Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side

Recent clinical trials using patient’s own corrected hematopoietic stem cells (HSCs), such as for primary immunodeficiencies (Adenosine deaminase (ADA) deficiency, X-linked Severe Combined Immunodeficiency (SCID), X-linked chronic granulomatous disease (CGD), Wiskott–Aldrich Syndrome (WAS)), have yielded promising results in the clinic; endorsing gene therapy to become standard therapy for a number of diseases. However, the journey to achieve such a successful therapy is not easy, and several challenges have to be overcome. In this review, we will address several different challenges in the development of gene therapy for immune deficiencies using our own experience with Recombinase-activating gene 1 (RAG1) SCID as an example. We will discuss product development (targeting of the therapeutic cells and choice of a suitable vector and delivery method), the proof-of-concept (in vitro and in vivo efficacy, toxicology, and safety), and the final release steps to the clinic (scaling up, good manufacturing practice (GMP) procedures/protocols and regulatory hurdles)

Mechanical Control of Cell Migration by the Metastasis Suppressor Tetraspanin CD82/KAI1

International audienceThe plasma membrane is a key actor of cell migration. For instance, its tension controls persistent cell migration and cell surface caveolae integrity. Then, caveolae constituents such as caveolin-1 can initiate a mechanotransduction loop that involves actin- and focal adhesion-dependent control of the mechanosensor YAP to finely tune cell migration. Tetraspanin CD82 (also named KAI-1) is an integral membrane protein and a metastasis suppressor. Its expression is lost in many cancers including breast cancer. It is a strong inhibitor of cell migration by a little-known mechanism. We demonstrated here that CD82 controls persistent 2D migration of EGF-induced single cells, stress fibers and focal adhesion sizes and dynamics. Mechanistically, we found that CD82 regulates membrane tension, cell surface caveolae abundance and YAP nuclear translocation in a caveolin-1-dependent manner. Altogether, our data show that CD82 controls 2D cell migration using membrane-driven mechanics involving caveolin and the YAP pathway

Professional and political education at realengo military academy

O artigo aborda a primeira etapa do processo de formação profissional de oficiais do Exército Brasileiro que iniciaram suas carreiras no decorrer da década de 1920. Abordando fundamentalmente a Escola Militar do Realengo, instituição que pretendia formar oficiais ‘apolíticos’, investiga-se, a partir de depoimentos e relatos biográficos, aspectos organizacionais e experiências que teriam marcado mais profundamente as primeiras articulações entre a formação profissional e as inclinações para agir politicamente dessa geração. Constata- -se que a Escola constituía um espaço politizado no qual os alunos cultivavam disposições para ação política em nome de uma ‘tradição’ oriunda da Escola Militar da Praia Vermelha e de uma missão regeneradora do país.The article analyses the education of the Brazilian Army officers in the 1920s. Focusing on Realengo Military Academy, it argues that the intention of the military authorities to provide apolitical training for Brazilian officers was not successful. The sources, testimonies and autobiographies drawn on show Realengo Military Academy to have been a place of political socialization where students shared dispositions for political action on behalf of a ‘tradition’ inherited from the Praia Vermelha Military Academy and a mission of national regeneration

Wild orangutan males plan and communicate their travel direction one day in advance

The ability to plan for the future beyond immediate needs would be adaptive to many animal species, but is widely thought to be uniquely human. Although studies in captivity have shown that great apes are capable of planning for future needs, it is unknown whether and how they use this ability in the wild. Flanged male Sumatran orangutans (Pongo abelii) emit long calls, which females use to maintain earshot associations with them. We tested whether long calls serve to communicate a male's ever-changing predominant travel direction to facilitate maintaining these associations. We found that the direction in which a flanged male emits his long calls predicts his subsequent travel direction for many hours, and that a new call indicates a change in his main travel direction. Long calls given at or near the night nest indicate travel direction better than random until late afternoon on the next day. These results show that male orangutans make their travel plans well in advance and announce them to conspecifics. We suggest that such a planning ability is likely to be adaptive for great apes, as well as in other taxa

FTO genotype is associated with phenotypic variability of body mass index

There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000

Global attitudes in the management of acute appendicitis during COVID-19 pandemic: ACIE Appy Study

Background: Surgical strategies are being adapted to face the COVID-19 pandemic. Recommendations on the management of acute appendicitis have been based on expert opinion, but very little evidence is available. This study addressed that dearth with a snapshot of worldwide approaches to appendicitis. Methods: The Association of Italian Surgeons in Europe designed an online survey to assess the current attitude of surgeons globally regarding the management of patients with acute appendicitis during the pandemic. Questions were divided into baseline information, hospital organization and screening, personal protective equipment, management and surgical approach, and patient presentation before versus during the pandemic. Results: Of 744 answers, 709 (from 66 countries) were complete and were included in the analysis. Most hospitals were treating both patients with and those without COVID. There was variation in screening indications and modality used, with chest X-ray plus molecular testing (PCR) being the commonest (19\ub78 per cent). Conservative management of complicated and uncomplicated appendicitis was used by 6\ub76 and 2\ub74 per cent respectively before, but 23\ub77 and 5\ub73 per cent, during the pandemic (both P < 0\ub7001). One-third changed their approach from laparoscopic to open surgery owing to the popular (but evidence-lacking) advice from expert groups during the initial phase of the pandemic. No agreement on how to filter surgical smoke plume during laparoscopy was identified. There was an overall reduction in the number of patients admitted with appendicitis and one-third felt that patients who did present had more severe appendicitis than they usually observe. Conclusion: Conservative management of mild appendicitis has been possible during the pandemic. The fact that some surgeons switched to open appendicectomy may reflect the poor guidelines that emanated in the early phase of SARS-CoV-2