Run-time scheduling and execution of loops on message passing machines

Sparse system solvers and general purpose codes for solving partial differential equations are examples of the many types of problems whose irregularity can result in poor performance on distributed memory machines. Often, the data structures used in these problems are very flexible. Crucial details concerning loop dependences are encoded in these structures rather than being explicitly represented in the program. Good methods for parallelizing and partitioning these types of problems require assignment of computations in rather arbitrary ways. Naive implementations of programs on distributed memory machines requiring general loop partitions can be extremely inefficient. Instead, the scheduling mechanism needs to capture the data reference patterns of the loops in order to partition the problem. First, the indices assigned to each processor must be locally numbered. Next, it is necessary to precompute what information is needed by each processor at various points in the computation. The precomputed information is then used to generate an execution template designed to carry out the computation, communication, and partitioning of data, in an optimized manner. The design is presented for a general preprocessor and schedule executer, the structures of which do not vary, even though the details of the computation and of the type of information are problem dependent

Environmental and circadian regulation combine to shape the rhythmic selenoproteome

The circadian clock orchestrates an organism’s endogenous processes with environmental 24 h cycles. Redox homeostasis and the circadian clock regulate one another to negate the potential effects of our planet’s light/dark cycle on the generation of reactive oxygen species (ROS) and attain homeostasis. Selenoproteins are an important class of redox-related enzymes that have a selenocysteine residue in the active site. This study reports functional understanding of how environmental and endogenous circadian rhythms integrate to shape the selenoproteome in a model eukaryotic cell. We mined quantitative proteomic data for the 24 selenoproteins of the picoeukaryote Ostreococcus tauri across time series, under environmentally rhythmic entrained conditions of light/dark (LD) cycles, compared to constant circadian conditions of constant light (LL). We found an overrepresentation of selenoproteins among rhythmic proteins under LL, but an underrepresentation under LD conditions. Rhythmic selenoproteins under LL that reach peak abundance later in the day showed a greater relative amplitude of oscillations than those that peak early in the day. Under LD, amplitude did not correlate with peak phase; however, we identified high-amplitude selenium uptake rhythms under LD but not LL conditions. Selenium deprivation induced strong qualitative defects in clock gene expression under LD but not LL conditions. Overall, the clear conclusion is that the circadian and environmental cycles exert differential effects on the selenoproteome, and that the combination of the two enables homeostasis. Selenoproteins may therefore play an important role in the cellular response to reactive oxygen species that form as a consequence of the transitions between light and dark

Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFβ signaling in FTAAD

BACKGROUND: Thoracic aortic aneurysm / dissection (TAAD) is a common phenotype that may occur as an isolated manifestation or within the constellation of a defined syndrome. In contrast to syndromic TAAD, the elucidation of the genetic basis of isolated TAAD has only recently started. To date, defects have been found in genes encoding extracellular matrix proteins (fibrillin-1, FBN1; collagen type III alpha 1, COL3A1), proteins involved in transforming growth factor beta (TGFβ) signaling (TGFβ receptor 1 and 2, TGFBR1/2; and SMAD3) or proteins that build up the contractile apparatus of aortic smooth muscle cells (myosin heavy chain 11, MYH11; smooth muscle actin alpha 2, ACTA2; and MYLK). METHODS AND RESULTS: In 110 non-syndromic TAAD patients that previously tested negative for FBN1 or TGFBR1/2 mutations, we identified 7 ACTA2 mutations in a cohort of 43 familial TAAD patients, including 2 premature truncating mutations. Sequencing of MYH11 revealed an in frame splice-site alteration in one out of two probands with TAA(D) associated with PDA but none in the series of 22 probands from the cohort of 110 patients with non-syndromic TAAD. Interestingly, immunohistochemical staining of aortic biopsies of a patient and a family member with MYH11 and patients with ACTA2 missense mutations showed upregulation of the TGFβ signaling pathway. CONCLUSIONS: MYH11 mutations are rare and typically identified in patients with TAAD associated with PDA. ACTA2 mutations were identified in 16% of a cohort presenting familial TAAD. Different molecular defects in TAAD may account for a different pathogenic mechanism of enhanced TGFβ signaling

Hepatic saturated fatty acid fraction is associated with de novo lipogenesis and hepatic insulin resistance

Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Hepatic saturated fatty acids (SFA) may be a marker of DNL and are suggested to be most detrimental in contributing to insulin resistance. Here, we show in a cross-sectional study design (ClinicalTrials.gov ID: NCT03211299) that we are able to distinguish the fractions of hepatic SFA, mono- and polyunsaturated fatty acids in healthy and metabolically compromised volunteers using proton magnetic resonance spectroscopy (H-1-MRS). DNL is positively associated with SFA fraction and is elevated in patients with non-alcoholic fatty liver and type 2 diabetes. Intriguingly, SFA fraction shows a strong, negative correlation with hepatic insulin sensitivity. Our results show that the hepatic lipid composition, as determined by our H-1-MRS methodology, is a measure of DNL and suggest that specifically the SFA fraction may hamper hepatic insulin sensitivity. Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Here, the authors use H-1-MRS methodology to show hepatic SFA fraction is a measure of DNL and specifically may hamper hepatic insulin sensitivity.Peer reviewe

The DUNDRUM Quartet: validation of structured professional judgement instruments DUNDRUM-3 assessment of programme completion and DUNDRUM-4 assessment of recovery in forensic mental health services

<p>Abstract</p> <p>Background</p> <p>Moving a forensic mental health patient from one level of therapeutic security to a lower level or to the community is influenced by more than risk assessment and risk management. We set out to construct and validate structured professional judgement instruments for consistency and transparency in decision making</p> <p>Methods</p> <p>Two instruments were developed, the seven-item DUNDRUM-3 programme completion instrument and the six item DUNDRUM-4 recovery instrument. These were assessed for all 95 forensic patients at Ireland's only forensic mental health hospital.</p> <p>Results</p> <p>The two instruments had good internal consistency (Cronbach's alpha 0.911 and 0.887). Scores distinguished those allowed no leave or accompanied leave from those with unaccompanied leave (ANOVA F = 38.1 and 50.3 respectively, p < 0.001). Scores also distinguished those in acute/high security units from those in medium or in low secure/pre-discharge units. Each individual item distinguished these levels of need significantly. The DUNDRUM-3 and DUNDRUM-4 correlated moderately with measures of dynamic risk and with the CANFOR staff rated unmet need (Spearman r = 0.5, p < 0.001).</p> <p>Conclusions</p> <p>The DUNDRUM-3 programme completion items distinguished significantly between levels of therapeutic security while the DUNDRUM-4 recovery items consistently distinguished those given unaccompanied leave outside the hospital and those in the lowest levels of therapeutic security. This data forms the basis for a prospective study of outcomes now underway.</p

HBV DNA and HBsAg Levels at 24 Weeks Off-Treatment Predict Clinical Relapse and HBsAg Loss in HBeAg-Negative Patients Who Discontinued Antiviral Therapy

Background &amp; Aims: Patients who discontinue nucleo(s)tide analogue therapy are at risk of viral rebound and severe hepatitis flares, necessitating intensive off-treatment follow-up. Methods: We studied the association between hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels at off-treatment follow-up week 24 (FU W24), with subsequent clinical relapse, and HBsAg loss in a multicenter cohort of hepatitis B e antigen (HBeAg)–negative patients with chronic hepatitis B who discontinued nucleo(s)tide analogue therapy. Results: We studied 475 patients, 82% Asian, and 55% treated with entecavir. Patients with higher HBV DNA levels at FU W24 had a higher risk of clinical relapse (hazard ratio [HR], 1.576; P &lt;.001) and a lower chance of HBsAg loss (HR, 0.454; P &lt;.001). Similarly, patients with higher HBsAg levels at FU W24 had a higher risk of clinical relapse (HR, 1.579; P &lt;.001) and a lower chance of HBsAg loss (HR, 0.263; P &lt;.001). A combination of both HBsAg &lt;100 IU/mL and HBV DNA &lt;100 IU/mL at FU W24 identified patients with excellent outcomes (9.9% clinical relapse and 58% HBsAg loss at 216 weeks of follow-up). Conversely, relapse rates were high and HBsAg loss rates negligible among patients with both HBsAg &gt;100 IU/mL and HBV DNA &gt;100 IU/mL (P &lt;.001). Conclusions: Among HBeAg-negative patients with chronic hepatitis B who discontinued antiviral therapy and who did not experience clinical relapse before FU W24, serum levels of HBV DNA and HBsAg at FU W24 can be used to predict subsequent clinical relapse and HBsAg clearance. A combination of HBsAg &lt;100 IU/mL with HBV DNA &lt;100 IU/mL identifies patients with a low risk of relapse and excellent chances of HBsAg loss and could potentially be used as an early surrogate end point for studies aiming at finite therapy in HBV.</p

The XMM Cluster Survey: evolution of the velocity dispersion–temperature relation over half a Hubble time

We measure the evolution of the velocity dispersion–temperature (σv–TX) relation up to z = 1 using a sample of 38 galaxy clusters drawn from the XMM Cluster Survey. This work improves upon previous studies by the use of a homogeneous cluster sample and in terms of the number of high-redshift clusters included. We present here new redshift and velocity dispersion measurements for 12 z > 0.5 clusters observed with the Gemini Multi Object Spectographs instruments on the Gemini telescopes. Using an orthogonal regression method,we find that the slope of the relation is steeper than that expected if clusters were self-similar, and that the evolution of the normalization is slightly negative, but not significantly different from zero (σv ∝T0.86±0.14E(z)−0.37±0.33). We verify our results by applying our methods to cosmological hydrodynamical simulations. The lack of evolution seen in our data is consistent with simulations that include both feedback and radiative cooling

Strategic positioning:an integrated decision process for manufacturers

Purpose – This paper describes research that has sought to create a formal and rational process that guides manufacturers through the strategic positioning decision. Design/methodology/approach – The methodology is based on a series of case studies to develop and test the decision process. Findings – A decision process that leads the practitioner through an analytical process to decide which manufacturing activities they should carryout themselves. Practical implications – Strategic positioning is concerned with choosing those production related activities that an organisations should carry out internally, and those that should be external and under the ownership and control of suppliers, partners, distributors and customers. Originality/value – This concept extends traditional decision paradigms, such as those associated with “make versus buy” and “outsourcing”, by looking at the interactions between manufacturing operations and the wider supply chain networks associated with the organisation