T-cell help in the germinal center: homing in on the role of IL-21.

Interleukin 21 (IL-21) is a pleiotropic cytokine that is overproduced in multiple autoimmune settings. Provision of IL-21 from follicular helper T cells is an important component of T-cell help within germinal centers (GC), and the last few years have seen a resurgence of interest in IL-21 biology in the context of the GC environment. While it has been more than a decade since T cell-derived IL-21 was found to upregulate B-cell expression of the GC master transcription factor B-cell lymphoma 6 (Bcl-6) and to promote GC expansion, several recent studies have collectively delivered significant new insights into how this cytokine shapes GC B-cell selection, proliferation, and fate choice. It is now clear that IL-21 plays an important role in GC zonal polarization by contributing to light zone GC B-cell positive selection for dark zone entry as well as by promoting cyclin D3-dependent dark zone inertial cycling. While it has been established that IL-21 can contribute to the modulation of GC output by aiding the generation of antibody-secreting cells (ASC), recent studies have now revealed how IL-21 signal strength shapes the fate choice between GC cycle re-entry and ASC differentiation in vivo. Both provision of IL-21 and sensitivity to this cytokine are finely tuned within the GC environment, and dysregulation of this pathway in autoimmune settings could alter the threshold for germinal center B-cell selection and differentiation, potentially promoting autoreactive B-cell responses.

Steric Control of Luminescence in Phenyl-Substituted Trityl Radicals.

Triphenylmethyl (trityl) radicals have shown potential for use in organic optoelectronic applications, but the design of practical trityl structures has been limited to donor/radical charge-transfer systems due to the poor luminescence of alternant symmetry hydrocarbons. Here, we circumvent the symmetry-forbidden transition of alternant hydrocarbons via excited-state symmetry breaking in a series of phenyl-substituted tris(2,4,6-trichlorophenyl)methyl (TTM) radicals. We show that 3-fold phenyl substitution enhances the emission of the TTM radical and that steric control modulates the optical properties in these systems. Simple ortho-methylphenyl substitution boosts the photoluminescence quantum efficiency from 1% (for TTM) to 65% at a peak wavelength of 612 nm (for 2-T3TTM) in solution. In the crystalline solid state, the neat 2-T3TTM radical shows a remarkably high photoluminescence quantum efficiency of 25% for emission peaking at 706 nm. This has implications in the design of aryl-substituted radical structures where the electronic coupling of the substituents influences variables such as emission, charge transfer, and spin interaction.

An Age-Progression Intervention for Smoking Cessation: A Pilot Study Investigating the Influence of Two Sets of Instructions on Intervention Efficacy.

BACKGROUND: Research on age-progression facial morphing interventions for smoking cessation has not investigated the effect of different instructions for intervention delivery. The objective of this pilot study was to investigate the influence of two instruction types used to deliver the intervention on efficacy of the intervention. METHOD: Women were recruited and randomly allocated to an age-progression intervention session with (i) neutral instructions; (ii) instructions designed to reassure; or (iii) a condition that controlled for participant engagement ("control"). The conditions were delivered in a one-time procedure, after which primary (quitting intentions) and secondary (cigarettes/week, quit attempts) outcomes were measured immediately post-intervention, and at 1 and 3 months. RESULTS: Seventy-two women (M = 25.7; SD = 0.9) were recruited and randomly allocated to condition (Neutral n = 27, Reassuring n = 22, Control n = 23). Quitting intentions were higher in the Reassuring versus Control arm (3 months post-intervention, F = 4.37, p = 0.016, 95% CI [0.231, 2.539], eta2 = 0.11); quit attempts were greater in the two intervention arms (58%) versus Control (1-month post-intervention, 15%) (χ2 = 9.83, p < 0.05, OR 1.00 [0.28, 3.63]). CONCLUSIONS: Findings highlight the importance of optimising instructions to enhance intervention efficacy. TRIAL REGISTRATION: clinicaltrials.gov Record: NCT03749382.

Primary closure of fasciotomies has a reduced complication rate following compartment syndrome in the paediatric population.

PURPOSE: Currently no guidance exists within the literature regarding diagnostic criteria or the long-term outcomes for paediatric patients with acute compartment syndrome (ACS). We conducted a retrospective cohort study reviewing all cases of paediatric ACS managed at a single tertiary referral centre with the aim of characterising the factors responsible for the eventual outcomes. METHODS: The patient cohort was identified retrospectively by interrogating the hospital coding system for all paediatric patients between January 2014 and November 2022. The electronic emergency department, inpatient and operative notes as well as clinic letters for each patient were reviewed and data collected regarding presentation, associated injuries, management and subsequent complications plus length of follow-up. The data was analysed to determine if differences in presentation or management affected long term outcome. RESULTS: The final cohort consisted of 34 patients with a mean age of ten years at the time of presentation. The mean time from presentation to fasciotomy was 27.6 h (range 3.0 - 66.6). There was an overall complication rate of 37.5% with a mean follow-up period of 21 months. Patients who had direct closure of their fasciotomy wounds had a significantly lower complications rate and fewer operations compared to those who healed via other wound coverage methods or secondary intention (p < 0.05). CONCLUSIONS: Significantly higher complication rates were observed in patients who were unable to have direct wound closure following emergency fasciotomy. This information may be utilised to rationalise long term treatment plans and in counselling of patients and parents.

Can artificial intelligence make elective hand clinic letters easier for patients to understand?

We investigated whether ChatGPT was able to increase the Flesch reading ease and the Flesch-Kincaid reading level of elective clinic letters written by hand surgeons. ChatGPT could not reliably simplify the hand clinic letters any further.

Perceived benefits of patient support groups and their format for people with an implantable cardioverter defibrillator.

BACKGROUND: Support groups for people with Implantable Cardioverter Defibrillators (ICDs) are widely used, however, it is not clear what people with ICDs gain from a support group or what format they should take. OBJECTIVES: The aim of the present study is to define the perceived benefit of ICD support groups and develop practical recommendations for group format. METHODS: 14 individuals with ICDs were interviewed using a semi-structured interview guide. Reflexive thematic analysis methods were utilised to code and analyse the transcripts before generating themes. RESULTS: Four themes were defined: confronting mortality, coping through sharing, coping through learning, and providing space. Making connections with other people with ICDs, reassurance, access to information, and advice from health care professionals were important perceived benefits of the support group. CONCLUSION: People with ICDs may have to confront their own mortality and adapt to considerable life changes after implant. The findings from the present study have improved understanding of how support groups are perceived and how ICD indication and group format influence the experience. A blended format of in-person community meetings, online forums, HCP-led education and space for person-person interaction is recommended. Importantly, provision of support should not be time-limited to allow people to access it when it most likely to be of benefit to them.

The immunology of type 1 diabetes.

Following the seminal discovery of insulin a century ago, treatment of individuals with type 1 diabetes (T1D) has been largely restricted to efforts to monitor and treat metabolic glucose dysregulation. The recent regulatory approval of the first immunotherapy that targets T cells as a means to delay the autoimmune destruction of pancreatic ß-cells highlights the critical role of the immune system in disease pathogenesis and tends to pave the way for other immune-targeted interventions for T1D. Improving the efficacy of such interventions across the natural history of the disease will probably require a more detailed understanding of the immunobiology of T1D, as well as technologies to monitor residual ß-cell mass and function. Here we provide an overview of the immune mechanisms that underpin the pathogenesis of T1D, with a particular emphasis on T cells.

Inhibition of Receptor-Interacting Protein Kinase 1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study.

INTRODUCTION: Receptor-interacting protein kinase 1 (RIPK1), a key mediator of inflammation through necroptosis and proinflammatory cytokine production, may play a role in the pathogenesis of immune-mediated inflammatory diseases such as chronic plaque psoriasis. An experimental medicine study of RIPK1 inhibition with GSK2982772 immediate-release formulation at doses up to 60 mg three times daily in mild to moderate plaque psoriasis indicated that efficacy may be improved with higher trough concentrations of GSK2982772. METHODS: This multicenter, randomized, double-blind, placebo-controlled, repeat-dose study (NCT04316585) assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of 960 mg GSK2982772 (once-daily modified-release formulation) in patients with moderate to severe plaque psoriasis. Twenty-nine patients were randomized 2:1 to GSK2982772 (N = 19) or placebo (N = 10) for 12 weeks. RESULTS: GSK2982772 was well tolerated with trough concentrations greater than tenfold higher than the previous phase 1 study with immediate release. Despite near complete RIPK1 target engagement in blood and modest reduction in circulating inflammatory cytokines, the proportion of patients achieving 75% improvement from baseline in Psoriasis Area Severity Index score at week 12 was similar between GSK2982772 and placebo (posterior median 1.8% vs 4.9%, respectively), with an estimated median treatment difference of - 2.3%. This analysis incorporated historical placebo data through the use of an informative prior distribution on the placebo arm. Week 4 changes in skin biopsy gene expression suggested sufficient local drug exposure to elicit a pharmacodynamic response. CONCLUSION: Administration of the RIPK1 inhibitor GSK2982772 to patients with moderate to severe plaque psoriasis did not translate into meaningful clinical improvements.

Psoriasis is thought to be caused by problems with the immune system, including possibly receptor-interacting protein kinase 1 (RIPK1), which plays an important role in the development of inflammation. A previous study suggested that the drug, GSK2982772, which interferes with RIPK1, might improve symptoms in patients with psoriasis. This study examined whether higher doses of GSK2982772 than previously studied would be beneficial for patients with psoriasis. The study found that the severity of psoriasis was similar in patients treated with GSK2982772 for 12 weeks as in those who did not receive the drug, indicating that GSK298772 did not improve psoriasis.

TIGIT+Tfh show poor B-helper function and negatively correlate with SARS-CoV-2 antibody titre.

Circulating follicular helper T cells (cTfh) can show phenotypic alterations in disease settings, including in the context of tissue-damaging autoimmune or anti-viral responses. Using severe COVID-19 as a paradigm of immune dysregulation, we have explored how cTfh phenotype relates to the titre and quality of antibody responses. Severe disease was associated with higher titres of neutralising S1 IgG and evidence of increased T cell activation. ICOS, CD38 and HLA-DR expressing cTfh correlated with serum S1 IgG titres and neutralising strength, and interestingly expression of TIGIT by cTfh showed a negative correlation. TIGIT+cTfh expressed increased IFNγ and decreased IL-17 compared to their TIGIT-cTfh counterparts, and showed reduced capacity to help B cells in vitro. Additionally, TIGIT+cTfh expressed lower levels of CD40L than TIGIT-cTfh, providing a potential explanation for their poor B-helper function. These data identify phenotypic changes in polyclonal cTfh that correlate with specific antibody responses and reveal TIGIT as a marker of cTfh with altered function.

Near-infrared luminescent open-shell π-conjugated systems with a bright lowest-energy zwitterionic singlet excited state.

Open-shell systems with extensive π-conjugation have fascinating properties due to their narrow bandgaps and spin interactions. In this work, we report neutral open-shell di- and polyradical conjugated materials exhibiting intriguing optical and magnetic properties. Our key design advance is the planarized geometry allowing for greater interaction between adjacent spins. This results in absorption and emission in the near infrared at 803 and 1050 nanometers, respectively, and we demonstrate a unique electronic structure where a bright zwitterionic excited state is the lowest-accessible electronic transition. Electron paramagnetic resonance spectroscopy and superconducting quantum interference device measurements reveal that our materials are open-shell singlets with different degrees of spin interactions, dynamics, and antiferromagnetic properties, which likely contributed to the formation of their emissive zwitterionic singlet excited state and near-infrared emission. In addition, our materials show reversible and stable electrochromic switching with more than 500 cycles, indicating their potential for optoelectronic and electrochemical energy storage applications.

An IL-2 mutein increases IL-10 and CTLA-4-dependent suppression of dendritic cells by regulatory T cells.

Interleukin-2 (IL-2) variants with increased CD25 dependence that selectively expand Foxp3+ regulatory T (TR) cells are in clinical trials for treating inflammatory diseases. Using an Fc-fused IL-2 mutein (Fc.IL-2 mutein) we developed that prevents diabetes in non-obese diabetic (NOD) mice, we show that Fc.IL-2 mutein induced an activated TR population with elevated proliferation, a transcriptional program associated with Stat5- and TCR-dependent gene modules, and high IL-10 and CTLA-4 expression. Increased IL-10 signaling limited surface MHC class II upregulation during conventional dendritic cell (cDC) maturation, while increased CTLA-4-dependent transendocytosis led to the transfer of CD80 and CD86 costimulatory ligands from maturing cDCs to TR cells. In NOD mice, Fc.IL-2 mutein treatment promoted the suppression of cDCs in the inflamed pancreas and pancreatic lymph nodes resulting in T cell anergy. Thus, IL-2 mutein-expanded TR cells have enhanced functional properties and restrict cDC function, offering promise for targeted immunotherapy use in autoimmune disease.

Waste land / Lixo extraordinário

O documentário tem como pano de fundo o Jardim Gramacho, em Duque de Caxias, RJ, maior aterro sanitário da América Latina e relata a trajetória do lixo dispensado no aterro. A relação entre lixo e arte aproxima o universo intelectual à tão diferente realidade das pessoas que colhem o lixo, que acaba virando arte nas mãos do artista plástico Vik Muniz