Analysis of a Genomic DNA Expression Library of Mycobacterium tuberculosis Using Tuberculosis Patient Sera: Evidence for Modulation of Host Immune Response

DNA obtained from a human sputum isolate of Mycobacterium tuberculosis, NTI-64719, which showed extensive dissemination in the guinea pig model resulting in a high score for virulence was used to construct an expression library in the lambda ZAP vector. The size of DNA inserts in the library ranged from 1 to 3 kb, and recombinants represented 60% of the total plaques obtained. When probed with pooled serum from chronically infected tuberculosis patients, the library yielded 176 recombinants with a range of signal intensities. Among these, 93 recombinants were classified into 12 groups on the basis of DNA hybridization experiments, The polypeptides synthesized by the recombinants were predominantly LacZ fusion proteins, Serum obtained from patients who were clinically diagnosed to be in the early phase of M. tuberculosis infection was used to probe the 176 recombinants obtained. interestingly, some recombinants that gave very strong signals in the original screen did not react with early-phase serum; conversely, others whose signals were extremely weak in the original screen gave very intense signals with serum from recently infected patients, This indicates the differential nature of either the expression of these antigens or the immune response elicited by them as a function of disease progression.

Engagement of CF3 Group in N-H center dot center dot center dot F-C Hydrogen Bond in the Solution State: NMR Spectroscopy and MD Simulation Studies

Unambiguous evidence for the engagement of CF3 group in N-H center dot center dot center dot F-C hydrogen bond in a low polarity solvent, the first observation of its kind, is reported. The presence of such weak molecular interactions in the solution state is convincingly established by one and two-dimensional H-1, F-19, and natural abundant N-15 NMR spectroscopic studies. The strong and direct evidence is derived by the observation of through-space couplings, such as, (1h)J(FH), (1h)J(FN), and (2h)J(FF), where the spin polarization is transmitted through hydrogen bond. In an interesting example of a molecule containing two CF3 groups getting simultaneously involved in hydrogen bond, where hydrogen bond mediated couplings are not reflected in the NMR spectrum, F-19-F-19 NOESY experiment yielded confirmatory evidence. Significant deviations in the strengths of (1)J(NH), variable temperature, and the solvent induced perturbations yielded additional support. The NMR results are corroborated by both DFT calculations and MD simulations, where the quantitative information on different ways of involvement of fluorine in two and three centered hydrogen bonds, their percentage of occurrences, and geometries have been obtained. The hydrogen bond interaction energies have also been calculated.

SeaMo plus : a virtual real-time multimedia service framework on handhelds to enable remote real-time patient monitoring for mobile doctors

The key requirements for enabling real-time remote healthcare service on a mobile platform, in the present day heterogeneous wireless access network environment, are uninterrupted and continuous access to the online patient vital medical data, monitor the physical condition of the patient through video streaming, and so on. For an application, this continuity has to be sufficiently transparent both from a performance perspective as well as a Quality of Experience (QoE) perspective. While mobility protocols (MIPv6, HIP, SCTP, DSMIP, PMIP, and SIP) strive to provide both and do so, limited or non-availability (deployment) of these protocols on provider networks and server side infrastructure has impeded adoption of mobility on end user platforms. Add to this, the cumbersome OS configuration procedures required to enable mobility protocol support on end user devices and the user's enthusiasm to add this support is lost. Considering the lack of proper mobility implementations that meet the remote healthcare requirements above, we propose SeaMo+ that comprises a light-weight application layer framework, termed as the Virtual Real-time Multimedia Service (VRMS) for mobile devices to provide an uninterrupted real-time multimedia information access to the mobile user. VRMS is easy to configure, platform independent, and does not require additional network infrastructure unlike other existing schemes. We illustrate the working of SeaMo+ in two realistic remote patient monitoring application scenarios.

Capturability of augmented proportional navigation (APN) guidance with nonlinear engagement dynamics

Proportional Navigation (PN) and its variants are widely used guidance philosophies. However, in the presence of target maneuver, PN guidance law is effective only for a restrictive set of initial geometries. To account for target maneuvers, the concept of Augmented Proportional Navigation (APN) guidance law was introduced and analyzed in a linearized interceptor-target engagement framework presented in literature. However, there is no work in the literature, that addresses the capturability performance of the APN guidance law in a nonlinear engagement framework. This paper presents such an analysis and obtains the conditions for capturability. It also shows that a shorter time of interception is obtained when APN is formulated in the nonlinear framework as proposed in this paper. Simulation results are given to support the theoretical findings.

Biased PN based impact angle constrained guidance using a nonlinear engagement model

Impact angle constrained guidance laws are important in many applications such as guidance of torpedoes, anti-ballistic missiles and reentry vehicles. In this paper, we design a guidance law which is capable of achieving a wide range of impact angles. Biased proportional navigation guidance uses a bias term in addition to the basic PN command to satisfy additional constraints. Angle constrained BPNG (ACBPNG) uses small angle approximations to derive the bias term for impact angle requirement. We design a modified ACBPNG (MACBPNG) where the required bias term is derived in a closed form considering non-linear equations of motion. Simulations are carried out for a wide range of impact angle requirements. We also analyze capturability from different initial positions and also the launch angles possible at each initial position. The performance of the proposed law is compared with an existing law.

A Novel Mutation in the Transglutaminase-1 Gene in an Autosomal Recessive Congenital Ichthyosis Patient

Structure-function implication on a novel homozygous Trp250/Gly mutation of transglutaminase-1 (TGM1) observed in a patient of autosomal recessive congenital ichthyosis is invoked from a bioinformatics analysis. Structural consequences of this mutation are hypothesized in comparison to homologous enzyme human factor XIIIA accepted as valid in similar structural analysis and are projected as guidelines for future studies at an experimental level on TGM1 thus mutated.

Coordinate Hyperactivation of Notch1 and Ras/MAPK Pathways Correlates with Poor Patient Survival: Novel Therapeutic Strategy for Aggressive Breast Cancers

Aberrant activation of Notch and Ras pathways has been detected in breast cancers. A synergy between these two pathways has also been shown in breast cell transformation in culture. Yet, the clinical relevance of Notch-Ras cooperation in breast cancer progression remains unexplored. In this study, we show that coordinate hyperactivation of Notch1 and Ras/MAPK pathways in breast cancer patient specimens, as assessed by IHC for cleaved Notch1 and pErk1/2, respectively, correlated with early relapse to vital organs and poor overall survival. Interestingly, majority of such Notch1 (high)Erk(high) cases encompassed the highly aggressive triple-negative breast cancers (TNBC), and were enriched in stem cell markers. We further show that combinatorial inhibition of Notch1 and Ras/MAPK pathways, using a novel mAb against Notch1 and a MEK inhibitor, respectively, led to a significant reduction in proliferation and survival of breast cancer cells compared with individual inhibition. Combined inhibition also abrogated sphere-forming potential, and depleted the putative cancer stem-like cell subpopulation. Most importantly, combinatorial inhibition of Notch1 and Ras/MAPK pathways completely blocked tumor growth in a panel of breast cancer xenografts, including the TNBCs. Thus, our study identifies coordinate hyperactivation of Notch1 and Ras/MAPK pathways as novel biomarkers for poor breast cancer outcome. Furthermore, based on our preclinical data, we propose combinatorial targeting of these two pathways as a treatment strategy for highly aggressive breast cancers, particularly the TNBCs that currently lack any targeted therapeutic module. (C) 2014 AACR.