Showing papers by "Mark E. Cooper published in 2012"

A genome-wide association search for type 2 diabetes genes in African Americans.

Abstract: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals

Abstract: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Suppression of microRNA-29 expression by TGF-β1 promotes collagen expression and renal fibrosis.

Abstract: Synthesis and deposition of extracellular matrix (ECM) within the glomerulus and interstitium characterizes renal fibrosis, but the mechanisms underlying this process are incompletely understood. The profibrotic cytokine TGF-β1 modulates the expression of certain microRNAs (miRNAs), suggesting that miRNAs may have a role in the pathogenesis of renal fibrosis. Here, we exposed proximal tubular cells, primary mesangial cells, and podocytes to TGF-β1 to examine its effect on miRNAs and subsequent collagen synthesis. TGF-β1 reduced expression of the miR-29a/b/c/family, which targets collagen gene expression, and increased expression of ECM proteins. In both resting and TGF-β1–treated cells, ectopic expression of miR-29 repressed the expression of collagens I and IV at both the mRNA and protein levels by targeting the 3′untranslated region of these genes. Furthermore, we observed low levels of miR-29 in three models of renal fibrosis representing early and advanced stages of disease. Administration of the Rho-associated kinase inhibitor fasudil prevented renal fibrosis and restored expression of miR-29. Taken together, these data suggest that TGF-β1 inhibits expression of the miR-29 family, thereby promoting expression of ECM components. Pharmacologic modulation of these miRNAs may have therapeutic potential for progressive renal fibrosis.

Methylglyoxal modification of Na v 1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy

Abstract: Glucose and its metabolic derivatives are increased the plasma of patients with diabetes. Peter Nawroth and colleagues demonstrate that one such metabolite, methylglyoxal, is increased in patients with painful diabetic neuropathy, and find that it acts by modifying the excitability characteristics of a sodium channel protein.

A survey of the 2010 quartz crystal microbalance literature

Abstract: In 2010 there has again been an increase in the number of papers published involving piezoelectric acoustic sensors, or quartz crystal microbalances (QCM), when compared to the last period reviewed 2006-2009. The average number of QCM publications per annum was 124 in the period 2001-2005, 223 in the period 2006-9, and 273 in 2010. There are trends towards increasing use of QCM in the study of protein adsorption to surfaces (93% increase), homeostasis (67% increase), protein-protein interactions (40% increase), and carbohydrates (43% increase). New commercial systems have been released that are driving the uptake of the technology for characterisation of binding specificities, affinities, kinetics and conformational changes associated with a molecular recognition event. This article highlights theoretical and practical aspects of the principals that underpin acoustic analysis, then reviews exemplary papers in key application areas involving small molecular weight ligands, carbohydrates, proteins, nucleic acids, viruses, bacteria, cells, and membrane interfaces.

Distinguishing Hyperglycemic Changes by Set7 in Vascular Endothelial Cells

Abstract: Rationale: Epigenetic changes are implicated in the persisting vascular effects of hyperglycemia. The precise mechanism whereby chromatin structure and subsequent gene expression are regulated by glucose in vascular endothelial cells remain to be fully defined. Objective: We have studied the molecular and functional mechanism whereby the Set7 methyltransferase associates with chromatin formation and histone methylation in vascular cells in response to current and previous exposure to glucose. Methods and Results: To characterize the molecular and functional identity of the Set7 protein, we used vascular cells overexpressing or lacking Set7. Chromatin fractionation for mono-methylation of lysine 4 on histone H3 identified methyltransferase activity. Immunofluorescence experiments strongly suggest that Set7 protein accumulates in the nucleus in response to hyperglycemia. Moreover, activation of proinflammatory genes by high glucose is dependent on Set7 but distinguished by H3K4m1 gene patterns. We show that transient hyperglycemia regulates the expression of proinflammatory genes in vascular endothelial cells in vitro and the persistent increase in glucose-induced gene expression in the aorta of nondiabetic mice. Conclusions: This study uncovers that the response to hyperglycemia in vascular endothelial cells involves the H3K4 methyltransferase, Set7. This enzyme appears to regulate glucose-induced chromatin changes and gene expression not only by H3K4m1-dependent but also H3K4m1-independent pathways. Furthermore, Set7 appears to be responsible for sustained vascular gene expression in response to prior hyperglycemia and is a potential molecular mechanism for the phenomenon of hyperglycemic memory.

A Gene Regulatory Network Model for Floral Transition of the Shoot Apex in Maize and Its Dynamic Modeling

Abstract: The transition from the vegetative to reproductive development is a critical event in the plant life cycle. The accurate prediction of flowering time in elite germplasm is important for decisions in maize breeding programs and best agronomic practices. The understanding of the genetic control of flowering time in maize has significantly advanced in the past decade. Through comparative genomics, mutant analysis, genetic analysis and QTL cloning, and transgenic approaches, more than 30 flowering time candidate genes in maize have been revealed and the relationships among these genes have been partially uncovered. Based on the knowledge of the flowering time candidate genes, a conceptual gene regulatory network model for the genetic control of flowering time in maize is proposed. To demonstrate the potential of the proposed gene regulatory network model, a first attempt was made to develop a dynamic gene network model to predict flowering time of maize genotypes varying for specific genes. The dynamic gene network model is composed of four genes and was built on the basis of gene expression dynamics of the two late flowering id1 and dlf1 mutants, the early flowering landrace Gaspe Flint and the temperate inbred B73. The model was evaluated against the phenotypic data of the id1 dlf1 double mutant and the ZMM4 overexpressed transgenic lines. The model provides a working example that leverages knowledge from model organisms for the utilization of maize genomic information to predict a whole plant trait phenotype, flowering time, of maize genotypes.

Oxidative Stress, Nox Isoforms and Complications of Diabetes—Potential Targets for Novel Therapies

Abstract: Most diabetes-related complications and causes of death arise from cardiovascular disease and end-stage renal disease. Amongst the major complications of diabetes mellitus are retinopathy, neuropathy, nephropathy and accelerated atherosclerosis. Increased bioavailability of reactive oxygen species (ROS) (termed oxidative stress), derived in large part from the NADPH oxidase (Nox) family of free radical producing enzymes, has been demonstrated in experimental and clinical diabetes and has been implicated in the cardiovascular and renal complications of diabetes. The present review focuses on the role of Noxs and oxidative stress in some major complications of diabetes, including nephropathy, retinopathy and atherosclerosis. We also discuss Nox isoforms as potential targets for therapy.

Development of Anti-Infectives Using Phage Display: Biological Agents against Bacteria, Viruses, and Parasites

Abstract: The vast majority of anti-infective therapeutics on the market or in development are small molecules; however, there is now a nascent pipeline of biological agents in development. Until recently, phage display technologies were used mainly to produce monoclonal antibodies (MAbs) targeted against cancer or inflammatory disease targets. Patent disputes impeded broad use of these methods and contributed to the dearth of candidates in the clinic during the 1990s. Today, however, phage display is recognized as a powerful tool for selecting novel peptides and antibodies that can bind to a wide range of antigens, ranging from whole cells to proteins and lipid targets. In this review, we highlight research that exploits phage display technology as a means of discovering novel therapeutics against infectious diseases, with a focus on antimicrobial peptides and antibodies in clinical or preclinical development. We discuss the different strategies and methods used to derive, select, and develop anti-infectives from phage display libraries and then highlight case studies of drug candidates in the process of development and commercialization. Advances in screening, manufacturing, and humanization technologies now mean that phage display can make a significant contribution in the fight against clinically important pathogens.

A Comprehensive Review of Everolimus Clinical Reports: A New Mammalian Target of Rapamycin Inhibitor

Abstract: As new immunosuppressive agents are introduced to the market, clinicians are faced with the daunting task of sifting through the published literature to decide the value that the agent will add to their own practice. We often must extrapolate information provided through study in other solid-organ transplantation populations than our specific area of interest as we interpret the results and outcomes. With these challenges in mind, this compilation of published work for the newest mammalian target of rapamycin inhibitor everolimus (Certican; Novartis Pharmaceuticals, Hanover, NJ) (Zortress; Novartis Pharmaceuticals, Basel, Switzerland) is intended to provide a concise but thorough presentation of available literature so that the reader who may be unfamiliar with the agent can make their own judgment. Both Ovid and PubMed search engines were queried with a particular focus on high-impact articles noted in the Web of Science or Citation Index. Work described solely in abstract or case report form was excluded, as well as meta-analyses or those that were editorial or commentary in nature. Included were publications presented using the English language that described adult human subjects who received a heart, lung, kidney, or liver allograft. The goal of this strategy was to allow for the inclusion of pertinent literature in an unbiased fashion. Tables are provided that outline trial specific information, leaving a discussion of major outcomes to the text of the review.

Tumor-suppressor gene promoter hypermethylation in saliva of head and neck cancer patients

Abstract: Head and neck squamous cell carcinoma (HNSCC) accounts for a bulk of the oral and laryngeal cancers, the majority (70%) of which are associated with smoking and excessive drinking, major known risk factors for the development of HNSCC. In contrast to reports that suggest an inverse relationship between smoking and global DNA CpG methylation, hypermethylation of promoters of a number of genes was detected in saliva collected from patients with HNSCC. Using a sensitive methylation-specific polymerase chain reaction (MSP) assay to determine specific methylation events in the promoters of RASSF1A, DAPK1, and p16 genes, we demonstrate that we can detect tumor presence with an overall accuracy of 81% in the DNA isolated from saliva of patients with HNSCC (n = 143) when compared with the DNA isolated from the saliva of healthy nonsmoker controls (n = 31). The specificity for this MSP panel was 87% and the sensitivity was 80%(with a Fisher exact test P < .0001). In addition, the test panel performed extremely well in the detection of the early stages of HNSCCs, with a sensitivity of 94% and a specificity of 87%, and a high. concordance value of 0.8, indicating an excellent overall agreement between the presence of HNSCC and a positive MSP panel result. In conclusion, we demonstrate that the promoter methylation of RASSF1A, DAPK1, and p16 MSP panel is useful in detecting hypermethylation events in a noninvasive manner in patients with HNSCC.

Geochemical record of Holocene to Recent sedimentation on the Western Indus continental shelf, Arabian Sea

Abstract: [1] We present a multiproxy geochemical analysis of two cores recovered from the Indus Shelf spanning the Early Holocene to Recent (<14 ka). Indus-23 is located close to the modern Indus River, while Indus-10 is positioned ∼100 km further west. The Holocene transgression at Indus-10 was over a surface that was strongly weathered during the last glacial sea level lowstand. Lower Holocene sediments at Indus-10 have highereNdvalues compared to those at the river mouth indicating some sediment supply from the Makran coast, either during the deposition or via reworking of older sediments outcropping on the shelf. Sediment transport from Makran occurred during transgressive intervals when sea level crossed the mid shelf. The sediment flux from non-Indus sources to Indus-10 peaked between 11 ka and 8 ka. A hiatus at Indus-23 from 8 ka until 1.3 ka indicates non-deposition or erosion of existing Indus Shelf sequences. HighereNdvalues seen on the shelf compared to the delta imply reworking of older delta sediments in building Holocene clinoforms. Chemical Index of Alteration (CIA), Mg/Al and Sr isotopes are all affected by erosion of detrital carbonate, which reduced through the Holocene. K/Al data suggest that silicate weathering peaked ca. 4–6 ka and was higher at Indus-10 compared to Indus-23. Fine-grained sediments that make up the shelf have geochemical signatures that are different from the coarser grained bulk sediments measured in the delta plain. The Indus Shelf data highlight the complexity of reconstructing records of continental erosion and provenance in marine settings.

Alagebrium Reduces Glomerular Fibrogenesis and Inflammation Beyond Preventing RAGE Activation in Diabetic Apolipoprotein E Knockout Mice

Abstract: Advanced glycation end products (AGEs) are important mediators of diabetic nephropathy that act through the receptor for AGEs (RAGE), as well as other mechanisms, to promote renal inflammation and glomerulosclerosis. The relative contribution of RAGE-dependent and RAGE-independent signaling pathways has not been previously studied in vivo. In this study, diabetic RAGE apoE double-knockout (KO) mice with streptozotocin-induced diabetes were treated with the AGE inhibitor, alagebrium (1 mg/kg/day), or the ACE inhibitor, quinapril (30 mg/kg/day), for 20 weeks, and renal parameters were assessed. RAGE deletion attenuated mesangial expansion, glomerular matrix accumulation, and renal oxidative stress associated with 20 weeks of diabetes. By contrast, inflammation and AGE accumulation associated with diabetes was not prevented. However, treatment with alagebrium in diabetic RAGE apoE KO mice reduced renal AGE levels and further reduced glomerular matrix accumulation. In addition, even in the absence of RAGE expression, alagebrium attenuated cortical inflammation, as denoted by the reduced expression of monocyte chemoattractant protein-1, intracellular adhesion molecule-1, and the macrophage marker cluster of differentiation molecule 11b. These novel findings confirm the presence of important RAGE-independent as well as RAGE-dependent signaling pathways that may be activated in the kidney by AGEs. This has important implications for the design of optimal therapeutic strategies for the prevention of diabetic nephropathy.

Interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes.

Abstract: Local and systemic AngII (angiotensin II) levels are regulated by ACE2 (angiotensin-converting enzyme 2), which is reduced in diabetic tissues. In the present study, we examine the effect of ACE2 deficiency on the early cardiac and vascular changes associated with experimental diabetes. Streptozotocin diabetes was induced in male C57BL6 mice and Ace2-KO (knockout) mice, and markers of RAS (renin‐angiotensin system) activity, cardiac function and injury were assessed after 10 weeks. In a second protocol, diabetes was induced in male ApoE (apolipoprotein E)-KO mice and ApoE/Ace2-double-KO mice, and plaque accumulation and markers of atherogenesis assessed after 20 weeks. The induction of diabetes in wild-type mice led to reduced ACE2 expression and activity in the heart, elevated circulating AngII levels and reduced cardiac Ang(1‐7) [angiotensin-(1‐7)] levels. This was associated structurally with thinning of the LV (left ventricular) wall and mild ventricular dilatation, and histologically with increased cardiomyocyte apoptosis on TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) staining and compensatory hypertrophy denoted by an increased cardiomyocyte cross-sectional area. By contrast Ace2-KO mice failed to increase circulating AngII concentration, experienced a paradoxicalfallincardiacAngIIlevelsandnochangeinAng-(1‐7)following theonsetofdiabetes.At thesametimethemajorphenotypicdifferencesbetweenAce2-deficientandAce2-repletemicewith respect to BP (blood pressure) and cardiac hypertrophy were eliminated following the induction of diabetes. Consistent with findings in the heart, the accelerated atherosclerosis that was observed in diabetic ApoE-KO mice was not seen in diabetic ApoE/Ace2-KO mice, which experienced no further increase in plaque accumulation or expression in key adhesion molecules beyond that seen in ApoE/Ace2-KO mice. These results point to the potential role of ACE2 deficiency in regulating the tissue and circulating levels of AngII and their sequelae in the context of diabetes, as well as the preservation or augmentation of ACE2 expression or activity as a potential therapeutic target for the prevention of CVD (cardiovascular disease) in diabetes.

Activation of the Renin-Angiotensin System Mediates the Effects of Dietary Salt Intake on Atherogenesis in the Apolipoprotein E Knockout Mouse

Abstract: Dietary salt intake is a major determinant of the activation state of renin-angiotensin-aldosterone system. Given the important role of the renin-angiotensin-aldosterone system in plaque accumulation, we investigated its role in the development of atherogenesis associated with sodium intake in apolipoprotein E knockout mice. Six-weeks of a low-salt diet (containing 0.03% sodium) resulted in a 4-fold increase in plaque accumulation in apolipoprotein E knockout mice when compared with mice receiving normal chow (containing 0.30% sodium). This was associated with activation of the renin-angiotensin-aldosterone system, increased vascular expression of adhesion molecules and inflammatory cytokines, and increased adhesion of labeled leukocytes across the whole aorta on a dynamic flow assay. These changes were blocked with the angiotensin-converting enzyme inhibitor perindopril (2 mg/kg per day). A high-salt diet (containing 3% sodium) attenuated vascular inflammation and atherogenesis, associated with suppression of the renin-angiotensin-aldosterone system, although systolic blood pressure levels were modestly increased (5 ± 1 mmHg). Constitutive activation of the renin-angiotensin-aldosterone system in angiotensin-converting enzyme 2 apolipoprotein E knockout mice was also associated with increased atherosclerosis and vascular adhesion, and this was attenuated by a high-salt diet associated with suppression of the renin-angiotensin-aldosterone system. By contrast, a low-salt diet failed to further activate the renin-angiotensin-aldosterone system or to increase atherosclerosis in angiotensin-converting enzyme 2 apolipoprotein E knockout mice. Together, these data validate a relationship between salt-mediated renin-angiotensin-aldosterone system activation and atherogenesis, which may partly explain the inconclusive or paradoxical findings of recent observational studies, despite clear effects on blood pressure.

TNF-related apoptosis-inducing ligand significantly attenuates metabolic abnormalities in high-fat-fed mice reducing adiposity and systemic inflammation

Abstract: TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] has recently been shown to ameliorate the natural history of DM (diabetes mellitus). It has not been determined yet whether systemic TRAIL delivery would prevent the metabolic abnormalities due to an HFD [HF (high-fat) diet]. For this purpose, 27 male C57bl6 mice aged 8 weeks were randomly fed on a standard diet, HFD or HFD+TRAIL for 12 weeks. TRAIL was delivered weekly by intraperitoneal injection. Body composition was evaluated; indirect calorimetry studies, GTT (glucose tolerance test) and ITT (insulin tolerance test) were performed. Pro-inflammatory cytokines, together with adipose tissue gene expression and apoptosis, were measured. TRAIL treatment reduced significantly the increased adiposity associated with an HFD. Moreover, it reduced significantly hyperglycaemia and hyperinsulinaemia during a GTT and it improved significantly the peripheral response to insulin. TRAIL reversed the changes in substrate utilization induced by the HFD and ameliorated skeletal muscle non-esterified fatty acids oxidation rate. This was associated with a significant reduction of pro-inflammatory cytokines together with a modulation of adipose tissue gene expression and apoptosis. These findings shed light on the possible anti-adipogenic and anti-inflammatory effects of TRAIL and open new therapeutic possibilities against obesity, systemic inflammation and T2DM (Type 2 DM).

Identification of antitubercular benzothiazinone compounds by ligand-based design

Abstract: 1,3-Benzothiazin-4-ones (BTZs) are a novel class of TB drug candidates with potent activity against M. tuberculosis. An in silico ligand-based model based on structure–activity data from 170 BTZ compounds was used to design a new series. Compounds were tested against a panel of mycobacterial strains and were profiled for cytotoxicity, stability, and antiproliferative effects. Several of the compounds showed improved activity against MDR-TB while retaining low toxicity with higher microsomal, metabolic, and plasma stability.

Episodic arc-ophiolite emplacement and the growth of continental margins: Late accretion in the Northern Irish sector of the Grampian-Taconic orogeny

Abstract: In order to understand the progressive growth of continental margins and the evolution of continental crust, we must first understand the formation of allochthonous ophiolitic and island-arc terranes within ancient orogens and the nature of their accretion. During the early Paleozoic closure of the Iapetus Ocean, diverse sets of arc terranes, oceanic tracts, and ribbon-shaped microcontinental blocks were accreted to the passive continental margin of Laurentia during the Grampian-Taconic orogeny. In the northern Appalachians in central Newfoundland, Canada, three distinct phases of arc-ophiolite accretion have been recognized. New field mapping, high-resolution airborne geophysics, whole-rock and Nd-isotope geochemistry, and U-Pb zircon geochronology within the Tyrone Volcanic Group of Northern Ireland have allowed all three episodes to now be correlated into the British and Irish Caledonides. The Tyrone Volcanic Group (ca. 475–469 Ma) is characterized by mafic to intermediate lavas, tuffs, rhyolite, banded chert, ferruginous jasperoid, and argillaceous sedimentary rocks cut by numerous high-level intrusive rocks. Geochemical signatures are consistent with formation within an evolving peri-Laurentian island-arc/backarc, which underwent several episodes of intra-arc rifting prior to its accretion at ca. 470 Ma to an outboard peri-Laurentian microcontinental block. Outriding microcontinental blocks played a fundamental role within the orogen, explaining the range of ages for Iapetan ophiolites and the timing of their accretion, as well as discrepancies between the timing of ophiolite emplacement and the termination of the Laurentian Cambrian–Ordovician shelf sequences. Accretion of the Tyrone arc and its associated suprasubduction-zone ophiolite represents the third stage of arc-ophiolite emplacement to the Laurentian margin during the Grampian-Taconic orogeny in the British and Irish Caledonides.

Drug-likeness and increased hydrophobicity of commercially available compound libraries for drug screening.

Abstract: Most drug discovery programs today originate by selection of 'hit' molecules resulting from assays against large compound screening libraries. The chemical space in which these hits reside has implications for its biological activity in vivo and likelihood of progression to a drug candidate. We have created a database of commercially available screening compounds and natural products in order to analyse the drug- and lead-likeness of commercial screening compounds and compare them with i) orally administered drugs, ii) non-orally administered drugs, and iii) compounds with significant biological activity but unspecified or not yet determined route of administration from the public databases DrugBank and ChEMBL. The data set contained 15.5 million entries from 102 vendors, which resulted in just over 8 million unique chemical structures. We review these data for current drug/lead-likeness, then utilise substructure-based filters for promiscuity and unwanted groups, and finally compare chemical properties for structures within the different sub-sets. While the majority of the commercial compounds satisfy various drug-likeness rules, they show a larger molecular weight and higher hydrophobicity compared to orally available drugs, with generally higher aromaticity and lower solubility. This 'right shift' of chemical properties has also been found in the majority of the compounds with significant biological activity in ChEMBL, reflecting a common trend in current drug discovery, towards larger, more hydrophobic compounds and fewer drug-like compounds. In particular, successful drugs were found to possess much lower median logD values than those found for compound collections. In addition, commercial compounds show a quite narrow distribution in molecular weight, with a median absolute deviation of only 78 Da around a median of 387 Da. For high-throughput screening a highly stringent combination of several lead-likeness and substructure filters against unwanted groups could be applied, resulting in 2 million lead-like structures. For fragment based screening approaches the rule of three (Ro3) would select around 400,000 structures.

Diabetes: treating diabetic nephropathy-still an unresolved issue.

Abstract: Whether treatment of hyperglycaemia prevents progression of diabetic nephropathy is controversial. Intensive glycaemic control reduces the risk of microalbuminuria and macroalbuminuria, but there is no clear-cut evidence showing that it reduces doubling of serum creatinine levels or risk of death from kidney disease. Larger studies or further follow-up of previous trials are required to better assess renal outcomes.

Using label-free screening technology to improve efficiency in drug discovery

Abstract: Introduction: Screening assays have traditionally utilized reporter labels to quantify biological responses relevant to the disease state of interest. However, there are limitations associated with the use of labels that may be overcome with temporal measurements possible with label-free. Areas covered: This review comprises general and system-specific information from literature searches using PubMed, published books and the authors' personal experience. This review highlights the label-free approaches in the context of various applications. The authors also note technical issues relevant to the development of label-free assays and their application to HTS. Expert opinion: The limitations associated with the use of transfected cell lines and the use of label-based assays are gradually being realized. As such, greater emphasis is being placed on label-free biophysical techniques using native cell lines. The introduction of 96- and 384-well plate label-free systems is helping to broker a wider acceptance o...

Impact of the Reelin signaling cascade (ligands-receptors-adaptor complex) on cognition in schizophrenia.

Abstract: Our previous neurocognitive studies of schizophrenia outlined two clusters of affected subjects-cognitively spared (CS) and cognitive deficit (CD), the latter's characteristics pointing to developmental origins and impaired synaptic plasticity. Here we investigate the contribution of polymorphisms in major regulators of these processes to susceptibility to schizophrenia and to CD in patients. We examine variation in genes encoding proteins at the gateway of Reelin signaling: ligands RELN and APOE, their common receptors APOER2 and VLDLR, and adaptor DAB1. Association analysis with disease outcome and cognitive performance in the Western Australian Family Study of Schizophrenia (WAFSS) was followed by replication analysis in the Australian Schizophrenia Research Bank (ASRB) and in the Health in Men Study (HIMS) of normal aging males. In the WAFSS sample, we observed significant association of APOE, APOER2, VLDLR, and DAB1 SNPs with disease outcome in the case-control and CD-control datasets, and with pre-morbid intelligence and verbal memory in cases. HIMS replication analysis supported rs439401 (APOE regulatory region), and rs2297660 and rs3737983 (APOER2), with an effect on memory performance in normal aging subjects consistent with the findings in schizophrenia cases. APOER2 gene expression analysis revealed lower transcript levels in lymphoblastoid cells from cognitively impaired schizophrenia patients of the alternatively spliced exon 19, mediating Reelin signaling and synaptic plasticity in the adult brain. ASRB replication analysis produced marginally significant results, possibly reflecting a recruitment strategy biased toward CS patients. The data suggest a contribution of neurodevelopmental/synaptic plasticity genes to cognitive impairment in schizophrenia.

Molecular characterization of lipopolysaccharide binding to human α-1-acid glycoprotein

Abstract: The ability of AGP to bind circulating lipopolysaccharide (LPS) in plasma is believed to help reduce the proinflammatory effect of bacterial lipid A molecules Here, for the first time we have characterized human AGP binding characteristics of the LPS from a number of pathogenic Gram-negative bacteria: Escherichia coli, Salmonella typhimurium, Klebsiella pneumonia, Pseudomonas aeruginosa, and Serratia marcescens The binding affinity and structure activity relationships (SAR) of the AGP-LPS interactions were characterized by surface plasma resonance (SPR) In order to dissect the contribution of the lipid A, core oligosaccharide and O-antigen polysaccharide components of LPS, the AGP binding affinity of LPS from smooth strains, were compared to lipid A, Kdo2-lipid A, R(a), R(d), and R(e) rough LPS mutants The SAR analysis enabled by the binding data suggested that, in addition to the important role played by the lipid A and core components of LPS, it is predominately the unique species- and strain-specific carbohydrate structure of the O-antigen polysaccharide that largely determines the binding affinity for AGP Together, these data are consistent with the role of AGP in the binding and transport of LPS in plasma during acute-phase inflammatory responses to invading Gram-negative bacteria