Frzb modulates Wnt-9a-mediated β-catenin signaling during avian atrioventricular cardiac cushion development

AbstractNormal development of the cardiac atrioventricular (AV) endocardial cushions is essential for proper ventricular septation and morphogenesis of the mature mitral and tricuspid valves. In this study, we demonstrate spatially restricted expression of both Wnt-9a (formerly Wnt-14) and the secreted Wnt antagonist Frzb in AV endocardial cushions of the developing chicken heart. Wnt-9a expression is detected only in AV canal endocardial cells, while Frzb expression is detected in both endocardial and transformed mesenchymal cells of the developing AV cardiac cushions. We present evidence that Wnt-9a promotes cell proliferation in the AV canal and overexpression of Wnt-9a in ovo results in enlarged endocardial cushions and AV inlet obstruction. Wnt-9a stimulates β-catenin-responsive transcription in AV canal cells, duplicates the embryonic axis upon ventral injections in Xenopus embryos and appears to regulate cell proliferation by activating a Wnt/β-catenin signaling pathway. Additional functional studies reveal that Frzb inhibits Wnt-9a-mediated cell proliferation in cardiac cushions. Together, these data argue that Wnt-9a and Frzb regulate mesenchymal cell proliferation leading to proper AV canal cushion outgrowth and remodeling in the developing avian heart

Diurnal blood pressure pattern and development of prehypertension or hypertension in young adults: the CARDIA study

Nondippers (people whose sleep systolic blood pressure [SBP] fails to decrease >10% from daytime SBP) have increased risk of cardiovascular disease. The prevalence of nondipping in younger adults has not been well studied, nor has its value for predicting hypertension. We examined the prevalence of nondipping in a substudy of the Coronary Artery Risk Development in Young Adults (CARDIA) Study. We used Cox regression to estimate the hazard ratio (HR) conferred by nondipping for incident prehypertension or hypertension (preHTN/HTN) over 15 years. Of the 264 nonhypertensive participants at baseline, 118 (45%) were nondippers. Blacks were more likely than whites to be nondippers (52% versus 33%, P = .004). The incidence rate of preHTN/HTN was 29.2/1000 person-years among dippers and 36.2/1000 person-years among nondippers. Compared with those in the lowest quartile of nighttime to daytime SBP, those in the highest quartile were more likely to develop preHTN/HTN (HR 1.61; P = .06), but this relationship was attenuated after adjustment (HR 1.34; P = .27). Our results demonstrate that nondipping is common in young, nonhypertensive adults, and is more common in blacks than whites. Nondipping might predate a meaningful clinically detected increase in BP in some people, but more research in larger study samples is needed

The structural properties of sexual fantasies for sexual offenders : a preliminary model

While the phenomenon of sexual fantasy has been researched extensively, little contemporary inquiry has investigated the structural properties of sexual fantasy within the context of sexual offending. In this study, a qualitative analysis was used to develop a descriptive model of the phenomena of sexual fantasy during the offence process. Twenty-four adult males convicted of sexual offences provided detailed retrospective descriptions of their thoughts, emotions and behaviours—before, during and after their offences. A data-driven approach to model development, known as Grounded Theory, was undertaken to analyse the interview transcripts. A model was developed to elucidate the structural properties of sexual fantasy in the process of sexual offending, as well as the physiological and psychological variables associated with it. The Sexual Fantasy Structural Properties Model (SFSPM) comprises eight categories that describe various properties of sexual fantasy across the offence process. These categories are: origin, context, trigger, perceptual modality, clarity, motion, intensity and emotion. The strengths of the SFSPM are discussed and its clinical implications are reviewed. Finally, the limitations of the study are presented and future research directions discussed

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

The neuronal code(s) of the cerebellum

Understanding how neurons encode information in sequences of action potentials is of fundamental importance to neuroscience. The cerebellum is widely recognized for its involvement in the coordination of movements, which requires muscle activation patterns to be controlled with millisecond precision. Understanding how cerebellar neurons accomplish such high temporal precision is critical to understanding cerebellar function. Inhibitory Purkinje cells, the only output neurons of the cerebellar cortex, and their postsynaptic target neurons in the cerebellar nuclei, fire action potentials at high, sustained frequencies, suggesting spike rate modulation as a possible code. Yet, millisecond precise spatiotemporal spike activity patterns in Purkinje cells and inferior olivary neurons have also been observed. These results and ongoing studies suggest that the neuronal code used by cerebellar neurons may span a wide time scale from millisecond precision to slow rate modulations, likely depending on the behavioral context

Nighttime blood pressure dipping in young adults and coronary artery calcium 10-15 years later: the coronary artery risk development in young adults study

Nighttime blood pressure (BP) dipping can be quantified as the ratio of mean nighttime (sleep) BP to mean daytime (awake) BP. People whose dipping ratio is \u3e/= 0.90 have been referred to as nondippers, and nondipping is associated with cardiovascular disease events. We examined the relationship between systolic nighttime BP dipping in young adults and the presence of coronary artery calcium (CAC) 10 to 15 years later using data from the ambulatory BP monitoring substudy of the Coronary Artery Risk Development in Young Adults Study. Among 239 participants with adequate measures of both nighttime and daytime readings and coronary artery calcium, the systolic BP dipping ratio ranged from 0.72 to 1.24 (mean, 0.88; SD, 0.06), and CAC was present 10 to 15 years later in 54 participants (22.6%). Compared with those whose systolic BP dipping ratio ranged from 0.88 to 0.92 (quartile 3), the 57 participants (23.9%) with less pronounced or absent dipping (ratio, 0.92-1.24; quartile 4) had an unadjusted odds ratio of 4.08 (95% CI, 1.48-11.2) for the presence of CAC. The 60 participants (25.1%) with a more pronounced dipping (ratio, 0.72-0.85; quartile 1) also had greater odds for presence of CAC (odds ratio, 4.76 [95% CI, 1.76-12.9]). When modeled as a continuous predictor, a U-shaped relationship between systolic BP dipping ratio and future CAC was apparent and persisted after adjustment for multiple potential confounders (P\u3c0.001 for quadratic term). Both failure of systolic BP to dip sufficiently and overdipping during nighttime may be associated with future subclinical coronary atherosclerosis

Imaging specific cellular glycan structures using glycosyltransferases via click chemistry

Abstract Heparan sulfate (HS) is a polysaccharide fundamentally important for biologically activities. T/Tn antigens are universal carbohydrate cancer markers. Here, we report the specific imaging of these carbohydrates using a mesenchymal stem cell line and human umbilical vein endothelial cells (HUVEC). The staining specificities were demonstrated by comparing imaging of different glycans and validated by either removal of target glycans, which results in loss of signal, or installation of target glycans, which results in gain of signal. As controls, representative key glycans including O-GlcNAc, lactosaminyl glycans and hyaluronan were also imaged. HS staining revealed novel architectural features of the extracellular matrix (ECM) of HUVEC cells. Results from T/Tn antigen staining suggest that O-GalNAcylation is a rate-limiting step for O-glycan synthesis. Overall, these highly specific approaches for HS and T/Tn antigen imaging should greatly facilitate the detection and functional characterization of these biologically important glycans