Host responses influence on the induction of lambda prophage

Inactivation of bacteriophage lambda CI repressor leads almost exclusively to lytic development. Prophage induction can be initiated either by DNA damage or by heat treatment of a temperature-sensitive repressor. These two treatments also cause a concurrent activation of either the host SOS or heat-shock stress responses respectively. We studied the effects of these two methods of induction on the lytic pathway by monitoring the activation of different lambda promoters, and found that the lambda genetic network co-ordinates information from the host stress response networks. Our results show that the function of the CII transcriptional activator, which facilitates the lysogenic developmental pathway, is not observed following either method of induction. Mutations in the cro gene restore the CII function irrespective of the induction method. Deletion of the heat-shock protease gene ftsH can also restore CII function following heat induction but not following SOS induction. Our findings highlight the importance of the elimination of CII function during induction as a way to ensure an efficient lytic outcome. We also show that, despite the common inhibitory effect on CII function, there are significant differences in the heat- and SOS-induced pathways leading to the lytic cascade

A large local rotational speed for the Galaxy found from proper-motions: Implications for the mass of the Milky-Way

Predictions from a Galactic Structure and Kinematic model are compared to the absolute proper-motions of about 30,000 randomly selected stars with $9 < B_{\rm J} \le 19$ derived from the Southern Proper-Motion Program (SPM) toward the South Galactic Pole. The absolute nature of the SPM proper-motions allow us to measure not only the relative motion of the Sun with respect to the local disk, but also, and most importantly, the overall state of rotation of the local disk with respect to galaxies. The SPM data are best fit by models having a solar peculiar motion of +5 km~s$^{-1}$ in the V-component (pointing in the direction of Galactic rotation), a large LSR speed of 270 km~s$^{-1}$, and a disk velocity ellipsoid that points towards the Galactic center. We stress, however, that these results rest crucially on the assumptions of both axisymmetry and equilibrium dynamics. The absolute proper-motions in the U-component indicate a solar peculiar motion of $11.0 \pm 1.5$ km~s$^{-1}$, with no need for a local expansion or contraction term. The implications of the large LSR speed are discussed in terms of gravitational mass of the Galaxy inferred from the most recent and accurate determination for the proper-motion of the LMC. We find that our derived value for the LSR is consistent both with the mass of the Galaxy inferred from the motion of the Clouds ($3 - 4 \times 10^{12} M_\odot$ to $\sim 50$ kpc), as well as the timing argument, based on the binary motion of M31 and the Milky Way, and Leo I and the Milky Way ($\ge 1.2 \times 10^{12} M_\odot$ to $\sim 200$ kpc).Comment: 7 pages (AAS Latex macro v4.0), 2 B&W postscript figures, accepted for publication on ApJ, Letters sectio

Galactic Kinematics Towards the South Galactic Pole. First Results from the Yale-San Juan Southern Proper-Motion Program

The predictions from a Galactic Structure and Kinematic model code are compared to the color counts and absolute proper-motions derived from the Southern Proper-Motion survey covering more than 700 $\deg^2$ toward the South Galactic Pole in the range $9 < B_{\rm J} \le 19$. The theoretical assumptions and associated computational procedures, the geometry for the kinematic model, and the adopted parameters are presented in detail and compared to other Galactic Kinematic models of its kind. The data to which the model is compared consists of more than 30,000 randomly selected stars, and it is best fit by models with a solar peculiar motion of +5 km s$^{-1}$ in the V-component (pointing in the direction of Galactic rotation), a large LSR speed of 270 km s$^{-1}$, and a (disk) velocity ellipsoid that always points towards the Galactic center. The absolute proper-motions in the U-component indicate a solar peculiar motion of $11.0 \pm 1.5$ km s$^{-1}$, with no need for a local expansion or contraction term. The fainter absolute motions show an indication that the thick-disk must exhibit a rather steep velocity gradient of about -36 km s$^{-1}$ kpc$^{-1}$ with respect to the LSR. We are not able to set constraints on the overall rotation for the halo, nor on the thick-disk or halo velocity dispersions. Some substructure in the U & V proper-motions could be present in the brighter bins $10 < B_{\rm J} < 13$, and it might be indicative of (disk) moving groups.Comment: 24 double-column pages, 12 tables, AAS Latex macros v4.0, 19 B&W figures, 1 color figure. Accepted for publication on The Astronomical Journa

Imatinib mesylate alters the expression of genes related to disease progression in an animal model of uveal melanoma

Imatinib mesylate (IM) is a compound that inhibits both BCR-ABL tyrosine kinase and c-kit receptors. Tyrosine kinases are important in cellular signaling and mediate major cellular processes such as proliferation, differentiation, apoptosis, attachment, and migration. Twenty-six albino rabbits were injected with 1 x 10(6) human uveal melanoma (UM) cells (92.1) into the suprachoroidal space. Animals were immunosuppressed (cyclosporin A) over the course of the 12-week experiment and divided into two groups (n = 13). the experimental group received IM once daily by gavage while the control group received a placebo. One animal per group was sacrificed every week after the 2nd week. Upon necropsy, organs were harvested for histopathological examination. Cells from the primary tumors were recultured and tested in proliferation and invasion assays. A PCR array was used to investigate the differences in expression of 84 genes related to tumor metastasis. in the treated group, 4 rabbits developed intraocular tumors, with an average largest tumor dimension (LTD) of 2.5 mm and 5 animals reported metastatic disease. Whereas 6 rabbits in the control group developed intraocular tumors, with an average LTD of 5.8 mm and 6 animals reported metastatic disease. the recultured cells from the treated group demonstrated lower proliferation rates and were less invasive (p < 0.001). the PCR array showed differences in expression of genes related to metastasis. Notably, there was 290-fold increase in SERPINB5, a tumor suppressor gene, and a 10-fold higher expression of KISS I, a metastasis suppressor gene, in the treated group. Proangiogenic genes such as VEGFA, PDGFA and PDGFB were downregulated in the treated group. To the best of our knowledge, this is the first report detailing the altered expression of specific genes in UM cells after treatment with IM.McGill Univ, Ctr Hlth, Dept Ophthalmol & Pathol, Montreal, PQ, CanadaHenry C Witelson Ocular Pathol Lab, Montreal, PQ, CanadaUniversidade Federal de São Paulo UNIFESP EPM, Dept Ophthalmol, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP EPM, Dept Ophthalmol, São Paulo, BrazilWeb of Scienc

The major brain cholesterol metabolite 24(s)-hydroxycholesterol is a potent allosteric modulator of N-methyl-d-aspartate receptors

N-methyl-d-aspartate receptors (NMDARs) are glutamate-gated ion channels that are critical to the regulation of excitatory synaptic function in the CNS. NMDARs govern experience-dependent synaptic plasticity and have been implicated in the pathophysiology of various neuropsychiatric disorders including the cognitive deficits of schizophrenia and certain forms of autism. Certain neurosteroids modulate NMDARs experimentally but their low potency, poor selectivity, and very low brain concentrations make them poor candidates as endogenous ligands or therapeutic agents. Here we show that the major brain-derived cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC) is a very potent, direct, and selective positive allosteric modulator of NMDARs with a mechanism that does not overlap that of other allosteric modulators. At submicromolar concentrations 24(S)-HC potentiates NMDAR-mediated EPSCs in rat hippocampal neurons but fails to affect AMPAR or GABA(A) receptors (GABA(A)Rs)-mediated responses. Cholesterol itself and other naturally occurring oxysterols present in brain do not modulate NMDARs at concentrations ≤10 μm. In hippocampal slices, 24(S)-HC enhances the ability of subthreshold stimuli to induce long-term potentiation (LTP). 24(S)-HC also reverses hippocampal LTP deficits induced by the NMDAR channel blocker ketamine. Finally, we show that synthetic drug-like derivatives of 24(S)-HC, which potently enhance NMDAR-mediated EPSCs and LTP, restore behavioral and cognitive deficits in rodents treated with NMDAR channel blockers. Thus, 24(S)-HC may function as an endogenous modulator of NMDARs acting at a novel oxysterol modulatory site that also represents a target for therapeutic drug development

Endoplasmic Reticulum Stress Is Reduced in Tissues of Obese Subjects After Weight Loss

OBJECTIVE—Obesity is associated with insulin resistance and type 2 diabetes, although the mechanisms linking these pathologies remain undetermined. Recent studies in rodent models revealed endoplasmic reticulum (ER) stress in adipose and liver tissues and demonstrated that ER stress could cause insulin resistance. Therefore, we tested whether these stress pathways were also present in obese human subjects and/or regulated by weight loss