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Acta Pharmaceutica Sinica B 2015年第6期5卷 506-519页

作者： Marton Siklos Manel Ben Aissa gregory r.j.thatcher Department of Medicinal Chemistry and Pharmacognosy University of Illinois College of Pharmacy

Cysteine proteases continue to provide validated targets for treatment of human *** neurodegenerative disorders,multiple cysteine proteases provide targets for enzyme inhibitors,notably caspases,calpains,and *** reactive,active-site cysteine provides specificity for many inhibitor designs over other families of proteases,such as aspartate and serine;however,a)inhibitor strategies often use covalent enzyme modification,and b)obtaining selectivity within families of cysteine proteases and their isozymes is *** review provides a general update on strategies for cysteine protease inhibitor design and a focus on cathepsin B and calpain 1 as drug targets for neurodegenerative disorders;the latter focus providing an interesting query for the contemporary assumptions that irreversible,covalent protein modification and low selectivity are anathema to therapeutic safety and efficacy.

关键词： Cysteine protease Calpain Cathepsin Enzyme inhibitors Neurodegeneration Alzheimer’s disease

remembering your A, B, C’s: Alzheimer’s disease and ABCA1

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Acta Pharmaceutica Sinica B 2022年第3期12卷 995-1018页

作者： Cutler T.Lewandowski Megan S.Laham gregory r.j.thatcher Department of Pharmaceutical Sciences University of Illinois College of PharmacyChicagoIL 60612USA Department of Pharmacology and Toxicology University of Arizona College of PharmacyTucsonAZ 85721USA

The function of ATP binding cassette protein A1(ABCA1)is central to cholesterol *** ABCA1 expression or activity is implicated in Alzheimer’s disease(AD)and other *** approaches to boost ABCA1 activity have yet to be translated successfully to the *** risk factors for AD development and progression,including comorbid disorders such as type2 diabetes and cardiovascular disease,highlight the intersection of cholesterol transport and *** of ABCA1 can positively impact APOE lipidation,insulin sensitivity,peripheral vascular and blood-brain barrier integrity,and anti-inflammatory *** strategies towards ABCA1-boosting compounds have been described,with a bias toward nuclear hormone receptor(NHr)*** agonists display beneficial preclinical effects;however,important side effects have limited *** particular,ligands that bind liver X receptor(LXr),the primary NHr that controls ABCA1 expression,have shown positive effects in AD mouse models;however,lipogenesis and unwanted increases in triglyceride production are often *** longstanding approach,focusing on LXrβ*** selectivity,is over-simplistic and has *** approaches such as phenotypic screening may lead to small molecule NHr modulators that elevate ABCA1 function without inducing lipogenesis and are clinically translatable.

关键词： Alzheimer’s disease Cardiovascular disease Cholesterol Drug discovery Liver X receptor Nuclear hormone receptor Type 2 diabetes

A functional tacrolimus-releasing nerve wrap for enhancing nerve regeneration following surgical nerve repair

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Neural regeneration research 2025年第1期20卷 291-304页

作者： Simeon C.Daeschler Katelyn j.W.So Konstantin Feinberg Marina Manoraj jenny Cheung jennifer Zhang Kaveh Mirmoeini jPaul Santerre Tessa Gordon gregory HBorschel SickKids research Institute Neuroscience and Mental Health ProgramTorontoONCanada Institute of Biomaterials and Biomedical Engineering University of TorontoTorontoONCanada Indiana University School of Medicine IndianapolisINUSA Division of Plastic and reconstructive Surgery the Hospital for Sick ChildrenTorontoONCanada Translational Biology and Engineering Program Ted Rogers Centre for Heart ResearchInstitute of Biomedical EngineeringFaculty of DentistryUniversity of TorontoTorontoONCanada

Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong ***,there are no FDA-approved therapies available to promote nerve *** accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve *** authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site,with suitable properties for scalable production and clinical application,aiming to promote nerve regeneration and functional recovery with minimal systemic drug *** is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 *** and drug loading are adjustable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible *** released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80%compared with systemic *** its surgical suitability and preclinical efficacy and safety,this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

关键词： biodegradable local drug delivery nerve injury nerve regeneration nerve wrap tacrolimus

Global weirding at mass extinction horizons

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National Science review 2024年第1期11卷 10-12页

作者： gregory j.retallack Department of Earth Sciences University of Oregon

A strong motivation for studying mass extinctions is understanding how current climatic and biodiversity crises will affect creatures living on land such as ourselves. Perhaps the question is: how bad can it get? In that case, terrestrial Permian-Triassic mass extinctions are an irresistible worst-case scenario [1].

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The Emeishan large igneous province:A synthesis

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Geoscience Frontiers 2014年第3期5卷 369-394页

作者： j.gregory Shellnutt National Taiwan Normal University Department of Earth Science

The late Permian Emeishan large igneous province （EL1P） covers -0.3× 10-6 kmL of the western margin of the Yangtze Block and Tibetan Plateau with displaced, correlative units in northern Vietnam （Song Da zone）. The ELIP is of particular interest because it contains numerous world-class base metal deposits and is contemporaneous with the late Capitanian （-260 Ma） mass extinction. The flood basalts are the signature feature of the ELIP but there are also ultramafic and silicic volcanic rocks and layered mafic- ultramafic and silicic plutonic rocks exposed. The EL1P is divided into three nearly concentric zones （i.e. inner, middle and outer） which correspond to progressively thicker crust from the inner to the outer zone. The eruptive age of the ELIP is constrained by geological, paleomagnetic and geochronological evidence to an interval of 〈3 Ma. The presence of picritic rocks and thick piles of flood basalts testifies to high temperature thermal regime however there is uncertainty as to whether these magmas were derived from the subcontinental lithospheric mantle or sub-lithospheric mantle （i.e. asthenosphere or mantle plume） sources or both. The range of Sr （Isr ≈ 0.7040-0.7132）, Nd （ENd（t） ≈ -14 tO ＋8）, Pb （206-pb/204-pb1 ≈ 17.9-20.6） and Os （Yos ≈ -5 to ＋11） isotope values of the ultramafic and mafic rocks does not permit a conclusive answer to ultimate source origin of the primitive rocks but it is clear that some rocks were affected by crustal contamination and the presence of near-depleted isotope compo- sitions suggests that there is a sub-lithospheric mantle component in the system. The silicic rocks are derived by basaltic magmas/rocks through fractional crystallization or partial melting, crustal melting or by interactions between mafic and crustal melts. The formation of the Fe-Ti-V oxide-ore deposits is probably due to a combination of fractional crystallization of Ti-rich basalt and fluxing of C02-rich fluids whereas the Ni-Cu-（PGE） deposits are related

关键词： Late Permian Mantle plume Large igneous province Flood basalts Mineral deposits Uplift and doming

Potential of the neonicotinoid imidacloprid and the oxadiazine indoxacarb for controlling five coleopteran pests of stored grain

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Insect Science 2012年第1期19卷 96-101页

作者： gregory j. Daglish Manoj K. Nayak Agri-Science Queensland Department of Employment Economic Development and Innovation Brisbane Queensland Australia

The potential for using imidacloprid （a neonicotinoid） and indoxacarb （an oxadiazine） as grain protectants was investigated in bioassays against resistant strains of five stored grain beetles. The species investigated were rhyzopertha dominica （E）（the lesser grain borer）, Sitophilus oryzae （L.）（the rice weevil）, Tribolium castaneum （Herbst）（the rust-red flour beetle）, Oryzaephilus surinamensis （L.）（the saw tooth flour beetle）, and Cryptolestesferrugineus （Stephens）（the fiat grain beetle）. Each of these species has developed resistance to one or more protectants, including organophosphorus insecticides, synthetic pyrethroids and the juvenile hormone analogue methoprene. Mortality and re- production after a 2-week exposure of adults to treated wheat depended on species, dose and insecticide. Imidacloprid had no effect on S. oryzae at any dose, but none of the other species produced any live progeny at 10 mg/kg. Indoxacarb had no effect on T. castaneum at any dose, but none of the other species produced any live progeny at 5 mg/kg. The results show that although both imidacloprid and indoxacarb can control at least four of the five key pests tested at doses comparable to those used for organophosphorus protectants, more potent neonicotinoid or oxadiazine insecticides would be needed than either of these to provide broad spectrum protection of stored grain .

关键词： beetles imidacloprid indoxacarb stored grain

Enhancing sintering resistance of atomically dispersed catalysts in reducing environments with organic monolayers

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Green Energy & Environment 2022年第6期7卷 1263-1269页

作者： jing Zhang Chithra Asokan gregory Zakem Phillip Christopher j.Will Medlin Department of Chemical and Biological Engineering University of ColoradoBoulderCOUSA Department of Chemical Engineering University of CaliforniaSanta BarbaraSanta BarbaraCAUSA

Atomically dispersed precious metal catalysts maximize atom efficiency and exhibit unique ***,they are susceptible to *** reactions occurring in reducing environments tend to result in atomically dispersed metals sintering at lower temperatures than in oxidative or inert atmospheres due to the formation of mobile metal-H or metal-CO ***,we develop a new approach to mitigate sintering of oxide supported atomically dispersed metals in a reducing atmosphere using organophosphonate self-assembled monolayers(SAMs).We demonstrate this for the case of atomically dispersed rh on Al_(2)O_(3) and TiO_(2) using a combination of CO probe molecule FTIr,temperature programmed desorption,and alkene hydrogenation rate *** suggests that SAM functionalization of the oxide provides physical diffusion barriers for the metal and weakens the interactions between the reducing gas and metal,thereby discouraging the adsorbate-promoted diffusion of metal atoms on oxide *** results show that support functionalization by organic species can provide improved resistance to sintering of atomically dispersed metals with maintained catalytic reactivity.

关键词： Atomically dispersed catalysts Organic monolayers rh Single atom catalysis Sintering

Characterization of particle deposition during crossflow filtration as influenced by permeate flux and crossflow velocity using a microfluidic filtration system

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Frontiers of Chemical Science and Engineering 2021年第3期15卷 552-561页

作者： Hongzhan Di gregory j.O.Martin Dave E.Dunstan Department of Chemical and Biomolecular Engineering University of MelbourneParkvilleVictoria 3010Australia

Particle deposition during crossflow filtration is significantly influenced by the operating conditions,in particular the permeate flux and crossflow ***,there is a lack of detailed knowledge about how deposit layer structures and distributions depend on operating *** study uses a microfluidic visualisation filtration system to examine the influence of operating conditions on the deposition process during crossflow ultrafiltration from a microscopic *** the permeate flux caused an increasing amount of deposition and a thicker deposit *** crossflow velocities reduced the extent of *** degree of deposition varied over a range of operating conditions due to the altered hydrodynamic forces exerted on the particles,which can be examined by the deposition probability according to an existing *** on this,an empirical correlation between the deposition probability and volume of deposition as a function of filtration time was developed,which gave good agreement with experimental *** effect of solution conditions was also involved in this correlation as a interaction *** could be useful for predicting the dynamic deposition process during crossflow filtration over a range of operating and solution conditions.

关键词： particle deposition crossflow filtration microfluidics confocal microscopy

Numerical Simulation of Microphysics in Meso-β-Scale Convective Cloud System Associated with a Mesoscale Convective Complex

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Advances in Atmospheric Sciences 1990年第2期7卷 154-170页

作者：范蓓芬叶家东 William r.Cotton gregory j.Tripoli Department of Atmospheric Sciences Nanjing University Nanjing 210008 Department of Atmospheric Sciences Fort Collins CO 80523 U.S.A. University of Wisconsin

Numerical simulation of meso-β-scale convective cloud systems associated with a PrE-STOrM MCC case has been carried out using a 2-D version of the CSU regional Atmospheric Modeling System (rAMS) nonhydrostatic model with parameterized microphysics. It is found that the predicted meso-r-scale convective phenomena arc basically unsteady under the situation of strong shear at low-levels, while the meso-β-scale convective system is maintained up to 3 hours or more. The meso -β- scale cloud system exhibits characteristics of a multi-celled convective storm in which the meso-r-scale convective cells have lifetime of about 30 min. Pressure perturbation depicts a meso-low after a half hour in the low levels. As the cloud system evolves, the meso-low intensifies and extends to the upshear side and covers the entire domain in the mid-lower levels with the peak values of 5-8 hPa. Temperature perturbation depicts a warm region in the middle levels through the entire simulation period. The meso-r-scale warm cores with peak values of 4-8 ℃ are associated with strong convective cells. The cloud top evaporation causes a stronger cold layer around the cloud top *** of microphysics exhibits that graupel is primarily concentrated in the strong convective cells forming the main source of convective rainfall after one hour of simulation time. Aggregates are mainly located in the stratiform region and decaying convective cells which produce the stratiform rainfall. riming of the ice crystals is the predominant precipitation formation mechanism in the convection region, whereas aggregation of ice crystals is the predominant one in the stratiform region, which is consistent with observations. Sensitivity experiments of ice-phase mierophysical processes show that the microphysical structures of the convective cloud system can be simulated better with the diagnosed aggregation collection efficiencies.

关键词： Numerical Simulation of Microphysics in Meso Scale Convective Cloud System Associated with a Mesoscale Convective Complex Simulation

Alteration in immune function in patients with fatty liver disease

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Hepatoma research 2022年第1期8卷 363-375页

作者： Stephanie N.gregory Shruthi r.Perati Zachary j.Brown Department of Surgery Rutgers Robert Wood Johnson Medical SchoolNew BrunswickNJ 08901USA Division of Surgical Oncology Department of SurgeryThe Ohio State University Wexner Medical CenterColumbusOH 43210USA

Nonalcoholic fatty liver disease(NAFLD)is a disease spectrum that spans simple steatosis,fibrosis,and ultimately cirrhosis,and is a leading cause of chronic liver disease *** severe variant of NAFLD,non-alcoholic steatohepatitis(NASH),is characterized by triglyceride accumulation within hepatocytes and the subsequent inflammatory pathway activation,ultimately progressing to cirrhosis in 10%-20%of *** is a known major risk factor for the development of hepatocellular carcinoma(HCC),and there is emerging data demonstrating the impact of NASH on immune subsets and the tumor microenvironment that may influence therapeutic *** review describes the various ways in which the immune system is altered in patients with *** innate immune system in NASH shows alterations in dendritic and Kupffer cells,impaired cytotoxicity of Natural Killer cells,and an accumulation of ***,there is emerging evidence emphasizing the role of the adaptive immune system in the development and progression of NASH,seen in the alteration of B-cells,T-cells,and NKT *** to the complex interplay of the immune system in NAFLD/NASH and its progression to HCC,many current treatments focus on targeting immune cells for HCC ***,immune checkpoint inhibitors such as atezolizumab and bevacizumab have been approved as first-line therapy for unresectable *** an emerging field of research,further studies and clinical trials are needed to understand the complex interface of NASH,HCC and the immune response.

关键词： Non-alcoholic steatohepatitis nonalcoholic fatty liver disease steatohepatitis immunology hepatocellular carcinoma