Catalysis of proline isomerization and molecular chaperone activity in a tug-of-war

Catalysis of cis/trans isomerization of prolines is important for the activity and misfolding of intrinsically disordered proteins. Catalysis is achieved by peptidylprolyl isomerases, a superfamily of molecular chaperones. Here, we provide atomic insight into a tug-of-war between cis/trans isomerization and molecular chaperone activity. Catalysis of proline isomerization by cyclophilin A lowers the energy barrier for \u3b1-synuclein misfolding, while isomerase-binding to a separate, disease-associated protein region opposes aggregation. We further show that cis/trans isomerization outpowers the holding activity of cyclophilin A. Removal of the proline isomerization barrier through posttranslational truncation of \u3b1-synuclein reverses the action of the proline isomerase and turns it into a potent molecular chaperone that inhibits protein misfolding. The data reveal a conserved mechanism of dual functionality in cis/trans isomerases and define its molecular determinants acting on intrinsically disordered proteins

Quantitative estimation of nerve fiber engagement by vagus nerve stimulation using physiological markers

Background Cervical vagus nerve stimulation (VNS) is a rapidly emerging bioelectronic treatment for brain, metabolic, cardiovascular and immune disorders. Its desired and off-target effects are mediated by different nerve fiber populations and knowledge of their engagement could guide calibration and monitoring of VNS therapies. Objective /Hypothesis: Stimulus-evoked compound action potentials (eCAPs) directly provide fiber engagement information but are currently not feasible in humans. A method to estimate fiber engagement through common, noninvasive physiological readouts could be used instead of eCAP measurements. Methods In anesthetized rats, we recorded eCAPs while registering acute physiological response markers to VNS: cervical electromyography (EMG), changes in heart rate (ΔHR) and breathing interval (ΔBI). Quantitative models were established to capture the relationship between A-, B- and C-fiber type activation and those markers, and to quantitatively estimate fiber activation from physiological markers and stimulation parameters. Results In bivariate analyses, we found that EMG correlates with A-fiber, ΔHR with B-fiber and ΔBI with C-fiber activation, in agreement with known physiological functions of the vagus. We compiled multivariate models for quantitative estimation of fiber engagement from these markers and stimulation parameters. Finally, we compiled frequency gain models that allow estimation of fiber engagement at a wide range of VNS frequencies. Our models, after calibration in humans, could provide noninvasive estimation of fiber engagement in current and future therapeutic applications of VNS

Effective Population Size, Gene Flow, and Species Status in a Narrow Endemic Sunflower, Helianthus neglectus, Compared to Its Widespread Sister Species, H. petiolaris

Species delimitation has long been a difficult and controversial process, and different operational criteria often lead to different results. In particular, investigators using phenotypic vs. molecular data to delineate species may recognize different boundaries, especially if morphologically or ecologically differentiated populations have only recently diverged. Here we examine the genetic relationship between the widespread sunflower species Helianthus petiolaris and its narrowly distributed sand dune endemic sister species H. neglectus using sequence data from nine nuclear loci. The two species were initially described as distinct based on a number of minor morphological differences, somewhat different ecological tolerances, and at least one chromosomal rearrangement distinguishing them; but detailed molecular data has not been available until now. We find that, consistent with previous work, H. petiolaris is exceptionally genetically diverse. Surprisingly, H. neglectus harbors very similar levels of genetic diversity (average diversity across loci is actually slightly higher in H. neglectus). It is extremely unlikely that such a geographically restricted species could maintain these levels of genetic variation in isolation. In addition, the two species show very little evidence of any genetic divergence, and estimates of interspecific gene flow are comparable to gene flow estimates among regions within H. petiolaris. These results indicate that H. petiolaris and H. neglectus likely do not represent two distinct, isolated gene pools; H. neglectus is probably more accurately thought of as a geographically restricted, morphologically and ecologically distinct subspecies of H. petiolaris rather than a separate species

Expressions 1986

https://openspace.dmacc.edu/expressions/1007/thumbnail.jp

Trademarks, Certification Marks and Technical Standards

The names of many technical standards such as Wi-Fi, Bluetooth and DVD have become household terms known throughout the developed world. This chapter describes different approaches that have been taken with respect to the naming and legal protection of technical standards, ranging from those that are wholly unregulated to those that are administered under strict certification and compliance regimes. It concludes by questioning the need for aggressive protection of marks that exist largely to inform consumers about technical product features rather than the source of standards themselves

Exploring the symbiotic pangenome of the nitrogen-fixing bacterium Sinorhizobium meliloti

<p>Abstract</p> <p>Background</p> <p><it>Sinorhizobium meliloti </it>is a model system for the studies of symbiotic nitrogen fixation. An extensive polymorphism at the genetic and phenotypic level is present in natural populations of this species, especially in relation with symbiotic promotion of plant growth. AK83 and BL225C are two nodule-isolated strains with diverse symbiotic phenotypes; BL225C is more efficient in promoting growth of the <it>Medicago sativa </it>plants than strain AK83. In order to investigate the genetic determinants of the phenotypic diversification of <it>S. meliloti </it>strains AK83 and BL225C, we sequenced the complete genomes for these two strains.</p> <p>Results</p> <p>With sizes of 7.14 Mbp and 6.97 Mbp, respectively, the genomes of AK83 and BL225C are larger than the laboratory strain Rm1021. The core genome of Rm1021, AK83, BL225C strains included 5124 orthologous groups, while the accessory genome was composed by 2700 orthologous groups. While Rm1021 and BL225C have only three replicons (Chromosome, pSymA and pSymB), AK83 has also two plasmids, 260 and 70 Kbp long. We found 65 interesting orthologous groups of genes that were present only in the accessory genome, consequently responsible for phenotypic diversity and putatively involved in plant-bacterium interaction. Notably, the symbiosis inefficient AK83 lacked several genes required for microaerophilic growth inside nodules, while several genes for accessory functions related to competition, plant invasion and bacteroid tropism were identified only in AK83 and BL225C strains. Presence and extent of polymorphism in regulons of transcription factors involved in symbiotic interaction were also analyzed. Our results indicate that regulons are flexible, with a large number of accessory genes, suggesting that regulons polymorphism could also be a key determinant in the variability of symbiotic performances among the analyzed strains.</p> <p>Conclusions</p> <p>In conclusions, the extended comparative genomics approach revealed a variable subset of genes and regulons that may contribute to the symbiotic diversity.</p

Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loc