Synthesis of 2′-C-α-Methyl-2′,3′-dideoxynucleosides

Abstract

A general method for the synthesis of 2′-C-α-methyl-2′,3′-dideoxynucleosides is presented. Stereofacial selectivity of the 2-C-methylation reaction of γ-lactone has been investigated, in which the presence of a bulky group at the 5-hydroxymethyl produced the α-isomer as a major product. During glycosylation, the α-methyl group directed the formation of nucleosides in favor of the ß-isomer. This methodology is applied to the synthesis of some new pyrimidine and purine nucleosides.

     

DENS: data center energy-efficient network-aware scheduling

In modern data centers, energy consumption accounts for a considerably large slice of operational expenses. The existing work in data center energy optimization is focusing only on job distribution between computing servers based on workload or thermal profiles. This paper underlines the role of communication fabric in data center energy consumption and presents a scheduling approach that combines energy efficiency and network awareness, named DENS. The DENS methodology balances the energy consumption of a data center, individual job performance, and traffic demands. The proposed approach optimizes the tradeoff between job consolidation (to minimize the amount of computing servers) and distribution of traffic patterns (to avoid hotspots in the data center network).     

A two-phase heuristic for the energy-efficient scheduling of independent tasks on computational grids

The sensitivity analysis of a Cellular Genetic Algorithm (CGA) with local search is used to design a new and faster heuristic for the problem of mapping independent tasks to a distributed system (such as a computer cluster or grid) in order to minimize makespan (the time when the last task finishes). The proposed heuristic improves the previously known Min-Min heuristic. Moreover, the heuristic finds mappings of similar quality to the original CGA but in a significantly reduced runtime (1,000 faster). The proposed heuristic is evaluated across twelve different classes of scheduling instances. In addition, a proof of the energy-efficiency of the algorithm is provided. This convergence study suggests how additional energy reduction can be achieved by inserting low power computing nodes to the distributed computer system. Simulation results show that this approach reduces both energy consumption and makespan.     

Differential regulation of cell functions by CSD peptide subdomains

Background

In fibrotic lung diseases, expression of caveolin-1 is decreased in fibroblasts and monocytes. The effects of this deficiency are reversed by treating cells or animals with the caveolin-1 scaffolding domain peptide (CSD, amino acids 82–101 of caveolin-1) which compensates for the lack of caveolin-1. Here we compare the function of CSD subdomains (Cav-A, Cav-B, Cav-C, Cav-AB, and Cav-BC) and mutated versions of CSD (F92A and T90A/T91A/F92A).

Methods

Migration toward the chemokine CXCL12 and the associated expression of F-actin, CXCR4, and pSmad 2/3 were studied in monocytes from healthy donors and SSc patients. Fibrocyte differentiation was studied using PBMC from healthy donors and SSc patients. Collagen I secretion and signaling were studied in fibroblasts derived from the lung tissue of healthy subjects and SSc patients.

Results

Cav-BC and CSD at concentrations as low as 0.01 μM inhibited the hypermigration of SSc monocytes and TGFβ-activated Normal monocytes and the differentiation into fibrocytes of SSc and Normal monocytes. While CSD also inhibited the migration of poorly migrating Normal monocytes, Cav-A (and other subdomains to a lesser extent) promoted the migration of Normal monocytes while inhibiting the hypermigration of TGFβ-activated Normal monocytes. The effects of versions of CSD on migration may be mediated in part via their effects on CXCR4, F-actin, and pSmad 2/3 expression. Cav-BC was as effective as CSD in inhibiting fibroblast collagen I and ASMA expression and MEK/ERK signaling. Cav-C and Cav-AB also inhibited collagen I expression, but in many cases did not affect ASMA or MEK/ERK. Cav-A increased collagen I expression in scleroderma lung fibroblasts. Full effects on fibroblasts of versions of CSD required 5 μM peptide.

Conclusions

Cav-BC retains most of the anti-fibrotic functions of CSD; Cav-A exhibits certain pro-fibrotic functions. Results obtained with subdomains and mutated versions of CSD further suggest that the critical functional residues in CSD depend on the cell type and readout being studied. Monocytes may be more sensitive to versions of CSD than fibroblasts and endothelial cells because the baseline level of caveolin-1 in monocytes is much lower than in these other cell types.     

Biotic and Abiotic Soil Properties Influence Survival of Listeria monocytogenes in Soil

Listeria monocytogenes is a food-borne pathogen responsible for the potentially fatal disease listeriosis and terrestrial ecosystems have been hypothesized to be its natural reservoir. Therefore, identifying the key edaphic factors that influence its survival in soil is critical. We measured the survival of L. monocytogenes in a set of 100 soil samples belonging to the French Soil Quality Monitoring Network. This soil collection is meant to be representative of the pedology and land use of the whole French territory. The population of L. monocytogenes in inoculated microcosms was enumerated by plate count after 7, 14 and 84 days of incubation. Analysis of survival profiles showed that L. monocytogenes was able to survive up to 84 days in 71% of the soils tested, in the other soils (29%) only a short-term survival (up to 7 to 14 days) was observed. Using variance partitioning techniques, we showed that about 65% of the short-term survival ratio of L. monocytogenes in soils was explained by the soil chemical properties, amongst which the basic cation saturation ratio seems to be the main driver. On the other hand, while explaining a lower amount of survival ratio variance (11%), soil texture and especially clay content was the main driver of long-term survival of L. monocytogenes in soils. In order to assess the effect of the endogenous soils microbiota on L. monocytogenes survival, sterilized versus non-sterilized soils microcosms were compared in a subset of 9 soils. We found that the endogenous soil microbiota could limit L. monocytogenes survival especially when soil pH was greater than 7, whereas in acidic soils, survival ratios in sterilized and unsterilized microcosms were not statistically different. These results point out the critical role played by both the endogenous microbiota and the soil physic-chemical properties in determining the survival of L. monocytogenes in soils.     

Effect of Sequence and Stereochemistry Reversal on p53 Peptide Mimicry

Peptidomimetics effective in modulating protein-protein interactions and resistant to proteolysis have potential in therapeutic applications. An appealing yet underperforming peptidomimetic strategy is to employ D-amino acids and reversed sequences to mimic a lead peptide conformation, either separately or as the combined retro-inverso peptide. In this work, we examine the conformations of inverse, reverse and retro-inverso peptides of p53(15–29) using implicit solvent molecular dynamics simulation and circular dichroism spectroscopy. In order to obtain converged ensembles for the peptides, we find enhanced sampling is required via the replica exchange molecular dynamics method. From these replica exchange simulations, the D-peptide analogues of p53(15–29) result in a predominantly left-handed helical conformation. When the parent sequence is reversed sequence as either the L-peptide and D-peptide, these peptides display a greater helical propensity, feature reflected by NMR and CD studies in TFE/water solvent. The simulations also indicate that, while approximately similar orientations of the side-chains are possible by the peptide analogues, their ability to mimic the parent peptide is severely compromised by backbone orientation (for D-amino acids) and side-chain orientation (for reversed sequences). A retro-inverso peptide is disadvantaged as a mimic in both aspects, and further chemical modification is required to enable this concept to be used fruitfully in peptidomimetic design. The replica exchange molecular simulation approach adopted here, with its ability to provide detailed conformational insights into modified peptides, has potential as a tool to guide structure-based design of new improved peptidomimetics.     

Angiogenic Properties of Human Dental Pulp Stem Cells

Angiogenesis, the formation of capillaries from pre-existing blood vessels, is a key process in tissue engineering. If blood supply cannot be established rapidly, there is insufficient oxygen and nutrient transport and necrosis of the implanted tissue will occur. Recent studies indicate that the human dental pulp contains precursor cells, named dental pulp stem cells (hDPSC) that show self-renewal and multilineage differentiation capacity. Since these cells can be easily isolated, cultured and cryopreserved, they represent an attractive stem cell source for tissue engineering. Until now, only little is known about the angiogenic abilities and mechanisms of the hDPSC. In this study, the angiogenic profile of both cell lysates and conditioned medium of hDPSC was determined by means of an antibody array. Numerous pro-and anti-angiogenic factors such as vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1) and endostatin were found both at the mRNA and protein level. hDPSC had no influence on the proliferation of the human microvascular endothelial cells (HMEC-1), but were able to significantly induce HMEC-1 migration in vitro. Addition of the PI3K-inhibitor {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 and the MEK-inhibitor U0126 to the HMEC-1 inhibited this effect, suggesting that both Akt and ERK pathways are involved in hDPSC-mediated HMEC-1 migration. Antibodies against VEGF also abolished the chemotactic actions of hDPSC. Furthermore, in the chicken chorioallantoic membrane (CAM) assay, hDPSC were able to significantly induce blood vessel formation. In conclusion, hDPSC have the ability to induce angiogenesis, meaning that this stem cell population has a great clinical potential, not only for tissue engineering but also for the treatment of chronic wounds, stroke and myocardial infarctions.     

NADPH Oxidase Deficient Mice Develop Colitis and Bacteremia upon Infection with Normally Avirulent,TTSS-1- and TTSS-2-Deficient Salmonella Typhimurium

Infections, microbe sampling and occasional leakage of commensal microbiota and their products across the intestinal epithelial cell layer represent a permanent challenge to the intestinal immune system. The production of reactive oxygen species by NADPH oxidase is thought to be a key element of defense. Patients suffering from chronic granulomatous disease are deficient in one of the subunits of NADPH oxidase. They display a high incidence of Crohn’s disease-like intestinal inflammation and are hyper-susceptible to infection with fungi and bacteria, including a 10-fold increased risk of Salmonellosis. It is not completely understood which steps of the infection process are affected by the NADPH oxidase deficiency. We employed a mouse model for Salmonella diarrhea to study how NADPH oxidase deficiency (Cybb ^−/−) affects microbe handling by the large intestinal mucosa. In this animal model, wild type S. Typhimurium causes pronounced enteropathy in wild type mice. In contrast, an avirulent S. Typhimurium mutant (S.Tm^avir; invGsseD), which lacks virulence factors boosting trans-epithelial penetration and growth in the lamina propria, cannot cause enteropathy in wild type mice. We found that Cybb ^−/− mice are efficiently infected by S.Tm^avir and develop enteropathy by day 4 post infection. Cell depletion experiments and infections in Cybb ^−/− Myd88 ^−/− mice indicated that the S.Tm^avir-inflicted disease in Cybb ^−/− mice hinges on CD11c⁺CX₃CR1⁺ monocytic phagocytes mediating colonization of the cecal lamina propria and on Myd88-dependent proinflammatory immune responses. Interestingly, in mixed bone marrow chimeras a partial reconstitution of Cybb-proficiency in the bone marrow derived compartment was sufficient to ameliorate disease severity. Our data indicate that NADPH oxidase expression is of key importance for restricting the growth of S.Tm^avir in the mucosal lamina propria. This provides important insights into microbe handling by the large intestinal mucosa and the role of NADPH oxidase in maintaining microbe-host mutualism at this exposed body surface.