Behavioural evidence for parallel outcome-sensitive and outcome-insensitive Pavlovian learning systems in humans

There is a dichotomy in instrumental conditioning between goal-directed actions and habits that are distinguishable on the basis of their relative sensitivity to changes in outcome value. It is less clear whether a similar distinction applies in Pavlovian conditioning, where responses have been found to be predominantly outcome-sensitive. To test for both devaluation-insensitive and devaluation-sensitive Pavlovian conditioning in humans, we conducted four experiments combining Pavlovian conditioning and outcome-devaluation procedures while measuring multiple conditioned responses. Our results suggest that Pavlovian conditioning involves two distinct types of learning: one that learns the current value of the outcome, which is sensitive to devaluation, and one that learns about the spatial localization of the outcome, which is insensitive to devaluation. Our findings have implications for the mechanistic understanding of Pavlovian conditioning and provide a more nuanced understanding of Pavlovian mechanisms that might contribute to a number of psychiatric disorders

Behavioural evidence for parallel outcome-sensitive and outcome-insensitive Pavlovian learning systems in humans

There is a dichotomy in instrumental conditioning between goal-directed actions and habits that are distinguishable on the basis of their relative sensitivity to changes in outcome value. It is less clear whether a similar distinction applies in Pavlovian conditioning, where responses have been found to be predominantly outcome-sensitive. To test for both devaluation-insensitive and devaluation-sensitive Pavlovian conditioning in humans, we conducted four experiments combining Pavlovian conditioning and outcome-devaluation procedures while measuring multiple conditioned responses. Our results suggest that Pavlovian conditioning involves two distinct types of learning: one that learns the current value of the outcome, which is sensitive to devaluation, and one that learns about the spatial localization of the outcome, which is insensitive to devaluation. Our findings have implications for the mechanistic understanding of Pavlovian conditioning and provide a more nuanced understanding of Pavlovian mechanisms that might contribute to a number of psychiatric disorders

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.</p

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Averting biodiversity collapse in tropical forest protected areas

The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon¹⁻³. With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses⁴⁻⁹. As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world’s major tropical regions. Our analysis reveals great variation in reserve ‘health’: about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.Keywords: Ecology, Environmental scienc

Molecular characterization of the Aspergillus nidulans fbxA encoding an F-box protein involved in xylanase induction

The filamentous fungus Aspergillus nidulans has been used as a fungal model system to study the regulation of xylanase production. These genes are activated at transcriptional level by the master regulator the transcriptional factor XInR and repressed by carbon catabolite repression (CCR) mediated by the wide-domain repressor CreA. Here, we screened a collection of 42 A. nidulans F-box deletion mutants grown either in xylose or xylan as the single carbon source in the presence of the glucose analog 2-deoxy-D-glucose, aiming to identify mutants that have deregulated xylanase induction. We were able to recognize a null mutant in a gene (fbxA) that has decreased xylanase activity and reduced xInA and xInD mRNA accumulation. The Delta fbxA mutant interacts genetically with creAd-30, creB15, and creC27 mutants. FbxA is a novel protein containing a functional F-box domain that binds to Skp1 from the SCF-type ligase. Blastp analysis suggested that FbxA is a protein exclusive from fungi, without any apparent homologs in higher eukaryotes. Our work emphasizes the importance of the ubiquitination in the A. nidulans xylanase induction and CCR. The identification of FbxA provides another layer of complexity to xylanase induction and CCR phenomena in filamentous fungi. (C) 2011 Elsevier Inc. All rights reserved.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), BrazilConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazil [Universal 475393/2009-0, GENOPROT 42/2009]Deutsche Forschungsgemeinschaft (DFG), GermanyDeutsche Forschungsgemeinschaft (DFG), German

Molecular genetic mechanisms of allelic specific regulation of murine Comt expression

A functional allele of the mouse catechol-O-methyltransferase (Comt) gene is defined by the insertion of a B2 short interspersed repeat element in its 3′-untranslated region (UTR). This allele has been associated with a number of phenotypes, such as pain and anxiety. In comparison with mice carrying the ancestral allele (Comt(+)), Comt(B2i) mice show higher Comt mRNA and enzymatic activity levels. Here, we investigated the molecular genetic mechanisms underlying this allelic specific regulation of Comt expression. Insertion of the B2 element introduces an early polyadenylation signal generating a shorter Comt transcript, in addition to the longer ancestral mRNA. Comparative analysis and in silico prediction of Comt mRNA potential targets within the transcript 3′ to the B2 element was performed and allowed choosing microRNA (miRNA) candidates for experimental screening: mmu-miR-3470a, mmu-miR-3470b, and mmu-miR-667. Cell transfection with each miRNA downregulated the expression of the ancestral transcript and COMT enzymatic activity. Our in vivo experiments showed that mmu-miR-667-3p is strongly correlated with decreasing amounts of Comt mRNA in the brain, and lentiviral injections of mmu-miR-3470a, mmu-miR-3470b, and mmu-miR-667 increase hypersensitivity in the mouse formalin model, consistent with reduced COMT activity. In summary, our data demonstrate that the Comt(+) transcript contains regulatory miRNA signals in its 3′-untranslated region leading to mRNA degradation; these signals, however, are absent in the shorter transcript, resulting in higher mRNA expression and activity levels

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.</p

Flora vascular não-arbórea de uma floresta de grota na Serra da Mantiqueira, Zona da Mata de Minas Gerais, Brasil

A região da Serra Negra constitui um importante remanescente de floresta atlântica situado no sul da Zona da Mata mineira, na Serra da Mantiqueira, composta por um mosaico de campos rupestres (nos afloramentos de quartzito) a arbustais nebulares, florestas estacionais semideciduifólias a perenifólias e florestas nebulares, de ambientes inferomontanos a superomontanos ripícolas a interfluviais. A área de estudo é um fragmento de floresta de grota (floresta perenifólia ripícola), de aproximadamente 0,9 ha, situada no Cânion do Ribeirão do Funil, na Vila do Funil, município de Rio Preto, localizada no sul da Serra Negra. O presente trabalho foi realizado entre os anos de 2004 e 2009 e teve como objetivos o conhecimento da flora vascular não-arbórea, a discussão dos hábitos e habitats das plantas e a descrição da fisionomia do fragmento. Foram registrados 157 táxons de plantas vasculares (sendo 41 pteridófitas e 116 angiospermas), pertencentes a 48 famílias (10 de pteridófitas e 38 de angiospermas). As famílias de maior riqueza específica foram Orchidaceae, dentre as angiospermas, com 27 espécies e Pteridaceae, dentre as pteridófitas, apresentando 11 espécies. O hábito mais representativo foi o herbáceo (124 spp.), destacando-se as espécies epífitas (42 spp.), que perfazem cerca de 25% de todas as espécies registradas na área. Doze espécies estão incluídas na lista de espécies ameaçadas de extinção no estado de Minas Gerais (duas pteridófitas e 10 angiospermas). O elevado número de espécies encontradas em uma área consideravelmente pequena ressalta a importância deste fragmento para a diversidade da Serra Negra e aponta para a necessidade de implantação de um plano de ação para sua conservação