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Msh2 Acts in Medium-Spiny Striatal Neurons as an Enhancer of CAG Instability and Mutant Huntingtin Phenotypes in Huntington’s Disease Knock-In Mice
Marina Kovalenko, Ella Dragileva, Jason St. Claire, Tammy Gillis, Jolene R. Guide, Jaclyn New, Hualing Dong, Raju Kucherlapati, Melanie H. Kucherlapati, Michelle E. Ehrlich, Jong-Min Lee, Vanessa C. Wheeler
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044273
Abstract: The CAG trinucleotide repeat mutation in the Huntington’s disease gene (HTT) exhibits age-dependent tissue-specific expansion that correlates with disease onset in patients, implicating somatic expansion as a disease modifier and potential therapeutic target. Somatic HTT CAG expansion is critically dependent on proteins in the mismatch repair (MMR) pathway. To gain further insight into mechanisms of somatic expansion and the relationship of somatic expansion to the disease process in selectively vulnerable MSNs we have crossed HTT CAG knock-in mice (HdhQ111) with mice carrying a conditional (floxed) Msh2 allele and D9-Cre transgenic mice, in which Cre recombinase is expressed specifically in MSNs within the striatum. Deletion of Msh2 in MSNs eliminated Msh2 protein in those neurons. We demonstrate that MSN-specific deletion of Msh2 was sufficient to eliminate the vast majority of striatal HTT CAG expansions in HdhQ111 mice. Furthermore, MSN-specific deletion of Msh2 modified two mutant huntingtin phenotypes: the early nuclear localization of diffusely immunostaining mutant huntingtin was slowed; and the later development of intranuclear huntingtin inclusions was dramatically inhibited. Therefore, Msh2 acts within MSNs as a genetic enhancer both of somatic HTT CAG expansions and of HTT CAG-dependent phenotypes in mice. These data suggest that the selective vulnerability of MSNs may be at least in part contributed by the propensity for somatic expansion in these neurons, and imply that intervening in the expansion process is likely to have therapeutic benefit.
The Role that Personality and Motivation Play in the Consumer Behaviour: A Case Study on HSBC
Jolene Montgomery
Business Intelligence Journal , 2008,
Abstract: In today's information-oriented society, research and development, particularly information research, has become an important activity for business companies, institutions, and organizations, who want to know more about the consumer market, people who consider consumption as embedded and part of their everyday lives. Initially, commercialism of goods and services through advertising mainly focused on extant products and services that people need; nowadays, persuasive messages are extended through advertising, informing people about the goods and services that they should and ought to know and buy for themselves.
Mismatch Repair Genes Mlh1 and Mlh3 Modify CAG Instability in Huntington's Disease Mice: Genome-Wide and Candidate Approaches
Ricardo Mouro Pinto,Ella Dragileva,Andrew Kirby,Alejandro Lloret,Edith Lopez,Jason St. Claire,Gagan B. Panigrahi,Caixia Hou,Kim Holloway,Tammy Gillis,Jolene R. Guide,Paula E. Cohen,Guo-Min Li,Christopher E. Pearson,Mark J. Daly,Vanessa C. Wheeler
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003930
Abstract: The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease HdhQ111 mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.HdhQ111) than on a 129 background (129.HdhQ111). Linkage mapping in (B6x129).HdhQ111 F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier. Crossing B6.HdhQ111 mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons. HdhQ111 somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1–MLH3) complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2–MSH3). The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest that MLH1 protein levels play an important role in driving of the efficiency of somatic expansions.
Pluripotency and its layers of complexity
Jolene Ooi, Pentao Liu
Cell Regeneration , 2012, DOI: 10.1186/2045-9769-1-7
Abstract: Pluripotency is denoted by the capacity of a self-renewing cell to develop into the three germ layers. The conception of pluripotency emerged in the Classical Greek period where rudimentary methods were employed to examine the development of organs within chick embryos [1]. These observations were left unexplored for two thousand years and awareness was rekindled in the Renaissance period where the invention of the microscope enhanced the resolution of developing embryos. This elicited the establishment of several landmark discoveries and escalated our understanding of vertebrate developmental processes.The first testimony of pluripotency on a petri dish was portrayed using inbred strains of mice. Spontaneous incidences of teratocarinomas arose at low frequencies in 129 strain of mice [2]. This led to the isolation of pluripotent stem cells that were able to regenerate tumours consisting of the three germ layers [3]. Subsets of pluripotent cell populations came in quick succession, where various cell types within the mouse embryo were isolated and snapshots of distinct developmental stages were captured [4-9]. Other than naturally occurring instances in normal development, artificial states that are reflective of pluripotency have been accomplished. Cells from developing Rana pipiens embryos were demonstrated to undergo nuclear transplantation and revert to a primitive state capable of developing into an entire organism [10]. This highlighted the capacity of a non-pluripotent cell to reset its epigenetic marks and convert to a pluripotent derivative. Termed as nuclear reprogramming, these findings were extended in mice and further exemplified in alternative methods [11-14].The easy manipulation and cultivation of mouse pluripotent stem cells have provided a convenient platform to study the independent developmental stages. Furthermore, comparison of these pluripotent states and their necessary environmental milieu for sustenance provides indications of developmental
Where in the Internet is congestion?
Daniel Genin,Jolene Splett
Computer Science , 2013,
Abstract: Understanding the distribution of congestion in the Internet is a long-standing problem. Using data from the SamKnows US broadband access network measurement study, commissioned by the FCC, we explore patterns of congestion distribution in DSL and cable Internet service provider (ISP) networks. Using correlation-based analysis we estimate prevalence of congestion in the periphery versus the core of ISP networks. We show that there are significant differences in congestion levels and its distribution between DSL and cable ISP networks and identify bottleneck sections in each type of network.
A Broad Phenotypic Screen Identifies Novel Phenotypes Driven by a Single Mutant Allele in Huntington’s Disease CAG Knock-In Mice
Sabine M. H?lter, Mary Stromberg, Marina Kovalenko, Lillian Garrett, Lisa Glasl, Edith Lopez, Jolene Guide, Alexander G?tz, Wolfgang Hans, Lore Becker, Birgit Rathkolb, Jan Rozman, Anja Schrewed, Martin Klingenspor, Thomas Klopstock, Holger Schulz, Eckhard Wolf, Wolfgang Wursta, Tammy Gillis, Hiroko Wakimoto, Jonathan Seidman, Marcy E. MacDonald, Susan Cotman, Valérie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Jong-Min Lee, Vanessa C. Wheeler
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080923
Abstract: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing.
Large-Scale Phenotyping of an Accurate Genetic Mouse Model of JNCL Identifies Novel Early Pathology Outside the Central Nervous System
John F. Staropoli, Larissa Haliw, Sunita Biswas, Lillian Garrett, Sabine M. H?lter, Lore Becker, Sergej Skosyrski, Patricia Da Silva-Buttkus, Julia Calzada-Wack, Frauke Neff, Birgit Rathkolb, Jan Rozman, Anja Schrewe, Thure Adler, Oliver Puk, Minxuan Sun, Jack Favor, Ildikó Racz, Raffi Bekeredjian, Dirk H. Busch, Jochen Graw, Martin Klingenspor, Thomas Klopstock, Eckhard Wolf, Wolfgang Wurst, Andreas Zimmer, Edith Lopez, Hayat Harati, Eric Hill, Daniela S. Krause, Jolene Guide, Ella Dragileva, Evan Gale, Vanessa C. Wheeler, Rose-Mary Boustany, Diane E. Brown, Sylvie Breton, Klaus Ruether, Valérie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Susan L. Cotman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038310
Abstract: Cln3Δex7/8 mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3Δex7/8 mice. Homozygous Cln3Δex7/8 mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10–14 weeks of age. Homozygous Cln3Δex7/8 mice also displayed electroretinographic changes reflecting cone function deficits past 5 months of age and a progressive decline of retinal post-receptoral function. Metabolic analysis revealed increases in rectal body temperature and minimum oxygen consumption in 12–13 week old homozygous Cln3Δex7/8mice, which were also seen to a lesser extent in heterozygous Cln3Δex7/8 mice. Heart weight was slightly increased at 20 weeks of age, but no significant differences were observed in cardiac function in young adults. In a comprehensive blood analysis at 15–16 weeks of age, serum ferritin concentrations, mean corpuscular volume of red blood cells (MCV), and reticulocyte counts were reproducibly increased in homozygous Cln3Δex7/8 mice, and male homozygotes had a relative T-cell deficiency, suggesting alterations in hematopoiesis. Finally, consistent with findings in JNCL patients, vacuolated peripheral blood lymphocytes were observed in homozygous Cln3Δex7/8 neonates, and to a greater extent in older animals. Early onset, severe vacuolation in clear cells of the epididymis of male homozygous Cln3Δex7/8 mice was also observed. These data highlight additional organ systems in which to study CLN3 function, and early phenotypes have been established in homozygous Cln3Δex7/8 mice that merit further study for JNCL biomarker development.
The tailless Ortholog nhr-67 Regulates Patterning of Gene Expression and Morphogenesis in the C. elegans Vulva
Jolene S Fernandes,Paul W Sternberg
PLOS Genetics , 2007, DOI: 10.1371/journal.pgen.0030069
Abstract: Regulation of spatio-temporal gene expression in diverse cell and tissue types is a critical aspect of development. Progression through Caenorhabditis elegans vulval development leads to the generation of seven distinct vulval cell types (vulA, vulB1, vulB2, vulC, vulD, vulE, and vulF), each with its own unique gene expression profile. The mechanisms that establish the precise spatial patterning of these mature cell types are largely unknown. Dissection of the gene regulatory networks involved in vulval patterning and differentiation would help us understand how cells generate a spatially defined pattern of cell fates during organogenesis. We disrupted the activity of 508 transcription factors via RNAi and assayed the expression of ceh-2, a marker for vulB fate during the L4 stage. From this screen, we identified the tailless ortholog nhr-67 as a novel regulator of gene expression in multiple vulval cell types. We find that one way in which nhr-67 maintains cell identity is by restricting inappropriate cell fusion events in specific vulval cells, namely vulE and vulF. nhr-67 exhibits a dynamic expression pattern in the vulval cells and interacts with three other transcriptional regulators cog-1 (Nkx6.1/6.2), lin-11 (LIM), and egl-38 (Pax2/5/8) to generate the composite expression patterns of their downstream targets. We provide evidence that egl-38 regulates gene expression in vulB1, vulC, vulD, vulE, as well as vulF cells. We demonstrate that the pairwise interactions between these regulatory genes are complex and vary among the seven cell types. We also discovered a striking regulatory circuit that affects a subset of the vulval lineages: cog-1 and nhr-67 inhibit both one another and themselves. We postulate that the differential levels and combinatorial patterns of lin-11, cog-1, and nhr-67 expression are a part of a regulatory code for the mature vulval cell types.
Making Dioramas of Women Scientists Help Elementary Students Recognize Their Contributions  [PDF]
Jolene K. Teske, Phyllis Gray, Julie L. Klein, Audrey C. Rule
Creative Education (CE) , 2014, DOI: 10.4236/ce.2014.523223
Abstract: The STEM movement encourages girls to consider careers in science; however, for success, common misconceptions and biases need to be dispelled, while females’ spatial thinking skills are developed. All students, both girls and boys, need exposure to the accomplishments of women scientists to appreciate their contributions and to envision females as successful scientists. This one-week study conducted during a summer day camp examined upper elementary student (n = 15; 7 females, 8 males) attitudes toward science, women in science, and the possibility of a science career before and after participation in learning about diverse accomplished women scientists and making a diorama showcasing the professional work and caring actions of one of the scientists. The efficacy of this project for upper elementary students, conducted during a summer day camp, is supported by pretest-posttest data and attitude surveys. The five-day class showed positive changes in student plans for a career in science and improved attitudes toward the importance of females becoming scientists. Directions for constructing dioramas, examples of student-made work, and creative scenes made with given craft items are provided.
A model test system with a dynamic load device for geotechnical engineering in cold regions

ShuPing Zhao,Wei M,GuiDe Jiao,Fei Luo,

寒旱区科学 , 2012,
Abstract: A model test system with a dynamic load device for geotechnical engineering in cold regions is presented. This system consists of a model test tank, a refrigeration device and temperature controller, a dynamic load device, together with sensors and data loggers for detecting stress, deformation, and temperature changes. The system can accommodate soil blocks up to 3 m in length, 2.5 m in width, and 1 m in height. The lowest temperature provided by the refrigeration device is -20 °C. The maximum load provided by the dynamic load device is 100 kN and the vibration frequency of the dynamic load can range from 0.1 to 10 Hz. A number of waveforms, such as sine waves, rectangular waves, triangle waves, and other user-defined waves can be generated by the dynamic load device controller.
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