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Abstract Treatment options for T3N1 stage gastric cancer exhibit regional variation, with optimal approach remaining unclear. We derived our data from the SEER database, using Cox proportional risk regression models for univariate and multivariate analyses of 5-years overall survival (5yOS) and 5-years cancer-specific survival (5yCSS). The results showed that younger age, female, non-white race, highly differentiated histologic grade, non-Signet ring cell adenocarcinoma, low N stage, lesser curvature of the stomach, OP followed by adjuvant C/T with or without RT, partial gastrectomy, C/T and others, Radiation therapy, and Chemotherapy were significantly associated with better 5yOS and 5yCSS. For patients with stage T3N1-3 gastric cancer, multimodal treatment regimens demonstrate superior survival outcomes compared to surgery or radiotherapy alone. Among them, OP followed by adjuvant C/T with or without RT emerges as particularly efficacious, potentially offering enhanced benefits for non-Asian populations.

Due to the Earth’s rotation, the natural environment exhibits a light-dark diurnal cycle close to 24 hours. To adapt to this energy intake pattern, organisms have developed a 24-hour rhythmic diurnal cycle over long periods, known as the circadian rhythm, or biological clock. With the gradual advancement of research on the biological clock, it has become increasingly evident that disruptions in the circadian rhythm are closely associated with the occurrence of type 2 diabetes (T2D). To further understand the progress of research on T2D and the biological clock, this paper reviews the correlation between the biological clock and glucose metabolism and analyzes its potential mechanisms. Based on this, we discuss the potential factors contributing to circadian rhythm disruption and their impact on the risk of developing T2D, aiming to explore new possible intervention measures for the prevention and treatment of T2D in the future. Under the light-dark circadian rhythm, in order to adapt to this change, the human body forms an internal biological clock involving a variety of genes, proteins and other molecules. The main mechanism is the transcription-translation feedback loop centered on the CLOCK/BMAL1 heterodimer. The expression of important circadian clock genes that constitute this loop can regulate T2DM-related blood glucose traits such as glucose uptake, fat metabolism, insulin secretion/glucagon secretion and sensitivity in various peripheral tissues and organs. In addition, sleep, light, and dietary factors under circadian rhythms also affect the occurrence of T2DM.

AimThe study aims to systematically assess the efficacy and safety of Gegen Qinlian decoction in the treatment of type 2 diabetes mellitus.MethodsWe systematically searched a total of nine databases from the time of creation to 20 March 2023. The quality of the literature was assessed using the risk of bias assessment tool in the Cochrane Handbook. RevMan 5. 3 and Stata 14.0 were applied to conduct meta-analysis.ResultsA total of 17 studies, encompassing 1,476 patients, were included in the study. Gegen Qinlian decoction combined with conventional treatment was found to significantly reduce FBG (MD = −0.69 mmol/L, 95% CI −0.84 to −0.55, p < 0.01; I2 = 67%, p

Abstract The definitive treatment for end-stage renal disease is kidney transplantation, which remains limited by organ availability and post-transplant complications. Alternatively, an implantable bioartificial kidney could address both problems while enhancing the quality and length of patient life. An implantable bioartificial kidney requires a bioreactor containing renal cells to replicate key native cell functions, such as water and solute reabsorption, and metabolic and endocrinologic functions. Here, we report a proof-of-concept implantable bioreactor containing silicon nanopore membranes to offer a level of immunoprotection to human renal epithelial cells. After implantation into pigs without systemic anticoagulation or immunosuppression therapy for 7 days, we show that cells maintain >90% viability and functionality, with normal or elevated transporter gene expression and vitamin D activation. Despite implantation into a xenograft model, we find that cells exhibit minimal damage, and recipient cytokine levels are not suggestive of hyperacute rejection. These initial data confirm the potential feasibility of an implantable bioreactor for renal cell therapy utilizing silicon nanopore membranes.

IntroductionIn spontaneous type 1 diabetes (T1D) non-obese diabetic (NOD) mice, the insulin B chain peptide 9-23 (B:9-23) can bind to the MHC class II molecule (IAg7) in register 3 (R3), creating a bimolecular IAg7/InsulinB:9-23 register 3 conformational epitope (InsB:R3). Previously, we showed that the InsB:R3-specific chimeric antigen receptor (CAR), constructed using an InsB:R3-monoclonal antibody, could guide CAR-expressing CD8 T cells to migrate to the islets and pancreatic lymph nodes. Regulatory T cells (Tregs) specific for an islet antigen can broadly suppress various pathogenic immune cells in the islets and effectively halt the progression of islet destruction. Therefore, we hypothesized that InsB:R3 specific Tregs would suppress autoimmune reactivity in islets and efficiently protect against T1D.MethodsTo test our hypothesis, we produced InsB:R3-Tregs and tested their disease-protective effects in spontaneous T1D NOD.CD28-/- mice.ResultsInsB:R3-CAR expressing Tregs secrete IL-10 dominated cytokines upon engagement with InsB:R3 antigens. A single infusion of InsB:R3 Tregs delayed the onset of T1D in 95% of treated mice, with 35% maintaining euglycemia for two healthy lifespans, readily home to the relevant target whereas control Tregs did not. Our data demonstrate that Tregs specific for MHC class II: Insulin peptide epitope (MHCII/Insulin) protect mice against T1D more efficiently than polyclonal Tregs lacking islet antigen specificity, suggesting that the MHC II/insulin-specific Treg approach is a promising immune therapy for safely preventing T1D.

Abstract Beta cell replacement therapy (BCRT) for patients with type 1 diabetes (T1D) improves blood glucose regulation by replenishing the endogenous beta cells destroyed by autoimmune attack. Several limitations, including immune isolation, prevent this therapy from reaching its full potential. Cell encapsulation devices used for BCRT provide a protective physical barrier for insulin‐producing beta cells, thereby protecting transplanted cells from immune attack. However, poor device engraftment posttransplantation leads to nutrient deprivation and hypoxia, causing metabolic strain on transplanted beta cells. Prevascularization of encapsulation devices at the transplantation site can help establish a host vascular network around the implant, increasing solute transport to the encapsulated cells. Here, we present a replenishable prevascularized implantation methodology (RPVIM) that allows for the vascular integration of replenishable encapsulation devices in the subcutaneous space. Empty encapsulation devices were vascularized for 14 days, after which insulin‐producing cells were inserted without disrupting the surrounding vasculature. The RPVIM devices were compared with nonprevascularized devices (Standard Implantation Methodology [SIM]) and previously established prevascularized devices (Standard Prevascularization Implantation Methodology [SPVIM]). Results show that over 75% of RPVIM devices containing stem cell‐derived insulin‐producing beta cell clusters showed a signal after 28 days of implantation in subcutaneous space. Notably, not only was the percent of RPVIM devices showing signal significantly greater than SIM and SPVIM devices, but the intraperitoneal glucose tolerance tests and histological analyses showed that encapsulated stem‐cell derived insulin‐producing beta cell clusters retained their function in the RPVIM devices, which is crucial for the successful management of T1D.

To address the problem in model computations and the limited accuracy of current bridge deterioration prediction methods, this paper proposes a novel bridge deterioration prediction meth-od using the whale optimization algorithm and extreme learning machine (WOA-ELM). First, we collected a dataset consisting of 539 sets of bridge inspection data and determined the necessary influencing factors through correlation analysis. Subsequently, the WOA-ELM algorithm was applied to establish a nonlinear mapping relationship between each influencing factor and the bridge condition indicators. Furthermore, the extreme learning machine (ELM), back-propagation neural network (BPNN), decision trees (DT), and support vector machine (SVM) were employed for comparison to validate the superiority of the proposed method. In addition, this paper provides further substantiation of the model’s exceptional predictive capabilities across diverse bridge components. The results demonstrate the accurate predictive capability of the proposed method for bridge conditions. Compared with ELM, BPNN, DT, and SVM, the proposed method exhibits significant improvements in predictive accuracy, i.e., the correlation coefficient is increased by 4.1%, 11.4%, 24.5%, and 33.6%, and the root mean square error is reduced by 7.3%, 18.0%, 14.8%, and 18.1%, respectively. Moreover, the proposed method presents considerably enhanced generalization capabilities, resulting in the reduction in mean relative error by 11.6%, 15.3%, 6%, and 16.2%. The proposed method presents a robust framework for proactive bridge maintenance.

Aiming at comprehensively evaluating the status of a bridge monitoring system, an evaluation framework based on the improved Delphi, analytic Hierarchy process, Grey relations analysis and Fuzzy integrated evaluation (DHGF) is selected. Firstly, the evaluation indexes for the bridge monitoring system are determined by an anonymous group discussion and expert questionnaire using the improved Delphi method. Secondly, a comparison matrix of the evaluation indexes is constructed to determine the comprehensive weight via the analytic hierarchy process. Then, based on the gray relations analysis, the albino weight function is constructed, the evaluation gray class is determined, and the single-factor fuzzy evaluation matrix is obtained. Finally, the final evaluation result was obtained by the fuzzy comprehensive evaluation. The evaluation results of a real bridge monitoring system show that the evaluation level of the monitoring system was level II, and the proposed framework could better reflect the construction and operation status of the monitoring system.

The damage monitoring and identification of arch bridges provide an important means to ensure the safe operation of arch bridges. At present, many methods have been developed, and the applicability and effectiveness of these methods depend on the damage type, structural configuration and available data. To guide the practical application of these methods, a systematic review is implemented in this paper. Specifically, the damage monitoring and identification methods of arch bridges are divided into the damage monitoring of local diseases and damage identification of overall performance. Firstly, the research on the damage monitoring of the local diseases of arch bridges is reviewed. According to the disease type, it is divided into four categories, including suspender inspection, void monitoring, stress detection and corrosion detection. For each disease, this paper analyzes the principles, advantages and shortcomings of various methods. Then, the damage identification methods of the overall performance of arch bridges are reviewed, including masonry arch bridges, steel arch bridges, reinforced concrete arch bridges and concrete-filled steel tubular arch bridges. And the commonly used damage indexes of damage identification methods are summarized. This review aims to help researchers and practitioners in implementing existing damage detection methods effectively and developing more reliable and practical methods for arch bridges in the future.

TNFa blocking agents were the first-in-class biologic drugs used for the treatment of autoimmune disease. Paradoxically, however, exacerbation of autoimmunity was observed in some patients. TNFa is a pleiotropic cytokine that has both proinflammatory and regulatory effects on CD4+ T cells and can influence the adaptive immune response against autoantigens. Here, we critically appraise the literature and discuss the intricacies of TNFa signaling that may explain the controversial findings of previous studies. The pleiotropism of TNFa is based in part on the existence of two biologically active forms of TNFa, soluble and membrane-bound, with different affinities for two distinct TNF receptors, TNFR1 and TNFR2, leading to activation of diverse downstream molecular pathways involved in cell fate decisions and immune function. Distinct membrane expression patterns of TNF receptors by CD4+ T cell subsets and their preferential binding of distinct forms of TNFα produced by a diverse pool of cellular sources during different stages of an immune response are important determinants of the differential outcomes of TNFa-TNF receptor signaling. Targeted manipulation of TNFa-TNF receptor signaling on select CD4+ T cell subsets may offer specific therapeutic interventions to dampen inflammation while fortifying immune regulation for the treatment of autoimmune diseases.

IntroductionThe dipeptidyl peptidase-4 inhibitor (DPP-4i) drugs, such as evogliptin, as the second-line drugs for type 2 diabetes mellitus (T2DM) treatment have been reported to facilitate insulin secretion by reducing glucagon and inhibiting glucagon like peptides. With a vague consensus, the advantageous and non-inferior effects of evogliptin relative to other DPP-4i drugs were recently demonstrated on hemoglobin A1c (HbA1c) levels and overall adverse events in T2DM patients. Thus, the aim was to evaluate the overall influence of evogliptin on HbA1c levels and the adverse events in T2DM patients compared to sitagliptin and linagliptin.MethodsComplying with PRISMA guidelines, we conducted a systematic literature search in databases and a meta-analysis. Data about HbA1c levels and the adverse events of T2DM patients were collected and analyzed.ResultsFrom 1,397 studies, we found five matched studies involving 845 subjects (mean age: 54.7 ± 3 years). The meta-analysis revealed that evogliptin was non-inferior to sitagliptin/linagliptin with a mean difference of 0.062 (95% CI: -0.092 to 0.215. I2: 0%. P = 0.431) regarding the HbA1c level reduction, and the risk ratio was -0.006 (95% CI: -0.272 to 0.260. I2: 1.7%. P = 0.966) regarding the adverse effects, indicating no significant difference between evogliptin and linagliptin or sitagliptin in affecting the HbA1c level and adverse effects.ConclusionThe study provides preliminary evidence regarding the similarity in the efficacy of evogliptin compared to other DPP-4i drugs, including sitagliptin and linagliptin, for managing HbA1c levels and adverse events.

Rapid and accurate identification of moving load is crucial for bridge operation management and early warning of overload events. However, it is hard to obtain them rapidly via traditional machine learning methods, due to their massive model parameters and complex network structure. To this end, this paper proposes a novel method to perform moving loads identification using MobileNetV2 and transfer learning. Specifically, the dynamic responses of a vehicle–bridge interaction system are firstly transformed into a two-dimensional time-frequency image by continuous wavelet transform to construct the database. Secondly, a pre-trained MobileNetV2 model based on ImageNet is transferred to the moving load identification task by transfer learning strategy for describing the mapping relationship between structural response and these specified moving loads. Then, load identification can be performed through inputting bridge responses into the established relationship. Finally, the effectiveness of the method is verified by numerical simulation. The results show that it can accurately identify the vehicle weight, vehicle speed information, and presents excellent strong robustness. In addition, MobileNetV2 has faster identification speed and requires less computational resources than several traditional deep convolutional neural network models in moving load identification, which can provide a novel idea for the rapid identification of moving loads.

ObjectiveTo assess association between Hashimoto thyroiditis (HT) and clinical outcomes of papillary thyroid carcinoma (PTC).MethodsDatabases including Pubmed, Embase, Cochrane Library, and Web of Science were searched. Weighed mean differences (WMDs) and odds ratios (ORs) were used to evaluate association between HT and clinical outcomes of PTC, and the effect size was represented by 95% confidence intervals (CIs). Heterogeneity test was performed for each indicator. If the heterogeneity statistic I2≥50%, random-effects model analysis was carried out, otherwise, fixed-effect model analysis was performed. Sensitivity analysis was performed for all outcomes, and publication bias was tested by Begg's test.ResultsTotally 47,237 patients in 65 articles were enrolled in this study, of which 12909 patients with HT and 34328 patients without HT. Our result indicated that PTC patients with HT tended to have lower risks of lymph node metastasis (OR: 0.787, 95%CI: 0.686-0.903, P = 0.001), distant metastasis (OR: 0.435, 95%CI: 0.279-0.676, PConclusionsPTC patients with HT may have favorable clinicopathologic characteristics, compared to PTCs without HT. More prospective studies are needed to further elucidate this relationship.

Treg therapies are being tested in clinical trials in transplantation and autoimmune diseases, however, the impact of inflammation on Tregs remains controversial. We challenged human Tregs ex-vivo with pro-inflammatory cytokines IL-6 and TNFα and observed greatly enhanced proliferation stimulated by anti-CD3 and anti-CD28 (aCD3/28) beads or CD28 superagonist (CD28SA). The cytokine-exposed Tregs maintained high expression of FOXP3 and HELIOS, demethylated FOXP3 enhancer, and low IFNγ, IL-4, and IL-17 secretion. Blocking TNF receptor using etanercept or deletion of TNF receptor 2 using CRISPR/Cas9 blunted Treg proliferation and attenuated FOXP3 and HELIOS expression. These results prompted us to consider using CD28SA together with IL-6 and TNFα without aCD3/28 beads (beadless) as an alternative protocol for therapeutic Treg manufacturing. Metabolomics profiling revealed more active glycolysis and oxidative phosphorylation, increased energy production, and higher antioxidant potential during beadless Treg expansion. Finally, beadless expanded Tregs maintained suppressive functions in vitro and in vivo. These results demonstrate that human Tregs positively respond to proinflammatory cytokines with enhanced proliferation without compromising their lineage identity or function. This property can be harnessed for therapeutic Treg manufacturing.

We report on manufacturing outcomes for 41 autologous polyclonal regulatory T cell (PolyTreg) products for 7 different Phase 1 clinical trials over a 10-year period (2011-2020). Data on patient characteristics, manufacturing parameters, and manufacturing outcomes were collected from manufacturing batch records and entered into a secure database. Overall, 88% (36/41) of PolyTreg products met release criteria and 83% (34/41) of products were successfully infused into patients. Of the 7 not infused, 5 failed release criteria, and 2 were not infused because the patient became ineligible due to a change in clinical status. The median fold expansion over the 14-day manufacturing process was 434.8 -fold (range 29.8-2,232), resulting in a median post-expansion cell count of 1,841 x 106 (range 56.9-16,179 x 106). The main correlate of post-expansion cell number was starting cell number, which positively correlates with absolute circulating Treg cell count. Other parameters, including date of PolyTreg production, patient sex, and patient age did not significantly correlate with fold expansion of Treg during product manufacturing. In conclusion, PolyTreg manufacturing outcomes are consistent across trials and dates of production.

BACKGROUND A previous phase I study showed that the infusion of autologous Tregs expanded ex vivo into patients with recent-onset type 1 diabetes (T1D) had an excellent safety profile. However, the majority of the infused Tregs were undetectable in the peripheral blood 3 months postinfusion (Treg-T1D trial). Therefore, we conducted a phase I study (TILT trial) combining polyclonal Tregs and low-dose IL-2, shown to enhance Treg survival and expansion, and assessed the impact over time on Treg populations and other immune cells.METHODS Patients with T1D were treated with a single infusion of autologous polyclonal Tregs followed by one or two 5-day courses of recombinant human low-dose IL-2 (ld-IL-2). Flow cytometry, cytometry by time of flight, and 10x Genomics single-cell RNA-Seq were used to follow the distinct immune cell populations’ phenotypes over time.RESULTS Multiparametric analysis revealed that the combination therapy led to an increase in the number of infused and endogenous Tregs but also resulted in a substantial increase from baseline in a subset of activated NK, mucosal associated invariant T, and clonal CD8+ T cell populations.CONCLUSION These data support the hypothesis that ld-IL-2 expands exogenously administered Tregs but also can expand cytotoxic cells. These results have important implications for the use of a combination of ld-IL-2 and Tregs for the treatment of autoimmune diseases with preexisting active immunity.TRIAL REGISTRATION ClinicalTrials.gov NCT01210664 (Treg-T1D trial), NCT02772679 (TILT trial).FUNDING Sean N. Parker Autoimmune Research Laboratory Fund, National Center for Research Resources.

Infusion of regulatory T cells (Tregs) engineered with a chimeric antigen receptor (CAR) targeting donor-derived human leukocyte antigen (HLA) is a promising strategy to promote transplant tolerance. Here, we describe an anti-HLA-A2 CAR (A2-CAR) generated by grafting the complementarity-determining regions (CDRs) of a human monoclonal anti-HLA-A2 antibody into the framework regions of the Herceptin 4D5 single-chain variable fragment and fusing it with a CD28-ζ signaling domain. The CDR-grafted A2-CAR maintained the specificity of the original antibody. We then generated HLA-A2 mono-specific human CAR Tregs either by deleting the endogenous T-cell receptor (TCR) via CRISPR/Cas9 and introducing the A2-CAR using lentiviral transduction or by directly integrating the CAR construct into the TCR alpha constant locus using homology-directed repair. These A2-CAR+TCRdeficient human Tregs maintained both Treg phenotype and function in vitro. Moreover, they selectively accumulated in HLA-A2-expressing islets transplanted from either HLA-A2 transgenic mice or deceased human donors. A2-CAR+TCRdeficient Tregs did not impair the function of these HLA-A2+ islets, whereas similarly engineered A2-CAR+TCRdeficientCD4+ conventional T cells rejected the islets in less than 2 weeks. A2-CAR+TCRdeficient Tregs delayed graft-versus-host disease only in the presence of HLA-A2, expressed either by co-transferred peripheral blood mononuclear cells or by the recipient mice. Altogether, we demonstrate that genome-engineered mono-antigen-specific A2-CAR Tregs localize to HLA-A2-expressing grafts and exhibit antigen-dependent in vivo suppression, independent of TCR expression. These approaches may be applied towards developing precision Treg cell therapies for transplant tolerance.

Pulmonary arterial hypertension (PAH) is a chronic, incurable condition characterized by pulmonary vascular remodeling, perivascular inflammation, and right heart failure. Regulatory T cells (Tregs) stave off autoimmunity, and there is increasing evidence for their compromised activity in the inflammatory milieu of PAH. Abnormal Treg function is strongly correlated with a predisposition to PAH in animals and patients. Athymic Treg-depleted rats treated with SU5416, an agent causing pulmonary vascular injury, develop PAH, which is prevented by infusing missing CD4+CD25highFOXP3+ Tregs. Abnormal Treg activity may also explain why PAH disproportionately affects women more than men. This mini review focuses on the role of Tregs in PAH with a special view to sexual dimorphism and the future promise of Treg therapy.

Alloreactive regulatory T cells (arTregs) are more potent than polyclonal Tregs at suppressing immune responses to transplant antigens. Human arTregs can be expanded with allogeneic CD40L-stimulated B cells (sBcs) or stimulated-matured monocyte-derived dendritic cells (sDCs). Here, we compared the expansion efficiency and properties of arTregs stimulated ex vivo using these two types of antigen-presenting cells. Compared to sBcs, sDCs stimulated Tregs to expand two times more in number. The superior expansion-inducing capacity of sDCs correlated with their higher expression of CD80, CD86, and T cell-attracting chemokines. sBc- and sDC-arTregs expressed comparable levels of FOXP3, HELIOS, CD25, CD27, and CD62L, demethylated FOXP3 enhancer and in vitro suppressive function. sBc- and sDCs-arTregs had similar gene expression profiles that were distinct from primary Tregs. sBc- and sDC-arTregs exhibited similar low frequencies of IFN-γ, IL-4, and IL-17A-producing cells, and the cytokine-producing arTregs expressed high levels of FOXP3. Almost all sBc- and sDC-arTregs expressed CXCR3, which may enable them traffic to inflammatory sites. Thus, sDCs-arTregs that expand more readily, are phenotypically similar to sBc-arTregs, supporting sDCs as a viable alternative for arTreg production for clinical evaluation.

Anti-CD19 chimeric antigen receptor (CD19-CAR)-engineered T cells are approved therapeutics for malignancies. The impact of the hinge domain (HD) and the transmembrane domain (TMD) between the extracellular antigen-targeting CARs and the intracellular signaling modalities of CARs has not been systemically studied. In this study, a series of 19-CARs differing only by their HD (CD8, CD28, or IgG4) and TMD (CD8 or CD28) was generated. CARs containing a CD28-TMD, but not a CD8-TMD, formed heterodimers with the endogenous CD28 in human T cells, as shown by co-immunoprecipitation and CAR-dependent proliferation of anti-CD28 stimulation. This dimerization was dependent on polar amino acids in the CD28-TMD and was more efficient with CARs containing CD28 or CD8 HD than IgG4-HD. The CD28-CAR heterodimers did not respond to CD80 and CD86 stimulation but had a significantly reduced CD28 cell-surface expression. These data unveiled a fundamental difference between CD28-TMD and CD8-TMD and indicated that CD28-TMD can modulate CAR T-cell activities by engaging endogenous partners.

The shallow features extracted by the traditional artificial intelligence algorithm-based damage identification methods pose low sensitivity and ignore the timing characteristics of vibration signals. Thus, this study uses the high-dimensional feature extraction advantages of convolutional neural networks (CNNs) and the time series modeling capability of long short-term memory networks (LSTM) to identify damage to long-span bridges. Firstly, the features extracted by CNN and LSTM are fused as the input of the fully connected layer to train the CNN-LSTM model. After that, the trained CNN-LSTM model is employed for damage identification. Finally, a numerical example of a large-span suspension bridge was carried out to investigate the effectiveness of the proposed method. Furthermore, the performance of CNN-LSTM and CNN under different noise levels was compared to test the feasibility of application in practical engineering. The results demonstrate the following: (1) the combination of CNN and LSTM is satisfactory with 94% of the damage localization accuracy and only 8.0% of the average relative identification error (ARIE) of damage severity identification; (2) in comparison to the CNN, the CNN-LSTM results in superior identification accuracy; the damage localization accuracy is improved by 8.13%, while the decrement of ARIE of damage severity identification is 5.20%; and (3) the proposed method is capable of resisting the influence of environmental noise and acquires an acceptable recognition effect for multi-location damage; in a database with a lower signal-to-noise ratio of 3.33, the damage localization accuracy of the CNN-LSTM model is 67.06%, and the ARIE of the damage severity identification is 31%. This work provides an innovative idea for damage identification of long-span bridges and is conducive to promote follow-up studies regarding structural condition evaluation.

The advent of large-scale in vitro differentiation of human stem cell-derived insulin-producing cells (SCIPC) has brought us closer to treating diabetes using stem cell technology. However, decades of experiences from islet transplantation show that ischemia-induced islet cell death after transplant severely limits the efficacy of the therapy. It is unclear to what extent human SCIPC are susceptible to ischemia. In this study, we show that more than half of SCIPC die shortly after transplantation. Nutrient deprivation and hypoxia acted synergistically to kill SCIPC in vitro. Amino acid supplementation rescued SCIPC from nutrient deprivation, likely by providing cellular energy. Generating SCIPC under physiological oxygen tension of 5% conferred hypoxia resistance without affecting their differentiation or function. A two-pronged strategy of physiological oxygen acclimatization during differentiation and amino acid supplementation during transplantation significantly improved SCIPC survival after transplant.

Trains are prone to delays and deviations from train operation plans during their operation because of internal or external disturbances. Delays may develop into operational conflicts between adjacent trains as a result of delay propagation, which may disturb the arrangement of the train operation plan and threaten the operational safety of trains. Therefore, reliable conflict prediction results can be valuable references for dispatchers in making more efficient train operation adjustments when conflicts occur. In contrast to the traditional approach to conflict prediction that involves introducing random disturbances, this study addresses the issue of the fuzzification of time intervals in a train timetable based on historical statistics and the modeling of a high-speed railway train timetable based on the concept of a timed Petri net. To measure conflict prediction results more comprehensively, we divided conflicts into potential conflicts and certain conflicts and defined the judgment conditions for both. Two evaluation indexes, one for the deviation of a single train and one for the possibility of conflicts between adjacent train operations, were developed using a formalized computation method. Based on the temporal fuzzy reasoning method, with some adjustment, a new conflict prediction method is proposed, and the results of a simulation example for two scenarios are presented. The results prove that conflict prediction after fuzzy processing of the time intervals of a train timetable is more reliable and practical and can provide helpful information for use in train operation adjustment, train timetable improvement, and other purposes.

Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.

Introduction: In spontaneous type 1 diabetes (T1D) non-obese diabetic (NOD) mice, the insulin B chain peptide 9-23 (B:9-23) can bind to the MHC class II molecule (IAg7) in register 3 (R3), creating a bimolecular IAg7/InsulinB:9-23 register 3 conformational epitope (InsB:R3). Previously, we showed that the InsB:R3-specific chimeric antigen receptor (CAR), constructed using an InsB:R3-monoclonal antibody, could guide CAR-expressing CD8 T cells to migrate to the islets and pancreatic lymph nodes. Regulatory T cells (Tregs) specific for an islet antigen can broadly suppress various pathogenic immune cells in the islets and effectively halt the progression of islet destruction. Therefore, we hypothesized that InsB:R3 specific Tregs would suppress autoimmune reactivity in islets and efficiently protect against T1D. Methods: To test our hypothesis, we produced InsB:R3-Tregs and tested their disease-protective effects in spontaneous T1D NOD.CD28-/- mice. Results: InsB:R3-CAR expressing Tregs secrete IL-10 dominated cytokines upon engagement with InsB:R3 antigens. A single infusion of InsB:R3 Tregs delayed the onset of T1D in 95% of treated mice, with 35% maintaining euglycemia for two healthy lifespans, readily home to the relevant target whereas control Tregs did not. Our data demonstrate that Tregs specific for MHC class II: Insulin peptide epitope (MHCII/Insulin) protect mice against T1D more efficiently than polyclonal Tregs lacking islet antigen specificity, suggesting that the MHC II/insulin-specific Treg approach is a promising immune therapy for safely preventing T1D. [ABSTRACT FROM AUTHOR]

Introduction: In spontaneous type 1 diabetes (T1D) non-obese diabetic (NOD) mice, the insulin B chain peptide 9-23 (B:9-23) can bind to the MHC class II molecule (IAg7) in register 3 (R3), creating a bimolecular IAg7/InsulinB:9-23 register 3 conformational epitope (InsB:R3). Previously, we showed that the InsB:R3-specific chimeric antigen receptor (CAR), constructed using an InsB:R3-monoclonal antibody, could guide CAR-expressing CD8 T cells to migrate to the islets and pancreatic lymph nodes. Regulatory T cells (Tregs) specific for an islet antigen can broadly suppress various pathogenic immune cells in the islets and effectively halt the progression of islet destruction. Therefore, we hypothesized that InsB:R3 specific Tregs would suppress autoimmune reactivity in islets and efficiently protect against T1D. Methods: To test our hypothesis, we produced InsB:R3-Tregs and tested their disease-protective effects in spontaneous T1D NOD.CD28-/- mice. Results: InsB:R3-CAR expressing Tregs secrete IL-10 dominated cytokines upon engagement with InsB:R3 antigens. A single infusion of InsB:R3 Tregs delayed the onset of T1D in 95% of treated mice, with 35% maintaining euglycemia for two healthy lifespans, readily home to the relevant target whereas control Tregs did not. Our data demonstrate that Tregs specific for MHC class II: Insulin peptide epitope (MHCII/Insulin) protect mice against T1D more efficiently than polyclonal Tregs lacking islet antigen specificity, suggesting that the MHC II/insulin-specific Treg approach is a promising immune therapy for safely preventing T1D. [ABSTRACT FROM AUTHOR]