A course for teaching design research methodology

Design research informs and supports practice by developing knowledge to improve the chances of producing successful products.Training in design research has been poorly supported. Design research uses human and natural/technical sciences, embracing all facets of design; its methods and tools are adapted from both these traditions. However, design researchers are rarely trained in methods from both the traditions. Research in traditional sciences focuses primarily on understanding phenomena related to human, natural, or technical systems. Design research focuses on supporting improvement of such systems, using understanding as a necessary but not sufficient step, and it must embrace methods for both understanding reality and developing support for its improvement. A one-semester, postgraduate-level, credited course that has been offered since 2002, entitled Methodology for Design Research, is described that teaches a methodology for carrying out research into design. Its steps are to clarify research success; to understand relevant phenomena of design and how these influence success; to use this to envision design improvement and develop proposals for supporting improvement; to evaluate support for its influence on success; and, if unacceptable, to modify, support, or improve the understanding of success and its links to the phenomena of design. This paper highlights some major issues about the status of design research and describes how design research methodology addresses these. The teaching material, model of delivery, and evaluation of the course on methodology for design research are discussed.

Computationally Efficient Sub-optimal Mid Course Guidance Using Model Predictive Static Programming (MPSP)

For a homing interceptor, suitable initial condition must be achieved by mid course guidance scheme for its maximum effectiveness. To achieve desired end goal of any mid course guidance scheme, two point boundary value problem must be solved online with all realistic constrain. A Newly developed computationally efficient technique named as MPSP (Model Predictive Static Programming) is utilized in this paper for obtaining suboptimal solution of optimal mid course guidance. Time to go uncertainty is avoided in this formulation by making use of desired position where midcourse guidance terminate and terminal guidance takes over. A suitable approach angle towards desired point also can be specified in this guidance law formulation. This feature makes this law particularly attractive because warhead effectiveness issue can be indirectly solved in mid course phase.

Glycodelin-A interferes with IL-2/IL-2R signalling to induce cell growth arrest, loss of effector functions and apoptosis in T-lymphocytes

The progesterone-regulated glycoprotein glycodelin-A (GdA), secreted by the decidualized endometrium at high concentrations in primates, inhibits the maternal immune response against fetal antigens and thereby contributes to the tolerance of the semi-allogenic fetus during a normal pregnancy. Our earlier studies demonstrated the ability of GdA to induce an intrinsic apoptotic cascade in CD4 T-lymphocytes and suppress the cytolytic effector function of CD8 T-lymphocytes. In this report, we investigated further into the mechanism of action of GdA controlling perforin and granzyme B expression in CD8 T-lymphocytes and the mechanism of action of GdA leading to lymphocyte death. Flow cytometry analysis was performed to check for the surface expression of interleukin-2 receptor (IL-2R) and intracellular eomesodermin (Eomes) in activated T-lymphocytes, whereas quantitative RTPCR analysis was used to find out their mRNA profile upon GdA treatment. Western analysis was carried out to confirm the protein level of Bax and Bcl-2. GdA reduces the surface expression of the high-affinity IL-2R complex by down-regulating the synthesis of IL-2R (CD25). This disturbs the optimal IL-2 signalling and decreases the Eomes expression, which along with IL-2 directly regulates perforin and granzymes expression. Consequently, the CD8 T-lymphocytes undergo growth arrest and are unable to mature into competent cytotoxic T-lymphocytes. In the CD4 T-lymphocytes, growth factor IL-2 deprivation leads to proliferation inhibition, decreased Bcl-2/enhanced Bax expression, culminating in mitochondrial stress and cell death. GdA spurs cell cycle arrest, loss of effector functions and apoptosis in different T-cell subsets by making T-lymphocytes unable to respond to IL-2.

Antimony-resistant but not antimony-sensitive Leishmania donovani up-regulates host IL-10 to overexpress multidrug-resistant protein 1

The molecular mechanism of antimony-resistant Leishmania donovani ((SbLD)-L-R)-driven up-regulation of IL-10 and multidrug-resistant protein 1 (MDR1) in infected macrophages (M phi s) has been investigated. This study showed that both promastigote and amastigote forms of (SbLD)-L-R, but not the antimony-sensitive form of LD, express a unique glycan with N-acetylgalactosamine as a terminal sugar. Removal of it either by enzyme treatment or by knocking down the relevant enzyme, galactosyltransferase in (SbLD)-L-R (KD (SbLD)-L-R), compromises the ability to induce the above effects. Infection of M phi s with KD (SbLD)-L-R enhanced the sensitivity toward antimonials compared with infection with (SbLD)-L-R, and infection of BALB/c mice with KD (SbLD)-L-R caused significantly less organ parasite burden compared with infection induced by (SbLD)-L-R. The innate immune receptor, Toll-like receptor 2/6 heterodimer, is exploited by (SbLD)-L-R to activate ERK and nuclear translocation of NF-kappa B involving p50/c-Rel leading to IL-10 induction, whereas MDR1 up-regulation is mediated by PI3K/Akt and the JNK pathway. Interestingly both recombinant IL-10 and (SbLD)-L-R up-regulate MDR1 in M. with different time kinetics, where phosphorylation of PI3K was noted at 12 h and 48 h, respectively, but M phi s derived from IL-10(-/-) mice are unable to show MDR1 up-regulation on infection with (SbLD)-L-R. Thus, it is very likely that an IL-10 surge is a prerequisite for MDR1 up-regulation. The transcription factor important for IL-10-driven MDR1 up-regulation is c-Fos/c-Jun and not NF-kappa B, as evident from studies with pharmacological inhibitors and promoter mapping with deletion constructs.

Differential cellular recognition pattern to M. tuberculosis targets defined by IFN-gamma and IL-17 production in blood from TB plus patients from Honduras as compared to health care workers: TB and immune responses in patients from Honduras

Background: A better understanding of the quality of cellular immune responses directed against molecularly defined targets will guide the development of TB diagnostics and identification of molecularly defined, clinically relevant M.tb vaccine candidates. Methods: Recombinant proteins (n = 8) and peptide pools (n = 14) from M. tuberculosis (M.tb) targets were used to compare cellular immune responses defined by IFN-gamma and IL-17 production using a Whole Blood Assay (WBA) in a cohort of 148 individuals, i.e. patients with TB + (n = 38), TB- individuals with other pulmonary diseases (n = 81) and individuals exposed to TB without evidence of clinical TB (health care workers, n = 29). Results: M.tb antigens Rv2958c (glycosyltransferase), Rv2962c (mycolyltransferase), Rv1886c (Ag85B), Rv3804c (Ag85A), and the PPE family member Rv3347c were frequently recognized, defined by IFN-gamma production, in blood from healthy individuals exposed to M.tb (health care workers). A different recognition pattern was found for IL-17 production in blood from M.tb exposed individuals responding to TB10.4 (Rv0288), Ag85B (Rv1886c) and the PPE family members Rv0978c and Rv1917c. Conclusions: The pattern of immune target recognition is different in regard to IFN-gamma and IL-17 production to defined molecular M.tb targets in PBMCs from individuals frequently exposed to M.tb. The data represent the first mapping of cellular immune responses against M.tb targets in TB patients from Honduras.

Novel multimeric IL-1 receptor antagonist for the treatment of rheumatoid arthritis

Protein therapeutics targeting inflammatory mediators have shown great promise for the treatment of autoimmunities such as rheumatoid arthritis (RA). However, a significant challenge in this area has been their low in vivo stability and consequently their severely compromised therapeutic efficacy. One such therapeutic molecule IL-1 receptor antagonist (IL-1ra), used in the treatment of rheumatoid arthritis, has displayed only modest efficacy in human clinical trials owing to its short biological half-life. Herein, we report a novel approach to conglomerate individual protein entities into a drug depot by incorporation of an amyloidogenic motif Lys-Phe-Phe-Glu (KFFE) thereby dramatically improving their systemic persistence and in turn their therapeutic efficacy in a mice model of autoimmune arthritis. (C) 2014 Elsevier Ltd. All rights reserved.