Abstractions, accounts and grid usability

The vision of the Grid is one of seamless, virtual and constantly changing resources where users need not concern themselves about details, such as exactly where an application is running or where their data is being stored. However, seamless and virtual often imply a lack of control that users may be wary of, or even opposed to. Drawing upon our studies of HCI and of collaborative work, this paper examines whether the Grid development community should be taking this vision literally and argues for the need for accountability of systems ‘in interaction’. We give examples of an alternative approach that seeks to provide ways in which administrators, technical support and user communities can make sense of the behaviour of the complex socio-technical ensembles that are the reality of Grids

Are two commonly used self-report questionnaires useful for identifying antihypertensive medication nonadherence?

Objective: Medication nonadherence is a major cause of uncontrolled hypertension, but clinicians are poor at judging adherence, and the gold standard for measuring adherence, electronic monitoring, is rarely available in clinical settings. Self-report questionnaires (SRQs), by contrast, are inexpensive, easy to administer, and hence, may be useful for ‘diagnosing’ nonadherence. In this study, we evaluated the validity of two commonly used medication adherence SRQs among patients with uncontrolled hypertension, using electronic pillbox measurement as the gold standard. Methods: A total of 149 patients with uncontrolled hypertension had adherence to their antihypertensive medication regimen monitored using a four-compartment electronic pillbox (MedSignals) between two primary care visits (median 50 days). Participants completed the 8-item Morisky Medication Adherence Scale (MMAS-8) and the Visual Analog Scale (VAS) at the second visit. Likelihood ratios were calculated using less than 80% correct dosing adherence by electronic measurement as the gold standard. Results: SRQ scores indicating low adherence (MMAS-8 <6 and VAS <80%, 23 and 9% of participants, respectively) had likelihood ratios of 2.00 [95% confidence interval (CI) 1.10–3.65] and 7.72 (95% CI 1.77–33.6), respectively, for detecting nonadherence compared to electronic measurement. SRQ scores indicating highest adherence (MMAS-8 = 8 and VAS = 100%, 43 and 61% of participants, respectively) had likelihood ratios of 0.55 (95% CI 0.35–0.85) and 0.76 (95% CI 0.57–1.01), respectively, for detecting nonadherence. Conclusion: The MMAS-8 and VAS are modestly useful in identifying antihypertensive medication nonadherence. Other tools, including electronic measurement, may be needed to guide titration of antihypertensive medications among patients with uncontrolled hypertension

The cyanobacterial circadian clock follows midday in vivo and in vitro

Circadian rhythms are biological oscillations that schedule daily changes in physiology. Outside the laboratory, circadian clocks do not generally free-run but are driven by daily cues whose timing varies with the seasons. The principles that determine how circadian clocks align to these external cycles are not well understood. Here, we report experimental platforms for driving the cyanobacterial circadian clock both in vivo and in vitro. We find that the phase of the circadian rhythm follows a simple scaling law in light-dark cycles, tracking midday across conditions with variable day length. The core biochemical oscillator comprised of the Kai proteins behaves similarly when driven by metabolic pulses in vitro, indicating that such dynamics are intrinsic to these proteins. We develop a general mathematical framework based on instantaneous transformation of the clock cycle by external cues, which successfully predicts clock behavior under many cycling environments

The Structure of the Fusion Glycoprotein of Newcastle Disease Virus Suggests a Novel Paradigm for the Molecular Mechanism of Membrane Fusion

AbstractBackground: Membrane fusion within the Paramyxoviridae family of viruses is mediated by a surface glycoprotein termed the “F”, or fusion, protein. Membrane fusion is assumed to involve a series of structural transitions of F from a metastable (prefusion) state to a highly stable (postfusion) state. No detail is available at the atomic level regarding the metastable form of these proteins or regarding the transitions accompanying fusion.Results: The three-dimensional structure of the fusion protein of Newcastle disease virus (NDV-F) has been determined. The trimeric NDV-F molecule is organized into head, neck, and stalk regions. The head is comprised of a highly twisted β domain and an additional immunoglobulin-like β domain. The neck is formed by the C-terminal extension of the heptad repeat region HR-A, capped by a four-helical bundle. The C terminus of HR-A is encased by a further helix HR-C and a 4-stranded β sheet. The stalk is formed by the remaining visible portion of HR-A and by polypeptide immediately N-terminal to the C-terminal heptad repeat region HR-B. An axial channel extends through the head and neck and is fenestrated by three large radial channels located approximately at the head–neck interface.Conclusion: We propose that prior to fusion activation, the hydrophobic fusion peptides in NDV-F are sequestered within the radial channels within the head, with the central HR-A coiled coil being only partly formed. Fusion activation then involves, inter alia, the assembly of a complete HR-A coiled coil, with the fusion peptides and transmembrane anchors being brought into close proximity. The structure of NDV-F is fundamentally different than that of influenza virus hemagglutinin, in that the central coiled coil is in the opposite orientation with respect to the viral membrane

MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension

Rationale: The pathogenesis of PAH remains unclear. The four microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered. Objective: To elucidate the transcriptional regulation of the miR-143/145 cluster, and the role of miR-143 in PAH. Methods and Results: We identified the promoter region that regulates miR-143/145 miRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signalling pathways, including estrogens receptor (ER), liver X factor/retinoic X receptor (LXR/RXR), TGF-β (Smads), and hypoxia (HRE) that regulated levels of all pri-miR stem loop transcription and resulting miRNA expression. We observed that miR-143-3p is selectively upregulated compared to miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMCs-derived exosomes. Using assays with pulmonary arterial endothelial cells (PAECs) we demonstrated a paracrine pro-migratory and pro-angiogenic effect of miR-143-3p enriched exosomes from PASMC. Quantitative PCR and in situ hybridisation showed elevated expression of miR-143 in calf models of PAH as well as in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role for miR-143 in experimental PH in vivo in miR-143-/- and antimiR143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings. Conclusions: MiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, while inhibition of miR-143-3p blocked experimental PH. Taken together these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology

Production of Homozygous Transgenic Rainbow Trout with Enhanced Disease Resistance

Previous studies conducted in our laboratory showed that transgenic medaka expressing cecropin B transgenes exhibited resistant characteristic to fish bacterial pathogens, Pseudomonas fluorescens and Vibrio anguillarum. To confirm whether antimicrobial peptide gene will also exhibit anti-bacterial and anti-viral characteristics in aquaculture important fish species, we produced transgenic rainbow trout expressing cecropin P1 or a synthetic cecropin B analog, CF-17, transgene by sperm-mediated gene transfer method. About 30 % of fish recovered from electroporation were shown to carry the transgene as determined by polymerase chain reaction (PCR) amplification assay. Positive P(1) transgenic fish were crossed to non-transgenic fish to establish F(1) transgenic founder families, and subsequently generating F(2), and F(3) progeny. Expression of cecropin P1 and CF-17 transgenes was detected in transgenic fish by reverse transcription (RT)-PCR analysis. The distribution of body sizes among F(1) transgenic fish were not significantly different from those of non-transgenic fish. Results of challenge studies revealed that many families of F(2) and F(3) transgenic fish exhibited resistance to infection by Aeromonas salmonicida and infectious hematopoietic necrosis virus (IHNV). All-male homozygous cecropin P1 transgenic families were produced by androgenesis from sperm of F(3) heterozygous transgenic fish in one generation. The resistant characteristic to A. salmonicida was confirmed in progeny derived from the outcross of all-male fish to non-transgenic females. Results of our current studies confirmed the possibility of producing disease-resistant homozygous rainbow trout strains by transgenesis of cecropin P1 or CF-17 gene and followed by androgenesis

The Arabidopsis thaliana nucleotide sugar transporter GONST2 is a functional homolog of GONST1.

Glycosylinositolphosphorylceramides (GIPCs) are the predominant lipid in the outer leaflet of the plasma membrane. Characterized GIPC glycosylation mutants have severe or lethal plant phenotypes. However, the function of the glycosylation is unclear. Previously, we characterized Arabidopsis thaliana GONST1 and showed that it was a nucleotide sugar transporter which provides GDP-mannose for GIPC glycosylation. gonst1 has a severe growth phenotype, as well as a constitutive defense response. Here, we characterize a mutant in GONST1's closest homolog, GONST2. The gonst2-1 allele has a minor change to GIPC headgroup glycosylation. Like other reported GIPC glycosylation mutants, gonst1-1gonst2-1 has reduced cellulose, a cell wall polymer that is synthesized at the plasma membrane. The gonst2-1 allele has increased resistance to a biotrophic pathogen Golovinomyces orontii but not the necrotrophic pathogen Botrytis cinerea. Expression of GONST2 under the GONST1 promoter can rescue the gonst1 phenotype, indicating that GONST2 has a similar function to GONST1 in providing GDP-D-Man for GIPC mannosylation

Loss of mXinα, an intercalated disk protein, results in cardiac hypertrophy and cardiomyopathy with conduction defects

The intercalated disk protein Xin was originally discovered in chicken striated muscle and implicated in cardiac morphogenesis. In the mouse, there are two homologous genes, mXinα and mXinβ. The human homolog of mXinα, Cmya1, maps to chromosomal region 3p21.2–21.3, near a dilated cardiomyopathy with conduction defect-2 locus. Here we report that mXinα-null mouse hearts are hypertrophied and exhibit fibrosis, indicative of cardiomyopathy. A significant upregulation of mXinβ likely provides partial compensation and accounts for the viability of the mXinα-null mice. Ultrastructural studies of mXinα-null mouse hearts reveal intercalated disk disruption and myofilament disarray. In mXinα-null mice, there is a significant decrease in the expression level of p120-catenin, β-catenin, N-cadherin, and desmoplakin, which could compromise the integrity of the intercalated disks and functionally weaken adhesion, leading to cardiac defects. Additionally, altered localization and decreased expression of connexin 43 are observed in the mXinα-null mouse heart, which, together with previously observed abnormal electrophysiological properties of mXinα-deficient mouse ventricular myocytes, could potentially lead to conduction defects. Indeed, ECG recordings on isolated, perfused hearts (Langendorff preparations) show a significantly prolonged QT interval in mXinα-deficient hearts. Thus mXinα functions in regulating the hypertrophic response and maintaining the structural integrity of the intercalated disk in normal mice, likely through its association with adherens junctional components and actin cytoskeleton. The mXinα-knockout mouse line provides a novel model of cardiac hypertrophy and cardiomyopathy with conduction defects