Geotechnical Assessment and Evaluation of the Impact of Kachchh (Bhuj) India 2001 Earthquake

Intraplate earthquakes are ongoing activity in the Kachchh region. The area is seismically active and falls in Zone V of the seismic Zoning Map of India. The devastating Bhuj (Kachchh) Earthquake of MS 7.6 occurred in this zone on 26th January, 2001 causing severe damage to civil engineering structures and loss of human life. The surface manifestations of deformation of this earthquake include fractures/ fissures, lateral spread, slump, subsidence, upheaval, sand blows and craters. Bhuj Earthquake has caused considerable damage to earth dams lying in isoseist VIII and above in Kachchh. Damages to dams are in the form of longitudinal and transverse cracks, differential settlement, slumps/ slide, displacements and in some cases leakage. A review of the available geological, seismological and geotechnical data have been done to asses the impact of Bhuj Earthquake and subsequent seismic events in the area on ground deformation and engineering structures. Main cause of the ground deformation and damage is liquefaction of the soil under seismic shaking. Tectonic influence on the development of fissures/ cracks on the ground as well as on the earth dams has been observed

Geo-Engineering Problems in the Spillway Foundations and Their Treatment at Guhai Reservoir Project in Gujurat, India

During the initial stage of construction of a 23 m high composite dam across the Guhai river, the downstream dipping sedimentary rock sequence of conglomerate, sandstone and shale resting unconformably over quartzite and schist was encountered as a surprise during the excavation of the foundation. Besides, an 8 to 8.5 m wide major fault zone along with three minor faults running across the dam axis were also noticed. Extensive subsurface investigations to study the nature and characteristics of sedimentary rocks, fault zones, etc. met with in the foundations were undertaken concurrently with the construction activity. As a result, the construction schedule was greatly affected. The paper discusses the detailed evaluation of the geological flaws by thorough investigation and foundation treatment evolved to safeguard the structure

Development and automation of a test of impulse control in zebrafish.

Deficits in impulse control (difficulties in inhibition of a pre-potent response) are fundamental to a number of psychiatric disorders, but the molecular and cellular basis is poorly understood. Zebrafish offer a very useful model for exploring these mechanisms, but there is currently a lack of validated procedures for measuring impulsivity in fish. In mammals, impulsivity can be measured by examining rates of anticipatory responding in the 5-choice serial reaction time task (5-CSRTT), a continuous performance task where the subject is reinforced upon accurate detection of a briefly presented light in one of five distinct spatial locations. This paper describes the development of a fully-integrated automated system for testing impulsivity in adult zebrafish. We outline the development of our image analysis software and its integration with National Instruments drivers and actuators to produce the system. We also describe an initial validation of the system through a one-generation screen of chemically mutagenized zebrafish, where the testing parameters were optimized

GDNF-RET signaling in ER-positive breast cancers is a key determinant of response and resistance to aromatase inhibitors.

Most breast cancers at diagnosis are estrogen receptor-positive (ER(+)) and depend on estrogen for growth and survival. Blocking estrogen biosynthesis by aromatase inhibitors has therefore become a first-line endocrine therapy for postmenopausal women with ER(+) breast cancers. Despite providing substantial improvements in patient outcome, aromatase inhibitor resistance remains a major clinical challenge. The receptor tyrosine kinase, RET, and its coreceptor, GFRα1, are upregulated in a subset of ER(+) breast cancers, and the RET ligand, glial-derived neurotrophic factor (GDNF) is upregulated by inflammatory cytokines. Here, we report the findings of a multidisciplinary strategy to address the impact of GDNF-RET signaling in the response to aromatase inhibitor treatment. In breast cancer cells in two-dimensional and three-dimensional culture, GDNF-mediated RET signaling is enhanced in a model of aromatase inhibitor resistance. Furthermore, GDNF-RET signaling promoted the survival of aromatase inhibitor-resistant cells and elicited resistance in aromatase inhibitor-sensitive cells. Both these effects were selectively reverted by the RET kinase inhibitor, NVP-BBT594. Gene expression profiling in ER(+) cancers defined a proliferation-independent GDNF response signature that prognosed poor patient outcome and, more importantly, predicted poor response to aromatase inhibitor treatment with the development of resistance. We validated these findings by showing increased RET protein expression levels in an independent cohort of aromatase inhibitor-resistant patient specimens. Together, our results establish GDNF-RET signaling as a rational therapeutic target to combat or delay the onset of aromatase inhibitor resistance in breast cancer

N-Terminal Gly224–Gly411 Domain in Listeria Adhesion Protein Interacts with Host Receptor Hsp60

Listeria adhesion protein (LAP) is a housekeeping bifunctional enzyme consisting of N-terminal acetaldehyde dehydrogenase (ALDH) and C-terminal alcohol dehydrogenase (ADH). It aids Listeria monocytogenes in crossing the epithelial barrier through a paracellular route by interacting with its host receptor, heat shock protein 60 (Hsp60). To gain insight into the binding interaction between LAP and Hsp60, LAP subdomain(s) participating in the Hsp60 interaction were investigated.Using a ModBase structural model, LAP was divided into 4 putative subdomains: the ALDH region contains N1 (Met(1)-Pro(223)) and N2 (Gly(224)-Gly(411)), and the ADH region contains C1 (Gly(412)-Val(648)) and C2 (Pro(649)-Val(866)). Each subdomain was cloned and overexpressed in Escherichia coli and purified. Purified subdomains were used in ligand overlay, immunofluorescence, and bead-based epithelial cell adhesion assays to analyze each domain's affinity toward Hsp60 protein or human ileocecal epithelial HCT-8 cells.The N2 subdomain exhibited the greatest affinity for Hsp60 with a K(D) of 9.50±2.6 nM. The K(D) of full-length LAP (7.2±0.5 nM) to Hsp60 was comparable to the N2 value. Microspheres (1 µm diameter) coated with N2 subdomain showed significantly (P<0.05) higher binding to HCT-8 cells than beads coated with other subdomains and this binding was inhibited when HCT-8 cells were pretreated with anti-Hsp60 antibody to specifically block epithelial Hsp60. Furthermore, HCT-8 cells pretreated with purified N2 subdomain also reduced L. monocytogenes adhesion by about 4 log confirming its involvement in interaction with epithelial cells.These data indicate that the N2 subdomain in the LAP ALDH domain is critical in initiating interaction with mammalian cell receptor Hsp60 providing insight into the molecular mechanism of pathogenesis for the development of potential anti-listerial control strategies

Proteomic identification of secreted proteins as surrogate markers for signal transduction inhibitor activity

Epidermal growth factor receptor is a potential target for cancer treatment and new small-molecule tyrosine kinase inhibitor drugs have been designed to inhibit its activity. In this work we identify potential surrogate markers of drug activity using a proteomic analysis. Two-dimensional electrophoresis was optimised to compare expression patterns of proteins secreted from the cancer cell lines A431 and A549 treated with Gefitinib (Iressa) vs untreated or vehicle-only-treated samples. Upregulated or downregulated proteins were detected using Phoretix 2D image analysis software. Several proteins were then identified using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. In one case, upregulation of Protein Disulphide Isomerase in response to Gefitinib was confirmed by Western blot analysis, and the response was shown to be concentration dependent. The identification of surrogate markers may be of use for the evaluation of new drugs, in preclinical models, in clinical trials and in the therapy of individual patients to give optimal biological drug doses

Effects of edible bird's nest (EBN) on cultured rabbit corneal keratocytes

<p>Abstract</p> <p>Background</p> <p>There has been no effective treatment or agent that is available for corneal injury in promoting corneal wound healing. Previous studies on edible bird's nest extract (EBN) had reported the presence of hormone-like substance; avian epidermal growth factor that could stimulate cell division and enhance regeneration. This study aimed to investigate the effects of EBN on corneal keratocytes proliferative capacity and phenotypical changes.</p> <p>Methods</p> <p>Corneal keratocytes from six New Zealand White Rabbits were isolated and cultured until Passage 1. The proliferative effects of EBN on corneal keratocytes were determined by MTT assay in serum-containing medium (FDS) and serum-free medium (FD). Keratocytes phenotypical changes were morphologically assessed and gene expression of aldehyde dehydrogenase (ALDH), collagen type 1 and lumican were determined through RT-PCR.</p> <p>Results</p> <p>The highest cell proliferation was observed when both media were supplemented with 0.05% and 0.1% EBN. Cell proliferation was also consistently higher in FDS compared to FD. Both phase contrast micrographs and gene expression analysis confirmed the corneal keratocytes retained their phenotypes with the addition of EBN.</p> <p>Conclusions</p> <p>These results suggested that low concentration of EBN could synergistically induce cell proliferation, especially in serum-containing medium. This could be a novel breakthrough as both cell proliferation and functional maintenance are important during corneal wound healing. The in vitro test is considered as a crucial first step for nutri-pharmaceutical formation of EBN-based eye drops before in vivo application.</p

EGFR/HER2 inhibitor AEE788 increases ER-mediated transcription in HER2/ER-positive breast cancer cells but functions synergistically with endocrine therapy

BACKGROUND: Cross-talk between receptor tyrosine kinases and the oestrogen receptor (ER) is implicated in resistance to endocrine therapy. We investigated whether AEE788 (a combined inhibitor of EGFR, HER2 and VEGFR) plus tamoxifen or letrozole enhanced the individual anti-tumour effects of these agents. METHODS: Breast cancer cell lines modelling endocrine-resistant and -sensitive disease were engineered to express aromatase (A) and examined using proliferation, western blotting and ER-alpha transcription assays. RESULTS: AEE788 enhanced the anti-proliferative effect of tamoxifen and letrozole in ER+ cell lines (MCF-7 2A, ZR75.1 A3 and BT474 A3). This associated with an elevated G1 arrest and nuclear accumulation of p27. It is noteworthy that AEE788 alone or in combination with endocrine therapy increased the expression of progesterone receptor (PGR) and TFF1 in BT474 A3 cells. This may indicate a mechanism of resistance to AEE788 in ER+/HER2(+) breast cancers. In a ZR75.1 A3 xenograft, AEE788 alone or in combination with tamoxifen provided no further benefit compared with letrozole. However, letrozole plus AEE788 produced a significantly greater inhibition of tumour growth compared with letrozole alone. CONCLUSION: These data suggest that AEE788 plus letrozole in breast cancer overexpressing HER2 may provide superior anti-tumour activity, compared with single agents. British Journal of Cancer (2010) 102, 1235-1243. doi: 10.1038/sj.bjc.6605641 www.bjcancer.com (C) 2010 Cancer Research U

The Interaction of Canine Plasminogen with Streptococcus pyogenes Enolase: They Bind to One Another but What Is the Nature of the Structures Involved?

For years it has been clear that plasminogen from different sources and enolase from different sources interact strongly. What is less clear is the nature of the structures required for them to interact. This work examines the interaction between canine plasminogen (dPgn) and Streptococcus pyogenes enolase (Str enolase) using analytical ultracentrifugation (AUC), surface plasmon resonance (SPR), fluorescence polarization, dynamic light scattering (DLS), isothermal titration calorimetry (ITC), and simple pull-down reactions. Overall, our data indicate that a non-native structure of the octameric Str enolase (monomers or multimers) is an important determinant of its surface-mediated interaction with host plasminogen. Interestingly, a non-native structure of plasminogen is capable of interacting with native enolase. As far as we can tell, the native structures resist forming stable mixed complexes