Sprouty4 Is an Endogenous Negative Modulator of TrkA Signaling and Neuronal Differentiation Induced by NGF

The Sprouty (Spry) family of proteins represents endogenous regulators of downstream signaling pathways induced by receptor tyrosine kinases (RTKs). Using real time PCR, we detect a significant increase in the expression of Spry4 mRNA in response to NGF, indicating that Spry4 could modulate intracellular signaling pathways and biological processes induced by NGF and its receptor TrkA. In this work, we demonstrate that overexpression of wild-type Spry4 causes a significant reduction in MAPK and Rac1 activation and neurite outgrowth induced by NGF. At molecular level, our findings indicate that ectopic expression of a mutated form of Spry4 (Y53A), in which a conserved tyrosine residue was replaced, fail to block both TrkA-mediated Erk/MAPK activation and neurite outgrowth induced by NGF, suggesting that an intact tyrosine 53 site is required for the inhibitory effect of Spry4 on NGF signaling. Downregulation of Spry4 using small interference RNA knockdown experiments potentiates PC12 cell differentiation and MAPK activation in response to NGF. Together, these findings establish a new physiological mechanism through which Spry4 regulates neurite outgrowth reducing not only the MAPK pathway but also restricting Rac1 activation in response to NGF

PRimary carE digital Support ToOl in mental health (PRESTO): Design, development and study protocols

BACKGROUND: About 30-50% of Primary Care (PC) users in Spain suffer mental health problems, mostly mild to moderate anxious and depressive symptoms, which account for 2% of Spain's total Gross domestic product and 50% of the costs associated to all mental disorders. Mobile health tools have demonstrated to cost-effectively reduce anxious and depressive symptoms while machine learning (ML) techniques have shown to accurately detect severe cases. The main aim of this project is to develop a comprehensive ML digital support platform (PRESTO) to cost-effectively screen, assess, triage, and provide personalized treatments for anxious and depressive symptoms in PC. METHODS: The project will be carried out in 3 complementary phases: First, a ML predictive severity model will be built based on all the cases referred to the PC mental health support programme during the last 5 years in Catalonia. Simultaneously, a smartphone app to monitor and deliver psychological interventions for anxiety and depressive symptoms will be developed and tested in a clinical trial. Finally, the ML models and the app will be integrated in a comprehensive decision-support platform (PRESTO) which will triage and assign to each patient a specific intervention based on individual personal and clinical characteristics. The effectiveness of PRESTO to reduce waiting times in receiving mental healthcare will be tested in a stepped-wedge cluster randomized controlled trial in 5 PC centres. DISCUSSION: PRESTO will offer timely and personalized cost-effective mental health treatment to people with mild to moderate anxious and depressive symptoms. This will result in a reduction of the burden of mental health problems in PC and on society as a whole. TRIAL REGISTRATION: The project and their clinical trials were registered in Clinical Trials.gov: NCT04559360 (September 2020)

Investigation of a mpox outbreak in Central African Republic, 2021-2022

International audienceHuman monkeypox virus is spreading globally, and more information is required about its epidemiological and clinical disease characteristics in endemic countries. We report the investigation of an outbreak in November 2021 in Central African Republic (CAR). The primary case, a hunter, fell ill after contact with a non-human primate at the frontier between forest and savannah. The ensuing investigation in a small nearby town concerned two families and four waves of inter-human transmission, with 14 confirmed cases, 11 suspected cases and 17 non-infected contacts, and a secondary attack rate of 59.5% (25/42). Complications were observed in 12 of the 19 (63.2%) confirmed and suspected cases with available clinical follow-up data: eight cases of bronchopneumonia, two of severe dehydration, one corneal ulcer, one abscess, two cutaneous superinfections, and six cutaneous sequelae (cheloid scars, or depigmentation). There was one death, giving a case fatality ratio of 1/25 (4.0%) for confirmed and suspected cases. This outbreak, with the largest number of confirmed cases ever described in CAR, confirms the potential severity of the disease associated with clade I monkeypox viruses, and highlights the need for rapid control over virus circulation to prevent the further national and international spread of infection