Bootstrap Inference on Partially Linear Binary Choice Model

The partially linear binary choice model can be used for estimating structural equations where nonlinearity may appear due to diminishing marginal returns, different life cycle regimes, or hectic physical phenomena. The inference procedure for this model based on the analytic asymptotic approximation could be unreliable in finite samples if the sample size is not sufficiently large. This paper proposes a bootstrap inference approach for the model. Monte Carlo simulations show that the proposed inference method performs well in finite samples compared to the procedure based on the asymptotic approximation.Comment: 10 page

3,4-Bis(4-meth­oxy­phen­yl)-2,5-dihydro-1H-pyrrole-2,5-dione

In the title compound, C18H15NO4, the benzene rings form quite different dihedral angles [16.07 (1) and 59.50 (1)°] with the central pyrrole ring, indicating a twisted mol­ecule. Conjugation is indicated between the five- and six-membered rings by the lengths of the C—C bonds which link them [1.462 (3) and 1.477 (3) Å]. The most prominent feature of the crystal packing is the formation of inversion dimers via eight-membered {⋯HNCO}2 synthons

PDTD: a web-accessible protein database for drug target identification

<p>Abstract</p> <p>Background</p> <p>Target identification is important for modern drug discovery. With the advances in the development of molecular docking, potential binding proteins may be discovered by docking a small molecule to a repository of proteins with three-dimensional (3D) structures. To complete this task, a reverse docking program and a drug target database with 3D structures are necessary. To this end, we have developed a web server tool, TarFisDock (<it>Tar</it>get <it>Fis</it>hing <it>Dock</it>ing) <url>http://www.dddc.ac.cn/tarfisdock</url>, which has been used widely by others. Recently, we have constructed a protein target database, <it>P</it>otential <it>D</it>rug <it>T</it>arget <it>D</it>atabase (PDTD), and have integrated PDTD with TarFisDock. This combination aims to assist target identification and validation.</p> <p>Description</p> <p>PDTD is a web-accessible protein database for <it>in silico </it>target identification. It currently contains >1100 protein entries with 3D structures presented in the Protein Data Bank. The data are extracted from the literatures and several online databases such as TTD, DrugBank and Thomson Pharma. The database covers diverse information of >830 known or potential drug targets, including protein and active sites structures in both PDB and mol2 formats, related diseases, biological functions as well as associated regulating (signaling) pathways. Each target is categorized by both nosology and biochemical function. PDTD supports keyword search function, such as PDB ID, target name, and disease name. Data set generated by PDTD can be viewed with the plug-in of molecular visualization tools and also can be downloaded freely. Remarkably, PDTD is specially designed for target identification. In conjunction with TarFisDock, PDTD can be used to identify binding proteins for small molecules. The results can be downloaded in the form of mol2 file with the binding pose of the probe compound and a list of potential binding targets according to their ranking scores.</p> <p>Conclusion</p> <p>PDTD serves as a comprehensive and unique repository of drug targets. Integrated with TarFisDock, PDTD is a useful resource to identify binding proteins for active compounds or existing drugs. Its potential applications include <it>in silico </it>drug target identification, virtual screening, and the discovery of the secondary effects of an old drug (i.e. new pharmacological usage) or an existing target (i.e. new pharmacological or toxic relevance), thus it may be a valuable platform for the pharmaceutical researchers. PDTD is available online at <url>http://www.dddc.ac.cn/pdtd/</url>.</p

TarFisDock: a web server for identifying drug targets with docking approach

TarFisDock is a web-based tool for automating the procedure of searching for small molecule–protein interactions over a large repertoire of protein structures. It offers PDTD (potential drug target database), a target database containing 698 protein structures covering 15 therapeutic areas and a reverse ligand–protein docking program. In contrast to conventional ligand–protein docking, reverse ligand–protein docking aims to seek potential protein targets by screening an appropriate protein database. The input file of this web server is the small molecule to be tested, in standard mol2 format; TarFisDock then searches for possible binding proteins for the given small molecule by use of a docking approach. The ligand–protein interaction energy terms of the program DOCK are adopted for ranking the proteins. To test the reliability of the TarFisDock server, we searched the PDTD for putative binding proteins for vitamin E and 4H-tamoxifen. The top 2 and 10% candidates of vitamin E binding proteins identified by TarFisDock respectively cover 30 and 50% of reported targets verified or implicated by experiments; and 30 and 50% of experimentally confirmed targets for 4H-tamoxifen appear amongst the top 2 and 5% of the TarFisDock predicted candidates, respectively. Therefore, TarFisDock may be a useful tool for target identification, mechanism study of old drugs and probes discovered from natural products. TarFisDock and PDTD are available at

Hesperidin Protects against Acute Alcoholic Injury through Improving Lipid Metabolism and Cell Damage in Zebrafish Larvae

Alcoholic liver disease (ALD) is a series of abnormalities of liver function, including alcoholic steatosis, steatohepatitis, and cirrhosis. Hesperidin, the major constituent of flavanone in grapefruit, is proved to play a role in antioxidation, anti-inflammation, and reducing multiple organs damage in various animal experiments. However, the underlying mechanism of resistance to alcoholic liver injury is still unclear. Thus, we aimed to investigate the protective effects of hesperidin against ALD and its molecular mechanism in this study. We established an ALD zebrafish larvae model induced by 350 mM ethanol for 32 hours, using wild-type and transgenic line with liver-specific eGFP expression Tg (lfabp10α:eGFP) zebrafish larvae (4 dpf). The results revealed that hesperidin dramatically reduced the hepatic morphological damage and the expressions of alcohol and lipid metabolism related genes, including cyp2y3, cyp3a65, hmgcra, hmgcrb, fasn, and fads2 compared with ALD model. Moreover, the findings demonstrated that hesperidin alleviated hepatic damage as well, which is reflected by the expressions of endoplasmic reticulum stress and DNA damage related genes (chop, gadd45αa, and edem1). In conclusion, this study revealed that hesperidin can inhibit alcoholic damage to liver of zebrafish larvae by reducing endoplasmic reticulum stress and DNA damage, regulating alcohol and lipid metabolism

Comprehensive analysis reveals dual biological function roles of EpCAM in kidney renal clear cell carcinoma

Background: Epithelial cell adhesion molecule (EpCAM), a well-established marker for circulating tumor cells, plays a crucial role in the complex process of cancer metastasis. The primary objective of this investigation is to study EpCAM expression in pan-cancer and elucidate its significance in the context of kidney renal clear cell carcinoma (KIRC). Methods: Data obtained from the public database was harnessed for the comprehensive assessment of the EpCAM expression levels and prognostic and clinicopathological correlations in thirty-three types of cancer. EpCAM was validated in our own KIRC sequencing and immunohistochemical cohorts. Subsequently, an in-depth exploration was conducted to scrutinize the interrelationship between EpCAM and various facets, including immune cells, immune checkpoints, and chemotherapy drugs. We employed Cox regression analysis to identify prognostic immunomodulators associated with EpCAM, which were subsequently utilized in the development of a prognostic model. The model was validated in our own clinical cohort and public datasets, and compared with 137 published models. The role of EpCAM in KIRC was explored by biological function experiments in vitro. Results: While EpCAM exhibited pronounced overexpression across a wide spectrum of cancer types, a notable reduction was observed in KIRC tissues. As grade increased, EpCAM expression decreased. EpCAM expression decreased in patients without metastasis. EpCAM mRNA and protein levels were used as independent, favorable prognostic factors in patients with KIRC in our own cohort. The expression of EpCAM exhibited strong associations with immune-related pathways, demonstrating an inverse correlation with the majority of immune cell types. Immune checkpoint inhibitors exert better therapeutic effects on patients with low EpCAM expression. In addition, EpCAM can be used as a drug resistance indicator and guide the clinical medication of patients with KIRC. A robust model, which had good predictive accuracy and applicability, showed significant superiority over other models. Importantly, EpCAM played the dual roles of promoting proliferation and resisting metastasis in KIRC. Conclusion: In the context of KIRC, EpCAM assumes a surprising dual role, where it not only facilitates cell proliferation but also exerts resistance against the metastatic process. EpCAM serves as a standalone prognostic marker for patients with KIRC, and related models can also effectively predict prognosis. These discoveries offer novel perspectives on the functional significance of EpCAM in the context of KIRC

Metabolism of quinoline containing C-Met kinase inhibitors by aldehyde oxidase, effect of electron donating group and steric hindrance.

Quinoline-containing c-Met kinase inhibitors are known to be substrate of aldehyde oxidase (AO). 3-substituted quinoline analogues were synthesized to try to block the AO metabolism. Metabolic stability study for these quinoline analogues were carried out in liver cytosol fractions from mouse, rat, cyno monkey, and human. Several 3-N- substituted analogues were found to be extremely instable in monkey liver cytosol incubation (t1/2 < 10 min). Five compounds (63, 53, 51, 11, and 71) were selected for detailed study. Monooxygenated metabolite on the quinoline ring was identified by MS/MS fragments and the characteristic later retention time compared with parent compound in the LC/MS. Metabolite formation was inhibited by AO inhibitors menadione and raloxifene but not by xanthine oxidase inhibitor allopurinol. Electron donating group at 3-positon made it vulnerable to AO, larger 3- substituents were found to rescue molecule as half-life increased. Although species differences were observed, the general trend applies in all the species tested. Electron donating group at 3-positon increased both the affinity (decreased Km) and Vm towards AO in kinetic study, while steric hindrance had opposite effect. A common structure feature with high aldehyde oxidase liability was proposed. Our finding might be helpful to quinoline modification to avoid AO liability

Enhanced osteoinductivity and corrosion resistance of dopamine/gelatin/rhBMP-2-coated β-TCP/Mg-Zn orthopedic implants: An in vitro and in vivo study.

Magnesium-based biomaterials are attracting increasingly more attention for orthopedic applications based on their appropriate mechanical properties, biodegradability, and favorable biocompatibility. However, the high corrosion rate of these materials remains to be addressed. In this study, porous β-Ca3(PO4)2/Mg-Zn (β-TCP/Mg-Zn) composites were fabricated via a powder metallurgy method. The β-TCP/Mg-Zn composites with 6% porosity exhibited optimal mechanical properties, and thus, they were selected for surface modification. A novel dopamine/gelatin/recombinant human bone morphogenetic protein-2 (rhBMP-2) coating with demonstrated stability was prepared to further improve the corrosion resistance of the composite and enhance early osteoinductivity. The homogeneously coated β-TCP/Mg-Zn composite showed significantly improved corrosion resistance according to electrochemical and immersion tests. In addition, extracts from the dopamine/gelatin/rhBMP-2-coated β-TCP/Mg-Zn composite not only facilitated cell proliferation but also significantly enhanced the osteogenic differentiation of Sprague-Dawley rat bone marrow-derived mesenchymal stem cells in vitro. Furthermore, in vivo experiments were performed to evaluate the biodegradation, histocompatibility, and osteoinductive potential of the coated composite. No obvious pathological changes in the vital visceral organs were observed after implantation, and radiography and hematoxylin-eosin staining showed strong promotion of new bone formation, matched composite degradation and bone regeneration rates, and complete absorption of the released hydrogen gas. Collectively, these results indicate that the dopamine/gelatin/rhBMP-2-coated β-TCP/Mg-Zn composite offers improved corrosion resistance, favorable biocompatibility, and enhanced osteoinductive potential for use in the fabrication of orthopedic implants

Histone H3K79 methylation by DOT1L promotes Aurora B localization at centromeres in mitosis

Summary: Centromere localization of the chromosome passenger complex (CPC) is paramount for achieving accurate sister chromosome segregation in mitosis. Although it has been widely recognized that the recruitment of CPC is directly regulated by two histone codes, phosphorylation of histone H3 at threonine 3 (H3T3ph) and phosphorylation of histone H2A at threonine 120 (H2AT120ph), the regulation of CPC localization by other histone codes remains elusive. We show that dysfunction of disruptor of telomeric silencing 1 like (DOT1L) leads to mislocation of the CPC in prometaphase, caused by disturbing the level of H3T3ph and its reader Survivin. This cascade is initiated by over-dephosphorylation of H3T3ph mediated by the phosphatase RepoMan-PP1, whose scaffold RepoMan translocalizes to chromosomes, while the level of H3K79me2/3 is diminished. Together, our findings uncover a biological function of DOT1L and H3K79 methylation in mitosis and give insight into how genomic stability is coordinated by different histone codes