Blocking Src-PSD-95 interaction rescues glutamatergic signaling dysregulation in schizophrenia.

The complex and heterogeneous genetic architecture of schizophrenia inspires us to look beyond individual risk genes for therapeutic strategies and target their interactive dynamics and convergence. Postsynaptic NMDA receptor (NMDAR) complexes are a site of such convergence. Src kinase is a molecular hub of NMDAR function, and its protein interaction subnetwork is enriched for risk-genes and altered protein associations in schizophrenia. Previously, Src activity was found to be decreased in post-mortem studies of schizophrenia, contributing to NMDAR hypofunction. PSD-95 suppresses Src via interacting with its SH2 domain. Here, we devised a strategy to suppress the inhibition of Src by PSD-95 via employing a cell penetrating and Src activating PSD-95 inhibitory peptide (TAT-SAPIP). TAT-SAPIP selectively increased post-synaptic Src activity in humans and mice, and enhanced synaptic NMDAR currents in mice. Chronic ICV injection of TAT-SAPIP rescued deficits in trace fear conditioning in Src hypomorphic mice. We propose blockade of the Src-PSD-95 interaction as a proof of concept for the use of interfering peptides as a therapeutic strategy to reverse NMDAR hypofunction in schizophrenia and other illnesses.

COVID-19 impact on junior doctor education and training: a scoping review.

COVID-19 has had a significant impact on healthcare resources and the medical workforce. Clinically-based medical education is the principal source of learning, and this has been profoundly impacted by restrictions due to COVID-19. It follows that junior medical staff and their education would be significantly impacted due to the altered volume and breadth of their clinical exposure. Some literature has been published regarding the impact to medical training during COVID-19. This study sought to review junior medical staff perceptions and their reported impact of the COVID-19 pandemic on their education and training.Nine databases (three Ovid MEDLINE databases, Embase, Web of Science, Scopus, Cumulative Index to Nursing and Allied Health Literature, Educational Resources Information Centre and PsychINFO) were searched for studies published in 1 January 2020 through 24 August 2020. Via a scoping review protocol, an iterative process was used to perform the identification, review and charting analysis of the reported outcomes and themes. Descriptive analysis was performed using quantitative and qualitative methods.Of the 25 343 sources identified, 32 were included in the review. There were studies published from nearly all continents, predominantly in surgical journals, with a wide spread of specialties. Themes identified included the current impact of the pandemic in relation to continuation of and modifications to training programmes, as well as the future impact due to training requirements and career progression.Junior medical staff report that the COVID-19 pandemic has had a significant impact on their education and training. Whether the changes imposed by the pandemic on education are temporary measures or permanent fixtures, and whether standards of competence may be impacted, is not yet known. This scoping review forms a basis for further investigation in the field.

Vaccination reshapes the virus-specific T cell repertoire in unexposed adults.

We examined how baseline CD4+ T cell repertoire and precursor states impact responses to pathogen infection in humans using primary immunization with yellow fever virus (YFV) vaccine. YFV-specific T cells in unexposed individuals were identified by peptide-MHC tetramer staining and tracked pre- and post-vaccination by tetramers and TCR sequencing. A substantial number of YFV-reactive T cells expressed memory phenotype markers and contained expanded clones in the absence of exposure to YFV. After vaccination, pre-existing YFV-specific T cell populations with low clonal diversity underwent limited expansion, but rare populations with a reservoir of unexpanded TCRs generated robust responses. These altered dynamics reorganized the immunodominance hierarchy and resulted in an overall increase in higher avidity T cells. Thus, instead of further increasing the representation of dominant clones, YFV vaccination recruits rare and more responsive T cells. Our findings illustrate the impact of vaccines in prioritizing T cell responses and reveal repertoire reorganization as a key component of effective vaccination.