Loss of angiotensin II receptor expression in dopamine neurons in Parkinson’s disease correlates with pathological progression and is accompanied by increases in Nox4- and 8-OH guanosine-related nucleic acid oxidation and caspase-3 activation

In rodent models of Parkinsons disease (PD), dopamine neuron loss is accompanied by increased expression of angiotensin II (AngII), its type 1 receptor (AT1), and NADPH oxidase (Nox) in the nigral dopamine neurons and microglia. AT1 blockers (ARBs) stymie such oxidative damage and neuron loss. Whether changes in the AngII/AT1/Nox4 axis contribute to Parkinson neuropathogenesis is unknown. Here, we studied the distribution of AT1 and Nox4 in dopamine neurons in two nigral subregions: the less affected calbindin-rich matrix and the first-affected calbindin-poor nigrosome 1 of three patients, who were clinically asymptomatic, but had nigral dopamine cell loss and Braak stages consistent with a neuropathological diagnosis of PD (prePD). For comparison, five clinically- and neuropathologically-confirmed PD patients and seven age-matched control patients (AMC) were examined.AT1 and Nox4 immunoreactivity was noted in dopamine neurons in both the matrix and the nigrosome 1. The total cellular levels of AT1 in surviving dopamine neurons in the matrix and nigrosome 1 declined from AMC>prePD>PD, suggesting that an AngII/AT1/Nox4 axis orders neurodegenerative progression. In this vein, the loss of dopamine neurons was paralleled by a decline in total AT1 per surviving dopamine neuron. Similarly, AT1 in the nuclei of surviving neurons in the nigral matrix declined with disease progression, i.e., AMC>prePD>PD. In contrast, in nigrosome 1, the expression of nuclear AT1 was unaffected and similar in all groups. The ratio of nuclear AT1 to total AT1 (nuclear + cytoplasmic + membrane) in dopamine neurons increased stepwise from AMC to prePD to PD. The proportional increase in nuclear AT1 in dopamine neurons in nigrosome 1 of prePD and PD patients was accompanied by elevated nuclear expression of Nox4, oxidative damage to DNA, and caspase-3-mediated cell loss.Our observations are consistent with the idea that AngII/AT1/Nox4 axis-mediated oxidative stress gives rise to the dopamine neuron dysfunction and loss characteristic of the neuropathological and clinical manifestations of PD and suggest that the chance for a neuron to survive increases in association with lower total as well as nuclear AT1 expression. Our results support the need for further evaluation of ARBs as disease-modifying agents in PD

Endorepellin remodels the endothelial transcriptome toward a pro-autophagic and pro-mitophagic gene signature.

Regulation of autophagy by proteolytically cleaved fragments of heparan sulfate proteoglycans is a novel and current research focus in tumor biology. Endorepellin is the C-terminal angiostatic fragment of the heparan sulfate proteoglycan perlecan and induces autophagy in endothelial cells. To further investigate this property, we used NanoString, a digital PCR platform for measuring pre-defined transcripts in biological samples to analyze a custom subset of 95 autophagy-related genes in human umbilical vein endothelial cells treated with ultrapure human recombinant endorepellin. We discovered an endorepellin-evoked pro-autophagic and pro-mitophagic gene expression signatures, which included two coordinately up-regulated mitochondrial-associated genes encoding the E3 ubiquitin protein ligase Parkin and the tumor suppressor mitostatin. Induction of both proteins required the tyrosine kinase activity of vascular endothelial growth factor receptor 2 (VEGFR2). Furthermore, we discovered that endorepellin evoked mitochondrial depolarization in endothelial cells via a specific interaction between its two proximal LG1/2 domains and VEGFR2. We also found that following loss of membrane potential, mitostatin and parkin interact and that mitostatin associates with the established Parkin receptor mitofusin-2. In conclusion, we have identified a critical role for endorepellin in remodeling the autophagic transcriptome and influencing mitochondrial homeostasis

Infrared face recognition: a comprehensive review of methodologies and databases

Automatic face recognition is an area with immense practical potential which includes a wide range of commercial and law enforcement applications. Hence it is unsurprising that it continues to be one of the most active research areas of computer vision. Even after over three decades of intense research, the state-of-the-art in face recognition continues to improve, benefitting from advances in a range of different research fields such as image processing, pattern recognition, computer graphics, and physiology. Systems based on visible spectrum images, the most researched face recognition modality, have reached a significant level of maturity with some practical success. However, they continue to face challenges in the presence of illumination, pose and expression changes, as well as facial disguises, all of which can significantly decrease recognition accuracy. Amongst various approaches which have been proposed in an attempt to overcome these limitations, the use of infrared (IR) imaging has emerged as a particularly promising research direction. This paper presents a comprehensive and timely review of the literature on this subject. Our key contributions are: (i) a summary of the inherent properties of infrared imaging which makes this modality promising in the context of face recognition, (ii) a systematic review of the most influential approaches, with a focus on emerging common trends as well as key differences between alternative methodologies, (iii) a description of the main databases of infrared facial images available to the researcher, and lastly (iv) a discussion of the most promising avenues for future research.Comment: Pattern Recognition, 2014. arXiv admin note: substantial text overlap with arXiv:1306.160

Global DNA methylation and transcriptional analyses of human ESC-derived cardiomyocytes.

With defined culture protocol, human embryonic stem cells (hESCs) are able to generate cardiomyocytes in vitro, therefore providing a great model for human heart development, and holding great potential for cardiac disease therapies. In this study, we successfully generated a highly pure population of human cardiomyocytes (hCMs) (>95% cTnT(+)) from hESC line, which enabled us to identify and characterize an hCM-specific signature, at both the gene expression and DNA methylation levels. Gene functional association network and gene-disease network analyses of these hCM-enriched genes provide new insights into the mechanisms of hCM transcriptional regulation, and stand as an informative and rich resource for investigating cardiac gene functions and disease mechanisms. Moreover, we show that cardiac-structural genes and cardiac-transcription factors have distinct epigenetic mechanisms to regulate their gene expression, providing a better understanding of how the epigenetic machinery coordinates to regulate gene expression in different cell types

Advanced Magnetic Resonance Imaging in Glioblastoma: A Review

INTRODUCTION In 2017, it is estimated that 26,070 patients will be diagnosed with a malignant primary brain tumor in the United States, with more than half having the diagnosis of glioblas- toma (GBM).1 Magnetic resonance imaging (MRI) is a widely utilized examination in the diagnosis and post-treatment management of patients with glioblastoma; standard modalities available from any clinical MRI scanner, including T1, T2, T2-FLAIR, and T1-contrast-enhanced (T1CE) sequences, provide critical clinical information. In the last decade, advanced imaging modalities are increasingly utilized to further charac- terize glioblastomas. These include multi-parametric MRI sequences, such as dynamic contrast enhancement (DCE), dynamic susceptibility contrast (DSC), diffusion tensor imaging (DTI), functional imaging, and spectroscopy (MRS), to further characterize glioblastomas, and significant efforts are ongoing to implement these advanced imaging modalities into improved clinical workflows and personalized therapy approaches. A contemporary review of standard and advanced MR imaging in clinical neuro-oncologic practice is presented

Epigenomes in Cardiovascular Disease.

If unifying principles could be revealed for how the same genome encodes different eukaryotic cells and for how genetic variability and environmental input are integrated to impact cardiovascular health, grand challenges in basic cell biology and translational medicine may succumb to experimental dissection. A rich body of work in model systems has implicated chromatin-modifying enzymes, DNA methylation, noncoding RNAs, and other transcriptome-shaping factors in adult health and in the development, progression, and mitigation of cardiovascular disease. Meanwhile, deployment of epigenomic tools, powered by next-generation sequencing technologies in cardiovascular models and human populations, has enabled description of epigenomic landscapes underpinning cellular function in the cardiovascular system. This essay aims to unpack the conceptual framework in which epigenomes are studied and to stimulate discussion on how principles of chromatin function may inform investigations of cardiovascular disease and the development of new therapies

Linking recorded data with emotive and adaptive computing in an eHealth environment

Telecare, and particularly lifestyle monitoring, currently relies on the ability to detect and respond to changes in individual behaviour using data derived from sensors around the home. This means that a significant aspect of behaviour, that of an individuals emotional state, is not accounted for in reaching a conclusion as to the form of response required. The linked concepts of emotive and adaptive computing offer an opportunity to include information about emotional state and the paper considers how current developments in this area have the potential to be integrated within telecare and other areas of eHealth. In doing so, it looks at the development of and current state of the art of both emotive and adaptive computing, including its conceptual background, and places them into an overall eHealth context for application and development

Corticotropin-releasing hormone interacts with interleukin-1 to regulate prostaglandin H synthase-2 expression in human myometrium during pregnancy and labor

Context: The onset of labor appears to involve the activation of myometrial inflammatory pathways, and transcription factors such as nuclear factor-κB (NF-κB) control expression of the contraction-associated proteins required to induce a procontractile phenotype. These responses might involve CRH, which integrates immune and neuroendocrine systems. Objectives: In human myometrium we investigated cyclooxygenase 2 (PGHS2) expression and regulation by CRH and the proinflammatory cytokine IL-1β before and after labor. Design: Myometrial tissues obtained from pregnant women at term before (n = 12) or during labor (n = 10) and pathological cases of choriamnionitis-associated term labor (n = 5) were used to isolate primary myocytes and investigate in vitro, CRH effects on basal and IL-1β regulated p65 activation and PGHS2 expression. Results: In nonlaboring myometrial cells, CRH was unable to induce NF-κB nuclear translocation; however, it altered the temporal dynamics of IL-1β-driven NF-κB nuclear entry by initially delaying entry and subsequently prolonging retention. These CRH-R1-driven effects were associated with a modest inhibitory action in the early phase (within 2 hours) of IL-1β stimulated PGHS2 mRNA expression, whereas prolonged stimulation for 6–18 hours augmented the IL-1β effects. The early-phase effect required intact protein kinase A activity and was diminished after the onset of labor. The presence of chorioamnionitis led to exaggerated PGHS2 mRNA responses to IL-1β but diminished effects of CRH. Conclusions: CRH is involved in the inflammatory regulation of PGHS2 expression before and during labor; these actions might be important in priming and preparing the myometrium for labor and cellular adaptive responses to inflammatory mediator