A Subdivision-Based Combined Shape and Topology Optimization in Acoustics

We propose a combined shape and topology optimization approach in this research for 3D acoustics by using the isogeometric boundary element method with subdivision surfaces.The existing structural optimization methods mainly contain shape and topology schemes,with the former changing the surface geometric profile of the structure and the latter changing thematerial distribution topology or hole topology of the structure.In the present acoustic performance optimization,the coordinates of the control points in the subdivision surfaces fine mesh are selected as the shape design parameters of the structure,the artificial density of the sound absorbing material covered on the structure surface is set as the topology design parameter,and the combined topology and shape optimization approach is established through the sound field analysis of the subdivision surfaces boundary element method as a bridge.The topology and shape sensitivities of the approach are calculated using the adjoint variable method,which ensures the efficiency of the optimization.The geometric jaggedness and material distribution discontinuities that appear in the optimization process are overcome to a certain degree by the multiresolution method and solid isotropic material with penalization.Numerical examples are given to validate the effectiveness of the presented optimization approach.

Study on Undertaking-starting of New Generation Migrant Workers

New generation migrant workers have become mainstay of China's migrant workers and also major builders of China's urbanization process. Compared with last generation migrant workers,new generation migrant workers have greater awareness of starting an undertaking. In the new trend,undertaking-starting is inevitable for new generation migrant workers. This study analyzed problems encountered by new generation migrant workers in the course of starting an undertaking. It reached conclusions that competent authorities should set up support mechanism in undertaking-starting training,undertaking-starting fund,service platform,and preferential policies,to encourage and support new generation migrant workers to start an undertaking.

异源物代谢的表观遗传学变异影响抗癫痫药3,4-DCPB药物代谢动力学表型个体差异

抗癫痫药物治疗是控制癫痫的主要方法,但由于个体间对药物处置的差异性,患者对目前治疗的反应性并不一致。本研究通过在健康志愿者中进行的临床Ⅰ期剂量递增试验,考察了遗传和表观遗传变异是否影响抗癫痫药物氯桂丁胺(3,4-DCPB)的药代动力学表型。采用液相色谱-串联质谱(LC-MS/MS)法测定血浆中3,4-DCPB母药及其主要代谢物M1的浓度。通过基因分型和DNA甲基化水平分析细胞色素P4502D6(CYP2D6)、CYP2C9、CYP1A2、CYP2C19、CYP3A5、转运体ABCB1(C1236T)、核受体AhR、CAR和PXR的单核苷酸多态性(SNPs)。与野生型CYP2D6*1/*1纯合子(广泛代谢型,EMs)相比,变异等位基因CYP2D6*10携带者(中间代谢型,IMs)中,代谢产物M1与3,4-DCPB母药的药时曲线下面积(AUC0–t)的比值更低,血浆半衰期(t1/2)更久,DNA甲基化水平更高。这些数据表明胞嘧啶的丢失(CYP2D6*10,C>T)所诱导的表观基因突变可能解释3,4-DCPB基因型、表观基因型和药代动力学表型在个体差异之间的关系,为癫痫的个性化治疗提供新的思路。

More words but less investment:Rookie CEOs and firms’digital transformations

In digital economy,firm’s digital transformation is an important means of achieving high-quality development.Adopting career concerns theory,we examine rookie CEOs’impact on firms’digital transformations,using Chinese A-share listed firms from 2007 to 2019.(1)Rookie CEOs disclose more digital transformation information,but invest less in substantial transformation,i.e.,“more words but less investment”.(2)Under high performance pressure and difficult digital transformation,rookie CEOs are more likely to adopt the above strategy.(3)Internal and external governance mechanisms help effectively monitor and mitigate such behaviors.(4)The above strategy helps CEOs decrease short-term,but not long-term,dismissal probabilities.Our findings elucidate firms’digital transformation practices and the decision styles of CEOs with different experience levels.

PBPK modeling and simulation in drug research and development

Physiologically based pharmacokinetic(PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data.It can also explore the effects of various physiologic parameters such as age,ethnicity,or disease status on human pharmacokinetics,as well as guide dose and dose regiment selection and aid drug–drug interaction risk assessment.PBPK modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry,and has become an integral tool in drug discovery and development.In this mini-review,the concept and methodology of PBPK modeling are briefly introduced.Several case studies were discussed on how PBPK modeling and simulation can be utilized through various stages of drug discovery and development.These case studies are from our own work and the literature for better understanding of the absorption,distribution,metabolism and excretion(ADME) of a drug candidate,and the applications to increase efficiency,reduce the need for animal studies,and perhaps to replace clinical trials.The regulatory acceptance and industrial practices around PBPK modeling and simulation is also discussed.

High degree of pharmacokinetic compatibility exists between the five-herb medicine XueBiJing and antibiotics comedicated in sepsis care

Managing the dysregulated host response to infection remains a major challenge in sepsis care. Chinese treatment guideline recommends adding Xue Bi Jing, a five-herb medicine, to antibioticbased sepsis care. Although adding Xue Bi Jing further reduced 28-day mortality via modulating the host response, pharmacokinetic herbedrug interaction is a widely recognized issue that needs to be studied.Building on our earlier systematic chemical and human pharmacokinetic investigations of Xue Bi Jing, we evaluated the degree of pharmacokinetic compatibility for Xue Bi Jing/antibiotic combination based on mechanistic evidence of interaction risk. Considering both Xue Bi Jing-antibiotic and antibiotic-Xue Bi Jing interaction potential, we integrated informatics-based approach with experimental approach and developed a compound pair-based method for data processing. To reflect clinical reality, we selected for study Xue Bi Jing compounds bioavailable for drug interactions and 45 antibiotics commonly used in sepsis care in China. Based on the data of interacting with drug metabolizing enzymes and transporters, no Xue Bi Jing compound could pair, as perpetrator, with the antibiotics. Although some antibiotics could,due to their inhibition of uridine 50-diphosphoglucuronosyltransferase 2 B15, organic anion transporters1/2 and/or organic anion-transporting polypeptide 1 B3, pair with senkyunolide I, tanshinol and salvianolic acid B, the potential interactions(resulting in increased exposure) are likely desirable due to these Xue Bi Jing compounds’ low baseline exposure levels. Inhibition of aldehyde dehydrogenase by 7 antibiotics probably results in undesirable reduction of exposure to protocatechuic acid from Xue Bi Jing.Collectively, Xue Bi Jing/antibiotic combination exhibited a high degree of pharmacokinetic compatibility at clinically relevant doses. The methodology developed can be applied to investigate other drug combinations.

Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

Drug metabolism and pharmacokinetics(DMPK) is an important branch of pharmaceutical sciences.The nature of ADME(absorption,distribution,metabolism,excretion) and PK(pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems.Tremendous progress has been made in the past decade,not only in the characterization of physiochemical properties of drugs that influence their ADME,target organ exposure,and toxicity,but also in the identification of design principles that can minimize drug-drug interaction(DDI) potentials and reduce the attritions.The importance of membrane transporters in drug disposition,efficacy,and safety,as well as the interplay with metabolic processes,has been increasingly recognized.Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs,such as peptides,oligonucleotides,and antibody-drug conjugates,necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties.In this review,we highlight some of the most notable advances in the last decade,and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

Preclinical experimental models of drug metabolism and disposition in drug discovery and development

Drug discovery and development involve the utilization of in vitro and in vivo ex perimental models.Different models,ranging from test tube experiments to cell cultures,animals,healthy human subjects,and even small numbers of patients that are involved in clinical trials,are used at different stages of drug discovery and development for determination of efficacy and safety.The proper selection and applications of correct models,as well as appropriate data interpretation,are critically important in decision making and succesful advancement of drug candidates.In this review,we discuss strategies in the applications of both in vitro and in vivo.experimental models of drug metabolism and disposition.

Do companies compare employees'salaries?Evidence from stated-owned enterprise group

The mechanism by which enterprises set salaries is vitally important to employees and is especially relevant to the reform of state-owned enterprises(SOEs).This paper investigates the effect of comparing employee compensation based on a sample of A-share SOE groups from 2008 to 2018.We find that when employee compensation at one company sharply increases,the employee compensation of other companies controlled by the same group will increase sharply in the following year.Further analysis shows that when employees’sense of unfair compensation is stronger,when employees are less replaceable and when enterprises’ability to pay is stronger,the effect of employee pay comparison is stronger.Increased employee salary does not improve enterprise performance,however,suggesting that such salary adjustment is ineffective.This paper expands the research on employee compensation and provides useful insights for optimizing the design of compensation contracts and promoting compensation reform in SOEs.