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61.
Berger Andreas Valant-Vetschera Karin Schinnerl Johann Brecker Lothar 《Phytochemistry Reviews》2022,21(3):941-986
Phytochemistry Reviews - Tribes Palicoureeae and Psychotrieae (Rubiaceae, Gentianales) are complex and speciose sister groups with a pantropical distribution. Since the initial studies on... 相似文献
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Mark Lipson Po-Ru Loh Sriram Sankararaman Nick Patterson Bonnie Berger David Reich 《PLoS genetics》2015,11(11)
The human mutation rate is an essential parameter for studying the evolution of our species, interpreting present-day genetic variation, and understanding the incidence of genetic disease. Nevertheless, our current estimates of the rate are uncertain. Most notably, recent approaches based on counting de novo mutations in family pedigrees have yielded significantly smaller values than classical methods based on sequence divergence. Here, we propose a new method that uses the fine-scale human recombination map to calibrate the rate of accumulation of mutations. By comparing local heterozygosity levels in diploid genomes to the genetic distance scale over which these levels change, we are able to estimate a long-term mutation rate averaged over hundreds or thousands of generations. We infer a rate of 1.61 ± 0.13 × 10−8 mutations per base per generation, which falls in between phylogenetic and pedigree-based estimates, and we suggest possible mechanisms to reconcile our estimate with previous studies. Our results support intermediate-age divergences among human populations and between humans and other great apes. 相似文献
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Sushmita L. Allam Jean-Marie C. Bouteiller Eric Y. Hu Nicolas Ambert Renaud Greget Serge Bischoff Michel Baudry Theodore W. Berger 《PloS one》2015,10(10)
Glutamatergic synapses are the most prevalent functional elements of information processing in the brain. Changes in pre-synaptic activity and in the function of various post-synaptic elements contribute to generate a large variety of synaptic responses. Previous studies have explored postsynaptic factors responsible for regulating synaptic strength variations, but have given far less importance to synaptic geometry, and more specifically to the subcellular distribution of ionotropic receptors. We analyzed the functional effects resulting from changing the subsynaptic localization of ionotropic receptors by using a hippocampal synaptic computational framework. The present study was performed using the EONS (Elementary Objects of the Nervous System) synaptic modeling platform, which was specifically developed to explore the roles of subsynaptic elements as well as their interactions, and that of synaptic geometry. More specifically, we determined the effects of changing the localization of ionotropic receptors relative to the presynaptic glutamate release site, on synaptic efficacy and its variations following single pulse and paired-pulse stimulation protocols. The results indicate that changes in synaptic geometry do have consequences on synaptic efficacy and its dynamics. 相似文献
67.
Friederike Behmenburg Marianne Dorsch Ragnar Huhn David Mally André Heinen Markus W. Hollmann Marc M. Berger 《PloS one》2015,10(12)
Background
Mitochondrial large-conductance Ca2+-sensitive potassium (mBKCa) channels are involved in myocardial ischemic preconditioning. Their role in sildenafil-induced cardioprotection is unknown. We investigated whether sildenafil-induced acute cardioprotection is mediated by activation of mBKCa channels in the rat heart in vitro.Methods
Male Wistar rats (n = 8 per group) were randomized and anesthetized with pentobarbital (90 mg/kg). Hearts were isolated, mounted on a Langendorff system and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. Hearts underwent 30 min of global ischemia followed by 60 min of reperfusion. At the end of the experiments infarct size was determined by TTC staining. In the control group rats were not further treated. Sildenafil (3 μM) was administered over 10 min before the beginning of ischemia. The mBKCa channel inhibitor paxilline (1 μM) was administered with and without sildenafil before the onset of ischemia. The pathway underlying sildenafil-induced cardioprotection was further investigated with the protein kinase G blocker KT5823 (1 μM). Myocardial cGMP concentration was measured by ELISA. Data (mean±SD) were analysed with a one and two-way analysis of variance as appropriate.Results
In control animals infarct size was 52±8%. Sildenafil increased cGMP concentration and reduced infarct size to 35±6% (P<0.05 vs. control). Paxilline and KT5823 completely blocked sildenafil-induced cardioprotection (paxilline+sildenafil: 50±8%, KT5823+sildenafil: 45±8%; both P<0.05 vs. sildenafil). Functional heart parameters and coronary flow were not different between the study groups.Conclusion
This study shows that in male rats protein kinase G-dependent opening of mBKCa channels plays a pivotal role in sildenafil-induced cardioprotection. 相似文献68.
This paper identifies trends within and relationships between the amount of participation and the quality of contributions in three crowdsourced surveys. Participants were asked to perform a collective problem solving task that lacked any explicit incentive: they were instructed not only to respond to survey questions but also to pose new questions that they thought might-if responded to by others-predict an outcome variable of interest to them. While the three surveys had very different outcome variables, target audiences, methods of advertisement, and lengths of deployment, we found very similar patterns of collective behavior. In particular, we found that: the rate at which participants submitted new survey questions followed a heavy-tailed distribution; the distribution in the types of questions posed was similar; and many users posed non-obvious yet predictive questions. By analyzing responses to questions that contained a built-in range of valid response we found that less than 0.2% of responses lay outside of those ranges, indicating that most participants tend to respond honestly to surveys of this form, even without explicit incentives for honesty. While we did not find a significant relationship between the quantity of participation and the quality of contribution for both response submissions and question submissions, we did find several other more nuanced participant behavior patterns, which did correlate with contribution in one of the three surveys. We conclude that there exists an optimal time for users to pose questions early on in their participation, but only after they have submitted a few responses to other questions. This suggests that future crowdsourced surveys may attract more predictive questions by prompting users to pose new questions at specific times during their participation and limiting question submission at non-optimal times. 相似文献
69.
Martin Mehnert Franziska Sommermeyer Maren Berger Sathish Kumar Lakshmipathy Robert Gauss Markus Aebi Ernst Jarosch Thomas Sommer 《Molecular biology of the cell》2015,26(2):185-194
Misfolded proteins of the secretory pathway are extracted from the endoplasmic reticulum (ER), polyubiquitylated by a protein complex termed the Hmg-CoA reductase degradation ligase (HRD-ligase), and degraded by cytosolic 26S proteasomes. This process is termed ER-associated protein degradation (ERAD). We previously showed that the membrane protein Der1, which is a subunit of the HRD-ligase, is involved in the export of aberrant polypeptides from the ER. Unexpectedly, we also uncovered a close spatial proximity of Der1 and the substrate receptor Hrd3 in the ER lumen. We report here on a mutant Hrd3KR that is selectively defective for ERAD of soluble proteins. Hrd3KR displays subtle structural changes that affect its positioning toward Der1. Furthermore, increased quantities of the ER-resident Hsp70-type chaperone Kar2 and the Hsp40-type cochaperone Scj1 bind to Hrd3KR. Of note, deletion of SCJ1 impairs ERAD of model substrates and causes the accumulation of client proteins at Hrd3. Our data imply a function of Scj1 in the removal of malfolded proteins from the receptor Hrd3, which facilitates their delivery to downstream-acting components like Der1. 相似文献
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