RADIC scalability analysis: functional Mmodel

In parallel systems, a number of measures of performance are not accurate or representative of their functioning. These measures allow to quantify the benefit of parallelism. Very often, programs are designed and tested for smaller problems on fewer processing elements. However, the real problems these programs are intended to solve are much larger, and the machines contain a great number of processing elements. Hence, it is necessary to create a model that allows to extrapolate the application execution over a few processing elements to larger machine configurations. These measures are more complex if we consider faults. When we take measures we must understand the interaction among system architecture, application architecture and fault tolerant system. In this paper we present a model which analyzes the combination parallel computer, parallel application and RADIC fault tolerance architecture.Presentado en el IX Workshop Procesamiento Distribuido y Paralelo (WPDP)Red de Universidades con Carreras en Informática (RedUNCI

RADIC II : a fault tolerant architecture with flexible dynamic redundancy

The demand for computational power has been leading the improvement of the High Performance Computing (HPC) area, generally represented by the use of distributed systems like clusters of computers running parallel applications. In this area, fault tolerance plays an important role in order to provide high availability isolating the application from the faults effects. Performance and availability form an undissociable binomial for some kind of applications. Therefore, the fault tolerant solutions must take into consideration these two constraints when it has been designed. In this dissertation, we present a few side-effects that some fault tolerant solutions may presents when recovering a failed process. These effects may causes degradation of the system, affecting mainly the overall performance and availability. We introduce RADIC-II, a fault tolerant architecture for message passing based on RADIC (Redundant Array of Distributed Independent Fault Tolerance Controllers) architecture. RADIC-II keeps as maximum as possible the RADIC features of transparency, decentralization, flexibility and scalability, incorporating a flexible dynamic redundancy feature, allowing to mitigate or to avoid some recovery side-effects.La demanda de computadores más veloces ha provocado el incremento del área de computación de altas prestaciones, generalmente representado por el uso de sistemas distribuidos como los clusters de computadores ejecutando aplicaciones paralelas. En esta área, la tolerancia a fallos juega un papel muy importante a la hora de proveer alta disponibilidad, aislando los efectos causados por los fallos. Prestaciones y disponibilidad componen un binomio indisociable para algunos tipos de aplicaciones. Por eso, las soluciones de tolerancia a fallos deben tener en consideración estas dos restricciones desde el momento de su diseño. En esta disertación, presentamos algunos efectos colaterales que se puede presentar en ciertas soluciones tolerantes a fallos cuando recuperan un proceso fallado. Estos efectos pueden causar una degradación del sistema, afectando las prestaciones y disponibilidad finales. Presentamos RADIC-II, una arquitectura tolerante a fallos para paso de mensajes basada en la arquitectura RADIC (Redundant Array of Distributed Independent Fault Tolerance Controllers). RADIC-II mantiene al máximo posible las características de transparencia, descentralización, flexibilidad y escalabilidad existentes en RADIC, e incorpora una flexible funcionalidad de redundancia dinámica, que permite mitigar o evitar algunos efectos colaterales en la recuperación

Single-Cell RNA-seq Reveals Profound Alterations in Mechanosensitive Dorsal Root Ganglion Neurons with Vitamin E Deficiency.

Ninety percent of Americans consume less than the estimated average requirements of dietary vitamin E (vitE). Severe vitE deficiency due to genetic mutations in the tocopherol transfer protein (TTPA) in humans results in ataxia with vitE deficiency (AVED), with proprioceptive deficits and somatosensory degeneration arising from dorsal root ganglia neurons (DRGNs). Single-cell RNA-sequencing of DRGNs was performed in Ttpa-/- mice, an established model of AVED. In stark contrast to expected changes in proprioceptive neurons, Ttpa-/- DRGNs showed marked upregulation of voltage-gated Ca2+ and K+ channels in mechanosensitive, tyrosine-hydroxylase positive (TH+) DRGNs. The ensuing significant conductance changes resulted in reduced excitability in mechanosensitive Ttpa-/- DRGNs. A highly supplemented vitE diet (600 mg dl-α-tocopheryl acetate/kg diet) prevented the cellular and molecular alterations and improved mechanosensation. VitE deficiency profoundly alters the molecular signature and functional properties of mechanosensitive TH+ DRGN, representing an intriguing shift of the prevailing paradigm from proprioception to mechanical sensation

Clinical relevance of biomarkers of oxidative stress

SIGNIFICANCE Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. Recent Advances: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. CRITICAL ISSUES The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clinical use. FUTURE DIRECTIONS Several markers of oxidative stress still represent a viable biomarker opportunity for clinical use. However, positive findings with currently used biomarkers still need to be validated in larger sample sizes and compared with current clinical standards to establish them as clinical diagnostics. It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others. The vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker. Antioxid. Redox Signal. 00, 000-000

Teaching the Basics of Reactive Oxygen Species and their Relevance to Cancer Biology: Mitochondrial Reactive Oxygen Species Detection, Redox Signaling, and Targeted Therapies

Reactive oxygen species (ROS) have been implicated in tumorigenesis (tumor initiation, tumor progression, and metastasis). Of the many cellular sources of ROS generation, the mitochondria and the NADPH oxidase family of enzymes are possibly the most prevalent intracellular sources. In this article, we discuss the methodologies to detect mitochondria-derived superoxide and hydrogen peroxide using conventional probes as well as newly developed assays and probes, and the necessity of characterizing the diagnostic marker products with HPLC and LC-MS in order to rigorously identify the oxidizing species. The redox signaling roles of mitochondrial ROS, mitochondrial thiolperoxidases, and transcription factors in response to mitochondria-targeted drugs are highlighted. ROS generation and ROS detoxification in drug-resistant cancer cells and the relationship to metabolic reprogramming are discussed. Understanding the subtle role of ROS in redox signaling and in tumor proliferation, progression, and metastasis as well as the molecular and cellular mechanisms (e.g., autophagy) could help in the development of combination therapies. The paradoxical aspects of antioxidants in cancer treatment are highlighted in relation to the ROS mechanisms in normal and cancer cells. Finally, the potential uses of newly synthesized exomarker probes for in vivo superoxide and hydrogen peroxide detection and the low-temperature electron paramagnetic resonance technique for monitoring oxidant production in tumor tissues are discussed

Fault tolerance at system level based on RADIC architecture

The increasing failure rate in High Performance Computing encourages the investigation of fault tolerance mechanisms to guarantee the execution of an application in spite of node faults. This paper presents an automatic and scalable fault tolerant model designed to be transparent for applications and for message passing libraries. The model consists of detecting failures in the communication socket caused by a faulty node. In those cases, the affected processes are recovered in a healthy node and the connections are reestablished without losing data. The Redundant Array of Distributed Independent Controllers architecture proposes a decentralized model for all the tasks required in a fault tolerance system: protection, detection, recovery and masking. Decentralized algorithms allow the application to scale, which is a key property for current HPC system. Three different rollback recovery protocols are defined and discussed with the aim of offering alternatives to reduce overhead when multicore systems are used. A prototype has been implemented to carry out an exhaustive experimental evaluation through Master/Worker and Single Program Multiple Data execution models. Multiple workloads and an increasing number of processes have been taken into account to compare the above mentioned protocols. The executions take place in two multicore Linux clusters with different socket communications libraries

Challenges of managing people with multimorbidity in today’s healthcare systems

Multimorbidity is a growing issue and poses a major challenge to health care systems around the world. Multimorbidity is related to ageing but many studies have now shown that it is also socially patterned, being more common and occurring at an earlier age in areas of high socioeconomic deprivation. There is lack of research on patients with multimorbidity, and thus guidelines are based on single-conditions. Polypharmacy is common in multimorbidity, increasing drug-disease and drug-drug interactions. Multimorbid patients need holistic care, but secondary care services are highly specialised and thus are often duplicative and fragmented and thus increase treatment burden in multimorbid patients. The cost of care is high in multimorbidity, due to high rates of primary and secondary care consultations and unplanned hospital admissions. The combination of mental and physical conditions increases complexity of care, and costs. Mental-physical multimorbidity is especially common in deprived areas. General practitioners and primary care teams have a key role in managing patients with multimorbidity, using a patient-centred generalist approach. Consultation length and continuity of care may need to be substantially enhanced in order to enable such patients. This will require a radical change in how health care systems are organised and funded in order to effectively meet the challenges of multimorbidity

Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

The antiglycemic drug metformin, widely prescribed as first-line treatment of type II diabetes mellitus, has lifespan-extending properties. Precisely how this is achieved remains unclear. Via a quantitative proteomics approach using the model organism Caenorhabditis elegans, we gained molecular understanding of the physiological changes elicited by metformin exposure, including changes in branched-chain amino acid catabolism and cuticle maintenance. We show that metformin extends lifespan through the process of mitohormesis and propose a signaling cascade in which metformin-induced production of reactive oxygen species increases overall life expectancy. We further address an important issue in aging research, wherein so far, the key molecular link that translates the reactive oxygen species signal into a prolongevity cue remained elusive. We show that this beneficial signal of the mitohormetic pathway is propagated by the peroxiredoxin PRDX-2. Because of its evolutionary conservation, peroxiredoxin signaling might underlie a general principle of prolongevity signaling

Damage to Mitochondrial Complex I During Cardiac Ischemia Reperfusion Injury is Reduced Indirectly by Anti-anginal Drug Ranolazine

Ranolazine, an anti-anginal drug, is a late Na+ channel current blocker that is also believed to attenuate fatty acid oxidation and mitochondrial respiratory complex I activity, especially during ischemia. In this study, we investigated if ranolazine\u27s protective effect against cardiac ischemia/reperfusion (IR) injury is mediated at the mitochondrial level and specifically if respiratory complex I (NADH Ubiquinone oxidoreductase) function is protected. We treated isolated and perfused guinea pig hearts with ranolazine just before 30 min ischemia and then isolated cardiac mitochondria at the end of 30 min ischemia and/or 30 min ischemia followed by 10 min reperfusion. We utilized spectrophotometric and histochemical techniques to assay complex I activity, Western blot analysis for complex I subunit NDUFA9, electron paramagnetic resonance for activity of complex I Fe–S clusters, enzyme linked immuno sorbent assay (ELISA) for determination of protein acetylation, native gel histochemical staining for respiratory supercomplex assemblies, and high pressure liquid chromatography for cardiolipin integrity; cardiac function was measured during IR. Ranolazine treated hearts showed higher complex I activity and greater detectable complex I protein levels compared to untreated IR hearts. Ranolazine treatment also led to more normalized electron transfer via Fe–S centers, supercomplex assembly and cardiolipin integrity. These improvements in complex I structure and function with ranolazine were associated with improved cardiac function after IR. However, these protective effects of ranolazine are not mediated by a direct action on mitochondria, but rather indirectly via cytosolic mechanisms that lead to less oxidation and better structural integrity of complex I

SMCV: a Methodology for Detecting Transient Faults in Multicore Clusters

The challenge of improving the performance of current processors is achieved by increasing the integration scale. This carries a growing vulnerability to transient faults, which increase their impact on multicore clusters running large scientific parallel applications. The  requirement for enhancing the reliability of these systems, coupled with the high cost of rerunning the application from the beginning, create the motivation for having specific software strategies for the target systems. This paper introduces SMCV, which is a fully distributed technique that provides fault detection for message-passing parallel applications, by validating the contents of the messages to be sent, preventing the transmission of errors to other processes and leveraging the intrinsic hardware redundancy of the multicore. SMCV achieves a wide robustness against transient faults with a reduced overhead, and accomplishes a trade-off between moderate detection latency and low additional workload.Instituto de Investigación en Informátic