Compartmentalization and persistence of dominant (regulatory) T cell clones indicates antigen skewing in juvenile idiopathic arthritis

Autoimmune inflammation is characterized by tissue infiltration and expansion of antigen-specific T cells. Although this inflammation is often limited to specific target tissues, it remains yet to be explored whether distinct affected sites are infiltrated with the same, persistent T cell clones. Here we performed CyTOF analysis and T cell receptor (TCR) sequencing to study immune cell composition and (hyper-)expansion of circulating and joint-derived Tregs and non-Tregs in Juvenile Idiopathic Arthritis (JIA). We studied different joints affected at the same time, as well as over the course of relapsing-remitting disease. We found that the composition and functional characteristics of immune infiltrates are strikingly similar between joints within one patient, and observed a strong overlap between dominant T cell clones, especially Treg, of which some could also be detected in circulation and persisted over the course of relapsing remitting disease. Moreover, these T cell clones were characterized by a high degree of sequence similarity, indicating the presence of TCR clusters responding to the same antigens. These data suggest that in localized autoimmune disease there is auto-antigen driven expansion of both Teffector and Treg clones, that are highly persistent and are (re)circulating. These dominant clones might represent interesting therapeutic targets

Compartmentalization and persistence of dominant (regulatory) T cell clones indicates antigen skewing in juvenile idiopathic arthritis

Autoimmune inflammation is characterized by tissue infiltration and expansion of antigen-specific T cells. Although this inflammation is often limited to specific target tissues, it remains yet to be explored whether distinct affected sites are infiltrated with the same, persistent T cell clones. Here, we performed CyTOF analysis and T cell receptor (TCR) sequencing to study immune cell composition and (hyper-)expansion of circulating and joint-derived Tregs and non-Tregs in juvenile idiopathic arthritis (JIA). We studied different joints affected at the same time, as well as over the course of relapsing-remitting disease. We found that the composition and functional characteristics of immune infiltrates are strikingly similar between joints within one patient, and observed a strong overlap between dominant T cell clones, especially Treg, of which some could also be detected in circulation and persisted over the course of relapsing-remitting disease. Moreover, these T cell clones were characterized by a high degree of sequence similarity, indicating the presence of TCR clusters responding to the same antigens. These data suggest that in localized autoimmune disease, there is autoantigen-driven expansion of both Teffector and Treg clones that are highly persistent and are (re)circulating. These dominant clones might represent interesting therapeutic targets

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Stability and Bifurcation in a Predator–Prey Model with the Additive Allee Effect and the Fear Effect

We proposed and analyzed a predator–prey model with both the additive Allee effect and the fear effect in the prey. Firstly, we studied the existence and local stability of equilibria. Some sufficient conditions on the global stability of the positive equilibrium were established by applying the Dulac theorem. Those results indicate that some bifurcations occur. We then confirmed the occurrence of saddle-node bifurcation, transcritical bifurcation, and Hopf bifurcation. Those theoretical results were demonstrated with numerical simulations. In the bifurcation analysis, we only considered the effect of the strong Allee effect. Finally, we found that the stronger the fear effect, the smaller the density of predator species. However, the fear effect has no influence on the final density of the prey

Protein profiling of human gastric fluid and gastric cancer biomarker discovery.

Master'sMASTER OF SCIENC

A novel memristor-based rSRAM structure for multiple-bit upsets immunity

A radiation hardened resistive SRAM structure (rSRAM) is proposed for the SRAM-based FPGAs in this paper. The rSRAM extends the conventional 6T SRAM structure by connecting memristors between the information nodes and drains of the transistors which compose cross-coupled invertors. With memristors connected to drains of OFF transistors configured to high resistance state while others configured to low resistance state forming stable voltage dividing path, the rSRAM structure is immune to both multiple-node upsets and multiple-bit upsets (MBUs). The simulation result demonstrates that rSRAM cell can tolerate simultaneous disruptions affecting all sensitive nodes with an LET (Liner Energy Transfer) of 100Mev-cm2/mg.Published Versio

Intrinsic Catalytic Activity of Gold/Multi-Walled Carbon Nanotubes Composites in Squaric Acid-Iron(II/III) System

In this paper, gold/multi-walled carbon nanotube (Au/MWCNTs) composites were prepared via in situ reductions. The synthesized materials could effectively catalyze the system of square acid (SQA)-iron(II/III) to produce a significant color reaction. By designing the orthogonal test of three-factor and three-level, the three factors of sodium formate solution concentration, ultrasonic time and synthesis reaction time were optimized in the process of Au/MWCNTs preparation. Results showed that the Au/MWCNTs had the best catalytic activity under the conditions of sodium formate solution concentration of 400 mmol/L, ultrasonic for 30 min and reaction for 4 h. In a subsequent comparison with H2O2, it found that the catalytic performance of 1 mg of Au/MWCNTs composite was equivalent to that of H2O2 with the concentration of 0.28 mmol/L. It demonstrated that the prepared Au/MWCNTs composites had good catalytic activity, stable color and low background noise, indicating a good prospect in various fields including that of catalytic reaction, sensing analysis, and nanomaterials labeling

The Platelet-derived Growth Factor Receptor α Is Destabilized by Geldanamycins in Cancer Cells

The heat shock protein HSP90 serves as a chaperone for receptor protein kinases, steroid receptors, and other intracellular signaling molecules. Targeting HSP90 with ansamycin antibiotics disrupts the normal processing of clients of the HSP90 complex. The platelet-derived growth factor receptor α (PDGFRα) is a tyrosine kinase receptor up-regulated and activated in several malignancies. Here we show that the PDGFRα forms a complex with HSP90 and the co-chaperone cdc37 in ovarian, glioblastoma, and lung cancer cells. Treatment of cancer cell lines expressing the PDGFRα with the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) promotes degradation of the receptor. Likewise, phospho-Akt, a downstream target, is degraded after treatment with 17-AAG. In contrast, PDGFRα expression is not affected by 17-AAG in normal human smooth muscle cells or 3T3 fibroblasts. PDGFRα degradation by 17-AAG is inhibited by the proteasome inhibitor MG132. High molecular weight, ubiquitinated forms of the receptor are detected in cells treated with 17-AAG and MG132. Degradation of the receptor is also inhibited by a specific neutralizing antibody to the PDGFRα but not by a neutralizing antibody to PDGF or by imatinib mesylate (Gleevec). Ultimately, PDGFRα-mediated cell proliferation is inhibited by 17-AAG. These results show that 17-AAG promotes PDGFRα degradation selectively in transformed cells. Thus, not only mutated tyrosine kinases but also overexpressed receptors in cancer cells can be targeted by 17-AAG

Relationship between Serum 25OH-Vitamin D2 Level and Vitamin D Status of Children Aged 3–5 Years in China

Background: Vitamin D deficiency is prevalent globally and there is lack of evidence as to how 25(OH)D2 contributes to vitamin D status. The aim of this study was to describe vitamin D status and to assess the role of vitamin D2, a dietary vitamin D source, against the vitamin D status of children aged 3–5 years in China. Methods: Data were extracted from the Chinese National Nutrition and Health Surveillance (CNNHS) in 2013. The concentration of serum 25(OH)D2 and 25(OH)D3 was measured by using LC-MS/MS. Results: A total of 1435 subjects were enrolled and serum 25(OH)D were analyzed. The prevalence of total serum 25(OH)D < 30 nmol/L was 8.9%. Serum 25(OH)D2 was detected in 10.9% of the studied children. After adjusting for confounding factors, total 25(OH)D concentration was 8.48 nmol/L lower and odds ratio of vitamin D deficiency was 4.20 times (OR (95%CI): 4.20 (1.64, 10.77)) in children without 25(OH)D2 than those with 25(OH)D2 detected. Conclusions: Vitamin D deficiency was common among children aged 3–5 years in China. Vitamin D2 may play a role in preventing vitamin D deficiency in Chinese children aged 3–5 years