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Impaired glymphatic function in the early stages of disease in a TDP-43 mouse model of amyotrophic lateral sclerosis

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Translational Neurodegeneration 2022年第1期11卷 707-717页

作者： Akram Zamani Adam K.Walker Ben Rollo katie l.ayers Raysha Farah Terence J.O’Brien David K.Wright Department of Neuroscience Central Clinical SchoolMonash UniversityMelbourneVIC 3004Australia Queensland Brain Institute The University of QueenslandSt LuciaQLD 4072Australia The Murdoch Children’s Research Institute The Royal Children’s HospitalParkvilleVIC 3052Australia Department of Pediatrics The University of MelbourneParkvilleVIC 3052Australia Department of Medicine The Royal Melbourne HospitalThe University of MelbourneParkvilleVIC 3052Australia

Background: Multiple lines of evidence suggest possible impairment of the glymphatic system in amyotrophic lateral sclerosis (AlS). To investigate this, we used in vivo magnetic resonance imaging (MRI) to assess glymphatic func-tion early in the course of disease in a transgenic mouse with doxycycline (Dox)-controlled expression of cytoplasmic human TDP-43 (hTDP-43ΔNlS), mimicking the key pathology implicated in AlS. Methods: Adult TDP-43 transgenic and littermate monogenic control mice underwent longitudinal multimodal MRI one and three weeks after the cessation of Dox feed, together with weekly rotarod assessments of motor per-formance. Glymphatic function was assessed using dynamic contrast-enhanced MRI to track the clearance of an MR contrast agent injected into the cisterna magna. Results: Compared to their littermate controls, TDP-43 mice exhibited progressive neurodegeneration including that within the primary motor cortex, primary somatosensory cortex and corticospinal tract, significant weight loss includ-ing gastrocnemius atrophy, and shortened telomere length. Furthermore, in the presence of this AlS-like phenotype, these mice have significantly disrupted glymphatic function. Conclusions: Although the relationship between glymphatic clearance and AlS disease progression remains to be elucidated, these changes occurred very early in the disease course. This provides initial evidence to suggest that the glymphatic system might be a potential therapeutic target in the treatment of AlS.

关键词： Magnetic resonance imaging Diffusion-weighted imaging Neurodegeneration Cerebrospinal fluid Telomere

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Clinical lesson learned from genetic analysis in patients prior to surgical repair of hypospadias

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Asian Journal of Urology 2022年第2期9卷 186-189页

作者： Nurin A.listyasari Gorjana Robevska katie l.ayers Tiong Yang Tan Andrew H.Sinclair Sultana M.H.Faradz Division of Human Genetics Center for Biomedical ResearchFaculty of Medicine Diponegoro UniversitySemarangIndonesia Murdoch Children’s Research Institute MelbourneAustralia Department of Paediatrics University of MelbourneMelbourneAustralia Victorian Clinical Genetics Services Murdoch Children’s Research InstituteMelbourneAustralia Diponegoro National Hospital SemarangIndonesia

In Indonesia,undervirilisation in 46,XY males is the most common form of difference of sex development(DSD).This can include hypospadias(misplacement of the urethra),micropenis,bifid scrotum,and undescended testis[1].Undervirilisation or 46,XY DSD can be associated with a number of congenital syndromes,including Smith-lemli-Opitz Syndrome(OMIM 602858),caused by an inborn error of cholesterol synthesis,and characterised by growth delay,intellectual disability,microcephaly,distinctive facial features,cleft palate,limb anomalies,and hypospadias[2]or Opitz syndrome(also known as Opitz G/BBB syndrome).Opitz syndrome can be caused by variants in the X-linked midline 1(MID1)gene(Type I)or in an autosomal dominant manner by monoallelic variants in sperm antigen with calponin homology and coiled-coil domains 1-like(SPECC1l)on chromosome 22q11.2(Type II)[3].Opitz syndrome is characterised by hypospadias,hypertelorism,cleft lip/palate,and heart defects[4].The prevalence of X-linked Opitz syndrome is estimated to be from 1 in 50000 to 1 in 100000 males[5].Recognition of a syndrome informs appropriate clinical management and patient ***,although these syndromes are rare,hypospadias may be diagnosed before the emergence of other comorbidities meaning that it is crucial for clinicians to perform a thorough clinical evaluation with syndromic causes in mind.

关键词： cholesterol analysis prior

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Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors

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Eye and Vision 2016年第1期3卷 263-282页

作者： katie l.Pennington Margaret M.DeAngelis Department of Ophthalmology John A.Moran Eye CenterUniversity of UtahSalt Lake CityUTUSA

Age-related macular degeneration(AMD)is the leading cause of irreversible blindness in adults over 50 years ***,epidemiological,and molecular studies are beginning to unravel the intricate mechanisms underlying this complex disease,which implicate the lipid-cholesterol pathway in the pathophysiology of disease development and *** of the genetic and environmental risk factors associated with AMD are also associated with other complex degenerative diseases of advanced age,including cardiovascular disease(CVD).In this review,we present epidemiological findings associating AMD with a variety of lipid pathway genes,cardiovascular phenotypes,and relevant environmental *** a number of studies showing significant associations between AMD and these lipid/cardiovascular factors,results have been mixed and as such the relationships among these factors and AMD remain *** is imperative that researchers not only tease out the various contributions of such factors to AMD development but also the connections between AMD and CVD to develop optimal precision medical care for aging adults.

关键词： Atherosclerosis Hypertension Retina Statins Stroke Cholesterol Obesity BMI Antioxidants Genetic association

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THE CARE AND FEEDING OF A lONG-TERM INSTITUTIONAl COMMITMENT TO GREEN STORMWATER INFRASTRUCTURE: A CASE STUDY AT THE UNIVERSITY OF CONNECTICUT

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Journal of Green Building 2015年第3期10卷 1-13页

作者： Michael E.Dietz Chester l.Arnold katie D.Milardo Richard A.Miller Center for land Use Education and Research at the University of Connecticut Office of Environmental Policy at the University of Connecticut

In 2007,the Connecticut Department of Energy and Environmental Protection issued the first Total Maximum Daily load(TMDl)in the country based not on a specific pollutant or pollutants,but on impervious cover(IC)(Arnold et al.,2010).The water body in question was Eagleville Brook,a small tributary of the Willimantic River in eastern Connecticut that drains a majority of the University of Connecticut *** university is in effect a small city within a largely rural *** as a result of this,there has been a history of“town-gown”tension and controversy with regard to the university’s impact on the water resources of the *** tension reached a climax in September 2005,when a quarter-mile stretch of the Fenton River,which drains the part of campus not in the Eagleville watershed,ran dry(Merritt,2005).Water quantity concerns were frequently joined by water quality concerns,with area residents complaining about the pollution of their drinking water(Morse,2002).Although the Fenton incident precipitated increased efforts on the part of the university to conserve water,efforts to improve the way that campus addressed stormwater issues lagged behind until the advent of the impervious cover *** the intervening eight years since the issuance of the“IC-TMDl”-practically the wink of an eye in the deliberate world of land use decision making-the University of Connecticut campus has become a showcase for green stormwater infrastructure(GSI)practices,also known as low impact development(lID)*** the IC-TMDl served as the catalyst,an environmental regulation,no matter how innovative,cannot in itself produce such dramatic *** this to occur a number of interconnected efforts have to come together,including leadership,research,monitoring,coordination,and education both within and without the university *** paper is an attempt to capture these key elements,consider why they worked(or didn’t),and provide a status report on green storm-water

关键词： green stormwater infrastructure low impact development university

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Recent developments in topoisomerase-targeted cancer chemotherapy

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Acta Pharmaceutica Sinica B 2018年第6期8卷 844-861页

作者： Kirk E.Hevener Tatsiana A.Verstak katie E.lutat Daniel l.Riggsbee Jeremiah W.Mooney Department of Pharmaceutical Sciences University of Tennessee Health Science Center

The DNA topoisomerase enzymes are essential to cell function and are found ubiquitously in all domains of life. The various topoisomerase enzymes perform a wide range of functions related to the maintenance of DNA topology during DNA replication, and transcription are the targets of a wide range of antimicrobial and cancer chemotherapeutic agents. Natural product-derived agents, such as the camptothecin, anthracycline, and podophyllotoxin drugs, have seen broad use in the treatment of many types of cancer. Selective targeting of the topoisomerase enzymes for cancer treatment continues to be a highly active area of basic and clinical research. The focus of this review will be to summarize the current state of the art with respect to clinically used topoisomerase inhibitors for targeted cancer treatment and to discuss the pharmacology and chemistry of promising new topoisomerase inhibitors in clinical and preclinical development.

关键词： Topoisomerase Inhibition Cancer Oncology Clinical Pre-clinical

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Geographic segregation and evidence of density-dependent changes in sex ratios in an abundant colonial waterbird

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Integrative Zoology 2014年第5期9卷 570-582页

作者： Brian S.DORR katie C.HANSON-DORR Travis l.DeVAUlT Alban GUIllAUMET Scott C.BARRAS United States Department of Agriculture Wildlife Services(USDA-WS)National Wildlife Research CenterMississippi Field StationMississippi StateMississippiUSA USDA-WS National Wildlife Research CenterOhio Field StationSanduskyOhioUSA Department of Wildlife Fisheries and AquacultureMississippi State UniversityMississippi StateMississippiUSA USDA-WS MoseleyVirginiaUSA University of Hawaii Office of Research/PIPESHiloHIUSA.

Demographic information,such as geographic segregation of sexes and sex ratio data,is needed to develop,model and evaluate conservation and management strategies for wildlife.A variety of physiological,behavioral and environmental factors can influence segregation of sexes and sex ratios,many of which originate with density-dependent *** from 50:50 sex ratios of double-crested cormorants(Phalacrocorax auritus)collected during control efforts in breeding and wintering areas across their eastern range of the USA were evaluated using using a Z-test as well as Stouffer’s weighted *** addition,a specifically-designed randomization test was used to evaluate density-dependent effects on primary sex ratios in cormorants from egg collections and colony nest count data over a 21-year *** collected from breeding colonies were strongly male-biased,whereas cormorants collected from feeding flocks were slightly biased toward *** were partly segregated by sex on the wintering grounds,with significantly more males found in areas with intensive channel catfish *** null hypothesis that females produced a balanced sex ratio independent of number of nesting cormorants was rejected:more male embryos were produced during rapid population growth,whereas at maximum nesting number more female embryos were *** populations stabilized,the sex ratio was more *** examination of sex ratios indicates that different management methods and locations result in sex-biased culling of ***-biased culling in cormorants could make population reduction efforts more efficient and reduce overall *** suggest further research to examine density-dependent effects on primary sex ratios documented here.

关键词： Ashmole’s halo management Phalacrocorax auritus population growth sex ratio theory

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Time-lapse videography reveals different morphokinetic profiles of human embryos displaying direct or reverse cleavage at different stages of development: A retrospective sibling embryo study

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Asian pacific Journal of Reproduction 2020年第6期9卷 261-266页

作者： Chloé Brits katie Feenan Vince Chapple Phillip l.Matson Yan-he liu School of Medical and Health Science Edith Cowan UniversityJoondalupWestern AustraliaAustralia Fertility Specialists of Western Australia ClaremontWestern AustraliaAustralia Fertility North Joondalup Private HospitalJoondalupWestern AustraliaAustralia School of Human Sciences University of Western AustraliaCrawleyWestern AustraliaAustralia Monash IVF Group SouthportQueenslandAustralia

Objective:To investigate morphokinetic characteristics of embryos displaying either reverse cleavage or direct cleavage during the first,second or third cleavage ***:A total of 167 in vitro fertilization and/or intracytoplasmic sperm injection treatment cycles undertaken by 167 women[aged(35.0±4.6)years]were included for reverse cleavage analysis,and a total of 167 in vitro fertilization and/or intracytoplasmic sperm injection treatment cycles undertaken by 167 women[aged(33.8±4.3)years]were included for direct cleavage analysis in this *** a sibling-embryo design,morphokinetic profiles(both before and after the onset of abnormal event)of embryos displaying reverse cleavage(n=241)or direct cleavage(n=244)were compared with their unaffected siblings(the controls)in the first,second and third cell cycles(n=32,n=142,n=562;n=195,n=412,n=205,respectively),at different developmental stages up to day ***:Direct cleavage embryos demonstrated significantly delayed cleavage rates prior to the event regardless of developmental stage of the occurrence,while reverse cleavage embryos showed similar cleavage rates to their unaffected *** event,direct cleavage embryos sped up cleavage rates while reverse cleavage embryos slowed ***:Altered morphokinetic profiles are displayed by direct cleavage embryos both before and after their occurrence and reverse cleavage embryos after the occurrence,which could potentially confound morphokinetic comparisons if not separated from their unaffected sibling *** study is warranted in order to fully understand the biological mechanisms of such events.

关键词： Time-lapse Direct cleavage Reverse cleavage Morphokinetics Cleavage abnormality

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Targeting multiple signaling pathways:the new approach to acute myeloid leukemia therapy

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Signal Transduction and Targeted Therapy 2021年第1期6卷 41-69页

作者： Jenna lCarter katie Hege Jay Yang Hasini AKalpage Yongwei Su Holly Edwards Maik Hüttemann Jeffrey WTaub Yubin Ge Cancer Biology Graduate Program Wayne State University School of MedicineDetroitMIUSA MD/PhD Program Wayne State University School of MedicineDetroitMIUSA Department of Oncology Wayne State University School of MedicineDetroitMIUSA Molecular Therapeutics Program Barbara Ann Karmanos Cancer InstituteWayne State University School of MedicineDetroitMIUSA Center for Molecular Medicine and Genetics Wayne State University School of MedicineDetroitMIUSA National Engineering laboratory for AIDS Vaccine Key Laboratory for Molecular Enzymology and EngineeringThe Ministry of EducationSchool of Life SciencesJilin UniversityChangchunChina Division of Pediatric Hematology/Oncology Children’s Hospital of MichiganDetroitMIUSA Department of Pediatrics Wayne State University School of MedicineDetroitMIUSA

Acute myeloid leukemia(AMl)is the most common form of acute leukemia in adults and the second most common form of acute leukemia in *** this,very little improvement in survival rates has been achieved over the past few *** is partially due to the heterogeneity of AMl and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 *** the past 20 years,research has been diversifying the approach to treating AMl by investigating molecular pathways uniquely relevant to AMl cell proliferation and *** we review the development of novel therapeutics in targeting apoptosis,receptor tyrosine kinase(RTK)signaling,hedgehog(HH)pathway,mitochondrial function,DNA repair,and c-Myc *** has been an impressive effort into better understanding the diversity of AMl cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AMl *** addition,we describe clinical investigations that have led to FDA approval of new targeted AMl therapies and ongoing clinical trials of novel therapies targeting AMl survival *** also describe the complexity of targeting leukemia stem cells(lSCs)as an approach to addressing relapse and remission in AMl and targetable pathways that are unique to lSC *** comprehensive review details what we currently understand about the signaling pathways that support AMl cell survival and the exceptional ways in which we disrupt them.

关键词： myeloid approach approval

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Biodegradable elastomeric circuit boards from citric acid-based polyesters

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npj Flexible Electronics 2023年第1期7卷 307-320页

作者： Brendan l.Turner Jack Twiddy Michael D.Wilkins Srivatsan Ramesh katie M.Kilgour Eleo Domingos Olivia Nasrallah Stefano Menegatti Michael A.Daniele Joint Department of Biomedical Engineering North Carolina State University and University of North CarolinaChapel Hill911 Oval Dr.RaleighNC 27695USA Department of Electrical&Computer Engineering North Carolina State University890 Oval Dr.RaleighNC 27695USA Department of Chemical and Biomolecular Engineering North Carolina State University911 Partners WayRaleighNC 27695USA Biomanufacturing Training and Education Center(BTEC) North Carolina State University850 Oval DrRaleighNC 27606USA

Recyclable and biodegradable microelectronics,i.e.,“green”electronics,are emerging as a viable solution to the global challenge of electronic ***,flexible circuit boards represent a prime target for materials development and increasing the utility of green electronics in biomedical *** board substrates and packaging are good dielectrics,mechanically and thermally robust,and are compatible with microfabrication ***(octamethylene maleate(anhydride)citrate)(POMaC)–a citric acid-based elastomer with tunable degradation and mechanical properties–presents a promising alternative for circuit board substrates and ***,we report the characterization of Elastomeric Circuit Boards(ECBs).Synthesis and processing conditions were optimized to achieve desired degradation and mechanical properties for production of stretchable *** traces were characterized and exhibited sheet resistance of 0.599Ωcm^(−2),crosstalk distance ofle 0%strain resistances after 1000 strain cycles to 20%.Fabrication of single layer and encapsulated ECBs was demonstrated.

关键词： polyester resistance strain

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Hematopoietic stem cell-derived adipocytes and fibroblasts in the tumor microenvironment

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World Journal of Stem Cells 2015年第2期7卷 253-265页

作者： Ying Xiong lindsay T Mc Donald Dayvia l Russell Ryan R Kelly katie R Wilson Meenal Mehrotra Adam C Soloff Amanda C laRue Research Services Ralph H Johnson Veterans Affairs Medical Center Department of Pathology and laboratory Medicine Ralph H Johnson Veterans Affairs Medical Center the Hollings Cancer Center Medical University of South CarolinaRalph H Johnson Veterans Affairs Medical Center Department of Microbiology and Immunology Ralph H Johnson Veterans Affairs Medical Center

The tumor microenvironment(TME) is complex and constantly evolving. This is due, in part, to the crosstalk between tumor cells and the multiple cell types that comprise the TME, which results in a heterogeneous population of tumor cells and TME cells. This review will focus on two stromal cell types, the cancerassociated adipocyte(CAA) and the cancer-associated fibroblast(CAF). In the clinic, the presence of CAAs and CAFs in the TME translates to poor prognosis in multiple tumor types. CAAs and CAFs have an activated phenotype and produce growth factors, inflammatory factors, cytokines, chemokines, extracellular matrix components, and proteases in an accelerated and aberrant fashion. Through this activated state, CAAs and CAFs remodel the TME, thereby driving all aspects of tumor progression, including tumor growth and survival, chemoresistance, tumor vascularization, tumor invasion, and tumor cell metastasis. Similarities in the tumorpromoting functions of CAAs and CAFs suggest that a multipronged therapeutic approach may be necessary to achieve maximal impact on disease. While CAAs and CAFs are thought to arise from tissues adjacent to the tumor, multiple alternative origins for CAAs and CAFs have recently been identified. Recent studies from our lab and others suggest that the hematopoietic stem cell, through the myeloid lineage, may serve as a progenitor for CAAs and CAFs. We hypothesize that the multiple origins of CAAs and CAFs may contribute to the heterogeneity seen in the TME. Thus, a better understanding of the origin of CAAs and CAFs, how this origin impacts their functions in the TME, and thetemporal participation of uniquely originating TME cells may lead to novel or improved anti-tumor therapeutics.

关键词： Hematopoietic stem cell Cancer associatedadipocyte Mesenchymal stromal cell Tumor progression Cancer associated fibroblast Plasticity Metastasis Fibrocyte

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