Nonresonant Three-body Decays of D and B Mesons

Nonresonant three-body decays of D and B mesons are studied. It is pointed out that if heavy meson chiral perturbation theory (HMChPT) is applied to the heavy-light strong and weak vertices and assumed to be valid over the whole kinematic region, then the predicted decay rates for nonresonant charmless 3-body B decays will be too large and especially B^- --> pi^- K^+ K^- greatly exceeds the current experimental limit. This can be understood as chiral symmetry has been applied there twice beyond its region of validity. If HMChPT is applied only to the strong vertex and the weak transition is accounted for by the form factors, the dominant B^* pole contribution to the tree-dominated direct three-body B decays will become small and the branching ratio will be of order 10^{-6}. The decay modes B^- --> (K^- h^+ h^-)_{NR} and bar{B}^0 --> (bar{K}^0 h^+h^-)_{NR} for h = pi, K are penguin dominated. We apply HMChPT in two different cases to study the direct 3-body D decays and compare the results with experiment. Theoretical uncertainties are discussed.Comment: 24 pages, 2 figures. New experimental results of direct 3-body D decays as Reported at ICHEP2002 are included. To appear in Phys. Re

Women with type 1 diabetes exhibit a progressive increase in gut Saccharomyces cerevisiae in pregnancy associated with evidence of gut inflammation.

Aims: Studies of the gut microbiome have focused on its bacterial composition. We aimed to characterize the gut fungal microbiome (mycobiome) across pregnancy in women with and without type 1 diabetes. Methods: Faecal samples (n = 162) were collected from 70 pregnant women (45 with and 25 without type 1 diabetes) across all trimesters. Fungi were analysed by internal transcribed spacer 1 amplicon sequencing. Markers of intestinal inflammation (faecal calprotectin) and intestinal epithelial integrity (serum intestinal fatty acid binding protein; I-FABP), and serum antibodies to Saccharomyces cerevisiae (ASCA) were measured. Results: Women with type 1 diabetes had decreased fungal alpha diversity by the third trimester, associated with an increased abundance of Saccharomyces cerevisiae that was inversely related to the abundance of the anti-inflammatory butyrate-producing bacterium Faecalibacterium prausnitzii. Women with type 1 diabetes had higher concentrations of calprotectin, I-FABP and ASCA. Conclusions: Women with type 1 diabetes exhibit a shift in the gut mycobiome across pregnancy associated with evidence of gut inflammation and impaired intestinal barrier function. The relevance of these findings to the higher rate of pregnancy complications in type 1 diabetes warrants further study.Esther Bandala-Sanchez, Alexandra J. Roth-Schulze, Helena Oakey Megan A.S. Penno, Naiara G. Bediaga, Gaetano Naselli, Katrina M. Ngui, Alannah D. Smith, Dexing Huang, Enrique Zozaya-Valdes, Rebecca L. Thomson, James D. Brown, Peter J. Vuillermin, Simon C. Barry, Maria E. Craig, William D. Rawlinson, Elizabeth A. Davis, Mark Harris, Georgia Soldatos, Peter G. Colman, John M. Wentworth, Aveni Haynes, Grant Morahan, Richard O. Sinnott, Anthony T. Papenfuss, Jennifer J. Couper, Leonard C. Harrison, on behalf of the ENDIA Study Grou

Siglec-10 expression is up-regulated in activated human CD4+ T cells

Most sialic acid–binding immunoglobulin-like lectins (Siglecs) suppress immune cell function but are expressed at low levels on human T cells. We found that soluble CD52 inhibited T cell signalling by ligating Siglec-10, but the presence of Siglec-10 on human T cells has been questioned. To address this concern, we examined the expression of Siglec-10 at the RNA and protein level in human CD4+ T cells. Analysis by RNAseq, qPCR and flow cytometry demonstrated that, in contrast to other Siglecs, after activation of CD4+ T cells Siglec-10 was selectively upregulated in a subset of cells also high for CD52 expression. This observation is consistent with a homeostatic role for Siglec-10 in human CD4+ T cells.E. Bandala-Sanchez, N.G. Bediaga, G. Naselli, A.M. Neale, L.C. Harriso

Pre-mitotic genome re-organisation bookends the B cell differentiation process

During cellular differentiation chromosome conformation is intricately remodelled to support the lineage-specific transcriptional programs required for initiating and maintaining lineage identity. When these changes occur in relation to cell cycle, division and time in response to cellular activation and differentiation signals has yet to be explored, although it has been proposed to occur during DNA synthesis or after mitosis. Here, we elucidate the chromosome conformational changes in B lymphocytes as they differentiate and expand from a naive, quiescent state into antibody secreting plasma cells. We find gene-regulatory chromosome reorganization in late G1 phase before the first division, and that this configuration is remarkably stable as the cells massively and rapidly clonally expand. A second wave of conformational change occurs as cells terminally differentiate into plasma cells, coincident with increased time in G1 phase. These results provide further explanation for how lymphocyte fate is imprinted prior to the first division. They also suggest that chromosome reconfiguration occurs prior to DNA replication and mitosis, and is linked to a gene expression program that controls the differentiation process required for the generation of immunity.Wing Fuk Chan, Hannah D. Coughlan, Jie H. S. Zhou, Christine R. Keenan, Naiara G. Bediaga, Philip D. Hodgkin, Gordon K. Smyth, Timothy M. Johanson, Rhys S. Alla

Minimal variation of the plasma lipidome after delayed processing of neonatal cord blood

Published online: 25 September 2018Background: Cord blood lipids are potential disease biomarkers. We aimed to determine if their concentrations were affected by delayed blood processing. Method: Refrigerated cord blood from six healthy newborns was centrifuged every 12 h for 4 days. Plasma lipids were analysed by liquid chromatography/mass spectroscopy. Results: Of 262 lipids identified, only eight varied significantly over time. These comprised three dihexosylceramides, two phosphatidylserines and two phosphatidylethanolamines whose relative concentrations increased and one sphingomyelin that decreased. Conclusion: Delay in separation of plasma from refrigerated cord blood has minimal effect overall on the plasma lipidome.John M. Wentworth, Naiara G. Bediaga, Megan A. S. Penno, Esther Bandala, Sanchez, Komal N. Kanojia, Konstantinos A. Kouremenos, Jennifer J. Couper, Leonard C. Harrison, ENDIA Study Grou

Cytotoxicity-related gene expression and chromatin accessibility define a subset of CD4+ T cells that mark progression to type 1 diabetes.

This article contains supplementary material online at https://doi.org/10.2337/figshare.17185898.Type 1 diabetes in children is heralded by a preclinical phase defined by circulating autoantibodies to pancreatic islet antigens. How islet autoimmunity is initiated and then progresses to clinical diabetes remains poorly understood. Only one study has reported gene expression in specific immune cells of children at risk associated with progression to islet autoimmunity. We analyzed gene expression with RNA sequencing in CD4+ and CD8+ T cells, natural killer (NK) cells, and B cells, and chromatin accessibility by assay for transposase-accessible chromatin sequencing (ATAC-seq) in CD4+ T cells, in five genetically at risk children with islet autoantibodies who progressed to diabetes over a median of 3 years (“progressors”) compared with five children matched for sex, age, and HLA-DR who had not progressed (“nonprogressors”). In progressors, differentially expressed genes (DEGs) were largely confined to CD4+ T cells and enriched for cytotoxicity-related genes/pathways. Several top-ranked DEGs were validated in a semi-independent cohort of 13 progressors and 11 nonprogressors. Flow cytometry confirmed that progression was associated with expansion of CD4+ cells with a cytotoxic phenotype. By ATAC-seq, progression was associated with reconfiguration of regulatory chromatin regions in CD4+ cells, some linked to differentially expressed cytotoxicity-related genes. Our findings suggest that cytotoxic CD4+ T cells play a role in promoting progression to type 1 diabetes.Naiara G. Bediaga, Alexandra L. Garnham, Gaetano Naselli, Esther Bandala-Sanchez, Natalie L. Stone, Joanna Cobb, Jessica E. Harbison, John M. Wentworth, Annette-G. Ziegler, Jennifer J. Couper, Gordon K. Smyth, and Leonard C. Harriso

Simplifying prediction of disease progression in pre-symptomatic type 1 diabetes using a single blood sample.

AIMS/HYPOTHESIS: Accurate prediction of disease progression in individuals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood samples taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw. METHODS: Models to predict disease progression using a single OGTT time point (0, 30, 60, 90 or 120 min) were developed using TrialNet data collected from relatives with type 1 diabetes and validated in independent populations at high genetic risk of type 1 diabetes (TrialNet, Diabetes Prevention Trial-Type 1, The Environmental Determinants of Diabetes in the Young [1]) and in a general population of Bavarian children who participated in Fr1da. RESULTS: Cox proportional hazards models combining plasma glucose, C-peptide, sex, age, BMI, HbA1c and insulinoma antigen-2 autoantibody status predicted disease progression in all populations. In TrialNet, the AUC for receiver operating characteristic curves for models named M60, M90 and M120, based on sampling at 60, 90 and 120 min, was 0.760, 0.761 and 0.745, respectively. These were not significantly different from the AUC of 0.760 for the gold standard Diabetes Prevention Trial Risk Score, which requires five OGTT blood samples. In TEDDY, where only 120 min blood sampling had been performed, the M120 AUC was 0.865. In Fr1da, the M120 AUC of 0.742 was significantly greater than the M60 AUC of 0.615. CONCLUSIONS/INTERPRETATION: Prediction models based on a single OGTT blood draw accurately predict disease progression from stage 1 or 2 to stage 3 type 1 diabetes. The operational simplicity of M120, its validity across different at-risk populations and the requirement for 120 min sampling to stage type 1 diabetes suggest M120 could be readily applied to decrease the cost and complexity of risk stratification

A placental model of SARS-CoV-2 infection reveals ACE2-dependent susceptibility and differentiation impairment in syncytiotrophoblasts

Published online: 13 July 2023SARS-CoV-2 infection causes COVID-19. Several clinical reports have linked COVID-19 during pregnancy to negative birth outcomes and placentitis. However, the pathophysiological mechanisms underpinning SARS-CoV-2 infection during placentation and early pregnancy are not clear. Here, to shed light on this, we used induced trophoblast stem cells to generate an in vitro early placenta infection model. We identified that syncytiotrophoblasts could be infected through angiotensin-converting enzyme 2 (ACE2). Using a co-culture model of vertical transmission, we confirmed the ability of the virus to infect syncytiotrophoblasts through a previous endometrial cell infection. We further demonstrated transcriptional changes in infected syncytiotrophoblasts that led to impairment of cellular processes, reduced secretion of HCG hormone and morphological changes vital for syncytiotrophoblast function. Furthermore, different antibody strategies and antiviral drugs restore these impairments. In summary, we have established a scalable and tractable platform to study early placental cell types and highlighted its use in studying strategies to protect the placenta.J. Chen, J. A. Neil, J. P. Tan, R. Rudraraju, M. Mohenska, Y. B. Y. Sun, E. Walters, N. G. Bediaga, G. Sun, Y. Zhou, Y. Li, D. Drew, P. Pymm, W. H. Tham, F. J. Rossello, G. Nie, X. Liu, K. Subbarao and J. M. Pol