线上博彩合同的效力以及玩家在合同被认定为无效后能否要求返还所投入赌注的问题,向来存在争议。就前一问题,作者提出,因《德国博彩业州际协议》(2012)第4条第4款以及《德国刑法典》第284条都可被认定为《德国民法典》第134条意义上的禁止性规定,故线上博彩合同在民法上应被认定为无效;而在无效后的具体法律效果问题上,作者认为可能会产生非债清偿型不当得利(condictio indebiti)以及不正当原因之不当得利(condictio ob iniustam vel turpem causam)的竞合。前者固然可能因博彩玩家明知无给付义务而被排除(《德国民法典》第814条),但这一排除效力并不及于不正当原因的不当得利;后者的适用则取决于对不法原因给付制度的把握。作者主张从该规定的主观要件与规范目的出发,避免对玩家赌资返还请求权施以不当限制。一方面,不当得利返还请求权的排除对玩家而言是一项重大不利,因此在适用上要求其具备违反某一法律规定的意识;另一方面,该制度旨在贯彻“法律保护之拒绝”的规范理念,纵使认定博彩玩家一方具有不法性,考虑到其远低于博彩平台运营者所具备的不法性以及禁止性规定的规范目的,均应对之进行目的性限缩,承认玩家的赌资返还请求权。
As a receptor tyrosine kinase of insulin receptor (IR) subfamily, anaplastic lymphoma kinase (ALK) has been validated to play important roles in various cancers, especially anaplastic large cell lymphoma (ALCL), nonsm...
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As a receptor tyrosine kinase of insulin receptor (IR) subfamily, anaplastic lymphoma kinase (ALK) has been validated to play important roles in various cancers, especially anaplastic large cell lymphoma (ALCL), nonsmall cell lung cancer (NSCLC), and neuroblastomas. Currently, five small-molecule inhibitors of ALK, including Crizotinib, Ceritinib, Alectinib, Brigatinib, and Lorlatinib, have been approved by the U.S. Food and Drug Administration (FDA) against ALK-positive NSCLCs. Novel type-I-1/2 and type-II ALK inhibitors with improved kinase selectivity and enhanced capability to combat drug resistance have also been reported. Moreover, the "proteolysis targeting chimera" (PROTAC) technique has been successfully applied in developing ALK degraders, which opened a new avenue for targeted ALK therapies. This review provides an overview of the physiological and biological functions of ALK, the discovery and development of drugs targeting ALK by focusing on their chemotypes, activity, selectivity, and resistance as well as potential therapeutic strategies to overcome drug resistance.
Protein-protein interactions (PPIs) have been regarded as an attractive emerging class of therapeutic targets for the development of new treatments. Computational approaches, especially molecular docking, have been ex...
Protein-protein interactions (PPIs) have been regarded as an attractive emerging class of therapeutic targets for the development of new treatments. Computational approaches, especially molecular docking, have been extensively employed to predict the binding structures of PPI-inhibitors or discover novel small molecule PPI inhibitors. However, due to the relatively undruggable' features of PPI interfaces, accurate predictions of the binding structures for ligands towards PPI targets are quite challenging for most docking algorithms. Here, we constructed a non-redundant pose ranking benchmark dataset for small-molecule PPI inhibitors, which contains 900 binding poses for 184 protein-ligand complexes. Then, we evaluated the performance of MM/PB(GB)SA approaches to identify the correct binding poses for PPI inhibitors, including two Prime MM/GBSA procedures from the Schrodinger suite and seven different MM/PB(GB)SA procedures from the Amber package. Our results showed that MM/PBSA outperformed the Glide SP scoring function (success rate of 58.6%) and MM/GBSA in most cases, especially the PB3 procedure which could achieve an overall success rate of approximate to 74%. Moreover, the GB6 procedure (success rate of 68.9%) performed much better than the other MM/GBSA procedures, highlighting the excellent potential of the GBNSR6 implicit solvation model for pose ranking. Finally, we developed the webserver of Fast Amber Rescoring for PPI Inhibitors (farPPI), which offers a freely available service to rescore the docking poses for PPI inhibitors by using the MM/PB(GB)SA methods. Availability and implementation farPPI web server is freely available at http://***/farppi/. Supplementary information Supplementary data are available at Bioinformatics online.
Schizophrenia has often been viewed as a disorder of connectivity. The single nucleotide polymorphism rs1059004 in the oligodendrocyte lineage transcription factor 2 gene locus has been reported to be associated with ...
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Schizophrenia has often been viewed as a disorder of connectivity. The single nucleotide polymorphism rs1059004 in the oligodendrocyte lineage transcription factor 2 gene locus has been reported to be associated with schizophrenia. We measured the functional connectivity and functional brain network topology properties in 49 schizophrenic patients and 47 healthy controls. We compared the strength and diversity of the functional connectivity and topological properties of functional networks between different genotypes. The correlations among functional connectivity, topological properties and behavioral performances were also investigated in this study. We found that the connectivity strength of schizophrenic patients carrying the risk A allele was generally decreased whereas connectivity diversity was increased. Regarding topological properties, all groups showed small-world properties, the nodal efficiency showed significant differences in the right precuneus and left middle temporal pole between different genotypes in schizophrenic patients. Moreover, the nodal efficiency in the left middle temporal pole was positively correlated with the neuropsychological assessment battery results of the schizophrenic patients who were homozygous for the C allele. Our results elucidate the contribution of rs1059004 to the functional brain network, and may help enhance the present understanding of the role of risk gene in the functional dysconnectivity of schizophrenia.
To enhance the forming quality of the forging and minimize the forging cost in the concave radial forging process, this article examines the influence of process parameters (radial reduction increment h, rotation angl...
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To enhance the forming quality of the forging and minimize the forging cost in the concave radial forging process, this article examines the influence of process parameters (radial reduction increment h, rotation angle beta, friction coefficient mu) on the forging process through numerical simulation. A multi-objective optimization method is employed to balance the objective functions (strain homogeneity E, forging load F). First, sample points for different combinations of process parameters were obtained using a central composite experimental design. Then, a mathematical model between the process parameters and the objective function was established using the response surface method, which underwent variance analysis and sensitivity analysis. Finally, the optimal process parameter combination was determined based on the NSGA-II algorithm and satisfaction function. The optimization results were verified by finite element simulations. The optimized process combination: increment h = 0.25 mm, beta = 21.68 degrees, mu = 0.05. The corresponding E and F are 0.241367 and 577.029, respectively. Compared with the initial process, the standard deviation of the overall strain was reduced by 14.25%, and the forging load was reduced by 1.76%. The results indicate that the quality of the forgings was significantly improved while the forging cost was reduced to some extent.
As translated education resource plays an important role in healthcare providers' training and medical knowledge dissemination, we proposed a method to manage cross-lingual education resources with the goal of fac...
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ISBN:
(纸本)9781643680033;9781643680026
As translated education resource plays an important role in healthcare providers' training and medical knowledge dissemination, we proposed a method to manage cross-lingual education resources with the goal of facilitating the medical education and physician training. We created an English Chinese cancer knowledge base including bilingual description on cancer diagnosis, prevention, screening, treatments, etc. We developed a workflow to create the bilingual corpus, and applied it to six cancer monographs in PDQ (Physician Data Query).
Phase change material (PCM) cooling plays an important role in battery thermal management systems (BTMS). However, PCM has been suffering from low thermal conductivity and inefficient latent heat recovery. Based on th...
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Phase change material (PCM) cooling plays an important role in battery thermal management systems (BTMS). However, PCM has been suffering from low thermal conductivity and inefficient latent heat recovery. Based on this, this study designs a hybrid BTMS combining triply periodic minimal surface (TPMS), PCM, and liquid cooling, and proposes a cooling scheme that determines the operating time of the coolant based on the battery temperature. The system aims to improve the utilization of PCM in two different ways: structural design and cooling scheme. Numerical analysis was used to compare the effects of different structures on the melting rate of PCM and to study the thermal performance of the battery module under various cooling schemes. The results show that the effective thermal conductivity of PCM/TPMS composites reaches 21 W/(m & sdot;K), which can effectively enhance the heat absorption rate of PCM. In particular, the I-graph-and-wrapped-package (IWP) structure combined with PCM is the most effective. Under the continuous cooling scheme, when the coolant flow rate is 0.04 m/s, the temperature of the battery at a 3C discharge rate can be controlled at 308.28 K, but the PCM utilization rate is only 0.25. After adopting the delayed cooling scheme, the performance of the BTMS cooling remains excellent, with the battery temperature at only 309.88 K and the liquid phase rate of PCM reaching 0.97. For the first time, the heat absorbed by passive cooling is comparable to that of active cooling in the BTMS heat absorption energy distribution, with a 73 % reduction in pumping energy consumption. Furthermore, under cycling conditions, the delayed cooling scheme still performs well, keeping the battery temperature below 313.15 K. In addition, it should be noted that the flow rate of the coolant should be determined by the charging rate. Additionally, the BTMS is capable of addressing the heat dissipation challenges in different ambient temperatures. This study can guide for
In this paper, we prove the following Willmore-type inequality: on an unbounded closed convex set K subset of Rn+1$K\subset \mathbb {R}{n+1}$ (n >= 2$(n\geqslant 2$), for any embedded hypersurface Sigma subset of K...
In this paper, we prove the following Willmore-type inequality: on an unbounded closed convex set K subset of Rn+1$K\subset \mathbb {R}<^>{n+1}$ (n >= 2$(n\geqslant 2$), for any embedded hypersurface Sigma subset of K${\Sigma }\subset K$ with boundary partial derivative Sigma subset of partial derivative K$\partial {\Sigma }\subset \partial K$ satisfying a certain contact angle condition, there holds 1n+1 integral Sigma HndA >= AVR(K)|Bn+1|.$$\begin{equation*} {\frac{1}{n+1}\int _{{\Sigma }}{\left|{H}\right|}<^>n d A\geqslant \rm AVR}(K)\vert \mathbb {B}<^>{n+1}\vert . \end{equation*}$$Moreover, equality holds if and only if Sigma${\Sigma }$ a part of a sphere and K\Omega$K\setminus \Omega$ is a part of the solid cone determined by Sigma${\Sigma }$. Here, Omega$\Omega$ is the bounded domain enclosed by Sigma${\Sigma }$ and partial derivative K$\partial K$, H$H$ is the normalized mean curvature of Sigma${\Sigma }$, and AVR(K)${\rm AVR}(K)$ is the asymptotic volume ratio of K$K$. We also prove an anisotropic version of this Willmore-type inequality. As a special case, we obtain a Willmore-type inequality for anisotropic capillary hypersurfaces in a half-space.
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