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Parkinson's disease: From genetics to molecular dysfunction and targeted therapeutic approaches

Genes & Diseases 2023年第3期10卷 786-798页

作者： Yue Huang jun Wei Antony Cooper margaret j.morris China National Clinical Research Center for Neurological Diseases Beijing Tiantan HospitalCapital Medical UniversityBeijing 100070China Department of Neurology Beijing Tiantan HospitalCapital Medical UniversityBeijing 100070China Department of Pharmacology School of Medical SciencesFaculty of Medicine&HealthUNSWSydneyNSW 2052Australia The Garvan Institute of Medical Research SydneyNSW 2010Australia St Vincent's Clinical School Faculty of Medicine&Healthand School of Biotechnology and Biomolecular SciencesFaculty of ScienceUNSWSydneyNSW 2052Australia

Parkinson's disease (PD) is the most common neurodegenerative movement disorder in the elderly. As the pathogenesis of PD is still not fully understood, medications with the capacity of halting the disease progression are currently unavailable. The discovery of genes that are causative for, or increase susceptibility to PD is pivotal for the development of novel therapeutic approaches, as they are critical for the onset of PD and the molecular pathways underlying its pathogenesis. By reviewing relevant data, we discuss causative genes, and those associated with PD susceptibility and quantitative traits. Through Gene Ontology database and STRING analysis, we emphasize the roles of inorganic cation transmembrane transport pathways and hypothalamic pituitary thyroid axis, in addition to the established roles of inflammation/oxidative stress and mitochondrial dysfunction in the pathogenesis of PD. It is hoped these insights 1) untangle the clinical complex presentations of PD, 2) reveal the interwoven molecular network leading to PD, and 3) identify critical molecular targets to facilitate novel PD drug discovery, with a view to providing improved consultation and personalized medicine for patients with PD in the future.

关键词： Drug discovery Genetics Molecular function Parkinson's disease Quantitative traits

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Obesity-induced sperm DNA methylation changes at satellite repeats are reprogrammed in rat offspring

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Asian journal of Andrology 2016年第6期18卷 930-936页

作者： Neil A Youngson Virginie Lecomte Christopher A Maloney Preston Leung jia Liu Luke B Hesson Fabio Luciani Lutz Krause margaret j morris Department of Pharmacology School of Medical Sciences UNSW Australia Sydney NSW 2052 Australia Inflammation and Infection Research School of Medical Sciences UNSW Australia Sydney NSW 2052 Australia Adult Cancer Program Lowy Cancer Research Centre and Prince of Wales Clinical School UNSW Australia Sydney NSW 2052 Australia QIMR Berghofer Medical Research Institute Herston Brisbane Queensland 4006 Australia University of Queensland Diamantina Institute Translational Research Institute University of Queensland 37 Kent Street Woolleongabba Queensland 4102 Australia

There is now strong evidence that the paternal contribution to offspring phenotype at fertilisation is more than just DNA. However, the identity and mechanisms of this nongenetic inheritance are poorly understood. One of the more important questions in this research area is： do changes in sperm DNA methylation have phenotypic consequences for offspring？ We have previously reported that offspring of obese male rats have altered glucose metabolism compared with controls and that this effect was inherited through nongenetic means. Here, we describe investigations into sperm DNA methylation in a new cohort using the same protocol. Male rats on a high-fat diet were 30% heavier than control-fed males at the time of mating （16-19 weeks old, n = 14/14）. A small （0.25%） increase in total 5-methyl-2＇-deoxycytidine was detected in obese rat spermatozoa by liquid chromatography tandem mass spectrometry. Examination of the repetitive fraction of the genome with methyI-CpG binding domain protein-enriched genome sequencing （MBD-Seq） and pyrosequencing revealed that retrotransposon DNA methylation states in spermatozoa were not affected by obesity, but methylation at satellite repeats throughout the genome was increased. However, examination of muscle, liver, and spermatozoa from male 27-week-old offspring from obese and control fathers （both groups from n = 8 fathers） revealed that normal DNA methylation levels were restored during offspring development. Furthermore, no changes were found in three genomic imprints in obese rat spermatozoa. Our findings have implications for transgenerational epigenetic reprogramming. They suggest that postfertilization mechanisms exist for normalising some environmentally-induced DNA methylation changes in sperm cells.

关键词： methylation obesity spermatozoa

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Mechanisms behind early life nutrition and adult disease outcome

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World journal of Diabetes 2011年第8期2卷 127-132页

作者： Elena Velkoska margaret j morris Department of Medicine The University of Melbourne Heidelberg Repatriation Hospital Heidelberg Heights 3081 Victoria Australia Department of Pharmacology School of Medical Sciences University of New South Wales 2052 New South Wales Australia

Obesity is increasing around the globe. While adult lifestyle factors undoubtedly contribute to the incidence of obesity and its attendant disorders, mounting evidence suggests that programming of obesity may occur following underand over-nutrition during development. As hypothalamic control of appetite and energy expenditure is set early in life and can be perturbed by certain exposures such as under nutrition and altered metabolic and hormonal signals, in utero exposure to altered maternal nutrition and inadequate nutrition during early postnatal life may contribute to programming of obesity in offspring. Data from animal studies indicate both intrauterine and postnatal environments are critical determinants of the development of pathways regulating energy homeostasis. This review summarizes recent evidence of the impact of maternal nutrition as well as postnatal nutrition of the offspring on subsequent obesity and disease risk of the offspring. While much of the experimental work reviewed here was conducted in the rodent, these observations provide useful insights into avenues for future research into developing preventive measures to curb the obesity epidemic.

关键词： Maternal obesity Programming Postnatal overnutrition Postnatal undernutrition Leptin Neuropeptide Y

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Circumcision reduces prostate cancer risk

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Asian journal of Andrology 2012年第5期14卷 661-662页

作者： Brian j morris lake H Waskett School of Medical Sciences University of SydneySydney NSW 2006 Australia CircumcisionIndependent Reference and Commentary Service Manchester M26 1JR UK

There is a strong negative correlation between prostate cancer and circumcision rate across 181 countries （P〈0.0001）. Adding to the large protective effect of cir- cumcision seen in small studies over the past six decades, a recent large study in Seattle has shown a smaller protective effect. If verified by other large studies else- where, the finding would add to the wide array of benefits conferred by this safe, sim- ple procedure that is best performed in infancy.

关键词： INFECTION

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Overcoming maladaptive plasticity through plastic compensation

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Current Zoology 2013年第4期59卷 526-536页

作者： Matthew R.j. morris Sean M. ROGERS Department of Biological Sciences University of Calgary Calgary AB Canada T2N 1N4

Most species evolve within fluctuating environments, and have developed adaptations to meet the challenges posed by environmental heterogeneity. One such adaptation is phenotypic plasticity, or the ability of a single genotype to produce multiple environmentally-induced phenotypes. Yet, not all plasticity is adaptive. Despite the renewed interest in adaptive phenotypic plas- ticity and its consequences for evolution, much less is known about maladaptive plasticity. However, maladaptive plasticity is likely an important driver of phenotypic similarity among populations living in different environments. This paper traces four strategies for overcoming maladaptive plasticity that result in phenotypic similarity, two of which involve genetic changes （standing genetic variation, genetic compensation） and two of which do not （standing epigenetic variation, plastic compensation）. Plastic compensation is defined as adaptive plasticity overcoming maladaptive plasticity. In particular, plastic compensation may increase the likelihood of genetic compensation by facilitating population persistence. We provide key terms to disentangle these aspects of phenotypic plasticity and introduce examples to reinforce the potential importance of plastic compensation for under- standing evolutionary change

关键词： Homeostasis Canalization Ecological speciation Standing genetic variation Genetic compensation Countergradi-ent variation

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Reply to Letter by Dr. Christoph Kupferschmid： Commentary on ＂Countries with high circumcision prevalence have lower prostate cancer mortality＂

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Asian journal of Andrology 2016年第6期18卷 950-951页

作者： Mitchell S Wachtel Shengping Yang Brian j morris Texas Tech University Health Sciences Center Lubbock Texas USA School of Medical Sciences University of Sydney Sydney New South Wales Australia

Dear Editor, We thank Dr. Kupferschmid for his interest in our study, which examined male circumcision （MC） and prostate cancer mortality〉2 Considerable strong evidence has been accumulated since 1951.3 Most of his references4-10 do not address MC and the risk of death from prostate cancer. That is a different question than MC and the risk of developing prostate cancer, which none of his references validly assess. One reference addressed bacterial colonization,6 not prostate cancer. Another7 concerned sexually transmitted infections and prostate cancer.

关键词： EPIDEMIOLOGY RISK

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Dominant species of mid-elevation grasslands of the uKhahlamba-Drakensberg Park are predicted to be largely immune to climate change

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山地科学学报(英文) 2023年第9期20卷 2468-2486页

作者： Debbie jEWITT Craig D.morris Tim G.O’CONNOR Michelle j.TEDDER Ezemvelo KZN Wildlife Scientific ServicesPO Box 13053Cascades 3202South Africa School of Animal Plant and Environmental SciencesUniversity of the WitwatersrandJohannesburgPrivate Bag X3WITS 2050South Africa Agricultural Research Council-Animal Production(ARC-AP) ℅School of Life Sciences University of KwaZulu-NatalPrivate Bag X01Scottsville 3209PietermaritzburgSouth Africa School of Life Sciences University of KwaZulu-NatalPrivate Bag X01Scottsville 3209PietermaritzburgSouth Africa

Anticipating global change impact on natural vegetation,especially in poorly researched systems,requires an understanding of the environmental factors that most strongly influence the organisation of plant communities at different *** environmental relations of plant communities in the Drakensberg mountains of South Africa remain poorly *** study investigated the influence of selected environmental determinants on the dominant species of plant community organisation in this *** order to provide an overview of the influence of the environment on botanical composition and plant diversity,this study,conducted as four discrete exercises,investigated the interplay of altitude,aspect and slope on the abundance of selected species,and to examine the influence of latitude,geological substrate and local topography on species *** diversity showed no pattern of response to investigated environmental *** composition was related to temperature and solarradiation *** altitude sites facing east were distinct for non-graminoid *** and latitude exerted a pronounced effect on species composition,confounded by longitude and precipitation *** substrate,in concert with slope steepness and orientation,influenced composition,restricting the abundance but not distribution of some *** individualistic responses were found for C_3,C_4,and non-graminoid species in relation to altitude,slope and *** and aspect mediate the effects of altitude and hence temperature for some *** study has demonstrated the complexity of drivers influencing species and compositional distribution in the Drakensberg and permits a preliminary consideration of potential changes in the composition and dominance structure of mid-elevation grasslands in response to climate *** dominant grass species were widespread across environmental gradients,occupying currently warm,cool,moist and dry habitats

关键词： Drakensberg Environmental gradients Grasslands Mountain biodiversity Vegetation

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Pancreaticopleuralfistula:etiology,treatmentandlong-termfollow-up

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Hepatobiliary & Pancreatic Diseases International 2012年第2期11卷 215-219页

作者： Keith j Roberts Maria Sheridan Gareth morris-Stiff Andrew M Smith Department of Pancreatic Surgery St James University HospitalLeedsUK

BACKGROUND:Pancreaticopleural fistula(PPF) are *** multidisciplinary treatment is required due to nutritional compromise and *** is the first description of long-term follow-up of patients with ***:Eleven patients with PPF treated at a specialist unit were ***,investigation,treatment and outcomes were ***:Pancreatitis was the etiology of the PPF in 9 patients,and in the remaining 2 the PPF developed following distal ***-sectional imaging demonstrated the site of duct disruption in 10 cases,with endoscopic retrograde cholangiopancreatography identifying the final *** of pancreatic exocrine secretion and percutaneous drainage formed the mainstay of *** cases resolved following pancreatic duct stent insertion and three patients required surgical treatment for established *** were no *** all cases that resolved there has been no recurrence of PPF over a median follow-up of 50 months(range 15-62).CONCLUSIONS:PPF is an uncommon event complicating pancreatitis or pancreatectomy;pancreatic duct disruption is the common link.A step-up approach consisting of minimally invasive techniques treats the majority with surgery needed for refractory sepsis.

关键词： pancreatic disease pancreatitis pancreatic pseudocyst

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Fishing for Atlantic cod (Gadus morhua) with pots and gillnets: A catch comparison study along the southeast coast of Labrador

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Aquaculture and Fisheries 2022年第4期7卷 433-440页

作者： Khanh Q.Nguyen Corey j.morris Fisheries and Oceans Canada Northwest Atlantic Fisheries CentreSt.John’sNewfoundlandA1C5X1Canada

Gillnets are the primary fishing gear used to catch Atlantic cod(Gadus morhua)in coastal areas of Newfoundland and Labrador but are known to catch non-target species and produce lower quality fish than live-catch *** purpose of this study was to compare the catch efficiency of collapsible cod pots against gillnets near the Gilbert Bay Marine Protected Area(MPA),Labrador,where a reduction in by-catch is *** showed that one cod pot caught half as much Atlantic cod as a gillnet,and pots had a relatively stable catch rate throughout the sampling period,whereas gillnets caught relatively few fish later in the sampling ***,nearly all fish sampled with pots were caught alive undamaged,whereas most gillnet-caught fish experienced damage or *** a conservation measure pot-fishing would enable fishing within close proximity to the Gilbert Bay MPA and the live-release of visually distinguishable Gilbert Bay cod,thereby mitigating against the negative effects of commercial fishing on this protected Atlantic cod population.

关键词： Catch rates Cod pots Bycatch reduction Gillnets Conservation Atlantic cod fishery

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Exploding lakes in Vanuatu ＂Surtseyan-style＂ eruptions witnessed on Ambae Island

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Episodes 2006年第2期29卷 87-92页

作者： Károly Németh Shane j. Cronin Douglas Charley morris Harrison Esline Garae Volcanic Risk Solutions Institute of Natural Resources Massey University PO Box 11 222 Palmerston North New Zealand Department of Geology Mines and Water Resources Private Bag Port Vila Vanuatu

After a long silence, Lake Vui on Ambae Island burst into spectacular life on November 28, 2005, disrupting the lives of the 10,000 inhabitants on this sleepy tropical island in the SW Pacific. ＂Surtseyan-style＂ explosions burst through the Island＇s summit lake waters, forming a new tuff-cone, and threatening to form deadly lahars or volcanic floods. Such eruptions are rarely well observed, and these fleeting opportunities provide a chance to match volcanic processes with rock-sequences common in the geologic record...

关键词：瓦努阿图爆发湖泊岛屿

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