Regulatory T cells (Tregs) are required to control immune responses and maintain homeostasis, but are a significant barrier to anti-tumor immunity 1 . Conversely, Treg instability, characterized by loss of the master transcription factor Foxp3 and acquisition of pro-inflammatory properties 2 , can promote autoimmunity and/or facilitate more effective tumor immunity 3 , 4 . A comprehensive understanding of the pathways that regulate Foxp3 could lead to more effective Treg therapies for autoimmune disease and cancer. Despite improved functional genetic tools that now allow for systematic interrogation, dissection of the gene regulatory programs that modulate Foxp3 expression has not yet been reported. In this study, we developed a CRISPR-based pooled screening platform for phenotypes in primary mouse Tregs and applied this technology to perform a targeted loss-of-function screen of ~490 nuclear factors to identify gene regulatory programs that promote or disrupt Foxp3 expression. We discovered several novel modulators including ubiquitin-specific peptidase 22 (Usp22) and ring finger protein 20 (Rnf20). Usp22, a member of the deubiquitination module of the SAGA chromatin modifying complex, was discovered to be a positive regulator that stabilized Foxp3 expression; whereas the screen suggested Rnf20, an E3 ubiquitin ligase, can serve as a negative regulator of Foxp3. Treg-specific ablation of Usp22 in mice reduced Foxp3 protein and created defects in their suppressive function that led to spontaneous autoimmunity but protected against tumor growth in multiple cancer models. Foxp3 destabilization in Usp22-deficient Tregs could be rescued by ablation of Rnf20, revealing a reciprocal ubiquitin switch in Tregs. These results reveal novel modulators of Foxp3 and demonstrate a screening method that can be broadly applied to discover new targets for Treg immunotherapies for cancer and autoimmune disease.

No abstract

A major challenge in prevention and early treatment of acute cardiorenal syndrome (CRS) is the lack of highperformance predictors. To test the hypothesis that urinary angiotensinogen (uAGT) is an early predictor for acute CRS and 1-year prognosis in patients with acute decompensated heart failure (ADHF), we performed a prospective, two-stage, multicenter cohort study in patients with ADHF. In stage I (test set), 317 patients were recruited from four centers. In stage II (validation set), 119 patients were enrolled from two other centers. Daily uAGT levels were analyzed consecutively. AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines. In stage I, 104 (32.8%) patients developed AKI during hospitalization. Daily uAGT peaked on the first hospital day in patients who subsequently developed AKI. After multivariable adjustment, the highest quartile of uAGT on admission was associated with a 50-fold increased risk of AKI compared with the lowest quartile. For predicting AKI, uAGT (area under the receiveroperating characteristic curve [AUC]=0.84) outperformed urinary neutrophil gelatinase-associated lipocalin (AUC=0.78), the urinary albumin/creatinine ratio (AUC=0.71), and the clinical model (AUC=0.77). Survivors in stage I were followed prospectively for 1 year after hospital discharge. The uAGT level independently predicted the risk of 1-year mortality (adjusted odds ratio, 4.5; 95% confidence interval, 2.1 to 9.5) and rehospitalization (adjusted odds ratio, 3.6; 95% confidence interval, 1.6 to 5.7). The ability of uAGT in predicting AKI was validated in stage II (AUC=0.79). In conclusion, uAGT is a strong predictor for acute CRS and 1-year prognosis in ADHF.

No abstract

Epidemiology ObjectivesTo explore characteristics of urinary stone composition in China, and determine the effects of gender, age, body mass index (BMI), stone location, and geographical region on stone composition. Patients and methodsWe prospectively used Fourier-transform infrared spectroscopy to analyse stones from consecutive patients presenting with new-onset urolithiasis at 46 hospitals in seven geographical areas of China, between 1 June 2010 and 31 May 2015. Chi-squared tests and logistic regression analyses were used to determine associations between stone composition and gender, age, BMI, stone location, and geographical region. ResultsThe most common stone constituents were: calcium oxalate (CaOx; 65.9%), carbapatite (15.6%), urate (12.4%), struvite (2.7%), and brushite (1.7%). CaOx and urate stones occurred more frequently in males, whereas carbapatite and struvite were more common in females (P < 0.01). CaOx and carbapatite were more common in those aged 30-50 and 20-40 years than in other groups. Brushite and struvite were most common amongst those aged <20 and >70 years. The detection rate of urate increased with age, whilst cystine decreased with age. Obese patients were more likely to have urate stones than carbapatite or brushite stones (P < 0.01). CaOx, carbapatite, brushite, and cystine stones were more frequently found in the kidney than other types, whereas urate and struvite were more frequent in the bladder (P < 0.01). Stone composition varied by geographical region. ConclusionsThe most common stone composition was CaOx, followed by carbapatite, urate, struvite, and brushite. Stone composition differed significantly in patients grouped by gender, age, BMI, stone location, and geographical region.

No abstract

No abstract

No abstract