PESTICIDE REGULATION AND THE RULE-MAKING PROCESS

Agricultural and Food Policy,

The impact of peri-natal stress on psychosis risk: Results from the Bo-FEP incidence study

Objective: According to the gene-environment interaction model the pathogenesis of psychosis relies on an adverse neuro-socio-developmental pathway. Perinatal stress represents an important risk factor for the development of psychosis because of the increasingly evident interference with socio-neuro-development in the earlier phases of life. We aim to investigate the correlation of perinatal risk factors with the onset of psychosis with a case-control-incidence study. Results: Patients (and their mothers) were eligible if they presented with first-episode psychosis at the Bologna West Community Mental Health Centre (Bo-West CMHC) between 2002 and 2012. The Bo-West CMHC serves a catchment area of about 200,000 people. The controls were recruited in the same catchment area and study period. 42 patients, 26 controls and their mothers were included. We collected the history of peri-natal stress and calculated crude and adjusted Odds Ratios for onset of first-episode psychosis. Adjusted logistic regression showed that psychosis onset was significantly associated with stressful situations during pregnancy, lower level of maternal physical health before or during pregnancy, use of anti-inflammatory drugs during pregnancy, and low level of maternal education. The results of our study suggest that stress during perinatal period increases the risk of developing psychosis

Computer simulations of hard pear-shaped particles

We report results obtained from Monte Carlo simulations investi- gating mesophase formation in two model systems of hard pear-shaped particles. The first model considered is a hard variant of the trun- cated Stone-Expansion model previously shown to form nematic and smectic mesophases when embedded within a 12-6 Gay-Berne-like po- tential [1]. When stripped of its attractive interactions, however, this system is found to lose its liquid crystalline phases. For particles of length to breadth ratio k = 3, glassy behaviour is seen at high pressures, whereas for k = 5 several bi-layer-like domains are seen, with high intradomain order but little interdomain orientational correlation. For the second model, which uses a parametric shape parameter based on the generalised Gay-Berne formalism, results are presented for particles with elongation k = 3; 4 and 5. Here, the systems with k = 3 and 4 fail to display orientationally ordered phases, but that with k = 5 shows isotropic, nematic and, unusually for a hard-particle model, interdigitated smectic A2 phases.</p

Service composition in stochastic settings

With the growth of the Internet-of-Things and online Web services, more services with more capabilities are available to us. The ability to generate new, more useful services from existing ones has been the focus of much research for over a decade. The goal is, given a specification of the behavior of the target service, to build a controller, known as an orchestrator, that uses existing services to satisfy the requirements of the target service. The model of services and requirements used in most work is that of a finite state machine. This implies that the specification can either be satisfied or not, with no middle ground. This is a major drawback, since often an exact solution cannot be obtained. In this paper we study a simple stochastic model for service composition: we annotate the tar- get service with probabilities describing the likelihood of requesting each action in a state, and rewards for being able to execute actions. We show how to solve the resulting problem by solving a certain Markov Decision Process (MDP) derived from the service and requirement specifications. The solution to this MDP induces an orchestrator that coincides with the exact solution if a composition exists. Otherwise it provides an approximate solution that maximizes the expected sum of values of user requests that can be serviced. The model studied although simple shades light on composition in stochastic settings and indeed we discuss several possible extensions

Obesogenic Environments and Cardiovascular Disease: A Path Analysis Using US Nationally Representative Data

Introduction People living in obesogenic environments, with limited access to healthful food outlets and exercise facilities, generally have poor health. Previous research suggests that behavioral risk factors and indicators of physiological functioning may mediate this link; however, no studies to date have had the requisite data to investigate multi-level behavioral and physiological risk factors simultaneously. The present study conducted serial and parallel mediation analyses to examine behavioral and physiological pathways explaining the association between environmental obesogenicity and cardiovascular disease (CVD). Methods This cross-sectional observational study used data from the 2012–2016 Health and Retirement Study, a representative survey of US older adults (n = 12,482, mean age 65.9). Environmental obesogenicity was operationalized as a combined score consisting of nine environmental measures of food and physical activity. CVD and health-compromising behaviors (diet, alcohol consumption, smoking, and exercise) were self-reported. Physiological dysregulation was assessed with measured blood pressure, heart rate, HbA1c, cholesterol levels, BMI, and C-reactive protein. The Hayes Process Macro was used to examine serial and parallel paths through health-compromising behaviors and physiological dysregulation in the environmental obesogenicity-CVD link. Results People living in more obesogenic environments had greater odds of self-reported CVD (odds ratio = 1.074, 95% confidence interval (CI): 1.028, 1.122), engaged in more health-compromising behaviors (β = 0.026, 95% CI: 0.008, 0.044), and had greater physiological dysregulation (β = 0.035, 95% CI: 0.017, 0.054). Combined, health-compromising behaviors and physiological dysregulation accounted for 7% of the total effects of environmental obesogenicity on CVD. Conclusion Behavioral and physiological pathways partially explain the environmental obesogenicity-CVD association. Obesogenic environments may stymie the success of cardiovascular health-promotion programs by reducing access to resources supporting healthy lifestyles

Multifunctional thiosemicarbazones targeting sigma receptors: in vitro and in vivo antitumor activities in pancreatic cancer models

Purpose: Association of the metal chelating portion of thiosemicarbazone with the cytotoxic activity of sigma-2 receptors appears a promising strategy for the treatment of pancreatic tumors. Here, we developed a novel sigma-2 receptor targeting thiosemicarbazone (FA4) that incorporates a moiety associated with lysosome destabilization and ROS increase in order to design more efficient antitumor agents. Methods: The density of sigma receptors in pancreatic cancer cells was evaluated by flow cytometry. In these cells, cytotoxicity (MTT assay) and activation of ER- and mitochondria-dependent cell death pathways (mRNA expression of GRP78, ATF6, IRE1, PERK; ROS levels by MitoSOX and DCFDA-AM; JC-1 staining) induced by the thiosemicarbazones FA4, MLP44, PS3 and ACthio-1, were evaluated. The expression of autophagic proteins (ATG5, ATG7, ATG12, beclin, p62 and LC3-I) was also studied. In addition, the in vivo effect of FA4 in xenograft models with and without gemcitabine challenge was investigated. Results: We found that FA4 exerted a more potent cytotoxicity than previously studied thiosemicarbazones (MLP44, PS3 and ACthio-1), which were found to display variable effects on the ER or the mitochondria-dependent pro-apoptotic axis. By contrast, FA4 activated pro-apoptotic pathways and decreased autophagy, except in MiaPaCa2 cells, in which autophagic proteins were expressed at lower levels and remained unmodified by FA4. FA4 treatment of PANC-1 xenografted mouse models, poorly responsive to conventional chemotherapy, significantly reduced tumor volumes and increased intratumor apoptosis compared to gemcitabine, with no signs of toxicity. Conclusions: Our data indicate that FA4 exhibits encouraging activity in pancreatic cancer cells unresponsive to gemcitabine. These results warrant further investigation in patient-derived pancreatic cancers, and hold promise for the development of therapies that can more efficiently target the specific characteristics of individual tumor types

Unusual architecture of the p7 channel from hepatitis C virus

The Hepatitis C virus (HCV) has developed a small membrane protein, p7, which remarkably can self-assemble into a large channel complex that selectively conducts cations1-4. We are curious as to what structural solution has the viroporin adopted to afford selective cation conduction because p7 has no homology with any of the known prokaryotic or eukaryotic channel proteins. The p7 activity can be inhibited by amantadine and rimantadine2,5, which also happen to be potent blockers of the influenza M2 channel6 and licensed drugs against influenza infections7. The adamantane derivatives were subjects of HCV clinical trials8, but large variation in drug efficacy among the various HCV genotypes has been difficult to explain without detailed molecular structures. Here, we determined the structures of this HCV viroporin as well as its drug-binding site using the latest nuclear magnetic resonance (NMR) technologies. The structure exhibits an unusual mode of hexameric assembly, where the individual p7 monomers, i, not only interact with their immediate neighbors, but also reach farther to associate with the i+2 and i+3 monomers, forming a sophisticated, funnel-like architecture. The structure also alludes to a mechanism of cation selection: an asparagine/histidine ring that constricts the narrow end of the funnel serves as a broad cation selectivity filter while an arginine/lysine ring that defines the wide end of the funnel may selectively allow cation diffusion into the channel. Our functional investigation using whole-cell channel recording showed that these residues are indeed critical for channel activity. NMR measurements of the channel-drug complex revealed six equivalent hydrophobic pockets between the peripheral and pore-forming helices to which amantadine or rimantadine binds, and compound binding specifically to this position may allosterically inhibit cation conduction by preventing the channel from opening. Our data provide molecular explanation for p7-mediated cation conductance and its inhibition by adamantane derivatives