Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.

Molecular chaperones such as Hsp40 and Hsp70 hold the androgen receptor (AR) in an inactive conformation. They are released in the presence of androgens, enabling transactivation and causing the receptor to become aggregation-prone. Here we show that these molecular chaperones recognize a region of the AR N-terminal domain (NTD), including a FQNLF motif, that interacts with the AR ligand-binding domain (LBD) upon activation. This suggests that competition between molecular chaperones and the LBD for the FQNLF motif regulates AR activation. We also show that, while the free NTD oligomerizes, binding to Hsp70 increases its solubility. Stabilizing the NTD-Hsp70 interaction with small molecules reduces AR aggregation and promotes its degradation in cellular and mouse models of the neuromuscular disorder spinal bulbar muscular atrophy. These results help resolve the mechanisms by which molecular chaperones regulate the balance between AR aggregation, activation and quality control

An FBN1 Deep Intronic Variant Is Associated With Pseudoexon Formation and a Variable Marfan Phenotype in a Five Generation Family

Exome sequencing of genes associated with heritable thoracic aortic disease (HTAD) failed to identify a pathogenic variant in a large family with Marfan syndrome (MFS). A genome-wide linkage analysis for thoracic aortic disease identified a peak at 15q21.1, and genome sequencing identified a novel deep intronic FBN1 variant that segregated with thoracic aortic disease in the family (LOD score 2.7) and was predicted to alter splicing. RT-PCR and bulk RNA sequencing of RNA harvested from fibroblasts explanted from the affected proband revealed an insertion of a pseudoexon between exons 13 and 14 of the FBN1 transcript, predicted to lead to nonsense mediated decay (NMD). Treating the fibroblasts with an NMD inhibitor, cycloheximide, greatly improved the detection of the pseudoexon-containing transcript. Family members with the FBN1 variant had later onset aortic events and fewer MFS systemic features than typical for individuals with haploinsufficiency of FBN1. Variable penetrance of the phenotype and negative genetic testing in MFS families should raise the possibility of deep intronic FBN1 variants and the need for additional molecular studies

Author Correction: Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Metástase de carcinoma de colo de útero para ovário: um raro relato de caso

O câncer de colo de útero, em sua maioria, é desencadeado pela infecção do Papilomavírus Humano (HPV) e, embora as metástases mais comuns sejam por meio do canal linfático para órgãos adjacentes, podem ocorrer também para órgãos distantes, como os ovários. Em decorrência da sua menor prevalência para este órgão, o diagnóstico pode ser retardado, prejudicando o manejo adequado do quadro. A seguir, relata-se o caso de uma paciente de 57 anos com história de histerectomia total com salpingooforectomia bilateral, linfadenectomia pélvica e paraórtica com omentectomia por doença neoplásica, confirmada por anatomopatológico e imuno-histoquímica como adenocarcinoma endocervical bem diferenciado, estádio Ib2, com metástase ovariana. Após um ano do término da quimioterapia, iniciou com sangramento genital e dor em fossa ilíaca direita, associado a constipação intestinal, que ao exame especular apresentava lesão vegetante em fundo vaginal, cuja biópsia mostrou adenocarcinoma bem diferenciado (Grau 1). Foi indicado e realizado colpectomia, apresentando resultado anatomopatológico de adenocarcinoma viloglandular infiltrando espécime da parede vaginal. A paciente foi encaminhada para radioterapia e braquiterapia. Após término do tratamento, a paciente apresentou resultados de citologia oncótica e colposcopia dentro da normalidade. Portanto, apesar da baixa incidência de metástases ovarianas decorrentes de câncer de colo de útero, é essencial conhecer tal possibilidade e, dessa forma, estimar o prognóstico da doença por meio de fatores clínico-patológicos e exames imagenológicos, considerando a profundidade da invasão miometrial, o estado dos linfonodos e o tamanho do tumor

Bos d 13, a novel heat-stable beef allergen

[Scope]: Red meat, a staple food of Western diets, can also induce IgE-mediated allergic reactions. Yet, apart from the heat-labile protein serum albumin and the carbohydrate α-Gal, the molecules causing allergic reactions to red meat remain unknown.[Methods and results]: IgE reactivity profiles of beef-sensitized individuals are analyzed by IgE-immunoblotting with protein extracts from raw and cooked beef. Two IgE-reactive proteins are identified by peptide mass fingerprinting as myosinlight chain 1 (MYL1) and myosin light chain 3 (MYL3) in cooked beef extract and are designated Bos d 13 isoallergens. MYL1 and MYL3 are produced recombinantly in Escherichia coli. ELISAs proved their IgE reactivity and circular dichroism analysis showed that they represent folded molecules with remarkable thermal stability. In vitro gastrointestinal digestion experiments showed the higher stability of rMYL1 as compared to rMYL3. Exposure of a monolayer of Caco-2 cells to rMYL1 indicated that the molecule is able to cross intestinal epithelial cells without disturbing the integrity of the tight junctions, suggesting the sensitizing capacity of MYL1.[Conclusion]: MYLs are identified as novel heat-stable bovine meat allergens.This research was funded in whole by the Austrian Science Fund (FWF) P33867.Peer reviewe

Mowat-Wilson syndrome : growth charts

Background Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of theZEB2gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children. Results In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build. Conclusions These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.Peer reviewe

Manifestações Cutâneas do Lúpus Eritematoso Sistêmico: Desafios Diagnósticos e Estratégias de Manejo

Introduction: Cutaneous manifestations of systemic lupus erythematosus (SLE) represent a significant and challenging aspect of this autoimmune disease. This study aims to explore management strategies for these cutaneous manifestations, with the goal of improving understanding and treatment of this complex dermatological condition. Objective: The objective of this study is to analyze management strategies for cutaneous manifestations of SLE, highlighting diagnostic and therapeutic approaches, as well as challenges faced in clinical practice. The intention is to provide a comprehensive overview of available treatment options and identify areas in need of further investigation and development. Methodology: To achieve this objective, a systematic literature review was conducted using specific descriptors related to systemic lupus erythematosus and its cutaneous manifestations. Relevant studies were selected based on pre-defined inclusion criteria, considering their methodological quality and relevance to the topic at hand. Results: Analysis of selected studies revealed a variety of management strategies for cutaneous manifestations of SLE, including topical and systemic treatments, complementary therapies, and preventive measures. Additionally, diagnostic challenges such as overlap with other dermatological conditions, and therapeutic challenges such as the need for more effective treatment options with fewer side effects, were identified. Conclusion: Management of cutaneous manifestations of SLE requires a multidisciplinary and individualized approach, aiming to control disease activity, prevent complications, and improve patients' quality of life. Continuous research and development of new therapies are essential to advance the treatment of this challenging dermatological condition.  Introdução: As manifestações cutâneas do lúpus eritematoso sistêmico (LES) representam uma parte significativa e desafiadora dessa doença autoimune. Este estudo busca explorar as estratégias de manejo dessas manifestações cutâneas, com o objetivo de melhorar a compreensão e o tratamento dessa condição dermatológica complexa. Objetivo: O objetivo deste estudo é analisar as estratégias de manejo das manifestações cutâneas do LES, destacando abordagens diagnósticas, terapêuticas e desafios enfrentados na prática clínica. Pretende-se fornecer uma visão abrangente das opções de tratamento disponíveis e identificar áreas que necessitam de maior investigação e desenvolvimento. Metodologia Para alcançar este objetivo, foi realizada uma revisão sistemática da literatura, utilizando descritores específicos relacionados ao lúpus eritematoso sistêmico e suas manifestações cutâneas. Os estudos relevantes foram selecionados com base em critérios de inclusão definidos previamente, considerando sua qualidade metodológica e relevância para o tema em questão. Resultados: A análise dos estudos selecionados revelou uma variedade de estratégias de manejo das manifestações cutâneas do LES, incluindo tratamentos tópicos e sistêmicos, terapias complementares e medidas preventivas. Além disso, foram identificados desafios diagnósticos, como a sobreposição com outras condições dermatológicas, e terapêuticas, como a necessidade de opções de tratamento mais eficazes e com menos efeitos colaterais. Conclusão: O manejo das manifestações cutâneas do LES requer uma abordagem multidisciplinar e individualizada, visando controlar a atividade da doença, prevenir complicações e melhorar a qualidade de vida dos pacientes. A pesquisa contínua e o desenvolvimento de novas terapias são fundamentais para avançar no tratamento dessa condição dermatológica desafiadora