Furthermore, RPL11 and RPL5 suppressed ubiquitination-mediated P53 degradation through direct binding to MDM2. This study demonstrates that MeCP2 promotes breast cancer cell proliferation and inhibits apoptosis through suppressing RPL11 and RPL5 transcription by binding to their promoter regions.The antiandrogen enzalutamide (Enz) has improved survival in castration resistant prostate cancer (CRPC) patients. However, most patients eventually develop Enz resistance that may involve inducing the androgen receptor (AR) splicing variant 7 (ARv7). Here we report that high expression of monoamine oxidase-A (MAO-A) is associated with positive ARv7 detection in CRPC patients following Enz treatment. Targeting MAO-A with phenelzine or clorgyline, the FDA-approved drugs for antidepression, resensitize the Enz resistant (EnzR) cells to Enz treatment and further suppress EnzR cell growth in vitro and in vivo. Our findings suggest that Enz-increased ARv7 expression can transcriptionally enhance MAO-A expression resulting in Enz resistance via altering the hypoxia HIF-1α signals. Together, our results show that targeting the Enz/ARv7/MAO-A signaling with the antidepressants phenelzine or clorgyline can restore Enz sensitivity to suppress EnzR cell growth, which may indicate that these antidepression drugs can overcome the Enz resistance to further suppress the EnzR CRPC.Background Limited data exist on the association of obesity with both hospitalization and mortality in patients with heart failure with preserved ejection fraction (HFpEF), especially in the real-world ambulatory setting. We hypothesized that increasing body-mass index (BMI) in ambulatory heart failure with preserved ejection fraction would have a protective effect on these patients leading to decreased mortality and hospitalizations. Methods We studied the relationship between BMI and the time to all-cause mortality, time to heart failure (HF) hospitalization, and time to all-cause hospitalization over a 2-year follow-up in a national cohort of 2501 ambulatory HFpEF patients at 153 Veterans Affairs medical centers. Results Compared with normal BMI, overweight (HR 0.72; 95% CI 0.57-0.91), obesity class I (HR 0.59; 95% CI 0.45-0.77), obesity class II (HR 0.56; 95% CI 0.40-0.77), and obesity class III (HR 0.53; 95% CI 0.36-0.77) were associated with improved survival after adjustment for demographics and comorbidities. In contrast, the time to HF hospitalization showed an inverse relationship, with shorter time to HF hospitalization with increasing BMI compared with normal BMI; overweight (adjusted HR 1.30; 95% CI 0.88-1.90), obesity class I (HR 1.57; 95% CI 1.05-2.34), obesity class II (HR 1.79; 95% CI 1.15-2.78), and obesity class III (HR 1.96; 95% CI 1.23-3.12). However, time to first all-cause hospitalization was not significantly different by BMI groups. Conclusions In a large, national ambulatory HFpEF cohort, despite the presence of the obesity paradox with respect to survival, increasing BMI was independently associated with an increased risk of HF hospitalization and similar risk of all-cause hospitalization. Future longer-term prospective trials evaluating the safety and efficacy of weight loss on morbidity and mortality, in patients with severe obesity and HFpEF are needed.Girder design for suspension bridges has remained largely unchanged for the past 60 years. However, for future super-long bridges, aiming at record-breaking spans beyond 3 km, the girder weight is a limiting factor. Here we report on a design concept, inspired by computational morphogenesis procedures, demonstrating possible weight savings in excess of 28 percent while maintaining manufacturability. Although morphogenesis procedures are rarely used in civil engineering, often due to complicated designs, we demonstrate that even a crude extraction of the main features of the optimized design, followed by a simple parametric optimization, results in hitherto unseen weight reductions. We expect that further studies of the proposed design, as well as applications to other structures, will lead to even greater weight savings and reductions in carbon footprint in a construction industry, currently responsible for 39 percent of the world’s CO2 emissions.We profiled gene expression signatures to distinguish rheumatoid arthritis (RA) from non-inflammatory arthralgia (NIA), self-limiting arthritis (SLA), and undifferentiated arthritis (UA) as compared to healthy controls as novel potential biomarkers for therapeutic responsiveness. Global gene expression profiles of PBMCs from 43 drug-naïve patients presenting with joint symptoms were evaluated and differentially expressed genes identified by comparative analysis with 24 healthy volunteers. Patients were assessed at presentation with follow up at 6 and 12 months. Gene ontology and network pathway analysis were performed using DAVID Bioinformatics Resources v6.7. Gene expression profiles were also determined after disease-modifying anti-rheumatic drug (DMARD) treatment in the inflammatory arthritis groups (i.e. RA and UA) and confirmed by qRT-PCR. Receiver operating characteristic (ROC) curves analysis and Area Under the Curve (AUC) estimation were performed to assess the diagnostic value of candidate gene expreseful marker of disease activity in UA.Here we investigated the roles of Rab27a, a player in exosome release, and TRAF3IP2, an inflammatory mediator, in development and metastasis of breast cancer (BC) in vivo. Knockdown (KD) of Rab27a (MDAKDRab27a) or TRAF3IP2 (MDAKDTRAF3IP2) in triple negative MDA-MB231 cells reduced tumor growth by 70-97% compared to wild-type tumors (MDAw). While metastasis was detected in MDAw-injected animals, none was detected in MDAKDRab27a- or MDAKDTRAF3IP2-injected animals. Interestingly, micrometastasis was detected only in the MDAKDRab27a-injected group. In addition to inhibiting tumor growth and metastasis, silencing TRAF3IP2 disrupted inter-cellular inflammatory mediator-mediated communication with mesenchymal stem cells (MSCs) injected into contralateral mammary gland, evidenced by the lack of tumor growth at MSC-injected site. 8-OH-DPAT order Of translational significance, treatment of pre-formed MDAw-tumors with a lentiviral-TRAF3IP2-shRNA not only regressed their size, but also prevented metastasis. These results demonstrate that while silencing Rab27a and TRAF3IP2 each inhibited tumor growth and metastasis, silencing TRAF3IP2 is more effective; targeting TRAF3IP2 inhibited tumor formation, regressed preformed tumors, and prevented both macro- and micrometastasis.