N-Nitrosodimethylamine investigations in Muta™Mouse define point-of-departure values and demonstrate less-than-additive somatic mutant frequency accumulations.

The N-nitrosamine, N-nitrosodimethylamine (NDMA), is an environmental mutagen and rodent carcinogen. Small levels of NDMA have been identified as an impurity in some commonly used drugs, resulting in several product recalls. In this study, NDMA was evaluated in an OECD TG-488 compliant Muta™Mouse gene mutation assay (28-day oral dosing across seven daily doses of 0.02-4 mg/kg/day) using an integrated design that assessed mutation at the transgenic lacZ locus in various tissues and at the endogenous Pig-a gene-locus, along with micronucleus frequencies in peripheral blood. Liver pathology was determined together with NDMA exposure in blood and liver. The additivity of mutation induction was assessed by including two acute single-dose treatment groups (i.e. 5 and 10 mg/kg dose on Day 1), which represented the same total dose as two of the repeat dose treatment groups. NDMA did not induce statistically significant increases in mean lacZ mutant frequency (MF) in bone marrow, spleen, bladder, or stomach, nor in peripheral blood (Pig-a mutation or micronucleus induction) when tested up to 4 mg/kg/day. There were dose-dependent increases in mean lacZ MF in the liver, lung, and kidney following 28-day repeat dosing or in the liver and kidney after a single dose (10 mg/kg). No observed genotoxic effect levels (NOGEL) were determined for the positive repeat dose-response relationships. Mutagenicity did not exhibit simple additivity in the liver since there was a reduction in MF following NDMA repeat dosing compared with acute dosing for the same total dose. Benchmark dose modelling was used to estimate point of departure doses for NDMA mutagenicity in Muta™Mouse and rank order target organ tissue sensitivity (liver > kidney or lung). The BMD50 value for liver was 0.32 mg/kg/day following repeat dosing (confidence interval 0.21-0.46 mg/kg/day). In addition, liver toxicity was observed at doses of ≥ 1.1 mg/kg/day NDMA and correlated with systemic and target organ exposure. The integration of these results and their implications for risk assessment are discussed.

Topology regulatory elements: From shaping genome architecture to gene regulation.

The importance of 3D genome topology in the control of gene expression is becoming increasingly apparent, while regulatory mechanisms remain incompletely understood. Several recent studies have identified architectural elements that influence developmental gene expression by shaping locus topology. We refer to these elements as topological regulatory elements (TopoREs) to reflect their dual roles in genome organisation and gene expression. Importantly, these elements do not harbour autonomous transcriptional activation capacity, and instead appear to facilitate enhancer-promoter interactions, contributing to robust and precise timing of transcription. We discuss examples of TopoREs from two classes that are either dependent or independent of CTCF binding. Importantly, identification and interpretation of TopoRE function may shed light on multiple aspects of gene regulation, including the relationship between enhancer-promoter proximity and transcription, and enhancer-promoter specificity. Ultimately, understanding TopoRE diversity and function will aid in the interpretation of how human sequence variation can impact transcription and contribute to disease phenotypes.

Investigation of the human metabolism and disposition of the prolyl hydrolase inhibitor daprodustat using IV microtracer with Entero-Test bile string.

Daprodustat is an oral small molecule hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI) approved in Japan and the United States for the treatment of anemia associated with chronic kidney disease. This phase 1, nonrandomized, 2-period, crossover study in 6 healthy men characterized and quantified the metabolites generated after a microtracer IV infusion of 50 µg (125 nCi) [14 C]-daprodustat administered concomitantly with a nonradiolabeled therapeutic dose of a 6-mg daprodustat tablet, followed by a single oral solution dose of 25 mg (62.5 µCi) [14 C]-daprodustat. High-performance liquid chromatography (HPLC) coupled with radioactivity detection (TopCount or AMS) and HPLC-tandem mass spectrometry (HPLC-MSn ) were used for quantitative measurement and structural identification of radioactive metabolites in plasma, urine, feces, and bile. Following oral administration of [14 C]-daprodustat, unchanged daprodustat was the principal circulating drug-related component, accounting for 40% of plasma radioactivity. Predominant oxidative metabolites M2, M3, M4, and M13 individually represented 6-8% of the plasma radioactivity and together accounted for the majority of radioactivity in urine and feces (53% in both matrices; 12% and 41% of dose, respectively). Unchanged daprodustat was not detected in urine and was only 0.7% of total radioactivity in feces (<0.5% of dose), with the remainder of the dose accounted for by oxidative metabolites. The radio-metabolic profile of duodenal bile following IV infusion of [14 C]-daprodustat was similar to that observed in feces after oral administration. The data suggested that oral daprodustat was extensively absorbed, cleared exclusively by oxidative metabolism, and eliminated via hepatobiliary (primary) and urinary (secondary) excretion.

Multi-Focus Image Fusion via Distance-Weighted Regional Energy and Structure Tensor in NSCT Domain.

In this paper, a multi-focus image fusion algorithm via the distance-weighted regional energy and structure tensor in non-subsampled contourlet transform domain is introduced. The distance-weighted regional energy-based fusion rule was used to deal with low-frequency components, and the structure tensor-based fusion rule was used to process high-frequency components; fused sub-bands were integrated with the inverse non-subsampled contourlet transform, and a fused multi-focus image was generated. We conducted a series of simulations and experiments on the multi-focus image public dataset Lytro; the experimental results of 20 sets of data show that our algorithm has significant advantages compared to advanced algorithms and that it can produce clearer and more informative multi-focus fusion images.

Mapping high-resolution energy consumption CO2 emissions in China by integrating nighttime lights and point source locations.

High-resolution CO2 emission inventories are essential to accurately assess spatiotemporal patterns of carbon emissions, analyze factors affecting carbon emissions, and develop sound emission reduction policies. The top-down approach is often used to map CO2 emissions from energy consumption due to its simplicity. However, the spatial proxy variables commonly used in this method, such as nighttime light (NL), land use, and population, are difficult to reflect the spatial distribution of CO2 emissions from large point sources. Therefore, this study uses the active fire product provided by Visible Infrared Imaging Radiometer Suite (VIIRS) sensors on Suomi National Polar-Orbiting Partnership (Suomi-NPP) satellite to extract the location of industrial heat sources in China, and then develops an improved CO2 emission estimation model by integrating industrial heat sources, Global Energy Monitor (GEM) power plant location and nighttime lights. The model is used to map CO2 emissions from energy consumption at a resolution of 1 km*1 km from 2012 to 2019 in China. It is found that the overall accuracy of the model is greatly improved at the provincial level, the R2 value is >0.75, and RMSE is distributed in 40-110 Mt. At the grid level, the improved model allocates more carbon emissions to the grid where the point source is located, which makes the spatial distribution of CO2 emissions more reasonable.

Estimation of ground-level O3 concentration in the Yangtze River Delta region based on a high-performance spatiotemporal model MixNet.

In recent years, the escalating ozone (O3) concentration has significantly damaged human health. The machine learning models are widely used to estimate ground-level O3 concentrations, but the spatial and temporal features in the data are less considered. To address the issue, this study proposed a novel framework named MixNet to estimate daily O3 concentration from 2020 to 2021 over the Yangtze River Delta. The MixNet utilized image convolution to extract the potential spatial information related to O3 fully. The temporal features were extracted by a Long Short-Term Memory (LSTM). A U-Net, a new jump connection method with an attention mechanism and residual blocks, facilitated a more comprehensive extraction of spatial features in the data. The extracted temporal and spatial features were fused to estimate ground-level O3. Meanwhile, a novel training method was proposed to enhance the accuracy of MixNet. The daily mean O3 maps have high validation results in comparison with ground-level O3 measurement, with R2 (RMSE) of 0.903 (14.511 µg/m3) for sample-based validation, 0.831 (19.036 µg/m3) for site-based validation, and 0.712 (25.108 µg/m3) for time-based validation. The season-average maps indicate that O3 concentration is summer > autumn > spring > winter. The highest value was 137.41 µg/m3 in the summer of 2021 over the Yangtze River Delta urban agglomeration, and the lowest value was 52.73 µg/m3 in winter 2020. The MixNet showed better performance compared with other models, and thus the "point-plane image thinking" will contribute to future studies in developing better methods to estimate atmospheric pollutants.

Co-transcriptional genome surveillance by HUSH is coupled to termination machinery.

The HUSH complex recognizes and silences foreign DNA such as viruses, transposons, and transgenes without prior exposure to its targets. Here, we show that endogenous targets of the HUSH complex fall into two distinct classes based on the presence or absence of H3K9me3. These classes are further distinguished by their transposon content and differential response to the loss of HUSH. A de novo genomic rearrangement at the Sox2 locus induces a switch from H3K9me3-independent to H3K9me3-associated HUSH targeting, resulting in silencing. We further demonstrate that HUSH interacts with the termination factor WDR82 and-via its component MPP8-with nascent RNA. HUSH accumulates at sites of high RNAPII occupancy including long exons and transcription termination sites in a manner dependent on WDR82 and CPSF. Together, our results uncover the functional diversity of HUSH targets and show that this vertebrate-specific complex exploits evolutionarily ancient transcription termination machinery for co-transcriptional chromatin targeting and genome surveillance.

Evaluation and uncertainty analysis of Himawari-8 hourly aerosol product version 3.1 and its influence on surface solar radiation before and during the COVID-19 outbreak.

The hourly Himawari-8 version 3.1 (V31) aerosol product has been released and incorporates an updated Level 2 algorithm that uses forecast data as an a priori estimate. However, there has not been a thorough evaluation of V31 data across a full-disk scan, and V31 has yet to be applied in the analysis of its influence on surface solar radiation (SSR). This study firstly investigates the accuracy of V31 aerosol products, which includes three categories of aerosol optical depth (AOD) (AODMean, AODPure, and AODMerged) as well as the corresponding Ångström exponent (AE), using ground-based measurements from the AERONET and SKYNET. Results indicate that V31 AOD products are more consistent with ground-based measurements compared to previous products (V30). The highest correlation and lowest error were seen in the AODMerged, with a correlation coefficient of 0.8335 and minimal root mean square error of 0.1919. In contrast, the AEMerged shows a larger discrepancy with measurements unlike the AEMean and AEPure. Error analysis reveals that V31 AODMerged has generally stable accuracy across various ground types and geometrical observation angles, however, there are higher uncertainties in areas with high aerosol loading, particularly for fine aerosols. The temporal analysis shows that V31 AODMerged performs better compared to V30, particularly in the afternoon. Finally, the impacts of aerosols on SSR based on the V31 AODMerged are investigated through the development of a sophisticated SSR estimation algorithm in the clear sky. Results demonstrate that the estimated SSR is significant consistency with those of well-known CERES products, with preservation of 20 times higher spatial resolution. The spatial analysis reveals a significant reduction of AOD in the North China Plain before and during the COVID-19 outbreak, resulting in an average 24.57 W m-2 variation of the surface shortwave radiative forcing in clear sky daytime.

Methodological flaws in"diagnostic accuracy of blood biomarkers for Alzheimer's disease and amnestic mild cognitive impairment: A meta-analysis".

We read with interest the review by Chen et al. They intended to examine the diagnostic accuracy of blood-based biomarkers for detecting Alzheimer's disease and amnestic mild cognitive impairment. We believe that there were substantial methodological flaws in their meta-analysis. These methodological flaws included no comprehensive literature search details, neglect of the negative result research, no prespecified cut-off values, erroneous data input in their meta-analysis, and the issue of prevalence determined by the included studies. These factors potentially contributed to overestimation of the discriminative accuracy of blood-based biomarkers. Subsequently, the conclusion that blood-based biomarkers are effective tools for detecting Alzheimer's disease is debatable without correction of these methodological flaws and providing robust and trustworthy estimates.

Structural elements promote architectural stripe formation and facilitate ultra-long-range gene regulation at a human disease locus.

Enhancer clusters overlapping disease-associated mutations in Pierre Robin sequence (PRS) patients regulate SOX9 expression at genomic distances over 1.25 Mb. We applied optical reconstruction of chromatin architecture (ORCA) imaging to trace 3D locus topology during PRS-enhancer activation. We observed pronounced changes in locus topology between cell types. Subsequent analysis of single-chromatin fiber traces revealed that these ensemble-average differences arise through changes in the frequency of commonly sampled topologies. We further identified two CTCF-bound elements, internal to the SOX9 topologically associating domain, which promote stripe formation, are positioned near the domain's 3D geometric center, and bridge enhancer-promoter contacts in a series of chromatin loops. Ablation of these elements results in diminished SOX9 expression and altered domain-wide contacts. Polymer models with uniform loading across the domain and frequent cohesin collisions recapitulate this multi-loop, centrally clustered geometry. Together, we provide mechanistic insights into architectural stripe formation and gene regulation over ultra-long genomic ranges.

Recent progress and challenges in single-cell imaging of enhancer-promoter interaction.

In the past two years, approaches relying on high-resolution microscopy and live-cell imaging have increasingly contributed to our understanding of the 3D genome organization and its importance for transcriptional control. Here, we describe recent progress that has highlighted how flexible and heterogeneous 3D chromatin structure is, on the length scales relevant to transcriptional control. We describe work that has investigated how robust transcriptional outcomes may be derived from such flexible organization without the need for clearly distinct structures in active and silent cells. We survey the latest state of the art in directly observing the dynamics of chromatin interactions, and suggest how some recent, apparently contradictory conclusions may be reconciled.

Near-real-time estimation of hourly open biomass burning emissions in China using multiple satellite retrievals.

Open biomass burning (OBB) is an important source of air pollutants and greenhouse gases, but its dynamic emission estimation remains challenging. Existing OBB emission datasets normally provide daily estimates based upon Moderate Resolution Imaging Spectroradiometer (MODIS) retrievals but tend to underestimate the emissions due to the coarse spatial resolution and sparse observation frequency. In this study, we proposed a novel approach to improve OBB emission estimations by fusing multiple active fires detected by MODIS, Visible Infrared Imaging Radiometer onboard the Suomi National Polar-orbiting Partnership (VIIRS S-NPP) and Himawari-8. The fusion of multiple active fires can capture the missing small fires and the large fires take place during the non-overpass time of MODIS observations. Also, regional-based fire radiative power (FRP) cycle reconstruction models and OBB emission coefficients were developed to address the large spatial discrepancies of OBB emission estimations across China and to promote the estimate to an hourly resolution. Using the new approach, hourly gridded OBB emissions in China were developed and can be updated with a lag of 1-day, or even near-real-time when real-time multiple active fires are available. OBB emissions in China based on this approach were more than 3 times of those in previous datasets. Evaluations revealed that the spatial distribution of the estimated PM2.5 emissions from this study was more consistent with the ambient PM2.5 concentrations during several episodes than existing datasets. The hourly OBB emissions provide new insight into its spatiotemporal variations, enhance timely and reliable air quality modeling and forecast, and support the formulation of accurate prevention and control policies of OBB.

Clinical Pharmacokinetics of Daprodustat: Results of an Absorption, Distribution, and Excretion Study With Intravenous Microtracer and Concomitant Oral Doses for Bioavailability Determination.

Daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated for treatment of anemia in chronic kidney disease. This phase 1, nonrandomized, 2-period, crossover study in 6 healthy men characterized the absorption, distribution, and excretion of daprodustat when administered as oral and intravenous (IV) doses of unlabeled and radiolabeled daprodustat ([14 C]-GSK1278863). Tolerability and pharmacokinetic properties of daprodustat, and its 6 metabolites in the systemic circulation, were also evaluated. The mean recovery of radiolabeled daprodustat was ≈95% by day 5, with the majority in feces and minor renal elimination, indicating that daprodustat and metabolites are primarily eliminated via hepatobiliary and fecal routes. Approximately 40% of total circulating radioactivity in plasma following both IV and oral administration was daprodustat; thus, 60% was attributed to metabolites. It was estimated that ≈80% of daprodustat was absorbed across the gastrointestinal tract, and ≈18% cleared by hepatic extraction. Pharmacokinetics were essentially dose proportional, with moderate (≈66%) oral tablet bioavailability. Following IV administration, daprodustat plasma clearance (19.3 L/h) and volume of distribution (14.6 L) were low, suggesting low tissue distribution outside systemic circulation with likely low penetration into tissues. Daprodustat was generally well tolerated, with no deaths or serious or significant adverse events reported.

Efficacy of doxycycline versus azithromycin for the treatment of rectal chlamydia: a systematic review and meta-analysis.

BACKGROUND: Chlamydia trachomatis infection is the most common sexually transmitted infectious disease and carries a risk of complications. However, the optimal treatment for rectal chlamydial infection remains unclear. OBJECTIVES: To compare the efficacy of doxycycline and azithromycin for the treatment of rectal chlamydia by undertaking a systematic review and meta-analysis of published data. METHODS: We searched PubMed, EMBASE, Cochrane Library, Web of Science and clinicaltrials.gov databases from inception to 7 July 2021 for randomized controlled trials (RCTs) and observational studies that compared the efficacy of doxycycline and single-dose azithromycin on rectal chlamydia cure rates. Data were synthesized using a random-effects model, and subgroup analysis was conducted. RESULTS: All included studies were conducted in developed countries. Two RCTs and nine observational studies, with a total of 2457 patients, were analysed. Doxycycline had a higher microbiological cure rate than azithromycin (risk ratio = 1.21; 95% CI = 1.15-1.28; P < 0.05). Pooled results from two RCTs also revealed a higher microbiological cure rate for doxycycline than azithromycin (risk ratio = 1.27; 95% CI = 1.20-1.35; P < 0.05). The results remained consistent in subgroups of different study designs, countries and sexes. CONCLUSIONS: On the basis of our findings, we recommend doxycycline rather than azithromycin as a first-line treatment for rectal chlamydia in developed countries. More RCTs from developing countries are warranted.

Does tranexamic acid reduce risk of mortality on patients with hemoptysis?: A protocol for systematic review and meta-analysis.

BACKGROUND: Although tranexamic acid (TXA), a readily accessible antifibrinolytic agent, is widely adopted in hemorrhage scenarios, its role on mortality in patients with hemoptysis remains uncertain. New evidence is yet to be generated to evaluate the risk of mortality after using TXA in patients with hemoptysis. METHODS: PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus databases were searched from inception to May 2020. Randomized controlled trials and observational studies that evaluated the effect of TXA on patients with hemoptysis were included. Data were independently extracted by 2 reviewers and synthesized using a random-effects model. MAIN RESULTS: Five studies with a total of 20,047 patients were analyzed. When compared with the control, administration of TXA was associated with a reduction in short-term mortality (risk ratio = 0.78, 95% confidence interval [CI] 0.72-0.85; I2 = 0), shorter bleeding time (mean difference = - 24.61 hours, 95% CI - 35.96 to -13.26, I2 = 0), shorter length of hospital stay (mean difference = -1.94 days, 95% CI -2.48 to -1.40, I2 = 0), and lower need for intervention (risk ratio = 0.38, 95% CI 0.16-0.87, I2 = 0) in patients with hemoptysis. Compared with control, administration of TXA did not cause increased major or minor adverse effects. CONCLUSIONS: TXA provided benefits in terms of a lower short-term mortality rate, less bleeding time, shorter length of hospital stays, and less need for intervention in patients with hemoptysis. Use of TXA was not associated with increased adverse effects.

Considerations from the Innovation and Quality Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Guidelines on Model Fitting and Recommendations on Time Course for In Vitro Cytochrome P450 Induction Studies Including Impact on Drug Interaction Risk Assessment.

Translational and ADME Sciences Leadership Group Induction Working Group (IWG) presents an analysis on the time course for cytochrome P450 induction in primary human hepatocytes. Induction of CYP1A2, CYP2B6, and CYP3A4 was evaluated by seven IWG laboratories after incubation with prototypical inducers (omeprazole, phenobarbital, rifampicin, or efavirenz) for 6-72 hours. The effect of incubation duration and model-fitting approaches on induction parameters (Emax and EC50) and drug-drug interaction (DDI) risk assessment was determined. Despite variability in induction response across hepatocyte donors, the following recommendations are proposed: 1) 48 hours should be the primary time point for in vitro assessment of induction based on mRNA level or activity, with no further benefit from 72 hours; 2) when using mRNA, 24-hour incubations provide reliable assessment of induction and DDI risk; 3) if validated using prototypical inducers (>10-fold induction), 12-hour incubations may provide an estimate of induction potential, including characterization as negative if <2-fold induction of mRNA and no concentration dependence; 4) atypical dose-response ("bell-shaped") curves can be addressed by removing points outside an established confidence interval and %CV; 5) when maximum fold induction is well defined, the choice of nonlinear regression model has limited impact on estimated induction parameters; 6) when the maximum fold induction is not well defined, conservative DDI risk assessment can be obtained using sigmoidal three-parameter fit or constraining logistic three- or four-parameter fits to the maximum observed fold induction; 7) preliminary data suggest initial slope of the fold induction curve can be used to estimate Emax/EC50 and for induction risk assessment. SIGNIFICANCE STATEMENT: Regulatory agencies provide inconsistent guidance on the optimum length of time to evaluate cytochrome P450 induction in human hepatocytes, with EMA recommending 72 hours and FDA suggesting 48-72 hours. The Induction Working Group analyzed a large data set generated by seven member companies and determined that induction response and drug-drug risk assessment determined after 48-hour incubations were representative of 72-hour incubations. Additional recommendations are provided on model-fitting techniques for induction parameter estimation and addressing atypical concentration-response curves.

Effect of magnesium sulfate on renal colic pain: A PRISMA-compliant meta-analysis.

BACKGROUND: Magnesium sulfate (MgSO4) is widely used in analgesia for different conditions. Recent randomized controlled trials (RCTs) have evaluated the effects of MgSO4 on renal colic; however, this new evidence has not been synthesized. Thus, we conducted a systematic review and meta-analysis to assess the efficacy and safety of MgSO4 in comparison with control for renal colic. METHODS: PubMed, EMBASE, and Scopus databases were searched from inception to February 2020. We included RCTs that evaluated MgSO4 vs control for patients with renal colic. Data were independently extracted by 2 reviewers and synthesized using a random-effects model. RESULTS: Four studies with a total of 373 patients were analyzed. Intravenous MgSO4 15 to 50 mg/kg did not significantly reduce renal colic pain severity at 15 minutes (mean difference [MD] = 0.35, 95% confidence interval [CI] -0.51 to 1.21; 2 RCTs), 30 minutes (MD = 0.19, 95% CI -0.74 to 1.13; 4 RCTs), and 60 minutes (MD = -0.28, 95% CI -0.72 to 0.16; 3 RCTs) in comparison with controls. In patients who failed to respond to initial analgesics, intravenous MgSO4 15 mg/kg or 2 ml of 50% solution provided similar pain relief to ketorolac or morphine at 30 minutes (P = .90) and 60 minutes (P = .57). No significant hemodynamic changes were observed with short-term use of MgSO4 in these studies. CONCLUSION: MgSO4 provides no superior therapeutic benefits in comparison with control treatments. MgSO4 may be used as a rescue medication in patients not responding to initial analgesics. The short-term use of MgSO4 did not affect hemodynamic values.

The NMDA receptor subunit GluN3A regulates synaptic activity-induced and myocyte enhancer factor 2C (MEF2C)-dependent transcription.

N-Methyl-d-aspartate type glutamate receptors (NMDARs) are key mediators of synaptic activity-regulated gene transcription in neurons, both during development and in the adult brain. Developmental differences in the glutamate receptor ionotropic NMDA 2 (GluN2) subunit composition of NMDARs determines whether they activate the transcription factor cAMP-responsive element-binding protein 1 (CREB). However, whether the developmentally regulated GluN3A subunit also modulates NMDAR-induced transcription is unknown. Here, using an array of techniques, including quantitative real-time PCR, immunostaining, reporter gene assays, RNA-Seq, and two-photon glutamate uncaging with calcium imaging, we show that knocking down GluN3A in rat hippocampal neurons promotes the inducible transcription of a subset of NMDAR-sensitive genes. We found that this enhancement is mediated by the accumulation of phosphorylated p38 mitogen-activated protein kinase in the nucleus, which drives the activation of the transcription factor myocyte enhancer factor 2C (MEF2C) and promotes the transcription of a subset of synaptic activity-induced genes, including brain-derived neurotrophic factor (Bdnf) and activity-regulated cytoskeleton-associated protein (Arc). Our evidence that GluN3A regulates MEF2C-dependent transcription reveals a novel mechanism by which NMDAR subunit composition confers specificity to the program of synaptic activity-regulated gene transcription in developing neurons.

Carcinogenicity Assessment of Daprodustat (GSK1278863), a Hypoxia-Inducible Factor (HIF)-Prolyl Hydroxylase Inhibitor.

Daprodustat (GSK1278863) is a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor in development for treatment of anemia of chronic kidney disease. Daprodustat's biological activity simulates components of the natural response to hypoxia; inhibition of PHDs results in HIF stabilization and modulation of HIF-controlled gene products, including erythropoietin. The carcinogenic potential of daprodustat was evaluated in 2-year carcinogenicity studies in Sprague-Dawley rats and CD-1 mice, where once-daily doses were administered. The mouse study also included evaluation of daprodustat's 3 major circulating human metabolites. There were no neoplastic findings that were considered treatment related in either study. Exaggerated pharmacology resulted in significantly increased red cell mass and subsequent multiorgan congestion and secondary non-neoplastic effects in both species, similar to those observed in chronic toxicity studies. In rats, these included aortic thrombosis and an exacerbation of spontaneous rodent cardiomyopathy, which contributed to a statistically significant decrease in survival in high-dose males (group terminated in week 94). Survival was not impacted in mice at any dose. Systemic exposures (area under the plasma concentration-time curve) to daprodustat at the high doses in rats and mice exceed predicted maximal human clinical exposure by ≥143-fold. These results suggest that daprodustat and metabolites do not pose a carcinogenic risk at clinical doses.

Long-term (2006-2015) variations and relations of multiple atmospheric pollutants based on multi-remote sensing data over the North China Plain.

In this analysis, the Aqua/MODIS aerosol optical thickness (AOD), Aura/OMI tropospheric NO2 and SO2 column concentration from 2006 to 2015 were used to statistically analyze the spatial distribution characteristics and variation trends of three polluted parameters from three temporal scales of monthly, seasonal and annual average. The results showed that the minimum values of NO2 and SO2 column concentrations both appeared in July and August, and the maximum values appeared in December and January, which was contrary to the variations in AOD. The highly polluted levels were mainly distributed in Shijiazhuang, Xingtai, and Yancheng cities of Hebei Province, and gradually transported to Zhengzhou, Henan Province, north and southwest of Shandong Province, and Tianjin, along the main line of Taiyuan-Linyi, Shanxi Province. AOD and NO2 had significant differences on the seasonal average scale, whereas SO2 had little changes. These pollutants had declined year by year since 2011, in the 10-year period, AOD and SO2 respectively decreased by 17.14% and 10.57%, and only NO2 rose from 8.69 × 1015 molecules/cm2 in 2006 to 9.10 × 1015 molecules/cm2 in 2015 with the increase rate of 4.79%. Integrated with MODIS-released fire products and the Multi-resolution Emission Inventory for China (MEIC), high AOD values in summer were usually accompanied by frequent biomass burning, and heavy heating demand of coal burning led to largest NO2 and SO2 levels in winter. Both inter-annual variations of MEIC NOx and OMI-observed NO2 responded to emission reductions of vehicle exhaustions positively, but vehicle population in Henan and Shandong provinces need to be further controlled. The significant decline of SO2 is mainly attributed to the enforcement of de-sulfurization devices in power plants. Our study found that in the treatment of complex atmospheric pollution, in addition to strict control of common sources of emissions from AOD, NO2 and SO2, it is also necessary to consider their individual characteristics.