Structural Substrate Conditions Required for Neutral Endopeptidase-Mediated Natriuretic Peptide Degradation

Natriuretic peptides are cyclic vasoactive peptide hormones with great diagnostic and therapeutic relevance. The main catabolic pathway postulated for natriuretic peptides is the degradation by neutral endopeptidase (NEP). However, B-type natriuretic peptide has been found to be resistant to NEP. Here, we compared the degradation of various mature, truncated, and recombinant natriuretic peptides by NEP. The degradation was clearly dependent on the length of the N- or C-terminus as well as on distinct sequence differences within the essential loop structure of the natriuretic peptides. Based on these findings, we developed a model for the interaction of NEP and natriuretic peptides that enables new insights into the mode of action and prediction of substrates of NEP, a peptidase that plays a key role in crucial (patho-) physiological processes.     

Lactam based 7-amino suberoylamide hydroxamic acids as potent HDAC inhibitors

A series of SAHA-like molecules were prepared introducing different lactam-carboxyamides in position 7 of the suberoylanilide skeleton. The activity against different HDAC isoforms was tested and the data compared with the corresponding linear products, without substituent in position 7. In general, this modification provided an effective reinforcement of in vitro activity. While the lactam size or the CO/NH group orientation did not strongly influence the inhibition, the contemporary modification of the suberoylamide fragment gave vary active variants in the lactam series, with compound 28 (ST8078AA1) that showed IC₅₀ values between 2 and 10 nM against all Class I HDAC isoforms, demonstrating it to be a large spectrum pan-inhibitor. This strong affinity with HDAC was also confirmed by the value of IC₅₀ = 0.5 μM against H460 cells, ranking 28 as one of the most potent HDAC inhibitors described so far.     

Lactam sulfonamides as potent inhibitors of the Kv1.5 potassium ion channel

A series of lactam sulfonamides has been discovered and optimized as inhibitors of the Kv1.5 potassium ion channel for treatment of atrial fibrillation. In vitro structure–activity relationships from lead structure C to optimized structure 3y are described. Compound 3y was evaluated in a rabbit PD-model and was found to selectively prolong the atrial effective refractory period at submicromolar concentrations.     

Boosted Beta Regression

Regression analysis with a bounded outcome is a common problem in applied statistics. Typical examples include regression models for percentage outcomes and the analysis of ratings that are measured on a bounded scale. In this paper, we consider beta regression, which is a generalization of logit models to situations where the response is continuous on the interval (0,1). Consequently, beta regression is a convenient tool for analyzing percentage responses. The classical approach to fit a beta regression model is to use maximum likelihood estimation with subsequent AIC-based variable selection. As an alternative to this established - yet unstable - approach, we propose a new estimation technique called boosted beta regression. With boosted beta regression estimation and variable selection can be carried out simultaneously in a highly efficient way. Additionally, both the mean and the variance of a percentage response can be modeled using flexible nonlinear covariate effects. As a consequence, the new method accounts for common problems such as overdispersion and non-binomial variance structures.     

Characterization of miRNA160/164 and Their Targets Expression of Beet (Beta vulgaris) Seedlings Under the Salt Tolerance

Plant Molecular Biology Reporter - MicroRNAs (miRNAs) are non-coding endogenous small RNAs that play important roles in plant growth, development, and stress response. Soil salinization leads to...     

Beta diversity reconsidered

A simple analytical procedure to test for differences in beta diversity among sets of plots has been recently presented. Here, we describe an improved randomization procedure that replaces the one previously proposed. This procedure consists of shuffling within-group dissimilarities among groups and disregarding between-group dissimilarities. By repeating this operation many times, a distribution of the test statistics under the null hypothesis of no differences in the mean plot-to-plot dissimilarities within groups is obtained. This procedure ensures that the correct null model is selected. To describe this new procedure, we used plant and water beetle (Coleoptera) data collected from 45 permanent ponds. Beta diversity was compared between plant and water beetle (Coleoptera) assemblages.     

Thymosin Beta 4 and Thymosin Beta 10 Expression in Hepatocellular Carcinoma

Thymosin beta 4 (Tβ4) and thymosin beta 10 (Tβ10) are two members of the beta-thymosin family involved in many cellular processes such as cellular motility, angiogenesis, inflammation, cell survival and wound healing. Recently, a role for beta-thymosins has been proposed in the process of carcinogenesis as both peptides were detected in several types of cancer. The aim of the present study was to investigate the expression pattern of Tβ4 and Tβ10 in hepatocellular carcinoma (HCC). To this end, the expression pattern of both peptides was analyzed in liver samples obtained from 23 subjects diagnosed with HCC. Routinely formalin-fixed and paraffin-embedded liver samples were immunostained by indirect immunohistochemistry with polyclonal antibodies to Tβ4 and Tβ10. Immunoreactivity for Tβ4 and Tβ10 was detected in the liver parenchyma of the surrounding tumor area. Both peptides showed an increase in granular reactivity from the periportal to the periterminal hepatocytes. Regarding HCC, Tβ4 reactivity was detected in 7/23 cases (30%) and Tβ10 reactivity in 22/23 (96%) cases analyzed, adding HCC to human cancers that express these beta-thymosins. Intriguing finding was seen looking at the reactivity of both peptides in tumor cells infiltrating the surrounding liver. Where Tβ10 showed a strong homogeneous expression, was Tβ4 completely absent in cells undergoing stromal invasion.The current study shows expression of both beta-thymosins in HCC with marked differences in their degree of expression and frequency of immunoreactivity. The higher incidence of Tβ10 expression and its higher reactivity in tumor cells involved in stromal invasion indicate a possible major role for Tβ10 in HCC progression.Key words: β-thymosins, Tβ4, Tβ10, hepatocellular carcinoma, stromal invasion     

植物β-半乳糖苷酶

β-半乳糖苷酶是一个与细胞壁降解相关的酶,广泛分布于植物组织中,参与一系列的生理生化过程,如植物的花粉发育、果实成熟及生长过程中多糖的裂解。目前,已从多种植物中分离到β-半乳糖苷酶基因。β-半乳糖苷酶基因属于多基因家族,随着研究的深入,其不同水平的转录本在不同植物的不同组织中被发现。但目前β-半乳糖苷酶在植物发育中确切的作用机制尚不明确。现介绍目前这一领域内细胞与分子生物学方面的研究进展,并结合所在课题组的研究结果进行相关探讨,为进一步研究β-半乳糖苷酶在植物中的作用机制提供新的线索。     

Beta3-adrenergic receptor

The beta3-adrenergic receptor (beta3-AR) may play a key role in the regulation of lipid metabolism and glucose homeostasis. Adrenaline and noradrenaline beta3-AR stimulate lipolysis and thermogenesis in human fat cells and increase glucose uptake in skeletal muscle. Therefore, the beta3-AR gene may be associated with obesity and related diseases, such as type 2 diabetes, coronary heart disease and hypertension. Many studies in different ethnic groups showed an association of beta3-AR gene polymorphism with insulin resistance, obesity and its metabolic disorders such as type 2 diabetes, coronary heart disease and hypertension. A Trp64Arg mutation in the beta3-AR gene has been reported to be correlated with the occurrence of those disorders among obese. Several studies revealed also the influence of the Trp/Arg polymorphism on carcinogenesis and its contribution to the link between cancer and obesity. Since obesity is a serious problem as a civilization-related disease, it is very important to investigate genes suspected to be connected with it.     

Beta- Lactam Antibiotics Stimulate Biofilm Formation in Non-Typeable Haemophilus influenzae by Up-Regulating Carbohydrate Metabolism

Non-typeable Haemophilus influenzae (NTHi) is a common acute otitis media pathogen, with an incidence that is increased by previous antibiotic treatment. NTHi is also an emerging causative agent of other chronic infections in humans, some linked to morbidity, and all of which impose substantial treatment costs. In this study we explore the possibility that antibiotic exposure may stimulate biofilm formation by NTHi bacteria. We discovered that sub-inhibitory concentrations of beta-lactam antibiotic (i.e., amounts that partially inhibit bacterial growth) stimulated the biofilm-forming ability of NTHi strains, an effect that was strain and antibiotic dependent. When exposed to sub-inhibitory concentrations of beta-lactam antibiotics NTHi strains produced tightly packed biofilms with decreased numbers of culturable bacteria but increased biomass. The ratio of protein per unit weight of biofilm decreased as a result of antibiotic exposure. Antibiotic-stimulated biofilms had altered ultrastructure, and genes involved in glycogen production and transporter function were up regulated in response to antibiotic exposure. Down-regulated genes were linked to multiple metabolic processes but not those involved in stress response. Antibiotic-stimulated biofilm bacteria were more resistant to a lethal dose (10 µg/mL) of cefuroxime. Our results suggest that beta-lactam antibiotic exposure may act as a signaling molecule that promotes transformation into the biofilm phenotype. Loss of viable bacteria, increase in biofilm biomass and decreased protein production coupled with a concomitant up-regulation of genes involved with glycogen production might result in a biofilm of sessile, metabolically inactive bacteria sustained by stored glycogen. These biofilms may protect surviving bacteria from subsequent antibiotic challenges, and act as a reservoir of viable bacteria once antibiotic exposure has ended.     

Identification of Saccharopine and Its Lactam in Buckwheat Seeds (Fagopirum esculentum Moench)

Saccharopine and its lactam were isolated from the achenia of Fagopirum esculentum Moench. Their structure were determined by chemical and spectral data and were finally confirmed by direct comparison with authentic specimens.     

Tolerance nets

The concept of a tolerance net formalises simultaneously spatial closeness and nearness of neuronal activity. A method of constructing tolerance group nets is presented, leading to a means of construction of all very homogenous tolerance nets as group quotients. The dihedral group of order eight is taken as an illustrative example.