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This study utilizes panel data from 30 provinces in mainland China from 2011 to 2020 to investigate the impact of carbon-neutral development on economic high-quality development by constructing an economic high-quality development index and a carbon-neutral development index. Firstly, the study examines the effects of carbon-neutral development on economic high-quality development using baseline regression and spatial Durbin regression. The results indicate that carbon-neutral development has a positive direct effect on economic high-quality growth, but there are negative spatial spillover effects. Secondly, this study employs total factor productivity (TFP) as an intermediate variable in the mediation model regression. The findings demonstrate that carbon-neutral development significantly improves TFP, and the significant improvement in TFP promotes high-quality economic growth. Lastly, the study conducts regional heterogeneity analysis and finds a significant promoting effect of carbon-neutral development on economic high-quality development in the eastern and central regions of China, while it is not significant in the western region. Therefore, it is recommended that China, in the process of achieving carbon-neutral growth, consider the geographical connections between different regions to prevent negative spillover effects. Additionally, regional heterogeneity should be taken into account when formulating relevant policies to promote economic high-quality development. [ABSTRACT FROM AUTHOR]

Cree births in Quebec are characterized by the highest reported prevalence of macrosomia (~35%) in the world. It is unclear whether Cree births are at greater elevated risk of perinatal and infant mortality than other First Nations relative to non-Aboriginal births in Quebec, and if macrosomia may be related.This was a population-based retrospective birth cohort study using the linked birth-infant death database for singleton births to mothers from Cree (n = 5,340), other First Nations (n = 10,810) and non-Aboriginal (n = 229,960) communities in Quebec, 1996-2010. Community type was ascertained by residential postal code and municipality name. The primary outcomes were perinatal and infant mortality.Macrosomia (birth weight for gestational age >90th percentile) was substantially more frequent in Cree (38.0%) and other First Nations (21.9%) vs non-Aboriginal (9.4%) communities. Comparing Cree and other First Nations vs non-Aboriginal communities, perinatal mortality rates were 1.52 (95% confidence intervals 1.17, 1.98) and 1.34 (1.10, 1.64) times higher, and infant mortality rates 2.27 (1.71, 3.02) and 1.49 (1.16, 1.91) times higher, respectively. The risk elevations in perinatal and infant death in Cree communities attenuated after adjusting for maternal characteristics (age, education, marital status, parity), but became greater after further adjustment for birth weight (small, appropriate, or large for gestational age).Cree communities had greater risk elevations in perinatal and infant mortality than other First Nations relative to non-Aboriginal communities in Quebec. High prevalence of macrosomia did not explain the elevated risk of perinatal and infant mortality in Cree communities.

BACKGROUND:The optimal mode of delivery in twin pregnancies remains controversial. A recent randomized trial did not find any benefit of planned cesarean vs. vaginal delivery at 32-38 weeks gestation, but the trial was not powered to detect a moderate effect. We aimed to evaluate the impact of cesarean delivery on perinatal mortality and severe neonatal morbidity in twin pregnancies at ≥32 weeks through a large database exploration approach with the power to detect moderate risk differences. METHODS:In a retrospective birth cohort study using the U.S. matched multiple births, 1995-2000 (the available largest multiple birth dataset), we compared perinatal outcomes in twins (n = 181,810 pregnancies) delivered at 32-41 weeks gestation without congenital anomalies. The primary outcome was a composite of perinatal death and severe neonatal morbidity. Cox regression was used to estimate the adjusted hazard ratio (aHR) controlling for the propensity to cesarean delivery, fetal characteristics (sex, birth weight, birth weight discordance, same-sex twin or not) and twin-cluster level dependence. Prospective risks were calculated using the fetuses-at-risk denominators. RESULTS:The overall rates of the primary outcome were slightly lower in intended cesarean (6.20%) vs. vaginal (6.45%) deliveries. The aHRs of the primary outcome were in favor of vaginal delivery at 32 (aHR = 1.06, p = 0.03) or 33 (aHR = 1.22, p

ATP-binding cassette transporter A1 (ABCA1) plays a critical role in maintaining cellular cholesterol homeostasis. The purpose of this study is to identify the molecular mechanism(s) underlying ABCA1 epigenetic modification and determine its potential impact on ABCA1 expression in macrophage-derived foam cell formation and atherosclerosis development. DNA methylation induced foam cell formation from macrophages and promoted atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice. Bioinformatics analyses revealed a large CpG island (CGI) located in the promoter region of ABCA1. Histone methyltransferase enhancer of zeste homolog 2 (EZH2) downregulated ABCA1 mRNA and protein expression in THP-1 and RAW264.7 macrophage-derived foam cells. Pharmacological inhibition of DNA methyltransferase 1 (DNMT1) with 5-Aza-dC or knockdown of DNMT1 prevented the downregulation of macrophage ABCA1 expression, suggesting a role of DNA methylation in ABCA1 expression. Polycomb protein EZH2 induced DNMT1 expression and methyl-CpG-binding protein-2 (MeCP2) recruitment, and stimulated the binding of DNMT1 and MeCP2 to ABCA1 promoter, thereby promoting ABCA1 gene DNA methylation and atherosclerosis. Knockdown of DNMT1 inhibited EZH2-induced downregulation of ABCA1 in macrophages. Conversely, EZH2 overexpression stimulated DNMT1-induced ABCA1 gene promoter methylation and atherosclerosis. EZH2-induced downregulation of ABCA1 gene expression promotes foam cell formation and the development of atherosclerosis by DNA methylation of ABCA1 gene promoter.

Aortocaval fistula (AV) in rat is a unique model of volume-overload congestive heart failure and cardiac hypertrophy. Living donor kidney transplantation is regarded as beneficial to allograft recipients and not particularly detrimental to the donors. Impact of AV on animals with mild renal dysfunction is not fully understood. In this study, we explored the effects of AV in unilateral nephrectomized (UNX) rats.Adult male Sprague-Dawley (SD) rats were divided into Sham (n = 10), UNX (right kidney remove, n = 10), AV (AV established between the levels of renal arteries and iliac bifurcation, n = 18) and UNX+AV (AV at one week after UNX, n = 22), respectively. Renal outcome was measured by glomerular filtration rate, effective renal plasma flow, fractional excretion of sodium, albuminuria, plasma creatinine, and cystatin C. Focal glomerulosclerosis (FGS) incidence was evaluated by renal histology. Cardiac function was measured by echocardiography and hemodynamic measurements.UNX alone induced compensatory left kidney enlargement, increased plasma creatinine and cystatin C levels, and slightly reduced glomerular filtration rate and increased FGS. AV induced significant cardiac enlargement and hypertrophy and reduced cardiac function and increased FGS, these changes were aggravated in UNX+AV rats.Although UNX only induces minor renal dysfunction, additional chronic volume overload placement during the adaptation phase of the remaining kidney is associated with aggravated cardiac dysfunction and remodeling in UNX rats, suggesting special medical care is required for UNX or congenital monokidney subjects in case of chronic volume overload as in the case of pregnancy and hyperthyroidism to prevent further adverse cardiorenal events in these individuals.

Maternal smoking has been associated with elevated risk of type 2 diabetes among the offspring in adulthood. The mechanisms underlying this fetal "programming" effect remain unclear. The present study sought to explore whether maternal smoking affects metabolic health biomarkers in fetuses/newborns.In a prospective singleton pregnancy cohort (n = 248), we compared metabolic health biomarkers in the newborns of smoking and non-smoking mothers. Outcomes included cord plasma insulin, proinsulin, insulin-like growth factor I (IGF-I), IGF-II, leptin and adiponectin concentrations, glucose-to-insulin ratio (an indicator of insulin sensitivity) and proinsulin-to-insulin ratio (an indicator of β-cell function).Independent of maternal (glucose tolerance, age, ethnicity, parity, education, body mass index, alcohol use) and infant (sex, gestational age, birth weight z score, mode of delivery, cord blood glucose concentration) characteristics, the newborns of smoking mothers had lower IGF-I concentrations (mean: 6.7 vs. 8.4 nmol/L, adjusted p = 0.006), and marginally higher proinsulin-to-insulin ratios (0.94 vs. 0.72, adjusted p = 0.06) than the newborns of non-smoking mothers. Cord plasma insulin, proinsulin, IGF-II, leptin and adiponectin concentrations and glucose-to-insulin ratios were similar in the newborns of smoking and non-smoking mothers.Maternal smoking was associated with decreased fetal IGF-I levels, and borderline lower fetal β-cell function. Larger cohort studies are required to confirm the latter finding. The preliminary findings prompt the hypothesis that these early life metabolic changes may be involved in the impact of maternal smoking on future risk of metabolic syndrome related disorders in the offspring.

Arachidonic acid (AA; C20∶4 n-6) and docosahexaenoic acid (DHA; C22∶6 n-3) are important long-chain polyunsaturated fatty acids (LC-PUFA) in maintaining pancreatic beta-cell structure and function. Newborns of gestational diabetic mothers are more susceptible to the development of type 2 diabetes in adulthood. It is not known whether low circulating AA or DHA is involved in perinatally "programming" this susceptibility. This study aimed to assess whether circulating concentrations of AA, DHA and other fatty acids are associated with fetal insulin sensitivity or beta-cell function, and whether low circulating concentrations of AA or DHA are involved in compromised fetal insulin sensitivity in gestational diabetic pregnancies.In a prospective singleton pregnancy cohort, maternal (32-35 weeks gestation) and cord plasma fatty acids were assessed in relation to surrogate indicators of fetal insulin sensitivity (cord plasma glucose-to-insulin ratio, proinsulin concentration) and beta-cell function (proinsulin-to-insulin ratio) in 108 mother-newborn pairs. Cord plasma DHA levels (in percentage of total fatty acids) were lower comparing newborns of gestational diabetic (n = 24) vs. non-diabetic pregnancies (2.9% vs. 3.5%, P = 0.01). Adjusting for gestational age at blood sampling, lower cord plasma DHA levels were associated with lower fetal insulin sensitivity (lower glucose-to-insulin ratio, r = 0.20, P = 0.036; higher proinsulin concentration, r = -0.37, P

Tumor immunosurveillance is known to be of critical importance in controlling tumorigenesis and progression in various cancers. The role of gamma-interferon-inducible lysosomal thiol reductase (GILT) in tumor immunosurveillance has recently been studied in several malignant diseases, but its role in breast cancer remains to be elucidated. In the present study, we found GILT as a significant different expressed gene by cDNA microarray analysis. To further determine the role of GILT in breast cancer, we examined GILT expression in breast cancers as well as noncancerous breast tissues by immunohistochemistry and real-time PCR, and assessed its association with clinicopathologic characteristics and patient outcome. The absence of GILT expression increased significantly from 2.02% (2/99) in noncancerous breast tissues to 15.6% (34/218) in breast cancer tissues (P

Pregnancy-induced or gestational hypertension is a common pregnancy complication. Paradoxically, gestational hypertension has been associated with a protective effect against perinatal mortality in twin pregnancies in analytic models (logistic regression) without accounting for survival time. Whether this effect is real remains uncertain. This study aimed to validate the impact of gestational hypertension on perinatal mortality in twin pregnancies using a survival analysis approach.This was a retrospective cohort study of 278,821 twin pregnancies, using the U.S. 1995-2000 matched multiple birth dataset (the largest dataset available for multiple births). Cox proportional hazard models were applied to estimate the adjusted hazard ratios (aHR) of perinatal death (stillbirth and neonatal death) comparing gestational hypertensive vs. non-hypertensive pregnancies controlling for maternal characteristics and twin cluster-level dependence.Comparing births in gestational hypertensive vs. non-hypertensive twin pregnancies, perinatal mortality rates were significantly lower (1.20% vs. 3.38%), so were neonatal mortality (0.72% vs. 2.30%) and stillbirth (0.48% vs. 1.10%) rates. The aHRs (95% confidence intervals) were 0.34 (0.31-0.38) for perinatal death, 0.31 (0.27-0.34) for neonatal death, and 0.45 (0.38-0.53) for stillbirth, respectively. The protective effect of gestational hypertension against perinatal death became weaker over advancing gestational age; the aHRs in very preterm (

PURPOSE: Excessive brain iron accumulation contributes to cognitive impairments in hepatitis B virus (HBV)-related cirrhotic patients. The underlying mechanism remains unclear. Hepcidin, a liver-produced, 25-aminoacid peptide, is the major regulator of systemic iron metabolism. Abnormal hepcidin level is a key factor in some body iron accumulation or deficiency disorders, especially in those associated with liver diseases. Our study was aimed to explore the relationship between brain iron content in patients with HBV-related cirrhosis and serum hepcidin level. METHODS: Seventy HBV-related cirrhotic patients and forty age- sex-matched healthy controls were enrolled. Brain iron content was quantified by susceptibility weighted phase imaging technique. Serum hepcidin as well as serum iron, serum transferrin, ferritin, soluble transferrin receptor, total iron binding capacity, and transferrin saturation were tested in thirty cirrhotic patients and nineteen healthy controls. Pearson correlation analysis was performed to investigate correlation between brain iron concentrations and serum hepcidin, or other iron parameters. RESULTS: Cirrhotic patients had increased brain iron accumulation compared to controls in the left red nuclear, the bilateral substantia nigra, the bilateral thalamus, the right caudate, and the right putamen. Cirrhotic patients had significantly decreased serum hepcidin concentration, as well as lower serum transferring level, lower total iron binding capacity and higher transferrin saturation, compared to controls. Serum hepcidin level negatively correlated with the iron content in the right caudate, while serum ferritin level positively correlated with the iron content in the bilateral putamen in cirrhotic patients. CONCLUSIONS: Decreased serum hepcidin level correlated with excessive iron accumulation in the basal ganglia in HBV-related cirrhotic patients. Our results indicated that systemic iron overload underlined regional brain iron repletion. Serum hepcidin may be a clinical biomarker for brain iron deposition in cirrhotic patients, which may have therapeutic potential.

BACKGROUND: Diabetes in pregnancy has been associated with a paradoxically reduced risk of neonatal death in twin pregnancies. Risk "shift" may be a concern in that the reduction in neonatal deaths may be due to an increase in fetal deaths (stillbirths). This study aimed to clarify the impact of diabetes on the risk of perinatal death (neonatal death plus stillbirth) in twin pregnancies. METHODS: This was a retrospective cohort study of twin births using the largest available dataset on twin births (the U.S. matched multiple birth data 1995-2000; 19,676 neonates from diabetic pregnancies, 541,481 from non-diabetic pregnancies). Cox proportional hazard models were applied to estimate the adjusted hazard ratios (aHR) of perinatal death accounting for twin cluster-level dependence. RESULTS: Comparing diabetic versus non-diabetic twin pregnancies, overall perinatal mortality rate was counterintuitively lower [2.1% versus 3.3%, aHR 0.70 (95% confidence intervals 0.63-0.78)]. Individually, both stillbirth and neonatal mortality rates were lower in diabetic pregnancies, but we identified significant differences by gestational age and birth weight. Diabetes was associated with a survival benefit in pregnancies completed before 32 weeks [aHR 0.55 (0.48-0.63)] or with birth weight =2500 g [aHR 2.20 (1.55-3.13)]. CONCLUSIONS: Diabetes in pregnancy appears to be "protective" against perinatal death in twin pregnancies ending in very preterm or very low birth weight births. Prospective studies are required to clarify whether these patterns of risk are real, or they are artifacts of unmeasured confounders. Additional data correlating these outcomes with the types of diabetes in pregnancy are also needed to distinguish the effects of pre-gestational vs. gestational diabetes.

The cancer stem cell (CSC) model depicts that tumors are hierarchically organized and maintained by CSCs lying at the apex. CSCs have been "identified" in a variety of tumors through the tumor-forming assay, in which tumor cells distinguished by a certain cell surface marker (known as a CSC marker) were separately transplanted into immunodeficient mice. In such assays, tumor cells positive but not negative for the CSC marker (hereby defined as CSC(+) and CSC(-) cells, respectively) have the ability of tumor-forming and generating both progenies. However, here we show that CSC(+) and CSC(-) cells exhibit similar proliferation in the native states. Using a cell tracing method, we demonstrate that CSC(-) cells exhibit similar tumorigenesis and proliferation as CSC(+) cells when they were co-transplanted into immunodeficient mice. Through serial single-cell derived subline construction, we further demonstrated that CSC(+) and CSC(-) cells from CSC marker expressing tumors could invariably generate both progenies, and their characteristics are maintained among different generations irrespective of the origins (CSC(+)-derived or CSC(-)-derived). These findings demonstrate that tumorigenic cells cannot be distinguished by common CSC markers alone and we propose that cautions should be taken when using these markers independently to identify cancer stem cells due to the phenotypic plasticity of tumor cells.

BACKGROUND: Famine provides quasi-experimental conditions for testing the hypothesis of "programming" health effects by poor nutrition in early life. It remains uncertain whether early life exposure to famine increases the risk of hypertension in adulthood. There is a lack of data on the relative impact of exposure to famine during fetal development versus infancy (

OBJECTIVE: The aim of this study is to observe the chronic effects of diltiazem release capsules on patients with coronary slow flow (CSF) phenomenon. METHODS: From 2004 to 2009, 80 consecutive patients with chest pain and normal coronary arteries evidenced by coronary angiography and CSF were included in this randomized, double-blind, placebo-controlled trial. CSF patterns were evaluated by the corrected TIMI frame count. Patients were randomly assigned at 1:1 ratio to diltiazem sustained-release capsules treatment group (Dil, 90 mg twice daily) or placebo control group. Holter, liver and kidney function, treadmill exercise test, coronary angiography and left ventricular angiography were measured at baseline and after 6 months. The incidence of cardiovascular events (re-admission or progress in coronary heart disease, myocardial infarction, malignant arrhythmia or cardiac death) was evaluated during the 6 months follow up. RESULTS: Thirty-nine patients in control and 40 patients in Dil group completed the 6 months follow-up. There was no medication induced drug withdraw during follow up. Left ventricular ejection fraction was similar between the 2 groups at baseline and during follow up. Heart rate was significantly lower in Dil group than in control group and there was no symptomatic bradycardia and II and III degree atrioventricular conduction block in both groups. Significant improvement was observed in the onset of chest pain, treadmill exercise test and coronary blood flow in Dil group while these parameters remained unchanged in control group at the end of 6 months follow up. The incidence of cardiovascular events was similar between the two groups. CONCLUSION: Diltiazem slow-release capsules improved coronary blood flow and alleviated angina in patients with CSF. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TCC-11001864.

BACKGROUND: The inflammatory response plays a critical role in hypertension-induced cardiac remodeling. We aimed to study how interaction among inflammatory cells causes inflammatory responses in the process of hypertensive cardiac fibrosis. METHODOLOGY/PRINCIPAL FINDINGS: Infusion of angiotensin II (Ang II, 1500 ng/kg/min) in mice rapidly induced the expression of interferon γ (IFN-γ) and leukocytes infiltration into the heart. To determine the role of IFN-γ on cardiac inflammation and remodeling, both wild-type (WT) and IFN-γ-knockout (KO) mice were infused Ang II for 7 days, and were found an equal blood pressure increase. However, knockout of IFN-γ prevented Ang II-induced: 1) infiltration of macrophages and T cells into cardiac tissue; 2) expression of tumor necrosis factor α and monocyte chemoattractant protein 1 (MCP-1), and 3) cardiac fibrosis, including the expression of α-smooth muscle actin and collagen I (all p

Endothelial nitric oxide synthase (eNOS)-related vessel relaxation is a highly coordinated process that regulates blood flow and pressure and is dependent on caveolae. Here, we investigated the role of caveolar plasma membrane stabilization by the dynamin-related ATPase EHD2 on eNOS-nitric oxide (NO)-dependent vessel relaxation. Loss of EHD2 in small arteries led to increased numbers of caveolae that were detached from the plasma membrane. Concomitantly, impaired relaxation of mesenteric arteries and reduced running wheel activity were observed in EHD2 knockout mice. EHD2 deletion or knockdown led to decreased production of nitric oxide (NO) although eNOS expression levels were not changed. Super-resolution imaging revealed that eNOS was redistributed from the plasma membrane to internalized detached caveolae in EHD2-lacking tissue or cells. Following an ATP stimulus, reduced cytosolic Ca2+ peaks were recorded in human umbilical vein endothelial cells (HUVECs) lacking EHD2. Our data suggest that EHD2-controlled caveolar dynamics orchestrates the activity and regulation of eNOS/NO and Ca2+ channel localization at the plasma membrane. [ABSTRACT FROM AUTHOR]

Objective: Adjacent segment pathology (ASP) is a common complication presenting in patients with axial pain and dysfunction, requiring treatment or follow-up surgery. However, whether minimally invasive surgery (MIS), including MIS transforaminal / posterior lumbar interbody fusion (MIS-TLIF/PLIF) decreases the incidence rate of ASP remains unknown. The aim of this meta-analysis was to compare the incidence rate of ASP in patients undergoing MIS versus open procedures. Methods: This systematic review was undertaken by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. We searched electronic databases, including PubMed, EMBASE, SinoMed, and the Cochrane Library, without language restrictions, to identify clinical trials comparing MIS to open procedures. The results retrieved were last updated on June 15, 2016. Results: Overall, 9 trials comprising 770 patients were included in the study; the quality of the studies included 4 moderate and 5 low-quality studies. The pooled data analysis demonstrated low heterogeneity between the trials and a significantly lower ASP incidence rate in patients who underwent MIS procedure, compared with those who underwent open procedure (p = 0.0001). Single-level lumbar interbody fusion was performed in 6 trials of 408 patients and we found a lower ASP incidence rate in MIS group, compared with those who underwent open surgery (p = 0.002). Moreover, the pooled data analysis showed a significant reduction in the incidence rate of adjacent segment disease (ASDis) (p = 0.0003) and adjacent segment degeneration (ASDeg) (p = 0.0002) for both procedures, favoring MIS procedure. Subgroup analyses showed no difference in follow-up durations between the procedures (p = 0.93). Conclusion: Therefore, we conclude that MIS-TLIF/PLIF can reduce the incidence rate of ASDis and ASDeg, compared with open surgery. Although the subgroup analysis did not indicate a difference in follow-up duration between the two procedures, larger-scale, well-designed clinical trials with extensive follow-up are needed to confirm and update the findings of this analysis. [ABSTRACT FROM AUTHOR]

A fundamental computational problem in metabolic engineering is to find pathways between compounds. Pathfinding methods using atom tracking have been widely used to find biochemically relevant pathways. However, these methods require the user to define the atoms to be tracked. This may lead to failing to predict the pathways that do not conserve the user-defined atoms. In this work, we propose a pathfinding method called AGPathFinder to find biochemically relevant metabolic pathways between two given compounds. In AGPathFinder, we find alternative pathways by tracking the movement of atomic groups through metabolic networks and use combined information of reaction thermodynamics and compound similarity to guide the search towards more feasible pathways and better performance. The experimental results show that atomic group tracking enables our method to find pathways without the need of defining the atoms to be tracked, avoid hub metabolites, and obtain biochemically meaningful pathways. Our results also demonstrate that atomic group tracking, when incorporated with combined information of reaction thermodynamics and compound similarity, improves the quality of the found pathways. In most cases, the average compound inclusion accuracy and reaction inclusion accuracy for the top resulting pathways of our method are around 0.90 and 0.70, respectively, which are better than those of the existing methods. Additionally, AGPathFinder provides the information of thermodynamic feasibility and compound similarity for the resulting pathways. [ABSTRACT FROM AUTHOR]

Metabolic pathway alignment has been widely used to find one-to-one and/or one-to-many reaction mappings to identify the alternative pathways that have similar functions through different sets of reactions, which has important applications in reconstructing phylogeny and understanding metabolic functions. The existing alignment methods exhaustively search reaction sets, which may become infeasible for large pathways. To address this problem, we present an effective alignment method for accurately extracting reaction mappings between two metabolic pathways. We show that connected relation between reactions can be formalized as binary relation of reactions in metabolic pathways, and the multiplications of zero-one matrices for binary relations of reactions can be accomplished in finite steps. By utilizing the multiplications of zero-one matrices for binary relation of reactions, we efficiently obtain reaction sets in a small number of steps without exhaustive search, and accurately uncover biologically relevant reaction mappings. Furthermore, we introduce a measure of topological similarity of nodes (reactions) by comparing the structural similarity of the k-neighborhood subgraphs of the nodes in aligning metabolic pathways. We employ this similarity metric to improve the accuracy of the alignments. The experimental results on the KEGG database show that when compared with other state-of-the-art methods, in most cases, our method obtains better performance in the node correctness and edge correctness, and the number of the edges of the largest common connected subgraph for one-to-one reaction mappings, and the number of correct one-to-many reaction mappings. Our method is scalable in finding more reaction mappings with better biological relevance in large metabolic pathways. [ABSTRACT FROM AUTHOR]

Background: Cree births in Quebec are characterized by the highest reported prevalence of macrosomia (~35%) in the world. It is unclear whether Cree births are at greater elevated risk of perinatal and infant mortality than other First Nations relative to non-Aboriginal births in Quebec, and if macrosomia may be related. Methods: This was a population-based retrospective birth cohort study using the linked birth-infant death database for singleton births to mothers from Cree (n = 5,340), other First Nations (n = 10,810) and non-Aboriginal (n = 229,960) communities in Quebec, 1996–2010. Community type was ascertained by residential postal code and municipality name. The primary outcomes were perinatal and infant mortality. Results: Macrosomia (birth weight for gestational age >90th percentile) was substantially more frequent in Cree (38.0%) and other First Nations (21.9%) vs non-Aboriginal (9.4%) communities. Comparing Cree and other First Nations vs non-Aboriginal communities, perinatal mortality rates were 1.52 (95% confidence intervals 1.17, 1.98) and 1.34 (1.10, 1.64) times higher, and infant mortality rates 2.27 (1.71, 3.02) and 1.49 (1.16, 1.91) times higher, respectively. The risk elevations in perinatal and infant death in Cree communities attenuated after adjusting for maternal characteristics (age, education, marital status, parity), but became greater after further adjustment for birth weight (small, appropriate, or large for gestational age). Conclusions: Cree communities had greater risk elevations in perinatal and infant mortality than other First Nations relative to non-Aboriginal communities in Quebec. High prevalence of macrosomia did not explain the elevated risk of perinatal and infant mortality in Cree communities. [ABSTRACT FROM AUTHOR]

ATP-binding cassette transporter A1 (ABCA1) plays a critical role in maintaining cellular cholesterol homeostasis. The purpose of this study is to identify the molecular mechanism(s) underlying ABCA1 epigenetic modification and determine its potential impact on ABCA1 expression in macrophage-derived foam cell formation and atherosclerosis development. DNA methylation induced foam cell formation from macrophages and promoted atherosclerosis in apolipoprotein E-deficient (apoE−/−) mice. Bioinformatics analyses revealed a large CpG island (CGI) located in the promoter region of ABCA1. Histone methyltransferase enhancer of zeste homolog 2 (EZH2) downregulated ABCA1 mRNA and protein expression in THP-1 and RAW264.7 macrophage-derived foam cells. Pharmacological inhibition of DNA methyltransferase 1 (DNMT1) with 5-Aza-dC or knockdown of DNMT1 prevented the downregulation of macrophage ABCA1 expression, suggesting a role of DNA methylation in ABCA1 expression. Polycomb protein EZH2 induced DNMT1 expression and methyl-CpG-binding protein-2 (MeCP2) recruitment, and stimulated the binding of DNMT1 and MeCP2 to ABCA1 promoter, thereby promoting ABCA1 gene DNA methylation and atherosclerosis. Knockdown of DNMT1 inhibited EZH2-induced downregulation of ABCA1 in macrophages. Conversely, EZH2 overexpression stimulated DNMT1-induced ABCA1 gene promoter methylation and atherosclerosis. EZH2-induced downregulation of ABCA1 gene expression promotes foam cell formation and the development of atherosclerosis by DNA methylation of ABCA1 gene promoter. [ABSTRACT FROM AUTHOR]

Background: The optimal mode of delivery in twin pregnancies remains controversial. A recent randomized trial did not find any benefit of planned cesarean vs. vaginal delivery at 32–38 weeks gestation, but the trial was not powered to detect a moderate effect. We aimed to evaluate the impact of cesarean delivery on perinatal mortality and severe neonatal morbidity in twin pregnancies at ≥32 weeks through a large database exploration approach with the power to detect moderate risk differences. Methods: In a retrospective birth cohort study using the U.S. matched multiple births, 1995–2000 (the available largest multiple birth dataset), we compared perinatal outcomes in twins (n = 181,810 pregnancies) delivered at 32–41 weeks gestation without congenital anomalies. The primary outcome was a composite of perinatal death and severe neonatal morbidity. Cox regression was used to estimate the adjusted hazard ratio (aHR) controlling for the propensity to cesarean delivery, fetal characteristics (sex, birth weight, birth weight discordance, same-sex twin or not) and twin-cluster level dependence. Prospective risks were calculated using the fetuses-at-risk denominators. Results: The overall rates of the primary outcome were slightly lower in intended cesarean (6.20%) vs. vaginal (6.45%) deliveries. The aHRs of the primary outcome were in favor of vaginal delivery at 32 (aHR = 1.06, p = 0.03) or 33 (aHR = 1.22, p<0.001) weeks, neutral at 34–35 weeks, but in favor of cesarean delivery at 36 (aHR = 0.94, p = 0.004), 37, 38 and 39+ weeks (aHR: 0.72 to 0.78, all p<0.001). The lower risk of the primary outcome for cesarean vs. vaginal deliveries at 36+ weeks of gestation remained when the analyses were restricted to different-sex (dichorionic) twins (aHR = 0.84, 95% CI 0.80–0.88). Conclusion: Cesarean delivery may be beneficial for perinatal outcomes overall in twin pregnancies at ≥36 weeks gestation. [ABSTRACT FROM AUTHOR]

Background: Aboriginal populations are at substantially higher risks of adverse birth outcomes, perinatal and infant mortality than their non-Aboriginal counterparts even in developed countries including Australia, U.S. and Canada. There is a lack of data on recent trends in Canada. Methods: We conducted a population-based retrospective cohort study (n = 254,410) using the linked vital events registry databases for singleton births in Quebec 1996–2010. Aboriginal (First Nations, Inuit) births were identified by mother tongue, place of residence and Indian Registration System membership. Outcomes included preterm birth, small-for-gestational-age, large-for-gestational-age, low birth weight, high birth weight, stillbirth, neonatal death, postneonatal death, perinatal death and infant death. Results: Perinatal and infant mortality rates were 1.47 and 1.80 times higher in First Nations (10.1 and 7.3 per 1000, respectively), and 2.37 and 4.46 times higher in Inuit (16.3 and 18.1 per 1000, respectively) relative to non-Aboriginal (6.9 and 4.1 per 1000, respectively) births (all p<0.001). Compared to non-Aboriginal births, preterm birth rates were persistently (1.7–1.8 times) higher in Inuit, large-for-gestational-age birth rates were persistently (2.7–3.0 times) higher in First Nations births over the study period. Between 1996–2000 and 2006–2010, as compared to non-Aboriginal infants, the relative risk disparities increased for infant mortality (from 4.10 to 5.19 times) in Inuit, and for postneonatal mortality in Inuit (from 6.97 to 12.33 times) or First Nations (from 3.76 to 4.25 times) infants. Adjusting for maternal characteristics (age, marital status, parity, education and rural vs. urban residence) attenuated the risk differences, but significantly elevated risks remained in both Inuit and First Nations births for the risks of perinatal mortality (1.70 and 1.28 times, respectively), infant mortality (3.66 and 1.47 times, respectively) and postneonatal mortality (6.01 and 2.28 times, respectively) in Inuit and First Nations infants (all p<0.001). Conclusions: Aboriginal vs. non-Aboriginal disparities in adverse birth outcomes, perinatal and infant mortality are persistent or worsening over the recent decade in Quebec, strongly suggesting the needs for interventions to improve perinatal and infant health in Aboriginal populations, and for monitoring the trends in other regions in Canada. [ABSTRACT FROM AUTHOR]

Tumor immunosurveillance is known to be of critical importance in controlling tumorigenesis and progression in various cancers. The role of gamma-interferon-inducible lysosomal thiol reductase (GILT) in tumor immunosurveillance has recently been studied in several malignant diseases, but its role in breast cancer remains to be elucidated. In the present study, we found GILT as a significant different expressed gene by cDNA microarray analysis. To further determine the role of GILT in breast cancer, we examined GILT expression in breast cancers as well as noncancerous breast tissues by immunohistochemistry and real-time PCR, and assessed its association with clinicopathologic characteristics and patient outcome. The absence of GILT expression increased significantly from 2.02% (2/99) in noncancerous breast tissues to 15.6% (34/218) in breast cancer tissues (P<0.001). In accordance with its proliferation inhibiting function, GILT expression was inversely correlated with Ki67 index (P<0.05). In addition, absence of GILT was positively correlated with adverse characteristics of breast cancers, such as histological type, tumor size, lymph nodes status, and pTNM stage (P<0.05). Consistently, breast cancers with reduced GILT expression had poorer disease-free survival (P<0.005). Moreover, significantly decreased expression of GILT was found in both primary and metastatic breast cancer cells, in contrast to normal epithelial cells. These findings indicate that GILT may act as a tumor suppressor in breast cancer, in line with its previously suggested role in anti-tumor immunity. Thus, GILT has the potential to be a novel independent prognostic factor in breast cancer and further studies are needed to illustrate the underlying mechanism of this relationship. [ABSTRACT FROM AUTHOR]

A better understanding of metabolic fluxes is important for manipulating microbial metabolism toward desired end products, or away from undesirable by-products. A mutant strain, Gluconacetobacter xylinus AX2-16, was obtained by combined chemical mutation of the parent strain (G. xylinus CGMCC 2955) using DEC (diethyl sulfate) and LiCl. The highest bacterial cellulose production for this mutant was obtained at about 11.75 g/L, which was an increase of 62% compared with that by the parent strain. In contrast, gluconic acid (the main byproduct) concentration was only 5.71 g/L for mutant strain, which was 55.7% lower than that of parent strain. Metabolic flux analysis indicated that 40.1% of the carbon source was transformed to bacterial cellulose in mutant strain, compared with 24.2% for parent strain. Only 32.7% and 4.0% of the carbon source were converted into gluconic acid and acetic acid in mutant strain, compared with 58.5% and 9.5% of that in parent strain. In addition, a higher flux of tricarboxylic acid (TCA) cycle was obtained in mutant strain (57.0%) compared with parent strain (17.0%). It was also indicated from the flux analysis that more ATP was produced in mutant strain from pentose phosphate pathway (PPP) and TCA cycle. The enzymatic activity of succinate dehydrogenase (SDH), which is one of the key enzymes in TCA cycle, was 1.65-fold higher in mutant strain than that in parent strain at the end of culture. It was further validated by the measurement of ATPase that 3.53–6.41 fold higher enzymatic activity was obtained from mutant strain compared with parent strain. [ABSTRACT FROM AUTHOR]

Background: Pregnancy-induced or gestational hypertension is a common pregnancy complication. Paradoxically, gestational hypertension has been associated with a protective effect against perinatal mortality in twin pregnancies in analytic models (logistic regression) without accounting for survival time. Whether this effect is real remains uncertain. This study aimed to validate the impact of gestational hypertension on perinatal mortality in twin pregnancies using a survival analysis approach. Methods: This was a retrospective cohort study of 278,821 twin pregnancies, using the U.S. 1995–2000 matched multiple birth dataset (the largest dataset available for multiple births). Cox proportional hazard models were applied to estimate the adjusted hazard ratios (aHR) of perinatal death (stillbirth and neonatal death) comparing gestational hypertensive vs. non-hypertensive pregnancies controlling for maternal characteristics and twin cluster-level dependence. Results: Comparing births in gestational hypertensive vs. non-hypertensive twin pregnancies, perinatal mortality rates were significantly lower (1.20% vs. 3.38%), so were neonatal mortality (0.72% vs. 2.30%) and stillbirth (0.48% vs. 1.10%) rates. The aHRs (95% confidence intervals) were 0.34 (0.31–0.38) for perinatal death, 0.31 (0.27–0.34) for neonatal death, and 0.45 (0.38–0.53) for stillbirth, respectively. The protective effect of gestational hypertension against perinatal death became weaker over advancing gestational age; the aHRs in very preterm (<32 weeks), mild preterm (32–36 weeks) and term (37+ weeks) births were 0.29, 0.48 and 0.76, respectively. The largest risk reductions in neonatal mortality were observed for infections and immaturity-related conditions. Conclusions: Gestational hypertension appears to be beneficial for fetal survival in twin pregnancies, especially in those ending more prematurely or for deaths due to infections and immaturity-related conditions. Prospective studies are required to rule out the possibility of unmeasured confounders. [ABSTRACT FROM AUTHOR]

Background: Arachidonic acid (AA; C20∶4 n-6) and docosahexaenoic acid (DHA; C22∶6 n-3) are important long-chain polyunsaturated fatty acids (LC-PUFA) in maintaining pancreatic beta-cell structure and function. Newborns of gestational diabetic mothers are more susceptible to the development of type 2 diabetes in adulthood. It is not known whether low circulating AA or DHA is involved in perinatally “programming” this susceptibility. This study aimed to assess whether circulating concentrations of AA, DHA and other fatty acids are associated with fetal insulin sensitivity or beta-cell function, and whether low circulating concentrations of AA or DHA are involved in compromised fetal insulin sensitivity in gestational diabetic pregnancies. Methods and Principal Findings: In a prospective singleton pregnancy cohort, maternal (32-35 weeks gestation) and cord plasma fatty acids were assessed in relation to surrogate indicators of fetal insulin sensitivity (cord plasma glucose-to-insulin ratio, proinsulin concentration) and beta-cell function (proinsulin-to-insulin ratio) in 108 mother-newborn pairs. Cord plasma DHA levels (in percentage of total fatty acids) were lower comparing newborns of gestational diabetic (n = 24) vs. non-diabetic pregnancies (2.9% vs. 3.5%, P = 0.01). Adjusting for gestational age at blood sampling, lower cord plasma DHA levels were associated with lower fetal insulin sensitivity (lower glucose-to-insulin ratio, r = 0.20, P = 0.036; higher proinsulin concentration, r = −0.37, P <0.0001). The associations remained after adjustment for maternal and newborn characteristics. Cord plasma saturated fatty acids C18∶0 and C20∶0 were negatively correlated with fetal insulin sensitivity, but their levels were not different between gestational diabetic and non-diabetic pregnancies. Cord plasma AA levels were not correlated with fetal insulin sensitivity. Conclusion: Low circulating DHA levels are associated with compromised fetal insulin sensitivity, and may be involved in perinatally “programming” the susceptibility to type 2 diabetes in the offspring of gestational diabetic mothers. [ABSTRACT FROM AUTHOR]

Background:Diabetes in pregnancy has been associated with a paradoxically reduced risk of neonatal death in twin pregnancies. Risk “shift” may be a concern in that the reduction in neonatal deaths may be due to an increase in fetal deaths (stillbirths). This study aimed to clarify the impact of diabetes on the risk of perinatal death (neonatal death plus stillbirth) in twin pregnancies. Methods:This was a retrospective cohort study of twin births using the largest available dataset on twin births (the U.S. matched multiple birth data 1995-2000; 19,676 neonates from diabetic pregnancies, 541,481 from non-diabetic pregnancies). Cox proportional hazard models were applied to estimate the adjusted hazard ratios (aHR) of perinatal death accounting for twin cluster-level dependence. Results:Comparing diabetic versus non-diabetic twin pregnancies, overall perinatal mortality rate was counterintuitively lower [2.1% versus 3.3%, aHR 0.70 (95% confidence intervals 0.63-0.78)]. Individually, both stillbirth and neonatal mortality rates were lower in diabetic pregnancies, but we identified significant differences by gestational age and birth weight. Diabetes was associated with a survival benefit in pregnancies completed before 32 weeks [aHR 0.55 (0.48-0.63)] or with birth weight <1500 g [aHR 0.61 (0.53-0.69)]. In contrast, diabetes was associated with an elevated risk of perinatal death in pregnancies delivered between 32 and 36 weeks [aHR 1.38 (1.10-1.72)] or with birth weight >=2500 g [aHR 2.20 (1.55-3.13)]. Conclusions:Diabetes in pregnancy appears to be “protective” against perinatal death in twin pregnancies ending in very preterm or very low birth weight births. Prospective studies are required to clarify whether these patterns of risk are real, or they are artifacts of unmeasured confounders. Additional data correlating these outcomes with the types of diabetes in pregnancy are also needed to distinguish the effects of pre-gestational vs. gestational diabetes. [ABSTRACT FROM AUTHOR]

The halotolerant chlorophyte Dunaliella salina can accumulate up to 10% of its dry weight as β-carotene in chloroplasts when subjected to adverse conditions, including nutrient deprivation. However, the mechanisms of carotenoid biosynthesis are poorly understood. Here, the physiological and molecular responses to the deprivation of nitrogen (-N), sulfur (-S), phosphorus (-P) and different combinations of those nutrients (-N-P, -N-S, -P-S and -N-P-S) were compared to gain insights into the underlying regulatory mechanisms of carotenoid biosynthesis. The results showed that both the growth and photosynthetic rates of cells were decreased during nutrient deprivation, accompanied by lipid globule accumulation and reduced chlorophyll levels. The SOD and CAT activities of the cells were altered during nutrient deprivation, but their responses were different. The total carotenoid contents of cells subjected to multiple nutrient deprivation were higher than those of cells subjected to single nutrient deprivation and non-stressed cells. The β-carotene contents of cells subjected to -N-P, -N-S and -N-P-S were higher than those of cells subjected to single nutrient deprivation. Cells subjected to sulfur deprivation accumulated more lutein than cells subjected to nitrogen and phosphorous deprivation. In contrast, no cumulative effects of nutrient deprivation on the transcription of genes in the carotenogenic pathway were observed because MEP and carotenogenic pathway genes were up-regulated during single nutrient deprivation but were downregulated during multiple nutrient deprivation. Therefore, we proposed that the carotenoid biosynthesis pathway of D. salina is regulated at both the transcriptional and posttranscriptional levels and that a complex crosstalk occurs at the physiological and molecular levels in response to the deprivation of different nutrients.

A better understanding of metabolic fluxes is important for manipulating microbial metabolism toward desired end products, or away from undesirable by-products. A mutant strain, Gluconacetobacter xylinus AX2-16, was obtained by combined chemical mutation of the parent strain (G. xylinus CGMCC 2955) using DEC (diethyl sulfate) and LiCl. The highest bacterial cellulose production for this mutant was obtained at about 11.75 g/L, which was an increase of 62% compared with that by the parent strain. In contrast, gluconic acid (the main byproduct) concentration was only 5.71 g/L for mutant strain, which was 55.7% lower than that of parent strain. Metabolic flux analysis indicated that 40.1% of the carbon source was transformed to bacterial cellulose in mutant strain, compared with 24.2% for parent strain. Only 32.7% and 4.0% of the carbon source were converted into gluconic acid and acetic acid in mutant strain, compared with 58.5% and 9.5% of that in parent strain. In addition, a higher flux of tricarboxylic acid (TCA) cycle was obtained in mutant strain (57.0%) compared with parent strain (17.0%). It was also indicated from the flux analysis that more ATP was produced in mutant strain from pentose phosphate pathway (PPP) and TCA cycle. The enzymatic activity of succinate dehydrogenase (SDH), which is one of the key enzymes in TCA cycle, was 1.65-fold higher in mutant strain than that in parent strain at the end of culture. It was further validated by the measurement of ATPase that 3.53-6.41 fold higher enzymatic activity was obtained from mutant strain compared with parent strain.

Background: Famine provides quasi-experimental conditions for testing the hypothesis of "programming" health effects by poor nutrition in early life. It remains uncertain whether early life exposure to famine increases the risk of hypertension in adulthood. There is a lack of data on the relative impact of exposure to famine during fetal development versus infancy (<2 years postnatal). We sought to assess the impact of exposure to the 1959-1961 Chinese Great Famine (the largest in human history) during fetal development and infancy on the risks of hypertension, short stature and obesity in adulthood., Methodology/principal Findings: We conducted a retrospective cohort study of 12,065 adults (46-53 years of age) born 1957-1964 in the Zhongshan and Nanhai municipalities of Guangdong province, China. Adjusting for socio-demographic and lifestyle characteristics, as compared to subjects who were unexposed to famine, the risk of hypertension was not significantly elevated in subjects exposed to famine during fetal development only overall, but was 1.36-fold higher in those exposed during the first trimester of pregnancy only [adjusted odds ratio (OR) 1.36 (95% confidence intervals 1.03-1.79)], 1.83-fold higher in those exposed during infancy only [adjusted OR 1.83 (1.61-2.08)], and 1.31-fold higher in those exposed during both fetal development and infancy [adjusted OR 1.31 (1.14-1.51)]. Exposure to famine during infancy increased the risk of short stature. Early life exposure to famine did not increase the risk of obesity., Conclusions/significance: Exposure to the Chinese Great Famine during the first trimester of pregnancy only, or during infancy only, or during both fetal development and infancy increased the risk of hypertension in adulthood, suggesting an important role of changes in exposure to famine during fetal development and from prenatal to early postnatal life in developmental "programming" cardiovascular disease risk.