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

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2751-2777页

作者： Yurong lai xiaoyan Chu Li Di Wei Gao Yingying Guo xingrong Liu Chuang Lu Jialin Mao Hong Shen Huaping Tang Cindy q.xia Lei Zhang xinxin Ding Drug Metabolism Gilead Sciences Inc.Foster CityCA 94404USA Department of Pharmacokinetics Pharmacodynamics and Drug MetabolismMerck&Co.Inc.KenilworthNJ 07033USA Pharmacokinetics Dynamics and MetabolismPﬁzer Worldwide Research and DevelopmentGrotonCT 06340USA Eli Lilly and Company IndianapolisIN 46221USA Drug Metabolism and Pharmacokinetics BiogenCambridgeMA 02142USA Drug Metabolism and Pharmacokinetics Accent TherapeuticsInc.LexingtonMA 02421USA Department of Drug Metabolism and Pharmacokinetics GenentechA Member of the Roche GroupSouth San FranciscoCA 94080USA Drug Metabolism and Pharmacokinetics Department Bristol-Myers Squibb CompanyPrincetonNJ 08540USA Bioanalysis and Biomarkers Glaxo Smith KlineKing of the PrussiaPA 19406USA Department of Drug Metabolism and Pharmacokinetics Takeda Pharmaceuticals International Co.CambridgeMA 02139USA Ofﬁce of Research and Standards Ofﬁce of Generic DrugsCDERFDASilver SpringMD 20993USA Department of Pharmacology and Toxicology College of PharmacyUniversity of ArizonaTucsonAZ 85721USA Current afﬁliation:Translational Medicine EMD Serono Research&Development InstituteInc.BillericaMA 01821USA Current afﬁliation:Drug Metabolism Gilead Sciences Inc.Foster CityCA 94404USA

Drug metabolism and pharmacokinetics(DMPK) is an important branch of pharmaceutical *** 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 *** 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 *** importance of membrane transporters in drug disposition,efficacy,and safety,as well as the interplay with metabolic processes,has been increasingly *** 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 *** 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.

关键词： Drug discovery and development New drug application Biologics license application Pharmacokinetics ADME New modalities Model-informed drug development Micro-physiological systems

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Minimum Error Entropy Based EKF for GPS Code Tracking Loop

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Computers, Materials & Continua 2021年第6期67卷 2883-2898页

作者： Dah-Jing Jwo Jen-Hsien lai Department of Communications Navigation and Control EngineeringTaiwan Ocean University202301TaiwanChina Chunghwa Precision Test Tech.Co. Ltd.Taoyuan City324TaiwanChina

This paper investigates the minimum error entropy based extended Kalman filter(MEEKF)for multipath parameter estimation of the Global Positioning System(GPS).The extended Kalman filter(EKF)is designed to give a preliminary estimation of the *** scheme is designed by introducing an additional term,which is tuned according to the higher order moment of the estimation *** minimum error entropy criterion is introduced for updating the entropy of the innovation at each time *** to the stochastic information gradient method,an optimal filer gain matrix is *** mean square error criterion is limited to the assumption of linearity and ***,non-Gaussian noise is often encountered in many practical environments and their performances degrade dramatically in non-Gaussian *** of the existing multipath estimation algorithms are usually designed for Gaussian *** I(in-phase)and q(quadrature)accumulator outputs from the GPS correlators are used as the observational measurements of the EKF to estimate the multipath parameters such as amplitude,code delay,phase,and carrier *** reasonable way to obtain an optimal estimation is based on the minimum error entropy *** MEEKF algorithm provides better estimation accuracy since the error entropy involved can characterize all the randomness of the *** assessment is presented to evaluate the effectivity of the system designs for GPS code tracking loop with multipath parameter estimation using the minimum error entropy based extended Kalman filter.

关键词： Entropy extended Kalman filter multipath global positioning system tracking loop

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Effects of elevated carbon dioxide concentration and soil temperature on the growth and biomass responses of mountain maple (Acer spicatum) seedlings to light availability

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Journal of Plant Ecology 2014年第6期7卷 535-543页

作者： Gabriel Danyagri qing-lai Dang Faculty of Natural Resources Management Lakehead UniversityThunder BayOntario P7B 65E1Canada

Aims Some shade-tolerant understory tree species such as mountain maple(Acer spicatum L.)exhibit light-foraging growth *** in environmental conditions,such as the rise of carbon dioxide concentration([CO_(2)])in the atmosphere and soil warming,may affect the performance of these species under different light *** investigated how elevated[CO_(2)]and soil warm-ing influence the growth and biomass responses of mountain maple seedlings to light *** The treatments were two levels of light(100%and 30%of the ambient light in the greenhouse),two[CO_(2)](392μmol mol^(−1)(ambient)and 784μmol mol^(−1)(elevated))and two soil tempera-tures(Tsoil)(17 and 22℃).After one growing season,we measured seedling height,root collar diameter,leaf biomass,stem biomass and root *** findings We found that under the ambient[CO_(2)],the high-light level increased seedlings height by 70%and 56%at the low Tsoil and high Tsoil,*** the elevated[CO_(2)],however,the high-light level increased seedling height by 52%and 13%at the low Tsoil and high Tsoil,*** responses of biomasses to light generally followed the response patterns of height growth under both[CO_(2)]and Tsoil and the magnitude of biomass response to light was the lowest under the elevated[CO_(2)]and warmer *** results suggest that the elevated[CO_(2)]and warmer Tsoil under the projected future climate may have negative impact on the colonization of open sites and forest canopy gaps by mountain maple.

关键词： mountain maple elevated CO_(2) soil warming light availability height biomass

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Adrenal pheochromocytoma impacts three main pathways: cysteine-methionine, pyrimidine, and tyrosine metabolism

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第5期25卷 410-421页

作者： Chong lai qingling YANG Yunuo ZHANG Renjie GONG Majie WANG Jiankang LI Maode lai qingrong SUN Department of Urology the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China School of Basic Medical Sciences and Clinical Pharmacy China Pharmaceutical UniversityNanjing 210009China Department of Laboratory Medicine the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Laboratory of Behavioral Neuroscience Ningbo Kangning HospitalNingbo Institute of Microcirculation and HenbaneSchool of MedicineNingbo UniversityNingbo 315201China xi'an Key Laboratory of Stem Celland Regenerative Medicine Institute of Medical ResearchNorthwestern Polytechnical UniversityXi'an 710072China Department of Pathology Research Unit of Intelligence Classification of Tumor Pathology and Precision TherapyChinese Academy of Medical Sciences Key Laboratory of Disease Proteomics of Zhejiang ProvinceZhejiang University School of MedicineHangzhou 310058China

Pheochromocytomas and paragangliomas(PPGLs)cause symptoms by altering the circulation levels of catecholamines and peptide ***,the diagnosis of PPGLs relies on diagnostic imaging and the detection of *** this study,we used ultra-performance liquid chromatography(UPLC)/quadrupole time-of-flight mass spectrometry(q-TOF MS)analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma *** identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal *** conducting two steps of metabolomics analysis,we identified 111 differential metabolites between the healthy group and the patient group,among which 53 metabolites were *** integrating the information of differential metabolites and differentially expressed genes,we inferred that the cysteine-methionine,pyrimidine,and tyrosine metabolism pathways were the three main metabolic pathways altered by the *** analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma,whereas the pyrimidine pathway showed no significant ***,we developed an optimized diagnostic model of two metabolites,L-dihydroorotic acid and *** results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.

关键词： Pheochromocytoma and paraganglioma(PPGL) Metabolomics Gene set variation analysis L-Dihydroorotic acid Vanylglycol

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DNA序列数据压缩技术综述

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电子学报 2010年第5期38卷 1113-1121页

作者：纪震周家锐姜来 q.H.Wu 深圳大学计算机与软件学院广东深圳518060 利物浦大学电气电子工程系

DNA序列数据压缩技术是根据DNA数据特点针对性地构造编码算法,以提升整体压缩效率的数据处理方法.本文介绍了DNA序列的基本概念及数据特点,DNA序列压缩算法的一般性描述,DNA序列的典型压缩算法,以及评估DNA序列压缩算法性能的重要指标,... 详细信息

DNA序列数据压缩技术是根据DNA数据特点针对性地构造编码算法,以提升整体压缩效率的数据处理方法.本文介绍了DNA序列的基本概念及数据特点,DNA序列压缩算法的一般性描述,DNA序列的典型压缩算法,以及评估DNA序列压缩算法性能的重要指标,并对DNA序列压缩算法未来的发展趋势做了展望.

关键词： DNA数据压缩 DNA压缩算法压缩编码压缩评价标准

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Relationship between structure and microwave dielectric properties of Li_(3)Mg_(4)Nb_(1-x)Ta_(x)O_(8)ceramics

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Journal of Materiomics 2024年第1期10卷 245-252页

作者： Chongsheng Wu Kui Liu Honglan lai Fang xu School of Mechanical and Electrical Engineering Chengdu University of TechnologyChengduSichuan610059China School of Electronic Science and Engineering University of Electronic Science and Technology of ChinaChengdu610054China State Key Laboratory of Environment-friendly Energy Materials Southwest University of Science and TechnologyMianyang621010China

Herein,the sintering behavior and dielectric properties of Ta5+-doped Li3Mg4NbO8 ceramics were investigated by solid-phase reactions in combination with first-principles *** particular,Li_(3)Mg_(4)Nb_(0.96)Ta_(0.04)O_(8)illustrates the best dielectric properties after sintering at 1,175℃withεr=13.71±0.20,q×f=(132,112±2,391)GHz(increased by 25%)andτf=(25.07±1.36)×10^(−6)℃^(−1).The non-intrinsic factors reflect that a small amount of Ta^(5+)doping produces a secondary phase,increased densification,and grain size,all of which optimize the dielectric *** dominant intrinsic factors indicate that the increase in bond ionicity,the greater polarization of Ta^(5+),and the blueshift of the Raman characteristic peak all lead to an increase inε*** increase in lattice energy and the decrease in the damping behavior of the Nb/Ta-O bond vibrations lead to an increase in q×*** weakening of the Nb/TaO_(6) octahedral distortion leads to an optimization ofτ*** modified Li_(3)Mg_(4)Nb_(0.96)Ta_(0.04)O_(8) ceramics have promising applications in microwave communications.

关键词： First-principles Li_(3)Mg_(4)NbO_(8),dielectric properties Lattice vibration

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Real zeros of the zero-dimensional parametric piecewise algebraic variety

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Science China Mathematics 2009年第4期52卷 817-832页

作者： lai YiSheng WANG RenHong WU JinMing Department of Information and Computer Science Zhejiang Gongshang UniversityHangzhou 310018China Institute of Mathematical Sciences Dalian University of TechnologyDalian 116024China

The piecewise algebraic variety is the set of all common zeros of multivariate splines. We show that solving a parametric piecewise algebraic variety amounts to solve a finite number of parametric polynomial systems containing strict inequalities. With the regular decomposition of semi-algebraic systems and the partial cylindrical algebraic decomposition method, we give a method to compute the supremum of the number of torsion-free real zeros of a given zero-dimensional parametric piecewise algebraic variety, and to get distributions of the number of real zeros in every n-dimensional cell when the number reaches the supremum. This method also produces corresponding necessary and sufficient conditions for reaching the supremum and its distributions. We also present an algorithm to produce a necessary and sufficient condition for a given zero-dimensional parametric piecewise algebraic variety to have a given number of distinct torsion-free real zeros in every n-cell in the n-complex.

关键词： piecewise algebraic variety partial cylindrical algebraic decomposition number of real zeros 14M15 14q10 41A15 41A46 65D07 65D10

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Permian–Triassic Highly-Fractionated I-Type Granites from the Southwestern qaidam Basin(NW China)：Implications for the Evolution of the Paleo-Tethys in the Eastern Kunlun Orogenic Belt

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Journal of Earth Science 2017年第1期28卷 51-62页

作者： Yinjuan Ju xiaoli Zhang Shaocong lai Jiangfeng qin State Key Laboratory of Continental Dynamics Department of Geology Northwest University Xi' an 710069 China

Late Paleozoic to Early Mesozoic granites are widespread in the southern qaidam Basin, northern margin of the eastern Kunlun orogenic belt. Their petrogenesis can provide us insights into the tectonic evolution and crustal growth process in the qaidam Basin. This paper reports Permian–Triassic granites from the Kunbei area, southwestern qaidam Basin. Detailed zircon LA-ICP MS U-Pb dating reveals that the granites from the four drilling cores（q404, q406, q1612-8, q1613-8） have identical ages of 251±3, 256±4, 247±2, and 251±6 Ma, respectively, these ages are identical with the Permian–Triassic granites from the eastern qaidam Basin. Detailed geochemical analyses indicate that these granites display typical affinities of highly-fractionated I-type granites：（1） they have high SiO_2（up to 76.5 wt.%）, Na_2O＋K_2O（7.91 wt.% to 9.48 wt.%） contents and high FeO^T/MgO values of 4.7 to 9.3, suggesting significant fractional crystallization;（2） their low A/CNK values of 0.54 to 1.03, no normative Al-rich minerals, inconsistent with the per-aluminous S-type granites;（3） their low Ga（14.5 ppm to 20.7 ppm） and 10 000×Ga/Al（2.23 to 3.03, most of them 〈2.6） values are inconsistent with the A-type granites;（4） the high Rb（191 ppm to 406 ppm） contents and Rb/Sr（2.1 to 13.4） ratios, as well as the significant negative Eu anomalies（0.10 to 0.42） also indicate significant fractional crystallization of feldspars;（5） their low P_2O_5 contents（0.02 wt.% to 0.10 wt.%） suggest the limited solubility of phosphorus in primitive metaluminous melts. In combination with the geological background, we propose that the Permian–Triassic highly-fractionated I-type granites resulted from partial melting of intra-crustal mafic rocks, and the primitive I-type granitic melts underwent significant fractional crystallization of feldspars. The occurrence of highly-fractionated I-type granites in the southwestern qaidam Basin suggests a Permian–Triassic active continental margin in the northern margin of the Ea

关键词： highly-fractionated I-type granites Permain-Triassic qaidam Basin eastern Kunlunorogenic belt Paleo-Tethys.

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SiC nanowire-based SU-8 with enhanced mechanical properties for MEMS structural layer design

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Nanotechnology and Precision Engineering 2019年第4期2卷 169-176页

作者： Yu Yang Liyan lai Guifu Ding Ting Chen National Key Laboratory of Science and Technology on Micro/Nano Fabrication Shanghai Jiao Tong University

In addition to being used for pattern transfer,the negative photoresist SU-8 iswidely used as a structural material in microelectromechanical systems(MEMS).Due to its good photopatternability,SU-8 has lower manufacturing costs than many other materials,but its mechanical properties are relatively weak to some extent,which limits its *** mechanical properties of epoxy-like SU-8 can be enhanced by addingmicro-or nano-fillers such as carbon nanotube,clay,and SiC nanowire,which have superior elastic *** this study,SiC nanowires were used to improve the mechanical properties of SU-8 while the SU-8 retains its *** SiC nanowires were uniformly dispersed in SU-8 by stirring and ***-8 materials with different SiC nanowire contents were fabricated into dog bone samples by *** elastic modulus,storage modulus,and damping factor of the samples were measured by the Dynamic mechanical analysis(DMA)*** experiment result shows that the rigidity and toughness increased,and the damping *** 2 wt%SiC nanowires-reinforced SU-8 had a 73.88%increase in elastic modulus and a 103.4%increase in elongation at ***,a spring component made by SiC-doped SU-8 could withstand greater *** SiC nanowires-reinforced SU-8 has the potential tomeet higher requirements in the design andmanufacture of MEMS and greatly reduce the manufacturing costs of MEMS devices.

关键词： SU-8 SiC nanowires Elastic modulus Dynamic mechanical analysis(DMA)

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Primary hyperparathyroidism-induced acute pancreatitis in pregnancy:A systematic review with a diagnostic-treatment algorithm

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World Journal of Gastroenterology 2024年第32期30卷 3755-3765页

作者： Goran Augustin quirino lai Maja Cigrovski Berkovic Department of Surgery University Hospital Centre Zagreb and School of Medicine University of ZagrebZagreb 10000Croatia General Surgery and Organ Transplantation Unit Department of SurgerySapienza University of RomeRome 00018Italy Department for Sport and Exercise Medicine Faculty of KinesiologyUniversity of ZagrebZagreb 10000Croatia

BACKGROUND Primary hyperparathyroidism(PHPT)-induced acute pancreatitis(AP)during pregnancy has rarely been *** to this rarity,there are no diagnostic or treatment algorithms for pregnant *** To determine appropriate diagnostic methods,therapeutic options,and factors related to maternal and fetal outcomes for PHPT-induced AP in *** A literature search of articles in English,Japanese,German,Spanish,and Italian was performed using PubMed(1946-2023),PubMed Central(1900-2023),and Google *** Preferred Reporting Items for Systematic reviews and Meta-Analyses(PRISMA)protocol was *** search terms included“pancreatite acuta,”“iperparatiroidismo primario,”“gravidanza,”“travaglio,”“puerperio,”“postpartum,”“akute pankreatitis,”“primärer hyperparathyreoidismus,”“Schwangerschaft,”“Wehen,”“Wochenbett,”“pancreatitis aguda,”“hiperparatiroidismo primario,”“embarazo,”“parto,”“puerperio,”“posparto,”“acute pancreatitis,”“primary hyperparathyroidism,”“pregnancy,”“labor,”“puerperium,”and“postpartum.”Additional studies were identified by reviewing the reference lists of retrieved ***,imaging,surgical,obstetric,and outcome data were *** Fifty-four cases were collected from the 51 *** median maternal age was 29 ***-induced AP starts at the 20th gestational week;higher gestational weeks were seen in mothers who died(mean gestational week 28).Median values of amylase(1399,q1-q3=519-2072),lipase(2072,q1-q3=893-2804),serum calcium(3.5,q1-q3=3.1-3.9),and parathormone(PTH)(384,q1-q3=123-910)were *** 46 cases,adenoma was the cause of PHPT,followed by 2 cases of carcinoma and 1 case of *** the remaining 5 cases,the diagnosis was not *** ultrasound was positive in 34 cases,whereas sestamibi was performed in 3 cases,and neck computed tomography or magnetic resonance imaging was performed in 9 cases(the enlarged parathyroid gland was not localized in 3 cases).Surgery was the prefer

关键词： Primary hyperparathyroidism Acute pancreatitis Pregnancy Diagnosis Maternal mortality Fetal mortality Algorithm

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