Characterization and optimization of network traffic in cortical simulation

Considering the great variety of obstacles the Exascale systems have to face in the next future, a deeper attention will be given in this thesis to the interconnect and the power consumption. The data movement challenge involves the whole hierarchical organization of components in HPC systems — i.e. registers, cache, memory, disks. Running scientific applications needs to provide the most effective methods of data transport among the levels of hierarchy. On current petaflop systems, memory access at all the levels is the limiting factor in almost all applications. This drives the requirement for an interconnect achieving adequate rates of data transfer, or throughput, and reducing time delays, or latency, between the levels. Power consumption is identified as the largest hardware research challenge. The annual power cost to operate the system would be above 2.5 B$ per year for an Exascale system using current technology. The research for alternative power-efficient computing device is mandatory for the procurement of the future HPC systems. In this thesis, a preliminary approach will be offered to the critical process of co-design. Co-desing is defined as the simultaneos design of both hardware and software, to implement a desired function. This process both integrates all components of the Exascale initiative and illuminates the trade-offs that must be made within this complex undertaking

OXIDATIVE STRESS AND REDOX PROTEOMICS STUDIES IN MODELS OF NEURODEGENERATIVE DISORDERS: I. THE CANINE MODEL OF HUMAN AGING; II. INSIGHTS INTO SUCCESSFUL AGING; AND III. TRAUMATIC BRAIN INJURY

The studies presented in this dissertation were conducted with the objective ofgaining greater understanding into the mechanisms of successful aging, the role ofmitochondria dysfunction in traumatic brain injury, and also on the mechanisms ofimproved learning and cognitive function in the aging.Aging is usually characterized by impairments in physiological functionsincreasing its susceptibility to dementia and neurodegenerative disorders. In thisdissertation, the mechanisms of dementia-free aging were investigated. The use of anantioxidant fortified diet and a program of behavioral enrichment in the canine model ofhuman aging was shown to result in a significant decrease in the levels of oxidativestress. A proteomic analysis of these brains also demonstrated a significant decrease inthe oxidative modification of key brain proteins and an increase in the expression levelsof other key brain proteins associated with energy metabolism and antioxidant systemswhich correlated with improved learning and memory.We show that following TBI key mitochondrial-related proteins undergoextensive oxidative modification, possibly contributing to the severe loss ofmitochondrial energetics and neuronal cell death previously observed in experimentalTBI.Taken together, these findings support the role of oxidative stress in thepathophysiology of aging and age-related neurodegenerative disorders and in CNS injury.These studies also show that antioxidants and a program of behavioral enrichmentprovide protection against oxidative stress-mediated cognitive impairments

Palmitoylethanolamide modulates high-fat diet-shaped gut function and microbiota composition in obese mice

Introduction/Background & aims: Emerging data indicate a pivotal role for gut microbiota in the progression of obesity. Indeed, in the gut, high-fat diet (HFD) intake induces the loss of barrier integrity, causing the transfer of detrimental factors (i.e. lipopolysaccharide, LPS) into the systemic circulation, leading to metabolic dysfunctions and an overall state of low-grade inflammation, called “met- ainflammation” [1]. The metabolic and anti-inflammatory activities of palmitoylethanolamide (PEA), an endogenous lipid mediator, prompt us to evaluate its capability to improve intestinal homeostasis and shape gut microbiota composition altered in HFD-fed obese mice. Method/Summary of work: Male C57Bl/6 J mice received standard diet (STD) or HFD (n = 10 each group). After 12 weeks, a subgroup of HFD mice was treated with PEA (30 μg/kg/die per os) for 7 weeks. Body weight was monitored during the treatment and fat mass was evaluated at the end of experimental time. Systemic parameters and intestinal function were examined using ELISA assay, and Real-Time PCR analysis, respectively. Faecal microbiota was studied by per- forming 16S rDNA amplicon sequencing and linear discriminant analy- sis in order to obtain the operational taxonomic units (OTUs) defining the bacterial communities

Journal of Telecommunications and Information Technology, 2017, nr 2

kwartalni

Unraveling molecular signaling in neurodegenerative diseases:focus on a protective mechanism mediated by linalool

Neurodegenerative conditions such as Alzheimer`s disease (AD) and stroke are characterized by progressive nervous system dysfunction. The main aim of this work was to propose new therapeutic targets in neurodegeneration and to identify possible phospholipid biomarkers that reflect the progression of the disease. We demonstrated that administration of the terpene, linalool was able to reduce the main pathological markers of AD (extracellular β-amyloidosis, tauopathy) and of ischemic stroke. Linalool treatment in animals improved motor coordination and cognition, along with a reduction of astrogliosis and microgliosis in the hippocampus. Besides, we investigated whether and how linalool exert a neuroprotective effect against glutamate-induced oxidative stress and might affect mitochondrial function. Administration of linalool reduced cell death mediated by glutamate, mitochondrial ROS formation, mitochondrial calcium uptake, lipid peroxidation and mediated a recovery of mitochondrial membrane potential, together with an increase in mitochondrial respiration. In addition, we detected remarkable changes in phospholipids in ischemic stroke, AD and CADASIL in brain samples, CSF and serum. These data could help to unravel novel molecular mechanisms and propose different therapeutic targets to treat transversal pathogenesis. Finally, we showed in a review the role of microglia in neurodegenerative diseases and we present the results of a differentiation protocol of human microglia from iPSC demonstrating the maturity and functionality of these cells. In conclusion, we present various strategies to model and study neurodegeneration and provide answers in the field of inflammation, lipidomics and at the same time we propose a new molecule as a potential therapy against AD and cerebral ischemia

Small Molecule Hsp90 Modulator and Neuregulin-induced Peripheral Demyelination

Abstract Modulating molecular chaperones is emerging as an attractive approach to treat neurodegenerative diseases associated with protein aggregation, diabetic peripheral neuropathy (DPN) and possibly, demyelinating neuropathies. KU-32 is a small molecule inhibitor of heat shock protein 90 (Hsp90) and reverses sensory deficits associated with myelinated fiber dysfunction in DPN. Additionally, KU-32 prevented the loss of myelinated internodes induced by treating myelinated Schwann cell-dorsal root ganglia sensory neuron co-cultures with neuregulin-1 Type 1 (NRG1). Since KU-32 decreased NRG1-induced demyelination in an Hsp70-dependent manner, the goal of the current study was to clarify how Hsp70 may be mechanistically linked to preventing demyelination. The activation of p42/p44 MAPK and induction of the transcription factor c-jun function as negative regulators of myelination. NRG1 activated MAPK, induced c-jun expression and promoted a loss of myelin segments in DRG explants isolated from both wild type and Hsp70 KO mice. Although KU-32 did not block the activation of MAPK, it blocked c-jun induction and protected against a loss of myelinated segments in wildtype (WT) mice. KU-32 did not prevent the NRG1-dependent induction of c-jun and loss of myelin segments in explants from Hsp70 KO mice. Over-expression of Hsp70 in myelinated DRG explants prepared from WT or Hsp70 KO mice was sufficient to block the induction of c-jun and the loss of myelin segments induced by NRG1. Lastly, inhibiting the proteasome prevented KU-32 from decreasing c-jun levels. Collectively, these data support that Hsp70 induction is sufficient to prevent NRG1-induced demyelination by enhancing the proteasomal degradation of c-jun

Novel drug interaction for improving intracellular accumulation and efficacy of chemotherapeutics in retinoblastoma and mitochondrial localization of transporters in corneal epithelial cells

Title from PDF of title page, viewed on March 15, 2013Dissertation advisor: Ashim K. MitraVitaIncludes bibliographic references (p. 152-167)Thesis (Ph.D.)--School of Pharmacy and Dept. of Chemistry. University of Missouri--Kansas City, 2013Chemoreduction is the key treatment for retinoblastoma management. However, anticancer agents suffer from poor cell permeability and chemoresistance due to major interaction with multidrug resistant (MDR) efflux proteins (MDR1 and MRP2) over-expressed on retinoblastoma tumor. Ocular cells have shown good tolerability against antimicrobial moxifloxacin (fourth generation fluoroquinolone) at higher dose level. As majority of fluoroquinolones become ineffective due to efflux mediated acquired drug resistance therefore, we have first determined an interaction of moxifloxacin with efflux (MDR1 and MRP2) transporters. Our results provides direct evidence that moxifloxacin is an overlapping substrate of MDR1 and MRP2 efflux transporters. Since, literature has evident co-administration of overlapping drug substrate as a viable strategy to overcome MDR. Therefore, we have tested moxifloxacin potential to overcome chemoresistance in retinoblastoma. Our results showed that 2-2.5 fold increased uptakes of three anticancer drugs (etoposide, topotecan and vinblastine) were observed in the presence of moxifloxacin across model cell lines suggesting moxifloxacin mediated evasion of efflux pumps. Significant reductions in efflux ratio of these anticancer agents were also observed in the presence of moxifloxacin indicating moxifloxacin mediated improved anticancer transport. Following cytotoxicity study, tenfold reduction in IC50 value of topotecan and etoposide and twofold reduction in IC50 value of vinblastine was observed in the presence of moxifloxacin. Significant enhancement of anticancer mediated caspase-3 enzyme activity and reduction in proinflammatory cytokines (IL-8 and IL-6) release were also observed in the presence of moxifloxacin. There is a need to further explore this finding to confirm its clinical feasibility, if proven, ultimately it will aid to reduce the chemotherapeutic dose and associated dose-limiting toxicities. Considering the fact that most drug targets are indeed contained within specific intracellular compartments, the ability of a drug to accumulate into these sites is a critical determinant in the observed drug response. Mitochondrion is an attractive target for drug-delivery because there is a growing confirmation to support an association between mitochondrial dysfunctions and a number of ocular diseases. A range of possibilities exist for the selective drug delivery to the mitochondria one among such is a transporter targeted strategy. Localization of various influx and efflux transporters is generally considered to be restricted to cell surface level. However, cellular compartments may also be a potential site for these transporters. The functional localization of both efflux (MDR1) and influx (PepT-1) transporters in the mitochondrial membrane of primary corneal epithelial cells was studied. Isolation and purification of mitochondria was performed by optimized cell fractionation method. Functional activity of MDR1 and PepT-1 transporter was assessed by performing in vitro uptake studies on isolated mitochondria. Molecular characterization of both transporters was confirmed by western blot and confocal analysis. This knowledge of mitochondrial existence of MDR1 and PepT-1transporter may aid in the development of subcellular ocular drug delivery strategies.Literature review -- Moxifloxacin interaction with transporters and anticancer agents for retinoblastoma management -- Interaction of moxiflaxacin with influx transporter -- Interaction of moxifloxacin with anticancer agents for retinoblastoma management -- Mitochondrial localization of transporters -- Mitochondrial localization of p-glycoprotein and peptide transporters in corneal epithelial cells - Novel strategies for intracellualr drug targeting -- Summary and recommendation