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Heterozygous carriers of galactocerebrosidase mutations that cause Krabbe disease have impaired microglial function and defective repair of myelin damage

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Neural Regeneration Research 2018年第3期13卷 393-401页

作者： Nicole j.Scott-Hewitt Christopher j.Folts mark D.Noble Department of Biomedical Genetics University of Rochester School of Medicine and Dentistry

This review addresses two puzzling findings related to mutations in galactocerebrosidase （GALC） that cause Krabbe disease （KD）, a severe lysosomal storage disorder characterized by extensive myelin damage in children with mutations in both GALC alleles. First, heterozygous carriers of KD-causing mutations, which include the biological parents of children with KD, exhibit increased risk for developing other diseases. Second, variants in the GALC locus increase the risk of developing multiple sclerosis （MS）, another disease characterized by extensive myelin damage. What explains these correlations？ In studies on cuprizone-induced myelin damage in heterozygous （GALC＋/–） mice carrying one copy of a mutation that causes KD-like disease, the extent of damage was similar in GALC＋/– and wild-type （WT） mice. In contrast, GALC＋/- mice had striking defects in repair of cuprizone-induced damage. We further found unexpected microglial defects in myelin debris clearance and in the ability to up-regulate the Trem2 microglial protein critical for debris uptake. These defects were rescued by exposure to a lysosomal re-acidifying drug discovered in our studies on KD, and which provides multiple clinically relevant benefits in the twitcher （GALC＋/–） mouse model of KD. Thus, heterozygous GALC mutations cause effects on biological function that may help to understand the increased disease risk in heterozygous carriers of such mutations and to understand why GALC variations increase the risk of MS. Our findings indicate that while some genetic risk factors may contribute to complex diseases by increasing the risk of tissue damage, others may do so by compromising tissue repair.

关键词： vulnerability locus multiple sclerosis Krabbe disease galactocerebrosidase microglia myelin repair lysosomal storage disorders heterozygous carriers Trem2 demyelination

Practical Aspects for Designing Statistically Optimal Experiments

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j.urnal of Statistical Science and Application 2014年第3期2卷 85-92页

作者： mark j. Anderson Patrick j. Whitcomb Stat-Ease Inc. Minneapolis MN USA

Due to operational or physical considerations, standard factorial and response surface method （RSM） design of experiments （DOE） often prove to be unsuitable. In such cases a computer-generated statistically-optimal design fills the breech. This article explores vital mathematical properties for evaluating alternative designs with a focus on what is really important for industrial experimenters. To assess ＂goodness of design＂ such evaluations must consider the model choice, specific optimality criteria （in particular D and I）, precision of estimation based on the fraction of design space （FDS）, the number of runs to achieve required precision, lack-of-fit testing, and so forth. With a focus on RSM, all these issues are considered at a practical level, keeping engineers and scientists in mind. This brings to the forefront such considerations as subj.ct-matter knowledge from first principles and experience, factor choice and the feasibility of the experiment design.

关键词： design of experiments optimal design response surface methods fraction of design space.

Drosophila seizure disorders： genetic suppression of seizure susceptibility

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Frontiers in Biology 2016年第2期11卷 96-108页

作者： Arunesh Saras Laura E. Simon Harlan j. Brawer Richard E. Price mark A. Tanouye Division of Organismal Biology Department of Environmental Science Policy and Management University of California Berkeley CA 94720 USA Department of Molecular and Cell Biology University of California Berkeley CA 94720 USA Helen Wills Neuroscience Institute University of California Berkeley CA 94720 USA

Various Drosophila models of human disease have recently received increased interest. The main goal is to uncover the fundamental biological basis for human pathology taking advantage of the power of Drosophila genetics. This review examines a set of Drosophila seizure-sensitive mutations that model human seizure disorders, especially epilepsy. Also described is a novel set of mutations that act as seizure-suppressors that ameliorate epilepsy phenotypes in double mutant combinations.

关键词： Drosophila epilepsy seizure disorders sodium channel seizttre-suppressor genes

A Lack of Evidence for Global Ram-Pressure Induced Star Formation in the Merging Cluster Abell 3266

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International j.urnal of Astronomy and Astrophysics 2021年第1期11卷 95-132页

作者： mark j. Henriksen Scott Dusek Physics Department University of Maryland Baltimore MD USA

Interaction between the intracluster medium and the interstellar media of galaxies via ram-pressure stripping (RPS) has ample support from both observations and simulations of galaxies in clusters. Some, but not all of the observations and simulations show a phase of increased star formation compared to normal spirals. Examples of galaxies undergoing RPS induced star formation in clusters experiencing a merger have been identified in high resolution optical images supporting the existence of a star formation phase. We have selected Abell 3266 to search for ram-pressure induced star formation as a global property of a merging cluster. Abell 3266 (z = 0.0594) is a high mass cluster that features a high velocity dispersion, an infalling subcluster near to the line of sight, and a strong shock front. These phenomena should all contribute to making Abell 3266 an optimum cluster to see the global effects of RPS induced star formation. Using archival X-ray observations and published optical data, we cross-correlate optical spectral properties ([OII, Hβ]), indicative of starburst and post-starburst, respectively with ram-pressure, ρv2, calculated from the X-ray and optical data. We find that post-starburst galaxies, classified as E + A, occur at a higher frequency in this merging cluster than in the Coma cluster and at a comparable rate to intermediate redshift clusters. This is consistent with increased star formation due to the merger. However, both starburst and post-starburst galaxies are equally likely to be in a low or high ram pressure environment. From this result, we infer that the duration of the starburst phase must be very brief so that: 1) at any time only a small fraction of the galaxies in a high ram pressure environment show this effect, and 2) most post-starburst galaxies are in an environment of low ram pressure due to their continued orbital motion in the cluster.

关键词： X-Ray High Energy Galaxy Evolution Clusters of Galaxies

EXPRESSION OF BCRP GENE IN THE NORMAL LUNG TISSUE AND LUNG CANCER

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Chinese j.urnal of Cancer Research 2001年第1期13卷 22-26页

作者：毛友生 Austin Doyle Weidong Yang Yuetong Wei mark j. Krasna Douglas D. Ross Greenebaum Cancer Center University of Maryland Medical School

Obj.ctive: To investigate the expression of novel multidrug resistance transporter (BCRP gene) from human MCF-7/AdrVp breast cancer cells in normal lung tissue and non-small lung cancer tissue. Methods: RNA was extracted immediately from fresh normal lung tissue and viable tumor tissue harvested from surgically resected specimens of non-small cell lung cancer patients. cDNA of BCRP gene was prepared by RT-PCR and was then amplified by PCR. cDNA products from those specimens were transferred to blotting membrane through electrophoresis and transferring technique and southern blot hybridization was eventually performed to detect the expression of BCRP gene. Results: RNA were extracted from 8 tumor tissue alone and 12 pairs of tumor tissue and normal lung tissue harvested from the same lung. Four patients’ RNA samples with poor quality due to degrading were discarded. cDNA products of BCRP gene were obtained by RT-PCR and were then amplified by PCR in the remain 16 patients’ RNA samples. Through southern blot hybridization, BCRP gene was found to be slightly expressed in various amounts in all normal lung tissue (10/10) and only in a half of tumor tissue samples (8/16). Conclusion: BCRP gene is slightly expressed in different amount in all normal lung tissue and only in a half of tumor tissue of non-small cell lung cancer patients. It is possible to induce it’s overexpression and to develop multidrug resistance during chemotherapy if using anthracycline anticancer drugs.

关键词： Multidrug resistance BCRP gene Non-small cell lung cancer Chemotherapy

c-MET immunohistochemical expression in sporadic and inflammatory bowel disease associated lesions

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World j.urnal of Gastroenterology 2022年第13期28卷 1338-1346页

作者： Grant Halliday Ross j.Porter Catherine j.Black mark j.Arends Shahida Din Department of Pathology Western General HospitalNHS LothianScotland EH42XUUnited Kingdom Centre for Inflammation Research Queen’s Medical Research InstituteUniversity of EdinburghEdinburgh EH164TJUnited Kingdom Edinburgh Inflammatory Bowel Disease Unit Western General HospitalNHS LothianEdinburgh EH42XUUnited Kingdom Cancer Research UK Edinburgh Centre Institute of Cancer&GeneticsWestern General HospitalUniversity of EdinburghEdinburgh EH42XUUnited Kingdom

BACKGROUND Post-colonoscopy colorectal cancer(CRC)rates for patients with inflammatory bowel disease(IBD)are unacceptably *** colonoscopy,an intravenous fluorescent anti-c-MET probe may improve endoscopic detection of ***,c-MET expression in IBD lesions is poorly defined,limiting translational *** To comprehensively define c-MET expression in sporadic and IBD-associated colorectal *** c-MET expression was immunohistochemically assessed in 319 formalin-fixed paraffin-embedded tissue specimens,colonoscopically or surgically retrieved between *** included:30 normal colorectal biopsies,30 hyperplastic polyps(HP),31 sessile serrated lesions(SSL),55 tubular/tubulovillous adenomas with low(TA-LGD,n=32)or high grade dysplasia(TA-HGD,n=23),26 sporadic(s)-CRCs,16 quiescent IBD biopsies,11 active/inflamed IBD biopsies,18 IBDassociated dysplastic lesions(IBD-dys),and 102 *** was scored by two independent observers as:0=absent,1=weak,2=moderate or 3=***-Whitney U and Kruskal-Wallis tests were used to assess *** Positive epithelial cytoplasmic and membranous c-MET expression was observed in all tissues,indicating there is ubiquitous expression in the colorectum.c-MET expression was weak in normal colonic epithelium compared with each of the sporadic colonic lesions,including TA-LGD(Pith normal mucosa(Pith TA-HGD(P=0.004).However,there was no significant difference between TA-LGD and TA-HGD(P=0.852).Further,there was no difference in c-MET expression between HP and SSL(P=0.065).In IBD,expression was weaker in quiescent colonic mucosa compared with inflamed colonic mucosa(P<0.001).There was no difference between inflamed colonic mucosa and IBD-dys(P=0.512)or IBD-CRC(P=0.296).However,expression

关键词： Inflammatory bowel diseases Colorectal cancer Surveillance Detection c-MET Immunohistochemistry

INCIDENCE MATRIX APPROACH FOR CALCULATING READINESS LEVELS

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j.urnal of Systems Science and Systems Engineering 2014年第4期23卷 377-403页

作者： mark A.London Thomas H.Holzer Timothy j.Eveleigh Shahryar Sarkani School of Engineering and Applied Science George Washington University

Contemporary system maturity assessment approaches have failed to provide robust quantitative system evaluations resulting in increased program costs and developmental *** assessment metrics,such as Technology Readiness Levels（TRL）,do not sufficiently evaluate increasingly complex *** System Readiness Level（SRL）is a newly developed system development metric that is a mathematical function of TRL and Integration Readiness Level（IRL） values for the components and connections of a particular *** acceptance has been hindered because of concerns over SRL mathematical operations that may lead to inaccurate system readiness *** inaccurate system readiness assessments are called readiness reversals.A new SRL calculation method using incidence matrices is proposed to alleviate these mathematical *** presence of SRL readiness reversal is modeled for four SRL calculation methods across several system *** regression analysis demonstrates that the proposed Incidence Matrix SRL（IMSRL）method has a decreased presence of readiness reversal than other approaches suggested in the *** SRL methods will foster greater SRL adoption by systems engineering professionals and will support system development risk reduction goals.

关键词： Technology Readiness Level(TRL) integration readiness level(IRL) system readiness level(SRL) system readiness graph theory systems engineering

Antenna design for a massive multiple input environmental sensor network

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Digital Communications and Networks 2016年第4期2卷 256-259页

作者： j. Craig Prather Michael Bolt Haley Harrell j.hn Manobianco mark L. Adams Department of Electrical and Computer Engineering 200 Broun Hall Auburn University AL 36849 United States

This article describes the design and simulation of a pair of antennas on a small PCB with minimal coupling for a massive multiple input sensor network. The two antennas are planar inverted-F antennas （PIFA） that are fed with microstrip feed lines. The critical design factors are minimizing mass while creating ISM band and GPS L1 band antennas and developing data transmission schemes for maximum usage of all communication channels. The designed board is a 60 mm diameter, 0.6 mm thick circular FR4 board that weighs approximately 5 g.

关键词： Antenna Environmental sensing Remote sensing Massive multiple input network

Senescence-specific Alteration of Hydrogen Peroxide Levels in Arabidopsis thaliana and Oilseed Rape Spring Variety Brassica napus ***

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j.urnal of Integrative Plant Biology 2012年第8期54卷 540-554页

作者： Stefan Bieker Lena Riester mark Stahl j.rgen Franzaring Ulrike Zentgraf ZMBP (Center for Plant Molecular Biology) University of TübingenAuf der Morgenstelle 2872076 Tübingen Germany Institute for Landscape and Plant Ecology kologiezentrum 2August-von-Hartmann-Str.370599 StuttgartGermany

In order to analyze the signaling function of hydrogen peroxide （H202） production in senescence in more detail, we manipulated intracellular H202 levels in Arabidopsis thaliala （L.） Heynh by using the hydrogen- peroxide-sensitive part of the Escherichia coil transcription regulator OxyR, which was directed to the cytoplasm as well as into the peroxisomes. H202 levels were lowered and senescence was delayed in both transgenic lines, but OxyR was found to be more effective in the cytoplasm. To transfer this knowledge to crop plants, we analyzed oilseed rape plants Brassica napus L. cv. Mozart for H20~ and its scavenging enzymes catalase （CAT） and ascorbate peroxidase （APX） during leaf and plant development. H202 levels were found to increase during bolting and flowering time, but no increase could be observed in the very late stages of senescence. With increasing H202 levels, CAT and APX activities declined, so it is likely that similar mechanisms are used in oilseed rape and Arabidopsis to control H202 levels. Under elevated CO2 conditions, oilseed rape senescence was accelerated and coincided with an earlier increase in H202 levels, indicating that H202 may be one of the signals to inducing senescence in a broader range of Brassicaceae.

关键词： Arabidopsis thaliana Brassica napus E. coil Oxy-RD intracellular hydrogen peroxide senescence phenotype catalase ascorbatePeroxidase elevated CO2.