The cyclic GMP-AMP synthase (cGAS), upon cytosolic DNA stimulation, catalyzes the formation of the second messenger 2′3′-cGAMP, which then binds to stimulator of interferon genes (STING) and activates downstream signaling. It remains to be elucidated how the cGAS enzymatic activity is modulated dynamically. Here, we reported that the ER ubiquitin ligase RNF185 interacted with cGAS during HSV-1 infection. Ectopic-expression or knockdown of RNF185 respectively enhanced or impaired the IRF3-responsive gene expression. Mechanistically, RNF185 specifically catalyzed the K27-linked poly-ubiquitination of cGAS, which promoted its enzymatic activity. Additionally, Systemic Lupus Erythematosus (SLE) patients displayed elevated expression of RNF185 mRNA. Collectively, this study uncovers RNF185 as the first E3 ubiquitin ligase of cGAS, shedding light on the regulation of cGAS activity in innate immune responses.

Sorption and desorption experiments for phenanthrene and pyrene, using untreated (UTR) and treated (bleaching and hydrolysis) aspen wood fibers, were examined to understand their sorption mechanisms. The wood was characterized by elemental and porosity analysis, solid-state 13C NMR, and diffuse reflectance infrared Fourier transform spectroscopy. Bleaching removed aromatic components, yielding the highest polarity and increased porosity, whereas hydrolysis removed a large percentage of hemicellulose and parts of amorphous cellulose, producing a matrix with more aromatic moieties, lower polarity, and higher porosity than that of the UTR wood fibers. All isotherms fitted well to the Freundlich equation and the N values had a decreasing trend from bleached (BL), UTR, low-temperature hydrolyzed to high-temperature hydrolyzed (HHY) wood fibers. BL fibers had the lowest sorption capacity (Koc) for both phenanthrene and pyrene. HHY had the highest Koc because of its high aromatic carbon content and low polarity. The results suggest that aromatic moieties and polarity of wood fibers play significant roles in polycyclic aromatic hydrocarbon (PAHs) sorption and desorption. Thus, both aromatic components and polarity should be considered when predicting the PAHs sorption/desorption by aspen wood fibers. This study demonstrated that aspen wood fibers are a potential sorbentfor PAHs and that chemical modifications of the wood matrix can effectively increase its sorption efficiency. These results may have implications for the treatment of stormwater runoff and other PAH-contaminated liquids.

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Objective-To identify clinical and demographic factors predictive of midurethral sling failure.Methods-Overall treatment failure was defined by one or more of the following objective outcomes: a positive stress test, positive 24-hour pad test or re-treatment for stress urinary incontinence (SUI); subjective outcomes: self reported SUI by the Medical, Epidemiologic and Social Aspect of Aging questionnaire (MESA), incontinent episodes by 3-day diary, or retreatment for SUI, or a combination of these. Logistic regression models adjusting for sling type and clinical site were used to predict odds of overall treatment failure after univariable analysis. Models were also fit to compare factors associated with objective failure versus subjective failure only. Financial Disclosure: Dr. Richter has been a consultant for Xanodyne Pharmaceuticals, Uromedica, and IDEO. She has received research grants and has been a consultant for Pfizer and Astellas. She has also received an education grant from Warner Chilcott. Dr. Lukacz has been a consultant and advisor to Pfizer and Watson. Dr. Fitzgerald has received a research grant from Astellas and speaker honorarium from Astellas, Pfizer, and Ferring. She also has been a consultant to Pfizer and Astellas. Dr. Rickey received research support from Pfizer and is a consultant for Ethicon. The other authors did not report any potential conflicts of interest. Conclusion-Twelve months after surgery, risk factors for overall and objective treatment failure were similar in women undergoing retropubic and transobturator sling procedures. This information may assist in counseling patients regarding efficacy of sling procedures and in setting expectations for women at increased odds for treatment failure. NIH Public Access

Purpose We determined whether baseline urodynamic study variables predict failure after midurethral sling surgery. Materials and Methods Pre-operative urodynamic study variables and post operative continence status were analyzed from women participating in a randomized trial comparing retropubic to transobturator midurethral sling. Objective failure was defined by positive standardized stress test, or 15 ml or greater on 24-hour pad test, or re-treatment for stress urinary incontinence (SUI). Subjective failure criteria were self-reported stress symptoms, or leakage on 3-day diary, or retreatment for stress urinary incontinence. Logistic regression assessed associations between covariates and failure controlling for treatment group and clinical variables. Receiver operator curves were constructed for relationships between objective failure and measures of urethral function. Results Objective continence outcomes were available at 12 months from 565 of 597 (95%) women. Treatment failed in 260 (245 subjective criteria, 124 by objective criteria). No urodynamic variable was significantly associated with subjective failure on multivariate analysis. Valsalva leak point pressure (VLPP) and maximum urethral closure pressure (MUCP) were the only urodynamic variables consistently associated with objective failure on multivariate analysis. No specific cut-point was determined for predicting failure for VLPP or MUCP by ROC; the lowest quartile (VLPP <86 cm H2O; MUCP <45 cm H2O) conferred an almost two fold increased odds of objective failure regardless of sling route [OR 2.23 (1.20– 4.14) for VLPP and OR 1.88 (1.04–3.41)] for MUCP. Conclusions Women with either a VLPP or MUCP in the lowest quartile are nearly 2-fold more likely to experience SUI one year after transobturator or retropubic MUS.

Introduction and Hypothesis The purpose of this study is to describe risk factors for post-operative urinary tract infection (UTI) the first year after stress urinary incontinence surgery. Methods Multivariable logistic regression analyses were performed on data from 1,252 women randomized in two surgical trials, Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr) and Trial Of Mid-Urethral Slings (TOMUS). Results Baseline recurrent UTI (rUTI; ≥ 3 in 12 months) increased the risk of UTI in the first 6 weeks in both study populations, as did sling procedure and self-catheterization in SISTEr, and bladder perforation in TOMUS. Baseline rUTI, UTI in first 6 weeks, and PVR > 100 cc at 12 months were independent risk factors for UTI between 6 weeks and 12 months in the SISTEr population. Few (2.3-2.4%) had post-operative rUTI, precluding multivariable analysis. In women with pre-operative rUTI, successful surgery (negative cough stress test) at 1 year did not appear to decrease the risk of persistent rUTI. Conclusions Pre-operative rUTI is the strongest risk factor for post-operative UTI.

Purpose To compare urinary incontinence (UI) severity measures and impact of stress UI in normal, overweight and obese women. Materials and Methods Baseline characteristics of subjects in the Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr, N=655) and the TOMUS (N=597) were analyzed. Body mass index [BMI] was defined as normal (<25 kg/m2), overweight (25kg/m2 ≤BMI<30 kg/m2) and obese (≥30 kg/m2). Independent UI severity measures included 3 day diary including incontinence episode frequency (IEF), Urogenital Distress Inventory (UDI) scores, and valsalva leak point pressure (VLPP) from urodynamic testing (UDS). Impact was measured using the Incontinence Impact Questionnaire (IIQ). Multivariable regression models were fit for each severity measures (UDI, IEF, VLPP and IIQ) on weight category. Covariates included age and variables significantly associated with BMI in bivariate analysis. Results Mean age (SD) of participants was 51.9 (10.3) in SISTEr and 52.9 (11.0) in TOMUS. In each trial, 45% of subjects were obese. In SISTEr, multivariable regression analyses showed that increasing BMI was independently associated with higher mean UDI scores (p=0.003), IEF (p<0.0001), VLPP (p=0.003) and IIQ score (p=0.0004). In TOMUS, increasing BMI was not associated with UDI scores (p=0.24), but was associated with higher IEF (p=0.0003), VLPP (p=0.0006) and IIQ score (p<0.0001). Conclusion Obese women undergoing surgery for stress urinary incontinence report more incontinence episodes, more symptom distress and worse quality of life despite better measure of urethral function (higher VLPP) on urodynamics.

MicroRNAs (miRNAs) possess an important regulating effect among numerous renal diseases, while their functions in the process of epithelial-to-mesenchymal transition (EMT) after podocyte injury remain unclear. The purpose of our study is to identify the potential functions of miR-30a in EMT of podocytes and explore the underlying mechanisms of miR-30a in the impaired podocytes. The results revealed that downregulation of miR-30a in podocyte injury animal models and patients, highly induced the mesenchymal markers of EMT including Collagen I, Fibronectin and Snail. Furthermore, overexpression of miR-30a enhances epithelial markers (E-cadherin) but diminished mesenchymal markers (Collagen I, Fibronectin and Snail) in podocytes. In addition, we established miR-30a target NFATc3, an important transcription factor of Non-canonical Wnt signaling pathway. More importantly, our findings demonstrated that the augmentation of miR-30a level in podocytes inhibits the nuclear translocation of NFATc3 to protect cytoskeleton disorder or rearrangement. In summary, we uncovered the protective function of miR30a targeting NFATc3 in the regulation of podocyte injury response to EMT.