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Immune tolerance is executed partly by Foxp3 + regulatory T (Treg) cells, which suppress autoreactive T cells. In autoimmune type 1 diabetes (T1D) impaired tolerance promotes destruction of insulin-producing β-cells. The development of autoantigen-specific vaccination strategies for Foxp3 + Treg-induction and prevention of islet autoimmunity in patients is still in its infancy. Here, using human haematopoietic stem cell-engrafted NSG-HLA-DQ8 transgenic mice, we provide direct evidence for human autoantigen-specific Foxp3 + Treg-induction in vivo . We identify HLA-DQ8-restricted insulin-specific CD4 + T cells and demonstrate efficient human insulin-specific Foxp3 + Treg-induction upon subimmunogenic vaccination with strong agonistic insulin mimetopes in vivo . Induced human Tregs are stable, show increased expression of Treg signature genes such as Foxp3, CTLA4, IL-2Rα and TIGIT and can efficiently suppress effector T cells. Such Foxp3 + Treg-induction does not trigger any effector T cells. These T1D vaccine candidates could therefore represent an expedient improvement in the challenge to induce human Foxp3 + Tregs and to develop novel precision medicines for prevention of islet autoimmunity in children at risk of T1D. Type 1 diabetes is associated with the loss of self-tolerance to the insulin-producing β-cells in the pancreas. Here the authors show that vaccination with insulin mimetopes can induce human insulin-specific regulatory T cells to mediate tolerance in a humanized mouse model.

Light-matter interaction has played a central role in understanding as well as engineering new states of matter. Reversible coupling of excitons and photons enabled groundbreaking results in condensation and superfluidity of nonequilibrium quasiparticles with a photonic component. We investigated such cavity-polaritons in the presence of a high-mobility two-dimensional electron gas, exhibiting strongly correlated phases. When the cavity was on resonance with the Fermi level, we observed previously unknown many-body physics associated with a dynamical hole-scattering potential. In finite magnetic fields, polaritons show distinct signatures of integer and fractional quantum Hall ground states. Our results lay the groundwork for probing nonequilibrium dynamics of quantum Hall states and exploiting the electron density dependence of polariton splitting so as to obtain ultrastrong optical nonlinearities.

Aims/hypothesisThe aim of this study was to develop strategies that identify children from the general population who have late-stage presymptomatic type 1 diabetes and may, therefore, benefit from immune intervention.MethodsWe tested children from Bavaria, Germany, aged 1.75–10 years, enrolled in the Fr1da public health screening programme for islet autoantibodies (n=154,462). OGTT and HbA1c were assessed in children with multiple islet autoantibodies for diagnosis of presymptomatic stage 1 (normoglycaemia) or stage 2 (dysglycaemia) type 1 diabetes. Cox proportional hazards and penalised logistic regression of autoantibody, genetic, metabolic and demographic information were used to develop a progression likelihood score to identify children with stage 1 type 1 diabetes who progressed to stage 3 (clinical) type 1 diabetes within 2 years.ResultsOf 447 children with multiple islet autoantibodies, 364 (81.4%) were staged. Undiagnosed stage 3 type 1 diabetes, presymptomatic stage 2, and stage 1 type 1 diabetes were detected in 41 (0.027% of screened children), 30 (0.019%) and 293 (0.19%) children, respectively. The 2 year risk for progression to stage 3 type 1 diabetes was 48% (95% CI 34, 58) in children with stage 2 type 1 diabetes (annualised risk, 28%). HbA1c, islet antigen-2 autoantibody positivity and titre, and the 90 min OGTT value were predictors of progression in children with stage 1 type 1 diabetes. The derived progression likelihood score identified substages corresponding to ≤90th centile (stage 1a, n=258) and >90th centile (stage 1b, n=29; 0.019%) of stage 1 children with a 4.1% (95% CI 1.4, 6.7) and 46% (95% CI 21, 63) 2 year risk of progressing to stage 3 type 1 diabetes, respectively.Conclusions/interpretationPublic health screening for islet autoantibodies found 0.027% of children to have undiagnosed clinical type 1 diabetes and 0.038% to have undiagnosed presymptomatic stage 2 or stage 1b type 1 diabetes, with 50% risk to develop clinical type 1 diabetes within 2 years.

Diel vertical migration (DVM) is a common behavior of many pelagic herbivorous zooplankton species in response to predation pressure. It is characterized by a twice daily habitat shift of the zooplankton species: staying in the epilimnion only during night time and migrating down in the crack of dawn in deeper water layers, staying there during the day time. This causes a discontinuous grazing regime and previous studies have shown that the direction and strength of phytoplankton community responses to zooplankton DVM most probably depends on the size of phytoplankton species. To examine the influence of zooplankton DVM on different sized phytoplankton communities, we designed an experiment where we manipulated the size distribution of a natural phytoplankton community a priori in field mesocosms. We investigated the influence of DVM of the cladoceran Daphnia hyalina on two different phytoplankton communities, by the use of deep (10 m) field enclosures. Epilimnetic lake water, containing a summer phytoplankton community, was filtered with two different mesh sizes (11 mm and 64 mm). The 11 mm phytoplankton community (“small”) contained mainly small algal species, while the 64 mm community (“large”) had a wider range of phytoplankton sizes. To simulate zooplankton DVM, D. hyalina were placed in mesh cages that were lowered or raised (“migration”) as dictated by the study design; a “no migration” (representing absence of DVM) treatment was also tested. Phytoplankton abundance was measured using chlorophyll-a and biovolume; size distribution of the algae and nutrient availability was also determined in each treatment. The results indicated that DVM had contrasting effects on the two evaluated phytoplankton communities. Comparison of “migration” and “no migration” zooplankton treatments showed that nutrient availability and total phytoplankton biovolume was higher in (1) “no migration” treatments with phytoplankton communities comprising mainly small algae and (2) “migration” treatments with phytoplankton communities of a broader size spectrum of algae. Hence our study showed two different mechanisms of how zooplankton DVM may influence the phytoplankton community dynamics. Nutrient cycling was an important factor in phytoplankton communities of mainly small algae, whereas the refuge effect was the main driver of phytoplankton dynamics in phytoplankton communities of a large size spectrum of algae.

Type 1 diabetes begins with autoimmunity against pancreatic islet antigens, including insulin. The aim of the Primary Oral Insulin Trial (POInT) was to evaluate the efficacy and safety of daily high-dose oral insulin to prevent the development of islet autoantibodies and diabetes. In this randomised, controlled, primary prevention trial, genetic screening in seven obstetric and paediatric clinics in Germany, Poland, Sweden, Belgium, and the UK identified newborns with a greater than 10% risk of developing islet autoimmunity. Eligible infants aged 4–7 months were randomly assigned in a 1:1 ratio to receive insulin manufactured from human zinc–insulin crystals administered orally at a once-daily dose of 7·5 mg for 2 months, increasing to 22·5 mg for 2 months and 67·5 mg until age 3 years, or placebo. Participants were randomly assigned via a web-based application and were stratified by site. The primary outcome was the development of two or more islet autoantibodies or diabetes assessed throughout follow-up until a maximum age of 6·5 years. A secondary outcome was the development of dysglycaemia or diabetes. Islet autoantibodies were measured in samples collected at baseline and during study visits conducted at outpatient clinics at 2, 4, and 8 months after randomisation, at age 18 months, and every 6 months thereafter. All participants and their family members, investigators of the study, and laboratory personnel remained masked to treatment allocation during the whole study. All randomly assigned participants who correctly fulfilled eligibility criteria and had not reached the primary outcome at the baseline visit (modified intention-to-treat) were included in the primary analysis. All participants who received at least one dose of study drug were included in the safety analysis. POInT is registered with ClinicalTrials.gov (NCT03364868) and is complete. Of 241 977 screened newborns, 2750 (1·14%) had an elevated genetic risk of developing islet autoimmunity and 1050 (38·2%) of the eligible infants (531 males [51%], 519 females [49%]), were assigned to oral insulin or placebo between Feb 7, 2018, and March 24, 2021. Two participants in the oral insulin group and none in the placebo group were excluded from the modified intention-to-treat analysis. The primary outcome developed in 52 (10%) participants in the insulin group and 46 (9%) in the placebo group (hazard ratio 1·12 [95% CI 0·76–1·67], p=0·57). An interaction between treatment and the INS rs1004446 genotype was observed, with an increase in the primary outcome in participants in the insulin group carrying non-susceptible INS genotypes compared with the placebo group (2·10 [1·08–4·09]) and protection against diabetes or dysglycaemia in participants in the insulin group carrying susceptible INS genotypes compared with the placebo group (0·38 [0·17–0·86]). Blood glucose values less than 50 mg/dL were observed in two (0·03%) of 7210 measurements in the insulin group and six (0·08%) of 7070 measurements in the placebo group. Of 10 252 reported adverse events, 5076 (49·5%) occurred in 507 (96·0%) of 528 participants in the oral insulin group and 5176 (50·5%) occurred in 500 (95·8%) of 522 participants in the placebo group. One death occurred in the oral insulin group and was unrelated to the study drug following independent review. There was no evidence that high-dose, daily oral insulin prevents the development of islet autoantibodies. Further studies are needed to assess the benefit of primary oral insulin therapy for preventing diabetes in INS genotype-selected infants. Leona M and Harry B Helmsley Charitable Trust.

One of the core principles in service oriented computing is that services are always on and available. There are however domains where running services all the time is not suitable, for example when applying simulation workflows in the eScience domain. The simulation services orchestrated by these workflows are typically used only rarely and irregularly, keeping them running all the time would result in a significant waste of resources. As a consequence, we developed the approach of on-demand provisioning of workflow middleware and services. In this paper we will give an overview about our work. We will present the motivation and main idea of our solution approach and will also provide details about some of the results of our work. The overview about our previous and current work is then complemented by a detailed discussion and comparison of the roles involved in both concepts, traditional service oriented computing as well as our newly developed on-demand provisioning approach.

Aims/hypothesis Progression to type 1 diabetes in children and adolescents is not uniform. Based on individual genetic background and environment, islet autoimmunity may develop at variable age, exhibit different autoantibody profiles and progress to clinical diabetes at variable rates. Here, we aimed to quantify the qualitative dynamics of sequential islet autoantibody profiles in order to identify longitudinal patterns that stratify progression rates to type 1 diabetes in multiple-autoantibody-positive children. Methods Qualitative changes in antibody status on follow-up and progression rate to diabetes were analysed in 88 children followed from birth in the prospective BABYDIAB study who developed multiple autoantibodies against insulin (IAA), GAD (GADA), insulinoma-associated antigen-2 (IA-2A) and/or zinc transporter 8 (ZnT8A). An algorithm was developed to define similarities in sequential autoantibody profiles and hierarchical clustering was performed to group children with similar profiles. Results We defined nine clusters that distinguished children with respect to their sequential profiles of IAA, GADA, IA-2A and ZnT8A. Progression from first autoantibody appearance to clinical diabetes between clusters ranged from 6% (95% CI [0, 16.4]) to 73% (28.4, 89.6) within 5 years. Delayed progression was observed in children who were positive for only two autoantibodies, and for a cluster of 12 children who developed three or four autoantibodies but were IAA-negative in their last samples, nine of whom lost IAA positivity during follow-up. Among all children who first seroconverted to IAA positivity and developed at least two other autoantibodies ( n  = 57), the 10 year risk of diabetes was 23% (0, 42.9) in those who became IAA-negative during follow-up compared with 76% (58.7, 85.6) in those who remained IAA-positive ( p  = 0.004). Conclusions/interpretation The novel clustering approach provides a tool for stratification of islet autoantibody-positive individuals that has prognostic relevance, and new opportunities in elucidating disease mechanisms. Our data suggest that losing IAA reactivity is associated with delayed progression to type 1 diabetes in multiple-islet-autoantibody-positive children.

ObjectiveINGR1D (INvestigating Genetic Risk for type 1 Diabetes) was a type 1 diabetes (T1D) genetic screening study established to identify participants for a primary prevention trial (POInT, Primary Oral Insulin Trial).MethodsThe majority of participants were recruited by research midwives in antenatal clinics from 18 weeks’ gestation. Using the NHS Newborn Bloodspot Screening Programme (NBSP) infrastructure, participants enrolled in INGR1D had an extra sample taken from their day 5 bloodspot card sent for T1D genetic screening. Those at an increased risk of T1D were informed of the result, given education about T1D and the opportunity to take part in POInT.ResultsBetween April 2018 and November 2020, 66% of women approached about INGR1D chose to participate. 15 660 babies were enrolled into INGR1D and 14 731 blood samples were processed. Of the processed samples, 157 (1%) had confirmed positive results, indicating an increased risk of T1D, of whom a third (n=49) enrolled into POInT (20 families were unable to participate in POInT due to COVID-19 lockdown restrictions).ConclusionThe use of prospective consent to perform personalised genetic testing on samples obtained through the routine NBSP represents a novel mechanism for clinical genetic research in the UK and provides a model for further population-based genetic studies in the newborn.

The development of type 1 diabetes (T1D) is potentially influenced by nutrition. The aim of our study was to assess food and nutrient intakes of children at increased risk of T1D. Dietary intake of the last 4 weeks was assessed using a diet history interview. The daily nutrient and food intakes were compared with the German Dietary Reference Intakes, the Optimized Mixed Diet recommendations and those of a representative sample of children from the EsKiMo study. Children included in the analysis participated in the prospective TEENDIAB study. First-degree relatives of people with T1D (n 268), aged 8-12 years. The TEENDIAB children consumed 52·0 % of their total energy from carbohydrates, 32·6 % from fat and 14·3 % from protein. Compared with the reference values, their intake was lowest for folate at 61·3 % of the reference, for iodine at 58·1 % and for vitamin D at 8·9 %, and exceeded the reference for vitamin K about 5-fold, for Na about 3·5-fold and for protein about 1·5-fold. Their nutrient intakes were similar to those of a control cohort without increased T1D risk. The consumption of non-desirable food groups (meat products, sweets/snacks) was above the recommendations and the consumption of desirable food groups (fruits, vegetables, carbohydrate-rich foods) was below the recommendations. The TEENDIAB children had intakes considerably below the recommendations for vitamin D, iodine, folate and plant-based foods, and intakes above for vitamin K, Na, protein, meat products and sweets/snacks. They showed similar dietary patterns to non-risk children.