Modelling Energy Consumption based on Resource Utilization

Power management is an expensive and important issue for large computational infrastructures such as datacenters, large clusters, and computational grids. However, measuring energy consumption of scalable systems may be impractical due to both cost and complexity for deploying power metering devices on a large number of machines. In this paper, we propose the use of information about resource utilization (e.g. processor, memory, disk operations, and network traffic) as proxies for estimating power consumption. We employ machine learning techniques to estimate power consumption using such information which are provided by common operating systems. Experiments with linear regression, regression tree, and multilayer perceptron on data from different hardware resulted into a model with 99.94\% of accuracy and 6.32 watts of error in the best case.Comment: Submitted to Journal of Supercomputing on 14th June, 201

Enhancement of CD4+ T Cell Function as a Strategy for Improving Antibiotic Therapy Efficacy in Tuberculosis: Does It Work?

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) remains a major public health problem worldwide due in part to the lack of an effective vaccine and to the lengthy course of antibiotic treatment required for successful cure. Combined immuno/chemotherapeutic intervention represents a major strategy for developing more effective therapies against this important pathogen. Because of the major role of CD4+ T cells in containing Mtb infection, augmentation of bacterial specific CD4+ T cell responses has been considered as an approach in achieving this aim. Here we present new data from our own research aimed at determining whether boosting CD4+ T cell responses can promote antibiotic clearance. In these studies, we first characterized the impact of antibiotic treatment of infected mice on Th1 responses to major Mtb antigens and then performed experiments aimed at sustaining CD4+ T cell responsiveness during antibiotic treatment. These included IL-12 infusion, immunization with ESAT-6 and Ag85B immunodominant peptides and adoptive transfer of Th1-polarized CD4+ T cells specific for ESAT-6 or Ag85B during the initial month of chemotherapy. These approaches failed to enhance antibiotic clearance of Mtb, indicating that boosting Th1 responses to immunogenic Mtb antigens highly expressed by actively dividing bacteria is not an effective strategy to be used in the initial phase of antibiotic treatment, perhaps because replicating organisms are the first to be eliminated by the drugs. These results are discussed in the context of previously published findings addressing this concept along with possible alternate approaches for harnessing Th1 immunity as an adjunct to chemotherapy

Cross-species genomic and functional analyses identify a combination therapy using a CHK1 inhibitor and a ribonucleotide reductase inhibitor to treat triple-negative breast cancer

INTRODUCTION: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is diagnosed in approximately 15% of all human breast cancer (BrCa) patients. Currently, no targeted therapies exist for this subtype of BrCa and prognosis remains poor. Our laboratory has previously identified a proliferation/DNA repair/cell cycle gene signature (Tag signature) that is characteristic of human TNBC. We hypothesize that targeting the dysregulated biological networks in the Tag gene signature will lead to the identification of improved combination therapies for TNBC. METHODS: Cross-species genomic analysis was used to identify human breast cancer cell lines that express the Tag signature. Knock-down of the up-regulated genes in the Tag signature by siRNA identified several genes that are critical for TNBC cell growth. Small molecule inhibitors to two of these genes were analyzed, alone and in combination, for their effects on cell proliferation, cell cycle, and apoptosis in vitro and tumor growth in vivo. Synergy between the two drugs was analyzed by the Chou-Talalay method. RESULTS: A custom siRNA screen was used to identify targets within the Tag signature that are critical for growth of TNBC cells. Ribonucleotide reductase 1 and 2 (RRM1 and 2) and checkpoint kinase 1 (CHK1) were found to be critical targets for TNBC cell survival. Combination therapy, to simultaneously attenuate cell cycle checkpoint control through inhibition of CHK1 while inducing DNA damage with gemcitabine, improved therapeutic efficacy in vitro and in xenograft models of TNBC. CONCLUSIONS: This combination therapy may have translational value for patients with TNBC and improve therapeutic response for this aggressive form of breast cancer

IL-12p40 is essential but not sufficient for Francisella tularensis LVS clearance in chronically infected mice.

IL-12p40 plays an important role in F. tularensis Live Vaccine Strain (LVS) clearance that is independent of its functions as a part of the heterodimeric cytokines IL-12p70 or IL-23. In contrast to WT, p35, or p19 knockout (KO) mice, p40 KO mice infected with LVS develop a chronic infection that does not resolve. Here, we further evaluated the role of IL-12p40 in F. tularensis clearance. Despite reduced IFN-γ production, primed splenocytes from p40 KO and p35 KO mice appeared functionally similar to those from WT mice during in vitro co-culture assays of intramacrophage bacterial growth control. Gene expression analysis revealed a subset of genes that were upregulated in re-stimulated WT and p35 KO splenocytes, but not p40 KO splenocytes, and thus are candidates for involvement in F. tularensis clearance. To directly evaluate a potential mechanism for p40 in F. tularensis clearance, we reconstituted protein levels in LVS-infected p40 KO mice using either intermittent injections of p40 homodimer (p80) or treatment with a p40-producing lentivirus construct. Although both delivery strategies yielded readily detectable levels of p40 in sera and spleens, neither treatment had a measurable impact on LVS clearance by p40 KO mice. Taken together, these studies demonstrate that clearance of F. tularensis infection depends on p40, but p40 monomers and/or dimers alone are not sufficient

Production of IFN-γ by splenic dendritic cells during innate immune responses against Francisella tularensis LVS depends on MyD88, but not TLR2, TLR4, or TLR9.

Production of IFN-γ is a key innate immune mechanism that limits replication of intracellular bacteria such as Francisella tularensis (Ft) until adaptive immune responses develop. Previously, we demonstrated that the host cell types responsible for IFN-γ production in response to murine Francisella infection include not only natural killer (NK) and T cells, but also a variety of myeloid cells. However, production of IFN-γ by mouse dendritic cells (DC) is controversial. Here, we directly demonstrated substantial production of IFN-γ by DC, as well as hybrid NK-DC, from LVS-infected wild type C57BL/6 or Rag1 knockout mice. We demonstrated that the numbers of conventional DC producing IFN-γ increased progressively over the course of 8 days of LVS infection. In contrast, the numbers of conventional NK cells producing IFN-γ, which represented about 40% of non-B/T IFN-γ-producing cells, peaked at day 4 after LVS infection and declined thereafter. This pattern was similar to that of hybrid NK-DC. To further confirm IFN-γ production by infected cells, DC and neutrophils were sorted from naïve and LVS-infected mice and analyzed for gene expression. Quantification of LVS by PCR revealed the presence of Ft DNA not only in macrophages, but also in highly purified, IFN-γ producing DC and neutrophils. Finally, production of IFN-γ by infected DC was confirmed by immunohistochemistry and confocal microscopy. Notably, IFN-γ production patterns similar to those in wild type mice were observed in cells derived from LVS-infected TLR2, TLR4, and TLR2xTLR9 knockout (KO) mice, but not from MyD88 KO mice. Taken together, these studies demonstrate the pivotal roles of DC and MyD88 in IFN-γ production and in initiating innate immune responses to this intracellular bacterium

Anti-LVS antibody titers of HK-LVS vaccinated BALB/cByJ mice do not correlate with survival.

<p>Sera from BALB/cByJ mice vaccinated with different doses of HK-LVS were individually analyzed six weeks after vaccination for anti-LVS total IgG. Mice were then challenged IP with a maximal lethal dose of LVS. Error bars depict standard deviation of the mean of triplicates samples tested in the ELISA. * indicates the antibody responses of the mice that eventually survived the lethal challenge. Results shown are from one representative experiment of two independent experiments of similar design and outcome.</p

IFN-γ and NO production exhibit patterns mostly similar to that of <i>in vitro</i> LVS replication.

<p>Supernatants from co-cultures described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126570#pone.0126570.g001" target="_blank">Fig 1</a> using splenocytes of BALB/cByJ mice (Panels A and C) and BKO mice (Panels B and D) were collected after two days of co-culture, and separated from cells for analyses of IFN-γ by ELISA (Panels A and B) and NO by Griess reaction (Panels C and D). Concentrations were calculated using standard curves as reference. Values shown are the mean concentration in ng/ml (IFN-γ) or μmoles (NO) ± standard deviation of triplicate samples. Results shown are from one representative experiment of seven (using splenocytes of BALB/cByJ mice) or four (using splenocytes of BKO mice) independent experiments of similar design and outcome. Brackets indicate a significant difference (<i>P</i> < 0.05) between amounts of IFN-γ or NO produced in co-cultures. There were no significant differences in IFN-γ production between the co-cultures using LVS-immune cells and the co-cultures using LVS-G-immune cells (Panel A), between the co-cultures using LVS-G-immune cells and the co-cultures using LVS-R-immune cells (Panel A), and between the co-cultures using LVS-immune cells and the co-cultures using LVS-G-immune cells or LVS-R-immune cells (Panel B).</p

Humoral immune responses patterns to LVS-related vaccines differ between BALB/cByJ and C57BL/6J mice.

<p>Pooled sera from five mice for each vaccine group were obtained from BALB/cByJ mice (Panel A) and from C57BL/6J mice (Panel B) six weeks after vaccination, and analyzed for anti-LVS total IgG. Error bars depict standard deviation of the mean of triplicates samples tested in the ELISA. Results shown are from one representative experiment of four independent experiments of similar design and outcome.</p

Splenocytes from LVS-related vaccinated mice exhibit a hierarchy of control of intramacrophage LVS growth.

<p>BMMΦ from BALB/cByJ mice were infected with LVS (Macs), and co-cultured with splenocytes obtained from naïve or vaccinated BALB/cByJ mice (Panel A), and from naive or vaccinated BKO mice (Panel B), as indicated. After two days of co-culture, BMMΦ were washed, lysed, and plated to evaluate the recovery of intracellular bacteria. Values shown are the mean numbers of CFU/ml ± SD of viable bacteria for triplicate samples. Results shown are from one representative experiment of seven (using splenocytes of BALB/cByJ mice) or four (using splenocytes of BKO mice) independent experiments of similar design and outcome. Brackets indicate a significant difference (<i>P</i> < 0.05) between the recoveries of bacteria in co-cultures. There were no significant differences between the recovery of bacteria from co-cultures using LVS-immune cells and LVS-G-immune cells (Panel A) and the recovery of bacteria from co-cultures using LVS-G-immune cells and LVS-R-immune cells (Panel B).</p