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Discovery of N-benzyl hydroxypyridone carboxamides as a novel and potent antiviral chemotype against human cytomegalovirus (HcMV)

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1671-1684页

作者： Sameera Senaweera Tiffany C.Edwards Jayakanth Kankanala Yan Wang Rajkumar Lalji Sahani Jiashu Xie Robert J.Geraghty Zhengqiang Wang center for Drug Design College of PharmacyUniversity of MinnesotaMinneapolisMN 55455USA Translational Medicine R&D center Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China

current drugs for treating human cytomegalovirus(HcMV)infections are limited by resistance and treatment-associated toxicities.In developing mechanistically novel HcMV antivirals,we discovered an N-benzyl hydroxypyridone carboxamide antiviral hit(8a)inhibiting HcMV in submicromolar range.We describe herein the structure–activity relationship(SAR)for 8a,and the characterization of potent analogs for cytotoxicity/cytostatic property,the preliminary mechanism of action,and the absorption,distribution,metabolism and excretion(ADME)properties.The SAR revealed a few pharmacophore features conferring optimal antiviral profile,including the 5-OH,the N-1 benzyl,at least one–cH_(2)−in the linker,and a di-halogen substituted phenyl ring in the amide moiety.In the end,we identified numerous analogs with sub-micromolar antiviral potency and good selectivity index.The preliminary mechanism of action characterization used a pUL89-c biochemical endonuclease assay,a virus entry assay,a time-of-addition assay,and a compound withdrawal assay.ADME profiling measuring aqueous solubility,plasma and liver microsomal stability,and parallel artificial membrane permeability assay(PAMPA)permeability demonstrated largely favorable drug-like properties.Together,these studies validate the N-benzyl hydroxypyridone carboxamide as a viable chemotype for potent and mechanistically distinct antivirals against HcMV.

关键词： Human cytomegalovirus N-Benzyl hydroxypyridone carboxamides Structureeactivity relationship Mechanism of action

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comparison of trigeminal lateralization with differing stimulants

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World Journal of Otorhinolaryngology-Head and Neck Surgery 2024年第1期10卷 66-69页

作者： tiffany chen Nicolas S.Poupore Michael c.Shih Thomas S.edwards Shaun A.Nguyen Zachary M.Soler Rodney J.Schlosser Department of Otolaryngology‐Head and Neck Surgery Medical University of South CarolinaCharlestonSouth CarolinaUSA

Trigeminal-specific stimulants have been shown to activate different receptors preferentially and this likely accounts for variation in sensory perception.It is unclear whether trigeminal sensitivity is similar across different transient receptor potential(TRP)receptors or if dysfunction of different receptors results in differing patient symptoms.Therefore,a prospective cohort study was conducted,consisting of trigeminal lateralization testing with three different stimulants(eucalyptol,isothiocyanate,acetic acid),olfaction testing with Sniffin'Sticks,and measurement of various patient‐reported outcome measures(PROMs).A total of 50 participants were enrolled across the olfactory spectrum.Mean TDI score was 27.1±8.3(range 7.0–39.5)with 38%normosmic and 62%dysosmic.Mean trigeminal lateralization scores out of 20 in the overall cohort were 16.18(2.78)for eucalyptol,14.94(3.49)for mustard oil,and 15.28(3.68)for vinegar.Eucalyptol showed a significant correlation with threshold scores of Sniffin'Sticks.A significant correlation was found between acetic acid and various PROMs.None of the lateralization scores of the trigeminal stimulants correlated to each other significantly and there was no correlation to age.The lack of correlation suggests that the measured sensitivity of one type of TRP receptor may not translate to similar sensitivity of the other receptors.Additional investigations with TRPV1 and TRPA1 agonists are needed to corroborate our findings.

关键词： chemosensory olfaction trigeminal TRP receptor

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Trends and seasonality in hospitalizations for acute alcohol-related and biliary pancreatitis in the USA

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Hepatobiliary & Pancreatic Diseases International 2021年第2期20卷 173-181页

作者： Artem Shmelev Anne M Sill tiffany Horrigan Steven c cunningham Department of Surgery Saint Agnes HealthcareBaltimoreMDUSA

Background:The incidence of acute pancreatitis(AP)is characterized by circannual and geographical variation.The aim of this study was to describe seasonal variation and trends in hospitalizations for AP in the USA with respect to AP etiology.Methods:The Nationwide Inpatient Sample data(2000–2016)from the Healthcare cost and Utilization Project were used.The study population included all primary hospitalizations for AP.Biliary AP(BAP)and alcohol-induced AP(AAP)were distinguished by diagnostic and procedural IcD codes.Seasonal trend decomposition was performed.Results:There was a linear increase in annual incidence(per 100000 population)of AAP in the USA(from 17.0 in 2000 to 22.9 in 2016),while incidence of BAP,equaled 19.9 in 2000,peaked at 22.1 in 2006 and decreased to 17.4 in 2016.AP incidence demonstrated 18%annual incidence amplitude with summer peak and winter trough,more prominent in AAP.In 2016,within AAP,the highest incidence(per 100000 population)was noted among African-Americans(up to 50.4),followed by males aged 56–70 years(26.5)and Asians of low income(25.5);within BAP,above the average incidence was observed in Hispanic(up to 25.8)and Asian(up to 25.0)population.The most consistent and rapid increase in AP incidence was noted in males aged 56–70 years with an alcoholic etiology(average 6%annual incidence growth).conclusions:The incidence and annual trends of AP vary significantly among demographic and socioeconomic groups and this knowledge may be useful for the planning of healthcare resources and identification of at-risk populations.

关键词： Pancreatitis Alcoholic pancreatitis Incidence Seasonal variation

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Surgical management of facial dog bite trauma:A contemporary perspective and review

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World Journal of Otorhinolaryngology-Head and Neck Surgery 2023年第2期9卷 123-130页

作者： tiffany chen Maria Karim Zachary T.Grace Andrew R.Magdich Eric c.carniol Brian E.Benson Peter F.Svider Hackensack Meridian School of Medicine NutleyNew JerseyUSA carniol Plastic Surgery SummitNew JerseyUSA Hackensack Meridian Health Hackensack University Medical CenterHackensackNew JerseyUSA Bergen Medical Associates EmersonNew JerseyUsA

Objective:To perform a review evaluating management of and complications stemming from dog bite trauma sustained to the head and neck over the past decade.Data Sources:PubMed and cochrane Library.Methods:The authors searched the PubMed and cochrane Library databases for relevant published literature.A total of 12 peer-reviewed canine-exclusive series inclusive of 1384 patient cases describing facial dog bite trauma met inclusion criteria.Wounds including fractures,lacerations,contusions,and other soft-tissue injuries were evaluated.Demographics related to clinical course and management,operating room requirements,and antibiotic usage were compiled and analyzed.Initial trauma and surgical management complications were also assessed.Results:75.5%of patients sustaining dog bites required surgical intervention.Of these patients,7.8%suffered from postsurgical complications,including hypertrophic scarring(4.3%),postoperative infection(0.8%),or nerve deficits and persistent paresthesias(0.8%).Prophylactic antibiotics were administered to 44.3%of patients treated for facial dog bites and the overall infection rate was 5.6%.concomitant fracture was present in 1.0%of patients.conclusion:Primary closure,often in the OR may be necessary,with few cases requiring grafts or flaps.Surgeons should be aware that the most common complication is hypertrophic scarring.Further research is needed to elucidate the role of prophylactic antibiotics.

关键词： bite canine dog face facial injury laceration trauma

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cOVID-19 vaccination produces exercise-responsive SARS-coV-2 specific T-cells regardless of infection history

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Journal of Sport and Health Science 2024年第1期13卷 99-107页

作者： Kyle A.Smith tiffany M.Zúñiga Forrest L.Baker Helena Batatinha charles R.Pedlar Shane c.Burgess Michael P.Gustafson Emmanuel Katsanis Richard J.Simpson School of Nutritional Sciences and Wellness The University of ArizonaTucsonAZ 85721USA Department of Pediatrics The University of ArizonaTucsonAZ 85724USA Faculty of Sport Allied Health and Performance ScienceSt.Mary's UniversityTwickenham TW14SXUK Institute of Sport Exercise and Health University College LondonLondon WC1E 7HUUK Department of Animal and comparative Biomedical Sciences The University of ArizonaTucsonAZ 85721USA The University of Arizona cancer center The University of ArizonaTucsonAZ 85719USA Laboratory Medicine and Pathology Mayo Clinic ArizonaPhoenixAZ 85054USA Department of Immunobiology The University of ArizonaTucsonAZ 85724USA Department of Medicine The University of ArizonaTucsonAZ 85724USA Department of Pathology The University of ArizonaTucsonAZ 85724USA

Background:The mobilization and redistribution of severe acute respiratory syndrome coronavirus 2(SARS-coV-2)specific T-cells and neutralizing antibodies(nAbs)during exercise is purported to increase immune surveillance and protect against severe coronavirus disease 2019(cOVID-19).We sought to determine if cOVID-19 vaccination would elicit exercise-responsive SARS-coV-2 T-cells and transiently alter nAb titers.Methods:Eighteen healthy participants completed a 20-min bout of graded cycling exercise before and/or after receiving a cOVID-19 vaccine.All major leukocyte subtypes were enumerated before,during,and after exercise by flow cytometry,and immune responses to SARS-coV-2 were determined using whole blood peptide stimulation assays,T-cell receptor(TcR)-βsequencing,and SARS-coV-2 nAb serology.Results:cOVID-19 vaccination had no effect on the mobilization or egress of major leukocyte subsets in response to intensity-controlled graded exercise.However,non-infected participants had a significantly reduced mobilization of cD4+and cD8+naive T-cells,as well as cD4+central memory T-cells,after vaccination(synthetic immunity group);this was not seen after vaccination in those with prior SARS-coV-2 infection(hybrid immunity group).Acute exercise after vaccination robustly mobilized SARS-coV-2 specific T-cells to blood in an intensity-dependent manner.Both groups mobilized T-cells that reacted to spike protein;however,only the hybrid immunity group mobilized T-cells that reacted to membrane and nucleocapsid antigens.nAbs increased significantly during exercise only in the hybrid immunity group.conclusion:These data indicate that acute exercise mobilizes SARS-coV-2 specific T-cells that recognize spike protein and increases the redistribution of nAbs in individuals with hybrid immunity.

关键词： Anti-viral cOVID-19 Exercise immunology SARS-coV-2 T-cells Vaccine

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Impact of modern antiviral therapy of chronic hepatitis B and c on clinical outcomes of liver disease

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World Journal of Gastroenterology 2021年第29期27卷 4831-4845页

作者： tiffany Khoo Danielle Lam John K Olynyk Department of Gastroenterology and Hepatology Fiona Stanley HospitalMurdoch 6150Australia School of Medical and Health Sciences Edith Cowan UniversityJoondalup 6027Australia

chronic infections with the hepatitis B and c viruses have significant worldwide health and economic impacts.Previous treatments for hepatitis c such as interferon and ribavirin therapy were ineffective and poorly tolerated by patients.The introduction of directly acting curative antiviral therapy for hepatitis c and the wider use of nucleos(t)ide analogues for suppression of chronic Hepatitis B infection have resulted in many positive developments.Decreasing the prevalence of hepatitis B and c have concurrently reduced transmission rates and hence,the number of new infections.Antiviral treatments have decreased the rates of liver decompensation and as a result,lowered hospitalisation and mortality rates for both chronic hepatitis B and c infection.The quality of life of chronically infected patients has also been improved significantly by modern treatment.Antiviral therapy has stopped the progression of liver disease to cirrhosis in certain patient cohorts and prevented ongoing hepatocellular damage in patients with existing cirrhosis.Longer term benefits of antiviral therapy include a reduced risk of developing hepatocellular carcinoma and decreased number of patients requiring liver transplantation.This review article assesses the literature and summarises the impact of modern antiviral therapy of chronic hepatitis B and c on clinical outcomes from liver disease.

关键词： Hepatitis B Hepatitis c Nucleotide analogues Directly acting antiviral therapy clinical outcomes Liver disease

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Ultraefficient thermoacoustic conversion through a split ring resonator

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Advanced Photonics 2020年第3期2卷 69-77页

作者： Lu Lan Yueming Li tiffany Yang-Tran Ying Jiang Yingchun cao Ji-Xin cheng Boston University Department of Biomedical EngineeringBostonMassachusettsUnited States Boston University Department of Mechanical EngineeringBostonMassachusettsUnited States Boston University Department of Electrical and Computer EngineeringBostonMassachusettsUnited States Boston University Photonics center BostonMassachusettsUnited States

Microwaves,which have a∼10-cm wavelength,can penetrate deeper into tissue than photons,heralding exciting deep tissue applications such as modulation or imaging via the thermoacoustic effect.Thermoacoustic conversion efficiency is however very low,even with an exogenous contrast agent.We break this low-conversion limit,using a split ring resonator to effectively collect and confine the microwaves into a submillimeter hot spot for ultrasound emission and achieve a conversion efficiency over 2000 times higher than other reported thermoacoustic contrast agents.Importantly,the frequency of emitted ultrasound can be precisely tuned and multiplexed by modulation of the microwave pulses.Such performance is inaccessible by a piezoelectric-based transducer or a photoacoustic emitter and,therefore,split ring resonators open up new opportunities to study the frequency response of cells in ultrasonic biomodulation.For applications in deep tissue localization,a split ring resonator can be used as a wireless,battery-free ultrasound beacon placed under a breast phantom.

关键词： thermoacoustic effect metamaterial photoacoustic effect split ring resonator ultrasound

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鼠疫耶尔森菌纤维蛋白溶解酶原激活因子蛋白及其特异性片段的原核表达

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中国地方病学杂志 2012年第5期31卷 482-485页

作者：杜春红王鹏 tiffany c.Ho 董兴齐宋志忠吴锡南张建中云南省地方病防治所云南省鼠疫防控技术重点实验室大理671000 昆明医科大学公共卫生学院中国疾病预防控制中心传染病预防控制所

目的重组表达鼠疫耶尔森菌纤维蛋白溶解酶原激活因子（Plasminogen activator，PIa）蛋白及其特异性片段并检测其免疫反应性。方法以鼠疫EV76株为模板，PcR扩增pla,pla-c基因，并与质粒原核表达载体（prokaryotic expression vector，pE... 详细信息

目的重组表达鼠疫耶尔森菌纤维蛋白溶解酶原激活因子（Plasminogen activator，PIa）蛋白及其特异性片段并检测其免疫反应性。方法以鼠疫EV76株为模板，PcR扩增pla,pla-c基因，并与质粒原核表达载体（prokaryotic expression vector，pET）32a（＋）连接，将pET32a（＋）-pla、pET32a（＋）-pla—c分别转化E．coliBL21（DE3）诱导表达；产物经镍离子金属螯合亲和层析纯化，免疫印迹（Westernblot）法鉴定其免疫反应性。结果所表达的Pla蛋白相对分子质量（Mr）为52．8×10。，以包涵体形式存在；Pla—c蛋白Mr为24．0x10s，以可溶形式存在；这两个蛋白质均可与鼠疫免疫血清产生特异结合反应。结论所表达的鼠疫菌Pla及其特异性片段具有免疫反应性，为辅助诊断鼠疫提供了选择。

关键词：鼠疫耶尔森菌纤维蛋白溶解酶原激活因子蛋白原核表达免疫

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Fabrication of all-transparent polymer-based and encapsulated nanofluidic devices using nano-indentation lithography

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Microsystems & Nanoengineering 2017年第1期3卷 373-381页

作者： cong Wu tiffany G.Lin Zhikun Zhan Yi Li Steve c.H.Tung William c.Tang Wen J.Li Department of Mechanical and Biomedical Engineering City University of Hong KongHong Kong 999077China Department of Biomedical Engineering University of CaliforniaIrvineCA 92697-2715USA Department of Automation Yanshan UniversityQinghuangdao 066004China Department of Mechanical Engineering University of ArkansasFayettevilleAR 72701USA

In this paper,we describe a novel and simple process for the fabrication of all-transparent and encapsulated polymeric nanofluidic devices using nano-indentation lithography.First,a nanomechanical probe is used to‘scratch’nanoscale channels on polymethylmethacrylate(PMMA)substrates with sufficiently high hardness.Next,polydimethylsiloxane(PDMS)is used twice to duplicate the nanochannels onto PDMS substrates from the‘nano-scratched’PMMA substrates.A number of experiments are conducted to explore the relationships between the nano-indentation parameters and the nanochannel dimensions and to control the aspect ratio of the fabricated nanochannels.In addition,traditional photolithography combined with soft lithography is employed to fabricate microchannels on another PDMS‘cap’substrate.After manually aligning the substrates,all uncovered channels on two separate PDMS substrates are bonded to achieve a sealed and transparent nanofluidic device,which makes the dimensional transition from microscale to nanoscale feasible.The smallest dimensions of the achievable nanochannels that we have demonstrated thus far are of~20 nm depth and~800 nm width,with lengths extendable beyond 100μm.Fluid flow experiments are performed to verify the reliability of the device.Two types of colloidal solution are used to visualize the fluid flow through the nanochannels,that is,ethanol is mixed with gold colloid or fluorescent dye(fluorescein isothiocyanate),and the flow rate and filling time of liquid in the nanochannels are estimated based on time-lapsed image data.The simplicity of the fabrication process,bio-compatibility of the polymer substrates,and optical transparency of the nanochannels for flow visualization are key characteristics of this approach that will be very useful for nanofluidic and biomolecular research applications in the future.

关键词： indentation lithography nanochannel nanofluidic device nanofluidic flow

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Blastomyces dermatitidis: Stability studies on different yeast lysate antigens

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Open Journal of Immunology 2013年第3期3卷 98-102页

作者： tiffany R. Allison Joshua c. Wright Gene M. Scalarone Department of Biological Sciences Idaho State University Pocatello USA

In Trial 1, 19 lots of Blastomyces dermatitidis (T-58;Tennessee dog isolate) were assayed to determine the stability of the reagents following storage. The reactivity of the antigens, produced from 1989 to 2012 and stored at 4°c, was determined by comparing antibody detection (enzyme-linked immunosorbent assay;ELISA) in 12 serum specimens from immunized rabbits. All of the 19 reagents produced during this 23-year period exhibited a high degree of stability and were able to detect antibody in the sera. Mean absorbance values ranged from 0.798 (1989) to 0.827 (2012) and a mean value for all 19 antigens of 0.728. In a related evaluation, Trial 2, B. dermatitidis lysate antigens prepared from 8 isolates (dog, human, soil) at two different time periods were assayed as above to determine reactivity. The time of storage between the first and second reagents varied from 4 to 17 years. The results indicated that all 16 of the lysate antigens detected antibody in the 15 rabbit serum specimens with mean absorbance values ranging from 0.346 to 0.682, but variations in reactivity were observed depending on the lysate and the serum specimen assayed. This comparative study provided evidence that the antigenic reagents do exhibit some lot-to-lot variation in reactivity, but they did not lose any appreciable potency during prolonged storage.

关键词： Blastomyces dermatitidis Lysate Antigens Antibody Detection Stability ELISA

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