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Classical bovine spongiform encephalopathy and chronic wasting disease:two sides of the prion coin

Animal Diseases 2024年第1期4卷 1-18页

作者： nicholas j.Haley juergen A.Richt Department of Microbiology and Immunology College of Graduate StudiesMidwestern UniversityGlendaleAZUSA Department of Diagnostic Medicine/Pathobiology College of Veterinary MedicineKansas State UniversityManhattanKSUSA

Transmissible spongiform encephalopathies(TSEs)are a group of progressive and ultimately fatal neurologic diseases of man and animals,all resulting from the propagated misfolding of the host's normal cellular prion protein.These diseases can be spontaneous,heritable,anthropogenic/iatrogenic,or in some cases horizontally transmissible,and include such notable TSEs as bovine spongiform encephalopathy(BSE)of cattle and chronic wasting disease(CWD)of cervids.Although they are both unequivocally protein misfolding disorders,they differ markedly in their pathogenesis,transmissibility,and zoonotic potential.While the BSE epidemic has largely abated over the past three decades following global feed bans on ruminant meat and bone meal,CWD,which is readily transmitted through various forms of excreta,has rapidly expanded from its original endemic zone to encompass much of North America,along with recently identified foci in Scandinavia.Most importantly,although the classical form of BSE has proven transmissible to humans consuming contaminated beef or beef products,so far there have been no conclusive reports on the zoonotic transmission of cWD to humans.The underlying basis for these differences-whether host or agent directed-are not well understood,though may be due to inherent differences in the three-dimensional structure of the misfolded BSE or CWD prion proteins or the expression levels and tissue distribution of respective cellular prion proteins.With the uncontrolled geographic spread of CWD,it is imperative that we improve our understanding of the factors governing prion disease pathogenesis,transmission,and zoonotic potential.

关键词： Prion Bovine Spongiform Encephalopathy Chronic Wasting Disease Transmission Pathogenesis Zoonosis

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HDPairFinder:A data processing platform for hydrogen/deuterium isotopic labeling-based nontargeted analysis of trace-level amino-containing chemicals in environmental water

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journal of Environmental Sciences 2024年第2期136卷 583-593页

作者： Tingting Zhao Kristin Carroll Caley B.Craven nicholas j.P.Wawryk Shipei Xing jian Guo Xing-Fang Li Tao Huan Department of Chemistry Faculty of ScienceUniversity of British ColumbiaVancouver Campus2036 Main MallVancouverBritish ColumbiaV6T 1Z1Canada Division of Analytical and Environmental Toxicology Department of Laboratory Medicine and PathologyFaculty of Medicine and DentistryUniversity of AlbertaEdmontonAlberta T6G 2G3Canada

The combination of hydrogen/deuterium(H/D)formaldehyde-based isotopic methyl labeling with solid-phase extraction and high-performance liquid chromatography–high resolution mass spectrometry(HPLC-HRMS)is a powerful analytical solution for nontargeted analysis of trace-level amino-containing chemicals in water samples.Given the huge amount of chemical information generated in HPLC-HRMS analysis,identifying all possible H/Dlabeled amino chemicals presents a significant challenge in data processing.To address this,we designed a streamlined data processing pipeline that can automatically extract H/D-labeled amino chemicals from the raw HPLC-HRMS data with high accuracy and efficiency.First,we developed a cross-correlation algorithm to correct the retention time shift resulting from deuterium isotopic effects,which enables reliable pairing of H-and D-labeled peaks.Second,we implemented several bioinformatic solutions to remove false chemical features generated by in-source fragmentation,salt adduction,and natural13C isotopes.Third,we used a data mining strategy to construct the AMINES library that consists of over 38,000 structure-disjointed primary and secondary amines to facilitate putative compound annotation.Finally,we integrated these modules into a freely available R program,HDPairFinder.R.The rationale of each module was justified and its performance tested using experimental H/D-labeled chemical standards and authentic water samples.We further demonstrated the application of HDPairFinder to effectively extract N-containing contaminants,thus enabling the monitoring of changes of primary and secondary N-compounds in authentic water samples.HDPairFinder is a reliable bioinformatic tool for rapid processing of H/D isotopic methyl labeling-based nontargeted analysis of water samples,and will facilitate a better understanding of N-containing chemical compounds in water.

关键词： Isotope labeling Nontargeted analysis Reactive N-compounds HPLC-HRMS Source water

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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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Considerations for the use of porcine organ donation models in preclinical organ donor intervention research

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Animal Models and Experimental Medicine 2024年第3期7卷 283-296页

作者： Frazer I.Heinis Shaheed Merani nicholas W.Markin Kim F.Duncan Michael j.Moulton Lance Fristoe William E.Thorell Raechel A.Sherrick Tami R.Wells Matthew T.Andrews Marian Urban School of Natural Resources Institute of Agriculture and Natural ResourcesUniversity of Nebraska-LincolnLincolnNebraskaUSA Division of Transplantation and Vascular Surgery Department of SurgeryUniversity of Nebraska Medical CenterOmahaNebraskaUSA Department of Anesthesiology University of Nebraska Medical CenterOmahaNebraskaUSA Division of Cardiothoracic Surgery Department of SurgeryUniversity of Nebraska Medical CenterOmahaNebraskaUSA Clinical Perfusion Nebraska Medicine-Nebraska Medical CenterOmahaNebraskaUSA Department of Neurosurgery University of Nebraska Medical CenterOmahaNebraskaUSA Nutrition and Health Sciences College of Education and Human SciencesUniversity of Nebraska-LincolnLincolnNebraskaUSA Department of Comparative Medicine University of Nebraska Medical CenterOmahaNebraskaUSA

Use of animal models in preclinical transplant research is essential to the optimization of human allografts for clinical transplantation.Animal models of organ donation and preservation help to advance and improve technical elements of solid organ recovery and facilitate research of ischemia-reperfusion injury,organ preservation strategies,and future donor-based interventions.Important considerations include cost,public opinion regarding the conduct of animal research,translational value,and relevance of the animal model for clinical practice.We present an overview of two porcine models of organ donation:donation following brain death(DBD)and donation following circulatory death(DCD).The cardiovascular anatomy and physiology of pigs closely resembles those of humans,making this species the most appropriate for pre-clinical research.Pigs are also considered a potential source of organs for human heart and kidney xenotransplantation.It is imperative to minimize animal loss during procedures that are surgically complex.We present our experience with these models and describe in detail the use cases,procedural approach,challenges,alternatives,and limitations of each model.

关键词： animal model brain death circulatory death organ transplantation

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P2X7 receptor in skin biology and diseases

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World journal of Dermatology 2016年第2期5卷 72-83页

作者： nicholas j.geraghty Debbie Watson Sam R Adhikary Ronald Sluyter School of Biological Sciences University of Wollongong Illawarra Health and Medical Research Institute

The P2X7 receptor is a trimeric ligand-gated cation channel present on immune and other cells. Activation of this receptor by its natural ligand extracellular adenosine triphosphate results in a variety of downstream responses, including the release of pro-inflammatory mediators and cell death. In normal skin, P2X7 is present on keratinocytes, Langerhans cells and fibroblasts, while the presence of this receptor on other cutaneous cells is mainly inferred from studies of equivalent cell types present in other tissues. Mast cells in normal skin however express negligible amounts of P2X7, which can be upregulated in cutaneous disease. This review discusses the potential significance of P2X7 in skin biology, and the role of this receptor in inflammatory skin disorders such as irritant and chronic dermatitis, psoriasis, graft-versus-host disease, as well is in wound healing, transplantation and skin cancer.

关键词： P2X7 receptor Purinergic receptor Extracellular adenosine triphosphate CD39 Skin biology Skin immune system

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Breaking the biotrophic interfacial complex:How genome editing can lead to rice blast resistance

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Molecular Plant 2023年第8期16卷 1243-1245页

作者： Vincent Were nicholas j.Talbot The Sainsbury Laboratory University of East AngliaNorwich Research ParkNorwich NR47UHUK

Genome editing is a transformational technology—by precisely altering the coding or regulatory sequence of a specific gene,it is now possible to change specific traits within a wide variety of organisms.As a consequence,plant breeding can be taken to a new level of precision,and many countries are moving rapidly to adopt new legislation to permit genome editing(Greenwood et al.,2023).However,genome editing has so far seldom been used to develop disease-resistant crops.This is because plant immunity often depends on single dominant resistance genes,which encode immune receptors that recognize secreted effectors deployed by plant pathogens(jones and Dangl,2006).In this context,genetic modification has proven to be a much more powerful technology so far to introduce these genes from distinct varieties,or even different species,to develop disease resistant crop species(Greenwood et al.,2023),especially when multiple disease-resistance loci can be introduced together to provide more durable resistance(Luo et al.,2021).Genome editing can be used in an innovative way to resurrect previously effective resistance genes(Contreras et al.,2023),but it has been less effective at introducing new forms of disease resistance to crops.

关键词： breeding resistance editing

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Shedding light on neurons:optical approaches for neuromodulation

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National Science Review 2022年第10期9卷 34-54页

作者： Shan jiang Xiang Wu nicholas j.Rommelfanger Zihao Ou Guosong Hong Department of Materials Science and Engineering Stanford University Wu Tsai Neurosciences Institute Stanford University Department of Applied Physics Stanford University

Today’ s optical neuromodulation techniques are rapidly evolving,benefiting from advances in photonics,genetics and materials science.In this review,we provide an up-to-date overview of the latest optical approaches for neuromodulation.We begin with the physical principles and constraints underlying the interaction between light and neural tissue.We then present advances in optical neurotechnologies in seven modules:conventional optical fibers,multifunctional fibers,optical waveguides,light-emitting diodes,upconversion nanoparticles,optical neuromodulation based on the secondary effects of light,and unconventional light sources facilitated by ultrasound and magnetic fields.We conclude our review with an outlo ok on new methods and mechanisms that afford optical neuromodulation with minimal invasiveness and footprint.

关键词： optical neuromodulation optogenetics neural interfaces

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Prospective associations between joint categories of physical activity and insomnia symptoms with onset of poor mental health in a population-based cohort

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journal of Sport and Health Science 2023年第3期12卷 295-303页

作者： Mitch j Duncan Elizabeth G Holliday Nicola W Burton nicholas Glozier Stina Oftedal School of Medicine and Public Health College of HealthMedicineand WellbeingThe University of NewcastleCallaghanNSW 2308Australia Priority Research Centre for Physical Activity and Nutrition The University of NewcastleCallaghanNSW 2308Australia School of Applied Psychology Griffith UniversityBrisbaneQLD 4122Australia Menzies Health Institute Queensland Griffith UniversityBrisbaneQLD 4122Australia Brain and Mind Centre Central Clinical SchoolThe University of SydneyNSW 2050Australia

Background:Physical inactivity and insomnia symptoms are independently associated with increased risk of depression and anxiety;however,few studies jointly examine these risk factors.This study aimed to prospectively examine the joint association of physical activity(PA)and insomnia symptoms with onset of poor mental health in adults.Methods:Participants from the 2013 to 2018 annnual waves of the Household Income and Labour Dynamics in Australia panel study who had good mental health(Mental Health Inventory-5>54)in 2013,and who completed at least 1 follow-up survey(2014-2018),were included(n=10,977).Poor mental health(Mental Health Inventory-5≤54)was assessed annually.Baseline(2013)PA was classified as high/moderate/low,and insomnia symptoms(i.e.,trouble sleeping)were classified as no insomnia symptoms/insomnia symptoms,with 6 mutually exclusive PAinsomnia symptom groups derived.Associations of PA-insomnia symptom groups with onset of poor mental health were examined using discrete-time proportional-hazards logit-hazard models.Results:There were 2322 new cases of poor mental health(21.2%).Relative to the high PA/no insomnia symptoms group,there were higher odds(odds ratio and 95%confidence interval(95%CI))of poor mental health among the high PA/insomnia symptoms(OR=1.87,95%CI:1.57-2.23),moderate PA/insomnia symptoms(OR=1.93,95%CI:1.61-2.31),low PA/insomnia symptoms(OR=2.33,95%CI:1.96-2.78),and low PA/no insomnia symptoms(OR=1.14,95%CI:1.01-1.29)groups.Any level of PA combined with insomnia symptoms was associated with increased odds of poor mental health,with the odds increasing as PA decreased.Conclusion:The se findings highlight the potential benefit of interventions targeting both PA and insomnia symptoms for promoting mental health.

关键词： Depression Physical activity Sleep quality

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Role of c-Myc in lung cancer:Progress,challenges,and prospects

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Chinese Medical journal Pulmonary and Critical Care Medicine 2023年第3期1卷 129-138页

作者： nicholas j.Wallbillich Hua Lu Department of Biochemistry and Molecular Biology Tulane University School of Medicine1430 Tulane AvenueNew OrleansLA 70112USA Tulane Cancer Center Tulane University School of Medicine1700 Tulane AvenueNew OrleansLA 70112USA

Lung cancer remains the leading cause of cancer-related deaths worldwide.Despite the recent advances in cancer therapies,the 5-year survival of non-small cell lung cancer(NSCLC)patients hovers around 20%.Inherent and acquired resistance to therapies(including radiation,chemotherapies,targeted drugs,and combination therapies)has become a significant obstacle in the successful treatment of NSCLC.c-Myc,one of the critical oncoproteins,has been shown to be heavily associated with the malignant cancer phenotype,including rapid proliferation,metastasis,and chemoresistance across multiple cancer types.The c-Myc proto-oncogene is amplified in small cell lung cancers(SCLCs)and overexpressed in over 50%of NSCLCs.c-Myc is known to actively regulate the tran-scription of cancer stemness genes that are recognized as major contributors to tumor progression and therapeutic resistance;thus,targeting c-Myc either directly or indirectly in mitigation of the cancer stemness phenotype be-comes a promising approach for development of a new strategy against drug resistant lung cancers.This review will summarize what is currently known about the mechanisms underlying c-Myc regulation of cancer stemness and its involvement in drug resistance and offer an overview on the current progress and future prospects in therapeutically targeting c-Myc in both SCLC and NSCLC.

关键词： Cancer dormancy Cancer stem cells c-Myc Drug resistance Epidermal growth factor receptor Lung cancer Non-small cell lung cancer Small cell lung cancer

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Putting PLX5622 into perspective:microglia in central nervous system viral infection

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Neural Regeneration Research 2023年第6期18卷 1269-1270页

作者： Alanna G.Spiteri nicholas j.C.King Viral Immunopathology Laboratory InfectionImmunity and Inflammation Research ThemeSchool of Medical SciencesFaculty of Medicine and HealthThe University of SydneySydneyNSWAustralia Sydney Cytometry The University of Sydney and Centenary InstituteSydneyNSWAustralia Ramaciotti Facility for Human Systems Biology The University of Sydney and Centenary InstituteSydneyNSWAustralia Charles Perkins Centre The University of SydneyAustralia The University of Sydney Institute for Infectious Diseases The University of SydneySydneyNSWAustralia The University of Sydney Nano Institute the University of SydneySydneyNSWAustralia

Elucidating the exact contribution of microglia to central nervous system(CNS)pathology has historically been extremely challenging.These resident parenchymal myeloid cells are considered to have critical roles as frontline responders during pathogen invasion and CNS perturbation.Thus,understanding the precise temporal kinetics of microglial function is central to the evolution of novel therapeutics for disease intervention and/or resolution(Spiteri et al.,2022a).The development of PLX5622,a colony-stimulating factor 1 receptor(CSF-1R)inhibitor typically formulated into a rodent chow for simple oral administration has facilitated exploration of microglial functions in disease(Spangenberg et al.,2019).

关键词： invasion system precise

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