Time to Take Action on Climate Communication BOWMAN, THOMAS E.; MAIBACH, EDWARD; MANN, MICHAEL E. ...
Science (American Association for the Advancement of Science),
11/2010, Letnik:
330, Številka:
6007
Journal Article
Hooking up! Hsp90 is a molecular chaperone involved in the stabilisation of numerous client proteins including those involved in oncogenic transformations. Through a high‐throughput biochemical ...fragment screen, we have identified novel fragment inhibitors of Hsp90. Two fragment hits were combined to give a dual‐fragment Hsp90 complex, and the following successful fragment‐linking resulted in a 1000‐fold improvement in activity.
Heat shock protein 90 (Hsp90) plays a key role in stress response and protection of the cell against the effects of mutation. Herein we report the identification of an Hsp90 inhibitor identified by ...fragment screening using a high‐concentration biochemical assay, as well as its optimisation by in silico searching coupled with a structure‐based drug design (SBDD) approach.
Heat shock protein 90 (Hsp90) plays a key role in stress response and protection of the cell against the effects of mutation. Herein we report the identification of an Hsp90 inhibitor identified by fragment screening using a high‐concentration biochemical assay, as well as its optimisation by in silico searching coupled with a structure‐based drug design (SBDD) approach.
Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in developed countries. To identify common PrCa susceptibility alleles, we previously conducted a genome-wide association study ...in which 541,129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and in 1,894 controls. We have now extended the study to evaluate promising associations in a second stage in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls and in a third stage involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to replicating previous associations, we identified seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11 and 22 (with P = 1.6 x 10(-8) to P = 2.7 x 10(-33)).
A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant ...single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10(-17)). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31). The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction.
An observational study of Koronis family members’ spin properties was undertaken with two primary objectives: to reduce selection biases for object rotation period and lightcurve amplitude in the ...sample of members’ known spin vectors, and to better constrain future modeling of spin properties evolution. Here we report rotation lightcurves of nineteen Koronis family members, and derived results that increase the sample of determined spin vectors in the Koronis family to include 34 of the largest 36 family members, completing it to H≈11.3 (D∼16 km) for the largest 32 members. The program observations were made during a total of 72 apparitions between 2005–2021, and are reported here along with several earlier unpublished lightcurves. All of the reported data were analyzed together with previously published lightcurves to determine the objects’ sidereal rotation periods, spin vector orientations, and convex model shape solutions. The derived distributions of retrograde rotation rates and pole obliquities appear to be qualitatively consistent with outcomes of modification by thermal YORP torques. The distribution of spin rates for the prograde rotators remains narrower than that for the retrograde rotators; in particular, the absence of prograde rotators having periods longer than about 20 h is real, while among the retrograde rotators are several objects having longer periods up to about 65 h. None of the prograde objects newly added to the sample appear to be trapped in an s6 spin–orbit resonance that is characteristic of most of the largest prograde objects (Vokrouhlický et al., 2003); these smaller objects either could have been trapped previously and have already evolved out, or have experienced spin evolution tracks that did not include the resonance.
•Koronis family spin vector sample completed to largest 32 members (∼16 km diameter).•Removal of sample selection biases for interpreting and modeling spin evolution.•The absence of prograde spins having rotation periods longer than about 20 h is real.•Smaller prograde objects avoided or escaped the spin–orbit trapping of larger objects.•Epochs analysis combined with convex inversion is effective to determine spin vectors.
Summary Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant ...tuberculosis, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxic effects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained.
It is known that bimesogenic liquid crystals exhibit a marked "odd-even" effect in the flexoelastic ratio (the effective flexoelectric coefficient to the average elastic coefficient), with the ratio ...being higher for the "odd-spaced" bimesogens (those with an odd number of alkyl groups in the spacer chain) than their neighboring even-spaced counterparts. To determine the contribution of each property to the flexoelastic ratio, we present experimental results on the flexoelectric and elastic coefficients of two homologous nonsymmetric bimesogens which possess odd and even alkyl spacers. Our results show that, although there are differences in the flexoelectric coefficients, there are substantially larger differences in the effective elastic coefficient. Specifically, the odd bimesogen is found to have both a low splay elastic coefficient and a very low bend elastic coefficient which, when combined, results in a significantly lower effective elastic coefficient and consequently a higher flexoelastic ratio.
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