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Identification of novel small-molecule inhibitors of SARS-coV-2 by chemical genetics

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4028-4044页

作者： chris chun-Yiu chan Qian Guo jasper fuk-woo chan Kaiming Tang Jian-Piao cai Kenn Ka-Heng chik Yixin Huang Mei Dai Bo Qin chon Phin Ong Allen wing-Ho chu wan-Mui chan Jonathan Daniel Ip Lei wen Jessica Oi-Ling Tsang Tong-Yun wang Yubin Xie Zhenzhi Qin Jianli cao Zi-wei Ye Hin chu Kelvin Kai-wang To Xing-Yi Ge Tao Ni Dong-Yan Jin Sheng cui Kwok-Yung Yuen Shuofeng Yuan State Key Laboratory of Emerging Infectious Diseases Carol Yu Centre for InfectionDepartment of MicrobiologySchool of Clinical MedicineLi Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China Department of Infectious Diseases and Microbiology the University of Hong Kong-Shenzhen HospitalShenzhen 518000China centre for Virology Vaccinology and TherapeuticsHong Kong Science and Technology ParkHong Kong SAR 999077China Academician workstation of Hainan Province Hainan Medical University-the University of Hong Kong Joint Laboratory of Tropical Infectious DiseasesHaikou 571100China School of Biomedical Sciences Li Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China NHc Key Laboratory of Systems Biology of Pathogens Institute of Pathogen Biology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China college of Biology Hunan Provincial Key Laboratory of Medical VirologyHunan UniversityChangsha 410082China

There are only eight approved small molecule antiviral drugs for treating *** them,four are nucleotide analogues(remdesivir,JT001,molnupiravir,and azvudine),while the other four are protease inhibitors(nirmatrelvir,ensitrelvir,leritrelvir,and simnotrelvir-ritonavir).Antiviral resistance,unfavourable drug‒drug interaction,and toxicity have been reported in previous *** there is a dearth of new treatment options for *** this work,a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-coV-2 *** compound,designated 172,demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-coV-2 variants of *** studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease(3cLpro)by binding to an allosteric site and reduces 3cLpro dimerization.A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in *** vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized AcE2 ***,this study identified an alternative druggable site on the SARS-coV-23cLpro,proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.

关键词： SARS-coV-2 High throughput screening Broad-spectrum antiviral treatment 3cLpro inhibitor Allosteric-site inhibitor Animal models chemical genetics Reverse genetics

The Arabidopsis thaliana RNA Editing factorSLO2, which Affects the Mitochondrial ElectronTransport chain, Participates in Multiple Stressand Hormone Resoonses

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Molecular Plant 2014年第2期7卷 290-310页

作者： Qiang Zhu jasper Dugardeyn chunyi Zhang Laboratory of functional Plant Biology Department of Physiology Ghent University Milieudienst Midden west-Vlaanderen Biotechnology Research Ins. chinese Academy of Agricultural Sciences

Recently, we reported that the novel mitochondrial RNA editing factor SLO2 is essential for mitochondrialelectron transport, and vital for plant growth through regulation of carbon and energy metabolism. Here, we show thatmutation in SL02 causes hypersensitivity to ABA and insensitivity to ethylene, suggesting a link with stress ***, slo2 mutants are hypersensitive to salt and osmotic stress during the germination stage, while adult plantsshow increased drought and salt tolerance. Moreover, slo2 mutants are more susceptible to Botrytis cinerea *** increased expression of nuclear-encoded stress-responsive genes, as well as mitochondrial-encoded NAD genes ofcomplex I and genes of the alternative respiratory pathway, was observed in slo2 mutants, further enhanced by ABAtreatment. In addition, H202 accumulation and altered amino acid levels were recorded in slo2 mutants. we conclude thatSLO2 is required for plant sensitivity to ABA, ethylene, biotic, and abiotic stress. Although two stress-related RNA editingfactors were reported very recently, this study demonstrates a unique role of SLO2, and further supports a link betweenmitochondrial RNA editing events and stress response.

关键词： ABA Arabidopsis thaliana ethylene plant stress mitochondria RNA editing PPR protein SLO2 stress

Structural study of Yb^(3+), Eu^(3+) and Pr^(3+) doped ca_9Lu(PO_4)_7

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Journal of Rare Earths 2015年第9期33卷 977-982页

作者： fabio Piccinelli Mattia Trevisani jasper R.Plaisier Marco Bettinelli Luminescent Materials Laboratory DB University of Verona and INSTM UdR VeronaStrada Le Grazie 15 37134 Verona Italy Synchrotron Light Laboratory (ELETTRA) Trieste S.c.p.A. Strada Statale 14 - km 1635 in AREA Science Park

The whitlockite-like crystal structure of ca9Lu（PO4）7 when doped with several ions （Yb3＋, EU3＋ and Pr3＋） at different concentrations （1 tool.%, 5 mol.% and 10 tool.%） was studied, by means of synchrotron X-ray diffraction. In particular for Eu3＋ and Pr3＋, the presence of the dopant ion significantly changed the occupation factors （Ofs） of the ca2＋ and Lu3＋ cations and gave rise to a distortion of the metal-oxygen polyhedra. The observed structural features clearly showed significant impact of the dopant ion on the crystal structure of the host.

关键词： Rietveld refinement crystal structure X-ray diffraction synchrotron radiation rare earths

2000年后中国Q热的临床表现及诊疗研究进展

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中国感染与化疗杂志 2024年第2期24卷 231-239页

作者：邓超文孙林琳叶海燕陈福和邢凡凡香港大学深圳医院感染性疾病医学部感染科广东深圳518000

Q热(Q fever)是贝纳柯克斯体(coxiella burnetii)感染引起的一种世界性分布的人畜共患病,可累及颅脑、肺脏、肝脏、心脏瓣膜、血管、骨关节等部位。Q热侵入人体网状内皮系统可引起多系统发热性急性或持续性局灶感染,急性感染表现为发热... 详细信息

Q热(Q fever)是贝纳柯克斯体(coxiella burnetii)感染引起的一种世界性分布的人畜共患病,可累及颅脑、肺脏、肝脏、心脏瓣膜、血管、骨关节等部位。Q热侵入人体网状内皮系统可引起多系统发热性急性或持续性局灶感染,急性感染表现为发热、头痛、肺炎、肝炎等,持续性局灶感染表现为心内膜炎、血管感染、骨髓炎等。由于Q热的临床表现多样、流行病学史资料无特异性、未纳入我国法定传染性疾病、医务工作者对其诊断和治疗方面存在认识不足以及实验室检查方法未被广泛应用等原因,导致误诊和延误诊断时有发生。另一方面,国内关于Q热的研究更多聚焦在畜牧业领域或病例报告,较少有临床或研究工作者对该病进行分析总结。

关键词： Q热贝纳柯克斯体诊断治疗

NIR Hyperspectral Imaging Measurement of Sugar content in Peach Using PLS Regression

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Journal of Shanghai Jiaotong university(Science) 2007年第5期12卷 597-601页

作者：郭峰曹其新 Nagata Masteru jasper Tallada Research Institute of Robotics Shanghai Jiaotong Univ. faculty of Agriculture Miyazaki Univ.

Near infrared （NIR） hyperspectral imaging measurement of sugar content in peach was introauced. NIR spectral images （650～1 000 nm, resolution： 2 nm） of peach samples were captured with developed hyperspectral imaging setup. Partial least square （PLS） regression prediction model was developed to estimate the sugar content in peach; step-wise backward method was utilized to determine optimal wavelength subsets. Experimental results show that the calibration model with optimal wavelength subsets has a correlation coefficient of prediction of 0.97 and a standard error of prediction of 0.19, the prediction accuracy is higher than the calibration model applied over the whole wavelength, which proves that variable selection plays an important role in improving the prediction accuracy of PLS regression model.

关键词： near infrared hyperspectral imaging system sugar content partial least square regression

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地拉那金字塔

世界建筑导报 2024年第4期39卷 121-125页

作者： Ronald Hoogeveen Stavros Gargaretas Guido Boeters Angel Sanchez Navarro Boris Tikvarski jasper van der Ven Mirco facchinelli Manuel Magnaguagno Leo Stuckardt MVRDV

地拉那金字塔是一个新型的文化中心,位于阿尔巴尼亚首都的中心地带。地拉那金字塔最初是作为纪念共产主义者恩维尔·霍查(EnverHoxha)而建的博物馆,MVRDV对其进行了巨大的改造,现在的地拉那金字塔重新使用了混凝土结构,已经成为了一个... 详细信息

地拉那金字塔是一个新型的文化中心,位于阿尔巴尼亚首都的中心地带。地拉那金字塔最初是作为纪念共产主义者恩维尔·霍查(EnverHoxha)而建的博物馆,MVRDV对其进行了巨大的改造,现在的地拉那金字塔重新使用了混凝土结构,已经成为了一个新公园中的开放式雕塑。公园和雕塑中散布着一个个五颜六色的盒子,这些盒子散落在原来的建筑中及其周围,里面有咖啡馆、工作室、工作坊、创业办公室、孵化器、节庆活动,还有供阿尔巴尼亚青年免费学习各种技术和知识的教室。建筑倾斜的外墙还增加了台阶,让阿尔巴尼亚人民可以在这位前共产主义者的杰作上漫步。

关键词：工作坊金字塔节庆活动孵化器阿尔巴尼亚咖啡馆工作室混凝土结构

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Repeated occurrence of palaeo-wildfires during deposition of the Bahariya formation(early cenomanian) of Egypt

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Journal of Palaeogeography 2019年第4期8卷 332-345页

作者： Haytham El Atfy Tarek Anan Andre jasper Dieter Uhl Department of Geology Faculty of ScienceMansoura UniversityMansoura 35516Egypt Programa de Pos-Graduacao em Ambiente e Desenvolvimento PPGADUniversidade do Vale do Taquari UnivatesLajeadoRio Grande do SulBrazil Senckenberg Research Institute and Natural History Museum 60325 Frankfurt am MainGermany Senckenberg centre for Human Evolution and Palaeoenvironment Tubingen University72076 TubingenGermany

The Upper cretaceous(early cenomanian)Bahariya formation of Egypt has an outstanding reputation for its wealth of vertebrate remains,including a variety of iconic dinosaurs,like the carnivorous Spinosaurus and carcharodontosaurus,as well as the herbivorous Aegyptosaurus and *** these dinosaur fossils,the Bahariya formation yielded also a wealth of invertebrate and plant remains,but even today many aspects concerning the continental palaeoenvironments reflected in these deposits(including the occurrence of palaeo-wildfires)have not been studied in *** far six distinct macro-charcoal bearing levels could be identified within the type section of the Bahariya formation at Gabal El Dist profile,one of the most prolific outcrops of this formation in terms of fossil occurrence located in the north of the Bahariya Oasis,western Desert,*** of the charcoal investigated by means of SEM originates from ferns,pointing to a considerable proportion of this plant group within the palaeo-ecosystems that experienced *** and(putative)angiosperms have less frequently been *** collected data present evidence that the landscapes at the northern shores of Gondwana repeatedly experienced palaeo-wildfires,adding extra proof to previous statements that the Late cretaceous was a fiery world on a global scale.

关键词： Bahariya Oasis Gabal El Dist charcoal wildfire Dinosaurs Upper cretaceous Early cenomanian Egypt

Let’s get moving:The Global Status Report on Physical Activity 2022 calls for urgent action

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Journal of Sport and Health Science 2023年第1期12卷 5-6页

作者： Karen Milton Sjaan R.Gomersall jasper Schipperijn Norwich Medical School University of East AngliaNorwichNR47TJUK School of Human Movement and Nutrition Sciences and School of Health and Rehabilitation Sciences University of QueenslandBrisbaneQLD 4072Australia Department of Sports Science and clinical Biomechanics University of Southern DenmarkOdense 5230Denmark

Physical activity has many benefits for individual health and well-being,including a reduced risk of noncommunicable diseases,as well as improved mental health,sleep,and cognitive function.1 Being physically active also has broader social and environmental benefits and has a key role to play in achieving the 2030 Sustainable Development Goals.2,3 However,over 80%of adolescents and around a quarter of adults are insufficiently active and these figures have remained largely unchanged for the past 20 years.4,5 A recent economic analysis estimated that the total cost of inactive lifestyles equates to USD 27 billion(INT 48 billion)annually.

关键词： diseases annually unchanged

Latent structure of irritable bowel syndrome symptom severity

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world Journal of Gastroenterology 2015年第1期21卷 292-300页

作者： fabian jasper Boris Egloff Andrea Roalfe Michael witthft Department of Psychological Diagnostics University of Salzburg5020 SalzburgAustria Department of Personality Psychology and Diagnostics University of Mainz55099 MainzGermany Primary care clinical Sciences University of BirminghamEdgbastonBirmingham B15 2TTUnited Kingdom Department of Health Psychology University of Mannheim68161 MannheimGermany

AIM: To investigate the latent structure of an irritable bowel syndrome(IBS) symptom severity scale in a population of healthy ***: The Birmingham IBS symptom questionnaire which consists of three symptom specific scales(diarrhea,constipation,pain) was evaluated by meansof structural equation *** compared the original 3-factor solution to a general factor model and a bifactor solution in a large internet sample of college students(n = 875).Statistical comparisons of competing models were conducted by means of χ2 difference *** the evaluation of model fit,we examined the comparative fit index(cfI) and the Root Mean Square Error of Approximation(RMSEA).RESULTS: Results clearly favored a bifactor model of IBS symptom severity(cfI = 0.99,RMSEA = 0.05) which consisted of a strong general IBS somatization factor and three symptom specific factors(diarrhea,constipation,pain) based on the subscales of the Birmingham IBS symptom *** fit indices of the competing one factor model(cfI = 0.85,RMSEA = 0.17) and three factor model(cfI = 0.97,RMSEA = 0.08) were clearly inferior.χ2 difference tests showed that the differences between the models were indeed significant in favor of the bifactor model(P correlations of the four latent factors with measures of pain sensitivity,somatoform dissociation,fatigue severity,and demographic variables support the validity of our bifactor model of IBS specific symptom ***: The findings suggest that IBS symptom severity might best be understood as a continuous and multidimensional construct which can be reliably and validly assessed with the B-IBS.

关键词： Irritable bowel syndrome Bifactor Gastrointestinal