12 research outputs found
Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists
Although there is no shortage of potential drug targets, there are only a handful known low-molecular-weight inhibitors of protein-protein interactions (PPIs). One problem is that current efforts are dominated by low-yield high-throughput screening, whose rigid framework is not suitable for the diverse chemotypes present in PPIs. Here, we developed a novel pharmacophore-based interactive screening technology that builds on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel compounds. Application of this approach to the MDM2/p53 cancer target led to high hit rates, resulting in a large and diverse set of confirmed inhibitors, and co-crystal structures validate the designed compounds. Our unique open-access technology promises to expand chemical space and the exploration of the human interactome by leveraging in-house small-scale assays and user-friendly chemistry to rationally design ligands for PPIs with known structure. © 2012 Koes et al
Mechanical Behavior of Nanocomposite Aerogels
International audienceAerogels are generally described in terms of brittle and elastic materials, like glasses or ceramics with poor and not predictable mechanical properties. We propose the synthesis of a nanocomposite aerogels with improved mechanical properties by addition of silica particles (aerosil; 20â100 nm) in the monomer solution. The elastic modulus and rupture strength increase, stiffening and strengthening the structure by a factor 5â8. The toughness, the critical flaw size, and the fracture energy increase also versus the silica particle concentration. Moreover, the mechanical strength distribution and the Weibull modulus, m, characterizing the statistical nature of flaw size in brittle materials show a more homogeneous flaw size distribution. Pores are considered as integral part of flaws, and small angle X-ray scattering shows that the usual fractal structure observed in aerogel disappears with the silica particle addition. The fractal structure in aerogel is characteristic of a large pore size distribution, but also of a large flaw size distribution. If nanocomposites behave as brittle material under a tension stress, they exhibit a different response when the structure is submitted to a compression: densification and plastic hardening. These opposite behaviors (brittle and plastic) are surprisingly related to the same kinds of gel features: pore volume, silanol content, and the pore size distribution. Because of improved mechanical properties, these nanocomposites aerogels could be used as host matrices for the synthesis of glass ceramics, doped glasses, and composites
An overview of road safety in Greece
Two related, novel, zoonotic paramyxoviruses have been described recently. Hendra virus was first reported in horses and thence humans in Australia in 1994; Nipah virus was first reported in pigs and thence humans in Malaysia in 1998. Human cases of Nipah virus infection, apparently unassociated with infection in livestock, have been reported in Bangladesh since 2001. Species of fruit bats (genus Pteropus ) have been identified as natural hosts of both agents. Anthropogenic changes (habitat loss, hunting) that have impacted the population dynamics of Pteropus species across much of their range are hypothesised to have facilitated emergence. Current strategies for the management of henipaviruses are directed at minimising contact with the natural hosts, monitoring identified intermediate hosts, improving biosecurity on farms, and better disease recognition and diagnosis. Investigation of the emergence and ecology of henipaviruses warrants a broad, cross-disciplinary ecosystem health approach that recognises the critical linkages between human activity, ecological change, and livestock and human health
Aerogel Processing
International audienceOne of the problems largely commented in the sol-gel science is how to make large bodies, because gels tend to crack during drying. The drying stresses are attributed to capillary phenomena and differential strain which result from a pressure gradient in the pore liquid. By the supercritical drying (SCD), the capillary stresses are eliminated and monolithic aerogel can be obtained. This chapter focuses on silica aerogel, the most studied aerogel. It presents an overview of the supercritical drying techniques, but also some of the remarkable aerogel properties (optical, mechanical, thermal and acoustical, etc.) with respect to its peculiar microstructure. The chapter briefly presents other kinds of aerogels (oxides and chalcogenideaerogels, composite aerogels, organic aerogels, etc.) and a panel of potential applications
Multilocus enzyme electrophoresis typing of Candida albicans populations isolated from healthy children according to socioeconomic background
Incidence of tuberculosis among HIV-infected patients receiving highly active antiretroviral therapy in Europe and North America
Background. We obtained estimates of the incidence of tuberculosis (TB) among patients receiving HAART and identified determinants of the incidence. Methods. We analyzed the incidence of TB during the first 3 years after initiation of HAART among 17,142 treatment-naive, AIDS- free persons starting HAART who were enrolled in 12 cohorts from Europe and North America. We used univariable and multivariable Poisson regression models to identify factors associated with the incidence. Results. During the first 3 years (36,906 person-years), 173 patients developed TB (incidence, 4.69 cases per 1000 person-years). In multivariable analysis, the incidence rate was lower for men who have sex with men, compared with injection drug users (relative rate, 2.46; 95% confidence interval [CI], 1.51-4.01), heterosexuals (relative rate, 2.42; 95% CI, 1.64-3.59), those with other suspected modes of transmission (relative rate, 1.66; 95% CI, 0.91-3.06), and those with a higher CD4(+) count at the time of HAART initiation (relative rate per log(2) cells/mL, 0.87; 95% CI, 0.84-0.91). During 28,846 person-years of follow-up after the first 6 months of HAART, 88 patients developed TB (incidence, 3.1 cases per 1000 person-years of follow-up). In multivariable analyses, a low baseline CD4(+) count (relative rate per log(2) cells/mL, 0.89; 95% CI, 0.83-0.96), 6-month CD4(+) count (relative rate per log(2) cells/mL, 0.90; 95% CI, 0.81-0.99), and a 6-month HIV RNA level 1400 copies/mL (relative rate, 2.21; 95% CI, 1.33-3.67) were significantly associated with the risk of acquiring TB after 6 months of HAART. Conclusion. The level of immunodeficiency at which HAART is initiated and the response to HAART are important determinants of the risk of TB. However, this risk remains appreciable even among those with a good response to HAART, suggesting that other interventions may be needed to control the TB epidemic in the HIV-infected population
Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal.
Abstract
BackgroundâThe extent to which mortality differs following individual acquired
immunodeficiency syndrome (AIDS)âdefining events (ADEs) has not been assessed among
patients initiating combination antiretroviral therapy.
MethodsâWe analyzed data from 31,620 patients with no prior ADEs who started combination
antiretroviral therapy. Cox proportional hazards models were used to estimate mortality hazard
ratios for each ADE that occurred in >50 patients, after stratification by cohort and adjustment for
sex, HIV transmission group, number of anti-retroviral drugs initiated, regimen, age, date of
starting combination antiretroviral therapy, and CD4+ cell count and HIV RNA load at initiation
of combination antiretroviral therapy. ADEs that occurred in <50 patients were grouped together
to form a ârare ADEsâ category.
ResultsâDuring a median follow-up period of 43 months (interquartile range, 19â70 months),
2880 ADEs were diagnosed in 2262 patients; 1146 patients died. The most common ADEs were
esophageal candidiasis (in 360 patients), Pneumocystis jiroveci pneumonia (320 patients), and
Kaposi sarcoma (308 patients). The greatest mortality hazard ratio was associated with non-
Hodgkinâs lymphoma (hazard ratio, 17.59; 95% confidence interval, 13.84â22.35) and progressive
multifocal leukoencephalopathy (hazard ratio, 10.0; 95% confidence interval, 6.70â14.92). Three
groups of ADEs were identified on the basis of the ranked hazard ratios with bootstrapped
confidence intervals: severe (non-Hodgkinâs lymphoma and progressive multifocal
leukoencephalopathy [hazard ratio, 7.26; 95% confidence interval, 5.55â9.48]), moderate
(cryptococcosis, cerebral toxoplasmosis, AIDS dementia complex, disseminated Mycobacterium
avium complex, and rare ADEs [hazard ratio, 2.35; 95% confidence interval, 1.76â3.13]), and
mild (all other ADEs [hazard ratio, 1.47; 95% confidence interval, 1.08â2.00]).
ConclusionsâIn the combination antiretroviral therapy era, mortality rates subsequent to an
ADE depend on the specific diagnosis. The proposed classification of ADEs may be useful in
clinical end point trials, prognostic studies, and patient management