Stabilizing short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells

Mucosal-associated invariant T (MAIT) cells are activated by unstable antigens formed by reactions of 5-amino-6-D-ribitylaminouracil (a vitamin B2 biosynthetic intermediate) with glycolysis metabolites such as methylglyoxal. Here we show superior preparations of antigens in dimethylsulfoxide, avoiding their rapid decomposition in water (t1/2 1.5 h, 37 °C). Antigen solution structures, MAIT cell activation potencies (EC50 3–500 pM), and chemical stabilities are described. Computer analyses of antigen structures reveal stereochemical and energetic influences on MAIT cell activation, enabling design of a water stable synthetic antigen (EC50 2 nM). Like native antigens, this antigen preparation induces MR1 refolding and upregulates surface expression of human MR1, forms MR1 tetramers that detect MAIT cells in human PBMCs, and stimulates cytokine expression (IFNγ, TNF) by human MAIT cells. These antigens also induce MAIT cell accumulation in mouse lungs after administration with a co-stimulant. These chemical and immunological findings provide new insights into antigen properties and MAIT cell activation

Associations between long-term blood pressure trajectory and all-cause and CVD mortality among old people in China

BackgroundOptimal blood pressure (BP) management strategy among the elderly remains controversial, with insufficient consideration of long-term BP trajectory. This study aimed to identify BP trajectory patterns as well as terminal BP trajectory among the Chinese elderly and to explore the relationships between BP trajectories and all-cause mortality and cardiovascular disease (CVD) mortality.MethodsWe included 11,181 participants older than 60 at baseline (mean age, 80.98 ± 10.71) with 42,871 routine BP measurements from the Chinese Longitudinal Healthy Longevity Survey. Latent class trajectory analysis and Cox proportional hazard model were conducted to identify trajectory patterns and their associations with mortality. Furthermore, we also applied mixed-effects model to identify terminal BP trajectories among the elderly.ResultsCompared with stable at normal high level trajectory, excess systolic BP (SBP) trajectory with decreasing trend was associated with a 34% (HR = 1.34, 95% CI: 1.23–1.45) higher risk of all-cause mortality. Considering the competing risk of non-CVD death, excess BP trajectory with decreasing trend had a more pronounced effect on CVD mortality, in which HR (95% CI) was 1.67 (1.17, 2.37). Similar results were also found in diastolic BP (DBP), pulse pressure (PP), and mean arterial pressure (MAP) trajectories. We further conducted a mixed-effects model and observed that SBP and PP trajectories first increased and began to decline slightly six years before death. In contrast, DBP and MAP showed continuous decline 15 years before death.ConclusionLong-term BP trajectory was associated with all-cause mortality, especially CVD mortality. Keeping a stable BP over time may be an important way for CVD prevention among the elderly

Efficacy of chimeric antigen receptor T cell therapy and autologous stem cell transplant in relapsed or refractory diffuse large B-cell lymphoma: A systematic review

BackgroundWe aimed to compare the efficacy of chimeric antigen receptor T (CAR-T) cell therapy with that of autologous stem cell transplantation (auto-HSCT) in relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL).Research design and methodsWe searched eligible publications up to January 31st, 2022, in PubMed, Cochrane Library, Springer, and Scopus. A total of 16 publications with 3484 patients were independently evaluated and analyzed using STATA SE software.ResultsPatients who underwent CAR-T cell therapy showed a better overall response rate (ORR) and partial response (PR) than those treated with auto-HSCT (CAR-T vs. auto-HSCT, ORR: 80% vs. 73%, HR:0.90,95%CI:0.76-1.07,P = 0.001; PR: 20% vs. 14%, HR:0.65,95%CI:0.62-0.68,P = 0.034). No significant difference was observed in 6-month overall survival (OS) (CAR-T vs. auto-HSCT, six-month OS: 81% vs. 84%, HR:1.23,95%CI:0.63-2.38, P = 0.299), while auto-HSCT showed a favorable 1 and 2-year OS (CAR-T vs. auto-HSCT, one-year OS: 64% vs. 73%, HR:2.42,95%CI:2.27-2.79, P < 0.001; two-year OS: 54% vs. 68%, HR:1.81,95%CI:1.78-1.97, P < 0.001). Auto-HSCT also had advantages in progression-free survival (PFS) (CAR-T vs. auto-HSCT, six-month PFS: 53% vs. 76%, HR:2.81,95%CI:2.53-3.11,P < 0.001; one-year PFS: 46% vs. 61%, HR:1.84,95%CI:1.72-1.97,P < 0.001; two-year PFS: 42% vs. 54%, HR:1.62,95%CI:1.53-1.71, P < 0.001). Subgroup analysis by age, prior lines of therapy, and ECOG scores was performed to compare the efficacy of both treatment modalities.ConclusionAlthough CAR-T cell therapy showed a beneficial ORR, auto-HSCT exhibited a better long-term treatment superiority in R/R DLBCL patients. Survival outcomes were consistent across different subgroups

Identification of microtubule-associated biomarkers in diffuse large B-cell lymphoma and prognosis prediction

Background: Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease with a complicated prognosis. Even though various prognostic evaluations have been applied currently, they usually only use the clinical factors that overlook the molecular underlying DLBCL progression. Therefore, more accurate prognostic assessment needs further exploration. In the present study, we constructed a novel prognostic model based on microtubule associated genes (MAGs).Methods: A total of 33 normal controls and 1360 DLBCL samples containing gene-expression from the Gene Expression Omnibus (GEO) database were included. Subsequently, the univariate Cox, the least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis were used to select the best prognosis related genes into the MAGs model. To validate the model, Kaplan-Meier curve, and nomogram were analyzed.Results: A risk score model based on fourteen candidate MAGs (CCDC78, CD300LG, CTAG2, DYNLL2, MAPKAPK2, MREG, NME8, PGK2, RALBP1, SIGLEC1, SLC1A1, SLC39A12, TMEM63A, and WRAP73) was established. The K-M curve presented that the high-risk patients had a significantly inferior overall survival (OS) time compared to low-risk patients in training and validation datasets. Furthermore, knocking-out TMEM63A, a key gene belonging to the MAGs model, inhibited cell proliferation noticeably.Conclusion: The novel MAGs prognostic model has a well predictive capability, which may as a supplement for the current assessments. Furthermore, candidate TMEM63A gene has therapeutic target potentially in DLBCL

Mucosal-associated invariant T cells augment immunopathology and gastritis in chronic helicobacter pyloriInfection

Mucosal-associated invariant T (MAIT) cells produce inflammatory cytokines and cytotoxic granzymes in response to by-products of microbial riboflavin synthesis. Although MAIT cells are protective against some pathogens, we reasoned that they might contribute to pathology in chronic bacterial infection. We observed MAIT cells in proximity to Helicobacter pylori bacteria in human gastric tissue, and so, using MR1-tetramers, we examined whether MAIT cells contribute to chronic gastritis in a mouse H. pylori SS1 infection model. Following infection, MAIT cells accumulated to high numbers in the gastric mucosa of wild-type C57BL/6 mice, and this was even more pronounced in MAIT TCR transgenic mice or in C57BL/6 mice where MAIT cells were preprimed by Ag exposure or prior infection. Gastric MAIT cells possessed an effector memory Tc1/Tc17 phenotype, and were associated with accelerated gastritis characterized by augmented recruitment of neutrophils, macrophages, dendritic cells, eosinophils, and non-MAIT T cells and by marked gastric atrophy. Similarly treated MR1−/− mice, which lack MAIT cells, showed significantly less gastric pathology. Thus, we demonstrate the pathogenic potential of MAIT cells in Helicobacter-associated immunopathology, with implications for other chronic bacterial infections

Francisella tularensis induces Th1 like MAIT cells conferring protection against systemic and local infection

Mucosal-associated Invariant T (MAIT) cells are recognized for their antibacterial functions. The protective capacity of MAIT cells has been demonstrated in murine models of local infection, including in the lungs. Here we show that during systemic infection of mice with Francisella tularensis live vaccine strain results in evident MAIT cell expansion in the liver, lungs, kidney and spleen and peripheral blood. The responding MAIT cells manifest a polarised Th1-like MAIT-1 phenotype, including transcription factor and cytokine profile, and confer a critical role in controlling bacterial load. Post resolution of the primary infection, the expanded MAIT cells form stable memory-like MAIT-1 cell populations, suggesting a basis for vaccination. Indeed, a systemic vaccination with synthetic antigen 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil in combination with CpG adjuvant similarly boosts MAIT cells, and results in enhanced protection against both systemic and local infections with different bacteria. Our study highlights the potential utility of targeting MAIT cells to combat a range of bacterial pathogens

Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells

The major-histocompatibility-complex-(MHC)-class-I-related molecule MR1 can present activating and non-activating vitamin-B-based ligands to mucosal-associated invariant T cells (MAIT cells). Whether MR1 binds other ligands is unknown. Here we identified a range of small organic molecules, drugs, drug metabolites and drug-like molecules, including salicylates and diclofenac, as MR1-binding ligands. Some of these ligands inhibited MAIT cells ex vivo and in vivo, while others, including diclofenac metabolites, were agonists. Crystal structures of a T cell antigen receptor (TCR) from a MAIT cell in complex with MR1 bound to the non-stimulatory and stimulatory compounds showed distinct ligand orientations and contacts within MR1, which highlighted the versatility of the MR1 binding pocket. The findings demonstrated that MR1 was able to capture chemically diverse structures, spanning mono- and bicyclic compounds, that either inhibited or activated MAIT cells. This indicated that drugs and drug-like molecules can modulate MAIT cell function in mammals

Association of sleep behavior with depression: a cross-sectional study in northwestern China

BackgroundThis study aimed to examine the association between sleep duration, sleep problems, and depression in Northwest China.MethodDepression was diagnosed at the hospital and self-reported by the participants in the baseline survey. Sleep duration and problems, including difficulty initiating and maintaining sleep, early morning awakening, daytime dysfunction, use of sleeping pills or drugs, and any sleep problems, were obtained by a self-reported questionnaire. Logistic regression was used to estimate odds ratios (ORs) with corresponding 95% confidence intervals (CIs) for exploring the association between sleep duration, sleep problems, and depression, adjusting for demographic and socioeconomic characteristics and health behaviors. The association between depression and sleep duration was also evaluated continuously with restricted cubic spline curves based on logistic models.Results36,515 adults from Regional Ethnic Cohort Study in Northwest China were included. About 24.04% of participants reported short sleep duration (<7 h), and 15.64% reported long sleep duration (≥9 h). Compared with standard sleep duration (7–9 h), short sleep duration was associated with a higher risk of depression (OR: 1.69, 95%CI: 1.26–2.27, p = 0.001). Self-reported sleep problems were also related to four times depression risk increased (OR: 4.02, 95%CI: 3.03–5.35, p < 0.001) compared with no sleep problems. In addition, a nonlinear relationship was found between sleep duration and depression after adjusting covariates (p = 0.043).ConclusionSleep duration and sleep problems are associated with depression. Enough sleep time and healthy sleep habits in life course might be a practical health promotion approach to reduce depression risk in Northwest Chinese adults. A further study from cohort study is needed to verify the temporal association

Clustering Complex Trajectories Based on Topologic Similarity and Spatial Proximity: A Case Study of the Mesoscale Ocean Eddies in the South China Sea

Many real-world dynamic features such as ocean eddies, rain clouds, and air masses may split or merge while they are migrating within a space. Topologically, the migration trajectories of such features are structurally more complex as they may have multiple branches due to the splitting and merging processes. Identifying the spatial aggregation patterns of the trajectories could help us better understand how such features evolve. We propose a method, a Global Similarity Measuring Algorithm for the Complex Trajectories (GSMCT), to examine the spatial proximity and topologic similarity among complex trajectories. The method first transforms the complex trajectories into graph structures with nodes and edges. The global similarity between two graph structures (i.e., two complex trajectories) is calculated by averaging their topologic similarity and the spatial proximity, which are calculated using the Comprehensive Structure Matching (CSM) and the Hausdorff distance (HD) methods, respectively. We applied the GSMCT, the HD, and the Dynamic Time Warping (DTW) methods to examine the complex trajectories of the 1993–2016 mesoscale eddies in the South China Sea (SCS). Based on the similarity evaluation results, we categorized the complex trajectories across the SCS into four groups, which are similar to the zoning results reported in previous studies, though difference exists. Moreover, the yearly numbers of complex trajectories in the clusters in the northernmost (Cluster 1) and the southernmost SCS (Cluster 4) are almost the same. However, their seasonal variation and migration characteristics are totally opposite. Such new knowledge is very useful for oceanographers of interest to study and numerically simulate the mesoscale ocean eddies in the SCS