Hijacking of the Pleiotropic Cytokine Interferon-γ by the Type III Secretion System of Yersinia pestis

Yersinia pestis, the causative agent of bubonic plague, employs its type III secretion system to inject toxins into target cells, a crucial step in infection establishment. LcrV is an essential component of the T3SS of Yersinia spp, and is able to associate at the tip of the secretion needle and take part in the translocation of anti-host effector proteins into the eukaryotic cell cytoplasm. Upon cell contact, LcrV is also released into the surrounding medium where it has been shown to block the normal inflammatory response, although details of this mechanism have remained elusive. In this work, we reveal a key aspect of the immunomodulatory function of LcrV by showing that it interacts directly and with nanomolar affinity with the inflammatory cytokine IFNγ. In addition, we generate specific IFNγ mutants that show decreased interaction capabilities towards LcrV, enabling us to map the interaction region to two basic C-terminal clusters of IFNγ. Lastly, we show that the LcrV-IFNγ interaction can be disrupted by a number of inhibitors, some of which display nanomolar affinity. This study thus not only identifies novel potential inhibitors that could be developed for the control of Yersinia-induced infection, but also highlights the diversity of the strategies used by Y. pestis to evade the immune system, with the hijacking of pleiotropic cytokines being a long-range mechanism that potentially plays a key role in the severity of plague

Dilaton dominance relaxes LHC and cosmological constraints in supersymmetric models

It has been pointed out recently that the presence of dilaton field in the early Universe can dilute the neutralino dark matter (DM) abundance, if Universe is not radiation dominated at DM decoupling, due to its dissipative-like coupling to DM. In this scenario two basic mechanisms compete, the modified Hubble expansion rate tending to increase the relic density and a dissipative force that tends to decrease it. The net effect can lead to an overall dramatic decrease of the predicted relic abundance, sometimes by amounts of the order of O(10^2) or so. This feature is rather generic, independent of any particular assumption on the underlying string dynamics, provided dilaton dominates at early eras after the end of inflation but before Big Bang Nucleosynthesis (BBN). The latter ensures that BBN is not upset by the presence of the dilaton. In this paper, within the context of such a scenario, we study the phenomenology of the constrained minimal supersymmetric model (CMSSM) by taking into account all recent experimental constraints, including those from the LHC searches. We find that the allowed parameter space is greatly enlarged and includes regions that are beyond the reach of LHC. The allowed regions are compatible with Direct Dark Matter searches since the small neutralino annihilation rates, that are now in accord with the cosmological data on the relic density, imply small neutralino-nucleon cross sections below the sensitivities of the Direct Dark Matter experiments. It is also important that the new cosmologically accepted regions are compatible with Higgs boson masses larger than 120 GeV, as it is indicated from the LHC experimental data. The smaller annihilation cross sections needed to explain WMAP data require that the detector performances of current and planned indirect DM search experiments through gamma rays should be greatly improved in order to probe the CMSSM regions.Comment: 20 pages, 10 eps figures. Revised and extended version to appear in JHEP; a section on gamma rays adde

Late-emerging strains of HIV induce T-cell homeostasis failure by promoting bystander cell death and immune exhaustion in naive CD4 and all CD8 T-cells

The mechanisms involved in the decline of CD4 and CD8 T-cells that lead to HIV-induced immune dysregulation are not clearly understood. We hypothesize that late-emerging strains of HIV, such as CXCR4-tropic (X4) virions, induce T-cell homeostasis failure by promoting significantly more bystander cell death, and immune exhaustion in naïve CD4 and all CD8 T-cells, when compared to strain of HIV, such as CCR5-tropic (R5) virions, found early during the course of infection. In the reported study, inactivated X4 virions induced greater bystander cell death in sort-purified naïve CD4 T-cells compared to R5 virions, which was significant (p = 0.013), and in memory CD8 T-cells, though the latter was not significant. A clearer understanding of the mechanisms involved in HIV-induced depletion of T-cell numbers and function could lead to therapies that prevent T-cell death and restore immune function. These therapies could improve current anti-retroviral and cure-related treatments by boosting the immune system’s own ability to combat the virus

Effects of a malaria elimination program: a retrospective study of 623 cases from 2008 to 2013 in a Chinese county hospital near the China – Myanmar border

The southwestern region of China, along the Myanmar border, has accounted for the highest number of cases of imported malaria since China shifted from a malaria control program to an elimination strategy in 2010. We conducted a retrospective study, in which 623 medical charts were analyzed to provide an epidemiological characterization of malaria cases that were diagnosed and treated at the People's Hospital of Tengchong County (PHTC), located in southwestern China, from 2008 to 2013. Our aim was to understand the characteristics of malaria in this region, which is a high-endemic region with imported cases. The majority of patients were male (91.7%), and the average age was 32.4 years. Most of the patients (86.4%) had visited Myanmar; labor was the purpose of travel for 63.9% of the patients. Plasmodium vivax and Plasmodium falciparum were responsible for 53.8% and 34.9% of the infections, respectively. The number of hospitalized patients rose gradually from 2008 to 2010 and reached its peak in 2010 (191). After 2010, the number of hospitalized cases fell rapidly from 191 (2010) to 45 (2013), and the proportion of patients who lived in the forest and the number infected with P. falciparum also fell. In conclusion, the number of hospitalized patients in the southwestern region of China, Tengchong county, decreased after China implemented a malaria elimination strategy in 2010. However, migrant workers returning from Myanmar remained important contributors to cases of imported malaria. The management of imported malaria should be targeted by the malaria elimination program in China

Schoen manifold with line bundles as resolved magnetized orbifolds

We give an alternative description of the Schoen manifold as the blow-up of a Z2xZ2 orbifold in which one Z2 factor acts as a roto-translation. Since for this orbifold the fixed tori are only identified in pairs but not orbifolded, four-dimensional chirality can never be obtained in heterotic string compactifications using standard techniques alone. However, chirality is recovered when its tori become magnetized. To exemplify this, we construct an E8xE8' heterotic SU(5) GUT on the Schoen manifold with Abelian gauge fluxes, which becomes an MSSM with three generations after an appropriate Wilson line is associated to its freely acting involution. We reproduce this model as a standard heterotic orbifold CFT of the (partially) blown down Schoen manifold with a magnetic flux. Finally, in analogy to a proposal for non--perturbative heterotic models by Aldazabal et al. we suggest modifications to the heterotic orbifold spectrum formulae in the presence of magnetized tori.Comment: 1+27 pages, 2 figures; v2: matches published versio

Anaplastic Myoepithelial Carcinoma of the Sinonasal Tract: an Underrecognized Salivary-Type Tumor Among the Sinonasal Small Round Blue Cell Malignancies? Report of One Case and a Review of the Literature

We present a 45 year old female patient with a nasal carcinoma showing high-grade/anaplastic histomorphological features and with a distinct myoepithelial immunohistochemical phenotype including positivity for smooth muscle actin, p63, S100 protein with no sustentacular pattern, calponin, cytokeratin 14, vimentin and cytokeratins (AE1-3 and CK5/6). A minority (<5%) of the cells showed focal and variable immunoreactivity for EMA with no cuticular/canalicular pattern. Bcl-2, CD99, CD117 and CD56 were variously positive, but chromogranin and synaptophysin were negative. Weak to moderate nuclear p53 immunoreactivity was seen in 50% of tumor cells. Mib-1/Ki-67 showed an average proliferation of 60–70%. Fluorescent in situ hybridization revealed no EWS-gene translocation. In situ hybridization for EBER was negative