The FastMap Algorithm for Shortest Path Computations

We present a new preprocessing algorithm for embedding the nodes of a given edge-weighted undirected graph into a Euclidean space. The Euclidean distance between any two nodes in this space approximates the length of the shortest path between them in the given graph. Later, at runtime, a shortest path between any two nodes can be computed with A* search using the Euclidean distances as heuristic. Our preprocessing algorithm, called FastMap, is inspired by the data mining algorithm of the same name and runs in near-linear time. Hence, FastMap is orders of magnitude faster than competing approaches that produce a Euclidean embedding using Semidefinite Programming. FastMap also produces admissible and consistent heuristics and therefore guarantees the generation of shortest paths. Moreover, FastMap applies to general undirected graphs for which many traditional heuristics, such as the Manhattan Distance heuristic, are not well defined. Empirically, we demonstrate that A* search using the FastMap heuristic is competitive with A* search using other state-of-the-art heuristics, such as the Differential heuristic

Developmental dynamics of mitochondrial mRNA abundance and editing reveal roles for temperature and the differentiation-repressive kinase RDK1 in cytochrome oxidase subunit II mRNA editing.

Developmental regulation of mitochondrial uridine insertion/deletion editing in Trypanosoma brucei is necessary to modulate parasite metabolism as it shifts from dependence on glycolysis for ATP production in the mammalian bloodstream form (BSF) to oxidative phosphorylation in the insect procyclic form (PCF). However, the timing and stimuli that regulate mRNA editing have been poorly characterized. Here, we utilized a pleomorphic T. brucei strain and quantitative RT-PCR and droplet digital PCR analyses to evaluate the changes in total mRNA abundance and editing as parasites progressively differentiate from slender BSF to PCF and investigate the effect of individual stimuli on mitochondrial gene expression. We observed little change during the slender-to-stumpy BSF transition. Rather, we found that mainly the mitochondrial cytochrome (COI, COII, COIII, and CYb) mRNAs are upregulated within 24 h after stumpy BSF is stimulated to differentiate to PCF in vitro and during in vivo tsetse fly infections. Temperature reduction from 37°C to 27°C is a critical factor for increasing the editing of COII and COIII mRNAs and COIV protein expression but not the editing of CYb mRNA or RISP protein expression. We further demonstrate that the depletion of the differentiation-repressive kinase RDK1 couples with temperature reduction to stimulate COII mRNA editing, and the accessory factor p22 is required for the cold-responsive upregulation of COII mRNA editing. Overall, we show that cytochrome mRNAs are regulated during development by distinct stimuli through a variety of methods to increase their abundance and/or editing. IMPORTANCE Trypanosoma brucei is the unicellular parasite that causes African sleeping sickness and nagana disease in livestock. The parasite has a complex life cycle consisting of several developmental forms in the human and tsetse fly insect vector. Both the mammalian and insect hosts provide different nutritional environments, so T. brucei must adapt its metabolism to promote its survival and to complete its life cycle. As T. brucei is transmitted from the human host to the fly, the parasite must regulate its mitochondrial gene expression through a process called uridine insertion/deletion editing to achieve mRNAs capable of being translated into functional respiratory chain proteins required for energy production in the insect host. Therefore, it is essential to understand the mechanisms by which T. brucei regulates mitochondrial gene expression during transmission from the mammalian host to the insect vector

SFRP4 signalling of apoptosis and angiostasis uses nitric oxide-cGMP-permeability axis of endothelium

Nitric oxide (NO) plays a critical role in endothelial functions such as cellular migration, vascular permeability and angiogenesis. Angiogenesis, the formation of new blood vessels from "pre-existing" ones is a carefully regulated process and essential during reproduction, development and wound healing. Previously our lab group reported that Secreted Frizzled-Related Protein 4 (sFRP4) could inhibit angiogenesis in both in vitro and in vivo conditions. sFRP4 belongs to a family of secreted glycoproteins that function as antagonists of the canonical Wnt signalling pathway. Although the pro-apoptotic role of sFRP4 is well discussed in literature, little is known in regards to its anti-angiogenic property. The objective of this study was to elucidate sFRP4 implications in NO biology of the endothelium. Results demonstrate that sFRP4 causes endothelial dysfunction by suppressing NO-cGMP signaling and elevating corresponding ROS levels. The imbalance between NO and ROS levels results in apoptosis and subsequent leakiness of endothelium as confirmed in vivo (Texas red/Annxin - CAM assay) and in vitro (Monolayer permeability assay) conditions. Furthermore utilizing peptides synthesized from the CRD domain of sFRP4, our results showed that while these peptides were able to cause endothelial dysfunctions, they did not cause apoptosis of the endothelial cells. Thereby confirming that sFRP4 can mediate its anti-angiogenic effect independent of its pro-apoptotic property. In conclusion, the current study reports that sFRP4-mediated anti-angiogenesis occurs as a result of impaired NO-cGMP signaling which in turn allow for elevation of redox levels and promotion of apoptosis of endothelial cells

Breast cancer stem-like cells are inhibited by diosgenin, a steroidal saponin, by the attenuation of the Wnt ß-catenin signaling via the Wnt antagonist secreted frizzled related protein-4

Background: Identification of breast cancer stem cells as the chemo-resistant and tumor-initiating population represents an important milestone in approaching anticancer therapies. Targeting this minor subpopulation of chemo- and radio-resistant stem-like cells, termed as the cancer stem cells (CSCs) and their eradication could significantly enhance clinical outcomes. Most of the presently administered chemotherapeutics target the tumor bulk but are ineffective against the CSCs. We report here that diosgenin (DG), a naturally occurring steroidal saponin, could effectively inhibit CSCs from three breast cancer cell lines, MCF7, T47D and MDA-MB-231, by inducing apoptosis and inhibiting the CSC associated phenotypes. Methods: CSCs were enriched in these cells lines, characterized for CSC traits by immunocytochemistry and flow cytometry. Proliferation and apoptosis assays were performed in these breast CSCs in the presence of DG to obtain the inhibitory concentration. Apoptosis was confirmed with gene expression analysis, Western blotting and propidium iodide staining. TCF-LEF reporter assay, sFRP overexpression and RNAi silencing studies were performed to study regulation of the Wnt pathway. Statistical significance was evaluated by a two-sided Student's t-test. Results: Using the TCF-LEF reporter system, we show the effect of DG on CSCs is predominantly through the network regulating CSC self renewal, the Wnt ß-catenin pathway. Specifically, the Wnt antagonist, the secreted frizzled related protein 4, (sFRP4), had a defining role in the action of DG. Gain-of-function of sFRP4 in CSCs could improve the response to DG wherein CSC mediators were inhibited, ß-catenin was down regulated and the effectors of epithelial to mesenchymal transition and pro-invasive markers were repressed. Conversely, the loss-of-function of sFRP4 had a reverse effect on the CSC population which therein became enriched, their response to DG treatment was modest, ß-catenin levels increased, GSK3ß expression decreased and the expression of epithelial markers of CSC was completely abrogated. Conclusion: These findings demonstrate the effect of DG on inhibiting the resilient breast CSCs which could provide a benchmark for the development of DG-based therapies in breast cancer treatment. © 2017 Bhuvanalakshmi, Basappa, Rangappa, Dharmarajan, Sethi, Kumar and Warrier

Ion cyclotron and spin-flip emissions from fusion products in tokamaks

Power emission by fusion products of tokamak plasmas in their ion cyclotron range of frequencies (ICRF) and at their spin-flip resonance frequency is calculated for some specific model fusion product velocity-space distribution functions. The background plasma of say deuterium (D) is assumed to be in equilibrium with a Maxwellian distribution both for the electrons and ions. The fusion product velocity distributions analyzed here are: (1) A monoenergetic velocity space ring distribution. (2) A monoenergetic velocity space spherical shell distribution. (3) An anisotropic Maxwellian distribution with T [perpendicular] [ne] T[parallel]and with appreciable drift velocity along the confining magnetic field. Single dressed'' test particle spontaneous emission calculations are presented first and the radiation temperature for ion cyclotron emission (ICE) is analyzed both for black-body emission and nonequilibrium conditions. Thresholds for instability and overstability conditions are then examined and quasilinear and nonlinear theories of the electromagnetic ion cyclotron modes are discussed. Distinctions between kinetic or causal instabilities'' and hydrodynamic instabilities'' are drawn and some numerical estimates are presented for typical tokamak parameters. Semiquantitative remarks are offered on wave accessibility, mode conversion, and parametric decay instabilities as possible for spatially localized ICE. Calculations are carried out both for k[parallel] = 0 for k[parallel] [ne] 0. The effects of the temperature anisotropy and large drift velocities in the parallel direction are also examined. Finally, proton spin-flip resonance emission and absorption calculations are also presented both for thermal equilibrium conditions and for an inverted'' population of states

Ion cyclotron and spin-flip emissions from fusion products in tokamaks

Power emission by fusion products of tokamak plasmas in their ion cyclotron range of frequencies (ICRF) and at their spin-flip resonance frequency is calculated for some specific model fusion product velocity-space distribution functions. The background plasma of say deuterium (D) is assumed to be in equilibrium with a Maxwellian distribution both for the electrons and ions. The fusion product velocity distributions analyzed here are: (1) A monoenergetic velocity space ring distribution. (2) A monoenergetic velocity space spherical shell distribution. (3) An anisotropic Maxwellian distribution with T {perpendicular} {ne} T{parallel}and with appreciable drift velocity along the confining magnetic field. Single ``dressed`` test particle spontaneous emission calculations are presented first and the radiation temperature for ion cyclotron emission (ICE) is analyzed both for black-body emission and nonequilibrium conditions. Thresholds for instability and overstability conditions are then examined and quasilinear and nonlinear theories of the electromagnetic ion cyclotron modes are discussed. Distinctions between ``kinetic or causal instabilities`` and ``hydrodynamic instabilities`` are drawn and some numerical estimates are presented for typical tokamak parameters. Semiquantitative remarks are offered on wave accessibility, mode conversion, and parametric decay instabilities as possible for spatially localized ICE. Calculations are carried out both for k{parallel} = 0 for k{parallel} {ne} 0. The effects of the temperature anisotropy and large drift velocities in the parallel direction are also examined. Finally, proton spin-flip resonance emission and absorption calculations are also presented both for thermal equilibrium conditions and for an ``inverted`` population of states

TIPE family of proteins and its implications in different chronic diseases

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. The tumor necrosis factor-a-induced protein 8-like (TIPE/TNFAIP8) family is a recently identified family of proteins that is strongly associated with the regulation of immunity and tumorigenesis. This family is comprised of four members, namely, tumor necrosis factor-a-induced protein 8 (TIPE/TNFAIP8), tumor necrosis factor-a-induced protein 8-like 1 (TIPE1/TNFAIP8L1), tumor necrosis factor-a-induced protein 8-like 2 (TIPE2/TNFAIP8L2), and tumor necrosis factor-a-induced protein 8-like 3 (TIPE3/TNFAIP8L3). Although the proteins of this family were initially described as regulators of tumorigenesis, inflammation, and cell death, they are also found to be involved in the regulation of autophagy and the transfer of lipid secondary messengers, besides contributing to immune function and homeostasis. Interestingly, despite the existence of a significant sequence homology among the four members of this family, they are involved in different biological activities and also exhibit remarkable variability of expression. Furthermore, this family of proteins is highly deregulated in different human cancers and various chronic diseases. This review summarizes the vivid role of the TIPE family of proteins and its association with various signaling cascades in diverse chronic diseases

Coherent and turbulent fluctuations in TFTR

Classification of the sawteeth observed in the TFTR tokamak has been carried out to highlight the differences between the many types observed. Three types of sawteeth are discussed: ''simple,'' ''small,'' and ''compound.'' During the enhanced confinement discharges on TFTR, sawteeth related to q = 1 are usually not present, but a sawtooth-like event is sometimes observed. ..beta.. approaches the Troyon limit only at low q/sub cyl/ with a clear reduction of achievable ..beta../sub n/ at high q/sub cyl/. This suggests that a ..beta../sub p/ limit, rather than the Troyon-Gruber limit, applies at high q/sub cyl/ in the enhanced confinement discharges. These discharges also reach the stability boundary for n ..-->.. infinity ideal MHD ballooning modes. Turbulence measurements in the scrape-off region with Langmuir and magnetic probes show strong edge density turbulence n-tilde/n = 0.3 - 0.5, with weak magnetic turbulence B-tilde/sub theta/B/sub theta/ > 5 x 10/sup -6/ measured at the wall, but these measurements are very sensitive to local edge conditions

The globalizability of temporal discounting

Economic inequality is associated with preferences for smaller, immediate gains over larger, delayed ones. Such temporal discounting may feed into rising global inequality, yet it is unclear whether it is a function of choice preferences or norms, or rather the absence of sufficient resources for immediate needs. It is also not clear whether these reflect true differences in choice patterns between income groups. We tested temporal discounting and five intertemporal choice anomalies using local currencies and value standards in 61 countries (N = 13,629). Across a diverse sample, we found consistent, robust rates of choice anomalies. Lower-income groups were not significantly different, but economic inequality and broader financial circumstances were clearly correlated with population choice patterns

Prevalence of gastro-oesophageal reflux disease symptoms and reflux-associated respiratory symptoms in asthma

<p>Abstract</p> <p>Background</p> <p>Gastro-oesophageal reflux disease (GORD) symptoms are common in asthma and have been extensively studied, but less so in the Asian continent. Reflux-associated respiratory symptoms (RARS) have, in contrast, been little-studied globally. We report the prevalence of GORD symptoms and RARS in adult asthmatics, and their association with asthma severity and medication use.</p> <p>Methods</p> <p>A cross-sectional analytical study. A validated interviewer-administered GORD scale was used to assess frequency and severity of seven GORD symptoms. Subjects were consecutive asthmatics attending medical clinics. Controls were matched subjects without respiratory symptoms.</p> <p>Results</p> <p>The mean (SD) composite GORD symptom score of asthmatics was significantly higher than controls (21.8 (17.2) versus 12.0 (7.6); <it>P </it>< 0.001) as was frequency of each symptom and RARS. Prevalence of GORD symptoms in asthmatics was 59.4% (95% CI, 59.1%-59.6%) versus 28.5% in controls (95% CI, 29.0% - 29.4%). 36% of asthmatics experienced respiratory symptoms in association with both typical and atypical GORD symptoms, compared to 10% of controls (<it>P </it>< 0.001). An asthmatic had a 3.5 times higher risk of experiencing a GORD symptom after adjusting for confounders (OR 3.5; 95% CI 2.5-5.3). Severity of asthma had a strong dose-response relationship with GORD symptoms. Asthma medication use did not significantly influence the presence of GORD symptoms.</p> <p>Conclusions</p> <p>GORD symptoms and RARS were more prevalent in a cohort of Sri Lankan adult asthmatics compared to non-asthmatics. Increased prevalence of RARS is associated with both typical and atypical symptoms of GORD. Asthma disease and its severity, but not asthma medication, appear to influence presence of GORD symptoms.</p