Allosteric activation of Hsp70 reduces mutant huntingtin levels, the clustering of N-terminal fragments, and their nuclear accumulation

AIMS: Huntington's disease (HD) is caused by a mutant huntingtin protein that misfolds, yields toxic N-terminal fragments, aggregates, and disrupts proteostasis. The Hsp70 chaperone is a potential therapeutic target as it prevents proteotoxicity by favouring protein folding, disaggregation, or degradation. We tested the hypothesis that allosteric Hsp70 activation with a pharmacological mimetic of the Hsp70 co-chaperone Hip, YM-1, could modulate huntingtin proteostasis. MAIN METHODS: We used HD cell models expressing either N-terminal or full-length huntingtin. Using single-cell analysis we studied huntingtin aggregation in different cellular compartments by fluorescence microscopy. Protein interaction was evaluated by immunoprecipitation, while protein levels were quantified by immunofluorescence and western-blot. KEY FINDINGS: N-terminal huntingtin interacted with Hsp70 and increased its levels. Treatment with YM-1 reduced N-terminal huntingtin clustering and nuclear aggregation. Full-length mutant huntingtin also interacted with Hsp70, and treatment with YM-1 reduced huntingtin levels when combined with Hsp70 induction by heat shock. Mechanistically, YM-1 increases the Hsp70 affinity for substrates, promoting their proteasomal degradation. Consistently, YM-1 reduced the levels of ubiquitinated proteins. Interestingly, YM-1 accumulated in mitochondria, interfered with its Hsp70 isoform involved in protein import, and increased NRF1 levels, a regulator of proteasome genes. We thus suggest that YM-1 may trigger the coordination of mitochondrial and cytosolic proteostasis, enhancing protein degradation. SIGNIFICANCE: Our findings show that the strategy of allosteric Hsp70 activation holds potential for HD. While drug efficacy may be limited to tissues with elevated Hsp70, combined therapies with Hsp70 elevating strategies could harness the full potential of allosteric Hsp70 activators for HD

CARATkids questionnaire development process

Introdução: A asma e a rinite alérgica (ARA) são doenças inflamatórias crónicas das vias aéreas que frequentemente coexistem. O questionário para avaliação do controlo da asma e da rinite alérgica (CARAT) encontra‑se validado para o adulto. O objectivo foi desenvolver o questionário CARATkids para crianças entre os 4 e os 12 anos de idade, com o diagnóstico médico de ARA. Este trabalho pretende descrever o processo do desenvolvimento do questionário. Métodos: O desenvolvimento do questionário foi estruturado em três fases: 1) revisão da literatura sobre questionários pediátricos existentes; 2) realização de reuniões de consenso que permitiu a criação de uma versão preliminar do CARATkids, com duas versões (crianças e pais), composto por 17 itens. Para as crianças, as perguntas foram acompanhadas por ilustrações para cada questão, com formato de resposta dicotómica (sim / não). Para os pais o questionário manteve o formato de CARAT17, com questões com 4 pontos de Likert e outras questões com opção de resposta com escala dicotómica; 3) realização de um estudo transversal através de entrevistas cognitivas efectuadas a 29 crianças e respectivos pais. Resultados: Foram incluídas 29 crianças (11 do sexo feminino) e respectivos pais. A mediana de idades (P25‑P75) foi de 8 (6‑10) anos. As crianças com 4 a 5 anos não sabiam ler o questionário; com 6‑8 eram capazes de ler / compreender as perguntas, embora referindo dificuldades para algumas expressões. As crianças com mais de 9 anos consideraram o questionário muito simples e claro. O grau de concordância entre as crianças e seus pais foi de 61%, tendo ambos considerado as ilustrações muito claras e esclarecedoras quanto aos conceitos subjacentes. Os pais concordaram que a versão destinada aos pais estava muito completa, considerando a versão da criança muito clara e adequada. Consideraram ainda a escala dicotómica como mais apropriada para crianças, em comparação com a escala de Likert do questionário aplicado aos pais. As expressões identificadas como de difícil entendimento foram alteradas. Conclusão: O questionário CARATkids é o primeiro que avalia o controlo da asma e da rinite na criança. Os testes cognitivos demonstraram a sua aplicabilidade dos 6 aos 12 anos de idade.info:eu-repo/semantics/publishedVersio

Development Process and Cognitive Testing of CARATkids - Control of Allergic Rhinitis and Asthma Test for Children

Background: Allergic rhinitis and asthma (ARA) are chronic inflammatory diseases of the airways that often coexist in children. The only tool to assess the ARA control, the Control of Allergic Rhinitis and Asthma Test (CARAT) is to be used by adults. We aimed to develop the Pediatric version of Control of Allergic Rhinitis and Asthma Test (CARATkids) and to test its comprehensibility in children with 4 to 12 years of age. Methods: The questionnaire development included a literature review of pediatric questionnaires on asthma and/or rhinitis control and two consensus meetings of a multidisciplinary group. Cognitive testing was carried out in a cross-sectional qualitative study using cognitive interviews. Results: Four questionnaires to assess asthma and none to assess rhinitis control in children were identified. The multidisciplinary group produced a questionnaire version for children with 17 questions with illustrations and dichotomous (yes/no) response format. The version for caregivers had 4-points and dichotomous scales. Twenty-nine children, 4 to 12 years old, and their caregivers were interviewed. Only children over 6 years old could adequately answer the questionnaire. A few words/expressions were not fully understood by children of 6 to 8 years old. The drawings illustrating the questions were considered helpful by children and caregivers. Caregivers considered the questionnaire complete and clear and preferred dichotomous over the 4-points scales. The proportion of agreement between children and their caregivers was 61%. The words/expressions that were difficult to understand were amended. Conclusion: CARATkids, the first questionnaire to assess a child’s asthma and rhinitis control was developed and its content validity was assured. Cognitive testing showed that CARATKids is well-understood by children 6 to 12 years old. The questionnaire’s measurement properties can now be assessed in a validation study

Life satisfaction and time-use among full-time and part-time working mothers in Brazil

BACKGROUND: Working part-time or full-time is a persistent dilemma for women, especially mothers, as they strive to manage their time across various roles. However, the existing literature remains unclear on whether part-time work contributes more to life satisfaction than full-time work. OBJECTIVE: This study aims to describe and compare time-use patterns in different occupational roles and levels of life satisfaction among 795 mothers in Brazil who are employed either part-time or full-time. METHODS: Data was collected through an online survey and the snowball technique. Regression and correlation analyses were performed on the data obtained from the following instruments: the Role Checklist for assessing time-use within occupational roles, the Satisfaction with Life Scale, and demographic information. RESULTS: Our analysis revealed no significant differences in life satisfaction between mothers working full-time and those working part-time (t (793)=1.160, p = 0.24). However, life satisfaction scores were positively correlated with the number of occupational roles performed (r = 0.222, p <  0.01), higher family income (P <  0.001), and engagement in social roles such as Friend (r = 0.106, p = 0.003), Hobbyist/Amateur (r = 0.08, p = 0.018), and Caregiver (r = 0.07, p = 0.026). CONCLUSION: While our society places significant emphasis on time spent at work, our findings highlight that life satisfaction extends far beyond the dichotomy of working part-time or full-time. There are deeper dimensions to consider, including the number of occupational roles, family income, and engagement in social roles, which have a more substantial impact on overall life satisfaction

Frequência da Anafilaxia Induzida pelo Exercício numa Consulta de Imunoalergologia

Introdução: A anafilaxia induzida pelo exercício (AIE) é uma forma rara de alergia física que ocorre na sequência de esforços físicos. A verdadeira incidência e prevalência da AIE permanecem por esclarecer, não existindo até à data dados publicados a nível nacional. Objectivos: Estimar a frequência da AIE no ambulatório de um serviço de Imunoalergologia e incrementar o conhecimento em relação a esta patologia. Métodos: De 7699 doentes observados na consulta de Imunoalergologia durante o período de um ano, incluímos os correspondentes a quadros de anafilaxia notificados pelo corpo clínico (“pelo menos um episódio de reacção sistémica grave”). Resultados: A AIE foi reportada em 5 de 103 doentes com história de anafilaxia; correspondendo a uma frequência de 0,06% na população observada na consulta. A média etária destes doentes era de 20,2 ± 10,3 anos (entre 10 e 37 anos) e a distribuição por sexo masculino/feminino de 4:1. Todos tinham história pessoal de atopia e de rinite alérgica; dois doentes (40%) tinham asma. As actividades desencadeantes das crises foram a corrida, o futebol, a natação e a dança. Todos os doentes tinham sintomas com o exercício dependente da ingestão prévia de alimentos: cereais em três doentes (trigo – dois, cevada – um), leguminosas em dois (amendoim – um, feijão -frade e feijão -verde – um); com teste cutâneo por picada positivo para os referidos alimentos. Conclusões: A AIE representa 5% dos casos de anafi laxia reportados. Todos os casos identifi cados apresentavam AIE dependente de alimentos, encontrando-se os doentes controlados com a evicção dos alimentos referidos 6 horas antes da prática de exercício e sendo portadores de dispositivo para autoadministração de adrenalina

Direct determination of molybdenum in polyvitaminic tablets by voltammetry in non-aqueous media.

Adsorptive stripping voltammetry carried out in a homogeneous ternary solvent composed of N,N-dimethylformamide, water and ethanol, with alpha-benzoinoxime (alpha BO) as the complexing agent for Mo(VI) and a 0.5 mol L-1 acetic acid - sodium acetate buffer as supporting electrolyte was successfully used for the determination of molybdenum in polyvitamin-polymineral tablets. Tablet samples were analyzed and the results were compared with those obtained both by graphite furnace atomic absorption and by recovery tests, with good correlations. indicating that this may be considered as an alternative procedure for routine determination of Mo(VI) in pharmaceutical samples.29115315

The Value of Right Ventricular Longitudinal Strain in the Evaluation of Adult Patients With Repaired Tetralogy of Fallot: a New Tool for a Contemporary Challenge

OBJECTIVE: The role of right ventricular longitudinal strain for assessing patients with repaired tetralogy of Fallot is not fully understood. In this study, we aimed to evaluate its relation with other structural and functional parameters in these patients. METHODS: Patients followed-up in a grown-up CHD unit, assessed by transthoracic echocardiography, cardiac MRI, and treadmill exercise testing, were retrospectively evaluated. Right ventricular size and function and pulmonary regurgitation severity were assessed by echocardiography and MRI. Right ventricular longitudinal strain was evaluated in the four-chamber view using the standard semiautomatic method. RESULTS: In total, 42 patients were included (61% male, 32±8 years). The mean right ventricular longitudinal strain was -16.2±3.7%, and the right ventricular ejection fraction, measured by MRI, was 42.9±7.2%. Longitudinal strain showed linear correlation with tricuspid annular systolic excursion (r=-0.40) and right ventricular ejection fraction (r=-0.45) (all p<0.05), which in turn showed linear correlation with right ventricular fractional area change (r=0.50), pulmonary regurgitation colour length (r=0.35), right ventricular end-systolic volume (r=-0.60), and left ventricular ejection fraction (r=0.36) (all p<0.05). Longitudinal strain (β=-0.72, 95% confidence interval -1.41, -0.15) and left ventricular ejection fraction (β=0.39, 95% confidence interval 0.11, 0.67) were independently associated with right ventricular ejection fraction. The best threshold of longitudinal strain for predicting a right ventricular ejection fraction of <40% was -17.0%. CONCLUSIONS: Right ventricular longitudinal strain is a powerful method for evaluating patients with tetralogy of Fallot. It correlated with echocardiographic right ventricular function parameters and was independently associated with right ventricular ejection fraction derived by MRI.info:eu-repo/semantics/publishedVersio

Bang-bang control of fullerene qubits using ultra-fast phase gates

Quantum mechanics permits an entity, such as an atom, to exist in a superposition of multiple states simultaneously. Quantum information processing (QIP) harnesses this profound phenomenon to manipulate information in radically new ways. A fundamental challenge in all QIP technologies is the corruption of superposition in a quantum bit (qubit) through interaction with its environment. Quantum bang-bang control provides a solution by repeatedly applying `kicks' to a qubit, thus disrupting an environmental interaction. However, the speed and precision required for the kick operations has presented an obstacle to experimental realization. Here we demonstrate a phase gate of unprecedented speed on a nuclear spin qubit in a fullerene molecule (N@C60), and use it to bang-bang decouple the qubit from a strong environmental interaction. We can thus trap the qubit in closed cycles on the Bloch sphere, or lock it in a given state for an arbitrary period. Our procedure uses operations on a second qubit, an electron spin, in order to generate an arbitrary phase on the nuclear qubit. We anticipate the approach will be vital for QIP technologies, especially at the molecular scale where other strategies, such as electrode switching, are unfeasible

Transcriptome analysis of Loxosceles laeta (Araneae, Sicariidae) spider venomous gland using expressed sequence tags

<p>Abstract</p> <p>Background</p> <p>The bite of spiders belonging to the genus <it>Loxosceles </it>can induce a variety of clinical symptoms, including dermonecrosis, thrombosis, vascular leakage, haemolysis, and persistent inflammation. In order to examine the transcripts expressed in venom gland of <it>Loxosceles laeta </it>spider and to unveil the potential of its products on cellular structure and functional aspects, we generated 3,008 expressed sequence tags (ESTs) from a cDNA library.</p> <p>Results</p> <p>All ESTs were clustered into 1,357 clusters, of which 16.4% of the total ESTs belong to recognized toxin-coding sequences, being the Sphingomyelinases D the most abundant transcript; 14.5% include "possible toxins", whose transcripts correspond to metalloproteinases, serinoproteinases, hyaluronidases, lipases, C-lectins, cystein peptidases and inhibitors. Thirty three percent of the ESTs are similar to cellular transcripts, being the major part represented by molecules involved in gene and protein expression, reflecting the specialization of this tissue for protein synthesis. In addition, a considerable number of sequences, 25%, has no significant similarity to any known sequence.</p> <p>Conclusion</p> <p>This study provides a first global view of the gene expression scenario of the venom gland of <it>L. laeta </it>described so far, indicating the molecular bases of its venom composition.</p