M S-medecine Sciences最新文献

Recent work on bacterial insertion sequences reveals that some of them use an RNA sequence (called Bridge RNA or Seek RNA) to define both donor and target DNA specificity. This opens the way to easy insertion of kilobase DNA sequences at pre-defined sites in the genome, announcing a host of new possibilities. The system still needs a lot of tweaking, as it has only been demonstrated in bacteria, but it holds great promise for genome editing and engineering.

Through their myogenic activity, adult muscle stem cells (MuSCs) are crucial for the regeneration of striated skeletal muscle. Once activated, they proliferate, differentiate and then fuse to repair or form new muscle fibers (myofibers). Their progression through myogenesis requires a complex regulation involving multiple players such as metabolism, in particular via AMPK. This protein kinase regulates the self-renewal and myonuclear accretion of MuSCs after acute skeletal muscle injury or skeletal muscle contraction. However, in a context of dystrophy such as Duchenne muscular dystrophy (DMD), the regenerative capacity of MuSCs is reduced, presumably due to an increase of the proliferation that is detrimental to differentiation. We are interested here in the potential of metabolism to regulate the myogenic activity of MuSCs in DMD via AMPK.

PAX3 plays a crucial role in embryonic myogenesis, controlling the specification, migration, proliferation, and differentiation of muscle progenitor cells to ensure normal skeletal muscle development in the embryo. However, PAX3 potential role in a context of muscle homeostasis and regeneration remains poorly investigated. The adult muscle stem cells, known as satellite cells (SCs) exhibit heterogeneity in Pax3 expression in various muscles throughout the body and display a bimodal response to environmental stress exposure. To explore the role of PAX3 in the context of tissue damage, we performed regeneration studies, which unveiled a functional heterogeneity of the SCs populations depending on Pax3 expression. Together, this project aims to decipher cell-type specific dysregulations linked to tissue damage and identify PAX3 downstream gene regulatory networks that can lead to specific SC behavior, thus potentially providing novel strategies for muscle disease preventive therapies.

Duchenne muscular dystrophy (DMD) is a severe degenerative genetic muscle disease affecting mainly young boys, characterized by a significant alteration or absence of dystrophin expression. Significant strides have been made in comprehending and treating DMD, particularly with the recent approval of the first gene therapy using a recombinant adeno-associated vector (rAAV) to deliver a shortened form of dystrophin (microdystrophin). Nevertheless, major challenges remain in improving therapeutic outcomes. The use of rAAV vectors is hindered by major limitations, notably the risks of immunotoxicity and hepatotoxicity, linked to high-dose administration. Additionally, microdystrophin exhibits inherent functional limitations and immunological risks. This article examines these challenges and explores the avenues for enhancing gene therapy for DMD.

The concept of treating diabetes with gut hormones was proposed in the early days of endocrinology (1902), but was not put into practice until the early 2000s. The discovery of the incretin effect (potentiation of insulin secretion when glucose is taken orally compared to intravenously) led to the discovery of the two main gut hormones responsible for this effect: GIP and GLP-1. The reduction of the incretin effect is directly involved in the pathogenesis of type 2 diabetes, which has led to the development of a series of innovative therapies such as GLP-1 analogues, GLP-1 receptor agonists, GIP/GLP-1 co-agonists and GIP/GLP-1/glucagon tri-agonists. These therapies, with their potent hypoglycaemic and weight-lowering effects, promote optimal control of excess weight and hyperglycaemia, avoiding the escalation of treatment that was once considered inevitable.

High-throughput sequencing has introduced the concept of "actionable genes". These genes are linked to diseases for which specific treatments or care exist. Accurate genetic diagnosis is therefore crucial for initiating interventions that can prevent or delay the progression of rare diseases. High-throughput sequencing has considerably increased the capacities of genetic analyses, but it has also led to an increase in requests for analyses, lengthening the time taken to obtain results. It is becoming necessary to prioritize analyses, especially when "actionable genes" are suspected to be implicated. In the case of myopathies, a French national study has identified 63 actionable genes, implicated in diseases for which a targeted treatment and/or priority care can be initiated, thereby improving the patient's prognosis. Despite advances, many rare diseases remain without specific treatments, underlining the continuing importance of research and innovation in medical genetics.

Smallpox was an endemic, very contagious disease which caused a high mortality rate during the age of enlightenment. In order to counter act this epidemic, smallpox inoculation was developed. This technique consisted in the inoculation of infected pus taken from a sick person into a healthy one in order to prevent the risks of natural smallpox infection. It was in this context that a German doctor in charge of inoculation wrote to Kant twice in 1799, and again in 1800, to ask him if inoculation was morally permissible. Kant wrote a draft of an answer, but it was never completed or published during his lifetime. These drafts provide elements of an answer that he nevertheless refused to give explicitly in the Doctrine of Virtue (1797) where the question of the morality of inoculation remained unanswered.

Multi-Cancer Early Detection is a highly popular topic, bringing the hope of being able to detect very early, non-symptomatic cancers and allowing more successful therapy. A major company in this space is GRAIL, which has attracted very significant financing and launched large-scale tests of its detection systems. However, the real clinical utility of these tests remains to be demonstrated, and fundamental issues are still pending.