Novel and Annotated Long Noncoding RNAs Associated with Ischemia in the Human Heart

Background: Long noncoding RNAs (lncRNAs) have been implicated in the pathogenesis of cardiovascular diseases. We aimed to identify novel lncRNAs associated with the early response to ischemia in the heart. Methods and Results: RNA sequencing data gathered from 81 paired left ventricle samples from patients undergoing cardiopulmonary bypass was collected before and after a period of ischemia. Novel lncRNAs were validated with Oxford Nanopore Technologies long-read sequencing. Gene modules associated with an early ischemic response were identified and the subcellular location of selected lncRNAs was determined with RNAscope. A total of 2446 mRNAs, 270 annotated lncRNAs and one novel lncRNA differed in response to ischemia (adjusted p < 0.001, absolute fold change >1.2). The novel lncRNA belonged to a gene module of highly correlated genes that also included 39 annotated lncRNAs. This module associated with ischemia (Pearson correlation coefficient = −0.69, p = 1 × 10⁻²³) and activation of cell death pathways (p < 6 × 10⁻⁹). A further nine novel cardiac lncRNAs were identified, of which, one overlapped five cis-eQTL eSNPs for the gene RWD Domain-Containing Sumoylation Enhancer (RWDD3) and was itself correlated with RWDD3 expression (Pearson correlation coefficient −0.2, p = 0.002). Conclusion: We have identified 10 novel lncRNAs, one of which was associated with myocardial ischemia and may have potential as a novel therapeutic target or early marker for myocardial dysfunction.     

Transcriptional Regulation of the Synaptic Vesicle Protein Synaptogyrin-3 (SYNGR3) Gene: The Effects of NURR1 on Its Expression

Synaptogyrin-3 (SYNGR3) is a synaptic vesicular membrane protein. Amongst four homologues (SYNGR1 to 4), SYNGR1 and 3 are especially abundant in the brain. SYNGR3 interacts with the dopamine transporter (DAT) to facilitate dopamine (DA) uptake and synaptic DA turnover in dopaminergic transmission. Perturbed SYNGR3 expression is observed in Parkinson’s disease (PD). The regulatory elements which affect SYNGR3 expression are unknown. Nuclear-receptor-related-1 protein (NURR1) can regulate dopaminergic neuronal differentiation and maintenance via binding to NGFI-B response elements (NBRE). We explored whether NURR1 can regulate SYNGR3 expression using an in silico analysis of the 5′-flanking region of the human SYNGR3 gene, reporter gene activity and an electrophoretic mobility shift assay (EMSA) of potential cis-acting sites. In silico analysis of two genomic DNA segments (1870 bp 5′-flanking region and 1870 + 159 bp of first exon) revealed one X Core Promoter Element 1 (XCPE1), two SP1, and three potential non-canonical NBRE response elements (ncNBRE) but no CAAT or TATA box. The longer segment exhibited gene promoter activity in luciferase reporter assays. Site-directed mutagenesis of XCPE1 decreased promoter activity in human neuroblastoma SH-SY5Y (↓43.2%) and human embryonic kidney HEK293 cells (↓39.7%). EMSA demonstrated NURR1 binding to these three ncNBRE. Site-directed mutagenesis of these ncNBRE reduced promoter activity by 11–17% in SH-SY5Y (neuronal) but not in HEK293 (non-neuronal) cells. C-DIM12 (Nurr1 activator) increased SYNGR3 protein expression in SH-SY5Y cells and its promoter activity using a real-time luciferase assay. As perturbed vesicular function is a feature of major neurodegenerative diseases, inducing SYNGR3 expression by NURR1 activators may be a potential therapeutic target to attenuate synaptic dysfunction in PD.     

Of Mouse and Man: Cross-Species Characterization of Hypertensive Cardiac Remodeling

Hypertension is a major public health concern and poses a significant risk for sudden cardiac death (SCD). However, the characterisation of human tissues tends to be macroscopic, with little appreciation for the quantification of the pathological remodelling responsible for the advancement of the disease. While the components of hypertensive remodelling are well established, the timeline and comparative quantification of pathological changes in hypertension have not been shown before. Here, we sought to identify the phasing of cardiac remodelling with hypertension using post-mortem tissue from SCD patients with early and advanced hypertensive heart disease (HHD). In order to study and quantify the progression of phenotypic changes, human specimens were contrasted to a well-described angiotensin-II-mediated hypertensive mouse model. While cardiomyocyte hypertrophy is an early adaptive response in the mouse that stabilises in established hypertension and declines as the disease progresses, this finding did not translate to the human setting. In contrast, optimising fibrosis quantification methods and applying them to each setting identified perivascular fibrosis as the prevailing possible cause for overall disease progression. Indeed, assessing myocardial inflammation highlights CD45+ inflammatory cell infiltration that precedes fibrosis and is an early-phase event in response to elevated arterial pressures that may underscore perivascular remodelling. Along with aetiology insight, we highlight cross-species comparison for quantification of cardiac remodelling in human hypertension. As such, this platform could assist with the development of therapies specific to the disease phase rather than targeting global components of hypertension, such as blood pressure lowering.     

Evidence for the use of an internal sense of direction in homing.

Path integration, the ability to maintain a representation of location and direction on the basis of internal cues, is thought to be important for navigation and the learning of spatial relationships. Representations of location and direction in the brain, such as head direction cells, grid cells, and place cells in the limbic system, are thought to underlie navigation by path integration. While this idea is generally consistent with lesion studies, the relationship between such neural activity and behavior has not been studied on a task where animals demonstrably use a path integration strategy. Here we report the development of such a task in rats: by slowly rotating rats before their return to a trial-unique home base, we could show subjects relied on internal cues only to navigate. To illustrate how this task can be combined with recording, we show examples of simultaneously recorded head direction cells in which neural activity is closely related to rats’ homing direction. These results support the notion that rats can navigate by path integration, that this ability depends on head direction cells, and suggest a convenient behavioral paradigm for investigating the neural basis of navigation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Constrained visual servoing under uncertain dynamics

In visual servoing, limitations in the field of view of the vision sensors are either ignored or treated at the kinematic level. The former can easily jeopardise task success, while the latter reduces the maximum achievable robotic motion speeds. In this work, the aforementioned literature gap is filled by designing and rigorously analysing a torque controller that guarantees prescribed transient and steady-state performance attributes on the image feature coordinate errors, while respecting the field-of-view constraints. No path planning and no information regarding the actual system dynamics are required. In addition, no approximation structures (i.e. neural networks, fuzzy systems, etc.) are utilised to acquire such knowledge. The proposed visual servo controller is static, involving very few and simple calculations to produce the control signal, making its implementation on embedded control platforms straightforward. Simulation studies are utilised to illustrate the motivation and to clarify–verify the theoretical findings.     

重构 荷兰乌得勒支大学图书馆

<正>乌得勒支大学(Utrecht University),作为荷兰最好的3所大学之一,也是所有13所大学中历史最悠久的一所。悠久的历史成就了该校深厚的文化底蕴,也成为他们不断发展的坚实基础。在校园的规划与建设上,该校一直走在时代前列。早在     

Guaranteeing prescribed performance and contact maintenance via an approximation free robot force/position controller

In this paper, we consider the problem of force/position tracking for a robot with revolute joints in compliant contact with a kinematically known planar surface. A novel controller is designed capable of guaranteeing, for an a priori known nonsingular initial robot condition, (i) certain predefined minimum speed of response, maximum steady state error as well as overshoot concerning the force/position tracking errors, (ii) contact maintenance and (iii) bounded closed loop signals. No information regarding either the robot dynamic model or the force deformation model is required and no approximation structures are utilized to estimate them. As the tracking performance is a priori guaranteed irrespectively of the control gains selection, the only concern is to adopt those values that lead to reasonable input torques. Finally, a comparative simulation study on a 6-DOF robot illustrates the performance of the proposed controller.     

Charge transport mechanisms and memory effects in amorphous TaNx thin films

Amorphous semiconducting materials have unique electrical properties that may be beneficial in nanoelectronics, such as low leakage current, charge memory effects, and hysteresis functionality. However, electrical characteristics between different or neighboring regions in the same amorphous nanostructure may differ greatly. In this work, the bulk and surface local charge carrier transport properties of a-TaN_x amorphous thin films deposited in two different substrates are investigated by conductive atomic force microscopy. The nitride films are grown either on Au (100) or Si [100] substrates by pulsed laser deposition at 157 nm in nitrogen environment. For the a-TaN_x films deposited on Au, it is found that they display a negligible leakage current until a high bias voltage is reached. On the contrary, a much lower threshold voltage for the leakage current and a lower total resistance is observed for the a-TaN_x film deposited on the Si substrate. Furthermore, I-V characteristics of the a-TaN_x film deposited on Au show significant hysteresis effects for both polarities of bias voltage, while for the film deposited on Si hysteresis, effects appear only for positive bias voltage, suggesting that with the usage of the appropriate substrate, the a-TaN_x nanodomains may have potential use as charge memory devices.