Impacto de estresse na infância na psicopatologia

OBJECTIVE: Advances in our knowledge of mental disorder (MD) genetics have contributed to a better understanding of their pathophysiology. Nonetheless, several questions and doubts persist. Recent studies have focused on environmental influences in the development of MDs, and the advent of neuroscientific methodologies has provided new perspectives. Early life events, such as childhood stress, may affect neurodevelopment through mechanisms such as gene-environment interactions and epigenetic regulation, thus leading to diseases in adulthood. The aim of this paper is to review the evidence regarding the role of the environment, particularly childhood stress, in the pathophysiology of MD. METHODOLOGY: We reviewed articles that evaluated environmental influences, with a particular focus on childhood trauma, brain morphology, cognitive functions, and the development of psychopathology and MD. RESULTS AND CONCLUSION: MRI studies have shown that exposure to trauma at an early age can result in several neurostructural changes, such as the reduction of the hippocampus and corpus callosum. Cognitive performance and functioning are also altered in this population. Finally, childhood stress is related to an increased risk of developing MD such as depression, bipolar disorder, schizophrenia and substance abuse. We conclude that there is robust evidence of the role of the environment, specifically adverse childhood experiences, in various aspects of MD.OBJETIVO: Avanços no conhecimento da genética dos transtornos mentais (TM) contribuíram para um melhor entendimento de suas bases fisiopatológicas. No entanto, dúvidas e questões ainda persistem. Estudos recentes têm se concentrado nas influências do ambiente no desenvolvimento de TM, e o advento de metodologias neurocientíficas oferece novas perspectivas. Eventos precoces de vida, como estresse na infância, podem ser capazes de alterar o neurodesenvolvimento através de mecanismos como interação gene-ambiente e regulação epigenética, resultando em patologias na idade adulta. O objetivo deste artigo é revisar as evidências referentes ao papel do ambiente, em especial o estresse na infância, na fisiopatologia de TM. METODOLOGIA: Revisamos artigos que avaliam as influências ambientais, com um foco especial no trauma na infância, na morfologia cerebral, nas funções cognitivas e no desenvolvimento de psicopatologias e TM. RESULTADOS E CONCLUSÃO: Estudos com ressonância magnética demonstram que a exposição a traumas em uma idade precoce pode levar a diversas alterações neuroestruturais, como a diminuição do hipocampo e do corpo caloso. O desempenho e o funcionamento cognitivo também são alterados nessa população. Por fim, o estresse na infância está ligado a um maior risco de desenvolver TM como depressão, transtorno bipolar, esquizofrenia e abuso de substâncias. Concluímos que existem evidências sólidas quanto à importância do ambiente, especificamente das experiências adversas na infância, em diversos aspectos dos TM.Universidade Federal de São Paulo (UNIFESP) Department of Psychiatry Recognition and Intervention in Individuals in at-Risk Mental StatesUniversidade Federal de São Paulo (UNIFESP) Department of Psychiatry Interdisciplinary Laboratory of Clinical NeurosciencesUniversidade Federal do Rio Grande do Sul Laboratory of Molecular PsychiatryPontifícia Universidade Católica do Rio Grande do Sul Nucleus of Studies and Research in Trauma and StressUNIFESP, Department of Psychiatry Recognition and Intervention in Individuals in at-Risk Mental StatesUNIFESP, Department of Psychiatry Interdisciplinary Laboratory of Clinical NeurosciencesSciEL

Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease

RFC1 disease, caused by biallelic repeat expansion in RFC1, is clinically heterogeneous in terms of age of onset, disease progression and phenotype. We investigated the role of the repeat size in influencing clinical variables in RFC1 disease. We also assessed the presence and role of meiotic and somatic instability of the repeat. In this study, we identified 553 patients carrying biallelic RFC1 expansions and measured the repeat expansion size in 392 cases. Pearson's coefficient was calculated to assess the correlation between the repeat size and age at disease onset. A Cox model with robust cluster standard errors was adopted to describe the effect of repeat size on age at disease onset, on age at onset of each individual symptoms, and on disease progression. A quasi-poisson regression model was used to analyse the relationship between phenotype and repeat size. We performed multi-variate linear regression to assess the association of the repeat size with the degree of cerebellar atrophy. Meiotic stability was assessed by Southern blotting on first-degree relatives of 27 probands. Finally, somatic instability was investigated by optical genome mapping on cerebellar and frontal cortex and unaffected peripheral tissue from four post-mortem cases. A larger repeat size of both smaller and larger allele was associated with an earlier age at neurological onset (smaller allele HR = 2.06, p < 0.001; larger allele HR = 1.53, p < 0.001) and with a higher hazard of developing disabling symptoms, such as dysarthria or dysphagia (smaller allele HR = 3.40, p < 0.001; larger allele HR = 1.71, p = 0.002) or loss of independent walking (smaller allele HR = 2.78, p < 0.001; larger allele HR = 1.60; p < 0.001) earlier in disease course. Patients with more complex phenotypes carried larger expansions (smaller allele: complex neuropathy RR = 1.30, p = 0.003; CANVAS RR = 1.34, p < 0.001; larger allele: complex neuropathy RR = 1.33, p = 0.008; CANVAS RR = 1.31, p = 0.009). Furthermore, larger repeat expansions in the smaller allele were associated with more pronounced cerebellar vermis atrophy (lobules I-V β=-1.06, p < 0.001; lobules VI-VII β=-0.34, p = 0.005). The repeat did not show significant instability during vertical transmission and across different tissues and brain regions. RFC1 repeat size, particularly of the smaller allele, is one of the determinants of variability in RFC1 disease and represents a key prognostic factor to predict disease onset, phenotype, and severity. Assessing the repeat size is warranted as part of the diagnostic test for RFC1 expansion

Suicidality in adolescents: epidemiologic-clincal analysis 2016-2021

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Vaginal Lactobacilli Supernatants Protect from Herpes Simplex Virus Type 1 Infection in Cell Culture Models

A healthy vaginal microbiota hosts Lactobacillus as the most predominant genus. Lactobacilli play a role in human health through the production of diverse antimicrobial substances that can act against human pathogens or modulate the immune system. Previous reports highlighted the ability of vaginal lactobacilli to counteract viruses causing STIs, e.g., HIV-1 and HSV-2. In this report, we analyze the activity of supernatants of vaginal lactobacilli against HSV-1 infection, which is becoming increasingly relevant as a STI. We show that the supernatants of two vaginal Lactobacillus species (i.e., L. crispatus and L. gasseri) were active at neutralizing HSV-1 infection in two different cell lines of human and simian origin. Specifically, we demonstrate that L. crispatus strains are the most effective in antiviral activity, as evidenced by the comparison with a vaginal pathogen taken as reference. The effect was specific and not attributable to the generic toxicity of the supernatants to the cells. Our results pave the way for the development of probiotics to limit the impact of HSV-1 infection on women’s health

Design, synthesis and biological evaluation of TAR and cTAR binders as HIV-​1 nucleocapsid inhibitors

We designed, synthesized and tested novel 2,6-disubstituted-anthraquinones able to bind dynamic secondary structures of nucleic acids, such as TAR RNA and its reverse transcript cTAR, leading to inhibition of the chaperone activities of the nucleocapsid NCp7, a highly conserved viral protein implied in crucial steps of HIV-1 replicatio

Targeting the Regulatory Subunit R2Alpha of Protein Kinase A in Human Glioblastoma through shRNA-Expressing Lentiviral Vectors

Glioblastoma is the most malignant and most common form of brain tumor, still today associated with a poor 14-months median survival from diagnosis. Protein kinase A, particularly its regulatory subunit R2Alpha, presents a typical intracellular distribution in glioblastoma cells compared to the healthy brain parenchyma and this peculiarity might be exploited in a therapeutic setting. In the present study, a third-generation lentiviral system for delivery of shRNA targeting the regulatory subunit R2Alpha of protein kinase A was developed. Generated lentiviral vectors are able to induce an efficient and stable downregulation of R2Alpha in different cellular models, including non-stem and stem-like glioblastoma cells. In addition, our data suggest a potential correlation between silencing of the regulatory subunit of protein kinase A and reduced viability of tumor cells, apparently due to a reduction in replication rate. Thus, our findings support the role of protein kinase A as a promising target for novel anti-glioma therapies

Gene therapy of AIDS: a novel approach combining anti HIV-1 siRNAs and a fusion inhibitor

Background: Gene therapy holds considerable promise for the functional cure of HIV-1 infection and, in this context, combinatorial approaches, aimed at interfering with different steps of viral replication, represent powerful strategies. To this end, we previously developed a series of self-inactivating lentiviral vectors expressing multiple small interfering (si)-RNAs targeting the CCR5 cellular gene as well as vif and tat/rev viral transcripts, under the control of different RNA polymerase III promoters (U6, 7SK, H1). The use of a single RNA polymerase III promoter driving the expression of a sequence giving rise to three siRNAs directed against the selected targets (e-shRNA) was also investigated. We identified two effective anti HIV combinatorial vectors that conferred protection against R5 and X4 tropic viruses in human primary CD4+ T lymphocytes. Methods: In the present study, these two vectors were further modified by the inclusion of a membrane-anchored peptide (maC46), which has been shown to efficiently block the entry of both CXCR-4 and CCR5 using viruses. The maC46 was inserted under the transcriptional control of the human Elongation Factor 1 promoter. Additionally, an optimized version of the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE*) was also inserted in the new generation of lentiviral vectors. The antiviral activity of the optimized vectors was assessed in different cellular models. Results: The developed vectors conferred to the transduced cells a sustained and significant protection against HIV-1 challenge. Conclusion: Overall our results contribute to gain further insights in the design of combinatorial gene therapy approaches against HIV-1 for clinical application

Combination of anti HIV-1 siRNAs and a fusion inhibitor for genetic treatment of AIDS.

Despite the remarkable success of highly active antiretroviral therapy (HAART) in lowering the plasma viral load in patients with HIV -1 infection and in slowing down the disease progression, many obstacles still remain, including the generation of drug-resistant viral species, the difficulty in eradicating latent reservoirs and the high costs of the therapy. The development of complementary strategies to completely eradicate or to control HIV-1 infection without daily drug intake is therefore a priority. In this context, anti HIV-1 gene therapy based on intracellular immunization of autologous T cells or their progenitors, i.e. the CD34+ hematopoietic stem cells, resistant to infection, appears a particularly promising approach to repopulate the immune system.In order to interfere with different steps of viral replication, we previously developed a series of self-inactivating lentiviral vectors expressing multiple small interfering (si)-RNAs targeting the CCR5 cellular gene as well as vif and tat/rev viral transcripts, under the control of different RNA polymerase III promoters (U6, 7SK, H1). The use of a single RNA polymerase III promoter driving the expression of a sequence giving rise to three siRNAs directed against the selected targets (e-shRNA) was also investigated. Two effective anti- HIV combinatorial vectors that conferred protection against R5 and X4 tropic virusesin human primary CD4+ T lymphocytes were identified. Further modification of the combinatorial vectors were accomplished by the inclusion of a membrane-anchored peptide (maC46), which has been shown to efficiently block the entry of both CXCR-4 and CCR5-using viruses. The maC46 was inserted under the transcriptional control of the human Elongation Factor 1 promoter. Additionally, an optimized version of the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE*) was also inserted in the new generation of lentiviral vectors. The antiviral activity of the optimized vectors was assessed in different cellular models. Overall our results contribute to gain further insights in the design of combinatorial gene therapy approaches against HIV-1 for clinical application