Reliability and performance optimization of pipelined real-time systems

We consider pipelined real-time systems that consist of a chain of tasks executing on a distributed platform. The processing of the tasks is pipelined: each processor executes only one interval of consecutive tasks. We are interested in minimizing both the input–output latency and the period of application mapping. For dependability reasons, we are also interested in maximizing the reliability of the system. We therefore assign several processors to each interval of tasks, so as to increase the reliability of the system. Both processors and communication links are unreliable and subject to transient failures. We assume that the arrival of the failures follows a constant parameter Poisson law, and that the failures are statistically independent events. We study several variants of this multiprocessor mapping problem, with several hypotheses on the target platform (homogeneous/heterogeneous speeds and/or failure rates). We provide NP-hardness complexity results, and optimal mapping algorithms for polynomial problem instances. Efficient heuristics are presented to solve the general case, and experimental results are provided.     

Discovery of Mitophagy Inhibitors with Therapeutic Potential in Different Familial Amyotrophic Lateral Sclerosis Mutations

Mitophagy is the selective degradation of mitochondria by autophagy. It promotes the turnover of mitochondria and prevents the accumulation of dysfunctional mitochondria, which can lead to cellular degeneration. Mitophagy is known to be altered in several pathological conditions, especially in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We recently demonstrated an increase in autophagy flux in lymphoblasts from ALS patients bearing a mutation in SOD1. Thus, the identification of mitophagy inhibitors may be a therapeutic option to recover mitochondrial homeostasis. Here, using a phenotypic mitophagy assay, we identified a new mitophagy inhibitor, the small molecule named IGS2.7 from the MBC library. Interestingly, the treatment of different cellular and in vivo models of ALS with mutations on SOD1 and TARDBP with this inhibitor restores autophagy to control levels. These results point mitophagy inhibitors, especially IGS2.7, to a new therapeutic approach for familial ALS patients.     

The SARS-CoV-2 Delta-Omicron Recombinant Lineage (XD) Exhibits Immune-Escape Properties Similar to the Omicron (BA.1) Variant

Recently, a recombinant SARS-CoV-2 lineage, XD, emerged that harbors a spike gene that is largely derived from the Omicron variant BA.1 in the genetic background of the Delta variant. This finding raised concerns that the recombinant virus might exhibit altered biological properties as compared to the parental viruses and might pose an elevated threat to human health. Here, using pseudotyped particles, we show that ACE2 binding and cell tropism of XD mimics that of BA.1. Further, XD and BA.1 displayed comparable sensitivity to neutralization by antibodies induced upon vaccination with BNT162b2/Comirnaty (BNT) or BNT vaccination followed by breakthrough infection. Our findings reveal important biological commonalities between XD and Omicron BA.1 host cell entry and its inhibition by antibodies.     

Proteomic Biomarkers of the Apnea Hypopnea Index and Obstructive Sleep Apnea: Insights into the Pathophysiology of Presence,Severity, and Treatment Response

Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea–hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI ≥ 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke.     

Reg-1α, a New Substrate of Calpain-2 Depending on Its Glycosylation Status

Reg-1α/lithostathine, a protein mainly associated with the digestive system, was previously shown to be overexpressed in the pre-clinical stages of Alzheimer’s disease. In vitro, the glycosylated protein was reported to form fibrils at physiological pH following the proteolytic action of trypsin. However, the nature of the protease able to act in the central nervous system is unknown. In the present study, we showed that Reg-1α can be cleaved in vitro by calpain-2, the calcium activated neutral protease, overexpressed in neurodegenerative diseases. Using chemical crosslinking experiments, we found that the two proteins can interact with each other. Identification of the cleavage site using mass spectrometry, between Gln⁴ and Thr⁵, was found in agreement with the in silico prediction of the calpain cleavage site, in a position different from the one reported for trypsin, i.e., Arg¹¹-Ile¹² peptide bond. We showed that the cleavage was impeded by the presence of the neighboring glycosylation of Thr⁵. Moreover, in vitro studies using electron microscopy showed that calpain-cleaved protein does not form fibrils as observed after trypsin cleavage. Collectively, our results show that calpain-2 cleaves Reg-1α in vitro, and that this action is not associated with fibril formation.     

Studies on curcumin and curcuminoids XXI. Variation in the content of curcuminoids in Curcuma longa L. and Curcuma aromatica Salisb. from India during one season

Summary Three varieties ofCurcuma longa andC. aromatica were investigated during a growth period of 17 weeks with respect to the content of curcuminoids in the bulbs and fingers. A decrease in pigment production as a function of maturity of the rhizomes was observed. The total content of curcuminoids was equal inC. longa andC. aromatica, but with a slight difference in distribution between the fingers and bulbs in the two species. Taking the biomass into account, the fingers will be more beneficial for the isolation of curcuminoids than the respective bulbs.

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Studien über Curcumin und Curcuminoide XXI. Unterschiede des Gehaltes an Curcuminoiden bei Curcuma longa L. und Curcuma aromatica Salisb. aus Indien während einer Saison

Zusammenfassung Drei Typen vonCurcuma longa undC. aromatica wurden während einer Wachstumsperiode von 17 Wochen auf ihren Curcuminoidgehalt in den Knollen und im Wurzelstock untersucht. Eine Abnahme der Pigmentproduktion in Abhängigkeit von dem Entwicklungsstadium der Rhizome wurde festgestellt. Der Gesamtgehalt an Curcuminoiden beiC. longa undC. aromatica war der gleiche, doch bestand ein geringer Unterschied in der Verteilung dieser zwischen Knolle und Wurzelstock bei den beiden Spezies. Bei Betrachtung der Biomasse ist der Wurzelstock für die Isolation von Curcuminoiden besser geeignet als die Knollen.

     

Echium oil is better than rapeseed oil in improving the response of barramundi to a disease challenge

Pathogen infection stimulates the fatty acid (FA) metabolism and the production of pro-inflammatory derivatives of FA. Barramundi, Lates calcarifer, was fed on a diet rich in preformed long-chain (?C₂₀) polyunsaturated fatty acids (LC-PUFA) from fish oil (FO), to compare with diets containing high levels of C₁₈ precursors for LC-PUFA – stearidonic (SDA) and γ-linolenic acid (GLA) – from Echium plantagineum (EO), or rapeseed oil (RO) rich in α-linolenic acid (ALA), but a poor source of LC-PUFA and their precursors. After 6 weeks, when growth rates were similar amongst the dietary treatments, a sub-lethal dose of Streptococcus iniae was administered to half of the fish, while the other half were maintained unchallenged and were pair-fed with the infected fish. Under a disease challenge situation, the tissue FA depots depleted at 3 days post-infection (DPI) and were then restored to their previous concentrations at 7 DPI. During the infection period, EO fish had a higher content of n3 and n6 PUFA in their tissues, higher n3:n6 PUFA ratio and reduced levels of the eicosanoids, TXB₂ and 6-keto-PGF_1α, in their plasma compared with RO fish. Fish fed on FO and EO had a longer lasting and enduring response in their FA and eicosanoid concentrations, following a week of bacterial infection, compared with those fed on RO. EO, containing SDA and GLA and with a comparatively higher n3:n6 PUFA ratio, proved more effective than RO in compensating for immunity stress.     

Adaptation of the ToxRTool to Assess the Reliability of Toxicology Studies Conducted with Genetically Modified Crops and Implications for Future Safety Testing

To determine the reliability of food safety studies carried out in rodents with genetically modified (GM) crops, a Food Safety Study Reliability Tool (FSSRTool) was adapted from the European Centre for the Validation of Alternative Methods’ (ECVAM) ToxRTool. Reliability was defined as the inherent quality of the study with regard to use of standardized testing methodology, full documentation of experimental procedures and results, and the plausibility of the findings. Codex guidelines for GM crop safety evaluations indicate toxicology studies are not needed when comparability of the GM crop to its conventional counterpart has been demonstrated. This guidance notwithstanding, animal feeding studies have routinely been conducted with GM crops, but their conclusions on safety are not always consistent. To accurately evaluate potential risks from GM crops, risk assessors need clearly interpretable results from reliable studies. The development of the FSSRTool, which provides the user with a means of assessing the reliability of a toxicology study to inform risk assessment, is discussed. Its application to the body of literature on GM crop food safety studies demonstrates that reliable studies report no toxicologically relevant differences between rodents fed GM crops or their non-GM comparators.