Additional Routes to Staphylococcus aureus Daptomycin Resistance as Revealed by Comparative Genome Sequencing, Transcriptional Profiling, and Phenotypic Studies

Daptomycin is an extensively used anti-staphylococcal agent due to the rise in methicillin-resistant Staphylococcus aureus, but the mechanism(s) of resistance is poorly understood. Comparative genome sequencing, transcriptomics, ultrastructure, and cell envelope studies were carried out on two relatively higher level (4 and 8 mu g/ml(-1)) laboratory-derived daptomycin-resistant strains (strains CB1541 and CB1540 respectively) compared to their parent strain (CB1118; MW2). Several mutations were found in the strains. Both strains had the same mutations in the two-component system genes waIK and agrA. In strain CB1540 mutations were also detected in the ribose phosphate pyrophosphokinase (prs) and polyribonucleotide nucleotidyltransferase genes (pnpA), a hypothetical protein gene, and in an intergenic region. In strain CB1541 there were mutations in clpP, an ATP-dependent protease, and two different hypothetical protein genes. The strain CB1540 transcriptome was characterized by upregulation of cap (capsule) operon genes, genes involved in the accumulation of the compatible solute glycine betaine, ure genes of the urease operon, and mscL encoding a mechanosensitive chanel. Downregulated genes included smpB, femAB and femH involved in the formation of the pentaglycine interpeptide bridge, genes involved in protein synthesis and fermentation, and spa encoding protein A. Genes altered in their expression common to both transcriptomes included some involved in glycine betaine accumulation, mscL, ure genes, femH, spa and smpB. However, the CB1541 transcriptome was further characterized by upregulation of various heat shock chaperone and protease genes, consistent with a mutation in clpP, and lytM and sceD. Both strains showed slow growth, and strongly decreased autolytic activity that appeared to be mainly due to decreased autolysin production. In contrast to previous common findings, we did not find any mutations in phospholipid biosynthesis genes, and it appears there are multiple pathways to and factors in daptomycin resistance

Ethylene induced stay-green gene expression regulates drought stress in wheat

Stay-green is an integrated drought adaptation trait characterized by a green leaf phenotype during grain filling under terminal drought. Ethylene is the key hormone for regulating the leaf senescence pathway under natural and stress conditions. The present study was conducted to assess the associative function of ethylene in regulating chlorophyll degrading enzymes viz., chlorophyllase (TaCHLase) and pheophorbide a oxygenase (TaPaO) in wheat (Triticum aestivum L.) under drought stress. Three wheat genotypes (HW 4059, HW 4022 and HW 2078) differing in drought tolerance efficiency were subjected to drought stress for ten days at the reproductive stage. A decline in stay-green traits was found in susceptible genotypes (HW 4059) with yield losses compared to tolerant ones (HW 4022 and HW 2078). The expression level of TaCHLase1 and TaPaO was higher in susceptible genotypes than tolerant ones under drought/osmotic stress. Ethylene upregulated, while ethylene inhibitors downregulated the gene expression. In this study, a novel gene annotated as TaCHLase1 was cloned. The complete cDNA sequence of TaCHLase1 is composed of 1054 bp nucleotides containing an open reading frame of 960 bp encoding 319 amino acids. The encoded protein contained conserved residues such as lipase motif GXSXGG at position 143-148 and putative active site Ser145. Sequence alignment showed TaCHLase1 shares a higher degree of identity with other species. The result suggested that ethylene upregulates the expression of TaCHLase1 gene, inducing chlorophyll degradation. The study further helps in understanding the mechanism of stay-green trait-induced drought tolerance mechanism in wheat

On-farm evidence on breaking yield barriers through optimizing wheat cropping system in Indo Gangetic Plain

The wheat production in the food basket of South Asia has plateaued with threats of environmental sustainability and posing a serious challenge to future food security. For sustainable wheat production in conventional rice-wheat (CTRW) systems under changing climatic scenario, atwo-year on-farm study was conducted. We evaluated system optimization practices (SOP) of legume inclusion with CTR-zero-tillage (ZT) wheat-mungbean (CTR-ZTWMb) and direct seeded rice-ZT wheat-mungbean (DSR-ZTWMb) and triple ZT (raised bed) based futuristic systems of maize-wheat-mungbean (ZTMWMb) and soybean-wheat-mungbean (ZTSWMb). The global warming potential (GWP) of wheat production was significantly reduced by 811 kg CO2 eq/ha (783−861) in the SOP compared to CTRW. Moreover, the water usein wheat reduced by 85.9 and 85.2 ha-mm/ha in CTR-ZTWMb and DSR-ZTWMb with higher reduction in ZTMWMb and ZTSWMb by128.7 and 118.0 ha-mm/ha, respectively over CTRW. Similarly, the total weed density was reduced at 60 (39 and 52 %) and 90 (38 and 49 %) days after sowing with CTR-ZTWMb and DSR-ZTWMb over CTRW. However, the weed density reduction was lesser with ZTSWMb and ZTMWMb at 60 (3.0 and 23.6 %), and 90 (9.8 and 31.0 %) days after sowingcompared to the CTRW.The partial factor productivity (PFP) of NPK applied was 8.5–19.0 % higher under SOP over the CTRW. The use of non-renewable energy in wheat cultivation was reduced by 24.4–28.9 % with SOP over CTRW. The enhancement in wheat grain yield (7.4–11.8 %) and net returns (98–169 US$/ha) was also recorded with CTR-ZTWMb and DSR-ZTWMb and this gain in futuristic systems (ZTMWMb and ZTSWMb) was much higher in grain yield (17.2–21.0$/ha) over CTRW. The adoption of these SOPs on 1 million ha could produce 0.37–1.05 million t additional wheat over CTRW. The on-farm study evidenced thatwheat production with system optimization practices of legume inclusion and zero tillage are better alternatives to achieve higher productivity and profitability with a lesserenvironmental footprint in Indo-Gangetic Plains and similar agroecological regions

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

PURPOSE Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer

The impact of women's social position on fertility in developing countries

This paper examines ideas about possible ways in which the extent of women's autonomy, women's economic dependency, and other aspects of their position vis-à-vis men influence fertility in Third World populations. Women's position or “status” seems likely to be related to the supply of children because of its links with age at marriage. Women's position may also affect the demand for children and the costs of fertility regulation, though some connections suggested in the literature are implausible. The paper ends with suggestions for future research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45660/1/11206_2005_Article_BF01124382.pd

Study the structural and magnetic properties of rare-earth ions (La and Gd) doped Ba0.9575Ca0.0025Ti0.80685Mn0.002475Nb0.002475Zr0.1782O3 (BCTMNZ) ceramics

In this paper, we investigated the influence of rare earth (RE=La and Gd) doped Ba0.9575RE0.04Ca0.0025Ti0.80685 Mn0.002475Nb0.002475Zr0.1782O3 (BCTMNZ) ceramics were fabricated by using a conventional solid-state reaction method. The doping effects of La and Gd on the structural and magnetic properties were studied. The structural pattern of the ceramic samples were investigated by X-ray diffraction and the results indicated that both samples shows an orthorhombic structure with pure phase. Strain and crystalline size values for Gd and La doped were 0.31–0.33% and 0.154–0.181μm, respectively. The room temperature hysteresis loops were obtained by using a vibrating sample magnetometer. La doped ceramic showed the higher value of magnetization i.e., 0.369μB/f.u. as compared to Gd doped BLTMNZ ceramics

Influence of BiFeTaO3 addition on the electrical properties of Na0.4725K0.4725Li0.055NbO3 ceramics system using impedance spectroscopy

Polycrystalline samples of (1 - x)(Na0.4725K0.4725Li0.055NbO3) - x(BiFe0.5Ta0.5O3) (where x = 0.005 and 0.007 were prepared by using a solid state reaction technique. The XRD patterns of the samples at room temperature shows perovskite phase with monoclinic structure. The dielectric constant for x = 0.007 is maximum. Detailed studies of dielectric and impedance properties of the materials in a wide range of frequency (100 Hz-1 MHz) and temperatures (RT-500 degrees C) shows that dielectric properties were strongly temperature and frequency dependent. Dielectric and electrical properties of samples, indicate that the Curie temperature shifted to higher temperature side with the increase in frequency. The AC conductivity also increases with increase in frequency. The low value of activation energy obtained for the ceramic samples could be attributed to the influence of electronic contribution to the conductivity. The plots of Z '' and M '' vs frequency at various temperatures shows peaks in the higher temperature range (>320 degrees C). The compounds show dielectric relaxation, which is found to be of non-Debye type and the relaxation frequency shifted to higher side with increase in temperature. The Nyquist plot and conductivity studies showed the NTCR character of samples. (C) 2015 Elsevier B.V. All rights reserved