Interpretable online network dictionary learning for inferring long-range chromatin interactions.

Dictionary learning (DL), implemented via matrix factorization (MF), is commonly used in computational biology to tackle ubiquitous clustering problems. The method is favored due to its conceptual simplicity and relatively low computational complexity. However, DL algorithms produce results that lack interpretability in terms of real biological data. Additionally, they are not optimized for graph-structured data and hence often fail to handle them in a scalable manner. In order to address these limitations, we propose a novel DL algorithm called online convex network dictionary learning (online cvxNDL). Unlike classical DL algorithms, online cvxNDL is implemented via MF and designed to handle extremely large datasets by virtue of its online nature. Importantly, it enables the interpretation of dictionary elements, which serve as cluster representatives, through convex combinations of real measurements. Moreover, the algorithm can be applied to data with a network structure by incorporating specialized subnetwork sampling techniques. To demonstrate the utility of our approach, we apply cvxNDL on 3D-genome RNAPII ChIA-Drop data with the goal of identifying important long-range interaction patterns (long-range dictionary elements). ChIA-Drop probes higher-order interactions, and produces data in the form of hypergraphs whose nodes represent genomic fragments. The hyperedges represent observed physical contacts. Our hypergraph model analysis has the objective of creating an interpretable dictionary of long-range interaction patterns that accurately represent global chromatin physical contact maps. Through the use of dictionary information, one can also associate the contact maps with RNA transcripts and infer cellular functions. To accomplish the task at hand, we focus on RNAPII-enriched ChIA-Drop data from Drosophila Melanogaster S2 cell lines. Our results offer two key insights. First, we demonstrate that online cvxNDL retains the accuracy of classical DL (MF) methods while simultaneously ensuring unique interpretability and scalability. Second, we identify distinct collections of proximal and distal interaction patterns involving chromatin elements shared by related processes across different chromosomes, as well as patterns unique to specific chromosomes. To associate the dictionary elements with biological properties of the corresponding chromatin regions, we employ Gene Ontology (GO) enrichment analysis and perform multiple RNA coexpression studies.

Hepsin enhances liver metabolism and inhibits adipocyte browning in mice.

Hepsin is a transmembrane serine protease primarily expressed in the liver. To date, the physiological function of hepsin remains poorly defined. Here we report that hepsin-deficient mice have low levels of blood glucose and lipids and liver glycogen, but increased adipose tissue browning and basal metabolic rates. The phenotype is caused by reduced hepatocyte growth factor activation and impaired Met signaling, resulting in decreased liver glucose and lipid metabolism and enhanced adipocyte browning. Hepsin-deficient mice exhibit marked resistance to high-fat diet-induced obesity, hyperglycemia, and hyperlipidemia. In db/db mice, hepsin deficiency ameliorates obesity and diabetes. These data indicate that hepsin is a key regulator in liver metabolism and energy homeostasis, suggesting that hepsin could be a therapeutic target for treating obesity and diabetes.

Acute effects of exposure to fine particulate matter and ozone on lung function, inflammation and oxidative stress in healthy adults.

Both fine particulate matter (PM2.5) and ozone (O3) may have adverse effects on human health. However, previous studies on the effects of air pollutants mainly have focused on susceptible population, and evidence on healthy young adults is limited. We aimed to examine the associations of the two main air pollutants (PM2.5 and O3) with lung function, inflammation and oxidative stress in healthy young adults. We recruited 30 healthy young adults for a longitudinal panel study in Beijing and implemented health examination seven times, including lung function (FEV1 and PEF) and biomarkers of inflammation and oxidative stress (i.e. C-reactive protein, CRP; interleukin-6, IL-6; malondialdehyde, MDA) from December 2019 to May 2021. Hourly ambient air pollutants data were obtained from the closest air quality monitoring station. Linear mixed-effect model was applied to explore the associations between air pollutants and lung function, inflammation and oxidative stress. We observed higher PM2.5 exposure was associated with decrement in lung function and increment in CRP and MDA. Each 10 µg/m3 increase in PM2.5 (lag 2 day) is associated with a 17.06 ml (95% CI: -31.53, -2.58) decrease in FEV1, 46.34 ml/s (95% CI: -76.41, -16.27) decrease in PEF and increments of 2.86% (95% CI: 1.47%, 4.27%) in CRP, 1.63% (95% CI: 0.14%, 3.14%) in MDA respectively. However, there is no significant association between ozone exposure and health indicators. The study suggested that short-term exposure to PM2.5 may decrease lung function and induce inflammation and oxidative stress in healthy adults, but there is no association between O3 and each outcome.

METHCOMP: a special purpose compression platform for DNA methylation data.

Motivation: DNA methylation is one of the most important epigenetic mechanisms in cells that exhibits a significant role in controlling gene expressions. Abnormal methylation patterns have been associated with cancer, imprinting disorders and repeat-instability diseases. As inexpensive bisulfite sequencing approaches have led to significant efforts in acquiring methylation data, problems of data storage and management have become increasingly important. The de facto compression method for methylation data is gzip, which is a general purpose compression algorithm that does not cater to the special format of methylation files. We propose METHCOMP, a new compression scheme tailor-made for bedMethyl files, which supports random access. Results: We tested the METHCOMP algorithm on 24 bedMethyl files retrieved from four randomly selected ENCODE assays. Our findings reveal that METHCOMP offers an average compression ratio improvement over gzip of up to 7.5x. As an example, METHCOMP compresses a 48 GB file to only 0.9 GB, which corresponds to a 98% reduction in size. Availability and implementation: METHCOMP is freely available at https://github.com/jianhao2016/METHCOMP. Supplementary information: Supplementary data are available at Bioinformatics online.

Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy.

In pregnancy, trophoblast invasion and uterine spiral artery remodelling are important for lowering maternal vascular resistance and increasing uteroplacental blood flow. Impaired spiral artery remodelling has been implicated in pre-eclampsia, a major complication of pregnancy, for a long time but the underlying mechanisms remain unclear. Corin (also known as atrial natriuretic peptide-converting enzyme) is a cardiac protease that activates atrial natriuretic peptide (ANP), a cardiac hormone that is important in regulating blood pressure. Unexpectedly, corin expression was detected in the pregnant uterus. Here we identify a new function of corin and ANP in promoting trophoblast invasion and spiral artery remodelling. We show that pregnant corin- or ANP-deficient mice developed high blood pressure and proteinuria, characteristics of pre-eclampsia. In these mice, trophoblast invasion and uterine spiral artery remodelling were markedly impaired. Consistent with this, the ANP potently stimulated human trophoblasts in invading Matrigels. In patients with pre-eclampsia, uterine Corin messenger RNA and protein levels were significantly lower than that in normal pregnancies. Moreover, we have identified Corin gene mutations in pre-eclamptic patients, which decreased corin activity in processing pro-ANP. These results indicate that corin and ANP are essential for physiological changes at the maternal-fetal interface, suggesting that defects in corin and ANP function may contribute to pre-eclampsia.

Distinct roles of N-glycosylation at different sites of corin in cell membrane targeting and ectodomain shedding.

Corin is a membrane-bound protease essential for activating natriuretic peptides and regulating blood pressure. Human corin has 19 predicted N-glycosylation sites in its extracellular domains. It has been shown that N-glycans are required for corin cell surface expression and zymogen activation. It remains unknown, however, how N-glycans at different sites may regulate corin biosynthesis and processing. In this study, we examined corin mutants, in which each of the 19 predicted N-glycosylation sites was mutated individually. By Western analysis of corin proteins in cell lysate and conditioned medium from transfected HEK293 cells and HL-1 cardiomyocytes, we found that N-glycosylation at Asn-80 inhibited corin shedding in the juxtamembrane domain. Similarly, N-glycosylation at Asn-231 protected corin from autocleavage in the frizzled-1 domain. Moreover, N-glycosylation at Asn-697 in the scavenger receptor domain and at Asn-1022 in the protease domain is important for corin cell surface targeting and zymogen activation. We also found that the location of the N-glycosylation site in the protease domain was not critical. N-Glycosylation at Asn-1022 may be switched to different sites to promote corin zymogen activation. Together, our results show that N-glycans at different sites may play distinct roles in regulating the cell membrane targeting, zymogen activation, and ectodomain shedding of corin.

Multifaceted roles of cohesin in regulating transcriptional loops.

Cohesin is required for chromatin loop formation. However, its precise role in regulating gene transcription remains largely unknown. We investigated the relationship between cohesin and RNA Polymerase II (RNAPII) using single-molecule mapping and live-cell imaging methods in human cells. Cohesin-mediated transcriptional loops were highly correlated with those of RNAPII and followed the direction of gene transcription. Depleting RAD21, a subunit of cohesin, resulted in the loss of long-range (>100 kb) loops between distal (super-)enhancers and promoters of cell-type-specific genes. By contrast, the short-range (<50 kb) loops were insensitive to RAD21 depletion and connected genes that are mostly housekeeping. This result explains why only a small fraction of genes are affected by the loss of long-range chromatin interactions due to cohesin depletion. Remarkably, RAD21 depletion appeared to up-regulate genes located in early initiation zones (EIZ) of DNA replication, and the EIZ signals were amplified drastically without RAD21. Our results revealed new mechanistic insights of cohesin's multifaceted roles in establishing transcriptional loops, preserving long-range chromatin interactions for cell-specific genes, and maintaining timely order of DNA replication.

Bio-inspired liposomal thrombomodulin conjugate through bio-orthogonal chemistry.

We report the synthesis of bioinspired liposomal thrombomodulin (TM) conjugates by chemoselective and site-specific liposomal conjugation of recombinant TM at C-terminus. TM is an endothelial cell membrane protein that acts as a major cofactor in the protein C anticoagulant pathway. To closely mimic membrane protein structural features of TM, we proposed membrane-mimetic re-expression of recombinant TM onto liposome. A recombinant TM containing the EGF-like 456 domains and an azidohomoalanine at C-terminus was expressed in E. coli. Conjugation of the recombinant TM onto liposome via Staudinger ligation and copper-free click chemistry were investigated as an optimal platform for exploring membrane protein TM's activity, respectively. The bioinspired liposomal TM conjugates were confirmed with Western blotting and protein C activation activity. The recombinant TM-liposome conjugates showed a 2-fold higher k(cat)/K(m) value for protein C activation than that of the recombinant TM alone, which indicated that the lipid membrane has a beneficiary effect on the recombinant TM's activity. The reported liposomal protein conjugate approach provides a rational design strategy for both studying membrane protein TM's functions and generating a membrane protein TM-based anticoagulant agent.

Small-Sample Estimation of the Mutational Support and Distribution of SARS-CoV-2.

We consider the problem of determining the mutational support and distribution of the SARS-CoV-2 viral genome in the small-sample regime. The mutational support refers to the unknown number of sites that may eventually mutate in the SARS-CoV-2 genome while mutational distribution refers to the distribution of point mutations in the viral genome across a population. The mutational support may be used to assess the virulence of the virus and guide primer selection for real-time RT-PCR testing. Estimating the distribution of mutations in the genome of different subpopulations while accounting for the unseen may also aid in discovering new variants. To estimate the mutational support in the small-sample regime, we use GISAID sequencing data and our state-of-the-art polynomial estimation techniques based on new weighted and regularized Chebyshev approximation methods. For distribution estimation, we adapt the well-known Good-Turing estimator. Our analysis reveals several findings: First, the mutational supports exhibit significant differences in the ORF6 and ORF7a regions (older versus younger patients), ORF1b and ORF10 regions (females versus males) and in almost all ORFs (Asia/Europe/North America). Second, even though the N region of SARS-CoV-2 has a predicted 10% mutational support, mutations fall outside of the primer regions recommended by the CDC.

Effects of Long-Term Cold Stress on Growth Performance, Behavior, Physiological Parameters, and Energy Metabolism in Growing Beef Cattle.

This study aimed to evaluate the effects of a long-term cold environment on growth performance, physiological behavior, biochemical blood indexes, and hormone levels in Simmental cattle. Thirty Simmental crossbred bulls (weight = 350 ± 17 kg, 13-14 months old) were selected for two trials at autumn suitable temperatures (A-ST) and winter cold temperatures (W-CT) (15 cattle per season). The results showed that compared with the A-ST group, dry matter intake (p < 0.05) and feed:gain (p < 0.01) of the W-CT group increased, while body weight (p < 0.01) and average daily gain (p < 0.01) significantly decreased. Long-term cold stress also increased lying time (p < 0.01), feeding time (p < 0.05), and pulse rate (p < 0.01) in the W-CT group, while the rumen volatile fatty acids content (p < 0.01) and apparent digestibility of nutrients (p < 0.05) were significantly decreased. In terms of blood indicators, long-term cold stress increased the concentrations of glucose, glucose metabolic enzymes, glucocorticoids, triiodothyronine, and tetraiodothyronine in the plasma of the W-CT group (p < 0.05), but the levels of triglycerides, ß-hydroxybutyrate, propionate, insulin, and growth hormone were decreased (p < 0.01). In summary, long-term cold stress may inhibit the digestive function of Simmental cattle and enhance the body's energy metabolism and stress hormone imbalance, ultimately damaging the normal growth and development of the body.

Influence of different concentrations of ozone on the alteration of mitochondrial DNA copy numbers in human peripheral blood.

By now, O3 pollution has become a main environmental problem. O3 is a prevalent risk factor for many diseases, but the regulatory factors linking O3 and diseases remain ambiguous. Mitochondrial DNA (mtDNA) is the genetic material in mitochondria, which plays a key role in the production of respiratory ATP. Due to a lack of histone protection, mtDNA is easily damaged by ROS, and O3 is an important source to stimulate the production of endogenous ROS in vivo. Therefore, we logically speculate that O3 exposure can alter mtDNA copy number by the induction of ROS. In the present study, we performed a panel study of 65 MSc students at the Chinese research academy of environmental sciences (CRAES) with 3 rounds of follow-up visits from August 2021 to January 2022. We examined the mtDNA copy numbers in the peripheral blood of subjects using quantitative polymerase chain reaction. Linear mixed-effect (LME) model and stratified analysis were used to investigate the association between O3 exposure and mtDNA copy numbers. We found a dynamic process of the association between the concentration of O3 exposure and the mtDNA copy number in the peripheral blood. The lower concentration of O3 exposure did not affect the mtDNA copy number. As the concentration of O3 exposure increased, the mtDNA copy number also increased. While, when O3 exposure reached a certain concentration, a decrease in mtDNA copy number was found. This correlation between the concentration of O3 and the mtDNA copy number could be ascribed to the severity of cellular damage induced by O3 exposure. Our results provide a new perspective for the discovery of a biomarker of O3 exposure and health response, as well as for the prevention and treatment of adverse health effects caused by different concentrations of O3.

Effects of ozone exposure on lipid metabolism in Huh-7 human hepatoma cells.

Ozone pollution is a major environmental concern. According to recent epidemiological studies, ozone exposure increases the risk of metabolic liver disease. However, studies on the mechanisms underlying the effects of ozone exposure on hepatic oxidative damage, lipid synthesis, and catabolism are limited. In this study, Huh-7 human hepatocellular carcinoma cells were randomly divided into five groups and exposed to 200 ppb O3 for 0, 1, 2, 4, and 8 h. We measured the levels of oxidative stress and analyzed the changes in molecules related to lipid metabolism. The levels of oxidative stress were found to be significantly elevated in Huh-7 hepatocellular carcinoma cells after O3 exposure. Moreover, the expression levels of intracellular lipid synthases, including SREBP1, FASN, SCD1, and ACC1, were enhanced. Lipolytic enzymes, including ATGL and HSL, and the mitochondrial fatty acid oxidase, CPT1α, were inhibited after O3 exposure. In addition, short O3 exposure enhanced the expression of the intracellular peroxisomal fatty acid ß-oxidase, ACOX1; however, its expression decreased adaptively with longer exposure times. Overall, O3 exposure induces an increase in intracellular oxidative stress and disrupts the normal metabolism of lipids in hepatocytes, leading to intracellular lipid accumulation.

Effect of acute PM2.5 exposure on PTGS2 and RNA m6A modification.

Particulate matter 2.5 (PM2.5) is a prevalent risk factor in many diseases, but its molecular mechanism remains ambiguous and may be diverse. RNA m6A is an important epigenetic modification that regulates gene expression at the post-transcriptional level. Some previous animal exposure studies found that PM2.5 exposure up-regulated m6A RNA methylation in the lung, but there is no research on m6A RNA methylation in humans from PM2.5 exposure now. Here, in the present experiment, we performed a panel study of 65 students at the Chinese research academy of environmental sciences (CRAES) with 3 rounds of follow-up visits from August 2021 to January 2022. We examined m6A RNA modification profiles of peripheral blood mononuclear cells (PBMCs) from subjects after low and high concentrations of ambient PM2.5 exposure. We applied a linear mixed-effect (LME) model to investigate the association between PM2.5 exposure and global m6A RNA methylation and PTGS2 level in peripheral blood. We found that increased levels of global m6A RNA methylation and PTGS2 level were associated with higher PM2.5 exposure. Among the methylated mRNAs, PTGS2 was hyper-methylated after high concentrations of PM2.5 exposure, which coincided with the increased expression of PTGS2 mRNA. In the present study, we determined that PM2.5 exposure promoted RNA m6A modification, and PTGS2 in peripheral blood could serve as a novel regulatory factor of inflammation induced by PM2.5 exposure. Furthermore, RNA m6A modification may contribute to the altered expression of PTGS2 induced by PM2.5 exposure. Our finding provided a new perspective for the prevention and treatment of PM2.5 exposure-induced adverse health effects.

Influence of temperature on the risk of gestational diabetes mellitus and hypertension in different pregnancy trimesters.

Previous studies have proved that exposure to extreme temperature in specific windows of pregnancy could cause some complications, such as pregnancy induced hypertension (PIH) and gestational diabetes mellitus (GDM), but differences in the effect of extreme temperature on the 2 complications are rarely studied. We carried a retrospective study on the impact of temperature on GDM/PIH in different trimesters based on data from a maternal and child health center in Beijing, China. Ambient temperatures (°C) were obtained from the China Meteorological Administration from January 1st, 2013 to May 15th, 2018. We use distributed lag non-linear models (DLNMs) combined with logistic regression to calculate the lag exposure-response relationships between the temperature and GDM/PIH from 1st to 24th/20th weeks of pregnancy. In both first and second trimesters, the risk of GDM was increased in summer with high temperatures; in second trimester, the risk of GDM increased in winter with low temperatures. In first half of pregnancy, risk of PIH was decreased in winter with low temperatures. These findings can provide the guideline for preventing the GDM and PIH induced by extreme temperature during pregnancy.

Air pollution exposure and the risk of macrosomia: Identifying specific susceptible months.

Birth weight is an important indicator of future growth and development for newborns. Few studies investigated the potential effects of air pollutants on macrosomia and their susceptible windows. We included 38,971 singleton full-term births from Beijing HaiDian Maternal and Child Health Hospital between 2014 and 2018, and assessed the associations of air pollutants exposure during preconception and pregnancy with macrosomia as well as the corresponding susceptible windows. The concentrations of air pollutants (PM2.5, PM10, SO2, NO2, CO and O3) for participants were calculated by the data from the nearest monitoring stations. Distributed lag models (DLM) incorporating logistic regression models were used to estimate the associations between air pollutants exposure during the 3 months before conception and pregnancy period and the risk of macrosomia, identifying susceptible windows of air pollutants. Weighted quantile sum (WQS) regression was applied to estimate the joint effect of air pollutants. A 10 µg/m3 increase in PM2.5 exposure from 3rd to 8th gestational month was positively associated with the risk of macrosomia, with the strongest effect in the 6th month (OR = 1.010, 95 % CI: 1.002-1.019). For a 10 µg/m3 increase in SO2, the windows of significant exposure were from the 1st preconception month to the 3rd gestational month, with the strongest effect in the 2nd month (OR = 1.030, 95 % CI: 1.010-1.049). We also observed the significant positive associations were in the 5th-8th gestational months for PM10, the 8th-9th gestational months for NO2 and the 3rd-7th gestational months for CO respectively. WQS regression also indicated a positive association between co-exposure to air pollutants and macrosomia. Our results suggest air pollution exposure is associated with increased risk of macrosomia. The windows of exposure for susceptibility to the risk of macrosomia vary between air pollutants. The susceptible exposure windows were middle and late pregnancy for PM, CO and NO2, while for SO2, early pregnancy is the window of vulnerability. Our findings provide the evidence that air pollution exposure is an independent risk factor for macrosomia and a basis for targeted environment policy.

Exposure to ambient air pollution from the preconceptional period and risk of gestational hypertension.

Although accumulative studies have revealed the associations between air pollutants and elevated risk of gestational hypertension (GH), evidence from developing countries with relatively higher levels of air pollutants remains limited. In this retrospective study, a total of 45,439 birth records were collected in Beijing, China from 2013 to 2018. For PM2.5, SO2, NO2, and O3, exposure windows from the 3rd month of preconception to the 6th month of conception and the averages of 3 months of preconception, trimester 1 and trimester 2 periods were all calculated for assessment of GH risks. The correlations between air pollutants and the risk of GH were analyzed by logistic regression model. Our results showed that exposure to PM2.5 and SO2 in the preconceptional and early pregnancy periods was related to the elevated risk of GH. Furthermore, 3 months preconceptional exposure to PM2.5 (PCPM2.5: OR = 1.134 (1.114, 1.155)) and SO2 (PCSO2: OR = 1.158 (1.135, 1.181)) showed a higher risk of GH than the results of the trimester 1 (T1PM2.5: OR = 1.131 (1.104, 1.159); T1SO2: OR = 1.164 (1.141, 1.187)) and the trimester 2 (T2PM2.5: OR = 1.154 (1.126, 1.182); T2SO2: OR = 1.121 (1.098, 1.144)). The study also found significant and higher OR values for PCPM2.5, and PCSO2 from 2013 to 2016 when air pollution was serious in Beijing compared with 2017 to 2018 when the air pollution was obviously improved. Subgroup analysis also found that during 3 months of preconception women with higher age and who exposure to higher temperatures showed higher GH risk from PM2.5 and SO2 than that of the younger group and who exposure to lower temperature, respectively. Collectively, our findings suggest that air pollution exposure was adversely associated with GH in pregnant women and the preconceptional period is a critical air pollution exposure window for GH. Improving air quality can benefit public health, especially for sensitive populations like pregnant women.

Ectodomain shedding and autocleavage of the cardiac membrane protease corin.

Corin is a cardiac membrane protease that activates natriuretic peptides. It is unknown how corin function is regulated. Recently, soluble corin was detected in human plasma, suggesting that corin may be shed from cardiomyocytes. Here we examined soluble corin production and activity and determined the proteolytic enzymes responsible for corin cleavage. We expressed human corin in HEK 293 cells and detected three soluble fragments of ∼180, ∼160, and ∼100 kDa, respectively, in the cultured medium by Western blot analysis. All three fragments were derived from activated corin molecules. Similar results were obtained in HL-1 cardiomyocytes. Using protease inhibitors, ionomycin and phorbol myristate acetate stimulation, small interfering RNA knockdown, and site-directed mutagenesis, we found that ADAM10 was primarily responsible for shedding corin in its juxtamembrane region to release the ∼180-kDa fragment, corresponding to the near-entire extracellular region. In contrast, the ∼160- and ∼100-kDa fragments were from corin autocleavage at Arg-164 in frizzled 1 domain and Arg-427 in LDL receptor 5 domain, respectively. In functional studies, the ∼180-kDa fragment activated atrial natriuretic peptide, whereas the ∼160- and ∼100-kDa fragments did not. Our data indicate that ADAM-mediated shedding and corin autocleavage are important mechanisms regulating corin function and preventing excessive, potentially hazardous, proteolytic activities in the heart.

Impaired sodium excretion and salt-sensitive hypertension in corin-deficient mice.

Corin is a protease that activates atrial natriuretic peptide, a cardiac hormone important in the control of blood pressure and salt-water balance. Here we examined the role of corin in regulating blood pressure and sodium homeostasis upon dietary salt challenge. Radiotelemetry-tracked blood pressure in corin knockout mice on a high-salt diet (4% sodium chloride) was significantly increased; however, there was no such change in similarly treated wild-type mice. In the knockout mice on the high-salt diet there was an impairment of urinary sodium excretion and an increase in body weight, but no elevation of plasma renin or serum aldosterone levels. When the knockout mice on the high-salt diet were treated with amiloride, an epithelial sodium channel blocker that inhibits renal sodium reabsorption, the impaired urinary sodium excretion and increased body weight were normalized. Amiloride treatment also reduced high blood pressure caused by the high-salt diet in these mice. Thus, the lack of corin in mice impairs their adaptive renal response to high dietary salt, suggesting that corin deficiency may represent an important mechanism underlying salt-sensitive hypertension.

The vasorelaxant mechanisms of a Rho kinase inhibitor DL0805 in rat thoracic aorta.

Rho-kinase has been suggested as a potential therapeutic target in the treatment of cardiovascular diseases. The Rho-kinase signaling pathway is substantially involved in vascular contraction. The aim of the present study was to evaluate the vasorelaxant effects of Rho kinase inhibitor DL0805 in isolated rat aortic rings and to investigate its possible mechanism(s). It was found that DL0805 exerted vasorelaxation in a dose-dependent manner in NE or KCl-induced sustained contraction and partial loss of the vasorelaxation under endothelium-denuded rings. The DL0805-induced vasorelaxation was significantly reduced by the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester, the guanylate cyclase inhibitor methylene blue and the cyclooxygenase inhibitor indomethacin. The voltage-dependent K⁺ channel blocker 4-aminopyridine remarkably attenuated DL0805-induced relaxations. However, the ATP-sensitive K⁺ channel blocker glibenclamide and Ca²âº-activated K⁺ channel blocker tetraethylammonium did not affect the DL0805-induced relaxation. In the endothelium-denuded rings, DL0805 also reduced NE-induced transient contraction and inhibited contraction induced by increasing external calcium. These findings suggested that DL0805 is a novel vasorelaxant compound associated with inhibition of Rho/ROCK signaling pathway. The NO-cGMP pathway may be involved in the relaxation of DL0805 in endothelium-intact aorta. The vasorelaxant effect of DL0805 is partially mediated by the opening of the voltage-dependent K⁺ channels.

Ozone exposure induced risk of gestational diabetes mellitus.

Numerous studies have shown that air pollution seems to be able to cause many diseases. Considering the possible mechanism of action and the same growth trend, the present study is designed to examine whether and how air pollutants, especially ozone (O3) exposure, are associated with the incidence of gestational diabetes mellitus (GDM). By a retrospective cohort, we analyzed the records of 45439 pregnant women from 2013 to 2018 and matched them to maternal exposure to O3. We found that the increased odds of GDM is associated with increased O3 concentrations from the 1st month before pregnancy to the 3rd month during pregnancy. Specially, the odds ratios (ORs) of these associations were largest in the 1st month before pregnancy, suggesting that the effect of O3 pollution on GDM occurred in pre-pregnancy period. Moreover, the exposure-response plot in the 1st month before pregnancy showed that the odds of GDM increased with the increasing concentration of O3. Our findings provide the evidence that O3 exposure in both pre-pregnancy and pregnancy period elevates the odds of GDM, suggesting that more intensive air pollution controls are needed to improve the health of pregnant women and their offspring.