Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Efficient use of execution resources in multicore processor architectures

As the microprocessor industry embraces multicore architectures, inherently parallel applications benefit directly as they easily transform into sets of homogeneous parallel threads. However, many applications do not t this model. These applications include legacy binaries compiled for a single thread of execution and inherently serial applications. The inability of these two kinds of applications to exploit multicore architectures has created a crisis for the microprocessor industry : customers have come to expect significant performance improvements in all of their application every processor generation, but recent multicore architectures have failed to meet those expectations for many applications. This dissertation explores ways in which these applications can run efficiently on multi core platforms. The performance of legacy binaries compiled for a single thread of execution can be improved through automatic parallelization. We introduce a new technique to automatically parallelize binaries as they are executing. The parallelization technique leverages the benefits of hardware transactional memory, a synchronization mechanism enabling optimistic concurrency. Our technique exploits this to parallelize code that a traditional parallelizing compiler would be unable to transform due to potential memory aliasing. Applications with fundamentally serial code can benefits from core customization. The more heterogeneous the cores are, the more likely that a given application will nd a core on which it runs efficiently. We investigate two forms of heterogeneity : that created on homogeneous hardware by unbalanced resource assignment, and heterogeneity created by hardware asymmetry. We first consider a homogeneous multicore system composed of multithreading cores. Often the best schedules on such a system are unbalanced. We propose a set of novel scheduling algorithms that consider unbalanced schedules to nd good application-to-core assignments. We consider objective functions of both performance and energy. We also explore how applications can benefit from diverse Isms by considering heterogeneous-ISA multicore systems. We propose a new technique to rapidly migrate a thread among cores of different Isms, allowing applications to take advantage of hardware heterogeneity for performance gain or energy saving

Exploiting unbalanced thread scheduling for energy and performance on a cmp of smt processors

This paper explores thread scheduling on an increasingly popular architecture: chip multiprocessors with simultaneous multithreading cores. Conventional multiprocessor scheduling, applied to this architecture, will attempt to balance the thread load across cores. This research demonstrates that such an approach eliminates one of the big advantages of this architecture – the ability to use unbalanced schedules to allocate the right amount of execution resources to each thread. However, accommodating unbalanced schedules creates several difficulties, the biggest being the fact that the search space of all schedules (both balanced and unbalanced) is much greater than that of the balanced schedules alone. This work proposes and evaluates scheduling policies that allow the system to identify and migrate toward good thread schedules, whether the best schedules are balanced or unbalanced.

Runtime Parallelization of Legacy Code on a Transactional Memory System

Thispaperproposesanewruntimeparallelization technique, based on a dynamic optimization framework, to automatically parallelize single-threaded legacy programs. It heavily leverages the optimistic concurrency of transactional memory. This work addresses a number of challenges posed by this type of parallelization and quantifies the trade-offs of some of the design decisions, such as how to select good loops for parallelization, how to partition the iteration space among parallel threads, how to handle loop-carried dependencies, and how to transition from serial to parallel execution and back. The simulated implementation of runtime parallelization shows apotentialspeedupof1.36 for theNAS benchmarks and a 1.34 speedup for the SPEC 2000 CPU floating point benchmarks when using two cores for parallel execution. Categories andSubject Descriptor

The soluble intracellular domain of megalin does not affect renal proximal tubular function in vivo

Megalin-mediated endocytic uptake constitutes the main pathway for clearance of plasma proteins from the glomerular filtrate in proximal tubules. Little is known, however, about mechanisms that control megalin expression and activity in the kidney. A widely discussed hypothesis states that upon ligand binding a regulated intramembrane proteolysis releases the cytosolic domain of megalin and this fragment subsequently modulates megalin gene transcription. Here, we tested this by generating a mouse model that co-expressed both the soluble intracellular domain and full-length megalin. Despite pronounced synthesis in the proximal tubules, the soluble intracellular domain failed to exert distinct effects on renal proximal tubular function, including megalin expression, endocytic retrieval of proteins, or global renal gene transcription. Hence, our study argues that the soluble intracellular domain does not have a role in regulating the activity of megalin in the kidney. Kidney International (2010) 78, 473-477; doi:10.1038/ki.2010.169; published online 9 June 201

A mouse model of early-onset renal failure due to a xanthine dehydrogenase nonsense mutation

Chronic kidney disease (CKD) is characterized by renal fibrosis that can lead to end-stage renal failure, and studies have supported a strong genetic influence on the risk of developing CKD. However, investigations of the underlying molecular mechanisms are hampered by the lack of suitable hereditary models in animals. We therefore sought to establish hereditary mouse models for CKD and renal fibrosis by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea, and identified a mouse with autosomal recessive renal failure, designated RENF. Three-week old RENF mice were smaller than their littermates, whereas at birth they had been of similar size. RENF mice, at 4-weeks of age, had elevated concentrations of plasma urea and creatinine, indicating renal failure, which was associated with small and irregularly shaped kidneys. Genetic studies using DNA from 10 affected mice and 91 single nucleotide polymorphisms mapped the Renf locus to a 5.8 Mbp region on chromosome 17E1.3. DNA sequencing of the xanthine dehydrogenase (Xdh) gene revealed a nonsense mutation at codon 26 that co-segregated with affected RENF mice. The Xdh mutation resulted in loss of hepatic XDH and renal Cyclooxygenase-2 (COX-2) expression. XDH mutations in man cause xanthinuria with undetectable plasma uric acid levels and three RENF mice had plasma uric acid levels below the limit of detection. Histological analysis of RENF kidney sections revealed abnormal arrangement of glomeruli, intratubular casts, cellular infiltration in the interstitial space, and interstitial fibrosis. TUNEL analysis of RENF kidney sections showed extensive apoptosis predominantly affecting the tubules. Thus, we have established a mouse model for autosomal recessive early-onset renal failure due to a nonsense mutation in Xdh that is a model for xanthinuria in man. This mouse model could help to increase our understanding of the molecular mechanisms associated with renal fibrosis and the specific roles of XDH and uric acid

Making the Most of SMT in HPC

This work presents an end-to-end methodology for quantifying the performance and power benefits of simultaneous multithreading (SMT) for HPC centers and applies this methodology to a production system and workload. Ultimately, SMT’s value system-wide depends on whether users effectively employ SMT at the application level. However, predicting SMT’s benefit for HPC applications is challenging; by doubling the number of threads, the application’s characteristics may change. This work proposes statistical modeling techniques to predict the speedup SMT confers to HPC applications. This approach, accurate to within 8%, uses only lightweight, transparent performance monitors collected during a single run of the application