An Ultrasensitive and Multispectral Refractive Index Sensor Design Based on Quad-Supercell Metamaterials

Plasmonics - Plasmonic metamaterials support the localized surface plasmon resonance (LSPR), which is sensitive to the change in the dielectric environment and highly desirable for ultrasensitive...     

Structure-activity relationship of pyrrole based S-nitrosoglutathione reductase inhibitors: carboxamide modification

The enzyme S-nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, gastrointestinal, and cardiovascular systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently in clinical development for acute asthma. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogs of N6022 focusing on carboxamide modifications on the pendant N-phenyl moiety. We have identified potent and novel GSNOR inhibitors that demonstrate efficacy in an ovalbumin (OVA) induced asthma model in mice.     

Discovery of novel 20S proteasome inhibitors by rational topology-based scaffold hopping of bortezomib

A series of structurally novel proteasome inhibitors 1–12 have been developed based rational topology-based scaffold hopping of bortezomib. Among these novel proteasome inhibitors, compound 10 represents an important advance due to the comparable proteasome-inhibitory activity (IC₅₀?=?9.7?nM) to bortezomib (IC₅₀?=?8.3?nM), the remarkably higher BEI and SEI values and the effectiveness in metabolic stability. Therefore, compound 10 provides an excellent lead suitable for further optimization.     

果袋类型对‘紫金红霞’葡萄果实品质及花色苷合成相关基因表达的影响

以‘紫金红霞’葡萄为试验材料,在果实转色前分别进行5种不同类型果袋(白色纸袋、无纺布 白纸双层袋、绿色纸袋、蓝色纸袋、棕色纸袋)套袋处理,以不套袋为对照,测定不同发育时期葡萄果实的单果重、果粒纵横径、可溶性固形物、可滴定酸,及总花色苷含量等生理指标,并利用qRT PCR技术分析不同发育时期花色苷合成相关基因的表达水平,探索不同类型果袋对‘紫金红霞’葡萄果实品质、花色苷含量及花色苷合成相关基因表达的影响。结果表明：(1)白色、蓝色和棕色果袋不利于成熟果实中可溶性固形物含量的升高,蓝色和棕色果袋不利于成熟果实中可滴定酸含量的降低。(2)套袋处理会使果实色泽指数显著降低,除无纺布 白纸双层袋未显著降低成熟期果皮中花色苷含量外,其他套袋处理均显著降低了果皮中总花色苷含量。(3)套袋处理对6个花色苷合成相关基因的表达主要表现为抑制作用,但无纺布 白纸双层袋对成熟期F3′H和UFGT基因的表达、白色纸袋对成熟期MYBA1、DFR和LDOX基因的表达则具有促进作用。研究发现,无纺布 白纸双层袋对成熟期果实的内在品质和果皮着色影响最小,可用于‘紫金红霞’果实套袋,其次为白色和绿色纸袋;蓝色和棕色纸袋可使葡萄果实的品质大幅降低,故不可用于实际生产中葡萄果实的套袋。     

A hierarchical method for molecular docking using cloud computing

Discovering small molecules that interact with protein targets will be a key part of future drug discovery efforts. Molecular docking of drug-like molecules is likely to be valuable in this field; however, the great number of such molecules makes the potential size of this task enormous. In this paper, a method to screen small molecular databases using cloud computing is proposed. This method is called the hierarchical method for molecular docking and can be completed in a relatively short period of time. In this method, the optimization of molecular docking is divided into two subproblems based on the different effects on the protein–ligand interaction energy. An adaptive genetic algorithm is developed to solve the optimization problem and a new docking program (FlexGAsDock) based on the hierarchical docking method has been developed. The implementation of docking on a cloud computing platform is then discussed. The docking results show that this method can be conveniently used for the efficient molecular design of drugs.     

COMMD1 expression is controlled by critical residues that determine XIAP binding

COMMD {COMM [copper metabolism Murr1 (mouse U2af1-rs1 region 1)] domain-containing} proteins participate in several cellular processes, ranging from NF-kappaB (nuclear factor kappaB) regulation, copper homoeostasis, sodium transport and adaptation to hypoxia. The best-studied member of this family is COMMD1, but relatively little is known about its regulation, except that XIAP [X-linked IAP (inhibitor of apoptosis)] functions as its ubiquitin ligase. In the present study, we identified that the COMM domain of COMMD1 is required for its interaction with XIAP, and other COMMD proteins can similarly interact with IAPs. Two conserved leucine repeats within the COMM domain were found to be critically required for XIAP binding. A COMMD1 mutant which was unable to bind to XIAP demonstrated a complete loss of basal ubiquitination and great stabilization of the protein. Underscoring the importance of IAP-mediated ubiquitination, we found that long-term expression of wild-type COMMD1 results in nearly physiological protein levels as a result of increased ubiquitination, but this regulatory event is circumvented when a mutant form that cannot bind XIAP is expressed. In summary, our findings indicate that COMMD1 expression is controlled primarily by protein ubiquitination, and its interaction with IAP proteins plays an essential role.     

Embryo vaccination against Eimeria tenella and E. acervulina infections using recombinant proteins and cytokine adjuvants

Avian coccidiosis is an intestinal disease caused by protozoa of the genus Eimeria. To investigate the potential of recombinant protein vaccines to control coccidiosis, we cloned 2 Eimeria sp. genes (EtMIC2 and 3-1E), expressed and purified their encoded proteins, and determined the efficacy of in ovo immunization to protect against Eimeria infections. Immunogen-specific serum antibody titers, parasite fecal shedding, and body weight gains were measured as parameters of disease. When administered alone, the recombinant EtMIC2 gene product induced significantly higher antibody responses, lower oocyst fecal shedding, and increased weight gains compared with nonvaccinated controls following infection with E. tenella. Combined embryo immunization with the EtMIC2 protein plus chicken cytokine or chemokine genes demonstrated that all 3 parameters of vaccination were improved compared with those of EtMIC2 alone. In particular, covaccination with EtMIC2 plus interleukin (IL)-8, IL-16, transforming growth factor-beta4, or lymphotactin significantly decreased oocyst shedding and improved weight gains beyond those achieved by EtMIC2 alone. Finally, individual vaccination with either EtMIC2 or 3-1E stimulated protection against infection by the heterologous parasite E. acervulina. Taken together, these results indicate that in ovo vaccination with the EtMIC2 protein plus cytokine/chemokine genes may be an effective method to control coccidiosis.     

Association of GSTP1 Ile105Val Polymorphism and Risk of Head and Neck Cancers: A Meta-Analysis of 28 Case-Control Studies

Background and Aims

The Glutathione S-transferase P1 (GSTP1) polymorphism have been considered a risk modifier for developing head and neck cancer (HNC) in many studies; however, the results of such studies are inconsistent. The aim of this study was to evaluate the possible association between the GSTP1 Ile105Val polymorphism and risk of HNC.

Method

We performed a search in the relevant electronic database and a meta-analysis based on 28 published case–control studies that included 6,404 cases and 6,523 controls. To take into account the possibility of heterogeneity across the studies, a Chi-square based I²-statistic test was performed. Crude pooled odds ratios (ORs) with 95% confidence intervals (CIs) were assessed using both fixed-effects and random-effects models.

Results

The results of this meta-analysis showed that the GSTP1 Ile105Val polymorphism was not significantly associated with risk of HNC in the overall study population (pooled OR 1.00, 95% CI 0.92–1.09) or in subgroup analyses stratified by ethnicity, sample size, tumor site or publication year. Moreover, substantial evidence of heterogeneity among the studies was observed. Publication year was identified as the main cause of heterogeneity.

Conclusion

This meta-analysis does not support a significant association between the GSTP1 Ile105Val polymorphism and risk of HNC.     

安徽东至华龙洞出土的人类化石

2006年在安徽省东至县华龙洞发现了1枚人类下颌第二臼齿和2件可以拼接在一起的额骨碎片化石。根据华龙洞动物群组成及地层情况,初步确定华龙洞化石层的时代为更新世中期。本文对在华龙洞发现的人类头骨和牙齿化石的形态特征进行了观测,并与相关古人类标本进行了对比。研究发现:华龙洞人额骨和下颌臼齿都呈现出一系列常见于东亚直立人的特征。华龙洞额骨曲度较小,具有粗壮的颞线和较厚的骨壁。此外,华龙洞额骨还具有额中缝结构和扩大的额窦。华龙洞下颌第二臼齿总体显得比较粗壮。齿冠咬合面具有第五尖、第六尖和第七尖。齿冠尺寸明显大于早期现代人、现代人类和欧洲更新世中期人类,位于直立人变异范围。结合对华龙洞人类额骨和牙齿形态对比所揭示的形态特点,在华龙洞发现的人类化石可能代表着生活在更新世中期的直立人。     

Mechanism of inhibition for N6022, a first-in-class drug targeting S-nitrosoglutathione reductase

N6022 is a novel, first-in-class drug with potent inhibitory activity against S-nitrosoglutathione reductase (GSNOR), an enzyme important in the metabolism of S-nitrosoglutathione (GSNO) and in the maintenance of nitric oxide (NO) homeostasis. Inhibition of GSNOR by N6022 and related compounds has shown safety and efficacy in animal models of asthma, chronic obstructive pulmonary disease, and inflammatory bowel disease [Sun, X., et al. (2011) ACS Med. Chem. Lett. 2, 402-406]. N6022 is currently in early phase clinical studies in humans. We show here that N6022 is a tight-binding, specific, and fully reversible inhibitor of GSNOR with an IC(50) of 8 nM and a K(i) of 2.5 nM. We accounted for the fact that the NAD(+)- and NADH-dependent oxidation and reduction reactions, catalyzed by GSNOR are bisubstrate in nature in our calculations. N6022 binds in the GSNO substrate binding pocket like a competitive inhibitor, although in kinetic assays it behaves with a mixed uncompetitive mode of inhibition (MOI) toward the GSNO substrate and a mixed competitive MOI toward the formaldehyde adduct, S-hydroxymethylglutathione (HMGSH). N6022 is uncompetitive with cofactors NAD(+) and NADH. The potency, specificity, and MOI of related GSNOR inhibitor compounds are also reported.