34 s.
Hydrogen/deuterium exchange monitored by mass spectrometry is a promising technique for rapidly fingerprinting structural and dynamical properties of proteins. The time-dependent change in the mass of any fragment of the polypeptide chain depends uniquely on the rate of exchange of its amide hydrogens, but determining the latter from the former is generally not possible. Here, we show that, if time-resolved measurements are available for a number of overlapping peptides that cover the whole sequence, rate constants for each amide hydrogen exchange (or equivalently, their protection factors) may be extracted and the uniqueness of the solutions obtained depending on the degree of peptide overlap. However, in most cases, the solution is not unique, and multiple alternatives must be considered. We provide a statistical method that clusters the solutions to further reduce their number. Such analysis always provides meaningful constraints on protection factors and can be used in situations in which obtaining more refined experimental data is impractical. It also provides a systematic way to improve data collection strategies to obtain unambiguous information at single-residue level (e.g., for assessing protein structure predictions at atomistic level).
The gut microbiome of primates, including humans, is reported to closely follow host evolutionary history, with gut microbiome composition being specific to the genetic background of its primate host. However, the comparative models used to date have mainly included a limited set of closely related primates. To further understand the forces that shape the primate gut microbiome, with reference to human populations, we expanded the comparative analysis of variation among gut microbiome compositions and their primate hosts, including 9 different primate species and 4 human groups characterized by a diverse set of subsistence patterns (n = 448 samples). The results show that the taxonomic composition of the human gut microbiome, at the genus level, exhibits increased compositional plasticity. Specifically, we show unexpected similarities between African Old World monkeys that rely on eclectic foraging and human populations engaging in nonindustrial subsistence patterns; these similarities transcend host phylogenetic constraints. Thus, instead of following evolutionary trends that would make their microbiomes more similar to that of conspecifics or more phylogenetically similar apes, gut microbiome composition in humans from nonindustrial populations resembles that of generalist cercopithecine monkeys. We also document that wild cercopithecine monkeys with eclectic diets and humans following nonindustrial subsistence patterns harbor high gut microbiome diversity that is not only higher than that seen in humans engaging in industrialized lifestyles but also higher compared to wild primates that typically consume fiber-rich diets.IMPORTANCE The results of this study indicate a discordance between gut microbiome composition and evolutionary history in primates, calling into question previous notions about host genetic control of the primate gut microbiome. Microbiome similarities between humans consuming nonindustrialized diets and monkeys characterized by subsisting on eclectic, omnivorous diets also raise questions about the ecological and nutritional drivers shaping the human gut microbiome. Moreover, a more detailed understanding of the factors associated with gut microbiome plasticity in primates offers a framework to understand why humans following industrialized lifestyles have deviated from states thought to reflect human evolutionary history. The results also provide perspectives for developing therapeutic dietary manipulations that can reset configurations of the gut microbiome to potentially improve human health.
- MeSH
- Bacteria classification isolation & purification MeSH
- Diet * MeSH
- Feces microbiology MeSH
- Phylogeny MeSH
- Genetic Variation * MeSH
- Humans MeSH
- Evolution, Molecular * MeSH
- Primates microbiology MeSH
- RNA, Ribosomal, 16S genetics MeSH
- Gastrointestinal Microbiome * MeSH
- Life Style MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
Recently, a growing number of plant essential oils (EOs) have been tested against a wide range of arthropod pests with promising results. EOs showed high effectiveness, multiple mechanisms of action, low toxicity on non-target vertebrates and potential for the use of byproducts as reducing and stabilizing agents for the synthesis of nanopesticides. However, the number of commercial biopesticides based on EOs remains low. We analyze the main strengths and weaknesses arising from the use of EO-based biopesticides. Key challenges for future research include: (i) development of efficient stabilization processes (e.g., microencapsulation); (ii) simplification of the complex and costly biopesticide authorization requirements; and (iii) optimization of plant growing conditions and extraction processes leading to EOs of homogeneous chemical composition.
- MeSH
- European Union MeSH
- Nuclear Energy legislation & jurisprudence MeSH
- Humans MeSH
- International Cooperation history legislation & jurisprudence MeSH
- Radiation Protection methods standards legislation & jurisprudence MeSH
- Radiometry methods trends utilization MeSH
- Public Health methods standards statistics & numerical data MeSH
- Check Tag
- Humans MeSH
- Publication type
- Guideline MeSH
- Geographicals
- Czech Republic MeSH
Recent studies undoubtedly show that the mammalian target of rapamycin (mTOR) and the Hippo-Yes-associated protein 1 (YAP) pathways are important mediators of mechanical cues. The crosstalk between these pathways as well as de-regulation of their signaling has been implicated in multiple tumor types, including liver tumors. Additionally, physical cues from 3D microenvironments have been identified to alter gene expression and differentiation of different cell lineages. However, it remains incompletely understood how physical constraints originated in 3D cultures affect cell plasticity and what the key mediators are of such process. In this work, we use collagen scaffolds as a model of a soft 3D microenvironment to alter cellular size and study the mechanotransduction that regulates that process. We show that the YAP-mTOR axis is a downstream effector of 3D cellular culture-driven mechanotransduction. Indeed, we found that cell mechanics, dictated by the physical constraints of 3D collagen scaffolds, profoundly affect cellular proliferation in a YAP-mTOR-mediated manner. Functionally, the YAP-mTOR connection is key to mediate cell plasticity in hepatic tumor cell lines. These findings expand the role of YAP-mTOR-driven mechanotransduction to the control hepatic tumor cellular responses under physical constraints in 3D cultures. We suggest a tentative mechanism, which coordinates signaling rewiring with cytoplasmic restructuring during cell growth in 3D microenvironments.
- Publication type
- Journal Article MeSH
Here, we report the efficient solid-phase synthesis of N-propargyl peptides using Fmoc-amino acids and propargyl alcohol as key building blocks. Gold-catalyzed nucleophilic addition to the triple bond induced C-N bond formation, which triggered intramolecular cyclization, yielding 1,3,4-trisubstituted-5-methyl-3,4-dihydropyrazin-2(1H)-ones. Conformations of acyclic and constrained peptides were compared using a two-step conformer distribution analysis at the molecular mechanics level and density functional theory. The results indicated that the incorporation of heterocyclic molecular scaffold into a short peptide sequence adopted extended conformation of peptide chain. The amide bond adjacent to the constraint did not show significant preference for either cis or trans isomerism. Prepared model compounds demonstrate a proof of concept for gold-catalyzed polymer-supported synthesis of variously substituted 3,4-dihydropyrazin-2(1H)-ones for applications in drug discovery and peptide backbone constraints.
EUR/HFA
21 s.
