Mosquito immune responses and compatibility between Plasmodium parasites and anopheline mosquitoes

<p>Abstract</p> <p>Background</p> <p>Functional screens based on dsRNA-mediated gene silencing identified several <it>Anopheles gambiae </it>genes that limit <it>Plasmodium berghei </it>infection. However, some of the genes identified in these screens have no effect on the human malaria parasite <it>Plasmodium falciparum</it>; raising the question of whether different mosquito effector genes mediate anti-parasitic responses to different <it>Plasmodium </it>species.</p> <p>Results</p> <p>Four new <it>An. gambiae </it>(G3) genes were identified that, when silenced, have a different effect on <it>P. berghei </it>(Anka 2.34) and <it>P. falciparum </it>(3D7) infections. Orthologs of these genes, as well as <it>LRIM1 </it>and <it>CTL4</it>, were also silenced in <it>An. stephensi </it>(Nijmegen Sda500) females infected with <it>P. yoelii </it>(17XNL). For five of the six genes tested, silencing had the same effect on infection in the <it>P. falciparum-An. gambiae </it>and <it>P. yoelii-An. stephensi </it>parasite-vector combinations. Although silencing <it>LRIM1 </it>or <it>CTL4 </it>has no effect in <it>An. stephensi </it>females infected with <it>P. yoelii</it>, when <it>An. gambiae </it>is infected with the same parasite, silencing these genes has a dramatic effect. In <it>An. gambiae </it>(G3), TEP1, LRIM1 or LRIM2 silencing reverts lysis and melanization of <it>P. yoelii</it>, while <it>CTL4 </it>silencing enhances melanization.</p> <p>Conclusion</p> <p>There is a broad spectrum of compatibility, the extent to which the mosquito immune system limits infection, between different <it>Plasmodium </it>strains and particular mosquito strains that is mediated by TEP1/LRIM1 activation. The interactions between highly compatible animal models of malaria, such as <it>P. yoelii </it>(17XNL)-<it>An. stephensi </it>(Nijmegen Sda500), is more similar to that of <it>P. falciparum </it>(3D7)-<it>An. gambiae </it>(G3).</p

Loss of Androgen Receptor-Dependent Growth Suppression by Prostate Cancer Cells Can Occur Independently from Acquiring Oncogenic Addiction to Androgen Receptor Signaling

The conversion of androgen receptor (AR) signaling as a mechanism of growth suppression of normal prostate epithelial cells to that of growth stimulation in prostate cancer cells is often associated with AR mutation, amplification and over-expression. Thus, down-regulation of AR signaling is commonly therapeutic for prostate cancer. The E006AA cell line was established from a hormone naïve, localized prostate cancer. E006AA cells are genetically aneuploid and grow equally well when xenografted into either intact or castrated male NOG but not nude mice. These cells exhibit: 1) X chromosome duplication and AR gene amplification, although paradoxically not coupled with increased AR expression, and 2) somatic, dominant-negative Serine-599-Glycine loss-of-function mutation within the dimerization surface of the DNA binding domain of the AR gene. No effect on the growth of E006AA cells is observed using targeted knockdown of endogenous mutant AR, ectopic expression of wild-type AR, or treatment with androgens or anti-androgens. E006AA cells represent a prototype for a newly identified subtype of prostate cancer cells that exhibit a dominant-negative AR loss-of-function in a hormonally naïve patient. Such loss-of-function eliminates AR-mediated growth suppression normally induced by normal physiological levels of androgens, thus producing a selective growth advantage for these malignant cells in hormonally naïve patients. These data highlight that loss of AR-mediated growth suppression is an independent process, and that, without additional changes, is insufficient for acquiring oncogene addiction to AR signaling. Thus, patients with prostate cancer cells harboring such AR loss-of-function mutations will not benefit from aggressive hormone or anti-AR therapies even though they express AR protein

Estimates of measles case fatality ratios: a comprehensive review of community-based studies.

BACKGROUND: Global deaths from measles have decreased notably in past decades, due to both increases in immunization rates and decreases in measles case fatality ratios (CFRs). While some aspects of the reduction in measles mortality can be monitored through increases in immunization coverage, estimating the level of measles deaths (in absolute terms) is problematic, particularly since incidence-based methods of estimation rely on accurate measures of measles CFRs. These ratios vary widely by geographic and epidemiologic context and even within the same community from year-to-year. METHODS: To understand better the variations in CFRs, we reviewed community-based studies published between 1980 and 2008 reporting age-specific measles CFRs. RESULTS: The results of the search consistently document that measles CFRs are highest in unvaccinated children under age 5 years; in outbreaks; the lowest CFRs occur in vaccinated children regardless of setting. The broad range of case and death definitions, study populations and geography highlight the complexities in extrapolating results for global public health planning. CONCLUSIONS: Values for measles CFRs remain imprecise, resulting in continued uncertainty about the actual toll measles exacts

An Outbreak of Rift Valley Fever in Northeastern Kenya, 1997-98

In December 1997, 170 hemorrhagic fever-associated deaths were reported in Carissa District, Kenya. Laboratory testing identified evidence of acute Rift Valley fever virus (RVFV). Of the 171 persons enrolled in a cross-sectional study, 31(18%) were anti-RVFV immunoglobulin (Ig) M positive. An age-adjusted IgM antibody prevalence of 14% was estimated for the district. We estimate approximately 27,500 infections occurred in Garissa District, making this the largest recorded outbreak of RVFV in East Africa. In multivariate analysis, contact with sheep body fluids and sheltering livestock in one’s home were significantly associated with infection. Direct contact with animals, particularly contact with sheep body fluids, was the most important modifiable risk factor for RVFV infection. Public education during epizootics may reduce human illness and deaths associated with future outbreaks

Loss of Androgen Receptor-Dependent Growth Suppression by Prostate Cancer Cells Can Occur Independently from Acquiring Oncogenic Addiction to Androgen Receptor Signaling

The conversion of androgen receptor (AR) signaling as a mechanism of growth suppression of normal prostate epithelial cells to that of growth stimulation in prostate cancer cells is often associated with AR mutation, amplification and over-expression. Thus, down-regulation of AR signaling is commonly therapeutic for prostate cancer. The E006AA cell line was established from a hormone naïve, localized prostate cancer. E006AA cells are genetically aneuploid and grow equally well when xenografted into either intact or castrated male NOG but not nude mice. These cells exhibit: 1) X chromosome duplication and AR gene amplification, although paradoxically not coupled with increased AR expression, and 2) somatic, dominant-negative Serine-599-Glycine loss-of-function mutation within the dimerization surface of the DNA binding domain of the AR gene. No effect on the growth of E006AA cells is observed using targeted knockdown of endogenous mutant AR, ectopic expression of wild-type AR, or treatment with androgens or anti-androgens. E006AA cells represent a prototype for a newly identified subtype of prostate cancer cells that exhibit a dominant-negative AR loss-of-function in a hormonally naïve patient. Such loss-of-function eliminates AR-mediated growth suppression normally induced by normal physiological levels of androgens, thus producing a selective growth advantage for these malignant cells in hormonally naïve patients. These data highlight that loss of AR-mediated growth suppression is an independent process, and that, without additional changes, is insufficient for acquiring oncogene addiction to AR signaling. Thus, patients with prostate cancer cells harboring such AR loss-of-function mutations will not benefit from aggressive hormone or anti-AR therapies even though they express AR protein.</p