The design of bioinspired nanostructures and materials of defined size and shape is challenging as it pushes our understanding of biomolecular assembly to its limits. In such endeavors, DNA is the current building block of choice because of its predictable and programmable self-assembly. The use of peptide- and protein-based systems, however, has potential advantages due to their more-varied chemistries, structures and functions, and the prospects for recombinant production through gene synthesis and expression. Here, we present the design and characterization of two complementary peptides programmed to form a parallel heterodimeric coiled coil, which we use as the building blocks for larger, supramolecular assemblies. To achieve the latter, the two peptides are joined via peptidic linkers of variable lengths to produce a range of assemblies, from flexible fibers of indefinite length, through large colloidal-scale assemblies, down to closed and discrete nanoscale objects of defined stoichiometry. We posit that the different modes of assembly reflect the interplay between steric constraints imposed by short linkers and the bulk of the helices, and entropic factors that favor the formation of many smaller objects as the linker length is increased. This approach, and the resulting linear and proteinogenic polypeptides, represents a new route for constructing complex peptide-based assemblies and biomaterials.
ContextInsulin autoimmune syndrome (IAS), spontaneous hyperinsulinemic hypoglycemia due to insulin-binding autoantibodies, may be difficult to distinguish from tumoral or other forms of hyperinsulinemic hypoglycemia, including surreptitious insulin administration. No standardized treatment regimen exists.ObjectivesTo evaluate an analytic approach to IAS and responses to different treatments.Design and SettingObservational study in the UK Severe Insulin Resistance Service.PatientsSix patients with hyperinsulinemic hypoglycemia and detectable circulating anti–insulin antibody (IA).Main Outcome MeasuresGlycemia, plasma insulin, and C-peptide concentrations by immunoassay or mass spectrometry (MS). Immunoreactive insulin was determined in the context of polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC). IA quantification using ELISA and RIA, and IA were further characterized using radioligand binding studies.ResultsAll patients were diagnosed with IAS (five IgG, one IgA) based on a high insulin/C-peptide ratio, low insulin recovery after PEG precipitation, and GFC evidence of antibody-bound insulin. Neither ELISA nor RIA result proved diagnostic for every case. MS provided a more robust quantification of insulin in the context of IA. One patient was managed conservatively, four were treated with diazoxide without sustained benefit, and four were treated with immunosuppression with highly variable responses. IA affinity did not appear to influence presentation or prognosis.ConclusionsIAS should be considered in patients with hyperinsulinemic hypoglycemia and a high insulin/C-peptide ratio. Low insulin recovery on PEG precipitation supports the presence of insulin-binding antibodies, with GFC providing definitive confirmation. Immunomodulatory therapy should be customized according to individual needs and clinical response.
ObjectivesTo investigate the static frictional resistance at the bracket/archwire interface in two recently introduced bracket systems and compare them to conventional ceramic and conventional metal bracket systems. Three variables were considered including the bracket system, archwire type and archwire angulation.Material and MethodsFour bracket systems were tested in vitro: Self ligating ceramic, ceramic with metal slot and module, conventional ceramic with module and conventional metal with module. A specially constructed jig and an Instron testing machine were used to measure the static frictional resistance for 0.014 inches round and 0.018 x 0.025 inches rectangular stainless steel wires at 0° and 7° angulations. Main outcome measures: static frictional force at the bracket/archwire interface; recorded and measured in units of force (Newtons).ResultsSelf ligating ceramic and metal slot ceramic bracket systems generated significantly less static frictional resistance than conventional ceramic bracket systems with the wire at both angulations (P < 0.05). Changing the wire from 0.014 round to 0.018 x 0.025 rectangular wire significantly increased frictional forces for metal slot ceramic and conventional metal bracket systems (P < 0.01). Increasing wire angulation significantly increased frictional resistance at the bracket/archwire interface for all four types of bracket systems tested (P < 0.001).ConclusionsCompared to conventional ceramic, self ligating ceramic and metal slot ceramic bracket systems should give improved clinical performance, matching that of conventional metal brackets.
Individuals with type 1 diabetes (T1D) are at increased risk of coeliac disease (CD), autoimmune thyroiditis and autoimmune gastritis, but the absolute risks are unclear. The aim of this study was to investigate the prevalence of autoantibodies to tissue transglutaminase (TGA), thyroid peroxidase (TPOA) and gastric H /K -ATPase (ATPA) and their genetic associations in a well-characterized population-based cohort of individuals with T1D from the Bart's-Oxford family study for whom islet autoantibody prevalence data were already available. Autoantibodies in sera from 1072 patients (males/females 604/468; median age 11·8 years, median T1D duration 2·7 months) were measured by radioimmunoassays; HLA class II risk genotype was analysed in 973 (91%) using polymerase chain reaction with sequence specific primers (PCR-SSP). The prevalence of TGA (and/or history of CD), TPOA and ATPA in patients was 9·0, 9·6 and 8·2%, respectively; 3·1% had two or more autoantibodies. Females were at higher risk of multiple autoimmunity; TGA/CD were associated with younger age and TPOA with older age. ATPA were uncommon in patients under 5 years, and more common in older patients. Anti-glutamate decarboxylase autoantibodies were predictive of co-existing TPOA/ATPA. TGA/CD were associated with human leucocyte antigen (HLA) DR3-DQ2, with the DR3-DQ2/DR3-DQ2 genotype conferring the highest risk, followed by DR4-DQ8/DR4-DQ8. ATPA were associated with DR3-DQ2, DRB1*0404 (in males) and the DR3-DQ2/DR4-DQ8 genotype. TPOA were associated with the DR3-DQ2/DR3-DQ2 genotype. Almost one-quarter of patients diagnosed with T1D aged under 21 years have at least one other organ-specific autoantibody. HLA class II genetic profiling may be useful in identifying those at risk of multiple autoimmunity.
Zinc transporter 8 (ZnT8), a protein highly specific to pancreatic insulin-producing beta cells, is vital for the biosynthesis and secretion of insulin. ZnT8 autoantibodies (ZnT8A) are among the most recently discovered and least-characterised islet autoantibodies. In combination with autoantibodies to several other islet antigens, including insulin, ZnT8A help predict risk of future type 1 diabetes. Often, ZnT8A appear later in the pathogenic process leading to type 1 diabetes, suggesting that the antigen is recognised as part of the spreading, rather than the initial, autoimmune response. The development of autoantibodies to different forms of ZnT8 depends on the genotype of an individual for a polymorphic ZnT8 residue. This genetic variant is associated with susceptibility to type 2 but not type 1 diabetes. Levels of ZnT8A often fall rapidly after diagnosis while other islet autoantibodies can persist for many years. In this review, we consider the contribution made by ZnT8 to our understanding of type 1 diabetes over the past decade and what remains to be investigated in future research.Electronic supplementary materialThe online version of this article (10.1007/s00125-019-04975-x) contains a slideset of the figures for download, which is available to authorised users.
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