The Bad, the Good, and the Ugly about Oxidative Stress

Alzheimer's disease (AD), Parkinson's disease (PD), and cancer (e.g., leukemia) are the most devastating disorders affecting millions of people worldwide. Except for some kind of cancers, no effective and/or definitive therapeutic treatment aimed to reduce or to retard the clinic and pathologic symptoms induced by AD and PD is presently available. Therefore, it is urgently needed to understand the molecular basis of these disorders. Since oxidative stress (OS) is an important etiologic factor of the pathologic process of AD, PD, and cancer, understanding how intracellular signaling pathways respond to OS will have a significant implication in the therapy of these diseases. Here, we propose a model of minimal completeness of cell death signaling induced by OS as a mechanistic explanation of neuronal and cancer cell demise. This mechanism might provide the basis for therapeutic design strategies. Finally, we will attempt to associate PD, cancer, and OS. This paper critically analyzes the evidence that support the “oxidative stress model” in neurodegeneration and cancer

Reflexões sobre a maternidade : um estudo exploratório com mulheres acima de 40 anos

Este artigo apresenta um estudo exploratório-descritivo de caráter qualitativo que busca conhecer como o conceito de maternidade é compreendido e vivenciado pelas mulheres, destacando vivências de libertação e cativeiro, segundo a Teoria do Espaço Consciente de Krista K. Burlae (2004). Através da Entrevista Biográfica proposta por Connie J. G. Gersick & Kathy. E. Kram (2002), seis mulheres acima de 40 anos relataram sobre sua vida no passado, presente e futuro. A análise dos resultados deu-se a partir da Análise do Discurso, proposto por Rosalind Gill (2002), baseando-se nos pressupostos epistemológicos dos estudos de gênero, perspectiva feminista, teoria do Desenvolvimento de Daniel Levinson (1996) e visão sistêmica. Os resultados trazem que as concepções e as vivências de maternidade são diversas, complexas e apresentam diferentes implicações na vida das mulheres. Perspectivas mais conservadoras interagem com visões mais críticas sobre as relações mãe-mulher.En este artículo se presenta un estudio cualitativo, exploratorio-descriptivo que busca entender cómo entienden y experimentan las mujeres el concepto de la maternidad, destacando las experiencias de la liberación y de la esclavitud, de acuerdo con la Teoría del Espacio Consciente Burlae (2004). A través de entrevista biográfica propuesto por Gersick y Kram (2002), 6 mujeres de más de 40 informaron sobre su vida en el pasado, presente y futuro. El análisis se llevó a cabo del análisis del discurso, propuesto por Gill (2002), sobre la base de los supuestos epistemológicos de los estudios de género, perspectiva feminista y vista sistémico. Los resultados traen a las concepciones y experiencias de la maternidad son diversos, complejos y tienen diferentes implicaciones para la vida de las mujeres. Perspectivas más conservadores interactúan con puntos de vista más críticos en las relaciones madre-mujer.This article presents an exploratory descriptive study of qualitative character, who seeks to understand how the notion of maternity is perceived and experienced by women, emphasizing experiences of liberation and captivity, as per Krista K. Burlae's Theory of Mindful Space (2004). Via the biographical interview proposed by Connie J. G. Gersick & Kathy. E. Kram (2002), six women over the age of 40 described their lives in the past, present and future. The analysis of results was conducted using the Discourse Analysis proposed by Rosalind Gill (2002), basing itself on epistemological assumptions from studies of gender, feminine perspective, Daniel Lenvinson's Development Theory (1996) and systemic vision. The results show that the conceptions and experiences of maternity are diverse and complex, presenting different implications in the lives of women. More conservative perspectives interact with more critical views of the mother-woman relationships

Avanços e retrocessos no combate da violência contra mulheres

Este texto es una reflexión sobre la violencia de género en la sociedad brasileña, apoyándose en el marco teórico de la teoría del patriarcado. Trae la contribución de las activistas feministas en el campo de la psicología social para hacer frente a la violencia de género, entendiendo que la autonomía individual y colectiva puede contribuir a la deconstrucción de los modelos jerárquicos y de género desiguales.Este texto é uma reflexão acerca da violência de gênero na sociedade brasileira, apoiando-se no referencial teórico da teoria do patriarcado. Traz a contribuição de militantes feministas do campo da psicologia social para o enfrentamento da violência de gênero, entendendo que o empoderamento individual e coletivo pode contribuir para a desconstrução de modelos hierarquizados e desiguais entre os gêneros.This text is a reflection of gender violence in Brazilian society, relying on the theoretical framework of the theory of patriarchy. It brings the contribution of feminist activists in the field of social psychology to face gender violence, understanding that the individual and collective empowerment can contribute to the deconstruction of hierarchical models and unequal between the genders

Variable frequency of LRRK2 variants in the Latin American research consortium on the genetics of Parkinson's disease (LARGE-PD), a case of ancestry

ABSTARCT: Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2), primarily located in codons G2019 and R1441, represent the most common genetic cause of Parkinson's disease in European-derived populations. However, little is known about the frequency of these mutations in Latin American populations. In addition, a prior study suggested that a LRRK2 polymorphism (p.Q1111H) specific to Latino and Amerindian populations might be a risk factor for Parkinson's disease, but this finding requires replication. We screened 1734 Parkinson's disease patients and 1097 controls enrolled in the Latin American Research Consortium on the Genetics of Parkinson's disease (LARGE-PD), which includes sites in Argentina, Brazil, Colombia, Ecuador, Peru, and Uruguay. Genotypes were determined by TaqMan assay (p.G2019S and p.Q1111H) or by sequencing of exon 31 (p.R1441C/G/H/S). Admixture proportion was determined using a panel of 29 ancestry informative markers. We identified a total of 29 Parkinson's disease patients (1.7%) who carried p.G2019S and the frequency ranged from 0.2% in Peru to 4.2% in Uruguay. Only two Parkinson's disease patients carried p.R1441G and one patient carried p.R1441C. There was no significant difference in the frequency of p.Q1111H in patients (3.8%) compared to controls (3.1%; OR 1.02, p = 0.873). The frequency of LRRK2-p.G2019S varied greatly between different Latin American countries and was directly correlated with the amount of European ancestry observed. p.R1441G is rare in Latin America despite the large genetic contribution made by settlers from Spain, where the mutation is relatively common

Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome

PURPOSE: The Retriever subunit VPS35L is the third responsible gene for Ritscher-Schinzel syndrome (RSS) after WASHC5 and CCDC22. To date, only one pair of siblings have been reported and their condition was significantly more severe than typical RSS. This study aimed to understand the clinical spectrum and underlying molecular mechanism in VPS35L-associated RSS. METHODS: We report three new patients with biallelic VPS35L variants. Biochemical and cellular analyses were performed to elucidate disease aetiology. RESULTS: In addition to typical features of RSS, we confirmed hypercholesterolaemia, hypogammaglobulinaemia and intestinal lymphangiectasia as novel complications of VPS35L-associated RSS. The latter two complications as well as proteinuria have not been reported in patients with CCDC22 and WASHC5 variants. One patient showed a severe phenotype and the other two were milder. Cells established from patients with the milder phenotypes showed relatively higher VPS35L protein expression. Cellular analysis found VPS35L ablation decreased the cell surface level of lipoprotein receptor-related protein 1 and low-density lipoprotein receptor, resulting in reduced low-density lipoprotein cellular uptake. CONCLUSION: VPS35L-associated RSS is a distinct clinical entity with diverse phenotype and severity, with a possible molecular mechanism of hypercholesterolaemia. These findings provide new insight into the essential and distinctive role of Retriever in human development

Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders

The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO. The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Although all individuals in this cohort present with developmental delay and a neuro-behavioral phenotype, individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly. Functional studies show that the spectrin and GEFD1 variants cause a TRIO-mediated hyper- or hypo-activation of RAC1, respectively, and we observe a striking correlation between RAC1 activation levels and the head size of the affected individuals. In addition, truncations in TRIO GEFD1 in the vertebrate model X. tropicalis induce defects that are concordant with the human phenotype. This work demonstrates distinct clinical and molecular disorders clustering in the GEFD1 and seventh spectrin repeat domains and highlights the importance of tight control of TRIO-RAC1 signaling in neuronal development.<br/

Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, <scp>genotype–phenotype</scp> correlations and common mechanisms

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (&gt;60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS‐like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or “DTRs”). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype–phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population

Os fatores determinantes e as complicações oriundas do crescimento fetal restrito: Determining factors and complications arising from restricted fetal growth

O feto portador de restrição do crescimento fetal intra-uterino evolui sem alcançar o seu potencial genético de crescimento. Destacando, que o Crescimento Intra-Uterino Restrito (CIUR) condiz a um complexo heterogêneo, caracterizado pela maioria ser de fetos biologicamente pequenos, mas não se encaixam na condição patológica, a qual urge por monitoramento. Neste contexto, pode estar ou não relacionado a inúmeras doenças a qual necessitam ser diagnosticadas. O objetivo deste estudo foi analisar os fatores relacionados na etiologia e das complicações da restrição do crescimento intra-uterino. As informações existentes na literatura evidenciam a existência de vários desencadeantes nesta ocorrência, a qual abordam a associação de fatores maternos, placentários e fetais. Os distintos grupos possivelmente podem coexistir de modo simultâneo, sendo parte destes passíveis de prevenção