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

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)

Lysine deacetylase inhibitors in parasites: past, present, and future perspectives.

Current therapies for human parasite infections rely on a few drugs, most of which have severe side effects, and their helpfulness is being seriously compromised by the drug resistance problem. Globally, this is pushing discovery research of antiparasitic drugs toward new agents endowed with new mechanisms of action. By using a "drug repurposing" strategy, histone deacetylase inhibitors (HDACi), which are presently clinically approved for cancer use, are now under investigation for various parasite infections. Because parasitic Zn2+- and NAD+-dependent HDACs play crucial roles in the modulation of parasite gene expression and many of them are pro-survival for several parasites under various conditions, they are now emerging as novel potential antiparasitic targets. This Perspective summarizes the state of knowledge of HDACi (both class I/II HDACi and sirtuin inhibitors) targeted to the main human parasitic diseases (schistosomiasis, malaria, trypanosomiasis, leishmaniasis, and toxoplasmosis) and provides visions into the main issues that challenge their development as antiparasitic agents

Preclinical Evaluation of Benzazepine-Based PET Radioligands (R)- and (S)-11C-Me-NB1 Reveals Distinct Enantiomeric Binding Patterns and a Tightrope Walk Between GluN2B- and σ1-Receptor–Targeted PET Imaging

The study aims to investigate the performance characteristics of the enantiomers of 11C-Me-NB1, a recently reported PET imaging probe that targets the GluN2B subunit of N-methyl-d-aspartate (NMDA) receptors. Methods: Reference compound Me-NB1 (inhibition constant for hGluN1/GluN2B, 5.4 nM) and the phenolic precursor were prepared via multistep synthesis. Following chiral resolution by high-performance liquid chromatography, enantiopure precursor compounds, (R)-NB1 and (S)-NB1, were labeled with 11C and validated in rodents using in vitro/ex vivo autoradiography, PET experiments, and dose-response studies. To illustrate the translational relevance, (R)- 11C-Me-NB1 was validated in autoradiographic studies using postmortem human GluN2B-rich cortical and GluN2B-deficient cerebellar brain slices. To determine target engagement, receptor occupancy was assessed at different plasma concentrations of CP101,606, a GluN2B receptor antagonist. Results: The radiosynthesis of (R)- and (S)- 11C-Me-NB1 was accomplished in 42% ± 9% (decay-corrected) radiochemical yields. Molar activity ranged from 40 to 336 GBq/μmol, and an excellent radiochemical purity of greater than 99% was achieved. Although (R)- 11C-Me-NB1 displayed heterogeneous accumulation with high selectivity for the GluN2B-rich forebrain, (S)- 11C-Me-NB1 revealed a homogeneous distribution across all brain regions in rodent brain autoradiograms and predominantly exhibited σ1-receptor binding. Similar to rodent brain, (R)- 11C-Me-NB1 showed in postmortem human brain tissues higher binding in the cortex than in the cerebellum. Coincubation of the GluN2B-antagonist CERC-301 (1 μM) reduced cortical but not cerebellar binding, demonstrating the specificity of (R)- 11C-Me-NB1 binding to the human GluN2B-containing NMDA receptor. In vivo specificity of (R)- 11C-Me-NB1 in the GluN2B-expressing cortex, striatum, thalamus, and hippocampus was demonstrated by PET imaging in rodents. Applying GluN2B-antagonist eliprodil, an evident dose-response behavior was observed with (R)- 11C-Me-NB1 but not with (S)- 11C-Me-NB1. Our findings further underline the tightrope walk between GluN2B- and σ1-receptor-targeted imaging, illustrated by the entirely different receptor binding behavior of the 2 radioligand enantiomers. Conclusion: (R)- 11C-Me-NB1 is a highly selective and specific PET radioligand for imaging the GluN2B subunit of the NMDA receptor. The entirely different receptor binding behavior of (R)- 11C-Me-NB1 and (S)- 11C-Me-NB1 raises awareness of a delicate balance that is underlying the selective targeting of either GluN2B-carrying NMDA or σ1-receptors

Photochromic histone deacetylase inhibitors based on dithienylethenes and fulgimides

Histone deacetylases (HDACs) play a crucial role in numerous biological processes and therefore are targeted in anticancer research and in the field of epigenetics. Dithienylethenes (DTEs) and fulgimides were functionalized with hydroxamic acids, which is a known moiety binding to zinc dependent HDACs, to gain photoswitchable HDAC inhibitors. The new DTE based inhibitors showed moderate photochromic properties in polar solvents and the inhibitory activity changes up to a factor of four. The photochromic performance of the prepared fulgimide inhibitors was very good, even in aqueous buffer. They achieved a maximum three-fold difference in inhibitory activity. Docking experiments using the crystal structures of the tested enzymes gave a rationale for the observed moderate differences in activities of the inhibitors

Selective agonist of TRPML2 reveals direct role in chemokine release from innate immune cells

Cytokines and chemokines are produced and secreted by a broad range of immune cells including macrophages. Remarkably, little is known about how these inflammatory mediators are released from the various immune cells. Here, the endolysosomal cation channel TRPML2 is shown to play a direct role in chemokine trafficking and secretion from murine macrophages. To demonstrate acute and direct involvement of TRPML2 in these processes, the first isoform-selective TRPML2 channel agonist was generated, ML2-SA1. ML2-SA1 was not only found to directly stimulate release of the chemokine CCL2 from macrophages but also to stimulate macrophage migration, thus mimicking CCL2 function. Endogenous TRPML2 is expressed in early/recycling endosomes as demonstrated by endolysosomal patch-clamp experimentation and ML2-SA1 promotes trafficking through early/recycling endosomes, suggesting CCL2 being transported and secreted via this pathway. These data provide a direct link between TRPML2 activation, CCL2 release and stimulation of macrophage migration in the innate immune response