Evocative gene-environment correlation between genetic risk for schizophrenia and bullying victimization

Bullying exposure concerns over 10% of adolescents in Europe. Moreover, bullying victimization is heritable and victims are liable to psychotic symptoms, partly because of shared heritability with psychosis. The genetic component of bullying victimization has been proposed to involve the social reactions elicited by victims – a mechanism called “evocative gene-environment correlation”. We hypothesized that genetic risk for schizophrenia, a heritable disease also associated with social stress during childhood and adolescence, is related with social experiences during adolescence and is involved in the risk of developing psychotic symptoms. We studied 908 individuals of the TRAILS sample and found that 13-14-year-old adolescents with greater genetic risk for schizophrenia are more exposed to bullying assessed via peer nomination scores than their peers with lower genetic risk. Importantly, bullying victimization mediated the path from genetic risk to the frequency of psychotic symptoms about three years later. These findings provide evidence of a previously unreported form of gene-environment interplay that may be a mechanism of risk for psychosis and schizophrenia. To the extent that genetic risk translation into clinical symptoms is mediated by environmental risk factors, this evidence supports mental health prevention aimed at antagonizing bullying victimization in vulnerable individuals

Cyclooxygenase-2 inhibitors. 1,5-diarylpyrrol-3-acetic esters with enhanced inhibitory activity toward cyclooxygenase-2 and improved cyclooxygenase-2/cyclooxygenase-1 selectivity.

he important role of cyclooxygenase-2 (COX-2) in the pathogenesis of inflammation and side effect limitations of current COX-2 inhibitor drugs illustrates a need for the design of new compounds based on alternative structural templates. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, along with their inhibitory activity toward COX enzymes. Several compounds proved to be highly selective COX-2 inhibitors and their affinity data were rationalized through docking simulations. In this paper, we describe the synthesis of new 1,5-diarylpyrrole derivatives that were assayed for their in vitro inhibitory effects toward COX isozymes. Among them, the ethyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-fluorophenyl]-1H-pyrrol-3- acetate (1d), which was the most potent and COX-2 selective compound, also showed a very interesting in vivo anti-inflammatory and analgesic activity, laying the foundations for developing new lead compounds that could be effective agents in the armamentarium for the management of inflammation and pain

Synthesis, in vitro, and in vivo biological evaluation and molecular docking simulations of chiral alcohol and ether derivatives of the 1,5-diarylpyrrole scaffold as novel anti-inflammatory and analgesic agents.

Following our previous research on anti-inflammatory drugs (NSAIDs), we report here the synthesis of chiral 1,5-diarylpyrroles derivatives that were characterized for their in vitro inhibitory effects toward cyclooxygenase (COX) isozymes. Analysis of enzymatic affinity and COX-2 selectivity led us to the selection of one compound (+/-)-10b that was further tested in vitro in the human whole blood (HWB) and in vivo for its anti-inflammatory activity in mice. The affinity data have been rationalized through docking simulations

2-(4-(Biphenyl-4-ylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (HZ52) - a novel type 5-lipoxygenase inhibitor with favorable molecular pharmacology and efficacy in vivo.

BACKGROUND AND PURPOSE: 5-Lipoxygenase (5-LO) is the key enzyme in the biosynthesis of pro-inflammatory leukotrienes (LTs) representing a potential target for pharmacological intervention with inflammation and allergic disorders. Although many LT synthesis inhibitors are effective in simple in vitro test systems, they frequently fail in vivo due to lack of efficacy. Here, we attempted to assess the pharmacological potential of the previously identified 5-LO inhibitor 2-(4-(biphenyl-4-ylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (HZ52). EXPERIMENTAL APPROACH: We evaluated the efficacy of HZ52 in vivo using carrageenan-induced pleurisy in rats and platelet-activating factor (PAF)-induced lethal shock in mice. We also characterized 5-LO inhibition by HZ52 at the cellular and molecular level in comparison with other types of 5-LO inhibitor, that is, BWA4C, ZM230487 and hyperforin. KEY RESULTS: HZ52, 1.5 mg·kg⁻¹ i.p., prevented carrageenan-induced pleurisy accompanied by reduced LTB(4) levels and protected mice (10 mg·kg⁻¹, i.p.) against PAF-induced shock. Detailed analysis in cell-based and cell-free assays revealed that inhibition of 5-LO by HZ52 (i) does not depend on radical scavenging properties and is reversible; (ii) is not impaired by an increased peroxide tone or by elevated substrate concentrations; and (iii) is little affected by the cell stimulus or by phospholipids, glycerides, membranes or Ca²⁺. CONCLUSIONS AND IMPLICATIONS: HZ52 is a promising new type of 5-LO inhibitor with efficacy in vivo and with a favourable pharmacological profile. It possesses a unique 5-LO inhibitory mechanism different from classical 5-LO inhibitors and seemingly lacks the typical disadvantages of former classes of LT synthesis blockers

A study on the Abruzzo 6 April 2009 earthquake by applying the RST approach to 15 years of AVHRR TIR observations

A self adaptive approach (RST, Robust Satellite Technique) has been proposed as a suitable tool for satellite TIR surveys in seismically active regions devoted to detect and monitor thermal anomalies possibly related to earthquake occurrence. In this work, RST approach has been applied to 15 years of AVHRR (Advanced Very High Resolution Radiometer) thermal infrared observations in order to study the 6 April 2009 Abruzzo earthquake. Preliminary results show clear differences in TIR anomalies occurrence during the periods used for validation (15 March–15 April 2009) and the one (15 March–15 April 2008) without earthquakes with <i>M</i><sub>L</sub>≥4.5, used for confutation purposes. Quite clear TIR anomalies appears also to mark main tectonic lineaments during the preparatory phases of others, low magnitude(3.9<<i>M</i><sub>L</sub><4.6) earthquakes, occurred in the area in the same period

Monitoring soil wetness variations by means of satellite passive microwave observations: the HYDROPTIMET study cases

International audienceSoil moisture is an important component of the hydrological cycle. In the framework of modern flood warning systems, the knowledge of soil moisture is crucial, due to the influence on the soil response in terms of infiltration-runoff. Precipitation-runoff processes, in fact, are related to catchment's hydrological conditions before the precipitation. Thus, an estimation of these conditions is of significant importance to improve the reliability of flood warning systems. Combining such information with other weather-related satellite products (i.e. rain rate estimation) might represent a useful exercise in order to improve our capability to handle (and possibly mitigate or prevent) hydro-geological hazards. Remote sensing, in the last few years, has supported several techniques for soil moisture/wetness monitoring. Most of the satellite-based techniques use microwave data, thanks to the all-weather and all-time capability of these data, as well as to their high sensitivity to water content in the soil. On the other hand, microwave data are unfortunately highly affected by the presence of surface roughness or vegetation coverage within the instantaneous satellite field of view (IFOV). Those problems, consequently, strongly limit the efficiency and the reliability of traditional satellite techniques. Recently, using data coming from AMSU (Advanced Microwave Sounding Unit), flying aboard NOAA (National Oceanic and Atmospheric Administration) satellites, a new methodology for soil wetness estimation has been proposed. The proposed index, called Soil Wetness Variation Index (SWVI), developed by a multi-temporal analysis of AMSU records, seems able to reduce the problems related to vegetation and/or roughness effects. Such an approach has been tested, with promising results, on the analysis of some flooding events which occurred in Europe in the past. In this study, results achieved for the HYDROPTIMET test cases will be analysed and discussed in detail. This analysis allows us to evaluate the reliability and the efficiency of the proposed technique in identifying different amounts of soil wetness variations in different observational conditions. In particular, the proposed indicator was able to document the actual effects of meteorological events, in terms of space-time evolution of soil wetness changes, for all the analysed HYDROPTIMET test cases. Moreover, in some circumstances, the SWVI was able to identify the presence of a sort of "early" signal in terms of soil wetness variations, which may be regarded as a timely indication of an anomalous value of soil water content. This evidence suggests the opportunity to use such an index in the pre-operational phases of the modern flood warning systems, in order to improve their forecast capabilities and their reliability

Monitoring soil wetness variations by means of satellite passive microwave observations: the HYDROPTIMET study cases

Soil moisture is an important component of the hydrological cycle. In the framework of modern flood warning systems, the knowledge of soil moisture is crucial, due to the influence on the soil response in terms of infiltration-runoff. Precipitation-runoff processes, in fact, are related to catchment's hydrological conditions before the precipitation. Thus, an estimation of these conditions is of significant importance to improve the reliability of flood warning systems. Combining such information with other weather-related satellite products (i.e. rain rate estimation) might represent a useful exercise in order to improve our capability to handle (and possibly mitigate or prevent) hydro-geological hazards. <P style='line-height: 20px;'> Remote sensing, in the last few years, has supported several techniques for soil moisture/wetness monitoring. Most of the satellite-based techniques use microwave data, thanks to the all-weather and all-time capability of these data, as well as to their high sensitivity to water content in the soil. On the other hand, microwave data are unfortunately highly affected by the presence of surface roughness or vegetation coverage within the instantaneous satellite field of view (IFOV). Those problems, consequently, strongly limit the efficiency and the reliability of traditional satellite techniques. <P style='line-height: 20px;'> Recently, using data coming from AMSU (Advanced Microwave Sounding Unit), flying aboard NOAA (National Oceanic and Atmospheric Administration) satellites, a new methodology for soil wetness estimation has been proposed. The proposed index, called Soil Wetness Variation Index (<I>SWVI</I>), developed by a multi-temporal analysis of AMSU records, seems able to reduce the problems related to vegetation and/or roughness effects. Such an approach has been tested, with promising results, on the analysis of some flooding events which occurred in Europe in the past. <P style='line-height: 20px;'> In this study, results achieved for the HYDROPTIMET test cases will be analysed and discussed in detail. This analysis allows us to evaluate the reliability and the efficiency of the proposed technique in identifying different amounts of soil wetness variations in different observational conditions. In particular, the proposed indicator was able to document the actual effects of meteorological events, in terms of space-time evolution of soil wetness changes, for all the analysed HYDROPTIMET test cases. Moreover, in some circumstances, the <I>SWVI</I> was able to identify the presence of a sort of 'early' signal in terms of soil wetness variations, which may be regarded as a timely indication of an anomalous value of soil water content. This evidence suggests the opportunity to use such an index in the pre-operational phases of the modern flood warning systems, in order to improve their forecast capabilities and their reliability

Assessing the potential of <i>SWVI</i> (Soil Wetness Variation Index) for hydrological risk monitoring by means of satellite microwave observations

International audienceIn the last years satellite remote sensing applications in hydrology have considerably progressed. A new multi-temporal satellite data-analysis approach has been recently suggested in order to estimate space-time changes of geophysical parameters possibly related to the increase of environmental and hydro-geological hazards. Such an approach has been already used both for flooded area mapping (using AVHRR data) and for soil wetness index estimation (using AMSU data). In this work, a preliminary sensitivity analysis of the proposed Soil Wetness Variation Index (SWVI) is made in the case of low intensity meteorological events by the comparison with hydrological (precipitation) data. This analysis, as a first step of a more complex work in progress, is targeted to a first evaluation of the reliability of the SWVI in describing soil response to precipitations of different duration and intensity

Urinary MicroRNA Profiling in the Nephropathy of Type 1 Diabetes

Background: Patients with Type 1 Diabetes (T1D) are particularly vulnerable to development of Diabetic nephropathy (DN) leading to End Stage Renal Disease. Hence a better understanding of the factors affecting kidney disease progression in T1D is urgently needed. In recent years microRNAs have emerged as important post-transcriptional regulators of gene expression in many different health conditions. We hypothesized that urinary microRNA profile of patients will differ in the different stages of diabetic renal disease. Methods and Findings: We studied urine microRNA profiles with qPCR in 40 T1D with >20 year follow up 10 who never developed renal disease (N) matched against 10 patients who went on to develop overt nephropathy (DN), 10 patients with intermittent microalbuminuria (IMA) matched against 10 patients with persistent (PMA) microalbuminuria. A Bayesian procedure was used to normalize and convert raw signals to expression ratios. We applied formal statistical techniques to translate fold changes to profiles of microRNA targets which were then used to make inferences about biological pathways in the Gene Ontology and REACTOME structured vocabularies. A total of 27 microRNAs were found to be present at significantly different levels in different stages of untreated nephropathy. These microRNAs mapped to overlapping pathways pertaining to growth factor signaling and renal fibrosis known to be targeted in diabetic kidney disease. Conclusions: Urinary microRNA profiles differ across the different stages of diabetic nephropathy. Previous work using experimental, clinical chemistry or biopsy samples has demonstrated differential expression of many of these microRNAs in a variety of chronic renal conditions and diabetes. Combining expression ratios of microRNAs with formal inferences about their predicted mRNA targets and associated biological pathways may yield useful markers for early diagnosis and risk stratification of DN in T1D by inferring the alteration of renal molecular processes. © 2013 Argyropoulos et al