and spine head area was diminished throughout the dendritic layers of MCU cKO mice versus control mice. Fragmented mitochondria might have functional changes, such as altered ATP production, that could explain the structural and functional deficits at cKO synapses. Differences in MCU expression across cell types and circuits might be a general mechanism to tune mitochondrial function to meet distinct synaptic demands.

The Relations Between Sensory Modulation, Hyper Arousability and Psychopathology in Adolescents with Anxiety Disorders

Background: Sensory modulation may play a significant role in psychiatric conditions, including anxiety, and explain arousability levels, behavioral disorders, and functional deficits. Yet, studies about sensory modulation in adolescents with anxiety disorders are scarce. Purpose: To profile the prevalence of sensory modulation difficulties (SMDs) in adolescents with anxiety and examine their relations to arousability and psychopathology. The study compared adolescents with anxiety disorders to healthy controls using physiological measures and self-reports that reflect daily life scenarios. Then, the study examined the relationship between SMDs, arousability, and psychopathological severity in the study group. Method: Participants were 106 adolescents, aged 10.5–18 years and their parents. The study group included 44 participants diagnosed with anxiety disorder by psychiatrists. The control group included 62 healthy participants matched by age and gender to the study group. Parents completed the demographic questionnaire and the Child Behavior Checklist (CBCL). The adolescents completed The Revised Children’s Manifest Anxiety Scale (RCMAS) and the Adolescent/Adult Sensory Profile (AASP) and underwent the electrodermal activity (EDA) and pulse rate tests while listening to extreme sensory stimuli of auditory startles. Results: Based on AASP, the study group had a higher prevalence of SMDs expressed in lower sensory seeking, difficulties in registering sensory stimuli, and higher sensory sensitivity and avoidance. The study group presented higher arousability while listening to the startles as manifested in higher heart rate and EDA responses. The physiological results correlated with SMD levels measured by the AASP self-reports. SMDs correlated with psychopathological severity. Conclusions: SMDs may characterize adolescents with anxiety disorders and impact their arousability, symptoms severity, and daily functioning. Therefore, sensory modulation should be evaluated using both self-reports (to reflect implications in real life from patients’ own voices) along with objective measures to explain daily behaviors by underlying physiological mechanisms. This may focus intervention towards better health, function, and development.

Chemogenetic Control of Striatal Astrocytes Improves Parkinsonian Motor Deficits in Mice.

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic nigrostriatal inputs, which causes striatal network dysfunction and leads to pronounced motor deficits. Recent evidence highlights astrocytes as a potential local source for striatal neuromodulation. There is substantial evidence for norepinephrine-mediated recruitment of cortical astrocyte activity during movement and locomotion. However, it is unclear how astrocytes in the striatum, a region devoid of norepinephrine neuromodulatory inputs, respond during locomotion. Moreover, it remains unknown how dopamine loss affects striatal astrocyte activity and whether astrocyte activity regulates behavioral deficits in PD. We addressed these questions by performing astrocyte-specific calcium recordings and manipulations using invivo fiber photometry and chemogenetics. We find that locomotion elicits astrocyte calcium activity over a slower timescale than neurons. Acute pharmacological blockade of dopamine receptors only moderately reduced locomotion-related astrocyte activity. Yet, unilateral dopamine depletion significantly attenuated astrocyte calcium responses. Chemogenetic stimulation of Gi-coupled receptors partially improved this functional astrocyte deficit in dopamine-lesioned mice. In parallel, chemogenetic manipulation restored asymmetrical motor deficits and moderately improved open-field exploratory behavior. Together, our results establish a novel role for functional striatal astrocyte signaling in modulating motor function in PD and highlight non-neuronal targets for potential PD therapeutics.

Glioma-induced neural functional remodeling in the hand motor cortex: precise mapping with ECoG grids during awake craniotomy—experimental research

Background: The dilemma of achieving ‘onco-functional balance’ in gliomas affecting the motor cortex highlights the importance of functionally-guided resection strategies. While accurate mapping of eloquent areas often requires frequent electrical stimulation, this practice can lead to side effects like seizures and postoperative deficits. To enhance safety in functional mapping, we studied how gliomas impact hand movement areas and assessed the effectiveness of cortical electrical activity for functional mapping in this setting. Materials and Methods: We recruited patients with gliomas affecting the motor cortex and individuals with an unaffected motor cortex for awake craniotomy. During the procedures, electrocorticography (ECoG) grids were employed to record signals under three conditions: resting state, finger movements, and wrist movements. We then quantified the distances from the positively stimulated sites to the specific anatomical landmarks. Additionally, we analyzed the relationship between the ECoG power features and the stimulation responses. Results: The cortical layout for finger activity in the MCG group was more dispersed and overlapped, typically clustering near the central sulcus and Sylvian fissure. The predictive performance of ECoG mapping exhibited significant variability across different frequency bands and clinical scenarios. Specifically, the area under the curve (AUC) for the Non-MCG group during the resting state reached its peak, with a value of 0.802 for Gamma3 (95% CI = 0.729-0.875) and 0.865 for broadband (95% CI = 0.804-0.926). In contrast, the MCG group achieved the highest AUC during wrist movements, with Gamma3 at 0.785 (95% CI = 0.719-0.849) and broadband at 0.824 (95% CI = 0.753-0.890). Conclusion: Gliomas in the motor cortex disrupt the distribution of hand activity, complicating intraoperative functional mapping. As a novel and reliable approach, ECoG technique can complement and guide direct cortical stimulation for precise mapping, potentially reducing its frequency, minimizing the risk of functional deficits, and achieving a balance between maximal tumor resection and neurological preservation.

Contribution of Brain Intrinsic Branched-Chain Amino Acid Metabolism in a Novel Mouse Model of Maple Syrup Urine Disease.

Maple syrup urine disease (MSUD) results from loss of branched-chain ketoacid dehydrogenase (BCKDH) activity, the committed, rate-limiting step of branched-chain amino acid (BCAA) oxidation. Current treatments, including a low protein diet and liver transplantation, improve peripheral biochemistry and limit episodes of metabolic decompensation but do not fully prevent chronic neuropsychiatric symptoms. The mechanisms underlying chronic neurologic phenotypes remain poorly understood. Currently available MSUD mouse models do not survive long enough to evaluate chronic central nervous system (CNS) pathology. To investigate if loss of brain-intrinsic BCAA metabolism contributes to chronic neurologic disease, we developed a new brain-specific knockout mouse model of MSUD. First, we generated a mouse harboring a floxed Dbt allele (Dbtflox/flox). Then we crossed this line with Cre recombinase driver lines to induce loss of Dbt expression in (1) all developing CNS cell populations (2) neurons alone or (3) astrocytes alone. We found that brain-specific KO mice have elevations in BCAA levels in cortex that are exacerbated by a high protein diet. They also have secondary changes in amino acids in brain that are important for neuronal function, including glutamine and glycine. These metabolic differences result in subtle functional deficits as measured by electroencephalogram and behavioral testing. Astrocyte and neuron-specific KO mice each also demonstrate mild biochemical features of MSUD in the cortex, suggesting that both cell populations may contribute to disease pathology. Collectively, these data suggest that therapies targeting the CNS directly, in addition to the periphery, may improve outcomes in MSUD.

Functional Deficits Associated with Dark Without Pressure.

To describe a patient with progressive visual symptoms and reduced retinal sensitivity corresponding to dark without pressure (DWP). Retrospective chart review of a single patient. Comprehensive ophthalmic examinations and multimodal imaging techniques, including optical coherence tomography (OCT), OCT-angiography, and microperimetry, were analyzed. A 23-year-old male presented with progressive peripheral areas of blurred vision superiorly in his right eye and temporally in his left eye. These disturbances corresponded with dark areas of retina inferiorly in his right eye and nasally in his left eye having characteristic features of DWP on multimodal imaging. Although Humphrey visual field (HVF) 24-2 testing was normal, microperimetry showed decreased retinal sensitivity in areas of DWP relative to adjacent areas without DWP. Prior descriptions of DWP have described it as a benign retinal finding showing no functional deficits. We demonstrate that DWP can be associated with progressive visual complaints showing decreased retinal sensitivity on microperimetry and undetected with HVF 24-2 testing.

Factors associated with impaired physical functionality in x-linked hypophosphatemia

Abstract X-linked hypophosphatemia (XLH) is a rare inherited disorder characterized by elevated levels of fibroblast growth factor-23 (FGF23), chronic hypophosphatemia, impaired bone mineralization and chronic long-term manifestations. Treatment for XLH has been mainly focused on normalizing its biochemical abnormalities. Despite treatment, patients with XLH often present impaired physical function and decreased quality of life (QoL). We hypothesize that physical functionality and QoL is more strongly associated with chronic pain and decreased muscle mass than persistent biochemical abnormalities or exposure to conventional treatment. We conducted an observational, cross-sectional study with patients with XLH. Clinical records and biochemical parameters were assessed. QoL surveys SF36v.2 and WOMAC were applied. Functional status was measured by a physiatrist and an occupational therapist. Appendicular lean mass (ALM) was measured and compared to age and sex-matched healthy controls. Enthesopathies and osteoarthritis were evaluated. Pain was assessed using the Brief Pain Inventory, the Visual Analog Scale and the Doleur Neuropathique-4 scales. Muscle strength was evaluated by the Quadriceps Muscle isometric Strength (QMS) and physical performance with the 6-minute walk test (6MWT) and the Functional Independence Measure (FIM) scale. A total of 30 patients were included: 21 females; median age of 32 years. All participants had significant functional deficits, chronic pain and reduced QoL. Limitations in daily activities were significantly associated with higher severity of pain, decreased ALM, lower QMS, and less distance in 6MWT (P<.05). Neither FIM scale, phosphate levels, FGF23, nor the lifetime exposure to conventional treatment were associated with these functional variables. In conclusion, impaired physical functionality in patients with XLH was associated with lower muscle mass, lower muscle strength and severe chronic pain. These findings highlight the importance of, in addition to optimizing the biochemical control of the disease, expanding patient care including pain prevention and management as well as comprehensive physical therapy and rehabilitation.

Abstract TP385: Vitamin D3 prevent blood-brain barrier dysfunction after ischemic stroke

Emerging research suggests that Vitamin D3 might help protect against brain damage caused by ischemic stroke, as a deficiency in Vitamin D3 can worsen the severity and outcomes of a stroke. To investigate this, we studied the impact of Vitamin D3 on maintaining the integrity of the blood-brain barrier (BBB) using a mouse model of stroke. The BBB is severely disrupted during all kinds of strokes, which can lead to further injury and functional deficits. We measured several biomarkers related to BBB disruption to see if Vitamin D3 treatment could protect the BBB after a stroke. Mice were randomly divided into two diet groups: one receiving a Vitamin D3-sufficient diet (VDHsuf) and the other a Vitamin D3-deficient diet (VDHdef). The VDHsuf group ate standard chow, while the VDHdef group consumed a diet lacking Vitamin D3 for 8 weeks. Both groups underwent middle cerebral artery occlusion (MCAO) surgery for 40 minutes followed by reperfusion for 72 h. We assessed BBB disruption by measuring even blue leakage, matrix metalloproteinase-9 (MMP-9/MMP-2) activity, and changes in tight junction (TJ) proteins. We also evaluated the expression of OPG, RANKL, osteopontin (OPN), and the Vitamin D receptor (VDR) in both diet groups. At the time of MCAO, mice on the Vitamin D3-deficient diet had low levels of Vitamin D3. After MCAO, Evans blue leakage, indicating more severe BBB injury, was significantly greater in the VDHdef group compared to the VDHsuf group. Additionally, the expression of MMP-9, GLUT1, VDR, OPG, and OPN increased, while TJ proteins occluding, claudin-5 and RANKL decreased in the VDHdef group. These findings suggest that Vitamin D3 deficiency can impair the BBB, potentially worsening stroke severity and its long-term effects.

Functional genomics of primary congenital glaucoma by pathway analysis and functional characterization of CYP1B1 mutations.

CYP1B1 is the most common gene implicated in primary congenital glaucoma (PCG) - the most common form of childhood glaucoma. How CYP1B1 mutations cause PCG is not known. Understanding the mechanism of PCG caused by CYP1B1 mutations is crucial for disease management, therapeutics development, and potential prevention. We performed a comprehensive metabolome/reactome analysis of CYP1B1 to enlist CYP1B1-mediated processes in eye development. The identified metabolic events were classified into major pathways. Functional analysis of these metabolic pathways was performed after cloning the CYP1B1 wild-type gene and expressing the wild-type and selected novel mutants (previously reported by our group L24R, F190L, H279D, and G329D) in heterologous hosts. Stability and enzymatic functions were investigated. Structural modeling of the wild-type and the variants was also performed. Reactome analysis revealed a total of 166 metabolic processes which could be classified into four major pathways including estradiol metabolism, retinoic acid metabolism, arachidonic acid metabolism, and melatonin metabolism. Stability assay revealed rapid denaturing of mutant proteins compared to wild-type. Enzymatic assays showed functional deficit in mutant proteins in metabolizing estradiol, retinoids, arachidonate, and melatonin. Modeling revealed that the examined mutations induced structural changes likely causative in functional loss in CYB1B1 as observed in enzymatic assays. Hence, mutations in the CYP1B1 gene are associated with a functional deficit in critical pathways of eye development. These findings implicate the potential contributions of altered metabolic regulations of estradiol, retinoids, arachidonate and melatonin to the pathogenesis of PCG during the processes of the formation of ocular structures and function.

"Psychiatric oblivion": considerations on the hypothesis of a law.

The introduction of a law on psychiatric oblivion, similar to the recent one for oncological oblivion, presents numerous complexities due to the differences between the two areas of illness, especially in terms of recovery and clinical stability. While a definitive cure is often achievable in oncological diseases, in severe mental disorders, such as schizophrenia or bipolar disorder, complete remission in the absence of therapies is rare. Even in cases of effective treatment response, patients may exhibit subclinical symptoms or cognitive and functional deficits, making the concept of psychiatric oblivion particularly problematic. Some diagnostic categories, such as brief psychotic disorder or postpartum depression, could theoretically benefit from oblivion legislation, given the potentially limited course and frequent absence of relapses. However, for the majority of psychiatric conditions the requirement of a long period of remission without therapy appears difficult to achieve. An alternative could be the introduction of criteria based on the stabilization of maintenance therapy, but this would require a more complex and less easily standardized clinical judgment. Other limitations are the residual vulnerability to relapses, the difficulty in determining a precise medical history and the influence of persistent social stigmatization, which could undermine the effects of oblivion. Therefore, the creation of a law on psychiatric oblivion would require a restrictive and selective approach, focused on specific diagnoses and long-term clinical remission criteria, tailored to the clinical and adaptive peculiarities of mental illness.

From movement to mind: Early fine motor skills are associated with cognitive performance at school age in very preterm infants.

Although preterm birth is associated with deficits in both motor and cognitive functioning, the association between early motor skills and cognitive outcomes at a later age remains underexplored. To evaluate associations between motor skills at age 5.5 and cognitive functioning at age 8. Single-center cohort study including children born below 30weeks' gestation or below 1000g, between September 1st 2010 and September 1st 2015. Three motor skills (aiming and catching, balance and manual dexterity) were assessed at age 5.5 using the Movement Assessment Battery for Children, 2nd edition (MABC-2-NL). Total intelligence quotient and its five subdomains (fluid reasoning, processing speed, verbal comprehension, visual spatial, and working memory) were assessed at age 8 using the fifth version of the Wechsler Intelligence Scale for Children (WISC-V-NL). Multiple linear regression analysis was used to investigate associations between MABC-2-NL scores and WISC-V-NL outcomes. In total, 327 live born children without congenital malformations were included, of whom 281 survived to 8years. Of these, 185 (66%) had follow-up assessments at both 5.5 and 8years. Scores on motor and cognitive subdomains were lower compared to the normative mean. Regression analysis showed that manual dexterity was significantly associated with better scores on all subdomains of cognitive performance, except for verbal comprehension. Our main finding is that fine motor function at age 5.5 is associated with later cognitive performance. Early assessment of motor performance may be helpful for early diagnosis and targeted intervention to support optimal cognitive development of preterm children.

Attenuated Doors-Locked P300 Amplitude and Elevated Depressive Symptoms: Effects of Age and Sex in Two Independent Samples of Youth.

Deficits in cognitive and reward-related functions, measured via reductions in the P300 and reward positivity (RewP) event-related potential (ERP) components, are commonly observed in adults suffering with depression. Considering higher risk for depression emerges among females in adolescence, examination of the neurological underpinnings of depression during this critical developmental period can help further elucidate our overall understanding of the etiology of depressive disorders. Therefore, the present study sought to first examine associations between doors-locked P300 amplitude, RewP amplitude, current depression symptoms, and age in an all-female youth sample (sample 1: n = 296; age, 8 to 14). Next, we examined these same associations, as well as sex, in a second independent sample consisting of male and female youths (sample 2: n = 605; age, 11 to 14). Blunted doors-locked P300 was associated with higher depressive symptoms in both samples. Moreover, the association between P300 and depression was stronger among older youths in both samples. Sex further moderated this relationship in sample 2 such that smaller P300 related to greater depression only in females. There were no consistent associations between RewP amplitude and depressive symptoms in either youth sample. These findings suggest that the doors-locked P300 component is a reliable neural correlate of depression in youth that might specifically relate to pathways linked to increased risk for depression among adolescent females.

Abstract TP373: Impaired resting state functional connectivity in CADASIL mutant mice

Objectives: Cerebral autosomal-dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is a leading monogenic cause of cerebral small-vessel disease. This study aimed to evaluate the functional integrity of long white matter tracts in CADASIL transgenic mice and assess the potential of tocotrienol (T3) as a therapeutic agent. Methods: Optical resting-state functional connectivity imaging and behavioral examinations were employed to characterize white matter tracts in CADASIL transgenic mice, both with and without focal white matter lesions in the corpus callosum. Functional connectivity and behavioral outcomes were compared between Notch3 R169C and Notch3 WT mice. The efficacy of T3, a neuroprotective vitamin E derivative, was also evaluated based on findings from previous clinical trials in small vessel disease. Results: After performing stepwise elimination using the Akaike Information Criterion (AIC), the diet variable was removed from the model and we pooled the data in the two diet arms for subsequent analyses of interhemispheric homotopic connectivity. At baseline, resting-state interhemispheric functional connectivity was significantly reduced in Notch3 R169C mice compared to Notch3 WT mice (p=0.004). No significant differences between genotypes were observed on day 1 and day 7 post-lesion. Behavioral analysis using the grid walk test revealed an increased number of foot faults in Notch3 R169C mice at baseline, with similar increases observed in both genotypes one week after lesion induction. Lesion volumes on day 7 did not differ between genotypes. Conclusions: The Notch3 R169C CADASIL model demonstrated impaired resting-state functional connectivity and increased foot faults, indicating significant functional and behavioral deficits. Future research will focus on evaluating therapeutic and preventive interventions in CADASIL models using these parameters.

A longitudinal study of resilience and social function in patients with colorectal cancer and stomas.

To explore the dynamic changes, influencing factors, and relationships between resilience and social function in patients with colorectal cancer (CRC) and stomas at different postoperative stages, and to inform precise psychosocial rehabilitation interventions. A longitudinal study was conducted at a tertiary hospital in eastern China from January 2021 to June 2023. Patients completed a self-designed socio-demographic questionnaire one month post-surgery, and the Connor and Davidson Resilience Scale (CD-RISC) and Social Dysfunction Screening Scale (SDSS) at 1, 3, and 5months post-surgery. Data were analyzed using repeated measures ANOVA, Spearman correlation, group-based trajectory modeling, and binary logistic regression. A total of 131 patients were included in the analysis. Resilience showed an initial increase followed by a decline, while social function consistently improved. A moderate negative correlation between social dysfunction and resilience was observed at all time points. Influencing factors for resilience and social function varied across different postoperative stages. Significant differences in resilience trajectories were observed based on education and family income. Resilience trajectories significantly impacted social function trajectories (OR 19.39, 95% CI 2.46-152.91, P<0.05). This study identifies distinct trajectories of resilience and social function in patients with colorectal cancer and stomas. Low resilience is linked to severe social function deficits. Stage-specific interventions are crucial to enhance social adaptation and improve overall quality of life. Tailored support is needed throughout recovery to address the unique challenges faced by these patients.

Evaluation of additional points in the 24-2C visual field test in pre-perimetric glaucoma.

Early detection and prevention of glaucoma progression are critical. However, studies of early visual field (VF) changes, particularly those using the 24-2C VF test, are limited. Evaluation of additional points in 2C may help identify glaucoma at an early stage, enabling timely intervention. Pre-perimetric glaucoma (PPG) is characterised by structural damage without noticeable VF loss in standard tests. Assessments of changes in retinal nerve fibre layer (RNFL) and macular ganglion cell complex (mGCC) thickness are valuable, but exploring how these structural changes are related to functional deficits is crucial. This study focused on the average of the additional points in the 24-2C test to understand their correlation with structural measures in the PPG. This study included 59 patients with PPG and 36 healthy individuals. All the patients underwent peripapillary and macular optical coherence tomography (OCT) (Nidek RS-3000 Advance; Nidek, Japan). RNFL thickness was evaluated using peripapillary OCT, and mGCC thickness was evaluated using the macular OCT glaucoma module. The mean deviation (MD), pattern standard deviation (PSD), visual field index (VFI), and average of additional points in the 2C (AAP-2C) were evaluated using the 24-2C SITA Faster VF Humphrey Field Analyser III Model 850 (HFAIII; Zeiss Meditec, Dublin, CA, USA). The relationship between structural and functional parameters was statistically evaluated. The PPG group showed significantly lower RNFL and mGCC thickness values than the healthy group. The MD, PSD, and VFI did not differ significantly between the groups. For AAP-2C, the PPG group showed significantly lower sensitivity than healthy individuals. A statistically significant positive correlation between was observed between AAP-2C and mGCC thickness (p = 0.003, r = 0.385). However, the RNFL and mGCC thickness values showed no statistically significant correlations with the MD, PSD, and VFI. Although no glaucomatous change was observed in the VF in patients with PPG, these patients showed reduced sensitivity of the additional points. The reduced sensitivity of the additional points in the 24-2C VF test may reflect early macular functional alterations that correlate with structural damage during the pre-perimetric period.

Executive function deficit in patients with long COVID syndrome: A systematic review

Executive function deficit in patients with long COVID syndrome: A systematic review

Abstract TP379: Post-stroke whole body vibration therapy alters transcriptome and reduces ischemic brain damage in reproductively senescent female rats.

Introduction: Rehabilitative physical therapy is essential for reducing stroke-related functional deficits; however, comorbidities may limit patient participation. Whole body vibration (WBV; 40 Hz) offers an exercise-like alternative. Our studies show that one month of post-stroke WBV reduces ischemic damage and improves motor and cognitive function in middle-aged rats. Notably, WBV significantly increased circulating irisin, a muscle-derived hormone. We hypothesize that post-stroke WBV modifies the cerebral transcriptome and irisin treatment improves stroke outcome in middle-aged female rats. Methods: Middle-aged Sprague-Dawley rats were randomized to sham or transient middle cerebral artery occlusion (tMCAO; 90 min) surgery and divided into two cohorts. A cohort received either no-WBV (steady platform) or WBV (platform vibrating at 40 Hz) for 15 minutes twice a day for a week. Cortical tissue was then collected for RNA sequencing (RNAseq) and gene enrichment analysis. The second cohort received either saline or irisin (PeproTech, 0.2 µg/g BW) treatment at 4.5 hours post-tMCAO and then once a week for a month. At 21 days post-tMCAO, rats were assessed for cognitive deficits via the Morris water maze. At 1-month post-tMCAO, brains were collected for histological analysis. Results: RNAseq revealed significant (p&lt;0.05) differential expression of 581 genes in the cortex due to WBV. Specifically, there was downregulation (log 2 (fold change) = -2.9; p= 0.03943) of Calcium Voltage-Gated Channel Auxiliary Subunit Gamma 7 ( Cacng7 ) and calcium-release channel activity (GO:0015278), which are both implicated in excitotoxicity following stroke. The expression of Vacuolar Protein Sorting-Associated Protein 37C ( Vps37c ), a component of an endosomal sorting complex that mediates apoptosis, was also downregulated (log 2 (fold change) = -7.1; p= 0.01888). In our second cohort, rats treated with irisin for 1-month post-tMCAO, as compared to saline, demonstrated significantly (p&lt;0.05) reduced cognitive deficits in spatial learning (hidden platform) and memory (probe trial). Additionally, irisin treatment significantly (p&lt;0.05) reduced infarct damage at 1-month post-tMCAO. Conclusion: Post-stroke WBV increases the expression of genes responsible for ischemic tolerance and irisin treatment improves cognitive outcomes in middle-aged rats. Future studies are needed to understand the underlying mechanism(s) responsible for irisin-conferred ischemic protection.

Neurodevelopmental Impairments as Long-term Effects of Iron Deficiency in Early Childhood: A Systematic Review.

Anemia within the first 1,000 days of life is primarily attributed to iron deficiency (ID). This period is critical as infants and young children have the highest iron demands. Failure to meet these increased needs exposes children to ID, which has been linked to persistent developmental challenges. Numerous studies have reported neurodevelopmental disorders in children with a history of early-life ID, though findings vary. This systematic review aimed to evaluate the long-term impact of early childhood ID on neurodevelopmental outcomes. Systematic review. A literature search was conducted across five electronic databases (PubMed, Cochrane, Scopus, Sage, and Embase) using the keywords "iron deficiency anemia" and "infant." The JBI critical appraisal tool for cohort studies was used to evaluate study quality. Seventeen relevant cohort studies were identified through the systematic search. Of these, 14 were rated as high quality, while 3 were classified as moderate quality. The neurodevelopmental domains assessed included cognitive deficits (seven studies), motor deficits (four studies), verbal deficits (seven studies), behavioral deficits (nine studies), auditory function (one study), and neuroendocrine function (two studies). Early-life ID disrupts neurodevelopment, leading to persistent cognitive, motor, behavioral, and neuroendocrine impairments. Children with a history of early childhood ID demonstrate poorer cognitive, motor, and behavioral outcomes compared with their non-ID counterparts. Preventing ID within the first 1,000 days of life is essential to mitigate irreversible deficits in motor, cognitive, and behavioral functions.

Executive functioning in subjects post COVID-19 infection in Mexico

Over the past three years, conflicting evidence has emerged regarding the impact of COVID-19 on executive functions and the frontal lobe. In this study, we evaluated executive functions in individuals from the state of Jalisco who had contracted COVID-19. Sixty individuals with a history of mild COVID-19 were included and compared to historical controls from the Mexican population, who had been assessed prior to the pandemic during the validation of the Trail Making Test Form B, the Stroop Color and Word Test, and the Modified Wisconsin Card Sorting Test (M-WCST). The post-infection group exhibited lower scores only on the M-WCST. Therefore, we concluded that individuals who have recovered from mild COVID-19 do not display widespread impairments in executive functions, with the exception of deficits observed on the M-WCST. This suggests possible neurophysiological alterations in the prefrontal cortex during SARS-CoV-2 infection, given that cognitive flexibility is primarily mediated in this region. These findings contribute to the growing body of evidence indicating that even non-hospitalized COVID-19 patients can experience executive function deficits, providing a foundation for further neurophysiological research into the mechanisms underlying this phenomenon.

Limiting cap-dependent translation increases 20S proteasomal degradation and protects the proteomic integrity in autophagy-deficient skeletal muscle

ABSTRACT Postmitotic skeletal muscle critically depends on tightly regulated protein degradation to maintain proteomic stability. Impaired macroautophagy/autophagy-lysosomal or ubiquitin-proteasomal protein degradation causes the accumulation of damaged proteins, ultimately accelerating muscle dysfunction with age. While in vitro studies have demonstrated the complementary nature of these systems, their interplay at the organism levels remains poorly understood. Here, our study reveals novel insights into this complex relationship in autophagy-deficient skeletal muscle. We demonstrated that despite a compensatory increase in proteasome level in response to autophagy impairment, 26S proteasome activity was not proportionally enhanced in autophagy-deficient skeletal muscle. This functional deficit was partly attributed to reduced ATP levels to fuel the 26S proteasome. Remarkably, we found that activation of EIF4EBP1, a crucial inhibitor of cap-dependent translation, restored and even augmented proteasomal function through dual mechanisms. First, genetically activating EIF4EBP1 enhanced both ATP-dependent 26S proteasome and ATP-independent 20S proteasome activities, thereby expanding overall protein degradation capacity. Second, EIF4EBP1 activation caused muscle fiber transformation and increased mitochondrial biogenesis, thus replenishing ATP levels for 26S proteasome activation. Notably, the improved performance of the 20S proteasome in EIF4EBP1-activated skeletal muscle was attributed to an increased abundance of the immunoproteasome, a subtype specially adapted to function under oxidative stress conditions. This dual action of EIF4EBP1 activation preserved proteomic integrity in autophagy-deficient skeletal muscle. Our findings uncover a novel role of EIF4EBP1 in improving protein quality control, presenting a promising therapeutic strategy for autophagy-related muscular disorders and potentially other conditions characterized by proteostatic imbalance.