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1.
PLoS One ; 19(7): e0306835, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38980891

RESUMEN

In the absence of a single comprehensive systematic review of Rational Emotive Behaviour Therapy interventions across all settings, we reviewed the methodological quality, effectiveness and efficacy of Rational Emotive Behaviour Therapy interventions on irrational/rational beliefs. We explored the impact of Rational Emotive Behaviour Therapy on wider outcomes (e.g., mental health) and identified the characteristics of successful interventions. PsycARTICLES, PsycINFO, Scopus, SPORTDiscus, and PubMed were systematically searched up to December 2023 with 162 Rational Emotive Behaviour Therapy intervention studies identified which included a validated measure of irrational/rational beliefs. Where possible, effect size for irrational/rational belief change was reported and data was analysed through a qualitative approach. Using the Mixed Methods Appraisal tool, methodological quality within the Sport and Exercise domain was assessed as good, whilst all other domains were considered low in quality, with insufficient detail provided on intervention characteristics and delivery. Most studies were conducted in the United States, within the Education domain, and assessed irrational beliefs in non-clinical adult samples. Overall, studies reported significant reductions in irrational beliefs, increases in rational beliefs and improvements in mental health outcomes (e.g., depression). More successful interventions were delivered by trained Rational Emotive Behaviour Therapy practitioners, adopted the ABC framework and were longer in duration. We highlight the importance of designing and conducting rigorous future Rational Emotive Behaviour Therapy research to generate clearer insights as to its impact on irrational/rational beliefs and mental health outcomes.


Asunto(s)
Terapia Conductista , Humanos , Terapia Conductista/métodos , Salud Mental
2.
Pract Neurol ; 2024 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-39059794

RESUMEN

Bariatric surgery is being undertaken more frequently in response to rising levels of obesity but is increasingly also requested as a cosmetic choice. Nutritional deficiencies are a recognised consequence of gastrectomy, with potentially severe and permanent neurological sequelae. We present two cases of acute, severe polyneuropathy following sleeve gastrectomy. Severe thiamine deficiency was considered in both cases but with delayed proof and a significant initial differential diagnosis. Neurologists must have a high index of suspicion for the peripheral as well as central presentations of thiamine deficiency to avoid permanent disability. We also call for explicit information resources warning of the risk and signs of thiamine deficiency to be provided routinely to patients after gastrectomy.

3.
Psychol Sport Exerc ; 75: 102706, 2024 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-39009102

RESUMEN

Until recently, research examining the application of Rational Emotive Behavior Therapy (REBT) in sports settings was virtually absent in South Africa. Despite the growing evidence of REBT's potential as a psychological intervention in Western nations, its use within the multicultural and sports-fervent context of South Africa remains unexplored. Moreover, limited research has addressed the impact of REBT on rugby players, with only a few case studies being reported. The current experiment employs a cluster randomized trial (CRT) to compare the effects of a 7-week preferential REBT program with a 7-week Mindfulness-Acceptance-Commitment (MAC) program on irrational beliefs, competitive anxiety and subjective performance, among adolescent South African rugby players. We also include a wait-list control group who received neither REBT nor MAC. Results indicate that athletes receiving REBT reported greater improvements in irrational beliefs, anxiety, and subjective performance, while that athletes receiving MAC also reported some improvements in anxiety. This study highlights the potential of REBT as a valuable psychological intervention in the context of South African adolescent rugby players.

4.
Eur J Immunol ; : e2451018, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38980256

RESUMEN

CD8+ T cells kill target cells by releasing cytotoxic molecules and proinflammatory cytokines, such as TNF and IFN-γ. The magnitude and duration of cytokine production are defined by posttranscriptional regulation, and critical regulator herein are RNA-binding proteins (RBPs). Although the functional importance of RBPs in regulating cytokine production is established, the kinetics and mode of action through which RBPs control cytokine production are not well understood. Previously, we showed that the RBP ZFP36L2 blocks the translation of preformed cytokine encoding mRNA in quiescent memory T cells. Here, we uncover that ZFP36L2 regulates cytokine production in a time-dependent manner. T cell-specific deletion of ZFP36L2 (CD4-cre) had no effect on T-cell development or cytokine production during early time points (2-6 h) of T-cell activation. In contrast, ZFP36L2 specifically dampened the production of IFN-γ during prolonged T-cell activation (20-48 h). ZFP36L2 deficiency also resulted in increased production of IFN-γ production in tumor-infiltrating T cells that are chronically exposed to antigens. Mechanistically, ZFP36L2 regulates IFN-γ production at late time points of activation by destabilizing Ifng mRNA in an AU-rich element-dependent manner. Together, our results reveal that ZFP36L2 employs different regulatory nodules in effector and memory T cells to regulate cytokine production.

5.
Lancet Neurol ; 23(7): 687-699, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38782015

RESUMEN

BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis. METHODS: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed. FINDINGS: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]). INTERPRETATION: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated. FUNDING: Orphazyme.


Asunto(s)
Esclerosis Amiotrófica Lateral , Fármacos Neuroprotectores , Humanos , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Masculino , Femenino , Método Doble Ciego , Persona de Mediana Edad , Anciano , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/efectos adversos , Resultado del Tratamiento , Adulto , Hidroxilaminas/uso terapéutico , Hidroxilaminas/efectos adversos , Hidroxilaminas/farmacología , Oxadiazoles/uso terapéutico , Oxadiazoles/efectos adversos
6.
Nat Rev Neurol ; 20(6): 364-376, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38769202

RESUMEN

Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.


Asunto(s)
Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Fenotipo , Humanos , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Demencia Frontotemporal/genética , Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/metabolismo , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/genética , Biomarcadores/metabolismo
7.
Brain Commun ; 6(3): fcae164, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38779353

RESUMEN

The progressive loss of motor function characteristic of amyotrophic lateral sclerosis is associated with widespread cortical pathology extending beyond primary motor regions. Increasing muscle weakness reflects a dynamic, variably compensated brain network disorder. In the quest for biomarkers to accelerate therapeutic assessment, the high temporal resolution of magnetoencephalography is uniquely able to non-invasively capture micro-magnetic fields generated by neuronal activity across the entire cortex simultaneously. This study examined task-free magnetoencephalography to characterize the cortical oscillatory signature of amyotrophic lateral sclerosis for having potential as a pharmacodynamic biomarker. Eight to ten minutes of magnetoencephalography in the task-free, eyes-open state was recorded in amyotrophic lateral sclerosis (n = 36) and healthy age-matched controls (n = 51), followed by a structural MRI scan for co-registration. Extracted magnetoencephalography metrics from the delta, theta, alpha, beta, low-gamma, high-gamma frequency bands included oscillatory power (regional activity), 1/f exponent (complexity) and amplitude envelope correlation (connectivity). Groups were compared using a permutation-based general linear model with correction for multiple comparisons and confounders. To test whether the extracted metrics could predict disease severity, a random forest regression model was trained and evaluated using nested leave-one-out cross-validation. Amyotrophic lateral sclerosis was characterized by reduced sensorimotor beta band and increased high-gamma band power. Within the premotor cortex, increased disability was associated with a reduced 1/f exponent. Increased disability was more widely associated with increased global connectivity in the delta, theta and high-gamma bands. Intra-hemispherically, increased disability scores were particularly associated with increases in temporal connectivity and inter-hemispherically with increases in frontal and occipital connectivity. The random forest model achieved a coefficient of determination (R2) of 0.24. The combined reduction in cortical sensorimotor beta and rise in gamma power is compatible with the established hypothesis of loss of inhibitory, GABAergic interneuronal circuits in pathogenesis. A lower 1/f exponent potentially reflects a more excitable cortex and a pathology unique to amyotrophic lateral sclerosis when considered with the findings published in other neurodegenerative disorders. Power and complexity changes corroborate with the results from paired-pulse transcranial magnetic stimulation. Increased magnetoencephalography connectivity in worsening disability is thought to represent compensatory responses to a failing motor system. Restoration of cortical beta and gamma band power has significant potential to be tested in an experimental medicine setting. Magnetoencephalography-based measures have potential as sensitive outcome measures of therapeutic benefit in drug trials and may have a wider diagnostic value with further study, including as predictive markers in asymptomatic carriers of disease-causing genetic variants.

9.
J Genet Couns ; 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38628040

RESUMEN

Predictive genetic testing is increasingly available for individuals with a heightened risk of motor neuron disease (MND). However, little is known about how they decide whether or not to get tested, and how they experience this process. This paper reports findings from a constructivist grounded theory-informed interview study with 24 family members of people with identified or suspected inherited MND (iMND). Fourteen did not know their genetic status, and nine had decided to have predictive testing, of whom six tested positive for the pathogenic gene variant identified in their family and three tested negative. One additional person was identified as negative through a parent's negative result. This paper explores the diverse ways people approached testing, and the many factors and motivations involved, based on personal attitudes and goals, experiences of living with genetic risk, and wider family considerations and circumstances. Results were met with a range of emotions; whatever the outcome, the news disrupted each person's view of the future, and they adapted in their own way and time. Support after results was variable and a perceived lack of support impacted coping and the ability to move forwards. This paper situates findings against literature on other genetic conditions, highlighting experiences as grounded in the unique characteristics of iMND. Thus, it emphasizes the need for disease-specific guidelines and support structures around predictive genetic testing in this context. Understanding people's experiences and responding to these needs is particularly timely given the uptake of testing amongst this group is anticipated to rise with increasing access to genetic testing for people with MND, and gene-specific clinical trials.

11.
Artículo en Inglés | MEDLINE | ID: mdl-38548323

RESUMEN

BACKGROUND: Venous thromboembolism (VTE) can occur in amyotrophic lateral sclerosis (ALS) and pulmonary embolism causes death in a minority of cases. The benefits of preventing VTE must be weighed against the risks. An accurate estimate of the incidence of VTE in ALS is crucial to assessing this balance. METHODS: This retrospective record-linkage cohort study derived data from the Hospital Episode Statistics database, covering admissions to England's hospitals from 1 April 2003 to 31 December 2019 and included 21 163 patients with ALS and 17 425 337 controls. Follow-up began at index admission and ended at VTE admission, death or 2 years (whichever came sooner). Adjusted HRs (aHRs) for VTE were calculated, controlling for confounders. RESULTS: The incidence of VTE in the ALS cohort was 18.8/1000 person-years. The relative risk of VTE in ALS was significantly greater than in controls (aHR 2.7, 95% CI 2.4 to 3.0). The relative risk of VTE in patients with ALS under 65 years was five times higher than controls (aHR 5.34, 95% CI 4.6 to 6.2), and higher than that of patients over 65 years compared with controls (aHR 1.86, 95% CI 1.62 to 2.12). CONCLUSIONS: Patients with ALS are at a higher risk of developing VTE, but this is similar in magnitude to that reported in other chronic neurological conditions associated with immobility, such as multiple sclerosis, which do not routinely receive VTE prophylaxis. Those with ALS below the median age of symptom onset have a notably higher relative risk. A reappraisal of the case for routine antithrombotic therapy in those diagnosed with ALS now requires a randomised controlled trial.

12.
Health Expect ; 27(2): e14024, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38528673

RESUMEN

BACKGROUND: Motor neuron disease (MND) (also known as amyotrophic lateral sclerosis) is a life-limiting neurodegenerative condition. In up to 20% of people with MND, a pathogenic variant associated with autosomal dominant inheritance can be identified. Children of people carrying a pathogenic variant have a 50% chance of inheriting this and a higher, although harder to predict, chance of developing the disease compared to the general adult population. This paper explores the experience of living with the genetic risk of MND. METHODS: We undertook a UK-based interview study with 35 individuals, including: 7 people living with genetically-mediated forms of MND; 24 asymptomatic relatives, the majority of whom had an increased risk of developing the disease; and 4 unrelated partners. RESULTS: We explore how individuals make sense of genetic risk, unpacking the interplay between genetic knowledge, personal perception, experiences of the disease in the family, age and life stage and the implications that living with risk has for different aspects of their lives. We balance an emphasis on the emotional and psychological impact described by participants, with a recognition that the salience of risk fluctuates over time. Furthermore, we highlight the diverse strategies and approaches people employ to live well in the face of uncertainty and the complex ways they engage with the possibility of developing symptoms in the future. Finally, we outline the need for open-ended, tailored support and information provision. CONCLUSIONS: Drawing on wider literature on genetic risk, we foreground how knowledge of MND risk can disrupt individuals' taken-for-granted assumptions on life and perceptions of the future, but also its contextuality, whereby its relevance becomes more prominent at critical junctures. This research has been used in the development of a public-facing resource on the healthtalk.org website. PATIENT OR PUBLIC CONTRIBUTION: People with experience of living with genetic risk were involved throughout the design and conduct of the study and advised on aspects including the topic guide, sampling and recruitment and the developing analysis. Two patient and public involvement contributors joined a formal advisory panel.


Asunto(s)
Esclerosis Amiotrófica Lateral , Enfermedad de la Neurona Motora , Adulto , Niño , Humanos , Enfermedad de la Neurona Motora/genética , Enfermedad de la Neurona Motora/diagnóstico , Enfermedad de la Neurona Motora/psicología , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/patología , Investigación Cualitativa , Incertidumbre , Emociones
13.
PLoS One ; 19(2): e0294777, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38354205

RESUMEN

Emotion regulation through cognitive reappraisal is well-studied, but less so are the predispositional and superordinate beliefs that influence reappraisal. Recently, researchers developed the cognitive mediation beliefs questionnaire (CMBQ), which measures two emotion beliefs, namely stimulus-response (S-R) generation beliefs and cognitive mediation (C-M) change beliefs. In working populations S-R generation beliefs are inversely related to cognitive reappraisal tendencies and positive mental health, and positively related to emotion reactivity. C-M change beliefs are positively related to cognitive reappraisal tendencies, and inversely related to emotion reactivity and positive mental health. As yet, there is no evidence for the validity of the CMBQ within student samples, or for the associations between its subscales and cognitive reappraisal, emotion reactivity, and positive mental health. Therefore, in the present study the CMBQ is tested for factorial, convergent (associations with cognitive reappraisal), and concurrent (associations with emotion reactivity and positive mental health) validity in a cohort of 621 undergraduate students in the United Kingdom (U.K.). Results indicate support for the factorial and convergent validity of the CMBQ, with mixed evidence for the concurrent validity of the CMBQ. A CM-SR discrepancy score appeared to provide a promising variable when associated with emotion reactivity and positive mental health. The findings are discussed in terms of practical and research implications of the findings.


Asunto(s)
Ira , Emociones , Humanos , Universidades , Emociones/fisiología , Estudiantes/psicología , Cognición/fisiología
14.
J Neurol Neurosurg Psychiatry ; 95(4): 360-365, 2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38050140

RESUMEN

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease of the motor network associated with brain structure and functional connectivity alterations that are implicated in disease progression. Whether such changes have a causal role in ALS, fitting with a postulated influence of premorbid cerebral architecture on the phenotypes associated with neurodegenerative disorders is not known. METHODS: This study considered causal effects and shared genetic risk of 2240 structural and functional MRI brain scan imaging-derived phenotypes (IDPs) on ALS using two sample Mendelian randomisation, with putative associations further examined with extensive sensitivity analysis. Shared genetic predisposition between IDPs and ALS was explored using genetic correlation analysis. RESULTS: Increased white matter volume in the cerebral hemispheres was causally associated with ALS. Weaker causal associations were observed for brain stem grey matter volume, parieto-occipital white matter surface and volume of the left thalamic ventral anterior nucleus. Genetic correlation was observed between ALS and intracellular volume fraction and isotropic free water volume fraction within the posterior limb of the internal capsule. CONCLUSIONS: This study provides evidence that premorbid brain structure, in particular white matter volume, contributes to the risk of ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral , Sustancia Blanca , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Esclerosis Amiotrófica Lateral/genética , Encéfalo/diagnóstico por imagen , Sustancia Gris/diagnóstico por imagen , Imagen por Resonancia Magnética , Sustancia Blanca/diagnóstico por imagen
15.
Eur J Immunol ; 54(2): e2350700, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38039407

RESUMEN

How individual T cells compete for and respond to IL-2 at the molecular level, and, as a consequence, how this shapes population dynamics and the selection of high-affinity clones is still poorly understood. Here we describe how the RNA binding protein ZFP36L1, acts as a sensor of TCR affinity to promote clonal expansion of high-affinity CD8 T cells. As part of an incoherent feed-forward loop, ZFP36L1 has a nonredundant role in suppressing multiple negative regulators of cytokine signaling and mediating a selection mechanism based on competition for IL-2. We suggest that ZFP36L1 acts as a sensor of antigen affinity and establishes the dominance of high-affinity T cells by installing a hierarchical response to IL-2.


Asunto(s)
Citocinas , Receptores de Antígenos de Linfocitos T , Interleucina-2 , Linfocitos T CD8-positivos , Células Clonales/metabolismo
16.
J Neurochem ; 168(2): 115-127, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38087504

RESUMEN

While unbiased proteomics of human cerebrospinal fluid (CSF) has been used successfully to identify biomarkers of amyotrophic lateral sclerosis (ALS), high-abundance proteins mask the presence of lower abundance proteins that may have diagnostic and prognostic value. However, developments in mass spectrometry (MS) proteomic data acquisition methods offer improved protein depth. In this study, MS with library-free data-independent acquisition (DIA) was used to compare the CSF proteome of people with ALS (n = 40), healthy (n = 15) and disease (n = 8) controls. Quantified protein groups were subsequently correlated with clinical variables. Univariate analysis identified 7 proteins, all significantly upregulated in ALS versus healthy controls, and 9 with altered abundance in ALS versus disease controls (FDR < 0.1). Elevated chitotriosidase-1 (CHIT1) was common to both comparisons and was proportional to ALS disability progression rate (Pearson r = 0.41, FDR-adjusted p = 0.035) but not overall survival. Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1; upregulated in ALS versus healthy controls) was proportional to disability progression rate (Pearson r = 0.53, FDR-adjusted p = 0.003) and survival (Kaplan Meier log-rank p = 0.013) but not independently in multivariate proportional hazards models. Weighted correlation network analysis was used to identify functionally relevant modules of proteins. One module, enriched for inflammatory functions, was associated with age at symptom onset (Pearson r = 0.58, FDR-adjusted p = 0.005) and survival (Hazard Ratio = 1.78, FDR = 0.065), and a second module, enriched for endoplasmic reticulum proteins, was negatively correlated with disability progression rate (r = -0.42, FDR-adjusted p = 0.109). DIA acquisition methodology therefore strengthened the biomarker candidacy of CHIT1 and UCHL1 in ALS, while additionally highlighted inflammatory and endoplasmic reticulum proteins as novel sources of prognostic biomarkers.


Asunto(s)
Esclerosis Amiotrófica Lateral , Humanos , Proteómica/métodos , Biomarcadores/líquido cefalorraquídeo , Pronóstico , Espectrometría de Masas
17.
Life Sci Alliance ; 7(2)2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38011999

RESUMEN

EIF4A1 and cofactors EIF4B and EIF4H have been well characterised in cancers, including B cell malignancies, for their ability to promote the translation of oncogenes with structured 5' untranslated regions. However, very little is known of their roles in nonmalignant cells. Using mouse models to delete Eif4a1, Eif4b or Eif4h in B cells, we show that EIF4A1, but not EIF4B or EIF4H, is essential for B cell development and the germinal centre response. After B cell activation in vitro, EIF4A1 facilitates an increased rate of protein synthesis, MYC expression, and expression of cell cycle regulators. However, EIF4A1-deficient cells remain viable, whereas inhibition of EIF4A1 and EIF4A2 by Hippuristanol treatment induces cell death.


Asunto(s)
Linfocitos B , Factor 4A Eucariótico de Iniciación , ARN Helicasas , Animales , Ratones , Factor 4A Eucariótico de Iniciación/genética , Factor 4A Eucariótico de Iniciación/metabolismo , ARN Helicasas/metabolismo
18.
Cell Rep ; 43(1): 113627, 2024 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-38157296

RESUMEN

Vascular morphogenesis requires a delicate gradient of Notch signaling controlled, in part, by the distribution of ligands (Dll4 and Jagged1). How Jagged1 (JAG1) expression is compartmentalized in the vascular plexus remains unclear. Here, we show that Jag1 mRNA is a direct target of zinc-finger protein 36 (ZFP36), an RNA-binding protein involved in mRNA decay that we find robustly induced by vascular endothelial growth factor (VEGF). Endothelial cells lacking ZFP36 display high levels of JAG1 and increase angiogenic sprouting in vitro. Furthermore, mice lacking Zfp36 in endothelial cells display mispatterned and increased levels of JAG1 in the developing retinal vascular plexus. Abnormal levels of JAG1 at the sprouting front alters NOTCH1 signaling, increasing the number of tip cells, a phenotype that is rescued by imposing haploinsufficiency of Jag1. Our findings reveal an important feedforward loop whereby VEGF stimulates ZFP36, consequently suppressing Jag1 to enable adequate levels of Notch signaling during sprouting angiogenesis.


Asunto(s)
Proteínas de la Membrana , Factor A de Crecimiento Endotelial Vascular , Animales , Ratones , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Proliferación Celular , Células Endoteliales/metabolismo , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Neovascularización Fisiológica , Receptores Notch/metabolismo , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo
19.
BMC Psychol ; 11(1): 442, 2023 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-38104142

RESUMEN

BACKGROUND: In the current study, we conducted a comparative analysis involving three distinct groups: one receiving group-based rational emotive behavior therapy (REBT), another undergoing a mindfulness-based intervention (MBI), and a third group serving as the control. The aim of the study was to explore the effectiveness of the two interventions on specific psychological (competitive anxiety, perfectionism, irrational beliefs), physiological (salivary cortisol levels), and neurocognitive (executive functions: working memory, inhibition, cognitive flexibility) functions in Hungarian junior ice hockey players. METHODS: The participants consisted of 10 females and 36 males (NREBT=12, NMINDFULNESS=14, NCONTROL=20). We used questionnaires to assess competitive anxiety, perfectionism, and irrational beliefs. The components of executive functions were measured using a computerized testing system, while cortisol levels were examined through salivary samples. Prior to and after the interventions, each participant underwent all measurements, after which we conducted repeated measures ANOVA on our data. RESULTS: We found REBT to be an effective intervention for the regulation of competitive anxiety, perfectionism, and irrational beliefs as well as for improving some components of executive functions (inhibition and cognitive flexibility). Mindfulness was found to improve athletes' processing speed and set-shifting abilities, which are related to cognitive flexibility and metacognitive processes. CONCLUSION: In conclusion, we explore implications of these findings regarding how each approach is posited to enhance sports performance, using neurocognitive functions as a proxy. These findings are useful for further research and practical implications.


Asunto(s)
Rendimiento Atlético , Atención Plena , Masculino , Femenino , Humanos , Función Ejecutiva , Hidrocortisona , Ansiedad/terapia
20.
Stress Health ; 2023 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-37924507

RESUMEN

Researchers have intimated that cognitions and emotions can change in the lead up to important events. However, previous research has adopted atemporal cross-sectional designs, making it challenging to understand how cognitions and emotions unfold in the lead up to a competition. In the current study, we extended previous research by examining the temporal patterns of cognitive appraisals, irrational beliefs, and challenge and threat evaluations in predicting pre-competitive affective states (hedonic balance and anxiety) in the lead up to an actual competition, among competitive elite Indian golfers (N = 107). We adopted a within-subjects repeated-measures design and collected data in the lead up to an actual golf tournament, at three timepoints; 1 week before (T1), the night before (T2), and an hour prior (T3). Self-reported measures of cognitive appraisals, irrational beliefs, challenge and threat evaluations, affect, and anxiety were completed. Also, objective golf performance was collected from participants. Crossed-lagged path analysis did not find a causal effect for irrational beliefs on any of the variables across the three time points. On the other hand, hierarchical multiple regression analysis determined that changes in irrational beliefs predicted changes in cognitive appraisals, threat evaluation, cognitive and somatic anxiety, and the directional interpretation of anxiety. The findings of temporal patterns in the current research indicated that sport psychologists should consider the dynamic nature of antecedent cognitions and affective states in the lead up to competition, and accordingly provide adequate support to the athletes. Further, limitations and future research is discussed with reference to the results.

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