Epstein-Barr Nuclear Antigen 1 (EBNA1) is essential for Epstein-Barr virus to immortalize naïve B-cells. Upon binding a cluster of 20 cognate binding-sites termed the family of repeats, EBNA1 transactivates promoters for EBV genes that are required for immortalization. A small domain, termed UR1, that is 25 amino-acids in length, has been identified previously as essential for EBNA1 to activate transcription. In this study, we have elucidated how UR1 contributes to EBNA1's ability to transactivate. We show that zinc is necessary for EBNA1 to activate transcription, and that UR1 coordinates zinc through a pair of essential cysteines contained within it. UR1 dimerizes upon coordinating zinc, indicating that EBNA1 contains a second dimerization interface in its amino-terminus. There is a strong correlation between UR1-mediated dimerization and EBNA1's ability to transactivate cooperatively. Point mutants of EBNA1 that disrupt zinc coordination also prevent self-association, and do not activate transcription cooperatively. Further, we demonstrate that UR1 acts as a molecular sensor that regulates the ability of EBNA1 to activate transcription in response to changes in redox and oxygen partial pressure (pO2). Mild oxidative stress mimicking such environmental changes decreases EBNA1-dependent transcription in a lymphoblastoid cell-line. Coincident with a reduction in EBNA1-dependent transcription, reductions are observed in EBNA2 and LMP1 protein levels. Although these changes do not affect LCL survival, treated cells accumulate in G0/G1. These findings are discussed in the context of EBV latency in body compartments that differ strikingly in their pO2 and redox potential.
Report prepared by ~. Lernmark 1, J. L. Molenaar 2, W. A. M. van Beers 2' Y. Yamaguchi3; S. Nagataki 3' J. Ludvigsson 4 and N. K. Maclaren s on behalf of the Immunology and Diabetes Workshops and participating laboratories*
Background: Bacterial pathogens use virulence proteins to inhibit the host innate immune system. Results: The Escherichia coli O157:H7 NleH1 protein interacts with the host CRKL protein. Conclusion: CRKL may recruit NleH1 to a host kinase on which NleH1 performs its inhibitory function. Significance: These data clarify a mechanism by which E. coli inhibits innate immunity.
Purpose: To develop a niosomal formulation for the delivery of isoniazid to achieve effective treatment of tuberculosis. Methods: Niosomes were prepared by reverse phase evaporation method and given a charge with a charge-inducing agent, dicetyl phosphate. Drug entrapment efficiency in the niosomes was determined spectrophotometrically. The niosomes were further characterized for their particle size, polydispersity index (PI) and zeta potential as well as by scanning electron microscopy and stability studies. Furthermore, in vitro drug release and cellular uptake studies on the niosomes by macrophage J744 A were undertaken. Results: Suitable isoniazid niosomes were obtained. The niosomes demonstrated a potential to remain in the treated site for prolonged periods and were also capable of maintaining steady drug concentrations for up to 30 h. Cellular uptake of the drug-loaded niosomes by macrophage cells was as high as 61.8 %, a level that is capable of achieving effective treatment of tuberculosis. Conclusion: The isoniazid niosomes developed are capable of reducing drug dose and toxicity as well as dosing frequency which should bring about improved patient compliance. More importantly, macrophage targeting should be feasible at sites where tuberculosis bacteria are harbored.
Construction workers are at high risk of heat-related illnesses during summer months in India. The personal cooling garment (PCG) is a microclimate assistive device that provides protection from heat stress. The applicability and efficacy of wearing PCG for the physiological and subjective responses were tested on 29 healthy construction workers at actual field worksites. During the test, the climatic conditions were 103.64 ± 38.3°F dry bulb temperature, 41.2 ± 13.4% relative humidity, and wet bulb globe temperature 91.43 ± 39.92°F. Mean weighted skin temperature was significantly lowered by 38.66 ± 33.98°F when wearing PCG as compared with wearing habitual clothing (HC), 32.36 ± 33.44°F (p < .05). Mean sweat loss was also significantly lower when wearing PCG: 0.365 ± 0.257 kg as compared with wearing HC: 0.658 ± 0.342 kg (p < .05). Heart rate, along with back and chest skin temperatures were significantly reduced with wearing PCG. The present study suggests that PCG provides an affordable way of alleviating the discomfort and physiological strain caused by environmental heat exposure.
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