Identification,design and synthesis of novel pyrazolopyridine influenza virus nonstructural protein 1 antagonists

Nonstructural protein 1 (NS1) plays a crucial function in the replication, spread, and pathogenesis of influenza virus by inhibiting the host innate immune response. Here we report the discovery and optimization of novel pyrazolopyridine NS1 antagonists that can potently inhibit influenza A/PR/8/34 replication in MDCK cells, rescue MDCK cells from cytopathic effects of seasonal influenza A strains, reverse NS1-dependent inhibition of IFN-β gene expression, and suppress the slow growth phenotype in NS1-expressing yeast. These pyrazolopyridines will enable researchers to investigate NS1 function during infection and how antagonists can be utilized in the next generation of treatments for influenza infection.     

Human Intestinal Allografts Contain Functional Hematopoietic Stem and Progenitor Cells that Are Maintained by a Circulating Pool

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CD1d degradation in Chlamydia trachomatis-infected epithelial cells is the result of both cellular and chlamydial proteasomal activity

Chlamydia trachomatis is an obligate intracellular pathogen that can persist in the urogenital tract. Mechanisms by which C. trachomatis evades clearance by host innate immune responses are poorly described. CD1d is MHC-like, is expressed by epithelial cells, and can signal innate immune responses by NK and NKT cells. Here we demonstrate that C. trachomatis infection down-regulates surface-expressed CD1d in human penile urethral epithelial cells through proteasomal degradation. A chlamydial proteasome-like activity factor (CPAF) interacts with the CD1d heavy chain, and CPAF-associated CD1d heavy chain is then ubiquitinated and directed along two distinct proteolytic pathways. The degradation of immature glycosylated CD1d was blocked by the proteasome inhibitor lactacystin but not by MG132, indicating that degradation was not via the conventional proteasome. In contrast, the degradation of non-glycosylated CD1d was blocked by lactacystin and MG132, consistent with conventional cellular cytosolic degradation of N-linked glycoproteins. Immunofluorescent microscopy confirmed the interruption of CD1d trafficking to the cell surface, and the dislocation of CD1d heavy chains into both the cellular cytosol and the chlamydial inclusion along with cytosolic CPAF. C. trachomatis targeted CD1d toward two distinct proteolytic pathways. Decreased CD1d surface expression may help C. trachomatis evade detection by innate immune cells and may promote C. trachomatis persistence.     

A Tolerant Behavior in Salt-Sensitive Tomato Plants can be Mimicked by Chemical Stimuli

Lycopersicon esculentum plants exhibit increased salt stress tolerance following treatment with adipic acid monoethylester and 1,3-diaminepropane (DAAME), known as an inducer of resistance against biotic stress in tomato and pepper. For an efficient water and nutrient uptake, plants should adapt their water potential to compensate a decrease in water soil potential produced by salt stress. DAAME-treated plants showed a faster and stronger water potential reduction and an enhanced proline accumulation. Salinity-induced oxidative stress was also ameliorated by DAAME treatments. Oxidative membrane damage and ethylene emission were both reduced in DAAME-treated plants. This effect is probably a consequence of an increase of both non-enzymatic antioxidant activity as well as peroxidase activity. DAAME-mediated tolerance resulted in an unaltered photosynthetic rate and a stimulation of the decrease in transpiration under stress conditions without a cost in growth due to salt stress. The reduction in transpiration rate was concomitant with a reduction in phytotoxic Na⁺ and Cl⁻ accumulation under saline stress. Interestingly, the ABA deficient tomato mutant sitiens was insensitive to DAAME-induced tolerance following NaCl stress exposure. Additionally, DAAME treatments increased the ABA content of leaves, therefore, an intact ABA signalling pathway seems to be important to express DAAME-induced salt tolerance. Here, we show a possibility of enhance tomato stress tolerance by chemical induction of the major plant defences against salt stress. DAAME-induced tolerance against salt stress could be complementary to or share elements with induced resistance against biotic stress. This might be the reason for the observed wide spectrum of effectiveness of this compound.Key Words: adipic acid monoethyl ester, 1,3-diaminepropane, Lycopersicon esculentum, salt stress, oxidative stress, ethylene, chemical induced tolerance