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McCullough Thomas posted an update 6 months, 2 weeks ago
The insulin-like peptide human relaxin-2 was identified as a hormone that, among other biological functions, mediates the hemodynamic changes occurring during pregnancy. Recombinant relaxin-2 (serelaxin) has shown beneficial effects in acute heart failure, but its full therapeutic potential has been hampered by its short half-life and the need for intravenous administration limiting its use to intensive care units. In this study, we report the development of long-acting potent single-chain relaxin peptide mimetics. Modifications in the B-chain of relaxin, such as the introduction of specific mutations and the trimming of the sequence to an optimal size, resulted in potent, structurally simplified peptide agonists of the relaxin receptor Relaxin Family Peptide Receptor 1 (RXFP1) (e.g., 54). Introduction of suitable spacers and fatty acids led to the identification of single-chain lipidated peptide agonists of RXFP1, with sub-nanomolar activity, high subcutaneous bioavailability, extended half-lives, and in vivo efficacy (e.g., 64).Lipases are enzymes able to catalyze the hydrolysis or synthesis of triglycerides, depending on the reaction conditions, whereas sterol esterases show the same ability on sterol esters. Structurally, both kinds of enzymes display an α/β-hydrolase fold, with a substrate-binding pocket formed by a hydrophobic cavity covered by a mobile lid. However, it has been reported that some lipases from the Candida rugosa-like family display wide substrate specificity on both triglycerides and sterol esters. Among them, enzymes with different biotechnological applications, such as the lipase isoenzymes produced by C. rugosa and the sterol esterase from Ophiostoma piceae, have been exhaustively characterized and their crystal structures are available. Differences in substrate affinity among these proteins have been attributed to changes in their hydrophobicity. In this work, we analyzed the full catalytic mechanisms of these proteins using molecular dynamics tools, gaining insight into their mechanistic properties. In addition, we developed an in silico protocol to predict the substrate specificity using C. rugosa and O. piceae lipases as model enzymes and triglycerides and cholesterol esters with different fatty acid chain lengths as model substrates. The protocol was validated by comparing the in silico results with those described in the literature. These results would be useful to perform virtual screening of substrates for enzymes of the C. rugosa-like family with unknown catalytic properties.In this study, a rapid and reliable method based on ultrahigh-performance liquid chromatography coupled with Q Exactive HF-X mass spectrometry (UHPLC-QE/MS) was established for the simultaneous quantification and validation of acrylamide, 5-hydroxymethylfurfural, and 14 heterocyclic aromatic amines in thermally processed foods. With the optimization of the pretreatment method, all 16 hazardous compounds with different polarities were simultaneously extracted and purified by one-step purification. By studying various acquisition modes in detail, full MS + PRM detection using an electrospray ionization source in the positive mode gives an excellent-shaped chromatographic peak and thereby achieves a better quantitative ability for analytes in the matrix. This method demonstrated good quantification recovery in the range of 68.85-146.42%. The limits of quantification were within the range from 0.1 to 50 ng/mL. With the method proposed, the simultaneous determination of 16 hazardous compounds in different thermally processed foods was successfully applied. selleck chemicals llc The all-fragment-ion approaches at high resolution have the ability to reduce false-positive peak detections arising from peak alignment software in the detection of samples significantly. The proposed isotope dilution UHPLC-QE/MS method was validated and demonstrated to be sensitive, accurate, and precise for the simultaneous quantification of multiple contaminants in one injection.The introduction of glycosides bearing basic nitrogen is challenging using conventional Lewis acid-promoted pathways owing to competitive coordination of the amine to the Lewis acid promoter. Additionally, because many aminoglycosides lack a C2 substituent, diastereomeric mixtures of O-glycosides are often produced. Herein, we present a method for the synthesis of α- or β- 2,3,6-trideoxy-3-amino- and 2,4,6-trideoxy-4-amino O-glycosides from a common precursor. Our strategy proceeds by the reductive lithiation of thiophenyl glycoside donors and trapping of the resulting anomeric anions with 2-methyltetrahydropyranyl peroxides. We apply this strategy to the synthesis of α- and β-forosamine, pyrrolosamine, acosamine, and ristosamine derivatives using primary and secondary peroxides as electrophiles. α-Linked products are obtained in 60-96% yield and with >501 selectivity. β-Linked products are obtained in 45-94% yield and with 1.7->501 stereoselectivity. Contrary to donors bearing an equatorial amine substituent, donors bearing an axial amine substituent favored β-products at low temperatures. This work establishes a general strategy to synthesize O-glycosides bearing a basic nitrogen.The characterization of photoexcited electrons on the surface of nanomaterial remains challenging. Herein, laser excitation mass spectrometry combined with a chemical thermometer and electron acceptor has been developed to characterize the energetics and population density of photoexcited electrons transferred from gold nanoparticles (AuNPs). In contrast to laser fluence and bias voltage, the hot spots of closely packed AuNPs play a more significant role in enhancing the average energetics of photoexcited electrons, which can be harvested effectively by the electron acceptor. By harvesting more energetic photoexcited electrons for the desorption and ionization process, it is anticipated that the sensitive detection of biomarkers can be achieved, which is beneficial to metabolomic studies and early disease diagnosis.Post-translational modifications of histones play an important chromatic role of a transcript activity in eukaryotes. Even though mRNA and long noncoding RNA (lncRNA) genes share similar biogenetic processes, these transcript classes may differ in many ways. However, knowledge about the crosstalk between histone methylations and the two types of sorghum genes is still ambiguous. In the present study, we reveal the genome-wide distribution of six histone modifications, namely, di- and trimethylation of H3K4 (H3K4me2 and H3K4me3), H3K27 (H3K27me2 and H3K27me3), and H3K36 (H3K36me2 and H3K36me3) in sorghum and analyze their functional relationships. Unlike other histone methylation, the codecoration of H3K4me3 and H3K36me3 is negatively associated with the production of lincRNAs in the context of active expression of mRNA genes. Our data demonstrated that H3K4me3 may act as a complementary component to H3K36me3 in the transcriptional regulatory process. Moreover, we observe that both H3K4me3 and H3K36me3 are involved in the negative-going regulation of plant lincRNA and mRNA genes.
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