p38α kinase governs muscle strength through PGC1α in mice.

AIMS: Skeletal muscle, with its remarkable plasticity and dynamic adaptation, serves as a cornerstone of locomotion and metabolic homeostasis in the human body. Muscle tissue, with its extraordinary capacity for force generation and energy expenditure, plays a fundamental role in the movement, metabolism, and overall health. In this context, we sought to determine the role of p38α in mitochondrial metabolism since mitochondrial dynamics play a crucial role in the development of muscle-related diseases that result in muscle weakness. METHODS: We conducted our study using male mice (MCK-cre, p38αMCK-KO and PGC1α MCK-KO) and mouse primary myoblasts. We analyzed mitochondrial metabolic, physiological parameters as well as proteomics, western blot, RNA-seq analysis from muscle samples. RESULTS: Our findings highlight the critical involvement of muscle p38α in the regulation of mitochondrial function, a key determinant of muscle strength. The absence of p38α triggers changes in mitochondrial dynamics through the activation of PGC1α, a central regulator of mitochondrial biogenesis. These results have substantial implications for understanding the complex interplay between p38α kinase, PGC1α activation, and mitochondrial content, thereby enhancing our knowledge in the control of muscle biology. CONCLUSIONS: This knowledge holds relevance for conditions associated with muscle weakness, where disruptions in these molecular pathways are frequently implicated in diminishing physical strength. Our research underscores the potential importance of targeting the p38α and PGC1α pathways within muscle, offering promising avenues for the advancement of innovative treatments. Such interventions hold the potential to improve the quality of life for individuals affected by muscle-related diseases.

IL-7-dependent and -independent lineages of IL-7R-dependent human T cells.

Infants with biallelic IL7R loss-of-function variants have severe combined immune deficiency (SCID) characterized by the absence of autologous T lymphocytes, but normal counts of circulating B and NK cells (T-B+NK+ SCID). We report 6 adults (aged 22 to 59 years) from 4 kindreds and 3 ancestries (Colombian, Israeli Arab, Japanese) carrying homozygous IL7 loss-of-function variants resulting in combined immunodeficiency (CID). Deep immunophenotyping revealed relatively normal counts and/or proportions of myeloid, B, NK, and innate lymphoid cells. By contrast, the patients had profound T cell lymphopenia, with low proportions of innate-like adaptive mucosal-associated invariant T and invariant NK T cells. They also had low blood counts of T cell receptor (TCR) excision circles, recent thymic emigrant T cells and naive CD4+ T cells, and low overall TCR repertoire diversity, collectively indicating impaired thymic output. The proportions of effector memory CD4+ and CD8+ T cells were high, indicating IL-7-independent homeostatic T cell proliferation in the periphery. Intriguingly, the proportions of other T cell subsets, including TCRγδ+ T cells and some TCRαß+ T cell subsets (including Th1, Tfh, and Treg) were little affected. Peripheral CD4+ T cells displayed poor proliferation, but normal cytokine production upon stimulation with mitogens in vitro. Thus, inherited IL-7 deficiency impairs T cell development less severely and in a more subset-specific manner than IL-7R deficiency. These findings suggest that another IL-7R-binding cytokine, possibly thymic stromal lymphopoietin, governs an IL-7-independent pathway of human T cell development.

Exercise and tumor proteome: Insights from a neuroblastoma model.

BACKGROUND/AIM: The impact of exercise on pediatric tumor biology is essentially unknown. We investigated the effects of regular exercise on tumor proteome profile (as assessed with liquid chromatography with tandem mass spectrometry) in a mouse model of one of the most aggressive childhood malignancies, high-risk neuroblastoma (HR-NB). METHODS: Tumor samples of 14 male mice (aged 6-8 weeks) that were randomly allocated into an exercise (5-week combined aerobic and resistance training) or nonexercise control group (6 and 8 mice per group, respectively) were analyzed. The Search Tool for the Retrieval of Interacting Genes/Proteins database was used to generate a protein-protein interaction (PPI) network and enrichment analyses. The Systems Biology Triangle (SBT) algorithm was applied for analyses at the functional category level. RESULTS: Tumors of exercised mice showed a higher and lower abundance of 101 and 150 proteins, respectively, compared to controls [false discovery rate (FDR)<0.05], which were enriched in metabolic pathways, aminoacid metabolism, regulation of hormone levels, and peroxisome proliferator-activated receptor signaling pathway (FDR<0.05). The SBT algorithm indicated that 184 and 126 categories showed a lower and higher abundance, respectively, in the tumors of exercised mice (FDR<0.01). Categories with lower abundance were involved in energy production while those with higher abundance were related to transcription/translation, apoptosis, and tumor suppression. CONCLUSION: Regular exercise altered the abundance of hundreds of intratumoral proteins and molecular pathways, particularly those involved in energy metabolism, apoptosis, and tumor suppression. These findings provide preliminary evidence of the molecular mechanisms underlying potential effects of exercise in HR-NB.

[Therapeutic effect of vitamin D supplementation in mexican patients with allergic rhinitis]. / Efecto de la suplementación con vitamina D en pacientes mexicanos con rinitis alérgica.

OBJETIVES: To evaluate the impact of cholecalciferol (D3) supplementation using clinical and paraclinical variables in patients with RA and vitamin D insufficiency and deficiency. METHODS: A randomized, double-blind, placebo-controlled study included patients from 5 to 40 years with a diagnosis of RA and vitamin D insufficiency and deficiency. They were supplemented for 8 weeks with 4000 or 5000 IU, depending on age. Total nasal symptoms score (TNSS) was measured monthly and 25(OH)D3 levels at baseline and at the end of the study. RESULTS: A total of 31 patients were included, with a mean age of 18.19 years. In the active group, there was a significant improvement in symptomatology with respect to the TNSS score and an increase in serum vitamin D levels (p < 0.01). There were no adverse reactions with cholecalciferol or placebo. CONCLUSIONS: Supplementing patients with vitamin D3, at the evaluated dose, together with conventional treatent for allergic rhinitis results in symptoms and quality of life improvement in patients with this disease.

OBJETIVOS: Evaluar el impacto de la suplementación con colecalciferol (D3) mediante variables clínicas y paraclínicas en pacientes con RA e insuficiencia y deficiencia de vitamina D. MÉTODOS: Estudio aleatorio, doble ciego, placebo controlado, en el que se incluyeron pacientes de 5 a 40 años, con diagnóstico de RA e insuficiencia y deficiencia de vitamina D. Fueron suplementados con 4000 o 5000 UI, dependiendo de la edad, durante 8 semanas. Mensualmente se midió la puntuación total síntomas nasales (TNSS) y las concentraciones de 25(OH)D3 al inicio y al final del estudio. RESULTADOS: Se incluyeron 31 pacientes, con una edad promedio de 18.19 años. En el grupo activo existió una mejoría significativa en la sintomatología respecto a la puntación de TNSS y un incremento en los niveles séricos de vitamina D (p < 0.01). No se presentaron reacciones adversas con la ingesta de colecalciferol o placebo. CONCLUSIONES: Suplementar a los pacientes con vitamina D3, a la dosis evaluada, junto con el tratamiento convencional para la rinitis alergica resulta en una mejoría sintomática y en la calidad de vida de los pacientes con esta enfermedad.

Assessment of Holmium:YAG, Pulsed-Thulium:YAG and Thulium Fiber Lasers for Urinary Stone Ablation. In Vitro Study.

Objective: To evaluate the ablation speed (AS), laser efficiency and direct thermal lesions during urinary stone lithotripsy with the current available laser technologies: Holmium:YAG (Ho:YAG), pulsed-Thulium:YAG (p-Tm:YAG) and thulium fiber laser (TFL) in vitro using different laser settings. Materials and Methods: Ho:YAG, p-Tm:YAG, and TFL laser system were used in an in vitro ureteral model with a volume of 125 mm3 Begostone. The following parameters were tested across all laser devices: 0.6J/10 Hz (6 W), 0.6 J/20 Hz (12 W), 1.5 J/10 Hz (15 W), and 1.5 J/20 Hz (30 W), employing short pulse width for all lasers and long pulse width for Ho:YAG and p-Tm:YAG. Ten participants conducted the experimental setup during 3-minutes laser on time, combining the laser technology, settings, and pulse widths, with a total of 20 different combinations. The efficiency, AS and ureteral damage resulting from each intervention were analyzed. Results: p-Tm:YAG and TFL demonstrated significantly higher efficiency compared with Ho:YAG (0.049 ± 0.02 Δgr/KJ and 0.042 ± 0.01 Δgr/KJ vs 0.029 ± 0.01 Δgr/KJ; p < 0.05). In all laser sources, as the power increases, the AS also increases (p < 0.05). Furthermore, only at high-energy settings (1.5 J) higher frequency led to increase AS (p < 0.05). Both, p-Tm:YAG and TFL exhibited higher AS compared to Ho:YAG (0.64 ± 0.33 Δgr/s and 0.62 ± 0.31 Δgr/s vs 0.44 ± 0.22 Δgr/s; p < 0.05). Regarding ureteral injuries, as the power increases, there is a higher chance of ureteral damage (p = 0.031). No differences were observed between laser technologies (p = 0.828). Conclusions: Both, p-Tm:YAG and TFL exhibited superior performances during laser lithotripsy compared with Ho:YAG, as they demonstrated higher efficiency and ablation speed. Thermal damage did not appear to be associated with specific laser equipment, but higher grades of lesions are described by increasing power.

Cefiderocol for the Treatment of Infections by VIM-Type-Producing Gram-Negative Bacteria.

VIM-type-producing Gram-negative bacteria (GNB) infections are difficult to treat. This is a retrospective single-center study of 34 patients who received cefiderocol for the treatment of VIM-type-producing GNB infections, including 25 Pseudomonas spp., 7 Enterobacterales, and 5 Achromobacter sp. Primary outcomes were clinical failure (defined as death, lack of clinical improvement, or a switch to another drug) at day 14 and 30-day all-cause mortality. The median age was 59 years (IQR 53.7-73.4), and the median Charlson comorbidity index was 3.5 (IQR 2-5). The main infections were respiratory tract infections (n = 9, 27%) and skin and soft tissue infections (n = 9, 27%). Eight patients exhibited bacteremia. In 9/17 patients with a drainable focus, drainage was performed. The median cefiderocol treatment duration was 13 days (IQR 8-24). Five patients (15%) experienced clinical failure on day 14, and the thirty-day mortality rate was 9/34 (27%); two cases occurred because of an uncontrolled infection source, and one was due to a new infection caused by the same bacteria. The other six deaths were unrelated to the index infection. Five patients experienced microbiological recurrence within three months. Susceptibility testing revealed the development of cefiderocol resistance in 1/7 cases with persistent or recurrent positive cultures. Cefiderocol, even in monotherapy, could be considered for the treatment of VIM-type-producing GNB infections.

A Flexible Laser-Induced Graphene Memristor with Volatile Switching for Neuromorphic Applications.

Two-dimensional graphene and graphene-based materials are attracting increasing interest in neuromorphic computing applications by the implementation of memristive architectures that enable the closest solid-state equivalent to biological synapses and neurons. However, the state-of-the-art fabrication methodology involves routine use of high-temperature processes and multistepped chemical synthesis, often on a rigid substrate constraining the experimental exploration in the field to high-tech facilities. Here, we demonstrate the use of a one-step process using a commercial laser to fabricate laser-induced graphene (LIG) memristors directly on a flexible polyimide substrate. For the first time, a volatile resistive switching phenomenon is reported in the LIG without using any additional materials. The absence of any precursor or patterning mask greatly simplifies the process while reducing the cost and providing greater controllability. The fabricated memristors show multilevel resistance-switching characteristics with high endurance and tunable timing characteristics. The recovery time and the trigger pulse-dependent state change are shown to be highly suitable for its use as a synaptic element and in the realization of leaky-integrate and fire neuron in neuromorphic circuits.

DRESS syndrome and tuberculosis: Implementation of a desensitization and re-desensitization protocol to recover antituberculosis drugs in a case series at a specialized TB Unit in Lima, Peru.

RATIONALE: Antituberculosis drugs (ATDs) could cause severe and rare reactions, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome. Recovering ATDs might guarantee a higher cure rate for tuberculosis patients. Our aim was to evaluate the results of desensitization and re-desensitization to recover ATDs in a case series of patients with DRESS syndrome. PATIENT CONCERNS AND DIAGNOSES: A retrospective case series study was conducted on patients with DRESS syndrome due to therapy with ATDs from 2021 to 2023. Desensitization and re-desensitization protocols, designed with an algorithm proposed by the Tuberculosis Specialized Unit of the Dos de Mayo National Hospital in Lima, Peru, were implemented. INTERVENTIONS AND OUTCOMES: A total of 18 patients underwent desensitization or re-desensitization protocols, achieving an overall success rate of 72.2%. The average time for the development of DRESS syndrome due to ATDs was 19 days. Rifampicin (84.2%), isoniazid (68.4%), and pyrazinamide (26.3%) were identified as the main drugs responsible for this adverse reaction. All patients presented with fever and skin rash, with an average eosinophil percentage of 16.7% (interquartile range: 4.5-28.8). Organ involvement (liver, kidney, and heart) was observed in 8 patients, but only 2 patients experienced severe complications due to DRESS syndrome. A significant association was found between the number of ATDs used and eosinophil levels (P =.03). LESSONS: The study introduced a desensitization and re-desensitization algorithm for the treatment of DRESS syndrome, notable for its safety, adaptability, and high success rate. This advancement provided healthcare professionals with safer and more effective therapeutic approaches for managing this complex condition.

Numerical and experimental analysis of thermal behaviour of high voltage power cable in unfilled ducts.

The work addresses the topic of the thermal study of high-voltage power cables installed inside plastic pipes in the absence of filling. The presence of air inside the pipe creates an insulating layer that does not favor heat exchange and makes the calculation of the flow rate more complex, as it is necessary to take into account the thermal phenomena of natural convection and radiation between the surface of the cable and the internal surface of the tube. The numerical model based on the finite element calculation was compared with the experimental results obtained on a simulacrum in which the temperatures on the different layers of the cable were measured. After this validation, some typical installation configurations of single and double energy transport triads were analyzed.

Urinary extracellular vesicles as a monitoring tool for renal damage in patients not meeting criteria for chronic kidney disease.

Background: Current definition of chronic kidney disease (CKD) identifies only advanced stages, but effective management demands early detection. Urinary albumin-to-creatinine ratio (ACR) 30 mg/g is a cut-off point for CKD clinical diagnosis. Patients with lower values (normoalbuminuria) and eGFR > 60 mL/min/1.73 m2 are considered at no increased cardiorenal risk. However, higher incidence of renal function decline and cardiovascular events have been shown within the normoalbuminuria range. Novel subclinical indicators may help to identify higher-risk patients. Urinary extracellular vesicles (uEVs) are sentinels of renal function non-invasively. Here we aimed to approach the early assessment of cardiorenal risk by investigating the protein cargo of uEVs. Methods: Hypertensive patients were classified in control group (C) with ACR < 10 mg/g, and high-normal group (HN) with ACR 10-30 mg/g. Isolated uEVs were characterized by western blotting and electron microscopy and the protein cargo was analyzed by untargeted proteomics (LC-MS/MS) in a first discovery cohort. Protein confirmation was performed in a different cohort by ExoView. Immunohistochemistry of human kidney biopsies was also performed to evaluate the potential of uEVs to reflect renal damage. Results: HN albuminuria does not affect the uEVs concentration, size, or tetraspanin profile. Among >6200 uEVs proteins identified, 43 define a panel significantly altered in HN patients without variation in urine, mostly annotated in the tubule (39 out of 43). The tubular transporter long-chain fatty acid transport protein 2 (SLC27A2) and the apical membrane protein amnionless (AMN) confirmed their alteration in HN patients evidencing impaired tubular reabsorption. SLC27A2 showed tubular expression and significantly reduced levels in patients with diagnostic criteria for CKD. Conclusions: Alterations in the EV-mediated molecular profile are evident before pathological ACR levels are reached. Direct quantitation of SLC27A2 and AMN in uEVs helps identifying normoalbuminuric subjects with higher cardiorenal risk in early monitoring of CKD.

Fragility of Kardar-Parisi-Zhang universality class in the presence of temporally correlated noise.

We study numerically a family of surface growth models that are known to be in the universality class of the Kardar-Parisi-Zhang equation when driven by uncorrelated noise. We find that, in the presence of noise with power-law temporal correlations with exponent θ, these models exhibit critical exponents that differ both quantitatively and qualitatively from model to model. The existence of a threshold value for θ below which the uncorrelated fixed point is dominant occurs for some models but not for others. In some models the dynamic exponent z(θ) is a smooth decreasing function, while it has a maximum in other cases. Despite all models sharing the same symmetries, critical exponents turn out to be strongly model dependent. Our results clearly show the fragility of the universality class concept in the presence of long-range temporally correlated noise.

Human Ascaris infection is associated with higher frequencies of IL-10 producing B cells.

INTRODUCTION: Ascaris lumbricoides has dual effects on the immune system of infected hosts. The IgE response to this parasite has been thoroughly studied, but little is known about cellular responses induced by infection. This study aims to explore the interplay between A. lumbricoides infection and B cell responses, especially B regulatory cells. METHODS: Participants from Santa Catalina, Bolívar, Colombia, a helminth-endemic town, were screened for soil-transmitted helminthiasis (STH) using stool examinations. Eighteen A. lumbricoides-infected and 11 non-infected subjects were selected. Blood samples were analyzed for Breg cells and related cytokines, and immunoglobulins specific to the A. lumbricoides excretory/secretory product, ABA-1. RESULTS: Infected subjects exhibited higher frequencies of Breg cells, especially those with a higher A. lumbricoides egg burden. Higher frequencies of different Breg subsets were observed in infected individuals, with CD25+CD71+CD73- B cells being notably increased in strongly infected individuals. Additionally, A. lumbricoides infection was associated with reduced levels of circulating ABA-1-specific IgG1 and IgE. IL-10+ B cell frequencies correlated inversely with ABA-1-specific IgE. CONCLUSIONS: A. lumbricoides infection has a significant impact on the immune response, particularly on Breg cell populations and antibody responses. Our findings suggest that A. lumbricoides infection mediates a dose-dependent immunosuppressive response characterized by an increase in Breg cells and concomitant suppression of ABA-1-specific humoral responses.

Remodeling p38 signaling in muscle controls locomotor activity via IL-15.

Skeletal muscle has gained recognition as an endocrine organ releasing myokines upon contraction during physical exercise. These myokines exert both local and pleiotropic health benefits, underscoring the crucial role of muscle function in countering obesity and contributing to the overall positive effects of exercise on health. Here, we found that exercise activates muscle p38γ, increasing locomotor activity through the secretion of interleukin-15 (IL-15). IL-15 signals in the motor cortex, stimulating locomotor activity. This activation of muscle p38γ, leading to an increase locomotor activity, plays a crucial role in reducing the risk of diabetes and liver steatosis, unveiling a vital muscle-brain communication pathway with profound clinical implications. The correlation between p38γ activation in human muscle during acute exercise and increased blood IL-15 levels highlights the potential therapeutic relevance of this pathway in treating obesity and metabolic diseases. These findings provide valuable insights into the molecular basis of exercise-induced myokine responses promoting physical activity.

BETA-HYDROXYBUTYRATE COUNTERACTS THE DELETERIOUS EFFECTS OF A SATURATED HIGH-FAT DIET ON SYNAPTIC AMPA RECEPTORS AND COGNITIVE PERFORMANCE.

The ketogenic diet, characterized by high fat and low carbohydrates, has gained popularity not only as a strategy for managing body weight but also for its efficacy in delaying cognitive decline associated with neurodegenerative diseases and the aging process. Since this dietary approach stimulates the liver's production of ketone bodies, primarily ß-hydroxybutyrate (BHB), which serves as an alternative energy source for neurons, we investigated whether BHB could mitigate impaired AMPA receptor trafficking, synaptic dysfunction, and cognitive decline induced by metabolic challenges such as saturated fatty acids. Here, we observe that, in cultured primary cortical neurons, exposure to palmitic acid (200µM) decreased surface levels of glutamate GluA1-containing AMPA receptors, whereas unsaturated fatty acids, such as oleic acid and ω-3 docosahexaenoic acid (200µM), and BHB (5mM) increased them. Furthermore, BHB countered the adverse effects of palmitic acid on synaptic GluA1 levels in hippocampal neurons, as well as excitability and plasticity in hippocampal slices. Additionally, daily intragastric administration of BHB (100 mg/kg/day) for two months reversed cognitive impairment induced by a saturated high-fat diet (49% of calories from fat) in a mouse experimental model of obesity. In summary, our findings underscore the significant impact of fatty acids and ketone bodies on AMPA receptors abundance, synaptic function and neuroplasticity, shedding light on the potential use of BHB to delay cognitive impairments associated with metabolic diseases.

Effects of the Regular Use of Virtual Environments on Spatial Navigation and Memory.

Introduction: The cognitive effects of video games have garnered increasing attention due to their potential applications in cognitive rehabilitation and evaluation. However, the underlying mechanisms driving these cognitive modifications remain poorly understood. Objectives: This study investigates the fundamental mnemonic processes of spatial navigation, pattern separation, and recognition memory, closely associated with the hippocampus. Our objective is to elucidate the interaction of these cognitive processes and shed light on rehabilitation mechanisms that could inform the design of video games aimed at stimulating the hippocampus. Method: In this study, we assessed 48 young adults, including both video game players and non-players. We utilized virtual reality and cognitive tasks such as the Lobato Virtual Water Maze and the Mnemonic Similarity Task to evaluate their cognitive abilities. Results: Our key findings highlight that gamers exhibit heightened pattern separation abilities and demonstrate quicker and more accurate spatial learning, attributed to the cognitive stimulation induced by video games. Additionally, we uncovered a significant relationship between spatial memory, guided by environmental cues, and pattern separation, which serves as the foundation for more efficient spatial navigation. Conclusions: These results provide valuable insights into the cognitive impact of video games and offer potential for monitoring changes in rehabilitation processes and early signs of cognitive decline through virtual reality-based assessments. Ultimately, we propose that examining the relationships between cognitive processes represents an effective method for evaluating neurodegenerative conditions, offering new possibilities for early diagnosis and intervention.

Enhancing spatial memory and pattern separation: Long-term effects of stimulant treatment in individuals with ADHD.

This study explores the under-researched domain of long-term stimulant treatment in children and adolescents diagnosed with attention deficit hyperactivity disorder (ADHD). The necessity for extended treatment duration, often accompanied by safety concerns and side effects leading to treatment discontinuation, underscores the significance of this investigation. Concurrently, comparative studies have revealed adverse impacts on vulnerable regions within the hippocampal formation, accompanied by behavioral perturbations. We employed computerized tests and virtual reality to assess spatial memory, pattern separation, and object recognition memory in a cohort of children diagnosed with ADHD receiving stimulant treatment. We compared their performance to a group of neurotypical peers. Our findings indicate that the ADHD group exhibited a lower performance in spatial memory, pattern separation, and object recognition memory than ND group. Intriguingly, a positive relationship emerged between the duration of stimulant treatment and performance in these variables. Notably, this improvement was not immediate to MPH treatment but becomes significant after 24 months of treatment. In contrast to previous comparative investigations, our study did not reveal a detrimental impact on spatial navigation, object recognition memory, or pattern separation, despite the known interplay of these cognitive processes with the hippocampal formation. These results shed new light on the nuanced effects of stimulant treatment in ADHD, underscoring the need for a more comprehensive understanding of long-term treatment outcomes.