Systemic Exosomal Delivery of shRNA Minicircles Prevents Parkinsonian Pathology

The development of new therapies to slow down or halt the progression of Parkinson's disease is a health care priority. A key pathological feature is the presence of alpha-synuclein aggregates, and there is increasing evidence that alpha-synuclein propagation plays a central role in disease progression. Consequently, the downregulation of alpha-synuclein is a potential therapeutic target. As a chronic disease, the ideal treatment will be minimally invasive and effective in the long-term. Knockdown of gene expression has clear potential, and siRNAs specific to alpha-synuclein have been designed; however, the efficacy of siRNA treatment is limited by its short-term efficacy. To combat this, we designed shRNA minicircles (shRNA-MCs), with the potential for prolonged effectiveness, and used RVG-exosomes as the vehicle for specific delivery into the brain. We optimized this system using transgenic mice expressing GFP and demonstrated its ability to downregulate GFP protein expression in the brain for up to 6 weeks. RVG-exosomes were used to deliver anti-alpha-synuclein shRNA-MC therapy to the alpha-synuclein preformed-fibril-induced model of parkinsonism. This therapy decreased alpha-synuclein aggregation, reduced the loss of dopaminergic neurons, and improved the clinical symptoms. Our results confirm the therapeutic potential of shRNA-MCs delivered by RVG-exosomes for long-term treatment of neurodegenerative diseases

Relationship between cognition and age at onset of first-episode psychosis: comparative study between adolescents, young adults, and adults

Psychotic disorders typically manifest from late adolescence to early adulthood, and an earlier onset might be associated with greater symptom severity and a worse long-term prognosis. This study aimed to compare the cognitive characteristics of patients with first-episode psychosis (FEP) by their age at onset. We included 298 patients diagnosed with FEP and classified them as having an early onset (EOS), youth onset (YOS), or adult onset (AOS) based on age limits of = 25 years (N = 116), respectively. Socio-demographic and clinical variables included age at baseline, gender, socio-economic status, antipsychotic medication, DSM-IV diagnoses assessed by clinical semi-structured interview, psychotic symptom severity, and age at onset. Neuropsychological assessment included six cognitive domains: premorbid intelligence, working memory, processing speed, verbal memory, sustained attention, and executive functioning. The EOS group had lower scores than the YOS or AOS groups in global cognition, executive functioning, and sustained attention. Although the scores in the YOS group were intermediate to those in the EOS and AOS groups for most cognitive factors, no statistically significant differences were detected between the YOS and AOS groups. Age at onset results in specific patterns of cognitive interference. Of note, impairment appears to be greater with EOS samples than with either YOS or AOS samples. A longitudinal study with a larger sample size is needed to confirm our findings

Annual dune plant communities in the Southwest coast of Europe

This study presents an updated sintaxonomic review of the annual communities from coastal dunes in the Southwest coast of Europe, specifically in the Iberian Peninsula, including both types: directly influenced by the sea salt spray and not affected by this influence. The floristic segregation of the different plant associations was obtained by statistical agglomerative processes (UPGMA, Unweighted Pair Group Method with Arithmetic Mean) plus principal coordinate analysis (PCoA) and discussed based on the interpretation of phytosociological tables. Three new communities in central western Portugal were found and are described: Pseudorlayo minusculae-Polycarpietum alsinifoli, Cerastio diffusae-Vulpietum fontqueranae and Omphalodo kunzinskyanae-Evacietum ramosissimae

Co-creation and regional adaptation of a resilience-based universal whole-school program in five European regions

The co-creation of educational services that promote youth resilience and mental health is still scarce. UPRIGHT (Universal Preventive Resilience Intervention Globally implemented in schools to improve and promote mental Health for Teenagers) is a research and intervention program in the Basque Country (Spain), Trentino (Italy), Low Silesia (Poland), Denmark and Reykjavik (Iceland). UPRIGHT implemented a co-creation research process whose results, outcomes and policy implications are presented here. The co-creation had a mixed-methods participatory research design with nine specific objectives linked to paired strategies of inquiry for adolescents, families, teachers and school staff. The overarching objective was to generate a valid and feasible regional adaptation strategy for UPRIGHT intervention model. Participants answered surveys (n= 794) or attended 16 group sessions (n= 217). The results integrate quantitative and qualitative information to propose a regional adaptation strategy that prioritizes resilience skills, adolescents' concerns, and preferred methods for implementation across countries and in each school community. In conclusion, a whole-school resilience program must innovate, include and connect different actors, services and communities, and must incorporate new technologies and activities outside the classroom. A participatory co-creation process is an indispensable step to co-design locally relevant resilience interventions with the involvement of the whole-school community

Diagnostic capacity for invasive fungal infections in advanced HIV disease in Africa: a continent-wide survey.

BACKGROUND: Fungal infections are common causes of death and morbidity in those with advanced HIV infection. Data on access to diagnostic tests in Africa are scarce. We aimed to evaluate the diagnostic capacity for invasive fungal infections in advanced HIV disease in Africa. METHODS: We did a continent-wide survey by collecting data from 48 of 49 target countries across Africa with a population of more than 1 million; for Lesotho, only information on the provision of cryptococcal antigen testing was obtained. This survey covered 99·65% of the African population. We did the survey in six stages: first, questionnaire development, adaptation, and improvement; second, questionnaire completion by in-country respondents; third, questionnaire review and data analysis followed by video conference calls with respondents; fourth, external validation from public or private sources; fifth, country validation by video conference with senior figures in the Ministry of Health; and sixth, through five regional webinars led by the Africa Centres for Disease Control and Prevention with individual country profiles exchanged by email. Data was compiled and visualised using the Quantum Geographic Information System software and Natural Earth vectors to design maps showing access. FINDINGS: Data were collected between Oct 1, 2020, and Oct 31, 2022 in the 48 target countries. We found that cryptococcal antigen testing is frequently accessible to 358·39 million (25·5%) people in 14 African countries. Over 1031·49 million (73·3%) of 1·4 billion African people have access to a lumbar puncture. India ink microscopy is frequently accessible to 471·03 million (33·5%) people in 23 African countries. About 1041·62 million (74·0%) and 1105·11 million (78·5%) people in Africa do not have access to histoplasmosis and Pneumocystis pneumonia diagnostics in either private or public facilities, respectively. Fungal culture is available in 41 countries covering a population of 1·289 billion (94%) people in Africa. MRI is routinely accessible to 453·59 million (32·2%) people in Africa and occasionally to 390·58 million (27·8%) people. There was a moderate correlation between antiretroviral therapy usage and external expenditure on HIV care (R2=0·42) but almost none between external expenditure and AIDS death rate (R2=0·18), when analysed for 40 African countries. INTERPRETATION: This survey highlights the enormous challenges in the diagnosis of HIV-associated Pneumocystis pneumonia, cryptococcal disease, histoplasmosis, and other fungal infections in Africa. Urgent political and global health leadership could improve the diagnosis of fungal infections in Africa, reducing avoidable deaths. FUNDING: Global Action For Fungal Infections

UPRIGHT, a resilience-based intervention to promote mental well-being in schools: study rationale and methodology for a European randomized controlled trial

Background: Adolescence is crucial period for laying the foundations for healthy development and mental wellbeing. The increasing prevalence of mental disorders amongst adolescents makes promotion of mental well-being and prevention interventions at schools important. UPRIGHT (Universal Preventive Resilience Intervention Globally implemented in schools to improve and promote mental Health for Teenagers) is designed as a whole school approach (school community, students and families) to promote a culture of mental well-being and prevent mental disorders by enhancing resilience capacities. The present article aims at describing the rationale, conceptual framework, as well as methodology of implementation and evaluation of the UPRIGHT intervention.Methods: UPRIGHT project is a research and innovation project funded by the European Union's Horizon 2020 Research and Innovation programme under grant agreement No. 754919 (Duration: 48 months). The theoretical framework has been developed by an innovative and multidisciplinary approach using a co-creation process inside the UPRIGHT Consortium (involving seven institutions from Spain, Italy, Poland, Norway, Denmark, and Iceland). Resulted is the UPRIGHT programme with 18 skills related to 4 components: Mindfulness, Coping, Efficacy and Social and Emotional Learning. Among the five Pan-European regions, 34 schools have been currently involved (17 control; 17 intervention) and around 6000 adolescents and their families are foreseen to participate along a 3-year period of evaluation. Effectiveness of the intervention will be evaluated as a randomized controlled trial including quantitative and qualitative analysis in the five Pan-European regions representative of the cultural and socioeconomic diversity. The cost-effectiveness assessment will be performed by simulation modelling methods.Discussion: We expect a short- to medium-term improvement of mental well-being in adolescents by enhancing resilience capacities. The study may provide robust evidence on intrapersonal, familiar and social environmental resilience factors promoting positive mental well-being.Trial registration: ClinicalTrials.gov Identifier: NCT03951376. Registered 15 May 2019

Opposite cannabis-cognition associations in psychotic patients depending on family history

The objective of this study is to investigate cognitive performance in a first-episode psychosis sample, when stratifying the interaction by cannabis use and familial or non-familial psychosis. Hierarchical-regression models were used to analyse this association in a sample of 268 first-episode psychosis patients and 237 controls. We found that cannabis use was associated with worse working memory, regardless of family history. However, cannabis use was clearly associated with worse cognitive performance in patients with no family history of psychosis, in cognitive domains including verbal memory, executive function and global cognitive index, whereas cannabis users with a family history of psychosis performed better in these domains. The main finding of the study is that there is an interaction between cannabis use and a family history of psychosis in the areas of verbal memory, executive function and global cognition: that is, cannabis use is associated with a better performance in patients with a family history of psychosis and a worse performance in those with no family history of psychosis. In order to confirm this hypothesis, future research should explore the actual expression of the endocannabinoid system in patients with and without a family history of psychosis

A longitudinal study of gene expression in first-episode schizophrenia; exploring relapse mechanisms by co-expression analysis in peripheral blood

Little is known about the pathophysiological mechanisms of relapse in first-episode schizophrenia, which limits the study of potential biomarkers. To explore relapse mechanisms and identify potential biomarkers for relapse prediction, we analyzed gene expression in peripheral blood in a cohort of first-episode schizophrenia patients with less than 5 years of evolution who had been evaluated over a 3-year follow-up period. A total of 91 participants of the 2EPs project formed the sample for baseline gene expression analysis. Of these, 67 provided biological samples at follow-up (36 after 3 years and 31 at relapse). Gene expression was assessed using the Clariom S Human Array. Weighted gene co-expression network analysis was applied to identify modules of co-expressed genes and to analyze their preservation after 3 years of follow-up or at relapse. Among the 25 modules identified, one module was semi-conserved at relapse (DarkTurquoise) and was enriched with risk genes for schizophrenia, showing a dysregulation of the TCF4 gene network in the module. Two modules were semi-conserved both at relapse and after 3 years of follow-up (DarkRed and DarkGrey) and were found to be biologically associated with protein modification and protein location processes. Higher expression of DarkRed genes was associated with higher risk of suffering a relapse and early appearance of relapse (p = 0.045). Our findings suggest that a dysregulation of the TCF4 network could be an important step in the biological process that leads to relapse and suggest that genes related to the ubiquitin proteosome system could be potential biomarkers of relapse. © 2021, The Author(s)

Floristic analysis of a high-speed railway embankment in a Mediterranean landscape

We analyzed the floristic composition of a 4.5 km-long segment of a high-speed railway in Lazio, central Italy, which travels on an artificial embankment through an intensively-farmed landscape. In total, 287 vascular plant species were recorded. The life-form distribution was found to be similar to that of the regional species pool, with high percentages of therophytes (38%) and phanerophytes (13%). In the chorological spectrum the Mediterranean floristic element prevailed (44%), while alien species were 8% of the flora. The phytosociological spectrum showed a high diversity of characteristic species from the class Stellarietea mediae or its subordinate syntaxa (26%), and in particular from the order Thero-Brometalia (Mediterranean, sub-nitrophilous annual communities). Species from forest syntaxa had a relatively high diversity (9%). These results suggest that the ecological filtering provided by the Mediterranean regional climate controlled species assemblage even in a completely artificial habitat, preventing floristic homogenization: the flora of the studied railway section is only partially »ruderalized«, while it keeps strong links with the regional (semi-) natural plant communities. However, in contrast to what is observed in central and north Europe, the railway sides studied in the present paper do not seem to represent a refugial habitat for rare species from grassland communities, mainly because in Italy semi-natural dry grasslands are still widely represented

Gene co-expression architecture in peripheral blood in a cohort of remitted first-episode schizophrenia patients

A better understanding of schizophrenia subtypes is necessary to stratify the patients according to clinical attributes. To explore the genomic architecture of schizophrenia symptomatology, we analyzed blood co-expression modules and their association with clinical data from patients in remission after a first episode of schizophrenia. In total, 91 participants of the 2EPS project were included. Gene expression was assessed using the Clariom S Human Array. Weighted-gene co-expression network analysis (WGCNA) was applied to identify modules of co-expressed genes and to test its correlation with global functioning, clinical symptomatology, and premorbid adjustment. Among the 25 modules identified, six modules were significantly correlated with clinical data. These modules could be clustered in two groups according to their correlation with clinical data. Hub genes in each group showing overlap with risk genes for schizophrenia were enriched in biological processes related to metabolic processes, regulation of gene expression, cellular localization and protein transport, immune processes, and neurotrophin pathways. Our results indicate that modules with significant associations with clinical data showed overlap with gene sets previously identified in differential gene-expression analysis in brain, indicating that peripheral tissues could reveal pathogenic mechanisms. Hub genes involved in these modules revealed multiple signaling pathways previously related to schizophrenia, which may represent the complex interplay in the pathological mechanisms behind the disease. These genes could represent potential targets for the development of peripheral biomarkers underlying illness traits in clinical remission stages after a first episode of schizophrenia