Role of metal-dependent regulation of ESX-3 secretion in intracellular survival of Mycobacterium tuberculosis

More people die every year from Mycobacterium tuberculosis infection than from infection by any other bacterial pathogen. Type VII secretion systems (T7SS) are used by both environmental and pathogenic mycobacteria to secrete proteins across their complex cell envelope. In the nonpathogen Mycobacterium smegmatis, the ESX-1 T7SS plays a role in conjugation, and the ESX-3 T7SS is involved in metal homeostasis. In M. tuberculosis, these secretion systems have taken on roles in virulence, and they also are targets of the host immune response. ESX-3 secretes a heterodimer composed of EsxG (TB9.8) and EsxH (TB10.4), which impairs phagosome maturation in macrophages and is essential for virulence in mice. Given the importance of EsxG and EsxH during infection, we examined their regulation. With M. tuberculosis, the secretion of EsxG and EsxH was regulated in response to iron and zinc, in accordance with the previously described transcriptional response of the esx-3 locus to these metals. While iron regulated the esx-3 expression in both M. tuberculosis and M. smegmatis, there is a significant difference in the dynamics of this regulation. In M. smegmatis, the esx-3 locus behaved like other iron-regulated genes such as mbtB. In M. tuberculosis, both iron and zinc modestly repressed esx-3 expression. Diminished secretion of EsxG and EsxH in response to these metals altered the interaction of M. tuberculosis with macrophages, leading to impaired intracellular M. tuberculosis survival. Our findings detail the regulatory differences of esx-3 in M. tuberculosis and M. smegmatis and demonstrate the importance of metal-dependent regulation of ESX-3 for virulence in M. tuberculosis

Analysis of Compression Pad Cavities for the Orion Heatshield

Current results of a program for analysis of the compression pad cavities on the Orion heatshield are reviewed. The program was supported by experimental tests, engineering modeling, and applied computations with an emphasis on the latter presented in this paper. The computational tools and approach are described along with calculated results for wind tunnel and flight conditions. Correlations of the computed results are shown which can produce a credible prediction of heating augmentation due to cavity disturbances. The models developed for use in preliminary design of the Orion heatshield are presented

Quantifying the Origin and Distribution of Intracluster Light in a Fornax-like Cluster

Using a cosmological $N$-body simulation, we investigate the origin and distribution of stars in the intracluster light (ICL) of a Fornax-like cluster. In a dark matter only simulation we identify a halo which, at $z=0$, has $M_200 \simeq 4.1 \times 10^{13}M_{sun}$ and $r_{200} = 700kpc$, and replace infalling subhalos with models that include spheroid and disc components. As they fall into the cluster, the stars in some of these galaxies are stripped from their hosts, and form the ICL. We consider the separate contributions to the ICL from stars which originate in the haloes and the discs of the galaxies. We find that disc ICL stars are more centrally concentrated than halo ICL stars. The majority of the disc ICL stars are associated with one initially disc-dominated galaxy that falls to the centre of the cluster and is heavily disrupted, producing part of the cD galaxy. At radial distances greater than 200kpc, well beyond the stellar envelope of the cD galaxy, stars formerly from the stellar haloes of galaxies dominate the ICL. Therefore at large distances, the ICL population is dominated by older stars.Comment: Paper published as MNRAS , 2017, 467, 4501 This version corrects a small typo in the authors fiel

The Ursinus Weekly, November 1, 1907

Phantom party at Olevian • Football • Historical Political meeting • The Schubert string quartette • Editorial: Smiles • Society • Personals • Seminary notes • College world • Alumni notes • Literary Supplement: The lack of appreciation of the beautiful; A defense of American poetry; The danger of hero worship in a democracy; Hallowe\u27en; The price of an experience; Hannibalhttps://digitalcommons.ursinus.edu/weekly/2882/thumbnail.jp

Complex-Temperature Singularities in the d=2d=2 Ising Model. III. Honeycomb Lattice

We study complex-temperature properties of the uniform and staggered susceptibilities $\chi$ and $\chi^{(a)}$ of the Ising model on the honeycomb lattice. From an analysis of low-temperature series expansions, we find evidence that $\chi$ and $\chi^{(a)}$ both have divergent singularities at the point $z=-1 \equiv z_{\ell}$ (where $z=e^{-2K}$), with exponents $\gamma_{\ell}'= \gamma_{\ell,a}'=5/2$. The critical amplitudes at this singularity are calculated. Using exact results, we extract the behaviour of the magnetisation $M$ and specific heat $C$ at complex-temperature singularities. We find that, in addition to its zero at the physical critical point, $M$ diverges at $z=-1$ with exponent $\beta_{\ell}=-1/4$, vanishes continuously at $z=\pm i$ with exponent $\beta_s=3/8$, and vanishes discontinuously elsewhere along the boundary of the complex-temperature ferromagnetic phase. $C$ diverges at $z=-1$ with exponent $\alpha_{\ell}'=2$ and at $v=\pm i/\sqrt{3}$ (where $v = \tanh K$) with exponent $\alpha_e=1$, and diverges logarithmically at $z=\pm i$. We find that the exponent relation $\alpha'+2\beta+\gamma'=2$ is violated at $z=-1$; the right-hand side is 4 rather than 2. The connections of these results with complex-temperature properties of the Ising model on the triangular lattice are discussed.Comment: 22 pages, latex, figures appended after the end of the text as a compressed, uuencoded postscript fil

Efficacy, safety, and dose of Pafuramidine, a new oral drug for treatment of first stage sleeping sickness, in a phase 2a clinical study and phase 2b randomized clinical studies

Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT.; The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent.; Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3

Identification of platform-independent gene expression markers of cisplatin nephrotoxicity.

Within the International Life Sciences Institute Committee on Genomics, a working group was formed to focus on the application of microarray technology to preclinical assessments of drug-induced nephrotoxicity. As part of this effort, Sprague-Dawley rats were treated with the nephrotoxicant cisplatin at doses of 0.3-5 mg/kg over a 4- to 144-hr time course. RNA prepared from these animals was run on a variety of microarray formats at multiple sites. A set of 93 differentially expressed genes associated with cisplatin-induced renal injury was identified on the National Institute of Environmental Health Sciences (NIEHS) custom cDNA microarray platform using quadruplicate measurements of pooled animal RNA. The reproducibility of this profile of statistically significant gene changes on other platforms, in pooled and individual animal replicate samples, and in an independent study was investigated. A good correlation in response between platforms was found among the 48 genes in the NIEHS data set that could be matched to probes on the Affymetrix RGU34A array by UniGene identifier or sequence alignment. Similar results were obtained with genes that could be linked between the NIEHS and Incyte or PHASE-1 arrays. The degree of renal damage induced by cisplatin in individual animals was commensurate with the number of differentially expressed genes in this data set. These results suggest that gene profiles linked to specific types of tissue injury or mechanisms of toxicity and identified in well-performed replicated microarray experiments may be extrapolatable across platform technologies, laboratories, and in-life studies