New approaches to disease mapping in admixed populations

Admixed populations such as African Americans and Hispanic Americans are often medically underserved and bear a disproportionately high burden of disease. Owing to the diversity of their genomes, these populations have both advantages and disadvantages for genetic studies of complex phenotypes. Advances in statistical methodologies that can infer genetic contributions from ancestral populations may yield new insights into the aetiology of disease and may contribute to the applicability of genomic medicine to these admixed population groups.     

Discovery of 3-hydroxy-4-cyano-isoquinolines as novel, potent, and selective inhibitors of human 11β-hydroxydehydrogenase 1 (11β-HSD1)

Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11β-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.     

MicroDSC study of Staphylococcus epidermidis growth

Background  

A microcalorimetric study was carried out using a Staphylococcus epidermidis population to determine the reproducibility of bacterial growth and the variability of the results within certain experimental parameters (temperature, bacterial concentration, sample thermal history). Reproducibility tests were performed as series of experiments within the same conditions using either freshly prepared populations or samples kept in cold storage. In both cases, the samples were obtained by serial dilution from a concentrated TSB bacterial inoculum incubated overnight.     

NADH oxidase activity of Bacillus subtilis nitroreductase NfrA1: Insight into its biological role

NfrA1 nitroreductase from the Gram-positive bacterium Bacillus subtilis is a member of the NAD(P)H/FMN oxidoreductase family. Here, we investigated the reactivity, the structure and kinetics of NfrA1, which could provide insight into the unclear biological role of this enzyme. We could show that NfrA1 possesses an NADH oxidase activity that leads to high concentrations of oxygen peroxide and an NAD⁺ degrading activity leading to free nicotinamide. Finally, we showed that NfrA1 is able to rapidly scavenge H₂O₂ produced during the oxidative process or added exogenously.

Structured summary

MINT-7990140: nfrA1 (uniprotkb:P39605) and nfrA1 (uniprotkb:P39605) bind (MI:0407) by X-ray crystallography (MI:0114)     

miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response

Although there is evidence that redox regulation has an essential role in malignancies, its impact on tumor prognosis remains unclear. Here we show crosstalk between oxidative stress and the miR-200 family of microRNAs that affects tumorigenesis and chemosensitivity. miR-141 and miR-200a target p38α and modulate the oxidative stress response. Enhanced expression of these microRNAs mimics p38α deficiency and increases tumor growth in mouse models, but it also improves the response to chemotherapeutic agents. High-grade human ovarian adenocarcinomas that accumulate miR-200a have low concentrations of p38α and an associated oxidative stress signature. The miR200a-dependent stress signature correlates with improved survival of patients in response to treatment. Therefore, the role of miR-200a in stress could be a predictive marker for clinical outcome in ovarian cancer. In addition, although oxidative stress promotes tumor growth, it also sensitizes tumors to treatment, which could account for the limited success of antioxidants in clinical trials.     

Identification of Treponema denticola in subgingival samples by PCR technology and its correlation with clinical diagnosis

Treponema denticola has been associated with gingivitis and chronic periodontitis. The aim of this study was to identify Treponema denticola in subgingival samples using PCR technology and to correlate it with clinical diagnosis of subjects. The study was carried out on seventy patients (20-84 years of age; mean age, 45.06 +/- 12.58) of which 22 individuals with no detectable gingivitis or periodontitis, 4 subjects with chronic gingivitis and 44 subjects with chronic periodontitis. Subgingival plaque samples were collected from five sites in each patient. DNA was extracted from the samples using QIAamp DNA Mini Kit (QIAGEN). Treponema denticola and other four periodontopathogens were found using multiplex polymerase chain reaction followed by a reverse hybridization. The relationship between clinical diagnoses and detection of Treponema denticola was determined with Fisher exact test. The results showed significant differences between diagnostic groups regarding subject proportion. Treponema denticola was detected in 2 out of 22 subjects with no detectable gingivitis or periodontitis, 2 out of 4 subjects with chronic gingivitis, and 40 out of 44 subjects with chronic periodontitis. Our findings suggest that Treponema denticola is closely connected to the initiation and progression of periodontal disease.     

Hepatitis B, C and D coinfection in HIV-infected patients: prevalence and progress

The HAART therapy has improved life expectancy enabling long latency conditions caused by the hepatitis viruses that became the leading cause of death in HIV infected patients. In this study a group of 300 patients aged from 18 to 63 years were selected in order to assess the prevalence and consequences of HIV and the hepatitis B (HBV), C (HCV) and D (HDV) viruses coinfections. Study groups were designed for each coinfection. These groups were in turn divided in case groups formed of coinfected participants and control groups consisting of mono-infected participants. This classification was obtained by testing the participants for the presence of specific infection markers using the ELISA technique. As a result, in regard to the HIV/HBV coinfection the study group consisted of 16 coinfected participants and 114 HBV-infected participants resulting in a prevalence of the coinfection of 14%. In the case of the HIV/HDV coinfection the study group consisted of 5 coinfected participants and 45 HDV-infected participants. The prevalence of the HIV/HCV coinfection was 25% out of the 170 HCV-infected participants. The effect of the coinfections on the expression and levels of the infection markers was analyzed in constrast to those encountered in the case of the mono-infection. The observed changes in the expression of the specific hepatitis markers indicate the impact of the coinfection with HIV on the progression of the hepatitis infections. In addition, the inadequate immune response towards the hepatitis viruses in the case of the coinfected participants leads to the development of cirrhosis and end stage liver disease.     

Probing field-induced tissue polarization using transillumination fluorescent imaging

Despite major successes of biophysical theories in predicting the effects of electrical shocks within the heart, recent optical mapping studies have revealed two major discrepancies between theory and experiment: 1), the presence of negative bulk polarization recorded during strong shocks; and 2), the unexpectedly small surface polarization under shock electrodes. There is little consensus as to whether these differences result from deficiencies of experimental techniques, artifacts of tissue damage, or deficiencies of existing theories. Here, we take advantage of recently developed near-infrared voltage-sensitive dyes and transillumination optical imaging to perform, for the first time that we know of, noninvasive probing of field effects deep inside the intact ventricular wall. This technique removes some of the limitations encountered in previous experimental studies. We explicitly demonstrate that deep inside intact myocardial tissue preparations, strong electrical shocks do produce considerable negative bulk polarization previously inferred from surface recordings. We also demonstrate that near-threshold diastolic field stimulation produces activation of deep myocardial layers 2-6 mm away from the cathodal surface, contrary to theory. Using bidomain simulations we explore factors that may improve the agreement between theory and experiment. We show that the inclusion of negative asymmetric current can qualitatively explain negative bulk polarization in a discontinuous bidomain model.     

Genetic diversity of ornamentalAllium species and cultivars assessed with isozymes

The aim of the study was to verify the similarity of 13 species and 5 cultivars of ornamental alliums and classify them into groups based on morphological and isozyme variation. The work embraced: Allium aflatunense, A. caeruleum, A. christophii, A. giganteum, A. karataviense, A. moly, A. nigrum, A. pyrenaicum, A. rosenbachianum, A. schubertii, A. siculum (syn. Nectaroscordum siculum), A. sphaerocephalon, A. strictum, A. stipitatum 'Album', A. 'Ivory Queen', A. 'Lucy Ball', A. 'Mont Blanc', and A. 'Purple Sensation'. Scape length, inflorescence diameter, and flowering period were recorded. Isozyme marker polymorphism was assessed by starch gel electrophoresis. Eight polymorphic isozyme systems (AAT, GPI, PGM, ALAT, ACP, DIAP, ALDO, PGD) were selected from 16 analysed in the taxa. Besides the differences between the taxa, the isozymes revealed intraspecific polymorphism in 5 systems. A total of 37 markers were obtained and used for dendrogram construction. The most similar taxa were A. karataviense with A. 'Ivory Queen', and A. karataviense with A. christophii (similarity level 0.78). A high similarity of 11 taxa belonging to one group (A. aflatunense, A. christophii, A. giganteum, A. karataviense, A. nigrum, A. schubertii, A. 'Ivory Queen', A. 'Lucy Ball', A. stipitatum 'Album', A. 'Mont Blanc', A. 'Purple Sensation') suggested that this group could be identified with the subgenus Melanocrommyum.     

A comparison of the levels of hepatocyte growth factor in serum in patients with type 1 diabetes mellitus with different stages of diabetic retinopathy

INTRODUCTION: The aim of this study was to evaluate the blood concentration of hepatocyte growth factor (HGF) in patients at various stages of retinopathy. We hypothesised that the high level of HGF found in diabetic patients may be an important marker of retinopathy progression and that HGF level may be an index of the risk of proliferative retinopathy. MATERIAL AND METHODS: The participants in the study were 76 patients with type 1 diabetes mellitus. Of these, 35 patients were without retinopathy and formed Group 1. Of the remaining 41 patients with retinopathy, 20 patients had non-proliferative diabetic retinopathy (NPDR) and formed Group 2, while 21 patients had proliferative diabetic retinopathy (PDR) and formed Group 3. We evaluated the concentration of HGF In the peripheral blood by an enzyme-linked immunosorbent assay. RESULTS: Mean serum concentrations of HGF in the control group were significantly lower than in the type 1 diabetic patients. We found a significant increase in HGF serum concentrations in diabetic patients with PDR compared with the control group. Mean serum HGF concentrations were significantly higher in diabetic subjects with PDR than in diabetic patients without retinopathy. CONCLUSION: HGF concentration is increased in patients with type 1 diabetes mellitus with proliferative retinopathy, and concentrations increase with the progression of retinopathy, suggesting that HGF plays a role in the pathogenesis of proliferative diabetic retinopathy.