Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a ...Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.
Summary
The SET‐ and chromo‐domains are recognized as signature motifs for proteins that contribute to epigenetic control of gene expression through effects on the regional organization of chromatin ...structure. This paper reports the identification of a novel subgroup of SET‐domain‐containing proteins in tobacco and Arabidopsis, which show highest homologies with the Drosophila position‐effect‐variegation repressor protein SU(VAR)3–9 and the yeast centromer silencing protein CLR4. The tobacco SET‐domain‐containing protein (NtSET1) was fused to the green fluorescence protein (GFP) that serves as a visual marker for localization of the recombinant protein in living cells. Whereas control GFP protein alone was uniformly dispersed within the nucleus and cytoplasm, the NtSET1‐GFP fusion protein showed a non‐uniform localization to multiple nuclear regions in interphase tobacco TBY2 cells. During mitosis, the NtSET1‐GFP associated with condensed chromosomes with a non‐random distribution. The NtSET1 thus appears to have distinct target regions in the plant chromatin. Overexpression of the NtSET1‐GFP in transgenic tobacco inhibited plant growth, implicating the possible involvement of the NtSET1 in transcriptional repression of growth control genes through the formation of higher‐order chromatin domains.
The nanocrystalline anatase TiO2 colloid has widely been applied in solar energy conversion, photo‐degradation of organic pollutions, photochemical disinfection, processing of sensors, and ...papermaking. It can be obtained from the hydrolysis of titanyl organic compounds TiO(OOCCH3)2 and Ti2O(OC4H9)2(OOCCH3)4 at low temperature and normal pressure. TEM (Transmission Electron Microscope), SEM (Scattering Electron Microscope), and LS (Layer Scattering) analysis showed that the colloidal particles are spherical and possess a narrow size distribution, that the mean size (80 °C, 2 h, sample B) is 8.9 nm and its isoelectric point is 6.67. The SBET of the gel powders are 262.7457 m2/g (60 °C, 2 h, sample A) and 258.0024 m2/g (80 °C, 2 h, sample B). Research experiments showed that the turbidities of colloidal solutions decreased along with the decrease of water content in the mixed water‐alcohol dispersants, which predicated that the colloidal stability fell when lowering the electrical conductivity of the dispersant. The zeta potentials of the colloids are 14 mV ∼ 30 mV at pH 4.5 ∼ 6.0 in the presence of 0.5 · 10–2 mol L–1 NaNO3 electrolyte. Furthermore, the UV absorbance of the nanocrystalline TiO2 colloidal solutions increased with a decrease in particle size. The experimental results of photocatalytic degradation of the dye rhodamine revealed that the nanocrystalline TiO2 colloidal particles from this preparation method have good photocatalytic activity, which is better if doped with 0.2 % Fe3+.
Stable nanocrystalline anatase TiO2 colloids were prepared at low temperature and normal pressure. Some of properties of the colloids, such as the particle size and distribution, stability in the mixed water‐alcohol dispersants, zeta potential and photo‐catalytic activity, etc., were reported.
In the study to identify key genes and molecular markers related to Pinus armandii Franch growth and to obtain shorten breeding cycles, we selected 209 single plants from six seed sources from a ...clonal P. armandii seed orchard on Zixi Mountain, Chuxiong City, Yunnan Province, China and examined tree height and diameter at breast height (DBH) traits. We then studied single nucleotide polymorphisms (SNP) markers related to tree height and DBH using Genome-Wide Association Studies (GWAS) and predicted candidate genes associated with growth traits using quantitative polymerase chain reaction (qPCR) to preliminarily verify these genes. We identified 13 SNP loci in the population, of which six and seven SNPs were related to DBH and tree height, respectively. We also identified a candidate gene caffeoyl-CoA-O-methyltransferase (CCoAOMT) which has important roles in lignin monomer synthesis. Another candidate gene cellulose synthase A2 (CesA2) was involved in cellulose synthesis in different organs, tissue, and the cell wall. The SNP marker (Marker227806) was associated with DBH, the genotypes of marker227806 in 209 samples of P. armandii. In total, 175 samples had homozygous (GG) and 34 had heterozygous (GT) genotypes, and average DBH values were 23.80 cm and 26.10 cm, respectively, indicating significant differences between two genotypes for DBH (P = 0.037, < 0.05), which could be used for optimal DBH selection. The candidate genes CCoAOMT and CesA2 were evaluated by qPCR and AT5G42190 was selected as an internal reference gene. Needle (ZY), bark (SP), root (SG), phloem (RP), and xylem (MZ) tissues from 15 samples were used to analyze gene expression, with CCoAOMT and CesA2 identified in all tissue, but expression was highest in RP and relatively low in SP tissue, with significant differences observed. Both genes were preliminarily related to P. armandii growth traits and may be implicated in DBH and tree height. Our study provides important information for the genetic improvement of P. armandii.
We aimed at investigating changes in the expression and physiological function of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in interstitial cells of Cajal (ICC) in diabetic ...state.
Twenty adult female Sprague-Dawley (SD) rats were randomly assigned to control and Zucker diabetic fatty (ZDF) group. The protein and mRNA expression of HCN isoforms and C-kit in the rat bladders were detected using Western blotting and reverse transcription-polymerase chain reaction (RT-PCR). The bladder contraction was evaluated using a bladder smooth muscle strip test. Whole cell patch-clamp techniques were used to detect the activity of HCN channels. Immunofluorescent staining was used to the positive expression of HCN and C-kit in ICC.
cAMP, as HCN channel-specific stimulant, could increase the frequency and amplitude of spontaneous contractions in both group, while cAMP inducing contraction of ZDF rats, was still significantly lower compared with the control group. Acute bladder ICCs were isolated by collagenase digestion. Classic Ih current pattern was recorded on ICCs while Ih current amplitude of ICCs from ZDF diabetic rats was significantly lower than the control group. The expression and mRNA of HCN1-4 isoforms in ZDF diabetic rats were both significantly lower compared with the control group. Meanwhile, the number of c-kit positive cells in ZDF diabetic rats showed no significant differences compared with controls. The morphological structure of ICC in the bladder of ZDF rats was relatively loose and the number of their cell process was apparently decreased.
The structure of ICCs in ZDF rats was relatively loose, their connection to each other was also diminished. The expression of HCN was down-regulated and its response to cAMP was also decreased. HCN channels in bladder ICCs might regulate detrusor contraction. Changes in HCN expression and activity in bladder ICCs might be one of the most important mechanisms of diabetic cystopathy.
This was a post hoc analysis of patients with non-squamous histology from a phase III maintenance pemetrexed study in advanced non-small cell lung cancer (NSCLC).
The six symptom items' average ...symptom burden index (ASBI) mean at baseline was calculated using the lung cancer symptom scale (LCSS). Low and high symptom burden (LSB, ASBI < 25; HSB, ASBI ≥ 25) and performance status (PS: 0, 1) subgroups were analyzed for treatment effect on progression-free survival (PFS) and overall survival (OS) using the Cox proportional hazard models adjusted for demographic/clinical factors.
Significantly longer PFS and OS for pemetrexed versus placebo occurred in LSB patients PFS: median 5.1 versus 2.4 months, hazard ratio (HR) 0.49, P < 0.0001; OS: median 17.5 versus 11.0 months, HR 0.63, P = 0.0012 and PS 0 patients (PFS: median 5.5 versus 1.7 months, HR 0.36, P < 0.0001; OS: median 17.7 versus 10.3 months, HR 0.54, P = 0.0019). Significantly longer PFS, but not OS, occurred in HSB patients (median 3.7 versus 2.8 months, HR 0.50, P = 0.0033) and PS 1 patients (median 4.4 versus 2.8 months, HR 0.60, P = 0.0002).
ASBI and PS are associated with survival for non-squamous NSCLC patients, suggesting that maintenance pemetrexed is useful for LSB or PS 0 patients following induction.
The role of postmastectomy radiotherapy following primary systemic treatment in patients with clinical T1-2N1 breast cancer remains a controversial issue. The purpose of this study was to evaluate ...the benefit of postmastectomy radiotherapy following primary systemic treatment.
Between 2005 and 2012, in two independent institutions, female patients with T1-2N1 breast cancer receiving primary systemic treatment followed by mastectomy and lymph node dissection because bad response, then treated with or without chest wall and regional lymph node irradiation have been studied retrospectively. The patients received normofractionated radiotherapy using 3D conformal photons or electron techniques. Locoregional recurrence-free survival, distant metastasis-free survival and disease-free survival were calculated using Kaplan-Meier method. Univariate analysis of potential prognostic factors was performed using log-rank test.
Eighty-eight patients have been studied. Of them, 75 patients received postmastectomy radiotherapy. At surgery, 53 patients achieved ypN0. Median follow-up was 67 months. Postmastectomy radiotherapy significantly improved locoregional recurrence-free survival, with a 5-year rate of 96.9% versus 78.6% in the group that did not have postmastectomy radiotherapy. In the subgroup of 53 patients achieving ypN0, postmastectomy radiotherapy improved locoregional recurrence-free survival (a 5-year rate of 94.7% vs. 72.9%), distant metastasis-free survival (a 5-year rate of 92.8% vs. 75%) and disease-free survival (a 5-year rate of 92.9% vs. 62.5%). By univariate analysis, postmastectomy radiotherapy was the only significant prognostic factor affecting locoregional recurrence-free survival.
For patients with clinical T1-2N1 disease, postmastectomy radiotherapy could significantly improve locoregional recurrence-free survival after primary systemic treatment and be even more therapeutic in the subgroup of patients with good response for primary systemic treatment by improving locoregional recurrence-free, distant metastasis-free and disease-free survival. Larger prospective studies are needed to confirm our findings.
L’intérêt de la radiothérapie après une chimiothérapie néoadjuvante et une mastectomie chez des patientes atteintes de tumeur de stade T1-2N1 reste parfois discuté. L’objectif de cette étude était d’évaluer le bénéfice de ce traitement dans cette population de patientes.
Entre 2005 et 2012, dans deux hôpitaux, des patientes atteintes d’un cancer du sein de stade T1-2N1 ont été prises en charge par une chimiothérapie néoadjuvante, suivie d’une mastectomie et curage en raison d’une réponse insuffisante. Ensuite, certaines patientes ont reçu une irradiation postopératoire dans la paroi thoracique et d’autres non, selon les protocoles de l’hôpital et leurs désirs. Les patientes qui ont reçu une irradiation, l’ont été dans la paroi thoracique et les ganglions avec des techniques conformationnelles tridimensionnelles de photons et/ou d’électrons. Les taux de survie sans récidive locorégionale, la survie sans métastase et la survie sans maladie ont été calculés selon la méthode de Kaplan-Meier. Le Log rank test a été utilisé pour évaluer les facteurs pronostiques.
Soixante-quinze des 98 patientes ont reçu une irradiation après la mastectomie et le curage. Après la chimiothérapie, 53 cancers étaient de stade ypN0. Le suivi médian était de 67 mois. La radiothérapie postopératoire a amélioré significativement les probabilités de survie sans récidive avec à 5 ans un taux de 94,7 % dans le groupe irradié, contre 72,9 % chez les patientes non irradiées. Les taux de survie sans métastases étaient de 92,8 % chez les patientes irradiées et 75 % chez les patientes non irradiées, ceux de survie sans maladie à 5 ans à respectivement de 92,9 % contre 62,5 %. L’analyse unifactorielle a trouvé comme seul facteur pronostique la radiothérapie postopératoire.
Pour les patientes atteintes de tumeur de stade T1-2N1, après une chimiothérapie néoadjuvante et une mastectomie, la radiothérapie améliore les résultats en termes de contrôle locorégional et de survie. De plus grandes études prospectives sont nécessaires pour confirmer les résultats.
Based on an approximation to Cayley transform, we propose an approximate Cayley transform method and its inexact version for solving inverse eigenvalue problems, which has the advantage over other ...known methods in the sense that it avoids solving systems in obtaining the approximate eigenvectors. Under the nonsingular condition used in D. Sun and J. Sun 29, we show that the proposed methods converge at least superlinearly. Moreover, numerical experiments are given which illustrate that, comparing with the Cayley transform methods, our methods need much less inner iterations and CPU time.
The structural, magnetic and magnetoelastic properties of TbxHo1−xFe1.9Mn0.1 (0.08 ≤ x ≤ 0.16) alloys have been investigated by means of X-ray diffraction (XRD), Mössbauer spectra, a vibrating sample ...magnetometer and a standard strain technique. The easy magnetization direction (EMD) at room temperature rotates continuously from the 〈100〉 axis for x = 0.10 to 〈111〉 for x = 0.14 through an intermediate direction around x = 0.12, subjected to the anisotropy compensation between Tb3+ and Ho3+ ions. The magnetocrystalline-anisotropy compensation can be obtained by performing XRD on magnetic-field aligned powders and by evaluating the EMD, magnetization process and magnetostriction. The compensation point achieved is around x = 0.12, shifting to the Ho-rich side at room temperature compared with the Mn-free system. Mn causes opposite contributions to the resultant anisotropy of the alloys as compared to Ho. A minimum in anisotropy is obtained for the Tb0.12Ho0.88Fe1.9Mn0.1 compound, which has a high low-field magnetostriction (λa ∼ 340 ppm @ 2 kOe).
•EMD is observed by Mössbauer spectra and XRD on magnetic-field aligned powders.•Composition-related anisotropy compensation has been realized.•Mn has an opposite role in magnetocrystalline anisotropy as compared to Ho.•Mn-substitution shifts the composition for anisotropy compensation to Ho-rich side.
We have simulated the performance of heterojunction with intrinsic thin-layer (HIT) solar cells on n-type c-Si substrates using the numerical simulator automat for simulation of heterostructures ...(AFORS-HET), with emphasis on the effect of density of defect states (DOS) in both p-type hydrogenated amorphous silicon ( a -Si:H) emitter and intrinsic a -Si:H buffer layers. A detailed and accurate DOS distribution, including both bandtail states and deep dangling-bond states, has been established in a -Si:H layers based on existing experimental results of a -Si:H films in the literature. The changes of DOS distribution for differently doped thin a -Si:H layers, depending on their doping concentrations (from intrinsic to highly doped), have explicitly been considered. With this DOS distribution model, we have calculated the charge trapped in defect states, which understands the mechanism of trapping effect, i.e., how the DOS influences the built-in field, space-charge region, and the cell performance within HIT solar cell structures. It is found that the DOS in the p-type a -Si:H emitter layer can cause an unfavorable trapping effect, which becomes more serious and even difficult to avoid in case of high doping concentration beyond 1 × 10 20 cm -3 . In contrast, the DOS in the intrinsic a -Si:H buffer layer will not sufficiently suppress the cell output until the density of dangling-bond states reaches 5 × 10 18 cm -3 . This paper presents a clear physical picture for the mechanism of trapping effect and concludes the suggestive DOS required for the high efficiency of HIT cells above 20%.
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