ALPHA-SYNUCLEIN MULTIMERIZATION IS DEPENDENT ON STRUCTURAL CHARACTERISTICS OF REPEATED KTKEGV REGIONS

Parkinson’s disease (PD) is the most common movement disorder and is characterized by neuronal loss and the presence of Lewy bodies in dopaminergic neurons of the substantia nigra pars compacta. PD is a chronic, progressive, and irreversible neurodegenerative disorder associated with the selective loss of dopaminergic neurons. Initially described in an Ayurvedic medical treatise and Galen’s writings, and later by James Parkinson in 1817, the most common symptoms of PD are resting tremors, abnormal posture and gait, and muscle rigidity. Approximately 1 million people are living with PD in the United States and worldwide estimates are between 7 and 10 million. Approximately 5-10% of PD cases are genetic, while the vast majority are sporadic and idiopathic. Mutations in genes such as SNCA, GBA, PRKN, PINK1, DJ-1 and LRRK2 along with environmental factors such as pesticides, gut-bacteria and metal toxicity have been associated with PD. The vast array of possible causes paired with the variance of appearance and rate of progression make the disease difficult to diagnose and study both at a clinical and molecular level. Perhaps the most studied protein in the field of PD is alpha-synuclein (a-syn). Indeed, the interest in the protein was sparked in 1997 by the finding that an alanine to threonine substitution (A53T) in a-syn co-segregated with PD subjects. Both genetic lesions in a-syn and the intrinsic accumulation of the protein in neurons are associated with early- and late-onset PD. A neuropathological hallmark of PD is the presence of insoluble intra-neuronal protein aggregates called Lewy Bodies (LB) which are highly enriched in a-syn. A-syn is an intrinsically disordered and natively unfolded protein with a theoretical size of 14 kDa, which has the propensity to form higher order multimers. Although the genetics of SNCA/a-syn are well known, the physiological function of a-syn is largely unknown as is its ability to influence neurodegeneration and cell death in PD. It has been suggested that a-syn may represent a prime target for future diagnostic and therapeutic intervention strategies. However, to further this notion, it will be important to understand the aggregation dynamics of a-syn and how intermediate a-syn multimers may indeed positively and/or negatively impact the death of neurons in PD

Vapor SIMD: Auto-Vectorize Once, Run Everywhere

International audienceJust-in-Time (JIT) compiler technology offers portability while facilitating target- and context-specific specialization. Single-Instruction-Multiple-Data (SIMD) hardware is ubiquitous and markedly diverse, but can be difficult for JIT compilers to efficiently target due to resource and budget constraints. We present our design for a synergistic auto-vectorizing compilation scheme. The scheme is composed of an aggressive, generic offline stage coupled with a lightweight, target-specific online stage. Our method leverages the optimized intermediate results provided by the first stage across disparate SIMD architectures from different vendors, having distinct characteristics ranging from different vector sizes, memory alignment and access constraints, to special computational idioms.We demonstrate the effectiveness of our design using a set of kernels that exercise innermost loop, outer loop, as well as straight-line code vectorization, all automatically extracted by the common offline compilation stage. This results in performance comparable to that provided by specialized monolithic offline compilers. Our framework is implemented using open-source tools and standards, thereby promoting interoperability and extendibility

Vapor SIMD: Auto-Vectorize Once, Run Everywhere

International audienceJust-in-Time (JIT) compiler technology offers portability while facilitating target- and context-specific specialization. Single-Instruction-Multiple-Data (SIMD) hardware is ubiquitous and markedly diverse, but can be difficult for JIT compilers to efficiently target due to resource and budget constraints. We present our design for a synergistic auto-vectorizing compilation scheme. The scheme is composed of an aggressive, generic offline stage coupled with a lightweight, target-specific online stage. Our method leverages the optimized intermediate results provided by the first stage across disparate SIMD architectures from different vendors, having distinct characteristics ranging from different vector sizes, memory alignment and access constraints, to special computational idioms.We demonstrate the effectiveness of our design using a set of kernels that exercise innermost loop, outer loop, as well as straight-line code vectorization, all automatically extracted by the common offline compilation stage. This results in performance comparable to that provided by specialized monolithic offline compilers. Our framework is implemented using open-source tools and standards, thereby promoting interoperability and extendibility

A Multicenter, Randomized, Open-Labeled, Parallel Group Trial of Sildenafil in Alcohol-Associated Erectile Dysfunction: The Impact on Psychosocial Outcomes

To examine the effect of sildenafil on erectile dysfunction (ED) and psychosocial outcomes in alcohol-dependent (AD) men, 108 men with these diagnoses were randomly assigned to either take sildenafil (50 mg) as add-on to standard treatment for AD, or the same treatment without sildenafil, for 12 weeks. Only 50 patients in sildenafil group and 51 in control group twice completed the International Index of Erectile Function (IIEF) and a battery of self-report questionnaires. IIEF scores and psychosocial functioning, self-esteem and support from friends improved only for sildenafil-treated patients (P < 0.001). The high effect sizes suggest that the observed benefits are unlikely to be a placebo effect, although their unspecific nature could not be ruled out. In men with ED associated with AD, sildenafil improves both ED and psychosocial outcomes. Further placebo-controlled clinical trial is warranted

ACOTES project: Advanced compiler technologies for embedded streaming

Streaming applications are built of data-driven, computational components, consuming and producing unbounded data streams. Streaming oriented systems have become dominant in a wide range of domains, including embedded applications and DSPs. However, programming efficiently for streaming architectures is a challenging task, having to carefully partition the computation and map it to processes in a way that best matches the underlying streaming architecture, taking into account the distributed resources (memory, processing, real-time requirements) and communication overheads (processing and delay). These challenges have led to a number of suggested solutions, whose goal is to improve the programmer’s productivity in developing applications that process massive streams of data on programmable, parallel embedded architectures. StreamIt is one such example. Another more recent approach is that developed by the ACOTES project (Advanced Compiler Technologies for Embedded Streaming). The ACOTES approach for streaming applications consists of compiler-assisted mapping of streaming tasks to highly parallel systems in order to maximize cost-effectiveness, both in terms of energy and in terms of design effort. The analysis and transformation techniques automate large parts of the partitioning and mapping process, based on the properties of the application domain, on the quantitative information about the target systems, and on programmer directives. This paper presents the outcomes of the ACOTES project, a 3-year collaborative work of industrial (NXP, ST, IBM, Silicon Hive, NOKIA) and academic (UPC, INRIA, MINES ParisTech) partners, and advocates the use of Advanced Compiler Technologies that we developed to support Embedded Streaming.Peer ReviewedPostprint (published version

The Association Between Poor Antiretroviral Adherence and Unsafe Sex: Differences by Gender and Sexual Orientation and Implications for Scale-up of Treatment as Prevention

Non-adherence to safer sex and non-adherence to ART can each have adverse health consequences for HIV-infected individuals and their sex partners, but little is known about the association of these behaviors with each other. This “dual risk” has potential negative public health consequences since non-adherence can lead to the development of resistant virus that can then be transmitted to sex partners

TDP-43 Is Not a Common Cause of Sporadic Amyotrophic Lateral Sclerosis

Background: TAR DNA binding protein, encoded by TARDBP, was shown to be a central component of ubiquitin-positive, tau-negative inclusions in frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). Recently, mutations in TARDBP have been linked to familial and sporadic ALS. Methodology/Principal Findings: To further examine the frequency of mutations in TARDBP in sporadic ALS, 279 ALS cases and 806 neurologically normal control individuals of European descent were screened for sequence variants, copy number variants, genetic and haplotype association with disease. An additional 173 African samples from the Human Gene Diversity Panel were sequenced as this population had the highest likelihood of finding changes. No mutations were found in the ALS cases. Several genetic variants were identified in controls, which were considered as non-pathogenic changes. Furthermore, pathogenic structural variants were not observed in the cases and there was no genetic or haplotype association with disease status across the TARDBP locus