Search

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]

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]