A Versatile Approach for Siteâ Specific Lysine Acylation in Proteins

Using amber suppression in coordination with a mutant pyrrolysylâ tRNA synthetaseâ tRNAPyl pair, azidonorleucine is genetically encoded in E. coli. Its genetic incorporation followed by traceless Staudinger ligation with a phosphinothioester allows the convenient synthesis of a protein with a siteâ specifically installed lysine acylation. By simply changing the phosphinothioester identity, any lysine acylation type could be introduced. Using this approach, we demonstrated that both lysine acetylation and lysine succinylation can be installed selectively in ubiquitin and synthesized histone H3 with succinylation at its K4 position (H3K4su). Using an H3K4suâ H4 tetramer as a substrate, we further confirmed that Sirt5 is an active histone desuccinylase. Lysine succinylation is a recently identified postâ translational modification. The reported technique makes it possible to explicate regulatory functions of this modification in proteins.Azidonorleucine, an azideâ containing amino acid, is genetically encoded and incorporated into model proteins. This incorporation followed by traceless Staudinger ligation potentiates the synthesis of proteins with a myriad of siteâ specific lysine acylations.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137311/1/anie201611415-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137311/2/anie201611415_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137311/3/anie201611415.pd

Rhodium(II)-catalyzed stereocontrolled synthesis of dihydrofuran-3-imines from 1-Tosyl-1,2,3-triazoles

Rhodium(II) acetate catalyzes the denitrogenative transformation of 5-substituted and 4,5-disubstituted 1-sulfonyl-1,2,3-triazoles with pendent allyl and propargyl ether motifs to oxonium ylides that undergo [2,3]-sigmatropic rearrangement to give substituted dihydrofuran-3-imines in high yield and diastereoselectivity

Concurrence of Danish Dementia and Cataract: Insights from the Interactions of Dementia Associated Peptides with Eye Lens α-Crystallin

Familial Danish Dementia (FDD) is an autosomal disease, which is distinguished by gradual loss of vision, deafness, progressive ataxia and dementia. Cataract is the first manifestation of the disease. In this article, we demonstrate a specific correlation between the poisoning of the chaperone activity of the rat eye lens α-crystallins, loss of lens transparency in organ culture by the pathogenic form of the Danish dementia peptide, i.e. the reduced Danish dementia peptide (redADan peptide), by a combination of ex vivo, in vitro, biophysical and biochemical techniques. The interaction of redADan peptide and lens crystallins are very specific when compared with another chaperone, HSP-70, underscoring the specificity of the pathogenic form of Danish dementia peptide, redADan, for the early onset of cataract in this disease

A New Basal Sauropod Dinosaur from the Middle Jurassic of Niger and the Early Evolution of Sauropoda

The early evolution of sauropod dinosaurs is poorly understood because of a highly incomplete fossil record. New discoveries of Early and Middle Jurassic sauropods have a great potential to lead to a better understanding of early sauropod evolution and to reevaluate the patterns of sauropod diversification.A new sauropod from the Middle Jurassic of Niger, Spinophorosaurus nigerensis n. gen. et sp., is the most complete basal sauropod currently known. The taxon shares many anatomical characters with Middle Jurassic East Asian sauropods, while it is strongly dissimilar to Lower and Middle Jurassic South American and Indian forms. A possible explanation for this pattern is a separation of Laurasian and South Gondwanan Middle Jurassic sauropod faunas by geographic barriers. Integration of phylogenetic analyses and paleogeographic data reveals congruence between early sauropod evolution and hypotheses about Jurassic paleoclimate and phytogeography.Spinophorosaurus demonstrates that many putatively derived characters of Middle Jurassic East Asian sauropods are plesiomorphic for eusauropods, while South Gondwanan eusauropods may represent a specialized line. The anatomy of Spinophorosaurus indicates that key innovations in Jurassic sauropod evolution might have taken place in North Africa, an area close to the equator with summer-wet climate at that time. Jurassic climatic zones and phytogeography possibly controlled early sauropod diversification

Identification of Ideal Locations and Stable High Biomass Sorghum Genotypes in semiarid Tropics

The dearth of proper delineation for energy sorghum cultivation has led to a prerequisite for evaluation and identification of test environments for the newly developed lines. This becomes of vital importance as the biomass yield is highly influenced by genotype and environmental (G × E) interactions. Several agronomic traits were considered to assess the biomass yield and the combined analysis of variance for G (genotype), L (location) and interaction effect of G × L. The variations in the yield caused by the interaction of G × L are very essential to acquire knowledge on the specific adaptation of a genotype. Thus, the multi-location trials conducted across locations and years have helped to identify the stable environments with specific adaptation for biomass sorghum. The presence of close association between the test locations suggested that the same information about the genotypes could be obtained from fewer test environments, and hence the potential to reduce evaluation costs. The two genotypes—IS 13762 and ICSV 25333—have shown stable performance for biomass traits across all the locations, in comparison with CSH 22SS (check). The top ten entries with stable and better performance for fresh biomass yield, dry biomass yield, grain yield and theoretical ethanol yield were ICSV 25333, IS 13762, CSH 22SS, IS 25302, IS 25301, IS 27246, IS 16529, DHBM2, ICSSH 28 and IS 17349

Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease:results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study

BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD).AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab.RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure.CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure

Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease:results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study

BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD).AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab.RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure.CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure

Effects of Dy sub lattice dilution on transport and magnetic properties in Dy1-xKxMnO3

Interaction of multiple oxidation states of manganese ions with rare earth ions in manganites leads to the observation of various magnetic ground states. To understand the effect of average ionic size on electrical conductivity and magnetic ground state properties in Dy1-xKxMnO3 (x=0.0, 0.1, 0.2 & 0.3), we have investigated electron transport as a function of temperature and magnetic properties as a function of temperature, frequency and magnetic field of these compounds. Although mixed valent manganese ions can facilitate a double exchange interaction via oxygen ion leading to a ferromagnetic metallic ground state, no insulator-metal transition was detected. On the other hand, in the compounds with x=0.0 to 0.2, transport properties suggested an adiabatic small polaron hopping conduction mechanism. However, x=0.3 compound followed a variable range hopping conduction. Temperature variation of magnetization data exhibited three different types of transitions involving Mn and Dy ions. The bifurcation between zero field cooled and field cooled magnetization data was observed in all the compounds. Field-dependent magnetization of all the compounds showed hysteresis loops for temperatures less than 10 K. Although large irreversibility between zero field cooled and field cooled magnetization data was observed with a peak for x=0.3, the peak temperatures did not alter with frequency ruling out the possibility of spin glass behavior. The presence of hysteresis loops and lack of saturation magnetization implied the simultaneous presence of ferromagnetic and antiferromagnetic exchange interactions well within the antiferromagnetic ordering of Mn ions