Evolutionary and functional insights into Leishmania META1: evidence for lateral gene transfer and a role for META1 in secretion.

BACKGROUND: Leishmania META1 has for long been a candidate molecule for involvement in virulence: META1 transcript and protein are up-regulated in metacyclic Leishmania. Yet, how META1 contributes to virulence remains unclear. We sought insights into the possible functions of META1 by studying its evolutionary origins. RESULTS: Using multiple criteria including sequence similarity, nucleotide composition, phylogenetic analysis and selection pressure on gene sequence, we present evidence that META1 originated in trypanosomatids as a result of a lateral gene transfer of a bacterial heat-inducible protein, HslJ. Furthermore, within the Leishmania genome, META1 sequence is under negative selection pressure against change/substitution. Using homology modeling of Leishmania META1 based on solved NMR structure of HslJ, we show that META1 and HslJ share a similar structural fold. The best hit for other proteins with similar fold is MxiM, a protein involved in the type III secretion system in Shigella. The striking structural similarity shared by META1, HslJ and MxiM suggests a possibility of shared functions. Upon structural superposition with MxiM, we have observed a putative hydrophobic cavity in META1. Mutagenesis of select hydrophobic residues in this cavity affects the secretion of the secreted acid phosphatase (SAP), indicating META1's involvement in secretory processes in Leishmania. CONCLUSIONS: Overall, this work uses an evolutionary biology approach, 3D-modeling and site-directed mutagenesis to arrive at new insights into functions of Leishmania META1

Clinical Study Evaluation of Diabetic Patients with Breast Cancer Treated with Metformin during Adjuvant Radiotherapy

. Purpose. The purpose of this study was to evaluate acute locoregional toxicity in patients with breast cancer receiving concurrent metformin plus radiation therapy. Methods and Materials. Diabetic breast cancer patients receiving concurrent metformin and radiation therapy were matched with nondiabetic patients and diabetic patients using an alternative diabetes medication. Primary endpoints included the presence of a treatment break and development of dry or moist desquamation. Results. There was a statistically significant increase in treatment breaks for diabetic patients receiving concurrent metformin when compared to the nondiabetic patients ( value = 0.02) and a trend toward significance when compared to diabetic patients receiving an alternate diabetes medication ( value = 0.08). Multiple logistic regression analysis demonstrated concurrent metformin use as being associated with a trend toward the predictive value of determining the incidence of developing desquamation in diabetic patients receiving radiation therapy compared to diabetic patients receiving an alternate diabetes medication ( value = 0.06). Conclusions. Diabetic patients treated with concurrent metformin and radiation therapy developed increased acute locoregional toxicity in comparison with diabetic patients receiving an alternate diabetes medication and nondiabetic patients. Further clinical investigation should be conducted to determine the therapeutic ratio of metformin in combination with radiation therapy

Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling.

Intracellular signals triggered by DNA breakage flow through proteins containing BRCT (BRCA1 C-terminal) domains. This family, comprising 23 conserved phosphopeptide-binding modules in man, is inaccessible to small-molecule chemical inhibitors. Here, we develop Bractoppin, a drug-like inhibitor of phosphopeptide recognition by the human BRCA1 tandem (t)BRCT domain, which selectively inhibits substrate binding with nanomolar potency in vitro. Structure-activity exploration suggests that Bractoppin engages BRCA1 tBRCT residues recognizing pSer in the consensus motif, pSer-Pro-Thr-Phe, plus an abutting hydrophobic pocket that is distinct in structurally related BRCT domains, conferring selectivity. In cells, Bractoppin inhibits substrate recognition detected by Förster resonance energy transfer, and diminishes BRCA1 recruitment to DNA breaks, in turn suppressing damage-induced G2 arrest and assembly of the recombinase, RAD51. But damage-induced MDC1 recruitment, single-stranded DNA (ssDNA) generation, and TOPBP1 recruitment remain unaffected. Thus, an inhibitor of phosphopeptide recognition selectively interrupts BRCA1 tBRCT-dependent signals evoked by DNA damage

Implementation Difficulties of JIT Distribution Process in Supply Chain Management of Indian Industries

Abstract Distribution of the finished product quickly and on time has become more and more important and requires the support of a logistics system. To carry out the distribution process we need to have quick Order processing mechanism, Quick and reliable transportation system, Quick delivery, Use of latest technology, efficient Ware housing and dedicated human factors. Companies can take advantage of the just-in-time (JIT) approach to integrate those requirements to achieve in cost reduction, lead-time reduction, quality assurance, and overall customer's satisfaction. And that is how company establishes a long lasting relationship with the customers. This paper examines the important factors attributing the JIT distribution process (JDP) in Indian Industries. To know the difficulties faced by Indian firms in implementing the concept is explored by the survey method. It is concluded that the implementation problem of JDP are short sightedness of top management, Well connectivity of Warehouses, Cross docking, Small shipment size, Multi functional workers and JIT adopting as culture

Assessment of land surface temperature variation due to change in elevation of area surrounding Jaipur, India

Land surface temperature (LST) is a key parameter for surface energy balance and urban climatology studies. LST is affected by the characteristics of the land surface such as vegetation cover and its type, land use-land cover and surface imperviousness. Incessant urbanization has resulted in many fold increase in the urban area and it has caused significant changes in the land surface. The difference in altitude of two points, that are located at different parts of a vast study area, may be large. The aim of the present study is to investigate the effect of change in elevation over LST. LST data from Moderate Resolution Imaging Spectroradiometer (MODIS) and digital elevation model from ASTER have been used. Consistent inverse linear trend is observed between LST and elevation for all the study seasons. High correlation (R2 = 0.73–0.87) is found between elevation and mean LST. It is seen that the change in LST due to elevation difference between two points separated in space in horizontal direction varies from 3.5 °C to 4.6 °C per 1000 m which is relatively lesser than the condition when two points are separated in vertical direction (5.0 °C–10.0 °C per 1000 m) i.e. along a vertical column of air. The study concludes that in any study related with spatial distribution of LST over a large area, effect of change in elevation at different locations shall also be considered and LSTs at different location shall be rationalized on the basis of their comparative elevations. Keywords: Land surface temperature, Elevation, MODIS, ASTE