Electroacupuncture at the Zusanli (ST-36) Acupoint Induces a Hypoglycemic Effect by Stimulating the Cholinergic Nerve in a Rat Model of Streptozotocine-Induced Insulin-Dependent Diabetes Mellitus

Animal studies have shown that electroacupuncture (EA) at Zusanli (ST-36) and Zhongwan (CV-12) acupoints reduces plasma glucose concentrations in rats with type II diabetes. However, whether EA reduces plasma glucose levels in type I diabetes is still unknown. In this study, we explore the various non-insulin-dependent pathways involved in EA-induced lowering of plasma glucose. Streptozotocin (STZ) (60 mg kg−1, i.v.) was administered via the femoral vein to induce insulin-dependent diabetes in non-adrenalectomized and in adrenalectomomized rats. EA (15 Hz) was applied for 30 min to bilateral ST-36 acupoints after administration of Atropine (0.1 mg kg−1 i.p.), Eserine (0.01 mg kg−1 i.p.), or Hemicholinium-3 (5 μg kg−1 i.p.) in non-adrenalectomized rats. Rats administered acetylcholine (0.01 mg kg−1 i.v.) did not undergo EA. Adrenalectomized rats underwent EA at bilateral ST-36 acupoints without further treatment. Blood samples were drawn from all rats before and after EA to measure changes in plasma glucose levels. Expression of insulin signaling proteins (IRS1, AKT2) in atropine-exposed rats before and after EA was measured by western blot. Atropine and hemicholinium-3 completely blocked the plasma glucose lowering effects of EA, whereas eserine led to a significant hypoglycemic response. In addition, plasma glucose levels after administration of acetylcholine were significantly lower than the fasting glucose levels. In STZ-adrenalectomized rats, EA did not induce a hypoglycemic response. EA stimulated the expression of IRS1 and AKT2 and atropine treatment blocked the EA-induced expression of those insulin signaling proteins. Taken together, EA at the ST-36 acupoint reduces plasma glucose concentrations by stimulating the cholinergic nerves

Electroacupuncture-Induced Cholinergic Nerve Activation Enhances the Hypoglycemic Effect of Exogenous Insulin in a Rat Model of Streptozotocin-Induced Diabetes

The aim of this study is to explore the mechanisms by which electroacupuncture (EA) enhances the hypoglycemic effect of exogenous insulin in a streptozotocin- (STZ-) diabetic rats. Animals in the EA group were anesthetized and subjected to the insulin challenge test (ICT) and EA for 60 minutes. In the control group, rats were subjected to the same treatment with the exception of EA stimulation. Blood samples were drawn to measure changes in plasma glucose, free fatty acids (FFA), and insulin levels. Western blot was used to assay proteins involved in insulin signaling. Furthermore, atropine, hemicholinium-3 (HC-3), and Eserine were used to explore the relationship between EA and cholinergic nerve activation during ICT. EA augmented the blood glucose-lowering effects of EA by activating the cholinergic nerves in STZ rats that had been exposed to exogenous insulin. This phenomenon may be related to enhancement of insulin signaling rather than to changes in FFA concentration

Peroxisome Proliferator–Activated Receptor γ Level Contributes to Structural Integrity and Component Production of Elastic Fibers in the AortaNovelty and Significance

Loss of integrity and massive disruption of elastic fibers are key features of abdominal aortic aneurysm (AAA). Peroxisome proliferator-activated receptor γ (PPARγ) has been shown to attenuate AAA through inhibition of inflammation and proteolytic degradation. However, its involvement in elastogenesis during AAA remains unclear. PPARγ was highly expressed in human AAA within all vascular cells, including inflammatory cells and fibroblasts. In the aortas of transgenic mice expressing PPARγ at 25% normal levels (PpargC/− mice), we observed the fragmentation of elastic fibers and reduced expression of vital elastic fiber components of elastin and fibulin-5. These were not observed in mice with 50% normal PPARγ expression (Pparg+/− mice). Infusion of a moderate dose of angiotensin II (AngII) (500 ng/kg/min) did not induce AAA but Pparg+/− aorta developed flattened elastic lamellae, while PpargC/− aorta showed severe destruction of elastic fibers. After infusion of AngII at 1000 ng/kg/min, 73% of PpargC/− mice developed atypical suprarenal aortic aneurysms: superior mesenteric arteries were dilated with extensive collagen deposition in adventitia and infiltrations of inflammatory cells. Although matrix metalloproteinase inhibition by doxycycline somewhat attenuated the dilation of aneurysm, it did not reduce the incidence nor elastic lamella deterioration in AngII-infused PpargC/− mice. Furthermore, PPARγ antagonism down-regulated elastin and fibulin-5 in fibroblasts, but not in vascular smooth muscle cells. Chromatin immunoprecipitation assay demonstrated PPARγ binding in the genomic sequence of fibulin-5 in fibroblasts. Our results underscore the importance of PPARγ in AAA development though orchestrating proper elastogenesis and preserving elastic fiber integrity

Role of DNA methylation and epigenetic silencing of HAND2 in endometrial cancer development

Background: Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development. Methods and Findings: Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression. Conclusions: HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies.publishedVersio

Cross-National Differences in Victimization : Disentangling the Impact of Composition and Context

Varying rates of criminal victimization across countries are assumed to be the outcome of countrylevel structural constraints that determine the supply ofmotivated o¡enders, as well as the differential composition within countries of suitable targets and capable guardianship. However, previous empirical tests of these ‘compositional’ and ‘contextual’ explanations of cross-national di¡erences have been performed upon macro-level crime data due to the unavailability of comparable individual-level data across countries. This limitation has had two important consequences for cross-national crime research. First, micro-/meso-level mechanisms underlying cross-national differences cannot be truly inferred from macro-level data. Secondly, the e¡ects of contextual measures (e.g. income inequality) on crime are uncontrolled for compositional heterogeneity. In this paper, these limitations are overcome by analysing individual-level victimization data across 18 countries from the International CrimeVictims Survey. Results from multi-level analyses on theft and violent victimization indicate that the national level of income inequality is positively related to risk, independent of compositional (i.e. micro- and meso-level) di¡erences. Furthermore, crossnational variation in victimization rates is not only shaped by di¡erences in national context, but also by varying composition. More speci¢cally, countries had higher crime rates the more they consisted of urban residents and regions with lowaverage social cohesion.

Effects of Reproductive Status, Social Rank, Sex and Group Size on Vigilance Patterns in Przewalski's Gazelle

Quantifying vigilance and exploring the underlying mechanisms has been the subject of numerous studies. Less attention has focused on the complex interplay between contributing factors such as reproductive status, social rank, sex and group size. Reproductive status and social rank are of particular interest due to their association with mating behavior. Mating activities in rutting season may interfere with typical patterns of vigilance and possibly interact with social rank. In addition, balancing the tradeoff between vigilance and life maintenance may represent a challenge for gregarious ungulate species rutting under harsh winter conditions. We studied vigilance patterns in the endangered Przewalski's gazelle (Procapra przewalskii) during both the rutting and non-rutting seasons to examine these issues.Field observations were carried out with focal sampling during rutting and non-rutting season in 2008-2009. Results indicated a complex interplay between reproductive status, social rank, sex and group size in determining vigilance in this species. Vigilance decreased with group size in female but not in male gazelles. Males scanned more frequently and thus spent more time vigilant than females. Compared to non-rutting season, gazelles increased time spent scanning at the expense of bedding in rutting season. During the rutting season, territorial males spent a large proportion of time on rutting activities and were less vigilant than non-territorial males. Although territorial males may share collective risk detection with harem females, we suggest that they are probably more vulnerable to predation because they seemed reluctant to leave rut stands under threats.Vigilance behavior in Przewalski's gazelle was significantly affected by reproductive status, social rank, sex, group size and their complex interactions. These findings shed light on the mechanisms underlying vigilance patterns and the tradeoff between vigilance and other crucial activities

Replication and Meta-Analysis of GWAS Identified Susceptibility Loci in Kawasaki Disease Confirm the Importance of B Lymphoid Tyrosine Kinase (BLK) in Disease Susceptibility

10.1371/journal.pone.0072037PLoS ONE88-POLN

cAMP/PKA Regulates Osteogenesis, Adipogenesis and Ratio of RANKL/OPG mRNA Expression in Mesenchymal Stem Cells by Suppressing Leptin

BACKGROUND: Mesenchymal stem cells (MSCs) are a pluripotent cell type that can differentiate into adipocytes, osteoblasts and other cells. The reciprocal relationship between adipogenesis and osteogenesis was previously demonstrated; however, the mechanisms remain largely unknown. METHODS AND FINDINGS: We report that activation of PKA by 3-isobutyl-1 methyl xanthine (IBMX) and forskolin enhances adipogenesis, the gene expression of PPARgamma2 and LPL, and downregulates the gene expression of Runx2 and osteopontin, markers of osteogenesis. PKA activation also decreases the ratio of Receptor Activator of the NF-kappaB Ligand to Osteoprotegerin (RANKL/OPG) gene expression - the key factors of osteoclastogenesis. All these effects are mediated by the cAMP/PKA/CREB pathway by suppressing leptin, and may contribute to PKA stimulators-induced in vivo bone loss in developing zebrafish. CONCLUSIONS: Using MSCs, the center of a newly proposed bone metabolic unit, we identified cAMP/PKA signaling, one of the many signaling pathways that regulate bone homeostasis via controlling cyto-differentiation of MSCs and altering RANKL/OPG gene expression

A Holistic Perspective on the Dynamics of G035.39-00.33 : The Interplay between Gas and Magnetic Fields

Magnetic field plays a crucial role in shaping molecular clouds and regulating star formation, yet the complete information on the magnetic field is not well constrained owing to the limitations in observations. We study the magnetic field in the massive infrared dark cloud G035.39-00.33 from dust continuum polarization observations at 850 mu m with SCUBA-2/POL-2 at JCMT for the first time. The magnetic field tends to be perpendicular to the densest part of the main filament (F-M), whereas it has a less defined relative orientation in the rest of the structure, where it tends to be parallel to some diffuse regions. A mean plane-of-the-sky magnetic field strength of similar to 50 mu G for F-M is obtained using the Davis-Chandrasekhar-Fermi method. Based on (CO)-C-13 (1-0) line observations, we suggest a formation scenario of F-M due to large-scale (similar to 10 pc) cloud-cloud collision. Using additional NH3 line data, we estimate that F-M will be gravitationally unstable if it is only supported by thermal pressure and turbulence. The northern part of F-M, however, can be stabilized by a modest additional support from the local magnetic field. The middle and southern parts of F-M are likely unstable even if the magnetic field support is taken into account. We claim that the clumps in F-M may be supported by turbulence and magnetic fields against gravitational collapse. Finally, we identified for the first time a massive (similar to 200 M-circle dot, collapsing starless clump candidate, "c8," in G035.39-00.33. The magnetic field surrounding "c8" is likely pinched, hinting at an accretion flow along the filament.Peer reviewe

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin