A screen of Crohn's disease-associated microbial metabolites identifies ascorbate as a novel metabolic inhibitor of activated human T cells.

Microbial metabolites are an emerging class of mediators influencing CD4+ T-cell function. To advance the understanding of direct causal microbial factors contributing to Crohn's disease, we screened 139 predicted Crohn's disease-associated microbial metabolites for their bioactivity on human CD4+ T-cell functions induced by disease-associated T helper 17 (Th17) polarizing conditions. We observed 15 metabolites with CD4+ T-cell bioactivity, 3 previously reported, and 12 unprecedented. A deeper investigation of the microbe-derived metabolite, ascorbate, revealed its selective inhibition on activated human CD4+ effector T cells, including IL-17A-, IL-4-, and IFNγ-producing cells. Mechanistic assessment suggested the apoptosis of activated human CD4+ T cells associated with selective inhibition of energy metabolism. These findings suggest a substantial rate of relevant T-cell bioactivity among Crohn's disease-associated microbial metabolites, and evidence for novel modes of bioactivity, including targeting of T-cell energy metabolism

G-Protein coupled receptors: structure and function in drug discovery

The G-protein coupled receptors (GPCRs) superfamily comprise similar proteins arranged into families or classes thus making it one of the largest in the mammalian genome. GPCRs take part in many vital physiological functions making them targets for numerous novel drugs. GPCRs share some distinctive features, such as the seven transmembrane domains, they also differ in the number of conserved residues in their transmembrane domain. Here we provide an introductory and accessible review detailing the computational advances in GPCR pharmacology and drug discovery. An overview is provided on family A-C GPCRs; their structural differences, GPCR signalling, allosteric binding and cooperativity. The dielectric constant (relative permittivity) of proteins is also discussed in the context of site-specific environmental effects

Sensory Measurements: Coordination and Standardization

Do sensory measurements deserve the label of “measurement”? We argue that they do. They fit with an epistemological view of measurement held in current philosophy of science, and they face the same kinds of epistemological challenges as physical measurements do: the problem of coordination and the problem of standardization. These problems are addressed through the process of “epistemic iteration,” for all measurements. We also argue for distinguishing the problem of standardization from the problem of coordination. To exemplify our claims, we draw on olfactory performance tests, especially studies linking olfactory decline to neurodegenerative disorders

Compressibility of titanosilicate melts

The effect of composition on the relaxed adiabatic bulk modulus (K0) of a range of alkali- and alkaline earth-titanosilicate [X 2 n/n+ TiSiO5 (X=Li, Na, K, Rb, Cs, Ca, Sr, Ba)] melts has been investigated. The relaxed bulk moduli of these melts have been measured using ultrasonic interferometric methods at frequencies of 3, 5 and 7 MHz in the temperature range of 950 to 1600°C (0.02 Pa s < s < 5 Pa s). The bulk moduli of these melts decrease with increasing cation size from Li to Cs and Ca to Ba, and with increasing temperature. The bulk moduli of the Li-, Na-, Ca- and Ba-bearing metasilicate melts decrease with the addition of both TiO2 and SiO2 whereas those of the K-, Rb- and Cs-bearing melts increase. Linear fits to the bulk modulus versus volume fraction of TiO2 do not converge to a common compressibility of the TiO2 component, indicating that the structural role of TiO2 in these melts is dependent on the identity of the cation. This proposition is supported by a number of other property data for these and related melt compositions including heat capacity and density, as well as structural inferences from X-ray absorption spectroscopy (XANES). The compositional dependence of the compressibility of the TiO2 component in these melts explains the difficulty incurred in previous attempts to incorporate TiO2 in calculation schemes for melt compressibility. The empirical relationship KV-4/3 for isostructural materials has been used to evaluate the compressibility-related structural changes occurring in these melts. The alkali metasilicate and disilicate melts are isostructural, independent of the cation. The addition of Ti to the metasilicate composition (i.e. X2TiSiO5), however, results in a series of melts which are not isostructural. The alkaline-earth metasilicate and disilicate compositions are not isostructural, but the addition of Ti to the metasilicate compositions (i.e. XTiSiO5) would appear, on the basis of modulus-volume systematics, to result in the melts becoming isostructural with respect to compressibility

Implications of sperm banking for health-related quality of life up to 1 year after cancer diagnosis.

Sperm banking is recommended for all men diagnosed with cancer where treatment is associated with risk of long-term gonadatoxicity, to offer the opportunity of fatherhood and improved quality of life. However, uptake of sperm banking is lower than expected and little is known about why men refuse. Our aims were to determine: (i) demographic and medical variables associated with decisions about banking and (ii) differences in quality of life between bankers and non-bankers at diagnosis (Time 1 (T1)) and 1 year later (Time 2 (T2))

Minimal in vivo efficacy of iminosugars in a lethal Ebola virus guinea pig model

The antiviral properties of iminosugars have been reported previously in vitro and in small animal models against Ebola virus (EBOV); however, their effects have not been tested in larger animal models such as guinea pigs. We tested the iminosugars N-butyl-deoxynojirimycin (NB-DNJ) and N-(9-methoxynonyl)-1deoxynojirimycin (MON-DNJ) for safety in uninfected animals, and for antiviral efficacy in animals infected with a lethal dose of guinea pig adapted EBOV. 1850 mg/kg/day NB-DNJ and 120 mg/kg/day MON-DNJ administered intravenously, three times daily, caused no adverse effects and were well tolerated. A pilot study treating infected animals three times within an 8 hour period was promising with 1 of 4 infected NB-DNJ treated animals surviving and the remaining three showing improved clinical signs. MON-DNJ showed no protective effects when EBOV-infected guinea pigs were treated. On histopathological examination, animals treated with NB-DNJ had reduced lesion severity in liver and spleen. However, a second study, in which NB-DNJ was administered at equally-spaced 8 hour intervals, could not confirm drug-associated benefits. Neither was any antiviral effect of iminosugars detected in an EBOV glycoprotein pseudotyped virus assay. Overall, this study provides evidence that NB-DNJ and MON-DNJ do not protect guinea pigs from a lethal EBOV-infection at the dose levels and regimens tested. However, the one surviving animal and signs of improvements in three animals of the NB-DNJ treated cohort could indicate that NB-DNJ at these levels may have a marginal beneficial effect. Future work could be focused on the development of more potent iminosugars

Extended Call-by-Push-Value: Reasoning About Effectful Programs and Evaluation Order

Traditionally, reasoning about programs under varying evaluation regimes (call-by-value, call-by-name etc.) was done at the meta-level, treating them as term rewriting systems. Levy’s call-by-push-value (CBPV) calculus provides a more powerful approach for reasoning, by treating CBPV terms as a common intermediate language which captures both call-by-value and call-by-name, and by allowing equational reasoning about changes to evaluation order between or within programs. We extend CBPV to additionally deal with call-by-need, which is non-trivial because of shared reductions. This allows the equational reasoning to also support call-by-need. As an example, we then prove that call-by-need and call-by-name are equivalent if nontermination is the only side-effect in the source language. We then show how to incorporate an effect system. This enables us to exploit static knowledge of the potential effects of a given expression to augment equational reasoning; thus a program fragment might be invariant under change of evaluation regime only because of knowledge of its effects

Haemoglobin mass and running time trial performance after recombinant human erythropoietin administration in trained men

&lt;p&gt;Recombinant human erythropoietin (rHuEpo) increases haemoglobin mass (Hbmass) and maximal oxygen uptake (v˙ O2 max).&lt;/p&gt; &lt;p&gt;Purpose: This study defined the time course of changes in Hbmass, v˙ O2 max as well as running time trial performance following 4 weeks of rHuEpo administration to determine whether the laboratory observations would translate into actual improvements in running performance in the field.&lt;/p&gt; &lt;p&gt;Methods: 19 trained men received rHuEpo injections of 50 IUNkg21 body mass every two days for 4 weeks. Hbmass was determined weekly using the optimized carbon monoxide rebreathing method until 4 weeks after administration. v˙ O2 max and 3,000 m time trial performance were measured pre, post administration and at the end of the study.&lt;/p&gt; &lt;p&gt;Results: Relative to baseline, running performance significantly improved by ,6% after administration (10:3061:07 min:sec vs. 11:0861:15 min:sec, p,0.001) and remained significantly enhanced by ,3% 4 weeks after administration (10:4661:13 min:sec, p,0.001), while v˙ O2 max was also significantly increased post administration (60.765.8 mLNmin21Nkg21 vs. 56.066.2 mLNmin21Nkg21, p,0.001) and remained significantly increased 4 weeks after rHuEpo (58.065.6 mLNmin21Nkg21, p = 0.021). Hbmass was significantly increased at the end of administration compared to baseline (15.261.5 gNkg21 vs. 12.761.2 gNkg21, p,0.001). The rate of decrease in Hbmass toward baseline values post rHuEpo was similar to that of the increase during administration (20.53 gNkg21Nwk21, 95% confidence interval (CI) (20.68, 20.38) vs. 0.54 gNkg21Nwk21, CI (0.46, 0.63)) but Hbmass was still significantly elevated 4 weeks after administration compared to baseline (13.761.1 gNkg21, p&#60;0.001).&lt;/p&gt; &lt;p&gt;Conclusion: Running performance was improved following 4 weeks of rHuEpo and remained elevated 4 weeks after administration compared to baseline. These field performance effects coincided with rHuEpo-induced elevated v˙ O2 max and Hbmass.&lt;/p&gt

Trayectorias laborales de jóvenes trabajadores de la actividad vitivinícola : departamento Maipú, Mendoza

La presente investigación tuvo como eje los vínculos entre educación y trabajo en la vitivinicultura mendocina desde 1990 . El objetivo general fue comprender los procesos de incorporación de jóvenes de ambos sexos al mundo del trabajo y su vínculo con las estrategias de formación y los esquemas de percepción en el mercado vitivinícola mendocino desde los 90. Se analizaron e identificaron los tipos de trayectorias educativas, laborales y transiciones existentes en los jóvenes. También los condicionantes de género que operan desde la perspectiva de las mujeres jóvenes. Se buscó comprender las formas que adquieren, cómo se manifiestan y varían las perspectivas acerca del trabajo, de las exigencias laborales y las condiciones del mercado de trabajo a lo largo de las trayectorias educativas y laborales y cuáles son los principales elementos constitutivos de las trayectorias de inserción, qué factores están asociados a sus variaciones y cómo se vinculan con las expectativas y estrategias de formación de inserción laboral.Fil: Martín, María Eugenia. CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas) - Universidad Nacional de CuyoFil: Zamarbide, Gabriela. Universidad Nacional de Cuy

Adjusting a cancer mortality-prediction model for disease status-related eligibility criteria

<p>Abstract</p> <p>Background</p> <p>Volunteering participants in disease studies tend to be healthier than the general population partially due to specific enrollment criteria. Using modeling to accurately predict outcomes of cohort studies enrolling volunteers requires adjusting for the bias introduced in this way. Here we propose a new method to account for the effect of a specific form of healthy volunteer bias resulting from imposing disease status-related eligibility criteria, on disease-specific mortality, by explicitly modeling the length of the time interval between the moment when the subject becomes ineligible for the study, and the outcome.</p> <p>Methods</p> <p>Using survival time data from 1190 newly diagnosed lung cancer patients at MD Anderson Cancer Center, we model the time from clinical lung cancer diagnosis to death using an exponential distribution to approximate the length of this interval for a study where lung cancer death serves as the outcome. Incorporating this interval into our previously developed lung cancer risk model, we adjust for the effect of disease status-related eligibility criteria in predicting the number of lung cancer deaths in the control arm of CARET. The effect of the adjustment using the MD Anderson-derived approximation is compared to that based on SEER data.</p> <p>Results</p> <p>Using the adjustment developed in conjunction with our existing lung cancer model, we are able to accurately predict the number of lung cancer deaths observed in the control arm of CARET.</p> <p>Conclusions</p> <p>The resulting adjustment was accurate in predicting the lower rates of disease observed in the early years while still maintaining reasonable prediction ability in the later years of the trial. This method could be used to adjust for, or predict the duration and relative effect of any possible biases related to disease-specific eligibility criteria in modeling studies of volunteer-based cohorts.</p