Novel Benzindoloazecines and Dibenzazecines: synthesis and affinities for the Dopamine receptors

Azecine sind eine neuartige Klasse von Dopaminrezeptor-Antagonisten, gekennzeichnet durch ihre nanomolare Affinitäten an den Dopaminrezeptoren und vor allem ihre Selektivität für die Rezeptoren der D1-Familie. Strukturwirkungsbeziehungen dieser Verbinungsklasse wurde umfassend erforscht. Die Strategie der vorliegenden Arbeit war die Strukturen der Leitverbindungen LE300 und LE404 so zu modifizieren, dass die erforderlichen strukturellen Merkmale weitgehend erhalten werden sollten. Das Benzindoloazecin LE300 wurde vielfältig modifiziert; z.B. durch Veränderung des Annellierungsmusters vom Ringgerüst oder Einfügen eines Substituents an verschiedenen Stellen. Außerdem wurde die phenolische Gruppe der Leitstruktur LE404 vom Dibenzazecin-Typ durch eine Methylendioxygruppe ersetzt. Das Ziel dieser Arbeit war die Strukturwirkungsbeziehungen dieser neuartigen Klasse von Dopaminrezeptor-Antagonisten weiter zu entwickeln, um Derivate mit höheren Affinitäten und besser ausgeprägten Subtypselektivität zu erreichen. Insgesamt wurden 29 Zielverbindungen synthetisiert und die Affinitäten an den verschiedenen Dopaminrezeptoren (human) durch Radioligandbindungsstudien ermittelt. Weiterhin wurde die Funktionalität der Verbindungen (Agonisten oder Antagonisten) mit Hilfe eines Calcium Assays bestimmt

Le décalage entre la communication sociétale et les pratiques de l'entreprise : le cas de l'intérim

The temporary employment sector has greatly democratized in recent decades and generates numerous negative externalities for civil society. Indeed, the temporary employment sector is a source of social vulnerability for the temporary workers, in a society where individuals are socially integrated through their jobs. The temporary employment sector contributes in the precarious of life and work conditions, relegation and social exclusion. To limit these social deviations and internalize societal issues, the temporary work companies (TWC) are encouraged, through extra-financial reporting, to engage in CSR. The TWC value their commitment through a voluntary social communication, which is based in particular on the production of a CSR/Sustainable Development report. The societal communication vehicle commitments by TWC to protect the temporary workers’s interests. The objectives of social communication are numerous : improve the image and the reputation, promote self-regulation activities, allowing continuous access to temporary resources, reduce supervision activities by public authorities, legitimize the existence of ETT despite these negative externalities, generate positive attitudes of stakeholders, contribute to the overall performance and reduce hidden costs due to the staff turnover. The CSR commitment must be deployed within the TWC and arouse the collective membership of the internal stakeholders. However, the academic literature on the CSR commitment in the temporary employment sector is a gap between social communication and the actual practices of TWC. In contrast, this gap causes the opposite effect and generates negative attitudes of stakeholders towards TWC. Given these challenges, the lack of information in the academic literature and the lack of empirical studies on the gap between social communication and the actual practices of TWC led us to formulate our overall research problem. Our research aim to make significant contributions in this emerging area of research.Le secteur de l’intérim s’est fortement démocratisé ces dernières décennies et génère de nombreuses externalités négatives pour la société civile. En effet, l’intérim est source de vulnérabilité sociale pour les intérimaires, dans une société où les individus s'intègrent socialement à travers leur emploi. L’intérim contribue à la précarisation des conditions de vie et de travail, à la relégation et à l’exclusion sociale. Pour limiter ces dérives sociales et internaliser les problématiques sociétales, les entreprises de travail temporaire (ETT) sont incitées, à travers le reporting extra-financier, à s’engager dans une démarche RSE. Les ETT valorisent leur engagement à travers une communication sociétale volontaire, qui repose notamment sur la production d’un rapport RSE/Développement Durable. La communication sociétale véhicule les engagements pris par les ETT pour protéger les intérêts des intérimaires. Les objectifs de la communication sociétale sont multiples : améliorer l’image et la réputation, favoriser l’autorégulation des activités, permettre un accès continu aux ressources intérimaires, diminuer l’encadrement des activités par les pouvoirs publics, légitimer l’existence des ETT malgré ces externalités négatives, générer une attitude positive des parties prenantes, contribuer à la performance globale et diminuer les coûts cachés relatifs au turn-over du personnel. L’engagement RSE doit être déployé au sein des ETT et susciter l’adhésion collective des parties prenantes internes. Cependant, la littérature académique relative à l’engagement RSE dans le secteur de l’intérim relève un décalage entre la communication sociétale et les pratiques réelles des ETT. Par contraste, ce décalage provoque des effets inverses et génère une attitude négative des parties prenantes envers les ETT. Compte tenu de ces enjeux, le manque d’informations dans la littérature académique ainsi que l’absence d’études empiriques relatives au décalage entre la communication sociétale et les pratiques réelles des ETT nous ont conduits à formuler notre problématique de recherche générale. Nos travaux de recherche ont pour objectif d’apporter des contributions significatives dans ce domaine de recherche émergent

Pyrido- and benzisothiazolones as inhibitors of histone acetyltransferases (HATs)

Histone acetyltransferases (HATs) are interesting targets for the treatment of cancer and HIV infections but reports on selective inhibitors are very limited. Here we report structure–activity studies of pyrido- and benzisothiazolones in the in vitro inhibition of histone acetyltransferases, namely PCAF, CBP, Gcn5 and p300 using a heterogeneous assay with antibody mediated quantitation of the acetylation of a peptidic substrate. Dependent on the chemical structure distinct subtype selectivity profiles can be obtained. While N-aryl derivatives usually are rather pan-HAT inhibitors, N-alkyl derivatives show mostly a preference for CBP/p300. Selected compounds were also shown to be inhibitors of MOF. The best inhibitors show submicromolar inhibition of CBP. Selected compounds affect growth of HL-60 leukemic cells and LNCaP prostate carcinoma cells with higher potency on the leukemic cells. Target engagement was shown with reduction of histone acetylation in LNCaP cells

Flow-duration curve integration into digital filtering algorithms for simulating climate variability based on river baseflow

A baseflow separation methodology combining the outcomes of the flow–duration curve and the digital filtering algorithms to cope with the restrictions of the traditional procedures has been assessed. Using this methodology as well as the monitored and simulated hydro-climatologic data, the baseflow annual variations due to climate change and human-induced activities were determined. The outcomes show that the long-term baseflow index at the upstream sub-basin is nearly half of that at the downstream from October to April, whereas, they are close to each other for the remaining months. Some of the groundwater reacts to precipitation and an evident rise in the groundwater contribution has been detected for the hydrological years 1998–2001 and 2006–2008. The contrary has been recorded for 1987. The water released from the reservoir in the dry periods lead to distinctions in the detected baseflow index between the pre-damming and post-damming periods of the river

An integrated study of urban microclimates in Chongqing, China: historical weather data, transverse measurement and numerical simulation

Chongqing is the largest central-government-controlled municipality in China, which is now under going a rapid urbanization. The question remains open: What are the consequences of such rapid urbanization in Chongqing in terms of urban microclimates? An integrated study comprising three different research approaches is adopted in the present paper. By analyzing the observed annual climate data, an average rising trend of 0.10◦C/decade was found for the annual mean temperature from 1951 to 2010 in Chongqing,indicating a higher degree of urban warming in Chongqing. In addition, two complementary types of field measurements were conducted: fixed weather stations and mobile transverse measurement. Numerical simulations using a house-developed program are able to predict the urban air temperature in Chongqing.The urban heat island intensity in Chongqing is stronger in summer compared to autumn and winter.The maximum urban heat island intensity occurs at around midnight, and can be as high as 2.5◦C. In the day time, an urban cool island exists. Local greenery has a great impact on the local thermal environment.Urban green spaces can reduce urban air temperature and therefore mitigate the urban heat island. The cooling effect of an urban river is limited in Chongqing, as both sides of the river are the most developed areas, but the relative humidity is much higher near the river compared with the places far from it

New model to estimate daily global solar radiation over Nigeria

This study focussed on developing an appropriate model for estimating daily global solar radiation for any location in Nigeria. Data for the study were obtained from the Nigeria Meteorological Agency, covering 12 sites, spread across the six geopolitical zones, for a period between 1987 and 2010. Various statistical methods were employed to determine the performance and accuracy of the model. A multivariate model that expresses global solar irradiance in terms of location latitude, daily relative sunshine, maximum daily temperature, daily average relative humidity, and cosine of day number was developed. The inclusion of the maximum daily temperature and daily mean relative humidity makes the model much more sensitive to climatic and weather changes. Also, the seasonal fluctuations of the humid tropical region are also well captured in the model. The analysis showed a good agreement between the measured data and computed results. Thus the model can be used to predict the global solar irradiance over Nigeria with minimum error. Further to this, the global solar radiation intensity values produced by this approach can be used in the design and estimation of the performance of solar applications

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ) and, due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935, which was used to treat schistosomula and adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 binds to the catalytic pocket of SmLSD1. Western blot analysis revealed that MC3935 inhibited SmLSD1 demethylation activity of H3K4me1/2. Knockdown of SmLSD1 by RNAi recapitulated MC3935 phenotypes in adult worms. RNA-Seq analysis of MC3935-treated parasites revealed significant differences in gene expression related to critical biological processes. Collectively, our findings show that SmLSD1 is a promising drug target for the treatment of schistosomiasis and strongly support the further development and in vivo testing of selective schistosome LSD1 inhibitors

Climate change and anthropogenic intervention impact on the hydrologic anomalies in a semi-arid area : lower Zab river basin, Iraq

Climate change impact, drought phenomena and anthropogenic stress are of increasing apprehension for water resource managers and strategists, particularly in arid regions. The current study proposes a generic methodology to evaluate the potential impact of such changes at a basin scale. The Lower Zab River Basin located in the north of Iraq has been selected for illustration purposes. The method has been developed through evaluating changes during normal hydrological years to separate the effects of climate change and estimate the hydrologic abnormalities utilising Indicators of Hydrologic Alteration. The meteorological parameters were perturbed by applying adequate delta perturbation climatic scenarios. Thereafter, a calibrated rainfall-runoff model was used for streamflow simulations. Findings proved that climate change has a more extensive impact on the hydrological characteristics of the streamflow than anthropogenic intervention (i.e. the construction of a large dam in the catchment). The isolated baseflow is more sensitive to the precipitation variations than to the variations of the potential evapotranspiration. The current hydrological anomalies are expected to continue. This comprehensive basin study demonstrates how climate change impact, anthropogenic intervention as well as hydro-climatic drought and hydrological anomalies can be evaluated with a new methodology

Nocturnal Surface Urban Heat Island over Greater Cairo: Spatial Morphology, Temporal Trends and Links to Land-Atmosphere Influences

This study assesses the spatial and temporal characteristics of nighttime surface urban heat island (SUHI) effects over Greater Cairo: the largest metropolitan area in Africa. This study employed nighttime land surface temperature (LST) data at 1 km resolution from the Moderate Resolution Imaging Spectroradiometer (MODIS) Aqua sensor for the period 2003–2019. We presented a new spatial anomaly algorithm, which allowed to define SUHI using the most anomalous hotspot and cold spot of LST for each time step over Greater Cairo between 2003 and 2019. Results demonstrate that although there is a significant increase in the spatial extent of SUHI over the past two decades, a significant decrease in the mean and maximum intensities of SUHI was noted. Moreover, we examined the dependency between SUHI characteristics and related factors that influence energy and heat fluxes between atmosphere and land in urban environments (e.g., surface albedo, vegetation cover, climate variability, and land cover/use changes). Results demonstrate that the decrease in the intensity of SUHI was mainly guided by a stronger warming in daytime and nighttime LST in the neighborhood of urban localities. This warming was accompanied by a decrease in surface albedo and diurnal temperature range (DTR) over these areas. Results of this study can provide guidance to local urban planners and decision-makers to adopt more effective mitigation strategies to diminish the negative impacts of urban warming on natural and human environments.</jats:p

Climate variability impact on the spatiotemporal characteristics of drought and aridity in arid and semi-arid regions

Investigating the spatiotemporal distribution of climate data and their impact on the allocation of the regional aridity and meteorological drought, particularly in semi-arid and arid climate, it is critical to evaluate the climate variability effect and propose sufficient adaptation strategies. The coefficient of variation, precipitation concentration index and anomaly index were used to evaluate the climate variability, while the Mann-Kendall and Sen’s slope were applied for trend analysis, together with homogeneity tests. The aridity was evaluated using the alpha form of the reconnaissance drought index (Mohammed & Scholz, Water Resour Manag 31(1):531–538, 2017c), whereas drought episodes were predicted by applying three of the commonly used meteorological drought indices, which are the standardised reconnaissance drought index, standardized precipitation index and standardized precipitation evapotranspiration index. The Upper Zab River Basin (UZRB), which is located in the northern part of Iraq and covers a high range of climate variability, has been considered as an illustrative basin for arid and semi-arid climatic conditions. There were general increasing trends in average temperature and potential evapotranspiration and decreasing trends in precipitation from the upstream to the downstream of the UZRB. The long-term analysis of climate data indicates that the number of dry years has temporally risen and the basin has experienced succeeding years of drought, particularly after 1994/1995. There was a potential link between drought, aridity and climate variability. Pettitt’s, SNHT, Buishand’s and von Neumann’s homogeneity test results demonstrated that there is an evident alteration in the mean of the drought and aridity between the pre- and post-alteration point (1994)