RESUMEN
Type 1 diabetes (T1D) is characterized by the destruction of pancreatic ß-cells. Several observations have renewed the interest in ß-cell RNA sensors and editors. Here, we report that N 6-methyladenosine (m6A) is an adaptive ß-cell safeguard mechanism that controls the amplitude and duration of the antiviral innate immune response at T1D onset. m6A writer methyltransferase 3 (METTL3) levels increase drastically in ß-cells at T1D onset but rapidly decline with disease progression. m6A sequencing revealed the m6A hyper methylation of several key innate immune mediators, including OAS1, OAS2, OAS3 and ADAR1 in human islets and EndoC-ßH1 cells at T1D onset. METTL3 silencing enhanced 2'-5'-oligoadenylate synthetase levels by increasing its mRNA stability. Consistently, in vivo gene therapy to prolong Mettl3 overexpression specifically in ß-cells delayed diabetes progression in the non-obese diabetic mouse model of T1 D. Mechanistically, the accumulation of reactive oxygen species blocked upregulation of METTL3 in response to cytokines, while physiological levels of nitric oxide enhanced METTL3 levels and activity. Furthermore, we report that the cysteines in position C276 and C326 in the zinc finger domains of the METTL3 protein are sensitive to S-nitrosylation and are important to the METTL3-mediated regulation of oligoadenylate synthase mRNA stability in human ß-cells. Collectively, we report that m6A regulates the innate immune response at the ß-cell level during the onset of T1D in humans.
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Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.
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Autoanticuerpos , Predisposición Genética a la Enfermedad , Interferón Tipo I , FN-kappa B , Humanos , Autoanticuerpos/inmunología , COVID-19/genética , COVID-19/inmunología , Mutación con Ganancia de Función , Heterocigoto , Proteínas I-kappa B/deficiencia , Proteínas I-kappa B/genética , Interferón Tipo I/antagonistas & inhibidores , Interferón Tipo I/inmunología , Mutación con Pérdida de Función , FN-kappa B/deficiencia , FN-kappa B/genética , Subunidad p52 de NF-kappa B/deficiencia , Subunidad p52 de NF-kappa B/genética , Neumonía Viral/genética , Neumonía Viral/inmunología , Timo/anomalías , Timo/inmunología , Timo/patología , Células Epiteliales Tiroideas/metabolismo , Células Epiteliales Tiroideas/patología , Proteína AIRE , Quinasa de Factor Nuclear kappa BRESUMEN
Mutations in the gene encoding the zinc-finger transcription factor Ikaros (IKZF1) are found in patients with immunodeficiency, leukemia, and autoimmunity. Although Ikaros has a well-established function in modulating gene expression programs important for hematopoietic development, its role in other cell types is less well defined. Here, we uncover functions for Ikaros in thymic epithelial lineage development in mice and show that Ikzf1 expression in medullary thymic epithelial cells (mTECs) is required for both autoimmune regulator-positive (Aire+) mTEC development and tissue-specific antigen (TSA) gene expression. Accordingly, TEC-specific deletion of Ikzf1 in mice results in a profound decrease in Aire+ mTECs, a global loss of TSA gene expression, and the development of autoimmunity. Moreover, Ikaros shapes thymic mimetic cell diversity, and its deletion results in a marked expansion of thymic tuft cells and muscle-like mTECs and a loss of other Aire-dependent mimetic populations. Single-cell analysis reveals that Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with IKZF1 mutations.
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Tolerancia Central , Timo , Humanos , Ratones , Animales , Diferenciación Celular , Factores de Transcripción , Regulación de la Expresión GénicaRESUMEN
Type 1 Diabetes (T1D) is characterized by autoimmune-mediated destruction of insulin-producing ß-cells. Several observations have renewed interest in the innate immune system as an initiator of the disease process against ß-cells. Here, we show that N 6 -Methyladenosine (m 6 A) is an adaptive ß-cell safeguard mechanism that accelerates mRNA decay of the 2'-5'-oligoadenylate synthetase (OAS) genes to control the antiviral innate immune response at T1D onset. m 6 A writer methyltransferase 3 (METTL3) levels increase drastically in human and mouse ß-cells at T1D onset but rapidly decline with disease progression. Treatment of human islets and EndoC-ßH1 cells with pro-inflammatory cytokines interleukin-1 ß and interferon α mimicked the METTL3 upregulation seen at T1D onset. Furthermore, m 6 A-sequencing revealed the m 6 A hypermethylation of several key innate immune mediators including OAS1, OAS2, and OAS3 in human islets and EndoC-ßH1 cells challenged with cytokines. METTL3 silencing in human pseudoislets or EndoC-ßH1 cells enhanced OAS levels by increasing its mRNA stability upon cytokine challenge. Consistently, in vivo gene therapy, to prolong Mettl3 overexpression specifically in ß-cells, delayed diabetes progression in the non-obese diabetic (NOD) mouse model of T1D by limiting the upregulation of Oas pointing to potential therapeutic relevance. Mechanistically, the accumulation of reactive oxygen species blocked METTL3 upregulation in response to cytokines, while physiological levels of nitric oxide promoted its expression in human islets. Furthermore, for the first time to our knowledge, we show that the cysteines in position C276 and C326 in the zinc finger domain of the METTL3 protein are sensitive to S-nitrosylation (SNO) and are significant for the METTL3 mediated regulation of OAS mRNA stability in human ß-cells in response to cytokines. Collectively, we report that m 6 A regulates human and mouse ß-cells to control the innate immune response during the onset of T1D and propose targeting METTL3 to prevent ß-cell death in T1D.
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Acquired lipodystrophy is often characterized as an idiopathic subtype of lipodystrophy. Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking. Here, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte-specific lipid droplet protein perilipin 1 (PLIN1) in a murine model of autoimmune polyendocrine syndrome type 1 (APS1). We then tested for PLIN1 autoantibodies in human subjects with acquired lipodystrophy with two independent severe breaks in immune tolerance (including APS1) along with control subjects using a specific radioligand binding assay and indirect immunofluorescence on fat tissue. We identified autoantibodies to PLIN1 in these two cases, including the first reported case of APS1 with acquired lipodystrophy and a second patient who acquired lipodystrophy as an immune-related adverse event following cancer immunotherapy. Lastly, we also found PLIN1 autoantibodies to be specifically enriched in a subset of patients with acquired generalized lipodystrophy (17 of 46 [37%]), particularly those with panniculitis and other features of autoimmunity. These data lend additional support to new literature that suggests that PLIN1 autoantibodies represent a marker of acquired autoimmune lipodystrophies and further link them to a break in immune tolerance.
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Lipodistrofia Generalizada Congénita , Lipodistrofia , Humanos , Animales , Ratones , Perilipina-1/metabolismo , Autoanticuerpos , Lipodistrofia Generalizada Congénita/metabolismo , Lipodistrofia Generalizada Congénita/patología , Lipodistrofia/metabolismo , Tejido Adiposo/metabolismoRESUMEN
In the present study, we aimed to provide a robust comparison of the fatigability of the knee extensors following isometric (ISO) and concentric (CON) tasks. Twenty young adults (25 ± 4 yr, 10 women) randomly performed the ISO and CON quadriceps intermittent fatigue test, consisting of ten (5 s on/5-s off, ISO) or one-hundred (0.5-s on/0.5-s off, CON) contractions with 10 % increments per stage until exhaustion. Performance fatigability was quantified as maximal isometric (MVIC) and concentric (MVCC) torque loss. Voluntary activation and contractile function (peak-twitch) were investigated using peripheral nerve stimulation. Number of stages (6.2 ± 0.7 vs. 4.9 ± 0.8; P < 0.001) and torque-time integral (20,166 ± 7,821 vs. 11,285 ± 4,933 Nm.s; P < 0.001) were greater for ISO than CON. MVIC, MVCC and voluntary activation decreased similarly between sessions (P > 0.05) whereas peak-twitch amplitude decreased more for CON (P < 0.001). The number of contractions was similar across sexes (ISO: men = 62 ± 8, women = 61 ± 5; CON: men = 521 ± 67, women = 458 ± 76, P > 0.05). MVCC was more reduced in women for both sessions (all P < 0.05), while MVIC loss was similar between sexes. We concluded that, despite greater torque-time integral and duration for ISO, both sessions induced a similar performance fatigability at exhaustion. Contractile function was more altered in CON. Finally, sex-related difference in fatigability depends on the contraction mode used during testing.
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Contracción Isométrica , Fatiga Muscular , Masculino , Adulto Joven , Femenino , Humanos , Fatiga Muscular/fisiología , Contracción Isométrica/fisiología , Electromiografía , Músculo Esquelético/fisiología , Estimulación Eléctrica , TorqueRESUMEN
BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic insulin-producing ß cells are specifically destroyed by the immune system. Understanding the initiation and progression of human T1D has been hampered by the lack of appropriate models that can reproduce the complexity and heterogeneity of the disease. The development of platforms combining multiple human pluripotent stem cell (hPSC) derived tissues to model distinct aspects of T1D has the potential to provide critical novel insights into the etiology and pathogenesis of the human disease. SCOPE OF REVIEW: In this review, we summarize the state of hPSC differentiation approaches to generate cell types and tissues relevant to T1D, with a particular focus on pancreatic islet cells, T cells, and thymic epithelium. We present current applications as well as limitations of using these hPSC-derived cells for disease modeling and discuss efforts to optimize platforms combining multiple cell types to model human T1D. Finally, we outline remaining challenges and emphasize future improvements needed to accelerate progress in this emerging field of research. MAJOR CONCLUSIONS: Recent advances in reprogramming approaches to create patient-specific induced pluripotent stem cell lines (iPSCs), genome engineering technologies to efficiently modify DNA of hPSCs, and protocols to direct their differentiation into mature cell types have empowered the use of stem cell derivatives to accurately model human disease. While challenges remain before complex interactions occurring in human T1D can be modeled with these derivatives, experiments combining hPSC-derived ß cells and immune cells are already providing exciting insight into how these cells interact in the context of T1D, supporting the viability of this approach.
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Diabetes Mellitus Tipo 1 , Células Madre Pluripotentes Inducidas , Células Secretoras de Insulina , Células Madre Pluripotentes , Humanos , Diabetes Mellitus Tipo 1/metabolismo , Células Madre Pluripotentes/metabolismo , Células Secretoras de Insulina/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Diferenciación CelularRESUMEN
Cell replacement therapy using ß cells derived from stem cells is a promising alternative to conventional diabetes treatment options. Although current differentiation methods produce glucose-responsive ß cells, they can also yield populations of undesired endocrine progenitors and other proliferating cell types that might interfere with long-term islet function and safety of transplanted cells. Here, we describe the generation of an array of monoclonal antibodies against cell surface markers that selectively label stem cell-derived islet cells. A high-throughput screen identified promising candidates, including three clones that mark a high proportion of endocrine cells in differentiated cultures. A scalable magnetic sorting method was developed to enrich for human pluripotent stem cell (hPSC)-derived islet cells using these three antibodies, leading to the formation of islet-like clusters with improved glucose-stimulated insulin secretion and reduced growth upon transplantation. This strategy should facilitate large-scale production of functional islet clusters from stem cells for disease modeling and cell replacement therapy.
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Células Secretoras de Insulina , Islotes Pancreáticos , Células Madre Pluripotentes , Diferenciación Celular , Glucosa/metabolismo , Humanos , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Células Madre Pluripotentes/metabolismoRESUMEN
PURPOSE: While the physiological determinants of road running have been widely studied, there is a lack of research in trail-running racing performance. The aim of our study was to determine the physiological predictors of trail-running performance in races of different distances in similar terrain and weather conditions. METHODS: Seventy-five trail runners participating in one of the races of the Ultra-Trail du Mont-Blanc were recruited. Previous to the race, each runner was evaluated with (1) an incremental treadmill test to determine maximal oxygen uptake, ventilatory thresholds, cost of running, and substrate utilization; (2) a power-force-velocity profile on a cycle ergometer; (3) maximal voluntary contractions of the knee extensors and plantar flexors; and (4) anthropometric characteristics. Neuromuscular fatigue was evaluated after the races. Twenty-four runners finished a SHORT (<55 km), 16 finished a MEDIUM (101 km), and 14 finished a LONG (>145 km) race. Correlations and multiple linear regressions were used to find the determinants of performance in each race distance. RESULTS: Performance in SHORT was explained by maximal oxygen uptake and lipid utilization at 10 km/h (r2 = .825, P < .001). Performance in MEDIUM was determined by maximal oxygen uptake, maximal isometric strength, and body fat percentage (r2 = .917, P < .001). A linear model could not be applied in LONG, but performance was correlated to peak velocity during the incremental test. CONCLUSIONS: Performance in trail running is mainly predicted by aerobic capacity, while lipid utilization also influences performance in races <60 km and performance in approximately 100 km is influenced by muscle strength and body composition.
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Resistencia Física , Carrera , Humanos , Rodilla , Lípidos , Oxígeno , Resistencia Física/fisiología , Carrera/fisiologíaRESUMEN
BACKGROUND: Myotonic dystrophy type 1 (DM1) is characterized by progressive and predominantly distal muscle atrophy and myotonia. Gait and balance impairments, resulting in falls, are frequently reported in this population. However, the extent to which individuals with DM1 rely more on a specific sensory system for balance than asymptomatic individuals (AI) is unknown. OBJECTIVE: Evaluate postural control performance in individuals with DM1 and its dependence on vision compared to AI. METHODS: 20 participants with DM1, divided into two groups based on their diagnosis, i.e. adult and congenital phenotype, and 12 AI participants were recruited. Quiet standing postural control was assessed in two visual conditions: eyes-open and eyes-closed. The outcomes measures were: center of pressure (CoP), mean velocity, CoP range of displacement in anteroposterior and mediolateral axis, and the 95% confidence ellipse's surface. Friedman and Kruskal-Wallis analysis of variance were used to compare outcomes between conditions and groups, respectively. RESULTS: Significant group effect and condition effect were observed on postural control performance. No significant difference was observed between the two DM1 groups. The significant differences observed between the AI group and the two DM1 groups in the eyes-open condition were also observed in the eyes-closed condition. CONCLUSIONS: The result revealed poorer postural control performance in people with DM1 compared to AI. The DM1 group also showed similar decrease in performance than AI in eyes-closed condition, suggesting no excessive visual dependency.
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Distrofia Miotónica , Accidentes por Caídas , Humanos , Distrofia Miotónica/complicaciones , Equilibrio Postural/fisiologíaRESUMEN
BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease characterized by impaired immune tolerance to ß-cell antigens and progressive destruction of insulin-producing ß-cells. Animal models have provided valuable insights for understanding the etiology and pathogenesis of this disease, but they fall short of reflecting the extensive heterogeneity of the disease in humans, which is contributed by various combinations of risk gene alleles and unique environmental factors. Collectively, these factors have been used to define subgroups of patients, termed endotypes, with distinct predominating disease characteristics. SCOPE OF REVIEW: Here, we review the gaps filled by these models in understanding the intricate involvement and regulation of the immune system in human T1D pathogenesis. We describe the various models developed so far and the scientific questions that have been addressed using them. Finally, we discuss the limitations of these models, primarily ascribed to hosting a human immune system (HIS) in a xenogeneic recipient, and what remains to be done to improve their physiological relevance. MAJOR CONCLUSIONS: To understand the role of genetic and environmental factors or evaluate immune-modifying therapies in humans, it is critical to develop and apply models in which human cells can be manipulated and their functions studied under conditions that recapitulate as closely as possible the physiological conditions of the human body. While microphysiological systems and living tissue slices provide some of these conditions, HIS mice enable more extensive analyses using in vivo systems.
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Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Animales , Diabetes Mellitus Tipo 1/genética , Humanos , Sistema Inmunológico/patología , Células Secretoras de Insulina/patología , RatonesRESUMEN
PURPOSE: Evaluate the relationship between different walking capacities and muscle strength in children with bilateral cerebral palsy (BCP) and assess these relationships in stronger and weaker children. MATERIALS AND METHODS: Thirty-two children with spastic BCP were included. All participants walked under three speed conditions: comfortable, fast, and for a longer period (6 min). Walking speeds, Energy Expenditure Index (EEI), and lower limb muscle strength were measured. A global strength index (GSI) was computed as the sum of each muscle group strength. Pearson's coefficient and regression models were computed between walking capacities and the GSI. RESULTS: GSI was correlated with the EEI and all walking speeds. Logarithmic regressions models explained between 24 and 34% of the variance of walking capacities. Then, the group was divided in two subgroups (weaker and stronger children). GSI was correlated with comfortable and endurance waking speed in weaker children, but not in stronger children. CONCLUSION: This study reports logarithmic relationship between muscle strength and walking capacities in children with BCP. The subgroup analysis implies that muscle strength has an impact on walking capacities solely in weaker children, suggesting that muscle strength must be preserved and reinforced in interventions targeting motor function in weaker children with BCP.Implications for rehabilitationIn a sample of children with spastic bilateral cerebral palsy, this study shows that global muscle strength is associated with walking capacities and the relationship seems more complex than linear.Based on the results, interventions should focus on maintaining or improving muscle strength in weaker children as no association was observed between muscle strength and walking capacities in stronger children.In stronger children, intervention should focus on factors other than muscle strength as it does not influence walking capacities.Based on this study, a more accurate screening of children who could benefit from strength training could be completed by initial global muscle strength.
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Parálisis Cerebral , Niño , Humanos , Extremidad Inferior , Espasticidad Muscular , Fuerza Muscular/fisiología , Caminata/fisiologíaRESUMEN
PURPOSE: Fatigue has previously been investigated in trail running by comparing maximal isometric force before and after the race. Isometric contractions may not entirely reflect fatigue-induced changes, and therefore dynamic evaluation is warranted. The aim of the present study was to compare the magnitude of the decrement of maximal isometric force versus maximal power, force, and velocity after trail running races ranging from 40 to 170 km. METHODS: Nineteen trail runners completed races shorter than 60 km, and 21 runners completed races longer than 100 km. Isometric maximal voluntary contractions (IMVCs) of knee extensors and plantar flexors and maximal 7-second sprints on a cycle ergometer were performed before and after the event. RESULTS: Maximal power output (Pmax; -14% [11%], P < .001), theoretical maximum force (F0; -11% [14%], P < .001), and theoretical maximum velocity (-3% [8%], P = .037) decreased significantly after both races. All dynamic parameters but theoretical maximum velocity decreased more after races longer than 100 km than races shorter than 60 km (P < .05). Although the changes in IMVCs were significantly correlated (P < .05) with the changes in F0 and Pmax, reductions in IMVCs for knee extensors (-29% [16%], P < .001) and plantar flexors (-26% [13%], P < .001) were larger (P < .001) than the reduction in Pmax and F0. CONCLUSIONS: After a trail running race, reductions in isometric versus dynamic forces were correlated, yet they are not interchangeable because the losses in isometric force were 2 to 3 times greater than the reductions in Pmax and F0. This study also shows that the effect of race distance on fatigue measured in isometric mode is true when measured in dynamic mode.
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Fatiga Muscular , Resistencia Física , Humanos , Contracción Isométrica , Rodilla , Extremidad Inferior , Músculo EsqueléticoRESUMEN
Stem cell-based replacement therapies hold the promise to restore function of damaged or degenerated tissue such as the pancreatic islets in people with type 1 diabetes. Wide application of these therapies requires overcoming the fundamental roadblock of immune rejection. To address this issue, we use genetic engineering to create human pluripotent stem cells (hPSCs) in which the majority of the polymorphic human leukocyte antigens (HLAs), the main drivers of allogeneic rejection, are deleted. We retain the common HLA class I allele HLA-A2 and less polymorphic HLA-E/F/G to allow immune surveillance and inhibition of natural killer (NK) cells. We employ a combination of in vitro assays and humanized mouse models to demonstrate that these gene manipulations significantly reduce NK cell activity and T-cell-mediated alloimmune response against hPSC-derived islet cells. In summary, our approach produces hypoimmunogenic hPSCs that can be readily matched with recipients to avoid alloimmune rejection.
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Eliminación de Gen , Rechazo de Injerto/inmunología , Antígenos HLA/metabolismo , Islotes Pancreáticos/inmunología , Células Madre Pluripotentes/citología , Alelos , Animales , Línea Celular , Células Clonales , Humanos , Células Asesinas Naturales/inmunología , Activación de Linfocitos/inmunología , Masculino , Ratones Endogámicos NOD , Linfocitos T/inmunologíaRESUMEN
INTRODUCTION: Women have been shown to experience less neuromuscular fatigue than men in knee extensors (KE) and less peripheral fatigue in plantar flexors (PF) after ultratrail running, but it is unknown if these differences exist for shorter trail running races and whether this may impact running economy. The purpose of this study was to characterize sex differences in fatigability over a range of running distances and to examine possible differences in the postrace alteration of the cost of running (Cr). METHODS: Eighteen pairs of men and women were matched by performance after completing different races ranging from 40 to 171 km, divided into SHORT versus LONG races (<60 and >100 km, respectively). Neuromuscular function and Cr were tested before and after each race. Neuromuscular function was evaluated on both KE and PF with voluntary and evoked contractions using electrical nerve (KE and PF) and transcranial magnetic (KE) stimulation. Oxygen uptake, respiratory exchange ratio, and ventilation were measured on a treadmill and used to calculate Cr. RESULTS: Compared with men, women displayed a smaller decrease in maximal strength in KE (-36% vs -27%, respectively, P < 0.01), independent of race distance. In SHORT only, women displayed less peripheral fatigue in PF compared with men (Δ peak twitch: -10% vs -24%, respectively, P < 0.05). Cr increased similarly in men and women. CONCLUSIONS: Women experience less neuromuscular fatigue than men after both "classic" and "extreme" prolonged running exercises but this does not impact the degradation of the energy Cr.
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Conducta Competitiva/fisiología , Carrera de Maratón/fisiología , Fatiga Muscular/fisiología , Resistencia Física/fisiología , Caracteres Sexuales , Proteína C-Reactiva/metabolismo , Creatina Quinasa/sangre , Estimulación Eléctrica , Electromiografía , Metabolismo Energético , Potenciales Evocados Motores , Femenino , Pie/fisiología , Humanos , Rodilla/fisiología , Masculino , Consumo de Oxígeno , Intercambio Gaseoso Pulmonar , Torque , Estimulación Magnética TranscranealRESUMEN
The etiology of changes in lower-limb neuromuscular function, especially to the central nervous system, may be affected by exercise duration. Direct evidence is lacking as few studies have directly compared different race distances. This study aimed to investigate the etiology of deficits in neuromuscular function following short versus long trail-running races. Thirty-two male trail runners completed one of five trail-running races as LONG (>100 km) or SHORT (<60 km). Pre- and post-race, maximal voluntary contraction (MVC) torque and evoked responses to electrical nerve stimulation during MVCs and at rest were used to assess voluntary activation and muscle contractile properties of knee-extensor (KE) and plantar-flexor (PF) muscles. Transcranial magnetic stimulation (TMS) was used to assess evoked responses and corticospinal excitability in maximal and submaximal KE contractions. Race distance correlated with KE MVC (ρ = -0.556) and twitch (ρ = -0.521) torque decreases (p ≤ .003). KE twitch torque decreased more in LONG (-28 ± 14%) than SHORT (-14 ± 10%, p = .005); however, KE MVC time × distance interaction was not significant (p = .073). No differences between LONG and SHORT for PF MVC or twitch torque were observed. Maximal voluntary activation decreased similarly in LONG and SHORT in both muscle groups (p ≥ .637). TMS-elicited silent period decreased in LONG (p = .021) but not SHORT (p = .912). Greater muscle contractile property impairment in longer races, not central perturbations, contributed to the correlation between KE MVC loss and race distance. Conversely, PF fatigability was unaffected by race distance.
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Potenciales Evocados Motores/fisiología , Contracción Muscular/fisiología , Músculo Esquelético/fisiología , Carrera/fisiología , Adulto , Rendimiento Atlético/fisiología , Proteína C-Reactiva/análisis , Creatina Quinasa/sangre , Estimulación Eléctrica , Electromiografía , Nervio Femoral/fisiología , Humanos , Recuento de Leucocitos , Masculino , Fatiga Muscular/fisiología , Resistencia Física/fisiología , Nervio Tibial/fisiología , Factores de Tiempo , Torque , Estimulación Magnética TranscranealRESUMEN
OBJECTIVE: The aim of this study was to evaluate kinematic changes and muscle fatigue in jump gait during a walking exercise and the relationship between kinematic changes and muscle fatigue and strength. DESIGN: This preliminary study included 10 children with cerebral palsy who walk with jump gait. Hip and knee maximal isometric muscle strength were measured using a dynamometer. Then, lower-limb kinematics and electromyography were collected while children walked continuously for 6 min at their self-selected speed. Electromyography median frequency and lower-limb joint angles were compared between the first and the sixth minutes of the walking exercise using t test and Wilcoxon rank test. The relationship between kinematic changes and muscle strength and changes in electromyography median frequency were assessed using correlation analyses. RESULTS: During stance, maximal knee flexion significantly increased at the sixth minute (P = 0.01) and was associated with knee extensor muscle weakness (ρ = -0.504, P = 0.03). Muscle fatigue was observed only in the gluteus medius muscle (P = 0.01). CONCLUSIONS: Children with cerebral palsy who walked with jump gait and who had knee extensor weakness were more prone to an increase in knee flexion during a continuous walk. The fatigue in the gluteus medius muscle suggests that physical intervention should target the endurance of this muscle to improve jump gait.
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Parálisis Cerebral/fisiopatología , Parálisis Cerebral/rehabilitación , Trastornos Neurológicos de la Marcha/fisiopatología , Trastornos Neurológicos de la Marcha/rehabilitación , Caminata , Adolescente , Fenómenos Biomecánicos , Parálisis Cerebral/complicaciones , Niño , Evaluación de la Discapacidad , Electromiografía , Femenino , Análisis de la Marcha , Trastornos Neurológicos de la Marcha/congénito , Cadera/fisiopatología , Humanos , Rodilla/fisiopatología , Masculino , Fatiga Muscular , Fuerza Muscular , Músculo Esquelético/fisiopatología , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
The thymus' key function in the immune system is to provide the necessary environment for the development of diverse and self-tolerant T lymphocytes. While recent evidence suggests that the thymic stroma is comprised of more functionally distinct subpopulations than previously appreciated, the extent of this cellular heterogeneity in the human thymus is not well understood. Here we use single-cell RNA sequencing to comprehensively profile the human thymic stroma across multiple stages of life. Mesenchyme, pericytes and endothelial cells are identified as potential key regulators of thymic epithelial cell differentiation and thymocyte migration. In-depth analyses of epithelial cells reveal the presence of ionocytes as a medullary population, while the expression of tissue-specific antigens is mapped to different subsets of epithelial cells. This work thus provides important insight on how the diversity of thymic cells is established, and how this heterogeneity contributes to the induction of immune tolerance in humans.