Automatic velocity picking with restricted weighted k-means clustering using prior information

Automatic picking of seismic velocity can be performed using k-means clustering. In simple k-means clustering, the number of clusters needs to be predetermined, while the picking result is affected by the initial value of each cluster center. In this study, we present an unsupervised weighted k-means clustering velocity-picking method that picks the centers of the energy clusters instead of the geometric centers of the clusters. This method works on the semblance velocity spectrum and requires an initial velocity function and three user-defined thresholds to limit the search area. The number of cluster centers and their initial times are obtained according to a rectangular signal resulting from the three thresholds, while the initial velocities of the cluster centers can be subsequently obtained using their initial times and the initial velocity function. Inaccurate selection of thresholds may merge two clusters wrongly, in which case only a stronger event is selected. In the weighted k-means clustering algorithm, weights are calculated by using the amplitudes of the velocity points. Meanwhile, points far from the center are gradually removed to ensure that each cluster center coincides with the respective energy cluster center. We also propose a method for ignoring non-primary velocities, such as multiples, by removing points that create sudden changes in the slope of the reference velocity beyond a user-defined limit. The processing of the model and real data show that the proposed seismic velocity-picking method has high efficiency and picking accuracy

Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer

Androgen receptor (AR) antagonist MDV3100 is the first therapeutic approach in treating castration-resistant prostate cancer (CRPC), but tumours frequently become drug resistant via multiple mechanisms including AR amplification and mutation. Here we identify the small molecule Ailanthone (AIL) as a potent inhibitor of both full-length AR (AR-FL) and constitutively active truncated AR splice variants (AR-Vs). AIL binds to the co-chaperone protein p23 and prevents AR's interaction with HSP90, thus resulting in the disruption of the AR-chaperone complex followed by ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4, and downregulates AR and its target genes in PCa cell lines and orthotopic animal tumours. In addition, AIL blocks tumour growth and metastasis of CRPC. Finally, AIL possesses favourable drug-like properties such as good bioavailability, high solubility, lack of CYP inhibition and low hepatotoxicity. In general, AIL is a potential candidate for the treatment of CRPC

Dual inhibition of AKT‐mTOR and AR signaling by targeting HDAC3 in PTEN‐ or SPOP‐mutated prostate cancer

Abstract AKT‐mTOR and androgen receptor (AR) signaling pathways are aberrantly activated in prostate cancer due to frequent PTEN deletions or SPOP mutations. A clinical barrier is that targeting one of them often activates the other. Here, we demonstrate that HDAC3 augments AKT phosphorylation in prostate cancer cells and its overexpression correlates with AKT phosphorylation in patient samples. HDAC3 facilitates lysine‐63‐chain polyubiquitination and phosphorylation of AKT, and this effect is mediated by AKT deacetylation at lysine 14 and 20 residues and HDAC3 interaction with the scaffold protein APPL1. Conditional homozygous deletion of Hdac3 suppresses prostate tumorigenesis and progression by concomitant blockade of AKT and AR signaling in the Pten knockout mouse model. Pharmacological inhibition of HDAC3 using a selective HDAC3 inhibitor RGFP966 inhibits growth of both PTEN‐deficient and SPOP‐mutated prostate cancer cells in culture, patient‐derived organoids and xenografts in mice. Our study identifies HDAC3 as a common upstream activator of AKT and AR signaling and reveals that dual inhibition of AKT and AR pathways is achievable by single‐agent targeting of HDAC3 in prostate cancer

Theoretical Studies of Conformational Preferences of NAD+ and NADH Analogs: Protonated nicotinamide and 1,4-dihydro-nicotinamide

The conformations of nicotinamide (N+) and 1,4-dihydronicotinamide (NH) have been studied by ab initio calculations at the MP2/6-31G{*}//6-31G{*} level. The amide group favors a cis conformation by about 1 kcal/mol for both N+ and NH. The rotational barrier for cis to trans interconversion is about 4 and 7 kcal/mol for N+ and NH, respectively. The amide group in the trans conformation is out of plane by about 20-degrees. The 1,4-dihydronicotinamide ring is slightly puckered and adopts a boat conformation. The calculated N-15 equilibrium isotope effect for hydride transfer is small, in agreement with experimental observations