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Androgen receptor deficiency in monocytes/ macrophages does not alter adiposity or glucose homeostasis in male mice

Asian journal of Andrology 2018年第3期20卷 276-283页

作者： Katya B Rubinow Barbara Houston Shari Wang Leela Goodspeed Kayoko Ogimoto gregory j morton Christopher McCarty Robert E Braun Stephanie T Page Division of Metabolism Endocrinology and Nutrition Department of Medicine University of Washington School of Medicine Seattle WA 98195 USA jackson Laboratory Bar Harbor ME 04609 USA

Androgen deprivation in men leads to increased adiposity, but the mechanisms underlying androgen regulation of fat mass have not been fully defined. Androgen receptor （AR） is expressed in monocytes/macrophages, which are resident in key metabolic tissues and influence energy metabolism in surrounding cells. Male mice bearing a cell-specific knockout of the AR in monocytes/macrophages （M-ARKO） were generated to determine whether selective loss of androgen signaling in these cells would lead to altered body composition. Wild-type （WT） and M-ARKO mice （12-22 weeks of age, n = 12 per group） were maintained on a regular chow diet for 8 weeks and then switched to a high-fat diet for 8 additional weeks. At baseline and on both the regular chow and high-fat diets, no differences in lean mass or fat mass were observed between groups. Consistent with the absence of differential body weight or adiposity, no differences in food intake （3.0 ± 0.5 g per day for WT mice vs 2.8 ± 0.4 g per day for M-ARKO mice） or total energy expenditure （0.6 ± 0.1 Kcal h-1 for WT mice vs 0.5 ± 0.1 Kcal h-1 for M-ARKO mice） were evident between groups during high-fat feeding. Liver weight was greater in M-ARKO than that in WT mice （1.5 ± 0.1 g vs 1.3 ± 0.0 g, respectively, P = 0.02）. Finally, M-ARKO mice did not exhibit impairments in glucose tolerance or insulin sensitivity relative to WT mice at any study time point. In aggregate, these findings suggest that AR signaling specifically in monocytes/macrophages does not contribute to the regulation of systemic energy balance, adiposity, or insulin sensitivity in male mice.

关键词： androgen receptor knockout mice macrophages male hypogonadism metabolic syndrome

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Diabetes exacerbates inflammatory bowel disease in mice with dietinduced obesity

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World journal of Gastroenterology 2023年第33期29卷 4991-5004页

作者： Kendra L Francis Kimberly M Alonge Maria Cristina Pacheco Shannon j Hu Cody A Krutzsch gregory j morton Michael W Schwartz jarrad M Scarlett Department of Pediatric Gastroenterology and Hepatology Seattle Children’s HospitalSeattleWA 98105United States 不详 Department of Medicinal Chemistry University of WashingtonSeattleWA 98195United States Department of Laboratory Medicine and Pathology Seattle Children's HospitalSeattleWA 98105United States

BACKGROUND The increased prevalence of inflammatory bowel disease(IBD)among patients with obesity and type 2 diabetes suggests a causal link between these diseases,potentially involving the effect of hyperglycemia to disrupt intestinal barrier *** To investigate whether the deleterious impact of diabetes on the intestinal barrier is associated with increased IBD severity in a murine model of colitis in mice with and without diet-induced *** Mice were fed chow or a high-fat diet and subsequently received streptozotocin to induce diabetic-range *** weeks later,dextran sodium sulfate was given to induce *** select experiments,a subset of diabetic mice was treated with the antidiabetic drug dapagliflozin prior to colitis *** included both clinical and histological measures of colitis activity as well as histochemical markers of colonic epithelial barrier *** In mice given a high-fat diet,but not chow-fed animals,diabetes was associated with significantly increased clinical colitis activity and histopathologic markers of disease *** was also associated with a decrease in key components that regulate colonic epithelial barrier integrity(colonic mucin layer content and epithelial tight junction proteins)in diet-induced obese *** of these effects of diabetes in diet-induced obese mice was ameliorated by restoring *** In obese mice,diabetes worsened clinical and pathologic outcomes of colitis via mechanisms that are reversible with treatment of ***-induced intestinal barrier dysfunction offers a plausible mechanism linking diabetes to increased colitis *** findings suggest that effective diabetes management may decrease the clinical severity of IBD.

关键词： Inflammatory bowel disease Type 2 diabetes Obesity Intestinal barrier Hyperglycemia Colitis in mice Tight junction proteins

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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

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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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Liver-gut axis in the regulation of iron homeostasis

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World journal of Gastroenterology 2007年第35期13卷 4737-4745页

作者： Deepak Darshan gregory j Anderson Iron Metabolism Laboratory The Queensland Institute of Medical ResearchBrisbaneAustralia

The human body requires about 1-2 mg of iron per day for its normal functioning, and dietary iron is the only source for this essential metal. Since humans do not possess a mechanism for the active excretion of iron, the amount of iron in the body is determined by the amount absorbed across the proximal small intestine and, consequently, intestinal iron absorption is a highly regulated process. In recent years, the liver has emerged as a central regulator of both iron absorption and iron release from other tissues. It achieves this by secreting a peptide hormone called hepcidin that acts on the small intestinal epithelium and other cells to limit iron delivery to the plasma. Hepcidin itself is regulated in response to various systemic stimuli including variations in body iron stores, the rate of erythropoiesis, inflammation and hypoxia, the same stimuli that have been known for many years to modulate iron absorption. This review will summarize recent findings on the role played by the liver and hepcidin in the regulation of body iron absorption.

关键词： Iron Homeostasis Intestinal iron absorption Liver Hepcidin

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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

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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

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Proteasome inhibition-induces endoplasmic reticulum dysfunction and cell death of human cholangiocarcinoma cells

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World journal of Gastroenterology 2007年第6期13卷 851-857页

作者： Yucel Ustundag Steven F Bronk gregory j Gores Mayo Clinic College of Medicine Rochester MN 55905 United States

AIM: To determine if proteasome inhibition induces apoptosis in human cholangiocarcinoma cells, and if so, to elucidate the cellular mechanisms. METHODS: Studies were performed in the human KMCH, KMBC, and Mz-ChA-1 cholangiocarcinoma, and normal rat cell lines. MG132, a peptide aldehyde, which inhibits the chymotrypsin-like activity of the proteaosome was employed for this study. Apoptosis was assessed morphologically by 4'-6-Diamidino-2-phenylindole (DAPI) nuclear staining and fluorescence microscopy. Mitochondrial membrane potential was examined using a fluorescent unquenching assay. Ultrastructural changes during cell death were examined using transmission electron microscopy (TEM). Caspase 3/7 activity was assessed using an enzymatic-based fluorescent assay. Cytosolic-free calcium concentrations were measured using Fura-2 and digitized fluorescent microscopy. RESULTS: MG132, a proteasome inhibitor, induced apoptosis in all the cholangiocarcinoma cell lines examined. In contrast, minimal cytotoxicity was observed in normal rat cholangiocytes. Apoptosis was time-and -concentration-dependent. There was no change in the mitochondrial membrane potential between treated and untreated cells. Ultrastructural examination by transmission electron microscopy displayed the classic features of apoptosis, but in addition, there was also dramatic vacuolization of the endoplasmic reticulum (ER). Unexpectedly, no increase in caspase 3/7 activity was observed in MG132 treated cells, nor did the pancaspase inhibitor, Q-VD-OPh prevent cell death. The protein synthesis inhibitor, cycloheximide, blocked apoptosis induced by proteosome inhibitor indicating that ER dysfunction was dependent upon the formation of new proteins. CONCLUSION: Proteosome inhibition induces ERdysfunction and caspase-independent cell death selectively in human cholangiocarcinoma cells. Proteasome inhibitors warrant evaluation as anticancer agents for the treatment of human cholangiocarcinoma.

关键词： MG132 Cholangiocarcinoma Proteosome Apoptosis Calcium

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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

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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

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