Role of Activator Protein-1 in the Down-Regulation of the Human \u3ci\u3eCYP2J2\u3c/i\u3e Gene in Hypoxia

The cytochrome P450 (CYP) 2J2 arachidonic acid epoxygenase gene was down-regulated at a pre-translational level in human hepatoma-derived HepG2 cells incubated in a hypoxic environment; under these conditions, the expression of c-Jun and c-Fos mRNA and protein was increased. The 5′-upstream region of the CYP2J2 gene was isolated by amplification of a 2341 bp fragment and putative regulatory elements that resembled activator protein-1 (AP-1)-like sequences were identified. From transient transfection analysis, c-Jun was found to strongly activate a CYP2J2–luciferase reporter construct, but co-transfection with plasmids encoding c-Fos or c-Fos-related antigens, Fra-1 and -2, abrogated reporter activity. Using a series of deletion-reporter constructs, a c-Jun-responsive module was identified between bp −152 and −50 in CYP2J2: this region contained an AP-1-like element be-tween bp −56 and −63. The capacity of this element to interact directly with c-Jun, but not c-Fos, was confirmed by electromobility-shift assay analysis. Mutagenesis of the −56/−63 element abolished most, but not all, of the activation of CYP2J2 by c-Jun, thus implicating an additional site within the c- Jun-responsive region. The present results establish an important role for c-Jun in the control of CYP2J2 expression in liver cells. Activation of c-Fos expression by hypoxia promotes the formation of c-Jun/c-Fos heterodimers, which decrease the binding of c-Jun to the CYP2J2 upstream region, leading to gene down-regulation

Coupling a model of human thermoregulation with computational fluid dynamics for predicting human-environment interaction

This paper describes the methods developed to couple a commercial CFD program with a multi-segmented model of human thermal comfort and physiology. A CFD model is able to predict detailed temperatures and velocities of airflow around a human body, whilst a thermal comfort model is able to predict the response of a human to the environment surrounding it. By coupling the two models and exchanging information about the heat transfer at the body surface the coupled system can potentially predict the response of a human body to detailed local environmental conditions. This paper presents a method of exchanging data, using shared files, to provide a means of dynamically exchanging simulation data with the IESD-Fiala model during the CFD solution process. Additional code is used to set boundary conditions for the CFD simulation at the body surface as determined by the IESD-Fiala model and to return information about local environmental conditions adjacent to the body surface as determined by the CFD simulation. The coupled system is used to model a human subject in a naturally ventilated environment. The resulting ventilation flow pattern agrees well with other numerical and experimental work

On vertex coloring without monochromatic triangles

We study a certain relaxation of the classic vertex coloring problem, namely, a coloring of vertices of undirected, simple graphs, such that there are no monochromatic triangles. We give the first classification of the problem in terms of classic and parametrized algorithms. Several computational complexity results are also presented, which improve on the previous results found in the literature. We propose the new structural parameter for undirected, simple graphs -- the triangle-free chromatic number $\chi_3$. We bound $\chi_3$ by other known structural parameters. We also present two classes of graphs with interesting coloring properties, that play pivotal role in proving useful observation about our problem. We give/ask several conjectures/questions throughout this paper to encourage new research in the area of graph coloring.Comment: Extended abstrac

A Combined Perceptual, Physico-Chemical, and Imaging Approach to ‘Odour-Distances’ Suggests a Categorizing Function of the Drosophila Antennal Lobe

How do physico-chemical stimulus features, perception, and physiology relate? Given the multi-layered and parallel architecture of brains, the question specifically is where physiological activity patterns correspond to stimulus features and/or perception. Perceived distances between six odour pairs are defined behaviourally from four independent odour recognition tasks. We find that, in register with the physico-chemical distances of these odours, perceived distances for 3-octanol and n-amylacetate are consistently smallest in all four tasks, while the other five odour pairs are about equally distinct. Optical imaging in the antennal lobe, using a calcium sensor transgenically expressed in only first-order sensory or only second-order olfactory projection neurons, reveals that 3-octanol and n-amylacetate are distinctly represented in sensory neurons, but appear merged in projection neurons. These results may suggest that within-antennal lobe processing funnels sensory signals into behaviourally meaningful categories, in register with the physico-chemical relatedness of the odours

Global Conformational Dynamics of a Y-Family DNA Polymerase during Catalysis

High-resolution analysis of protein, and DNA conformational changes during DNA polymerization, established relationships between the enzymatic function and conformational dynamics of individual domains for a DNA polymerase

real world dosing of regorafenib reg in metastatic colorectal cancer mcrc final results from the prospective observational correlate study

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In vivo Bioluminescence Imaging of Ca(2+) Signalling in the Brain of Drosophila

Many different cells' signalling pathways are universally regulated by Ca(2+) concentration [Ca(2+)] rises that have highly variable amplitudes and kinetic properties. Optical imaging can provide the means to characterise both the temporal and spatial aspects of Ca(2+) signals involved in neurophysiological functions. New methods for in vivo imaging of Ca(2+) signalling in the brain of Drosophila are required for probing the different dynamic aspects of this system. In studies here, whole brain Ca(2+) imaging was performed on transgenic flies with targeted expression of the bioluminescent Ca(2+) reporter GFP-aequorin (GA) in different neural structures. A photon counting based technique was used to undertake continuous recordings of cytosolic [Ca(2+)] over hours. Time integrals for reconstructing images and analysis of the data were selected offline according to the signal intensity. This approach allowed a unique Ca(2+) response associated with cholinergic transmission to be identified by whole brain imaging of specific neural structures. Notably, [Ca(2+)] transients in the Mushroom Bodies (MBs) following nicotine stimulation were accompanied by a delayed secondary [Ca(2+)] rise (up to 15 min. later) in the MB lobes. The delayed response was sensitive to thapsigargin, suggesting a role for intra-cellular Ca(2+) stores. Moreover, it was reduced in dunce mutant flies, which are impaired in learning and memory. Bioluminescence imaging is therefore useful for studying Ca(2+) signalling pathways and for functional mapping of neurophysiological processes in the fly brain

Restoration of Mitochondrial Cardiolipin Attenuates Cardiac Damage in Swine Renovascular Hypertension

BACKGROUND: Renovascular hypertension (RVH) impairs cardiac structure and left ventricular (LV) function, but whether mitochondrial injury is implicated in RVH-induced myocardial damage and dysfunction has not been defined. We hypothesized that cardiac remodeling in swine RVH is partly attributable to cardiac mitochondrial injury. METHODS AND RESULTS: After 12 weeks of hypercholesterolemic (HC)-RVH or control (n=14 each), pigs were treated for another 4 weeks with vehicle or with the mitochondrial-targeted peptide (MTP), Bendavia (0.1 mg/kg subcutaneously, 5 days/week), which stabilizes mitochondrial inner-membrane cardiolipin (n=7 each). Cardiac function was subsequently assessed by multidetector-computed tomography and oxygenation by blood-oxygen-level-dependent magnetic resonance imaging. Cardiolipin content, mitochondrial biogenesis, as well as sarcoplasmic-reticulum calcium cycling, myocardial tissue injury, and coronary endothelial function were assessed ex vivo. Additionally, mitochondrial cardiolipin content, oxidative stress, and bioenergetics were assessed in rat cardiomyocytes incubated with tert-butyl hydroperoxide (tBHP) untreated or treated with MTP. Chronic mitoprotection in vivo restored cardiolipin content and mitochondrial biogenesis. Thapsigargin-sensitive sarcoplasmic reticulum Ca(2+)-ATPase activity that declined in HC-RVH normalized in MTP-treated pigs. Mitoprotection also improved LV relaxation (E/A ratio) and ameliorated cardiac hypertrophy, without affecting blood pressure or systolic function. Myocardial remodeling and coronary endothelial function improved only in MTP-treated pigs. In tBHP-treated cardiomyocytes, mitochondrial targeting attenuated a fall in cardiolipin content and bioenergetics. CONCLUSIONS: Chronic mitoprotection blunted myocardial hypertrophy, improved LV relaxation, and attenuated myocardial cellular and microvascular remodeling, despite sustained HC-RVH, suggesting that mitochondrial injury partly contributes to hypertensive cardiomyopathy

Induced Disjoint Paths in Circular-Arc Graphs in Linear Time

The Induced Disjoint Paths problem is to test whether a graph G with k distinct pairs of vertices (si,ti) contains paths P1,…,Pk such that Pi connects si and ti for i=1,…,k, and Pi and Pj have neither common vertices nor adjacent vertices (except perhaps their ends) for 1≤

Reactive direction control for a mobile robot: A locust-like control of escape direction emerges when a bilateral pair of model locust visual neurons are integrated

Locusts possess a bilateral pair of uniquely identifiable visual neurons that respond vigorously to the image of an approaching object. These neurons are called the lobula giant movement detectors (LGMDs). The locust LGMDs have been extensively studied and this has lead to the development of an LGMD model for use as an artificial collision detector in robotic applications. To date, robots have been equipped with only a single, central artificial LGMD sensor, and this triggers a non-directional stop or rotation when a potentially colliding object is detected. Clearly, for a robot to behave autonomously, it must react differently to stimuli approaching from different directions. In this study, we implement a bilateral pair of LGMD models in Khepera robots equipped with normal and panoramic cameras. We integrate the responses of these LGMD models using methodologies inspired by research on escape direction control in cockroaches. Using ‘randomised winner-take-all’ or ‘steering wheel’ algorithms for LGMD model integration, the khepera robots could escape an approaching threat in real time and with a similar distribution of escape directions as real locusts. We also found that by optimising these algorithms, we could use them to integrate the left and right DCMD responses of real jumping locusts offline and reproduce the actual escape directions that the locusts took in a particular trial. Our results significantly advance the development of an artificial collision detection and evasion system based on the locust LGMD by allowing it reactive control over robot behaviour. The success of this approach may also indicate some important areas to be pursued in future biological research