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101.
Inspired by marine compounds the derivatization of the natural pyrrolo[2,3-d]pyrimidine lead scaffold led to a series of novel compounds targeting the histamine H3 receptor. The focus was set on improved binding towards the receptor and to establish an initial structure-activity relationship for this compound class based on the lead structure (compound V, Ki value of 126 nM). As highest binding affinities were found with 1,4-bipiperidines as basic part of the ligands, further optimization was focused on 4-([1,4′-bipiperidin]-1′-yl)-pyrrolo[2,3-d]pyrimidines. Related pyrrolo[2,3-d]pyrimidines that were isolated from marine sponges like 4-amino-5-bromopyrrolo[2,3-d]pyrimidine (compound III), showed variations in halogenation pattern, though in a next step the impact of halogenation at 2-position was evaluated. The chloro variations did not improve the affinity compared to the dehalogenated compounds. However, the simultaneous introduction of lipophilic cores with electron-withdrawing substitution patterns in 7-position and dehalogenation at 2-position (11b, 12b) resulted in compounds with significantly higher binding affinities (Ki values of 7 nM and 6 nM, respectively) than the initial lead structure compound V. The presented structures allow for a reasonable structure-activity relationship of pyrrolo[2,3-d]pyrimidines as histamine H3 receptor ligands and yielded novel lead structures within the natural compound library against this target.  相似文献   
102.
A fundamental part of the quantitative genetic theory deals with the partitioning of the phenotypic variance into additive genetic and environmental components. During interaction with conspecifics, the interaction partner becomes a part of the environment from the perspective of the focal individual. If the interaction effects have a genetic basis, they are called indirect genetic effects (IGEs) and can evolve along with direct genetic effects. Sexual reproduction is a classic context where potential conflict between males and females can arise from trade‐offs between current and future investments. We studied five female fecundity traits, egg length and number, egg pod length and number and latency to first egg pod, and estimated the direct and IGEs using a half‐sib breeding design in the grasshopper Chorthippus biguttulus. We found that the male IGEs were an order of magnitude lower than the direct genetic effects and were not significantly different from zero. However, there was some indication that IGEs were larger shortly after mating, consistent with the idea that IGEs fade with time after interaction. Female direct heritabilities were moderate to low. Simulation shows that the variance component estimates can appear larger with less data, calling for care when interpreting variance components estimated with low power. Our results illustrate that the contribution of male IGEs is overall low on the phenotypic variance of female fecundity traits. Thus, even in the relevant context of sexual conflict, the influence of male IGEs on the evolutionary trajectory of female reproductive traits is likely to be small.  相似文献   
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Sexual selection has repeatedly been shown to be the probable driving force behind the positive Darwinian evolution of genes affecting male reproductive success. Here we compare the sequence evolution of the sperm ligand zonadhesin with body mass dimorphism in primates. In contrast to previous related studies, the present approach takes into account not only catarrhine primates, but also platyrrhines and lemurs. In detail, we analyze the sequence evolution of concatenated zonadhesin fragments (555 bp) of four Lemuroidea, five Platyrrhini, and seven Catarrhini, using the rate ratio of nonsynonymous to synonymous substitutions (dn/ds=omega). Unexpectedly, subsequent regression analyzes between omega estimates for the terminal branches of a primate phylogeny and residual male body mass reveal that sequence evolution of zonadhesin decreases with increasing sexual dimorphism in body weight. Mapping published mating system classifications onto these results illustrates that unimale breeding species show a tendency for rather slow sequence evolution of zonadhesin and comparably pronounced sexual dimorphism in body weight. Female choice and sperm competition can be assumed to drive the evolution of zonadhesin. We speculate that the level of sperm competition is lower in more sexually dimorphic primates because males of these species monopolize access to fertile females more successfully. Thus, variation in sperm competition may be driving the observed negative correlation of sequence evolution and sexual dimorphism in body weight.  相似文献   
105.
ATP synthases convert an electrochemical proton gradient into rotational movement to produce the ubiquitous energy currency adenosine triphosphate. Tension generated by the rotational torque is compensated by the stator. For this task, a peripheral stalk flexibly fixes the hydrophilic catalytic part F1 to the membrane integral proton conducting part F(O) of the ATP synthase. While in eubacteria a homodimer of b subunits forms the peripheral stalk, plant chloroplasts and cyanobacteria possess a heterodimer of subunits I and II. To better understand the functional and structural consequences of this unique feature of photosynthetic ATP synthases, a procedure was developed to purify subunit I from spinach chloroplasts. The secondary structure of subunit I, which is not homologous to bacterial b subunits, was compared to heterologously expressed subunit II using CD and FTIR spectroscopy. The content of alpha-helix was determined by CD spectroscopy to 67% for subunit I and 41% for subunit II. In addition, bioinformatics was applied to predict the secondary structure of the two subunits and the location of the putative coiled-coil dimerization regions. Three helical domains were predicted for subunit I and only two uninterrupted domains for the shorter subunit II. The predicted length of coiled-coil regions varied between different species and between subunits I and II.  相似文献   
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Cirrhotic cardiomyopathy is the term used to describe a constellation of features indicative of abnormal heart structure and function in patients with cirrhosis. These include systolic and diastolic dysfunction, electrophysiological changes, and macroscopic and microscopic structural changes. The prevalence of cirrhotic cardiomyopathy remains unknown at present, mostly because the disease is generally latent and shows itself when the patient is subjected to stress such as exercise, drugs, hemorrhage and surgery. The main clinical features of cirrhotic cardiomyopathy include baseline increased cardiac output, attenuated systolic contraction or diastolic relaxation in response to physiologic, pharmacologic and surgical stress, and electrical conductance abnormalities (prolonged QT interval). In the majority of cases, diastolic dysfunction precedes systolic dysfunction, which tends to manifest only under conditions of stress. Generally, cirrhotic cardiomyopathy with overt severe heart failure is rare. Major stresses on the cardiovascular system such as liver transplantation, infections and insertion of transjugular intrahepatic portosystemic stent-shunts (TIPS) can unmask the presence of cirrhotic cardiomyopathy and thereby convert latent to overt heart failure. Cirrhotic cardiomyopathy may also contribute to the pathogenesis of hepatorenal syndrome. Pathogenic mechanisms of cirrhotic cardiomyopathy are multiple and include abnormal membrane biophysical characteristics, impaired β-adrenergic receptor signal transduction and increased activity of negative-inotropic pathways mediated by cGMP. Diagnosis and differential diagnosis require a careful assessment of patient history probing for excessive alcohol, physical examination for signs of hypertension such as retinal vascular changes, and appropriate diagnostic tests such as exercise stress electrocardiography, nuclear heart scans and coronary angiography. Current management recommendations include empirical, nonspecific and mainly supportive measures. The exact prognosis remains unclear. The extent of cirrhotic cardiomyopathy generally correlates to the degree of liver insufficiency. Reversibility is possible (either pharmacological or after liver transplantation), but further studies are needed.  相似文献   
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109.
In higher organisms, the functions of many proteins are modulated by post-translational modifications (PTMs). Glycosylation is by far the most diverse of the PTM processes. Natural protein production methods typically produce PTM or glycoform mixtures within which function is difficult to dissect or control. Chemical tagging methods allow the precise attachment of multiple glycosylation modifications to bacterially expressed (bare) protein scaffolds, allowing reconstitution of functionally effective mimics of glycoproteins in higher organisms. In this way combining chemical control of PTM with readily available protein scaffolds provides a systematic platform for creating probes of protein-PTM interactions. This protocol describes the modification of Cys residues in proteins using glycomethanethiosulfonates and glycoselenenylsulfides and the modification of azidohomoalanine residues, introduced by Met replacement using auxotrophic Met(-) Escherichia coli strains, with glycoalkynes and the combination of these techniques for the creation of dual-tagged proteins. Each glycosylation procedure outlined in this protocol can be achieved in half a day.  相似文献   
110.
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