Antidepressant Exposure and DNA Methylation: Insights from a Methylome-Wide Association Study.

Importance: Understanding antidepressant mechanisms could help design more effective and tolerated treatments. Objective: Identify DNA methylation (DNAm) changes associated with antidepressant exposure. Design: Case-control methylome-wide association studies (MWAS) of antidepressant exposure were performed from blood samples collected between 2006-2011 in Generation Scotland (GS). The summary statistics were tested for enrichment in specific tissues, gene ontologies and an independent MWAS in the Netherlands Study of Depression and Anxiety (NESDA). A methylation profile score (MPS) was derived and tested for its association with antidepressant exposure in eight independent cohorts, alongside prospective data from GS. Setting: Cohorts; GS, NESDA, FTC, SHIP-Trend, FOR2107, LBC1936, MARS-UniDep, ALSPAC, E-Risk, and NTR. Participants: Participants with DNAm data and self-report/prescription derived antidepressant exposure. Main Outcomes and Measures: Whole-blood DNAm levels were assayed by the EPIC/450K Illumina array (9 studies, N exposed = 661, N unexposed = 9,575) alongside MBD-Seq in NESDA (N exposed = 398, N unexposed = 414). Antidepressant exposure was measured by self- report and/or antidepressant prescriptions. Results: The self-report MWAS (N = 16,536, N exposed = 1,508, mean age = 48, 59% female) and the prescription-derived MWAS (N = 7,951, N exposed = 861, mean age = 47, 59% female), found hypermethylation at seven and four DNAm sites (p < 9.42x10 -8 ), respectively. The top locus was cg26277237 ( KANK1, p self-report = 9.3x10 -13 , p prescription = 6.1x10 -3 ). The self-report MWAS found a differentially methylated region, mapping to DGUOK-AS1 ( p adj = 5.0x10 -3 ) alongside significant enrichment for genes expressed in the amygdala, the "synaptic vesicle membrane" gene ontology and the top 1% of CpGs from the NESDA MWAS (OR = 1.39, p < 0.042). The MPS was associated with antidepressant exposure in meta-analysed data from external cohorts (N studies = 9, N = 10,236, N exposed = 661, f3 = 0.196, p < 1x10 -4 ). Conclusions and Relevance: Antidepressant exposure is associated with changes in DNAm across different cohorts. Further investigation into these changes could inform on new targets for antidepressant treatments. 3 Key Points: Question: Is antidepressant exposure associated with differential whole blood DNA methylation?Findings: In this methylome-wide association study of 16,536 adults across Scotland, antidepressant exposure was significantly associated with hypermethylation at CpGs mapping to KANK1 and DGUOK-AS1. A methylation profile score trained on this sample was significantly associated with antidepressant exposure (pooled f3 [95%CI]=0.196 [0.105, 0.288], p < 1x10 -4 ) in a meta-analysis of external datasets. Meaning: Antidepressant exposure is associated with hypermethylation at KANK1 and DGUOK-AS1 , which have roles in mitochondrial metabolism and neurite outgrowth. If replicated in future studies, targeting these genes could inform the design of more effective and better tolerated treatments for depression.

Indicadores de sustentabilidade socioambiental de pisciculturas familiares em área de Mata Atlântica, no Vale do Ribeira - SP / Social and Environmental Indicators of Family Fish Farms in the Atlantic Forest area in the Ribeira Valley - SP

O objetivo deste trabalho consistiu na aplicação de indicadores socioambientais em pisciculturas familiares localizadas na região do Vale do Ribeira, em área de Mata Atlântica, no sudoeste do estado de São Paulo. Para isso, foram identificadas 84 propriedades. Dessas, 40 foram selecionadas como unidades amostrais. Entre as principais características identificadas, 32% possuem lâmina d'água inferior a cinco hectares, com viveiros escavados em sistema semi-intensivo, 58% utilizam mão de obra familiar e 23% apontam a ausência de assistência técnica especializada como o principal problema enfrentado. A tilápia-do-nilo (Oreochromis niloticus) representa 57% das espécies produzidas em sistemas de monocultivo ou policultivo. Contudo, as pisciculturas familiares são classificadas como sistemas produtivos de pequeno porte, com destaque para a necessidade de adequação de recursos naturais, da capacidade de gestão e da eficiência das práticas de produção. Os indicadores sociais variaram de 0,75 a 1,00 para equidade salarial, proporção de autoemprego, uso de mão de obra local, inclusão de gênero e inclusão etária, demonstrando a capacidade que a aquicultura tem para auxiliar no desenvolvimento social local, por meio da geração de emprego e renda.(AU)

The objective of this work was to apply socioenvironmental indicators in family fish farms located in the Ribeira Valley region, Atlantic Forest area, southwest of São Paulo state, Brazil. Thus, we identified 84 production units. Of these, we selected 40 as sample units. Among the main characteristics identified, 32% have water depth of less than five hectares with excavated ponds in semi-intensive system, 58% use family labor and 23% report the lack of specialized technical assistance as the main problem faced. The Nile tilapia (Oreochromis niloticus) represents 57% of the species produced in monoculture or polyculture systems. Therefore, family fish farms are classified as small production systems with emphasis on the need to adapt natural resources, management capacity and efficiency of production practices. Social indicators ranged from 0.75 to 1.00 for salary equity, proportion of self-employment, use of local labor, gender inclusion and age inclusion, demonstrating the ability of aquaculture to assist local social development through job and income generation.(AU)

Food-the way to a man's heart: a mini-case series of Campylobacter perimyocarditis.

Campylobacter jejuni enteritis is 1 of the most common causes of food poisoning. Although an infrequent complication, Campylobacter associated perimyocarditis can have fatal consequences. This article illustrates 2 cases. We examine the types of Campylobacter jejuni responsible and report the observed male preponderance of this complication.

Integrins interact with focal adhesions through multiple distinct pathways.

Integrin signaling involves oligomerization and a transmembrane conformational change induced by receptor occupancy. Previous work has shown that subsets of focal adhesion-associated proteins are recruited to integrins as a result of clustering, ligand binding, or both. However, it is unclear whether these discrete subsets reflect the differential binding of cytoplasmic proteins to the integrin or whether a single protein or set of proteins binds the integrin and is differentially activated by receptor occupancy or clustering. To address this question, we made mutations of the beta1 integrin cytoplasmic domain in the context of a single subunit chimera and studied their activation of various known integrin-mediated signaling pathways. We show here that the indirect association of the integrin with actin is distinct from its interactions with both preformed focal adhesions and FAK. Therefore, multiple independent signaling pathways exist from the integrin to the focal adhesion, which may reflect the association of independent factors with the integrin beta1 cytoplasmic domain.

Integrin receptor signaling: the propagation of an alpha-helix model.

Upon ligand binding to integrin receptors, a transmembrane conformation change occurs, which is required for the engagement of the actin cytoskeleton. Integrin receptor latency clearly involves the proximal portions of the alpha and beta cytoplasmic domains. Several experiments suggest that these two regions, which are highly conserved among integrins, may be associated, and this association is the structural basis for latency. We propose that ligand binding leads to a disruption of this association, which allows for the folding of the proximal beta cytoplasmic domain. Thus, in this model, the alpha chain association keeps the beta unfolded, and ligand binding leads to the propagation of an alpha helix from the transmembrane domain through the proximal beta cytoplasmic domain, leading to signal transduction.

The membrane-cytoplasm interface of integrin alpha subunits is critical for receptor latency.

Localization of integrin receptors to focal contact sites occurs upon ligand binding. This activity is latent, since unoccupied integrin receptors do not localize to focal contacts. Deletion analysis has revealed that the alpha cytoplasmic domains is required for the maintenance of integrin receptor latency. Our current hypothesis for the mechanism of integrin post-ligand binding events is that there is a change in relationship of alpha and beta cytoplasmic domains, which overcomes receptor latency. One possible mechanism for such a change would involve the amino acid residues at the membrane-cytoplasm interface. To test this hypothesis, we have produced point mutations in the human integrin alpha 1 subunit. These mutations had no effect on the adhesion via alpha 1 beta 1 to its ligand, collagen IV. However, receptor latency is lost in one of these mutants, leading to constitutive focal contact localization. This effect did not occur in receptors with an exchange of intracellular domains, suggesting that the mechanism of loss of latency involves a relative motion of the integrin chains. These results suggest a model in which post-ligand binding events in integrin receptors are associated with changes in the position of the alpha and beta cytoplasmic domains.