Biology-inspired synthesis of compound libraries

Biologically active small molecules represent the basis for chemical biology applications in which small molecules are used as chemical tools to probe biological processes. In this report, we review two approaches to design and synthesize compound libraries for biological screenings, i.e., diversity-oriented synthesis (DOS) and biology-oriented synthesis (BIOS). Received 23 October 2007; received after revision 26 November 2007; accepted 28 November 2007     

Role of a novel photopigment,melanopsin, in behavioral adaptation to light

Adaptation to changes in the ambient light is of critical importance to life. In mammals, three principal photoadaptation mechanisms depend on ocular photoreception and exhibit spectral sensitivity suggestive of the opsin class of photopigment(s). These include rapid adaptation of the visual system to the ambient light by pupil constriction, direct modulation of neuroendocrine function and entrainment of the circadian clock to the day:night cycle. Surprisingly, these processes can largely function independent of classical rod/cone photoreceptors, suggesting a novel opsin-based signaling mechanism. They appear to involve a recently discovered network of intrinsically photosensitive retinal ganglion cells that make direct or indirect axonal connections to brain centers regulating photoadaptive behaviors. The discovery of a novel opsin, melanopsin, in these cells has offered an exciting entry point to explore, at the molecular level, how mammals adapt to their light environment. There is now genetic proof of a principal role for melanopsin in all three major photoadaptation processes.     

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10?12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10?11) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10??) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10?11) and a tag SNP for NAT2 acetylation status (P = 4 × 10?11), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.     

中国公路沥青路面水损害气候影响分区方案

为了了解中国气候条件对沥青路面水损害的影响情况,对沥青路面水损害研究成果进行了回顾与分析,认为影响沥青路面水损害的主要气候因素为:降水、高温以及冻融循环过程.降水与高温过程组合以及降水与冻融循环过程组合是影响沥青路面水损害的两个主要气候过程.针对这两个主要气候过程,构建了降水气温指数和降水冰冻指数,用于评价上述气候过程对沥青路面水损害的影响.分析结果表明:利用降水气温指数和降水冰冻指数划分中国公路沥青路面水损害气候影响分区是合理可行的;根据各个气候指数的工程意义和等概率原则,确定了分区界限,拟定了包含14个区的分区方案.     

Structural basis for Duffy recognition by the malaria parasite Duffy-binding-like domain

Molecular processes that govern pathogenic features of erythrocyte invasion and cytoadherence in malaria are reliant on Plasmodium-specific Duffy-binding-like domains (DBLs). These cysteine-rich modules recognize diverse host cell-surface receptors during pathogenesis. DBLs of parasite erythrocyte-binding proteins mediate invasion, and those from the antigenically variant P. falciparum erythrocyte membrane protein 1 (PfEMP1) have been implicated in cytoadherence. The simian and human malarial parasites, P. knowlesi and P. vivax, invade human erythrocytes exclusively through the host DARC receptor (Duffy antigen receptor for chemokines). Here we present the crystal structure of the P. knowlesi DBL domain (Pkalpha-DBL), which binds to DARC during invasion of human erythrocytes. Pkalpha-DBL retains the overall fold observed in DBLs from P. falciparum erythrocyte-binding antigen (EBA)-175 (ref. 4). Mapping the residues that have previously been implicated in binding highlights a fairly flat but exposed site for DARC recognition in subdomain 2 of Pkalpha-DBL; this is in sharp contrast to receptor recognition by EBA-175 (ref. 4). In Pkalpha-DBL, the residues that contact DARC and the clusters of residues under immune pressure map to opposite surfaces of the DBL, and suggest a possible mechanism for immune evasion by P. vivax. Our comparative structural analysis of Pkalpha-DBL and P. falciparum EBA-175 provides a framework for the understanding of malaria parasite DBLs, and may affect the development of new prophylactic and therapeutic strategies.     

Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy

In pregnancy, trophoblast invasion and uterine spiral artery remodelling are important for lowering maternal vascular resistance and increasing uteroplacental blood flow. Impaired spiral artery remodelling has been implicated in pre-eclampsia, a major complication of pregnancy, for a long time but the underlying mechanisms remain unclear. Corin (also known as atrial natriuretic peptide-converting enzyme) is a cardiac protease that activates atrial natriuretic peptide (ANP), a cardiac hormone that is important in regulating blood pressure. Unexpectedly, corin expression was detected in the pregnant uterus. Here we identify a new function of corin and ANP in promoting trophoblast invasion and spiral artery remodelling. We show that pregnant corin- or ANP-deficient mice developed high blood pressure and proteinuria, characteristics of pre-eclampsia. In these mice, trophoblast invasion and uterine spiral artery remodelling were markedly impaired. Consistent with this, the ANP potently stimulated human trophoblasts in invading Matrigels. In patients with pre-eclampsia, uterine Corin messenger RNA and protein levels were significantly lower than that in normal pregnancies. Moreover, we have identified Corin gene mutations in pre-eclamptic patients, which decreased corin activity in processing pro-ANP. These results indicate that corin and ANP are essential for physiological changes at the maternal-fetal interface, suggesting that defects in corin and ANP function may contribute to pre-eclampsia.     

Epigenetic choreography of stem cells: the DNA demethylation episode of development

Reversible DNA methylation is a fundamental epigenetic manipulator of the genomic information in eukaryotes. DNA demethylation plays a very significant role during embryonic development and stands out for its contribution in molecular reconfiguration during cellular differentiation for determining stem cell fate. DNA demethylation arbitrated extensive make-over of the genome via reprogramming in the early embryo results in stem cell plasticity followed by commitment to the principal cell lineages. This article attempts to highlight the sequential phases and hierarchical mode of DNA demethylation events during enactment of the molecular strategy for developmental transition. A comprehensive knowledge regarding the pattern of DNA demethylation during embryogenesis and organogenesis and study of the related lacunae will offer exciting avenues for future biomedical research and stem cell-based regenerative therapy.     

Fractional-order model of the disease Psoriasis: A control based mathematical approach

Autoimmune diseases are generated through irregular immune response of the human body. Psoriasis is one type of autoimmune chronic skin diseases that is differentiated by T-Cells mediated hyper-proliferation of epidermal Keratinocytes. Dendritic Cells and CD8⁺ T-Cells have a significant role for the occurrence of this disease. In this paper, the authors have developed a mathematical model of Psoriasis involving CD4⁺ T-Cells, Dendritic Cells, CD8⁺ T-Cells and Keratinocyte cell populations using the fractional differential equations with the effect of Cytokine release to observe the impact of memory on the cell-biological system. Using fractional calculus, the authors try to explore the suppressed memory, associated with the cell-biological system and to locate the position of Keratinocyte cell population as fractional derivative possess non-local property. Thus, the dynamics of Psoriasis can be predicted in a better way using fractional differential equations rather than its corresponding integer order model. Finally, the authors introduce drug into the system to obstruct the interaction between CD4⁺ T-Cells and Keratinocytes to restrict the disease Psoriasis. The authors derive the Euler-Lagrange conditions for the optimality of the drug induced system. Numerical simulations are made through Matlab by developing iterative schemes.