Fast and Efficient Postsynthetic DNA Labeling in Cells by Means of Strain-Promoted Sydnone-Alkyne Cycloadditions

Fast and efficient: DNA strands, modified with the novel bioorthogonal reporters sydnones, undergo fast and efficient labeling with cyclooctynes and have the potential to become essential tools for imaging DNA and possibly RNA in cells. Sydnones are highly stable mesoionic 1,3-dipoles that react with cyclooctynes through strain-promoted sydnone-alkyne cycloaddition (SPSAC). Although sydnones have been shown to be valuable bioorthogonal chemical reporters for the labeling of proteins and complex glycans, nucleic acids have not yet been tagged by SPSAC. Evaluation of SPSAC kinetics with model substrates showed fast reactions with cyclooctyne probes (up to k=0.59 M$^{-1}$ s$^{-1}$), and two different sydnones were effectively incorporated into both 2’-deoxyuridines at position 5, and 7-deaza-2’-deoxyadenosines at position 7. These modified nucleosides were synthetically incorporated into single-stranded DNAs, which were successfully postsynthetically labeled with cyclooctyne probes both in vitro and in cells. These results show that sydnones are versatile bioorthogonal tags and have the premise to become essential tools for tracking DNA and potentially RNA in living cells

Phenotype standardization for statin-induced myotoxicity

Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.</p

The possible site of trauma in leucodermic/vitiligenous skin

The histological, histochemical and ultrastructural changes in leucodermic skins are compared with those of normal human skins in order to find out if the former represents a traumatized skin. There were no significant differences in the histochemical features between the normal and leucodermic human skins, Ultrastructural studies however revealed that the melanocytes in the affected areas were undergoing degenerative changes such as loss of melanosomes, structural alterations in melanosomes and the presence of wide intracellular spaces. It is, therefore, suggested that in leucoderma, there occurs cellular traumatization rather than traumatisation at the organ level

Dissecting the genetic basis of wheat blast resistance in the Brazilian wheat cultivar BR 18-Terena.

Background: Wheat blast, caused by Magnaporthe oryzae Triticum (MoT) pathotype, is a global threat to wheat (Triticum aestivum L.) production. Few blast resistance (R) genes have been identified to date, therefore assessing potential sources of resistance in wheat is important. The Brazilian wheat cultivar BR 18-Terena is considered one of the best sources of resistance to blast and has been widely used in Brazilian breeding programmes, however the underlying genetics of this resistance are unknown. Results: BR 18-Terena was used as the common parent in the development of two recombinant inbred line (RIL) F6 populations with the Brazilian cultivars Anahuac 75 and BRS 179. Populations were phenotyped for resistance at the seedling and heading stage using the sequenced MoT isolate BR32, with transgressive segregation being observed. Genetic maps containing 1779 and 1318 markers, were produced for the Anahuac 75 × BR 18-Terena and BR 18- Terena × BRS 179 populations, respectively. Five quantitative trait loci (QTL) associated with seedling resistance, on chromosomes 2B, 4B (2 QTL), 5A and 6A, were identified, as were four QTL associated with heading stage resistance (1A, 2B, 4A and 5A). Seedling and heading stage QTL did not co-locate, despite a significant positive correlation between these traits, indicating that resistance at these developmental stages is likely to be controlled by different genes. BR 18-Terena provided the resistant allele for six QTL, at both developmental stages, with the largest phenotypic effect conferred by a QTL being 24.8% suggesting that BR 18-Terena possesses quantitative resistance. Haplotype analysis of 100 Brazilian wheat cultivars indicates that 11.0% of cultivars already possess a BR 18-Terenalike haplotype for more than one of the identified heading stage QTL. Conclusions: This study suggests that BR 18-Terena possesses quantitative resistance to wheat blast, with nine QTL associated with resistance at either the seedling or heading stage being detected. Wheat blast resistance is also largely tissue-specific. Identification of durable quantitative resistances which can be combined with race-specific R gene-mediated resistance is critical to effectively control wheat blast. Collectively, this work facilitates markerassisted selection to develop new varieties for cultivation in regions at risk from this emerging disease

Genetic association study of NF-κB genes in UK caucasian adult and juvenile onset idiopathic inflammatory myopathy

Objective. Treatment-resistant muscle wasting is an increasingly recognized problem in idiopathic inflammatory myopathy (IIM). TNF-α is thought to induce muscle catabolism via activation of nuclear factor-kappa B (NF-κB). Several genes share homology with the NF-κB family of proteins. This study investigated the role of NF-κB-related genes in disease susceptibility in UK Caucasian IIM. Methods. Data from 362 IIM cases [274 adults, 49 (±14.0) years, 72% female; 88 juveniles, 6 (±3.6) years, 73% female) were compared with 307 randomly selected Caucasian controls. DNA was genotyped for 63 single nucleotide polymorphisms (SNPs) from NF-κB-related genes. Data were stratified by IIM subgroup/serotype. Results. A significant allele association was observed in the overall IIM group vs controls for the IKBL-62T allele (rs2071592, odds ratio 1.5, 95% CI 1.21, 1.89, corrected P = 0.0086), which strengthened after stratification by anti-Jo-1 or -PM-Scl antibodies. Genotype analysis revealed an increase for the AT genotype in cases under a dominant model. No other SNP was associated in the overall IIM group. Strong pairwise linkage disequilibrium was noted between IKBL-62T, TNF-308A and HLA-B*08 (D′ = 1). Using multivariate regression, the IKBL-62T IIM association was lost after adjustment for TNF-308A or HLA-B*08. Conclusion. An association was noted between IKBL-62T and IIM, with increased risk noted in anti-Jo-1- and -PM-Scl antibody-positive patients. However, the IKBL-62T association is dependent on TNF-308A and HLA-B*08, due to strong shared linkage disequilibrium between these alleles. After adjustment of the 8.1 HLA haplotype, NF-κB genes therefore do not independently confer susceptibility in IIM

Antibody responses to single‐dose SARS‐CoV‐2 vaccination in patients receiving immunomodulators for immune‐mediated inflammatory disease

From Wiley via Jisc Publications RouterHistory: received 2021-04-13, rev-recd 2021-05-06, accepted 2021-05-08, pub-electronic 2021-06-04Article version: VoRPublication status: PublishedFunder: Psoriasis Association; Id: http://dx.doi.org/10.13039/10001312

In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class II haplotype, rather than by myositis subtype

The aim of this study was to investigate HLA class II associations in polymyositis (PM) and dermatomyositis (DM), and to determine how these associations influence clinical and serological differences. DNA samples were obtained from 225 UK Caucasian idiopathic inflammatory myopathy patients (PM = 117, DM = 108) and compared with 537 randomly selected UK Caucasian controls. All cases had also been assessed for the presence of related malignancy and interstitial lung disease (ILD), and a number of myositis-specific/myositis-associated antibodies (MSAs/MAAs). Subjects were genotyped for HLA-DRB1, DQA1 and DQB1. HLA-DRB1*03, DQA1*05 and DQB1*02 were associated with an increased risk for both PM and DM. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype demonstrated strong association with ILD, irrespective of myositis subtype or presence of anti-aminoacyl-transfer RNA synthetase antibodies. The HLA-DRB1*07-DQA1*02-DQB1*02 haplotype was associated with risk for anti-Mi-2 antibodies, and discriminated PM from DM (odds ratio 0.3, 95% confidence interval 0.1–0.6), even in anti-Mi-2 negative patients. Other MSA/MAAs showed specific associations with other HLA class II haplotypes, irrespective of myositis subtype. There were no genotype, haplotype or serological associations with malignancy. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype associations appear to not only govern disease susceptibility in Caucasian PM/DM patients, but also phenotypic features common to PM/DM. Though strongly associated with anti-Mi-2 antibodies, the HLA-DRB1*07-DQA1*02-DQB1*02 haplotype shows differential associations with PM/DM disease susceptibility. In conclusion, these findings support the notion that myositis patients with differing myositis serology have different immunogenetic profiles, and that these profiles may define specific myositis subtypes

Recommendations for the management of secondary hypogammaglobulinaemia due to B cell targeted therapies in autoimmune rheumatic diseases

OBJECTIVES: The association of B cell targeted therapies with development of hypogammaglobulinaemia and infection is increasingly recognized. Our aim was to develop consensus recommendations for immunoglobulin replacement therapy for management of hypogammaglobulinaemia following B cell targeted therapies in autoimmune rheumatic diseases. // METHODS: A modified Delphi exercise involved a 17-member Taskforce committee, consisting of immunologists, rheumatologists, nephrologists, haematologists, a gastroenterologist, an immunology specialist nurse and a patient representative. The first round identified the most pertinent topics to address in the recommendations. A search string was agreed upon for the identification of publications in PubMed focusing on these areas, for a systematic literature review. Original data was presented from this review to the Taskforce committee. Recommendations from the British Society for Rheumatology, the UK Department of Health, EULAR, the ACR, and the American Academy of Allergy, Asthma, and Immunology were also reviewed. The evidence was discussed in a face-to-face meeting to formulate recommendation statements. The levels of evidence and statements were graded according to Scottish Intercollegiate Guidelines Network methodology. // RESULTS: Three overarching principles, eight recommendation statements and a research agenda were formulated. The Taskforce committee voted on these statements, achieving 82–100% agreement for each recommendation. The strength of the recommendations was restricted by the low quality of the available evidence, with no randomized controlled trial data. The recommendations cover risk factors, monitoring, referral for hypogammaglobulinaemia; indications, dosage and discontinuation of immunoglobulin replacement therapy. // CONCLUSION: These are the first recommendations specifically formulated for B cell targeted therapies related to hypogammaglobulinaemia in autoimmune rheumatic diseases. The recommendations are to aid health-care professionals with clinical decision making for patients with hypogammaglobulinaemia