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Recent advances in targeting the“undruggable”proteins:from drugdiscover to clinical trials

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Signal Transduction and Targeted Therapy 2023年第10期8卷 4477-4547页

作者： Xin Xie Tingting Yu Xiang Li Nan Zhang leonard J.Foster Cheng Peng Wei Huang Gu He State Key Laboratory of Southwestern Chinese Medicine Resources College of Medical Technology and School of PharmacyChengdu University of Traditional Chinese Medicine611137 ChengduChina Michael Smith Laboratories University of British ColumbiaVancouverBC V6T 1Z4Canada Department of Dermatology and State Key Laboratory of Biotherapy West China HospitalSichuan University610041 ChengduChina

Undruggable proteins are a class of proteins that are often characterized by large,complex structures or functions that are diffcult to interfere with using conventional drug design *** such undruggable targets has been considered also a great opportunity for treatment of human diseases and has attracted substantial efforts in the field of ***,in this review,we focus on the recent development of drug discovery targeting"undruggable"proteins and their application in *** make this review well organized,we discuss the design strategies targeting the undruggable proteins,including covalent regulation,allosteric inhibition,protein-protein/DNA interaction inhibition,targeted proteins regulation,nucleic acid-based approach,immunotherapy and others.

关键词： drug diseases clinical

Some non-trivial Kazhdan-Lusztig coefficients of an affine Weyl group of type _n

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Science China Mathematics 2010年第8期53卷 1919-1930页

作者： SCOTT leonard Department of Mathematics University of Virginia

In this paper we show that the leading coeficient μ(y,w) of some Kazhdan-Lusztig polynomials Py,w with y,w in an affine Weyl group of type n is n + *** fact has some consequences on the dimension of first extension... 详细信息

关键词： Kazhdan-Lusztig coeficient Kazhdan-Lusztig polynomial first extension group

Accessibility and utilization of healthcare services among diabetic patients:Is diabetes a poor man’s ailment?

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World Journal of Diabetes 2023年第10期14卷 1493-1501页

作者： Chiedu Eseadi Amos Nnaemeka Amedu leonard Chidi Ilechukwu Millicent O Ngwu Osita Victor Ossai Department of Educational Psychology University of JohannesburgJohannesburg 2006GautengSouth Africa Department of Arts Education University of NigeriaNsukka 41001EnuguNigeria Department of Sociology and Anthropology University of NigeriaNsukka 41001EnuguNigeria Department of Childhood Education University of JohannesburgJohannesburg 2006GautengSouth Africa

Diabetes is a non-communicable ailment that has adverse effects on the individual’s overall well-being and productivity in *** main objective of this study was to examine the empirical literature concerning the association between diabetes and poverty and the accessibility and utilization of medical care services among diabetic *** diabetes literature was explored using a literature review *** review revealed that diabetes is an ailment that affects all individuals irrespective of socioeconomic status;however,its prevalence is high in low-income ***,despite the higher prevalence of diabetes in developing countries compared with developed countries,diabetes is not a poor man’s ailment because it affects individuals of all *** the number of diabetic patients that access and utilize diabetes medical care services has increased over the years,some personal and institutional factors still limit patients’access to the use of diabetes ***,there is a lacuna in the diabetes literature concerning the extent of utilization of available healthcare services by diabetic patients.

关键词： Accessibility Diabetes Healthcare services Patients Poverty

The first draft genome assembly and data analysis of the Malaysian mahseer (Tor tambroides)

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Aquaculture and Fisheries 2023年第5期8卷 481-491页

作者： Melinda Mei Lin Lau leonard Whye Kit Lim Hung Hui Chung Han Ming Gan Faculty of Resource Science and Technology Universiti Malaysia SarawakKota SamarahanSarawak94300Malaysia GeneSEQ Sdn Bhd Bandar Bukit BeruntungRawangSelangor48300Malaysia Centre for Integrative Ecology School of Life and Environmental SciencesDeakin UniversityGeelongVictoriaVIC3220Australia

The Malaysian mahseer(Tor tambroides),one of the most valuable freshwater fish in the world,is mainly targeted for human *** mitogenomic data of this species is available to date,but the genomic information is still *** the first time,we sequenced the whole genome of an adult fish on both Illumina and Nanopore *** hybrid genome assembly had resulted in a sum of 1.23 Gb genomic sequence from the 44,726 contigs found with 44 kb N50 length and BUSCO genome completeness of 87.6%.Four types of SSRs had been detected and identified within the genome with a greater AT abundance than that of *** protein sequences had been functionally annotated to public databases,namely GO,KEGG and COG.A maximum likelihood phylogenomic tree containing 52 Actinopterygii species and one Sarcopterygii species as outgroup was constructed,providing first insights into the genome-based evolutionary relationship of *** with other ray-finned *** data are crucial in facilitating the study of population genomics,species identification,morphological variations,and evolutionary biology,which are helpful in the conservation of this species.

关键词： Genome Gene annotation Tor tambroides Phylogenetic Functional annotation

Symmetrically Harmonic Kaluza-Klein Metrics on Tangent Bundles

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Journal of Applied Mathematics and Physics 2022年第12期10卷 3548-3561页

作者： Serge Degla leonard Todjihounde Institut de Mathématiques et de Sciences Physiques Porto-Novo Benin Institut de Mathématiques et de Sciences Physiques Porto-Novo Benin

Let (M, g) be a Riemannian manifold and G be a Kaluza-Klein metric on its tangent bundle TM. A metric H on TM is said to be symmetrically harmonic to G if the metrics G and H are harmonic w.r.t. each other;that is the identity maps id: (TM,G) → (TM,H) and id: (TM,H) → (TM,G) are both harmonic maps. In this work we study Kaluza-Klein metrics H on TM which are symmetrically harmonic to G. In particular, we characterize and determine horizontally and vertically conformal Kaluza-Klein metrics H on TM, which are symmetrically harmonic to G.

关键词： Harmonic Maps Kaluza-Klein Metrics Conformal Metrics

Australian children living with rare diseases:health service use and barriers to accessing care

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World Journal of Pediatrics 2023年第7期19卷 701-709页

作者： Suzy Teutsch Yvonne Zurynski Guy DEslick Marie Deverell John Christodoulou Helen leonard Troy Dalkeith Sandra LJJohnson Elizabeth JElliott Faculty of Medicine and Health Discipline of Child and Adolescent HealthThe University of SydneySydneyNSWAustraliaAustralian Australian Paediatric Surveillance Unit Kids ResearchSydney Children's Hospitals NetworkWestmeadNSWAustralia Australian Institute of Health Innovation Center for Healthcare Resilience and Implementation Scienceand NHMRC Partnership Centre in Health System SustainabilityMacquarie UniversitySydneyNSWAustraliaFaculty of Medicine and HealthDiscipline of Child and Adolescent HealthThe University of SydneySydneyNSWAustralia Government Department of Health Western Australia PerthWAAustralia Murdoch Children's Research Institute and Victorian Clinical Genetics Services Royal Children's HospitalParkvilleVICAustralia Department of Paediatrics The University of MelbourneParkvilleVICAustralia Telethon Kids Institute The University of Western AustraliaNedlandsWAAustralia Genetic Metabolic Disorders Service Sydney Children's Hospitals NetworkWestmeadNSWAustralia

Background Children with rare diseases experience challenges at home and school and frequently require multi-disciplinary *** aimed to determine health service utilization by Australian children with rare diseases and barriers to access-ing *** Parents completed an online survey on health professional and emergency department(ED)presentations,hospi-talization,and barriers to accessing *** barriers to service access included residential location(city,regional,remote)and child health-related functioning,determined using a validated,parent-completed measure-of-function *** Parents of 462 children with over 240 rare diseases completed the *** with the general population,these children were more likely to be hospitalized[odds ratio(OR)=17.25,95%confidence interval(CI)=15.50-19.20]and present to the ED(OR=4.15,95%CI=3.68-4.68)or a family physician(OR=4.14,95%CI=3.72-4.60).Child functional impairment was nil/mild(31%),moderate(48%)or severe(22%).Compared to children with nil/mild impair-ment,those with severe impairment were more likely to be hospitalized(OR=13.39,95%CI=7.65-23.44)and present to the ED(OR=11.16,95%CI=6.46-19.27).Most children(75%)lived in major cities,but children from regional(OR=2.78,95%CI=1.72-4.55)and remote areas(OR=9.09,95%CI=3.03-25.00)experienced significantly more barriers to healthcare access than children from major *** included distance to travel,out-of-pocket costs,and lack of specialist medical and other health *** Children with rare diseases,especially those with severe functional impairment have an enormous impact on health services,and better integrated multidisciplinary services with patient-centered care are *** must be improved for children living in rural and remote settings.

关键词： Access Health functioning Health service use Rare diseases

Sexual selection and hermaphroditic organisms： Testing theory

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Current Zoology 2013年第4期59卷 579-588页

作者： Janet L. leonard Joseph M. Long Marine Laboratory University of California-Santa Cruz Santa Cruz CA 94019 USA

Sexual selection is widespread if not ubiquitous in hermaphroditic organisms. Although many phenomena that have been described as sexual selection in gonochores, (e.g. harem polygamy, multiple mating, elaborate courtship, even secondary sexual characters) can be found in some hermaphrodites, what is more interesting is the ways in which sexual selection in hermaphrodites may differ from dioecious taxa. In hermaphrodites, an individual’s mating success includes its success from both sexual roles. Secondly, in many simultaneously hermaphroditic taxa there is strong evidence of sexual selection and yet the operational sex ratio is 1:1, by definition. Many simultaneous hermaphrodites have elaborate courtship and genital anatomy, suggesting sexual selection plays an important role in reproductive success. Sperm competition and cryptic female choice mean that the number of mates acquired is not necessarily a predictor of reproductive success. Even in simultaneous hermaphrodites with reciprocal mating, variance in reproductive success through the male role and through the female role may differ in a population. Moreover hermaphrodites may choose to emphasize one sexual role over the other. Data suggest that the preferred role varies in hermaphrodites, which creates an opportunity to test fundamental predictions and assumptions of sexual selection theory. Hermaphrodites may vary their emphasis on one sexual role over the other either developmentally or behaviorally in response to environmental or social parameters. How they use this capability in acquiring more or higher quality mates still requires study.

关键词：雌雄同体测试理论生物女性角色第二性征雌雄异株选择理论生殖器

Dynamic Simulations of Post-stall Performance in Multistage Axial Compressors

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Journal of Thermal Science 2012年第4期21卷 311-321页

作者： DU Wenhai ZHU JunQiang Olivier leonard University of Liege Turbomachinery Group B-4000 Liege Belgium Institute of Engineering Thermophysics ChineseAcademy of Sciences China Chinese Academy of Sciences China University of Liege Turbomachinery Group Chemin des chevreuils 1 B-4000 Liege Belgium

In this contribution a quasi-one-dimensional tool for stationary and transient simulations of post-stall flows in multistage axial compressors is presented. An adapted version of the 1D Euler equations with additional source terms is discretized with a finite volume method and solved in time by a fourth-order Runge-Kutta scheme. The equations are discretized at midspan both inside the blade rows and the non-bladed regions. The source terms express the blade-flow interactions and are estimated by calculating the velocity triangles for each blade row. Loss and deviation correlations are implemented and compared to experimental data in normal flow, stalled flow and reversed flow regions. Transient simulations are carried out and a parameter study is presented to analyze the shape of the surge cycles and the frequency of the surge oscillations. At last, a bleeding control strategy is implemented to study the recoverability of the instabilities in a compression system.

关键词：轴流压缩机动态模拟 Runge-Kutta 多级失速性能有限体积方法瞬态模拟

Galvanic corrosion of AZ31B joined to dual-phase steel with and without Zn layer by ultrasonic and friction stir welding

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Journal of Magnesium and Alloys 2023年第2期11卷 462-479页

作者： Jiheon Jun Vineet V.Joshi Alasdair Crawford Vilayanur Viswanathan Donovan N.leonard Jian Chen Piyush Updadhyay Yong Chae Lim Zhili Feng Oak Ridge National Laboratory Oak RidgeTNUSA Pacific Northwest National Laboratory RichlandWashingtonUSA

Galvanic corrosion of AZ31B joined with bare or Zn-coated DP590 steel by ultrasonic spot welding or linear friction stir welding was quantitatively studied by pre-defining anode and cathode in the lap joint samples. Corrosion volume and depth from Mg anode surfaces exposed to 0.1 M sodium chloride solution was analyzed as functions of cathode surface type and welding method. Characterization of as-welded joints was performed to identify any microstructural feature of the bonding zone that could impact galvanic corrosion *** modeling with modified user subroutine was conducted to simulate the progression of Mg corrosion in the same joint and electrode configurations used for the corrosion experiments. The experimental results indicated that Zn-coated cathode surface can reduce Mg galvanic corrosion significantly as galvanic polarization and cathodic current on Zn-coated surface remained relatively low for Mg in the weld *** modeling described the growth of Mg galvanic corrosion in a reasonable manner but showed limitation by underestimating the corrosion volume as it did not capture self-corrosion.

关键词： Mg alloy Zn coating Ultrasonic spot welding Friction stir welding Galvanic corrosion