IKK2 controls the inflammatory potential of tissue-resident regulatory T cells in a murine gain of function model.

Loss-of-function mutations have provided crucial insights into the immunoregulatory actions of Foxp3+ regulatory T cells (Tregs). By contrast, we know very little about the consequences of defects that amplify aspects of Treg function or differentiation. Here we show that mice heterozygous for an Ikbkb gain-of-function mutation develop psoriasis. Doubling the gene dose (IkbkbGoF/GoF) results in dactylitis, spondylitis, and characteristic nail changes, which are features of psoriatic arthritis. IkbkbGoF mice exhibit a selective expansion of Foxp3 + CD25+ Tregs of which a subset express IL-17. These modified Tregs are enriched in both inflamed tissues, blood and spleen, and their transfer is sufficient to induce disease without conventional T cells. Single-cell transcriptional and phenotyping analyses of isolated Tregs reveal expansion of non-lymphoid tissue (tissue-resident) Tregs expressing Th17-related genes, Helios, tissue-resident markers including CD103 and CD69, and a prominent NF-κB transcriptome. Thus, IKK2 regulates tissue-resident Treg differentiation, and overactivity drives dose-dependent skin and systemic inflammation.

EGCG-like non-competitive inhibitor of DYRK1A rescues cognitive defect in a down syndrome model.

Overexpression of the chromosome 21 DYRK1A gene induces morphological defects and cognitive impairments in individuals with Down syndrome (DS) and in DS mice models. Aging neurons of specific brain regions of patients with Alzheimer's disease, DS and Pick's disease have increased DYRK1A immunoreactivity suggesting a possible association of DYRK1A with neurofibrillary tangle pathology. Epigallocatechin-3-gallate (EGCG) displays appreciable inhibition of DYRK1A activity and, contrary to all other published inhibitors, EGCG is a non-competitive inhibitor of DYRK1A. Prenatal exposure to green tea polyphenols containing EGCG protects from brain defects induced by overexpression of DYRK1A. In order to produce more robust and possibly more active analogues of the natural compound EGCG, here we synthetized new EGCG-like molecules with several structural modifications to the EGCG skeleton. We replaced the ester boun of EGCG with a more resistant amide bond. We also replaced the oxygen ring by a methylene group. And finally, we positioned a nitrogen atom within this ring. The selected compound was shown to maintain the non-competitive property of EGCG and to correct biochemical and behavioral defects present in a DS mouse model. In addition it showed high stability and specificity.

Postnatal assessment for renal dysfunction in women with hypertensive disorders of pregnancy : A prospective observational study.

BACKGROUND: Hypertensive disorders of pregnancy are associated with chronic kidney disease. Early detection of renal dysfunction enables implementation of strategies to prevent progression. International guidelines recommend review at 6-8 weeks postpartum to identify persistent hypertension and abnormal renal function, but evidence for the efficacy of this review is limited. METHODS: All women attending a specialist fetal-maternal medicine clinic for hypertensive disorders of pregnancy (pre-eclampsia, chronic hypertension, gestational hypertension) were invited for a 6-8 weeks postpartum review of their blood pressure and renal function in order to establish the prevalence and independent predictors of renal dysfunction. Renal dysfunction was defined as low estimated Glomerular Filtration Rate (eGFR < 60 ml/min/1.73 m2) or proteinuria (24-h protein excretion > 150 mg or urinary albumin-to-creatinine ratio > 3 mg/mmol). All women attending a specialist clinic for hypertensive disorders were invited for a 6-8 weeks postpartum review of their blood pressure and renal function. Demographics, pregnancy and renal outcomes were prospectively collected. RESULTS: Between 2013 and 2019, 740 of 1050 (70.4%) women who had a pregnancy complicated by a hypertensive disorder attended their 6-8 weeks postpartum visit. Renal dysfunction was present in 32% of the total cohort and in 46% and 22% of women with and without pre-eclampsia, respectively. Multivariate logistic regression demonstrated that independent predictors were pre-eclampsia, chronic hypertension, highest measured antenatal serum creatinine, highest measured antenatal 24-h urinary protein, and blood pressure ≥ 140/90 mmHg at the postnatal visit. CONCLUSIONS: Renal dysfunction was present in one in three women with hypertensive disorders of pregnancy at 6-8 weeks postpartum. This includes women with gestational hypertension and chronic hypertension without superimposed pre-eclampsia, and thus these women should also be offered postnatal review.

Reactions of triflate esters and triflamides with an organic neutral super-electron-donor.

The bis-pyridinylidene 13 converts aliphatic and aryl triflate esters to the corresponding alcohols and phenols respectively, using DMF as solvent, generally in excellent yields. While the deprotection of aryl triflates has been seen with other reagents and by more than one mechanism, the deprotection of alkyl triflates is a new reaction. Studies with (18)O labelled DMF indicate that the C-O bond stays intact and hence it is the S-O bond that cleaves, underlining that the cleavage results from the extraordinary electron donor capability of 13. Trifluoromethanesulfonamides are converted to the parent amines in like manner, representing the first cleavage of such substrates by a ground-state organic reducing reagent.

A general synthetic approach to the amnesic shellfish toxins: total synthesis of (-)-isodomoic acid B, (-)-isodomoic acid E and (-)-isodomoic acid F.

The alkynylpyrrolidine 4 was made via a dearomatising cyclisation of an aromatic amide, and was elaborated by stannylcupration and palladium-catalysed coupling to achieve the first total synthesis of three members of the isodomoic acid family; the same alkyne can be envisaged as a precursor to several more of this class of amnesic shellfish toxins.