Molecular basis of protein tyrosine phosphatase inhibition by biologically important small molecules with relevance to cell signaling pathways

Title from PDF of title page (University of Missouri--Columbia, viewed on September 13, 2010).The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file.Dissertation advisor: Dr. Kent S. Gates.Vita.Includes bibliographical references.Ph. D. University of Missouri--Columbia 2009.Dissertations, Academic -- University of Missouri--Columbia -- Chemistry.Protein tyrosine phosphatase 1B (PTP1B) is an abundant mammalian enzyme and well known to be as a central player in the insulin and leptin signaling pathways. Peracetic acid is a strong oxidant molecule, endogenously produced by mammalian decarboxylase enzymes. Here we have presented the evidence that peracetic acid can reversibly inactivate the PTPs function in nanomolar concentration and the inactivation is potent in presence of glutathione. Our in vitro study demonstrates that 13S-HPODE (lipid peroxide), a dietary metabolite of linoleic acid can also inhibit the PTPase function in an identical manner as H₂O₂. Oltipraz is a cancer preventive agent and currently undergoing clinical phase trial II. Oltipraz potentiates its chemo preventive action by the inducing of cellular detoxifying enzymes. Our work shows that oltipraz inhibits PTPs function like other cys-dependent proteins by reversible covalent modification. Our study also raises the possibility that oltipraz mediated PTPs inhibition might have the potential to trigger the NF-[kappa]B activation. Hydrogen sulfide signaling has started getting attention in various aspects of cellular disease and therapeutics. Mechanism for many of the H₂S mediated signaling pathways is not yet known. Our work implicates that the metabolites of endogenous H₂S has potential to regulate the PTPase function during cell signaling

Modelling the Constraint Effect on Reference Temperature with Finite Element Parameters for Reactor Pressure Vessel Material 20MnMoNi55 Steel

A series of experiments were performed in the ductile to brittle transition region on three-point bending specimens of different thicknesses and a/W ratio of 20MnMoNi55 steel. master curve and reference temperature (T0) are obtained as per ASTM E1921-02 with different thickness and a/W ratio of the specimen and a variation of T0 is obtained, which indicates constant dependent on T0. Mathematic models are formulated to correlate T0 with Q-stress, T-stress and Triaxiality ratio to count for the constraint loss. Both the average value and also the maximum value of the finite element parameters are considered to predict T0 at different constraint label and compared with the experimental results

Relative orders and slowly changing functions oriented growth analysis of composite entire functions

Abstract In the paper we establish some new results depending on the comparative growth properties of composition of entire functions using relative L * -order (relative L * -lower order) as compared to their corresponding left and right factors where L ≡ L (r) is a slowly changing function

ON RELATIVE TYPE AND WEAK TYPE OF ENTIRE FUNCTIONS OF TWO COMPLEX VARIABLES

In the paper we introduce the idea of relative type and relative weak type of entire functions of two complex variables with respect to another entire function of two complex variables and prove some related growth properties of it

Oral Phytothymol ameliorates the stress induced IBS symptoms

Physical stressors play a crucial role in the progression of irritable bowel syndrome (IBS). Here we report a heterogeneous physical stress induced IBS rat model which shows depression and subsequent modulation of IBS by oral treatment of thymol. Oral administration of Thymol reduces the stress induced IBS significantly altering the stress induced gastrointestinal hypermotility, prolonged the whole gut transit time, and increased abdominal withdrawal reflex suggesting gastrointestinal hypermotility and visceral discomfort caused the onset of depression. Immunohistochemical analysis in small intestine and colon of rats shows the decreased 5-HT3AR expression level while thymol treatment normalized the 5-HT3AR expression in the stressed rats. Molecular docking studies showed that thymol competes with endogenous serotonin and an antagonist, Tropisetron and all have similar binding energies to 5-HT3AR. Molecular dynamics simulations revealed that thymol and tropisetron might have similar effects on 5-HT3AR. Our study suggest that thymol improves IBS symptoms through 5-HT3AR, could be useful for the treatment of IBS

Disproportional Effects in Populations of Concern for Pandemic Influenza: Insights from Seasonal Epidemics in Wisconsin, 1967-2004

Influenza infections pose a serious burden of illness in the United States. We explored age, influenza strains, and seasonal epidemic curves in relation to influenza associated mortality

Next-generation sequencing for identifying pyrazinamide resistance in Mycobacterium tuberculosis

No abstract available.http://cid.oxfordjournals.orgam201

Enhancing Chemotherapy Response with Bmi-1 Silencing in Ovarian Cancer

Undoubtedly ovarian cancer is a vexing, incurable disease for patients with recurrent cancer and therapeutic options are limited. Although the polycomb group gene, Bmi-1 that regulates the self-renewal of normal stem and progenitor cells has been implicated in the pathogenesis of many human malignancies, yet a role for Bmi-1 in influencing chemotherapy response has not been addressed before. Here we demonstrate that silencing Bmi-1 reduces intracellular GSH levels and thereby sensitizes chemoresistant ovarian cancer cells to chemotherapeutics such as cisplatin. By exacerbating ROS production in response to cisplatin, Bmi-1 silencing activates the DNA damage response pathway, caspases and cleaves PARP resulting in the induction apoptosis in ovarian cancer cells. In an in vivo orthotopic mouse model of chemoresistant ovarian cancer, knockdown of Bmi-1 by nanoliposomal delivery significantly inhibits tumor growth. While cisplatin monotherapy was inactive, combination of Bmi-1 silencing along with cisplatin almost completely abrogated ovarian tumor growth. Collectively these findings establish Bmi-1 as an important new target for therapy in chemoresistant ovarian cancer