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1

Therapeutic Efficacy of a {sup 188}Re-Labeled {alpha}-Melanocyte-Stimulating Hormone Peptide Analog in Murine and Human Melanoma-Bearing Mouse Models  

SciTech Connect

The purpose of this study was to examine the therapeutic efficacy of {sup 188}Re-(Arg{sup 11})CCMSH in the B16/F1 murine melanoma and TXM13 human melanoma bearing mouse models. Method: (Arg11)CCMSH was synthesized and labeled with {sup 188}Re to form {sup 188}Re-(Agr{sup 11})CCMSH. B16/F1 melanoma tumor bearing mice were administrated with 200 Ci, 600 Ci and 2x400 Ci of {sup 188}Re-(Arg{sup 11})CCMSH via the tail vein, respectively. TXM13 melanoma tumor hearing mice were separately injected with 600 Ci, 2x400 Ci and 1000 Ci of 100Re-(Arg{sup 11})CCMSH through the tail vein. Two groups of 10 mice bearing either B16/F1 or TXM13 tumors were injected with saline as untreated controls. Results: In contrast to the untreated control group, {sup 188}Re(Arg11)CCMSH yielded rapid and lasting therapeutic effects in the treatment groups with either B16/F1 or TXM13 tumors. The tumor growth rate was reduced and the survival rate was prolonged in the treatment groups. Treatment with 2x400 Ci of {sup 188}Re-Arg{sup 11}CCMSH significantly extended the mean life of B16/F1 tumor mice (p<0.05), while the mean life of TXm13 tumor mice was significantly prolonged after treatment with 600 Ci and 1000 Ci doses of {sup 188}Re-(Arg{sup 11})CCMSH (p<0.05 High-dose {sup 188}Re-(Arg{sup 11}))CCMSH produced no observed normal-tissue toxicity. Conclusions: The therapy study results revealed that {sup 188}Re-Arg11 CCMSH yielded significant therapeutic effects in both B16/F1 murine melanoma and TXM13 human melanoma bearing mouse models. {sup 188}Re-(Arg{sup 11})CCMSH appears to be a promising radiolabeled peptide for targeted radionuclide therapy of melanoma.

Miao, Yubin; Owen, Nellie K.; Fisher, Darrell R.; Hoffman, Timothy J.; Quinn, Thomas P.

2005-01-01

2

Antitumor therapeutic effects of Salmonella typhimurium containing Flt3 Ligand expression plasmids in melanoma-bearing mouse  

Microsoft Academic Search

An attenuated strain of Salmonella typhimurium has been tested in animals and clinically as an anticancer agent due to its in vivo tumor-targeting and tumoricidal properties.\\u000a We exploited a genetically-engineered S.\\u000a typhimurium harboring Flt3 Ligand (Flt3L) expression vectors as a tumoricidal agent to enhance its therapeutic efficacy. Flt3L showed\\u000a tumoricidal effects when expressed in tumor cells in vitro. When melanoma-bearing

Won Suck Yoon; Won Cheol Choi; Jeong-Im Sin; Yong Keun Park

2007-01-01

3

Human and mouse gene nomenclature.  

PubMed

Standard genetic nomenclature is necessary to help researchers, clinicians, and the public to access data on their genes of interest, and to communicate in a globally understood language of approved gene symbols. In both human and mouse, one unique symbol (acronym/abbreviation) and one name are assigned for each gene. Co-ordination between human and mouse gene nomenclature is a successful endeavor, due in part to the historical interaction between the two nomenclature committee groups. This interaction grew out of the Human Gene Mapping (HGM) Workshops. This appendix discusses development and organization of gene nomenclature, how to find a gene and how to name a new gene. PMID:18428336

Wain, Hester; Povey, Sue; Maltais, Lois

2003-02-01

4

Human\\/Mouse Homology Relationships  

Microsoft Academic Search

Conservation of genomic organization in different mammalian species has long been recognized, but only recently has it been possible to examine these relationships systematically on a genome-wide scale in some detail. Mapping of several mammalian species in progressing rapidly, but by far the most detailed information is still to be found in the human and mouse databases. Perhaps the most

Ronald W. DeBry; Michael F. Seldin

1996-01-01

5

Mouse models of human thalassemia  

SciTech Connect

The group of diseases called the thalassemias is the largest single-gene health problem in the world according the World Health Organization. The thalassemias are lethal hereditary anemias in which the infants cannot make their own blood. Three mouse mutants are shown to be models of the human disease ..cap alpha..-thalassemia. However, since an additional gene is affected, these mutants represent a particularly severe condition in which death occurs in the homozygous embryo even before globin genes are activated. Phenotypic and genotypic characteristics are described. (ACR)

Anderson, W.F.; Martinell, J.; Whitney, J.B. III; Popp, R.A.

1981-01-01

6

Suppression of Production of Mouse 28S Ribosomal RNA in Mouse-Human Hybrids Segregating Mouse Chromosomes  

Microsoft Academic Search

Mouse-human somatic cell hybrids that lose (segregate) human chromosomes produce only mouse 28S ribosomal RNA even when they retain copies of the human chromosomes that contain the genes for 28S ribosomal RNA. In contrast, mouse-human hybrid cells that segregate mouse chromosomes produce only human 28S ribosomal RNA even when they have retained copies of mouse chromosomes that contain the 28S

Carlo M. Croce; Antonio Talavera; Claudio Basilico; Orlando J. Miller

1977-01-01

7

Mouse Mammary Tumor Virus Infects Human Cells  

Microsoft Academic Search

Mouse mammary tumor virus (MMTV) has long been speculated to be involved in human breast cancer and more recently in human primary biliary cirrhosis. Despite complete proviral sequences markedly homologous to MMTV being identified in human breast cancer tissue, no convincing evidence has been presented to date that MMTV can infect human cells. Using both wild-type and a genetically marked

Stanislav Indik; Walter H. Gunzburg; Brian Salmons; Francoise Rouault

2005-01-01

8

Human-Mouse Alignments with BLASTZ  

Microsoft Academic Search

The Mouse Genome Analysis Consortium aligned the human and mouse genome sequences for a variety of purposes, using alignment programs that suited the various needs. For investigating issues regarding genome evolution, a particularly sensitive method was needed to permit alignment of a large proportion of the neutrally evolving regions. We selected a program called BLASTZ, an independent implementation of the

Scott Schwartz; William Kent; Arian F. A. Smit; Robert Baertsch; Zheng Zhang

2003-01-01

9

Activity of antioxidant enzymes and concentration of lipid peroxidation products in selected tissues of mice of different ages, both healthy and melanoma-bearing  

Microsoft Academic Search

Summary. The activity of antioxidant enzymes and the concentration of the lipid peroxidation product malondialdehyde (MDA) as indicator of oxidative damage were determined in selected tissues of healthy mice and transplanted B16 melanoma-bearing mice with increasing age. A total of 60 male mice were divided into 6 groups. Groups 1, 2 and 3 consisted of tumor-free, healthy mice aged 1,

A. Wozniak; G. Drewa; B. Wozniak; D. O. Schachtschabel

2004-01-01

10

Human-mouse cell hybrid with human multiple Y chromosomes  

Microsoft Academic Search

HUMAN-mouse cell hybrids usually exhibit preferential loss of human chromosomes1,2. After a time interval, which depends in part on the cell types used, most or sometimes all the human chromosomes segregate out from the hybrid cells3. In the course of investigation of the phenomenon of preferential loss of human chromosomes from hybrids between the mouse cell line RAG and human

Menashe Marcus; RAMANA TANTRAVAHI; VAITHILINGAM G. DEV; DOROTHY A. MILLER; ORLANDO J. MILLER

1976-01-01

11

Chronic alcohol consumption enhances myeloid-derived suppressor cells in B16BL6 melanoma-bearing mice  

PubMed Central

We previously found that chronic alcohol consumption decreases the survival of mice bearing subcutaneous B16BL6 melanoma. The underlying mechanism is still not completely understood. Antitumor T cell immune responses are important to inhibiting tumor progression and extending survival. Therefore, we examined the effects of chronic alcohol consumption on the functionality and regulation of these cells in C57BL/6 mice that chronically consumed 20% (w/v) alcohol and subsequently were inoculated subcutaneously with B16BL6 melanoma cells. Chronic alcohol consumption inhibited melanoma-induced memory T cell expansion and accelerated the decay of interferon (IFN)-? producing T cells in the tumor-bearing mice. Foxp3+CD4+CD25+ regulatory T cells were not affected; however, the percentage of myeloid-derived suppressor cells (MDSC) was significantly increased in the peripheral blood and spleen. T cell proliferation as determined by carboxyfluorescein succinimidyl ester labeling experiments in vitro was inhibited by alcohol consumption relative to control water-drinking melanoma-bearing mice. Collectively, these data show that chronic alcohol consumption inhibits proliferation of memory T cells, accelerates the decay of IFN-? producing CD8+ T cells, and increases MDSC, all of which could be associated with melanoma progression and reduced survival.

Zhang, Hui; Meadows, Gary G.

2010-01-01

12

Mouse Models of Human Thalassemia.  

National Technical Information Service (NTIS)

The group of diseases called the thalassemias is the largest single-gene health problem in the world according the World Health Organization. The thalassemias are lethal hereditary anemias in which the infants cannot make their own blood. Three mouse muta...

W. F. Anderson J. Martinell J. B. Whitney R. A. Popp

1981-01-01

13

Mouse Chromosome Engineering for Modeling Human Disease  

PubMed Central

Chromosomal rearrangements occur frequently in humans and can be disease-associated or phenotypically neutral. Recent technological advances have led to the discovery of copy-number changes previously undetected by cytogenetic techniques. To understand the genetic consequences of such genomic changes, these mutations need to be modeled in experimentally tractable systems. The mouse is an excellent organism for this analysis because of its biological and genetic similarity to humans, and the ease with which its genome can be manipulated. Through chromosome engineering, defined rearrangements can be introduced into the mouse genome. The resulting mouse models are leading to a better understanding of the molecular and cellular basis of dosage alterations in human disease phenotypes, in turn opening new diagnostic and therapeutic opportunities.

van der Weyden, Louise; Bradley, Allan

2008-01-01

14

Expression of Human and Suppression of Mouse Nucleolus Organizer Activity in Mouse-Human Somatic Cell Hybrids  

Microsoft Academic Search

Most mouse-human somatic cell hybrids show preferential loss of human chromosomes, absence of human 28S ribosomal RNA, and suppression of human nucleolus organizer activity, as visualized by the Ag-AS silver histochemical stain. In contrast, the mouse-human hybrids studied here show preferential loss of mouse chromosomes. The hybrids were made by fusion of HT-1080-6TG human fibrosarcoma cells with BALB\\/c mouse peritoneal

Orlando J. Miller; Dorothy A. Miller; Vaithilingam G. Dev; Ramana Tantravahi; Carlo M. Croce

1976-01-01

15

A smarter mouse with human astrocytes.  

PubMed

What is the biological basis for human cognition? Our understanding why human brains make us smarter than other animals is still in its infancy. In recent years, astrocytes have been shown to be indispensable for neuronal survival, growth, synapse formation, and synapse function. Now, in a new study from Maiken Nedergaard and Steven Goldman's groups (Han et al., 2013), human glia progenitor cells have been transplanted into mouse forebrains. These progenitors survived, migrated widely, and gave rise to astrocytes that displayed the characteristics of human astrocytes in the rodent host brains. Strikingly, the mice with transplanted human cells displayed improved long term potentiation (LTP) and learning, suggesting the potential importance of human astrocytes in the unique cognitive abilities of human brains. This landmark paper is an important first step toward future investigations of whether and how human astrocytes play a role in distinguishing the cognitive abilities of humans from those of other animals. PMID:23897758

Zhang, Ye; Barres, Ben A

2013-07-30

16

A Humanized Mouse Model of Tuberculosis  

PubMed Central

Mycobacterium tuberculosis (M.tb) is the second leading infectious cause of death worldwide and the primary cause of death in people living with HIV/AIDS. There are several excellent animal models employed to study tuberculosis (TB), but many have limitations for reproducing human pathology and none are amenable to the direct study of HIV/M.tb co-infection. The humanized mouse has been increasingly employed to explore HIV infection and other pathogens where animal models are limiting. Our goal was to develop a small animal model of M.tb infection using the bone marrow, liver, thymus (BLT) humanized mouse. NOD-SCID/?cnull mice were engrafted with human fetal liver and thymus tissue, and supplemented with CD34+ fetal liver cells. Excellent reconstitution, as measured by expression of the human CD45 pan leukocyte marker by peripheral blood populations, was observed at 12 weeks after engraftment. Human T cells (CD3, CD4, CD8), as well as natural killer cells and monocyte/macrophages were all observed within the human leukocyte (CD45+) population. Importantly, human T cells were functionally competent as determined by proliferative capacity and effector molecule (e.g. IFN-?, granulysin, perforin) expression in response to positive stimuli. Animals infected intranasally with M.tb had progressive bacterial infection in the lung and dissemination to spleen and liver from 2–8 weeks post infection. Sites of infection in the lung were characterized by the formation of organized granulomatous lesions, caseous necrosis, bronchial obstruction, and crystallization of cholesterol deposits. Human T cells were distributed throughout the lung, liver, and spleen at sites of inflammation and bacterial growth and were organized to the periphery of granulomas. These preliminary results demonstrate the potential to use the humanized mouse as a model of experimental TB.

Calderon, Veronica E.; Valbuena, Gustavo; Goez, Yenny; Judy, Barbara M.; Huante, Matthew B.; Sutjita, Putri; Johnston, R. Katie; Estes, D. Mark; Hunter, Robert L.; Actor, Jeffrey K.; Cirillo, Jeffrey D.; Endsley, Janice J.

2013-01-01

17

Loss of Mouse Chromosomes in Somatic Cell Hybrids between HT1080 Human Fibrosarcoma Cells and Mouse Peritoneal Macrophages  

Microsoft Academic Search

Somatic cell hybrids between mouse peritoneal macrophages and HT-1080 human fibrosarcoma cells lose mouse chromosomes and retain the entire complement of human chromosomes. In contrast, somatic cell hybrids between cells derived from two different mouse continuous cell lines and HT-1080 human cells were found to lose human chromosomes preferentially. Loss of mouse chromosomes is not a general property of hybrids

Carlo M. Croce

1976-01-01

18

Humanized Mouse Models of HIV Infection  

PubMed Central

Because of the limited tropism of HIV, in vivo modeling of this virus has been almost exclusively limited to other lentiviruses such as SIV that reproduce many important characteristics of HIV infection. However, there are significant genetic and biological differences among lentiviruses and some HIV-specific interventions are not effective against other lentiviruses in non-human hosts. For these reasons much emphasis has recently been placed on developing alternative animal models that support HIV replication and recapitulate key aspects of HIV infection and pathogenesis in humans. Humanized mice, CD34+ hematopoietic progenitor cell transplanted immunodeficient mice and in particular mice also implanted with human thymic/liver tissue (BLT mice) that develop a functional human immune system, have been the focus of a great deal of attention as possible models to study virtually all aspects of HIV biology and pathogenesis. Humanized mice are systemically reconstituted with human lymphoid cells offering rapid, reliable and reproducible experimental systems for HIV research. Peripheral blood of humanized mice can be readily sampled longitudinally to assess reconstitution with human cells and to monitor HIV replication permitting the evaluation of multiple parameters of HIV infection such as viral load levels, CD4+ T cell depletion, immune activation, as well as the effects of therapeutic interventions. Of high relevance to HIV transmission is the extensive characterization and validation of the reconstitution with human lymphoid cells of the female reproductive tract and of the gastrointestinal tract of humanized BLT mice that renders them susceptible to both vaginal and rectal HIV infection. Other important attributes of all types of humanized mice include: 1) their small size and cost that make them broadly accessible; 2) multiple cohorts of humanized mice can be made from multiple human donors and each cohort has identical human cells, permitting control of intragenetic variables; 3) continuous de novo production of human immune cells from the transplanted CD34+ cells within each humanized mouse facilitates long term experiments; 4) both primary and laboratory HIV isolates can be used for experiments; and 5) in addition to therapeutic interventions, rectal and vaginal HIV prevention approaches can be studied. In summary, humanized mice can have an important role in virtually all aspects of HIV research including the analysis of HIV replication, the evaluation of HIV restriction factors, the characterization of successful biomedical HIV prevention strategies, the evaluation of new treatment regimens and the evaluation of novel HIV eradication strategies.

Denton, Paul W.; Garcia, J. Victor

2013-01-01

19

A comparative genetic map of rat, mouse and human genomes.  

PubMed

The increasing availability of molecular markers and the development of highly efficient gene mapping strategies for the mouse, rat and human genomes have generated vast quantities of information allowing for the progressive refinement of comparative maps. In this publication we report on an updated version of our rat/mouse/human comparative genetic map, based on the mouse map. Databases for mouse, rat and human gene mapping were used for the collection of homologs mapped in the species. The comparative map was constructed with a total of 1,235 mouse loci having known homologs in the rat and/or human: 16 having homologs only in the rat, 884 having only in the human and 335 both in the rat and human. The combined length of the segments conserved between the rat and mouse spans 758 cM on the mouse map. This indicates that about 47% of the mouse genome is now covered by known rat homologous regions. Five novel regions homologous for the rat and mouse were identified. This comparative genetic map should be useful for researchers working on genetic studies in the rat, mouse and human. PMID:9498107

Serikawa, T; Cui, Z; Yokoi, N; Kuramoto, T; Kondo, Y; Kitada, K; Guénet, J L

1998-01-01

20

A Comparison of Senescence in Mouse and Human Cells  

Microsoft Academic Search

\\u000a Senescence is observed in both human and mouse cells, however, there are fundamental differences in how senescence is controlled\\u000a between the two species. Human fibroblasts undergo replicative senescence as a result of telomere shortening. In contrast,\\u000a mouse fibroblasts do not senesce when grown at a physiological oxygen concentration. In atmospheric oxygen, mouse cells enter\\u000a a state that resembles senescence, but

Vera Gorbunova; Andrei Seluanov

21

Comparative anatomy of mouse and human nail units.  

PubMed

Recent studies of mice with hair defects have resulted in major contributions to the understanding of hair disorders. To use mouse models as a tool to study nail diseases, a basic understanding of the similarities and differences between the human and mouse nail unit is required. In this study we compare the human and mouse nail unit at the macroscopic and microscopic level and use immunohistochemistry to determine the keratin expression patterns in the mouse nail unit. Both species have a proximal nail fold, cuticle, nail matrix, nail bed, nail plate, and hyponychium. Distinguishing features are the shape of the nail and the presence of an extended hyponychium in the mouse. Expression patterns of most keratins are similar. These findings indicate that the mouse nail unit shares major characteristics with the human nail unit and overall represents a very similar structure, useful for the investigation of nail diseases and nail biology. PMID:23408541

Fleckman, Philip; Jaeger, Karin; Silva, Kathleen A; Sundberg, John P

2013-03-01

22

A Mouse Model for Human Norovirus  

PubMed Central

ABSTRACT Human noroviruses (HuNoVs) cause significant morbidity and mortality worldwide. However, despite substantial efforts, a small-animal model for HuNoV has not been described to date. Since “humanized” mice have been successfully used to study human-tropic pathogens in the past, we challenged BALB/c mice deficient in recombination activation gene (Rag) 1 or 2 and common gamma chain (?c) (Rag-?c) engrafted with human CD34+ hematopoietic stem cells, nonengrafted siblings, and immunocompetent wild-type controls with pooled stool isolates from patients positive for HuNoV. Surprisingly, both humanized and nonhumanized BALB/c Rag-?c-deficient mice supported replication of a GII.4 strain of HuNoV, as indicated by increased viral loads over input. In contrast, immunocompetent wild-type BALB/c mice were not infected. An intraperitoneal route of infection and the BALB/c genetic background were important for facilitating a subclinical HuNoV infection of Rag-?c-deficient mice. Expression of structural and nonstructural proteins was detected in cells with macrophage-like morphology in the spleens and livers of BALB/c Rag-?c-deficient mice, confirming the ability of HuNoV to replicate in a mouse model. In summary, HuNoV replication in BALB/c Rag-?c-deficient mice is dependent on the immune-deficient status of the host but not on the presence of human immune cells and provides the first genetically manipulable small-animal model for studying HuNoV infection.

Taube, Stefan; Kolawole, Abimbola O.; Hohne, Marina; Wilkinson, John E.; Handley, Scott A.; Perry, Jeffrey W.; Thackray, Larissa B.; Akkina, Ramesh; Wobus, Christiane E.

2013-01-01

23

Insights from Human/Mouse genome comparisons  

SciTech Connect

Large-scale public genomic sequencing efforts have provided a wealth of vertebrate sequence data poised to provide insights into mammalian biology. These include deep genomic sequence coverage of human, mouse, rat, zebrafish, and two pufferfish (Fugu rubripes and Tetraodon nigroviridis) (Aparicio et al. 2002; Lander et al. 2001; Venter et al. 2001; Waterston et al. 2002). In addition, a high-priority has been placed on determining the genomic sequence of chimpanzee, dog, cow, frog, and chicken (Boguski 2002). While only recently available, whole genome sequence data have provided the unique opportunity to globally compare complete genome contents. Furthermore, the shared evolutionary ancestry of vertebrate species has allowed the development of comparative genomic approaches to identify ancient conserved sequences with functionality. Accordingly, this review focuses on the initial comparison of available mammalian genomes and describes various insights derived from such analysis.

Pennacchio, Len A.

2003-03-30

24

Three mouse models of human thalassemia  

SciTech Connect

Three types of mice with globin gene mutations, called 352HB, 27HB, and Hba/sup th-J/, appear to be true animal models of human thalassemia. Expression of the ..cap alpha..-globin genes in three stocks of mice, each one heterozygous for one of the ..cap alpha..-globin mutations, was examined at the polypeptide, RNA, and DNA levels. ..cap alpha..-globin polypeptide chains, relative to ..gamma..-globin chains in heterozygous thalassemic mice, are present at approximately 80% of normal. The ratios of ..cap alpha..-globin to ..gamma..-globin RNA sequences are also 75 to 80% normal, exactly reflecting the ..cap alpha..-globin to ..gamma..-globin chain ratios. In the case of mutant 352HB, at least one ..cap alpha..-globin gene is deleted. Thalassemic mouse erythroid cells appear to compensate partially for the loss of half of their ..cap alpha..-globin genes.

Martinell, J. (National Institutes of Health, Betheseda, MD); Whitney, J.B.; Popp, R.A.; Russell, L.B.; Anderson, W.F.

1981-08-01

25

HIV Latency in the Humanized BLT Mouse  

PubMed Central

Even after extended treatment with powerful antiretroviral drugs, HIV is not completely eliminated from infected individuals. Latently infected CD4+ T cells constitute one reservoir of replication-competent HIV that needs to be eliminated to completely purge virus from antiretroviral drug-treated patients. However, a major limitation in the development of therapies to eliminate this latent reservoir is the lack of relevant in vivo models that can be used to test purging strategies. Here, we show that the humanized BLT (bone marrow-liver-thymus) mouse can be used as both an abundant source of primary latently infected cells for ex vivo latency analysis and also as an in vivo system for the study of latency. We demonstrate that over 2% of human cells recovered from the spleens of HIV-infected BLT mice can be latently infected and that this virus is integrated, activation inducible, and replication competent. The non-tumor-inducing phorbol esters prostratin and 12-deoxyphorbol-13-phenylacetate can each induce HIV ex vivo from these latently infected cells, indicating that this model can be used as a source of primary cells for testing latency activators. Finally, we show activation-inducible virus is still present following suppression of plasma viral loads to undetectable levels by using the antiretroviral drugs zidovudine, indinavir sulfate, and didanosine, demonstrating that this model can also be used to assess the in vivo efficacy of latency-purging strategies. Therefore, the HIV-infected BLT mouse should provide a useful model for assessment of HIV latency activators and approaches to eliminate persistent in vivo HIV reservoirs.

Marsden, Matthew D.; Kovochich, Michael; Suree, Nuttee; Shimizu, Saki; Mehta, Roshni; Cortado, Ruth; Bristol, Gregory; An, Dong Sung

2012-01-01

26

Chromosomal localization of the human and mouse hyaluronan synthase genes  

SciTech Connect

We have recently identified a new vertebrate gene family encoding putative hyaluronan (HA) synthases. Three highly conserved related genes have been identified, designated HAS1, HAS2, and HAS3 in humans and Has1, Has2, and Has3 in the mouse. All three genes encode predicted plasma membrane proteins with multiple transmembrane domains and approximately 25% amino acid sequence identity to the Streptococcus pyogenes HA synthase, HasA. Furthermore, expression of any one HAS gene in transfected mammalian cells leads to high levels of HA biosynthesis. We now report the chromosomal localization of the three HAS genes in human and in mouse. The genes localized to three different positions within both the human and the mouse genomes. HAS1 was localized to the human chromosome 19q13.3-q13.4 boundary and Has1 to mouse Chr 17. HAS2 was localized to human chromosome 8q24.12 and Has2 to mouse Chr 15. HAS3 was localized to human chromosome 16q22.1 and Has3 to mouse Chr 8. The map position for HAS1 reinforces the recently reported relationship between a small region of human chromosome 19q and proximal mouse chromosome 17. HAS2 mapped outside the predicted critical region delineated for the Langer-Giedion syndrome and can thus be excluded as a candidate gene for this genetic syndrome. 33 refs., 2 figs.

Spicer, A.P.; McDonald, J.A. [Mayo Clinic Scottsdale, AZ (United States); Seldin, M.F. [Univ. of California Davis, CA (United States)] [and others

1997-05-01

27

Genomic responses in mouse models poorly mimic human inflammatory diseases  

PubMed Central

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

Seok, Junhee; Warren, H. Shaw; Cuenca, Alex G.; Mindrinos, Michael N.; Baker, Henry V.; Xu, Weihong; Richards, Daniel R.; McDonald-Smith, Grace P.; Gao, Hong; Hennessy, Laura; Finnerty, Celeste C.; Lopez, Cecilia M.; Honari, Shari; Moore, Ernest E.; Minei, Joseph P.; Cuschieri, Joseph; Bankey, Paul E.; Johnson, Jeffrey L.; Sperry, Jason; Nathens, Avery B.; Billiar, Timothy R.; West, Michael A.; Jeschke, Marc G.; Klein, Matthew B.; Gamelli, Richard L.; Gibran, Nicole S.; Brownstein, Bernard H.; Miller-Graziano, Carol; Calvano, Steve E.; Mason, Philip H.; Cobb, J. Perren; Rahme, Laurence G.; Lowry, Stephen F.; Maier, Ronald V.; Moldawer, Lyle L.; Herndon, David N.; Davis, Ronald W.; Xiao, Wenzhong; Tompkins, Ronald G.; Abouhamze, Amer; Balis, Ulysses G. J.; Camp, David G.; De, Asit K.; Harbrecht, Brian G.; Hayden, Douglas L.; Kaushal, Amit; O'Keefe, Grant E.; Kotz, Kenneth T.; Qian, Weijun; Schoenfeld, David A.; Shapiro, Michael B.; Silver, Geoffrey M.; Smith, Richard D.; Storey, John D.; Tibshirani, Robert; Toner, Mehmet; Wilhelmy, Julie; Wispelwey, Bram; Wong, Wing H

2013-01-01

28

PPAR? in human and mouse physiology  

PubMed Central

Summary The peroxisome proliferator activated receptor gamma (PPAR?) is a member in the nuclear receptor superfamily which mediates part of the regulatory effects of dietary fatty acids on gene expression. As PPAR? also coordinates adipocyte differentiation, it is an important component in storing the excess nutritional energy as fat. Our genes have evolved into maximizing energy storage, and PPAR? has a central role in the mismatch between our genes and our affluent western society which results in a broad range of metabolic disturbances, collectively known as the metabolic syndrome. A flurry of human and mouse studies has shed new light on the mechanisms how the commonly used insulin sensitizer drugs and PPAR? activators, thiazolidinediones, act, and which of their physiological effects are dependent of PPAR?. It is now evident that the full activation of PPAR? is less advantageous than targeted modulation of it's activity. Furthermore, new roles for PPAR? signaling have been discovered in inflammation, bone morphogenesis, endothelial function, cancer, longevity, and atherosclerosis, to mention a few. Here we draw together and discuss these recent advances in the research into PPAR? biology.

Heikkinen, Sami; Auwerx, Johan; Argmann, Carmen A

2007-01-01

29

Activation of human complement by mouse and mouse/human chimeric monoclonal antibodies.  

PubMed Central

The complement (C)-activating capabilities in human serum of 32 mouse and 10 mouse/human chimeric MoAbs of different isotypes, and their fragments, were tested in vitro. Activation of C via the classical pathway (CP) was performed in 1% factor D-deficient serum in gelatin containing Veronal buffer in the presence of calcium and magnesium (GVB++), while activation of the alternative pathway of C (AP) was assessed in 10% C1q-depleted serum in the presence of 5 mM MgCl2 in GVB++. The C-activating ability of MoAbs was expressed relative to the degree of activation of complement by aggregated IgG for the CP and relative to mouse IgG1 for the AP. All of seven mouse IgG2a MoAbs were potent activators of the CP. The results of CP activation by IgG1, IgG2b and IgG3 isotypes were different for individual MoAbs. Only three (two IgG1 and one IgG3) of 32 mouse MoAbs were potent activators of the AP. IgG2a and IgG2b were relatively poor AP activators. There were a few MoAbs which activated both the AP and CP. Of 10 chimeric MoAbs, two IgG1, one IgG2 and one IgG4 were poor or non-activators of the CP. On the other hand, IgG2 and IgG4 were good AP activators. IgG3 was the most potent AP activator. Most of the F(ab')2 fragments were activators of the AP and displayed no activation of the CP. Fc fragments only activated the CP, whereas Fab' did not activate the CP or the AP. These studies suggest that the route of complement activation by class and subclass MoAbs can not always be predicted in advance and based only on their subclass identity.

Seino, J; Eveleigh, P; Warnaar, S; van Haarlem, L J; van Es, L A; Daha, M R

1993-01-01

30

Laboratory Mouse Models for the Human Genome-Wide Associations  

PubMed Central

The agnostic screening performed by genome-wide association studies (GWAS) has uncovered associations for previously unsuspected genes. Knowledge about the functional role of these genes is crucial and laboratory mouse models can provide such information. Here, we describe a systematic juxtaposition of human GWAS-discovered loci versus mouse models in order to appreciate the availability of mouse models data, to gain biological insights for the role of these genes and to explore the extent of concordance between these two lines of evidence. We perused publicly available data (NHGRI database for human associations and Mouse Genome Informatics database for mouse models) and employed two alternative approaches for cross-species comparisons, phenotype- and gene-centric. A total of 293 single gene-phenotype human associations (262 unique genes and 69 unique phenotypes) were evaluated. In the phenotype-centric approach, we identified all mouse models and related ortholog genes for the 51 human phenotypes with a comparable phenotype in mice. A total of 27 ortholog genes were found to be associated with the same phenotype in humans and mice, a concordance that was significantly larger than expected by chance (p<0.001). In the gene-centric approach, we were able to locate at least 1 knockout model for 60% of the 262 genes. The knockouts for 35% of these orthologs displayed pre- or post-natal lethality. For the remaining non-lethal orthologs, the same organ system was involved in mice and humans in 71% of the cases (p<0.001). Our project highlights the wealth of available information from mouse models for human GWAS, catalogues extensive information on plausible physiologic implications for many genes, provides hypothesis-generating findings for additional GWAS analyses and documents that the concordance between human and mouse genetic association is larger than expected by chance and can be informative.

Kitsios, Georgios D.; Tangri, Navdeep; Castaldi, Peter J.; Ioannidis, John P. A.

2010-01-01

31

Humanized transgenic mouse models for drug metabolism and pharmacokinetic research.  

PubMed

Extrapolation of the metabolic, pharmacokinetic and toxicological data obtained from animals to humans is not always straightforward, given the remarkable species difference in drug metabolism that is due in large part to the differences in drug-metabolizing enzymes between animals and humans. Furthermore, genetic variations in drug-metabolizing enzymes may significantly alter pharmacokinetics, drug efficacy and safety. Thus, humanized transgenic mouse lines, in which the human drug-metabolizing enzymes are expressed in mouse tissues in the presence or absence of mouse orthologues, have been developed to address such challenges. These humanized transgenic mice are valuable animal models in understanding the significance of specific human drug-metabolizing enzymes in drug clearance and pharmacokinetics, as well as in predicting potential drug-drug interactions and chemical toxicity in humans. This review, therefore, aims to summarize the development and application of some humanized transgenic mouse models expressing human drug-metabolizing enzymes. The limitations of these genetically modified mouse models are also discussed. PMID:22023319

Shen, Hong-Wu; Jiang, Xi-Ling; Gonzalez, Frank J; Yu, Ai-Ming

2011-12-01

32

Cytoarchitecture of mouse and rat cingulate cortex with human homologies.  

PubMed

A gulf exists between cingulate area designations in human neurocytology and those used in rodent brain atlases with a major underpinning of the former being midcingulate cortex (MCC). The present study used images extracted from the Franklin and Paxinos mouse atlas and Paxinos and Watson rat atlas to demonstrate areas comprising MCC and modifications of anterior cingulate (ACC) and retrosplenial cortices. The laminar architecture not available in the atlases is also provided for each cingulate area. Both mouse and rat have a MCC with neurons in all layers that are larger than in ACC and layer Va has particularly prominent neurons and reduced neuron densities. An undifferentiated ACC area 33 lies along the rostral callosal sulcus in rat but not in mouse and area 32 has dorsal and ventral subdivisions with the former having particularly large pyramidal neurons in layer Vb. Both mouse and rat have anterior and posterior divisions of retrosplenial areas 29c and 30, although their cytology is different in rat and mouse. Maps of the rodent cingulate cortices provide for direct comparisons with each region in the human including MCC and it is significant that rodents do not have a posterior cingulate region composed of areas 23 and 31 like the human. It is concluded that rodents and primates, including humans, possess a MCC and this homology along with those in ACC and retrosplenial cortices permit scientists inspired by human considerations to test hypotheses on rodent models of human diseases. PMID:23229151

Vogt, Brent A; Paxinos, George

2012-12-11

33

End Sequencing and Finger Printing of Human & Mouse BAC Libraries  

SciTech Connect

This project provided for continued end sequencing of existing and new BAC libraries constructed to support human sequencing as well as to initiate BAC end sequencing from the mouse BAC libraries constructed to support mouse sequencing. The clones, the sequences, and the fingerprints are now an available resource for the community at large. Research and development of new metaodologies for BAC end sequencing have reduced costs and increase throughput.

Fraser, C.

2005-09-27

34

Comparative epigenomics of human and mouse mammary tumors.  

PubMed

Gene silencing by aberrant epigenetic chromatin alteration is a well-recognized event contributing to tumorigenesis. Although genetically engineered tumor-prone mouse models have proven a powerful tool in understanding many aspects of carcinogenesis, to date few studies have focused on epigenetic alterations in mouse tumors. To uncover epigenetically silenced tumor suppressor genes (TSGs) in mouse mammary tumor cells, we conducted initial genome-wide screening by combining the treatment of cultured cells with the DNA demethylating drug 5-aza-2'-deoxycytidine (5-azadC) and the histone deacetylase inhibitor trichostatin A (TSA) with expression microarray. By conducting this initial screen on EMT6 cells and applying protein function and genomic structure criteria to genes identified as upregulated in response to 5-azadC/TSA, we were able to identify two characterized breast cancer TSGs (Timp3 and Rprm) and four putative TSGs (Atp1B2, Dusp2, FoxJ1 and Smpd3) silenced in this line. By testing a panel of 10 mouse mammary tumor lines, we determined that each of these genes is commonly hypermethylated, albeit with varying frequency. Furthermore, by examining a panel of human breast tumor lines and primary tumors we observed that the human orthologs of ATP1B2, FOXJ1 and SMPD3 are aberrantly hypermethylated in the human disease whereas DUSP2 was not hypermethylated in primary breast tumors. Finally, we examined hypermethylation of several genes targeted for epigenetic silencing in human breast tumors in our panel of 10 mouse mammary tumor lines. We observed that the orthologs of Cdh1, RarB, Gstp1, RassF1 genes were hypermethylated, whereas neither Dapk1 nor Wif1 were aberrantly methylated in this panel of mouse tumor lines. From this study, we conclude that there is significant, but not absolute, overlap in the epigenome of human and mouse mammary tumors. PMID:18836996

Demircan, Berna; Dyer, Lisa M; Gerace, Mallory; Lobenhofer, Edward K; Robertson, Keith D; Brown, Kevin D

2009-01-01

35

Comparative Epigenomics of Human and Mouse Mammary Tumors  

PubMed Central

Gene silencing by aberrant epigenetic chromatin alteration is a well-recognized event contributing to tumorigenesis. While genetically engineered tumor-prone mouse models have proven a powerful tool in understanding many aspects of carcinogenesis, to date few studies have focused on epigenetic alterations in mouse tumors. To uncover epigenetically silenced tumor suppressor genes (TSGs) in mouse mammary tumor cells, we conducted initial genome-wide screening by combining the treatment of cultured cells with the DNA demethylating drug 5-aza-2?-deoxycytidine (5-azadC) and the histone deacetylase inhibitor trichostatin A (TSA) with expression microarray. By conducting this initial screen on EMT6 cells and applying protein function and genomic structure criteria to genes identified as upregulated in response to 5-azadC/TSA, we were able to identify 2 characterized breast cancer TSGs (Timp3 and Rprm) and 4 putative TSGs (Atp1B2, Dusp2, FoxJ1 and Smpd3) silenced in this line. By testing a panel of ten mouse mammary tumor lines, we determined that each of these genes is commonly hypermethylated, albeit with varying frequency. Furthermore, by examining a panel of human breast tumor lines and primary tumors we observed that the human orthologs of ATP1B2, FOXJ1 and SMPD3 are aberrantly hypermethylated in the human disease while DUSP2 was not hypermethylated in primary breast tumors. Finally, we examined hypermethylation of several genes targeted for epigenetic silencing in human breast tumors in our panel of ten mouse mammary tumor lines. We observed that the orthologs of Cdh1, RarB, Gstp1, RassF1 genes were hypermethylated, while neither Dapk1 nor Wif1 were aberrantly methylated in this panel of mouse tumor lines. From this study, we conclude that there is significant, but not absolute, overlap in the epigenome of human and mouse mammary tumors.

Demircan, Berna; Dyer, Lisa M.; Gerace, Mallory; Lobenhofer, Edward K.; Robertson, Keith D.; Brown, Kevin D.

2010-01-01

36

Technical approaches for mouse models of human disease  

PubMed Central

The mouse is the leading organism for disease research. A rich resource of genetic variation occurs naturally in inbred and special strains owing to spontaneous mutations. However, one can also obtain desired gene mutations by using the following processes: targeted mutations that eliminate function in the whole organism or in a specific tissue; forward genetic screens using chemicals or transposons; or the introduction of exogenous transgenes as DNAs, bacterial artificial chromosomes (BACs) or reporter constructs. The mouse is the only mammal that provides such a rich resource of genetic diversity coupled with the potential for extensive genome manipulation, and is therefore a powerful application for modeling human disease. This poster review outlines the major genome manipulations available in the mouse that are used to understand human disease: natural variation, reverse genetics, forward genetics, transgenics and transposons. Each of these applications will be essential for understanding the diversity that is being discovered within the human population.

Justice, Monica J.; Siracusa, Linda D.; Stewart, A. Francis

2011-01-01

37

Effects of exogenous melatonin and circadian synchronization on tumor progression in melanoma-bearing C57BL6 mice.  

PubMed

Circadian rhythmicity impairment reportedly becomes significant as a tumor progresses, while the incidence of cancer can be affected by disruption of the circadian system. Melatonin has oncostatic effects on several types of cancer (breast, prostate, and colorectal cancers), while it can be self-defeating in others, such as lymphoma. Melanoma is one of the most aggressive cancers in humans; however, it seems to respond positively to melatonin in vitro. The present work tested whether body temperature (BT) rhythms are impaired by tumor progression, and whether exogenous melatonin restricts tumor growth and restores circadian rhythmicity; therefore, enhancing survival. To this end, C57 mice were intraperitoneal implanted with a temperature data logger and subcutaneously inoculated with melanoma cells. Animals were then submitted to light-dark (LD) 12:12 cycles or continuous light (LL), with or without melatonin administration. Under LD light conditions, the BT rhythm exhibited a marked reduction in the first circadian harmonic amplitude, and increased phase instability (Rayleigh vector) as the tumor progressed. Melatonin administration (2 mg/kg BW/day), on the other hand, increased the BT rhythm amplitude and phase stability, reduced tumor weight and prevented intraperitoneal dissemination. Exposure to LL induced a free-running rhythm (1500 min), significantly increasing tumor malignity, and therefore reducing survival. Surprisingly, the highest tumor weights and morbidity by metastasis were seen in the LL group treated with melatonin probably because this indoleamine was being administered at different subjective hours to free-running animals. Circadian rhythmicity can thus be used as a marker rhythm for tumor progression, as rhythm impairment increases along with tumor malignancy. While melatonin administration improves rhythmicity and enhances survival under LD conditions, the results are self-defeating when they coexist with circadian disruption as it occurs under LL. This emphasizes the importance of taking into account endogenous rhythmicity and limiting melatonin administration to the subjective night in order to restrict melanoma progression. PMID:18339126

Otálora, B B; Madrid, J A; Alvarez, N; Vicente, V; Rol, M A

2008-04-01

38

Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR)  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. A human cDNA for MTHFR, 2.2 kb in length, has been expressed and shown to result in a catalytically active enzyme of approximately 70 kDa. Fifteen mutations have been identified in the MTHFR gene: 14 rare mutations associated with severe enzymatic deficiency and 1 common variant associated with a milder deficiency. The common polymorphism has been implicated in three multifactorial diseases: occlusive vascular disease, neural tube defects, and colon cancer. The human gene has been mapped to chromosomal region 1p36.3 while the mouse gene has been localized to distal Chromosome (Chr) 4. Here we report the isolation and characterization of the human and mouse genes for MTHFR. A human genomic clone (17 kb) was found to contain the entire cDNA sequence of 2.2 kb; there were 11 exons ranging in size from 102 bp to 432 bp. Intron sizes ranged from 250 bp to 1.5 kb with one exception of 4.2 kb. The mouse genomic clones (19 kb) start 7 kb 5' exon 1 and extend to the end of the coding sequence. The mouse amino acid sequence is approximately 90% identical to the corresponding human sequence. The exon sizes, locations of intronic boundaries, and intron sizes are also quite similar between the two species. The availability of human genomic clones has been useful in designing primers for exon amplification and mutation detection. The mouse genomic clones will be helpful in designing constructs for gene targeting and generation of mouse models for MTHFR deficiency. PMID:9680386

Goyette, P; Pai, A; Milos, R; Frosst, P; Tran, P; Chen, Z; Chan, M; Rozen, R

1998-08-01

39

A Simple Methodology for Conversion of Mouse Monoclonal Antibody to Human-Mouse Chimeric Form  

PubMed Central

Passive immunotherapy has mainly been used as a therapy against cancer and inflammatory conditions. Recent studies have shown that monoclonal antibody-(mAb-) based passive immunotherapy is a promising approach to combat virus infection. Specific mouse mAbs can be routinely generated in large amounts with the use of hybridoma technology but these cannot be used for therapy in human beings due to their immunogenicity. Therefore, the development of chimeric and humanized mAbs is important for therapeutic purpose. This is facilitated by a variety of molecular techniques like recombinant DNA technology and the better understanding of the structure and function of antibody. The human-mouse chimeric forms allow detailed analysis of the mechanism of inhibition and the potential for therapeutic applications. Here, a step-by-step description of the conversion process will be described. The commercial availability of the reagents required in each step means that this experimentation can be easily set up in research laboratories.

Dang, Vinh T.; Mandakhalikar, Kedar D.; Ng, Oi-Wing; Tan, Yee-Joo

2013-01-01

40

Human genetics and diseaseMouse models of male infertility  

Microsoft Academic Search

Spermatogenesis is a complex process that involves stem-cell renewal, genome reorganization and genome repackaging, and that culminates in the production of motile gametes. Problems at all stages of spermatogenesis contribute to human infertility, but few of them can be modelled in vitro or in cell culture. Targeted mutagenesis in the mouse provides a powerful method to analyse these steps and

Howard J. Cooke; Philippa T. K. Saunders

2002-01-01

41

Human and mouse proteases: a comparative genomic approach  

Microsoft Academic Search

The availability of the human and mouse genome sequences has allowed the identification and comparison of their respective degradomes — the complete repertoire of proteases that are produced by these organisms. Because of the essential roles of proteolytic enzymes in the control of cell behaviour, survival and death, degradome analysis provides a useful framework for the global exploration of these

Xose S. Puente; Luis M. Sánchez; Christopher M. Overall; Carlos López-Otín

2003-01-01

42

Liver immune-pathogenesis and therapy of human liver tropic virus infection in humanized mouse models.  

PubMed

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infect and replicate primarily in human hepatocytes. Few reliable and easy accessible animal models are available for studying the immune system's contribution to the liver disease progression during hepatitis virus infection. Humanized mouse models reconstituted with human hematopoietic stem cells (HSCs) have been developed to study human immunology, human immunodeficiency virus 1 infection, and immunopathogenesis. However, a humanized mouse model engrafted with both human immune and human liver cells is needed to study infection and immunopathogenesis of HBV/HCV infection in vivo. We have recently developed the humanized mouse model with both human immune and human liver cells (AFC8-hu HSC/Hep) to study immunopathogenesis and therapy of HCV infection in vivo. In this review, we summarize the current models of HBV/HCV infection and their limitations in immunopathogenesis. We will then present our recent findings of HCV infection and immunopathogenesis in the AFC8-hu HSC/Hep mouse, which supports HCV infection, human T-cell response and associated liver pathogenesis. Inoculation of humanized mice with primary HCV isolates resulted in long-term HCV infection. HCV infection induced elevated infiltration of human immune cells in the livers of HCV-infected humanized mice. HCV infection also induced HCV-specific T-cell immune response in lymphoid tissues of humanized mice. Additionally, HCV infection induced liver fibrosis in humanized mice. Anti-human alpha smooth muscle actin (?SMA) staining showed elevated human hepatic stellate cell activation in HCV-infected humanized mice. We discuss the limitation and future improvements of the AFC8-hu HSC/Hep mouse model and its application in evaluating novel therapeutics, as well as studying both HCV and HBV infection, human immune responses, and associated human liver fibrosis and cancer. PMID:23855307

Bility, Moses T; Li, Feng; Cheng, Liang; Su, Lishan

2013-08-01

43

Transcriptome-scale similarities between mouse and human skeletal muscles with normal and myopathic phenotypes  

Microsoft Academic Search

BACKGROUND: Mouse and human skeletal muscle transcriptome profiles vary by muscle type, raising the question of which mouse muscle groups have the greatest molecular similarities to human skeletal muscle. METHODS: Orthologous (whole, sub-) transcriptome profiles were compared among four mouse-human transcriptome datasets: (M) six muscle groups obtained from three mouse strains (wildtype, mdx, mdx5cv); (H1) biopsied human quadriceps from controls

Alvin T Kho; Peter B Kang; Isaac S Kohane; Louis M Kunkel

2006-01-01

44

Human equivalent of mouse disorganization: Has the case been made?  

PubMed

Temtamy and McKusick suggested mouse disorganization (Ds) as a model for human tibial agenesis, fibular duplication and mirror foot, but the concurrent papers by Winter and Donnai and Donnai and Winter in 1989 kindled interest and led to continued reports of patients hypothesized as human equivalent of Ds (HEDs). Subsequent reports have tended to follow one or other of the two categories outlined; (1) band/constriction with additional anomalies unexplained by bands (ABS); (2) patterns of malformation interpreted as resembling mouse Ds (non-ABS). A review of a series of cases led to a re-read of the original Ds mouse reports by Hummel in 1958 and 1959 and examination of current literature in an attempt to assess the strength of the argument that the patients might represent HEDs. Key to the approach was a paragraph in Hummel's introduction; "some of the developmental anomalies … from action of Ds are similar to those caused by other …genes…teratogens… others are unique…" The corollary is a patient is likelier to represent human DS if the anomaly(s) match these unique malformations/patterns. Presence of anomalies not specifically noted in Ds would weaken the argument for human equivalence. Reports of possible HEDs were ascertained using PubMed and literature cited by authors subsequent to the 1989 papers, up to and including January, 2010. This paper gives an overview of HEDs patients reported and concludes that the ABS type, even with non-band associated anomalies, is not likely to often represent HEDs. Many non-ABS HEDs patients had equally valid alternative hypothesis or diagnoses, malformations unreported or unusual for the Ds mouse, and/or paucity of the more unusual anomalies of the Ds mouse. PMID:21416595

Hunter, Alasdair G W

2011-03-17

45

Of mice and men: aligning mouse and human anatomies.  

PubMed

This paper reports on the alignment between mouse and human anatomies, a critical resource for comparative science as diseases in mice are used as mod-els of human disease. The two ontologies under investigation are the NCI Thesaurus (human anatomy) and the Adult Mouse Anatomical Dictionary, each comprising about 2500 anatomical concepts. This study compares two approaches to aligning ontologies. One is fully automatic, based on a combination of lexical and structural similarity; the other is manual. The resulting mappings were evaluated by an expert. 715 and 781 mappings were identified by each method respectively, of which 639 are common to both and all valid. The applications of the map-ping are discussed from the perspective of biology and from that of ontology. PMID:16779002

Bodenreider, Olivier; Hayamizu, Terry F; Ringwald, Martin; De Coronado, Sherri; Zhang, Songmao

2005-01-01

46

Improved human disease candidate gene prioritization using mouse phenotype  

PubMed Central

Background The majority of common diseases are multi-factorial and modified by genetically and mechanistically complex polygenic interactions and environmental factors. High-throughput genome-wide studies like linkage analysis and gene expression profiling, tend to be most useful for classification and characterization but do not provide sufficient information to identify or prioritize specific disease causal genes. Results Extending on an earlier hypothesis that the majority of genes that impact or cause disease share membership in any of several functional relationships we, for the first time, show the utility of mouse phenotype data in human disease gene prioritization. We study the effect of different data integration methods, and based on the validation studies, we show that our approach, ToppGene , outperforms two of the existing candidate gene prioritization methods, SUSPECTS and ENDEAVOUR. Conclusion The incorporation of phenotype information for mouse orthologs of human genes greatly improves the human disease candidate gene analysis and prioritization.

Chen, Jing; Xu, Huan; Aronow, Bruce J; Jegga, Anil G

2007-01-01

47

Of Mice and Men: Aligning Mouse and Human Anatomies  

PubMed Central

This paper reports on the alignment between mouse and human anatomies, a critical resource for comparative science as diseases in mice are used as models of human disease. The two ontologies under investigation are the NCI Thesaurus (human anatomy) and the Adult Mouse Anatomical Dictionary, each comprising about 2500 anatomical concepts. This study compares two approaches to aligning ontologies. One is fully automatic, based on a combination of lexical and structural similarity; the other is manual. The resulting mappings were evaluated by an expert. 715 and 781 mappings were identified by each method respectively, of which 639 are common to both and all valid. The applications of the mapping are discussed from the perspective of biology and from that of ontology.

Bodenreider, Olivier; Hayamizu, Terry F.; Ringwald, Martin; De Coronado, Sherri; Zhang, Songmao

2005-01-01

48

Characterization of human and mouse cartilage oligomeric matrix protein  

SciTech Connect

Cartilage oligomeric matrix protein (COMP) is a 524,000-Da protein that is expressed at high levels in the territorial matrix of chondrocytes. The sequences of rat and bovine COMP indicate that it is a member of the thrombospondin gene family. In this study, we have cloned and sequenced human COMP. Phylogenetic analysis using progressive sequence alignment and two parsimony-based algorithms indicates that the COMP gene and a precursor of the thrombospondin-3 and -4 genes were produced by a gene duplication that occurred 750 million years ago. An interspecific backcross mapping panel has been used to map the murine COMP gene to the central region of mouse chromosome 8. Southern blot analysis of a somatic cell hybrid DNA panel and in situ hybridization to human metaphase chromosomes indicate that the human COMP gene is located on chromosome 19 in band p13.1. These data confirm and extend the known regions of homology between human and mouse chromosomes and establish that COMP, like thrombospondin-1, -2, -3, and -4, is present in the human and mouse genomes. 26 refs., 5 figs.

Newton, G.; Lawler, J.; Weremowicz, S. [Harvard Medical School, Boston, MA (United States)] [and others

1994-12-01

49

Determinants of human and mouse melanoma cell sensitivities to oleandrin.  

PubMed

Oleandrin, a cardiac glycoside component of Nerium oleander, has been shown to induce apoptosis in malignant cells. While human tumor cells are very sensitive to growth inhibition by oleandrin, murine tumor cells are extremely resistant. Using human BRO and mouse B16 melanoma cell lines, we explored several possible determinants of cell sensitivity to oleandrin and compared with ouabain. The studies include Na+, K(+)-ATPase activity and its isoforms as well as the cellular uptake of these cardiac glycosides. Oleandrin and ouabain induced apoptosis was detected in BRO cells while no evidence of cell death was observed in B16 cells even at concentrations 1000-fold higher than that used for BRO cells. Cellular uptake of oleandrin and ouabain was 3-4 fold greater in human BRO tumor cells than murine tumor cells. Partially purified Na+, K(+)-ATPase from human BRO cells was inhibited at a concentration that was 1000-fold less than that was required to inhibit mouse B16 enzyme to the same extent. Using Western blot analyses, human BRO cells were found to express both the sensitive alpha3 isoform and the less sensitive alpha1 isoform of Na+, K(+)-ATPase while mouse B16 cells expressed only the alpha1 isoform. These data suggest that differential expressions of Na+, K(+)-ATPase activities and its isoforms in BRO and B16 cells as well as cellular drug uptake may be important determinants of tumor cell sensitivity to cardiac glycosides. PMID:19066128

Lin, Yun; Dubinsky, William P; Ho, Dah H; Felix, Edward; Newman, Robert A

2008-01-01

50

Genetically engineered mouse models and human osteosarcoma  

PubMed Central

Osteosarcoma is the most common form of bone cancer. Pivotal insight into the genes involved in human osteosarcoma has been provided by the study of rare familial cancer predisposition syndromes. Three kindreds stand out as predisposing to the development of osteosarcoma: Li-Fraumeni syndrome, familial retinoblastoma and RecQ helicase disorders, which include Rothmund-Thomson Syndrome in particular. These disorders have highlighted the important roles of P53 and RB respectively, in the development of osteosarcoma. The association of OS with RECQL4 mutations is apparent but the relevance of this to OS is uncertain as mutations in RECQL4 are not found in sporadic OS. Application of the knowledge or mutations of P53 and RB in familial and sporadic OS has enabled the development of tractable, highly penetrant murine models of OS. These models share many of the cardinal features associated with human osteosarcoma including, importantly, a high incidence of spontaneous metastasis. The recent development of these models has been a significant advance for efforts to improve our understanding of the genetics of human OS and, more critically, to provide a high-throughput genetically modifiable platform for preclinical evaluation of new therapeutics.

2012-01-01

51

Genetically engineered mouse models and human osteosarcoma.  

PubMed

Osteosarcoma is the most common form of bone cancer. Pivotal insight into the genes involved in human osteosarcoma has been provided by the study of rare familial cancer predisposition syndromes. Three kindreds stand out as predisposing to the development of osteosarcoma: Li-Fraumeni syndrome, familial retinoblastoma and RecQ helicase disorders, which include Rothmund-Thomson Syndrome in particular. These disorders have highlighted the important roles of P53 and RB respectively, in the development of osteosarcoma. The association of OS with RECQL4 mutations is apparent but the relevance of this to OS is uncertain as mutations in RECQL4 are not found in sporadic OS. Application of the knowledge or mutations of P53 and RB in familial and sporadic OS has enabled the development of tractable, highly penetrant murine models of OS. These models share many of the cardinal features associated with human osteosarcoma including, importantly, a high incidence of spontaneous metastasis. The recent development of these models has been a significant advance for efforts to improve our understanding of the genetics of human OS and, more critically, to provide a high-throughput genetically modifiable platform for preclinical evaluation of new therapeutics. PMID:23036272

Ng, Alvin Jm; Mutsaers, Anthony J; Baker, Emma K; Walkley, Carl R

2012-10-04

52

Genome-Wide Expression Profiling of Five Mouse Models Identifies Similarities and Differences with Human Psoriasis  

Microsoft Academic Search

Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments.However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional

William R. Swindell; Andrew Johnston; Steve Carbajal; Gangwen Han; Christian Wohn; Jun Lu; Xianying Xing; Rajan P. Nair; John J. Voorhees; James T. Elder; Xiao-Jing Wang; Shigetoshi Sano; Errol P. Prens; John Digiovanni; Mark R. Pittelkow; Nicole L. Ward; Johann E. Gudjonsson; Stefan Bereswill

2011-01-01

53

Regulatory Potential Scores From Genome-Wide Three-Way Alignments of Human, Mouse, and Rat  

Microsoft Academic Search

We generalize the computation of the Regulatory Potential (RP) score from two-way alignments of human and mouse to three-way alignments of human, mouse, and rat. This requires overcoming technical challenges that arise because the complexity of the models underlying the score increases exponentially with the number of species. Despite the close evolutionary proximity of rat to mouse, we find that

Diana Kolbe; James Taylor; Laura Elnitski; Pallavi Eswara; Jia Li; Webb Miller; Ross Hardison; Francesca Chiaromonte

2004-01-01

54

Overlapping genes in the human and mouse genomes  

Microsoft Academic Search

BACKGROUND: Increasing evidence suggests that overlapping genes are much more common in eukaryotic genomes than previously thought. In this study we identified and characterized the overlapping genes in a set of 13,484 pairs of human-mouse orthologous genes. RESULTS: About 10% of the genes under study are overlapping genes, the majority of which are different-strand overlaps. The majority of the same-strand

Chaitanya R Sanna; Wen-Hsiung Li; Liqing Zhang

2008-01-01

55

A 1 adenosine receptor of human and mouse adipose tissues  

Microsoft Academic Search

The aberrant functioning of the A1 adenosine receptor of adipose tissue has been implicated as a factor in obesity. To begin to address questions concerning this relationship, the possibility of a unique A1 adenosine receptor in adipose tissue must be investigated. Therefore, cDNAs encoding the A1 adenosine receptors of adipose tissues of a mouse and an obese human were isolated,

Irene Tatsis-Kotsidis; Bernard F Erlanger

1999-01-01

56

MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors.  

PubMed

Neurofibromatosis type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating the effects of hyperactive Ras in NF1 tumors are unknown. We performed cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs and identified global negative feedback of genes that regulate Ras/Raf/MEK/ERK signaling in both species. Nonetheless, ERK activation was sustained in mouse and human neurofibromas and MPNST. We used a highly selective pharmacological inhibitor of MEK, PD0325901, to test whether sustained Ras/Raf/MEK/ERK signaling contributes to neurofibroma growth in a neurofibromatosis mouse model (Nf1(fl/fl);Dhh-Cre) or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in more than 80% of mice tested. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide a strong rationale for testing MEK inhibitors in NF1 clinical trials. PMID:23221341

Jessen, Walter J; Miller, Shyra J; Jousma, Edwin; Wu, Jianqiang; Rizvi, Tilat A; Brundage, Meghan E; Eaves, David; Widemann, Brigitte; Kim, Mi-Ok; Dombi, Eva; Sabo, Jessica; Hardiman Dudley, Atira; Niwa-Kawakita, Michiko; Page, Grier P; Giovannini, Marco; Aronow, Bruce J; Cripe, Timothy P; Ratner, Nancy

2012-12-10

57

MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors  

PubMed Central

Neurofibromatosis type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating the effects of hyperactive Ras in NF1 tumors are unknown. We performed cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs and identified global negative feedback of genes that regulate Ras/Raf/MEK/ERK signaling in both species. Nonetheless, ERK activation was sustained in mouse and human neurofibromas and MPNST. We used a highly selective pharmacological inhibitor of MEK, PD0325901, to test whether sustained Ras/Raf/MEK/ERK signaling contributes to neurofibroma growth in a neurofibromatosis mouse model (Nf1fl/fl;Dhh-Cre) or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in more than 80% of mice tested. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide a strong rationale for testing MEK inhibitors in NF1 clinical trials.

Jessen, Walter J.; Miller, Shyra J.; Jousma, Edwin; Wu, Jianqiang; Rizvi, Tilat A.; Brundage, Meghan E.; Eaves, David; Widemann, Brigitte; Kim, Mi-Ok; Dombi, Eva; Sabo, Jessica; Hardiman Dudley, Atira; Niwa-Kawakita, Michiko; Page, Grier P.; Giovannini, Marco; Aronow, Bruce J.; Cripe, Timothy P.; Ratner, Nancy

2012-01-01

58

Classification of proliferative pulmonary lesions of the mouse: recommendations of the mouse models of human cancers consortium  

Microsoft Academic Search

Rapid advances in generating new mouse genetic models for lung neoplasia provide a continuous challenge for pathologists and investigators. Frequently, phenotypes of new models either have no precedents or are arbitrarily attributed according to incongruent human and mouse classifications. Thus, comparative characterization and validation of novel models can be difficult. To address these issues, a series of discussions was initiated

Alexander Yu. Nikitin; Ana Alcaraz; Miriam R. Anver; Roderick T. Bronson; Robert D. Cardiff; Darlene Dixon; Armando E. Fraire; Edward W. Gabrielson; William T. Gunning; Diana C. Haines; Matthew H. Kaufman

2004-01-01

59

From XenoMouse technology to panitumumab, the first fully human antibody product from transgenic mice  

Microsoft Academic Search

Therapeutic monoclonal antibodies have shown limited efficacy and safety owing to immunogenicity of mouse sequences in humans. Among the approaches developed to overcome these hurdles were transgenic mice genetically engineered with a 'humanized' humoral immune system. One such transgenic system, the XenoMouse, has succeeded in recapitulating the human antibody response in mice, by introducing nearly the entire human immunoglobulin loci

Rafael G Amado; Xiaodong Yang; Lorin Roskos; Gisela Schwab; Aya Jakobovits

2007-01-01

60

Further Improvements of the P. falciparum Humanized Mouse Model  

PubMed Central

Background It has been shown previously that it is possible to obtain growth of Plasmodium falciparum in human erythrocytes grafted in mice lacking adaptive immune responses by controlling, to a certain extent, innate defences with liposomes containing clodronate (clo-lip). However, the reproducibility of those models is limited, with only a proportion of animals supporting longstanding parasitemia, due to strong inflammation induced by P. falciparum. Optimisation of the model is much needed for the study of new anti-malarial drugs, drug combinations, and candidate vaccines. Materials/Methods We investigated the possibility of improving previous models by employing the intravenous route (IV) for delivery of both human erythrocytes (huRBC) and P. falciparum, instead of the intraperitoneal route (IP), by testing various immunosuppressive drugs that might help to control innate mouse defences, and by exploring the potential benefits of using immunodeficient mice with additional genetic defects, such as those with IL-2R? deficiency (NSG mice). Results We demonstrate here the role of aging, of inosine and of the IL-2 receptor ? mutation in controlling P. falciparum induced inflammation. IV delivery of huRBC and P. falciparum in clo-lip treated NSG mice led to successful infection in 100% of inoculated mice, rapid rise of parasitemia to high levels (up to 40%), long-lasting parasitemia, and consistent results from mouse-to-mouse. Characteristics were closer to human infection than in previous models, with evidence of synchronisation, partial sequestration, and receptivity to various P. falciparum strains without preliminary adaptation. However, results show that a major IL-12p70 inflammatory response remains prevalent. Conclusion The combination of the NSG mouse, clodronate loaded liposomes, and IV delivery of huRBC has produced a reliable and more relevant model that better meets the needs of Malaria research.

Meija, Pedro; Swetman, Claire; Gleeson, James; Perignon, Jean-Louis; Druilhe, Pierre

2011-01-01

61

Human More Complex than Mouse at Cellular Level  

PubMed Central

The family of transcription factors with the C2H2 zinc finger domain is expanding in the evolution of vertebrates, reaching its highest numbers in the mammals. The question arises: whether an increased amount of these transcription factors is related to embryogenesis, nervous system, pathology or more of them are expressed in individual cells? Among mammals, the primates have a more complex anatomical structure than the rodents (e.g., brain). In this work, I show that a greater number of C2H2-ZFgenes are expressed in the human cells than in the mouse cells. The effect is especially pronounced for C2H2-ZF genes accompanied with the KRAB domain. The relative difference between the numbers of C2H2-ZF(-KRAB) genes in the human and mouse cellular transcriptomes even exceeds their difference in the genomes (i.e. a greater subset of existing in the genome genes is expressed in the human cellular transcriptomes compared to the mouse transcriptomes). The evolutionary turnover of C2H2-ZF(-KRAB) genes acts in the direction of the revealed phenomenon, i.e. gene duplication and loss enhances the difference in the relative number of C2H2-ZF(-KRAB) genes between human and mouse cellular transcriptomes. A higher amount of these genes is expressed in the brain and embryonic cells (compared with other tissues), whereas a lower amount - in the cancer cells. It is specifically the C2H2-ZF transcription factors whose repertoire is poorer in the cancer and richer in the brain (other transcription factors taken together do not show this trend). These facts suggest that increase of anatomical complexity is accompanied by a more complex intracellular regulation involving these transcription factors. Malignization is associated with simplification of this regulation. These results agree with the known fact that human cells are more resistant to oncogenic transformation than mouse cells. The list of C2H2-ZF genes whose suppression might be involved in malignization is provided.

Vinogradov, Alexander E.

2012-01-01

62

Conservation of Regional Gene Expression in Mouse and Human Brain  

PubMed Central

Many neurodegenerative diseases have a hallmark regional and cellular pathology. Gene expression analysis of healthy tissues may provide clues to the differences that distinguish resistant and sensitive tissues and cell types. Comparative analysis of gene expression in healthy mouse and human brain provides a framework to explore the ability of mice to model diseases of the human brain. It may also aid in understanding brain evolution and the basis for higher order cognitive abilities. Here we compare gene expression profiles of human motor cortex, caudate nucleus, and cerebellum to one another and identify genes that are more highly expressed in one region relative to another. We separately perform identical analysis on corresponding brain regions from mice. Within each species, we find that the different brain regions have distinctly different expression profiles. Contrasting between the two species shows that regionally enriched genes in one species are generally regionally enriched genes in the other species. Thus, even when considering thousands of genes, the expression ratios in two regions from one species are significantly correlated with expression ratios in the other species. Finally, genes whose expression is higher in one area of the brain relative to the other areas, in other words genes with patterned expression, tend to have greater conservation of nucleotide sequence than more widely expressed genes. Together these observations suggest that region-specific genes have been conserved in the mammalian brain at both the sequence and gene expression levels. Given the general similarity between patterns of gene expression in healthy human and mouse brains, we believe it is reasonable to expect a high degree of concordance between microarray phenotypes of human neurodegenerative diseases and their mouse models. Finally, these data on very divergent species provide context for studies in more closely related species that address questions such as the origins of cognitive differences.

Strand, Andrew D; Aragaki, Aaron K; Baquet, Zachary C; Hodges, Angela; Cunningham, Philip; Holmans, Peter; Jones, Kevin R; Jones, Lesley; Kooperberg, Charles; Olson, James M

2007-01-01

63

Mouse genetic and phenotypic resources for human genetics  

PubMed Central

The use of model organisms to provide information on gene function has proved to be a powerful approach to our understanding of both human disease and fundamental mammalian biology. Large-scale community projects using mice, based on forward and reverse genetics, and now the pan-genomic phenotyping efforts of the International Mouse Phenotyping Consortium (IMPC), are generating resources on an unprecedented scale which will be extremely valuable to human genetics and medicine. We discuss the nature and availability of data, mice and ES cells from these large-scale programmes, the use of these resources to help prioritise and validate candidate genes in human genetic association studies, and how they can improve our understanding of the underlying pathobiology of human disease.

Schofield, Paul N.; Hoehndorf, Robert; Gkoutos, Georgios V.

2012-01-01

64

Long-term production of human monoclonal antibodies by human-mouse heterohybridomas  

Microsoft Academic Search

Production of monoclonal antibodies (mAbs) by fused somatic cells was first developed by Köhler and Milstein two decades ago, but its utilization for the production of human mAbs, particularly those bearing ? chains, has been difficult because heterohybridomas formed with mouse myeloma cells are unstable and tend to lose certain of their human chromosomes. We have stabilized two such heterohybridomas

Kaoru Yoshinari; Kenji Arai; Hideki Kimura; Kunio Matsumoto; Yutaka Yamaguchi

1995-01-01

65

The truth about mouse, human, worms and yeast  

PubMed Central

Genome comparisons are behind the powerful new annotation methods being developed to find all human genes, as well as genes from other genomes. Genomes are now frequently being studied in pairs to provide cross-comparison datasets. This 'Noah's Ark' approach often reveals unsuspected genes and may support the deletion of false-positive predictions. Joining mouse and human as the cross-comparison dataset for the first two mammals are: two Drosophila species, D. melanogaster and D. pseudoobscura; two sea squirts, Ciona intestinalis and Ciona savignyi; four yeast (Saccharomyces) species; two nematodes, Caenorhabditis elegans and Caenorhabditis briggsae; and two pufferfish (Takefugu rubripes and Tetraodon nigroviridis). Even genomes like yeast and C. elegans, which have been known for more than five years, are now being significantly improved. Methods developed for yeast or nematodes will now be applied to mouse and human, and soon to additional mammals such as rat and dog, to identify all the mammalian protein-coding genes. Current large disparities between human Unigene predictions (127,835 genes) and gene-scanning methods (45,000 genes) still need to be resolved. This will be the challenge during the next few years.

2004-01-01

66

Constitutive and inducible granulocyte-macrophage functions in mouse, rat, and human myeloid leukemia-derived continuous tissue culture lines  

Microsoft Academic Search

Fourteen continuous tissue culture cell lines derived from mouse, rat, or human granulocyte-macrophage can cers were studied for expression of spontaneous and inducible markers of differentiated cells. Five cell lines (two mouse, two rat, and one human) synthesized myelo- peroxidase spontaneously, and a fifth mouse line showed biochemically inducible enzyme. Twelve lines (6 mouse, 3 rat, and 3 human) produced

J S Greenberger; Peter E. Newburger; Abraham Karpas; William C. Moloney

1978-01-01

67

CYP1A1 and CYP1A2 expression: Comparing 'humanized' mouse lines and wild-type mice; comparing human and mouse hepatoma-derived cell lines  

SciTech Connect

Human and rodent cytochrome P450 (CYP) enzymes sometimes exhibit striking species-specific differences in substrate preference and rate of metabolism. Human risk assessment of CYP substrates might therefore best be evaluated in the intact mouse by replacing mouse Cyp genes with human CYP orthologs; however, how 'human-like' can human gene expression be expected in mouse tissues? Previously a bacterial-artificial-chromosome-transgenic mouse, carrying the human CYP1A1{sub C}YP1A2 locus and lacking the mouse Cyp1a1 and Cyp1a2 orthologs, was shown to express robustly human dioxin-inducible CYP1A1 and basal versus inducible CYP1A2 (mRNAs, proteins, enzyme activities) in each of nine mouse tissues examined. Chimeric mice carrying humanized liver have also been generated, by transplanting human hepatocytes into a urokinase-type plasminogen activator(+/+){sub s}evere-combined-immunodeficiency (uPA/SCID) line with most of its mouse hepatocytes ablated. Herein we compare basal and dioxin-induced CYP1A mRNA copy numbers, protein levels, and four enzymes (benzo[a]pyrene hydroxylase, ethoxyresorufin O-deethylase, acetanilide 4-hydroxylase, methoxyresorufin O-demethylase) in liver of these two humanized mouse lines versus wild-type mice; we also compare these same parameters in mouse Hepa-1c1c7 and human HepG2 hepatoma-derived established cell lines. Most strikingly, mouse liver CYP1A1-specific enzyme activities are between 38- and 170-fold higher than human CYP1A1-specific enzyme activities (per unit of mRNA), whereas mouse versus human CYP1A2 enzyme activities (per unit of mRNA) are within 2.5-fold of one another. Moreover, both the mouse and human hepatoma cell lines exhibit striking differences in CYP1A mRNA levels and enzyme activities. These findings are relevant to risk assessment involving human CYP1A1 and CYP1A2 substrates, when administered to mice as environmental toxicants or drugs.

Uno, Shigeyuki; Endo, Kaori [Department of Biochemistry, Nihon University School of Medicine, 30-1 Oyaguchikami-cho, Itabashi-ku, Tokyo 173-8610 (Japan); Ishida, Yuji; Tateno, Chise [PhenixBio Co., Ltd., 3-4-1 Kagamiyama, Higashihiroshima, Hiroshima 739-0046 (Japan); Makishima, Makoto [Department of Biochemistry, Nihon University School of Medicine, 30-1 Oyaguchikami-cho, Itabashi-ku, Tokyo 173-8610 (Japan); Yoshizato, Katsutoshi [PhenixBio Co., Ltd., 3-4-1 Kagamiyama, Higashihiroshima, Hiroshima 739-0046 (Japan); Nebert, Daniel W. [Department of Environmental Health and Center for Environmental Genetics (CEG) University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati OH 45267-0056 (United States)], E-mail: dan.nebert@uc.edu

2009-05-15

68

A mouse model for human osteogenesis imperfecta type VI.  

PubMed

Osteogenesis imperfecta type VI (OI type VI) has recently be linked to a mutation in the SERPINF1 gene, which encodes pigment epithelium-derived factor (PEDF), a ubiquitously expressed protein originally described for its neurotrophic and antiangiogenic properties. In this study, we characterized the skeletal phenotype of a mouse with targeted disruption of Pedf. In normal mouse bone, Pedf was localized to osteoblasts and osteocytes. Micro-computed tomography (µCT) and quantitative bone histomorphometry in femurs of mature Pedf null mutants revealed reduced trabecular bone volume and the accumulation of unmineralized bone matrix. Fourier transform infrared microscopy (FTIR) indicated an increased mineral:matrix ratio in mutant bones, which were more brittle than controls. In vitro, osteoblasts from Pedf null mice exhibited enhanced mineral deposition as assessed by Alizarin Red staining and an increased mineral:matrix determined by FTIR analysis of calcified nodules. The findings in this mouse model mimic the principal structural and biochemical features of bone observed in humans with OI type VI and consequently provide a useful model with which to further investigate the role of PEDF in this bone disorder. PMID:23413146

Bogan, Rosalind; Riddle, Ryan C; Li, Zhu; Kumar, Sarvesh; Nandal, Anjali; Faugere, Marie-Claude; Boskey, Adele; Crawford, Susan E; Clemens, Thomas L

2013-07-01

69

Agonists can discriminate between cloned human and mouse prostacyclin receptors  

Microsoft Academic Search

The ability of prostacyclin analogues to stimulate adenylyl cyclase (AC) and phospholipase C (PLC) in Chinese hamster ovary (CHO) cells expressing cloned human (hIP) or cloned mouse (mIP) prostacyclin receptors has been compared. For hIP, the order of potency (pEC50) for stimulating AC and PLC pathways was similar: AFP-07 (9.3, 8.4)>cicaprost (8.3, 6.9), iloprost (7.9, 6.8)>taprostene (7.4, 6.8)>carbacyclin (6.9, 6.6),

K. B. S. Chow; R. L. Jones; H. Wise

2004-01-01

70

INTERSPECIES SENSITIVITY TO CHEMICAL CARCINOGENS: RELATIONSHIPS BETWEEN MOUSE SKIN TUMORS AND HUMAN LUNG CANCER  

EPA Science Inventory

This review focuses on the relationships between mouse skin tumors and human lung cancer and discusses these relationships from several perspectives. hese perspectives include: mouse skin as an experimental test system; metabolic comparisons of the response of mouse skin and huma...

71

A Comprehensive Genetic Map of Murine Chromosome 11 Reveals Extensive Linkage Conservation between Mouse and Human  

PubMed Central

Interspecific backcross animals from a cross between C57BL/6J and Mus spretus mice were used to generate a comprehensive linkage map of mouse chromosome 11. The relative map positions of genes previously assigned to mouse chromosome 11 by somatic cell hybrid or genetic backcross analysis were determined (Erbb, Rel, Il-3, Csfgm, Trp53-1, Evi-2, Erba, Erbb-2, Csfg, Myhs, Cola-1, Myla, Hox-2 and Pkca). We also analyzed genes that we suspected would map to chromosome 11 by virtue of their location in human chromosomes and the known linkage homologies that exist between murine chromosome 11 and human chromosomes (Mpo, Ngfr, Pdgfr and Fms). Two of the latter genes, Mpo and Ngfr, mapped to mouse chromosome 11. Both genes also mapped to human chromosome 17, extending the degree of linkage conservation observed between human chromosome 17 and mouse chromosome 11. Pdgfr and Fms, which are closely linked to Il-3 and Csfgm in humans on chromosome 5, mapped to mouse chromosome 18 rather than mouse chromosome 11, thereby defining yet another conserved linkage group between human and mouse chromosomes. The mouse chromosome 11 linkage map generated in these studies substantially extends the framework for identifying homologous genes in the mouse that are involved in human disease, for elucidating the genes responsible for several mouse mutations, and for gaining insights into chromosome evolution and genome organization.

Buchberg, A. M.; Brownell, E.; Nagata, S.; Jenkins, N. A.; Copeland, N. G.

1989-01-01

72

Glycine receptor mouse mutants: model systems for human hyperekplexia.  

PubMed

Human hyperekplexia is a neuromotor disorder caused by disturbances in inhibitory glycine-mediated neurotransmission. Mutations in genes encoding for glycine receptor subunits or associated proteins, such as GLRA1, GLRB, GPHN and ARHGEF9, have been detected in patients suffering from hyperekplexia. Classical symptoms are exaggerated startle attacks upon unexpected acoustic or tactile stimuli, massive tremor, loss of postural control during startle and apnoea. Usually patients are treated with clonazepam, this helps to dampen the severe symptoms most probably by up-regulating GABAergic responses. However, the mechanism is not completely understood. Similar neuromotor phenotypes have been observed in mouse models that carry glycine receptor mutations. These mouse models serve as excellent tools for analysing the underlying pathomechanisms. Yet, studies in mutant mice looking for postsynaptic compensation of glycinergic dysfunction via an up-regulation in GABAA receptor numbers have failed, as expression levels were similar to those in wild-type mice. However, presynaptic adaptation mechanisms with an unusual switch from mixed GABA/glycinergic to GABAergic presynaptic terminals have been observed. Whether this presynaptic adaptation explains the improvement in symptoms or other compensation mechanisms exist is still under investigation. With the help of spontaneous glycine receptor mouse mutants, knock-in and knock-out studies, it is possible to associate behavioural changes with pharmacological differences in glycinergic inhibition. This review focuses on the structural and functional characteristics of the various mouse models used to elucidate the underlying signal transduction pathways and adaptation processes and describes a novel route that uses gene-therapeutic modulation of mutated receptors to overcome loss of function mutations. PMID:23941355

Schaefer, Natascha; Langlhofer, Georg; Kluck, Christoph J; Villmann, Carmen

2013-11-01

73

Chromosomal localization of mouse bullous pemphigoid antigens, BPAG1 and BPAG2: Identification of a new region of homology between mouse and human chromosomes  

SciTech Connect

Two bullous pemphigoid antigens, BPAG1 and BPAG2, have been recently cloned and mapped to human chromosomes 6p12-p11 and 10q24.3, respectively. In this study, we localized the corresponding mouse genes by interspecific backcross analysis. Bpag-1 mapped to the proximal region of mouse chromosome 1, identifying a new region of homology between human chromosome 6 and mouse chromosome 1. Bpag-2 mapped to the distal end of mouse chromosome 19 in a region of homology to human chromosome 10q. These assignments confirm and extend the relationships between the human and the mouse chromosomes. 13 refs., 1 fig.

Copeland, N.G.; Gilbert, D.J.; Jenkins, N.A. (NCI-Frederick Cancer Research and Development Center, MD (United States)); Li, K.; Sawamura, D.; Chu, Monli; Uitto, J. (Jefferson Medical College, Philadelphia, PA (United States)); Giudice, G.J. (Medical College of Wisconsin, Milwaukee (United States))

1993-01-01

74

An analysis of the human and mouse CXCR5 gene introns.  

PubMed

Both mouse and human chemokine receptor CXC motif 5 (CXCR5) genes exhibit one single intron interrupting the coding sequence. The mouse intron is 12053 nucleotides (nt) long; the human intron is 9603 nt long. Sections of the mouse intron significantly align plus/plus with sections of the human intron; the aligned segments are in the same order in mouse as in man and overall cover 13% of the mouse sequence and 17% of the human sequence. The human CXCR5 intron harbors sequences derived from retroviruses (human endogenous retroviruses). The mouse intron comprises very similar sequences. About 70% of the mouse intron sequence is 'specific' to this gene, while sequences in the rest of the intron are shared with many other genes located on different chromosomes. In the human the coverage by specific sequences is about 87%. Thus, the contribution of transposable elements is significantly higher in mouse (30%) than in man (13%). Intra-intronic plus/minus alignments exist in mouse (10 couples) and man (two couples): these may form stem and loop structures determining the secondary structure of the corresponding pre-mRNAs. PMID:20809769

Panaro, Maria Antonietta; Calvello, Rosa; Mitolo, Carlo Ivan; Sisto, Margherita; Saccia, Matteo; Cianciulli, Antonia

2010-09-01

75

Structure-function analysis of interleukin-5 utilizing mouse/human chimeric molecules.  

PubMed Central

Interleukin-5 (IL5) is a T cell derived glycoprotein that stimulates eosinophil production and activation. In the mouse, but apparently not in the human, it is active on B cells. The murine and human IL5 polypeptides exhibit 70% sequence similarity and yet display distinct species-specific activity. Whilst mouse and human IL5 are equally active in human cell assays, human IL5 is 100-fold less active than murine IL5 in mouse cell assays. Two restriction sites were utilized to divide the human and mouse sequences into three fragments. Hybrid molecules consisting of all combinations of these fragments were constructed and expressed. In the human cell assays [using bone marrow or the erythroleukaemic cell line (TF-1)] all the hybrid proteins generated activity comparable to that of the human and mouse IL5. This implies that replacing different domains does not result in detrimental effects to the tertiary structure of the molecule. In the mouse cell assays [using bone marrow or the pro-B cell line (B13)] the hybrids clearly identified the importance of residues in the C terminus for biological activity. The changing of only eight residues in this region of human IL5, to those of mouse IL5, resulted in the hybrid producing biological activity comparable to mouse IL5. In addition, competition binding assays showed that this region probably interacts with the receptor. Images

McKenzie, A N; Barry, S C; Strath, M; Sanderson, C J

1991-01-01

76

USE OF A HUMAN/MOUSE HYBRID CELL LINE TO DETECT ANEUPLOIDY INDUCED BY ENVIRONMENTAL CHEMICALS  

EPA Science Inventory

A short-term assay utilizing a human/mouse monochromosomal hybrid cell line R3-5, to detect chemically induced aneuploidy in mammalian cells is described. A single human chromosome transferred into mouse cells was used as a cytogenetic marker to quantitate abnormal chromosome seg...

77

Histologic Changes in Nude Mouse Skin and Human Skin Xenografts Following Exposure to Sulfhydryl Reagents: Arsenicals,  

National Technical Information Service (NTIS)

This report documents the histological changes in nude mouse skin and in human skin xenografts on nude mice following exposure to phenyldichloroarsine (PDA), a vesicant arsenical. Under light microscopy, the authors observed in PDA-treated human skin graf...

E. L. McGown T. Van Ravenswaay C. R. Dumlao

1987-01-01

78

The mouse QTL map helps interpret human genome-wide association studies for HDL cholesterol.  

PubMed

Genome-wide association (GWA) studies represent a powerful strategy for identifying susceptibility genes for complex diseases in human populations but results must be confirmed and replicated. Because of the close homology between mouse and human genomes, the mouse can be used to add evidence to genes suggested by human studies. We used the mouse quantitative trait loci (QTL) map to interpret results from a GWA study for genes associated with plasma HDL cholesterol levels. We first positioned single nucleotide polymorphisms (SNPs) from a human GWA study on the genomic map for mouse HDL QTL. We then used mouse bioinformatics, sequencing, and expression studies to add evidence for one well-known HDL gene (Abca1) and three newly identified genes (Galnt2, Wwox, and Cdh13), thus supporting the results of the human study. For GWA peaks that occur in human haplotype blocks with multiple genes, we examined the homologous regions in the mouse to prioritize the genes using expression, sequencing, and bioinformatics from the mouse model, showing that some genes were unlikely candidates and adding evidence for candidate genes Mvk and Mmab in one haplotype block and Fads1 and Fads2 in the second haplotype block. Our study highlights the value of mouse genetics for evaluating genes found in human GWA studies. PMID:21444760

Leduc, Magalie S; Lyons, Malcolm; Darvishi, Katayoon; Walsh, Kenneth; Sheehan, Susan; Amend, Sarah; Cox, Allison; Orho-Melander, Marju; Kathiresan, Sekar; Paigen, Beverly; Korstanje, Ron

2011-03-28

79

Transfected DNA is mutated in monkey, mouse, and human cells  

SciTech Connect

Papovavirus-based shuttle vectors containing the bacterial lacI gene were used to show that a mutation frequency in the range of 1% occurs in lacI when such vectors are transfected into COS7 and CV-1 simian cells, NIH 3T3, 3T6, L, and C127 mouse cells, and human 293 and HeLa cells. This frequency is approximately four orders of magnitude higher than the spontaneous mutation frequency in either mammalian or bacterial cells. The mutations are predominantly base substitutions and deletions and also include insertions from the mammalian genome. Time course experiments argue that mutagenesis occurs soon after arrival of the DNA into the nucleus. However, replication of the vector is not required since mutations occur even when the vector lacks all viral sequences. The high mutation frequency appears to be the characteristic outcome of transfection of DNA into mammalian cells.

Lebkowski, A.S.; Du Bridge, R.B.; Antell, E.A.; Greisen, K.S.; Calos, M.P.

1984-10-01

80

A mouse model of human mucopolysaccharidosis IX exhibits osteoarthritis.  

PubMed

Hyaluronidases are endoglycosidases that hydrolyze hyaluronan (HA), an abundant component of the extracellular matrix of vertebrate connective tissues. Six human hyaluronidase-related genes have been identified to date. Mutations in one of these genes cause a deficiency of hyaluronidase 1 (HYAL1) resulting in a lysosomal storage disorder, mucopolysaccharidosis (MPS) IX. We have characterized a mouse model of MPS IX and compared its phenotype with the human disease. The targeted Hyal1 allele in this model had a neomycin resistance cassette in exon 2 that replaced 753 bp of the coding region containing the predicted enzyme active site. As a result, Hyal1(-/-) animals had no detectable wild-type Hyal1 transcript, protein or serum activity. Hyal1 null animals were viable, fertile and showed no gross abnormalities at 1 year and 8 months of age. Histological studies of the knee joint showed a loss of proteoglycans occurring as early as 3 months that progressed with age. An increased number of chondrocytes displaying intense pericellular and/or cytoplasmic HA staining were detected in the epiphyseal and articular cartilage of null mice, demonstrating an accumulation of HA. Elevations of HA were not detected in the serum or non-skeletal tissues, indicating that osteoarthritis is the key disease feature in a Hyal1 deficiency. Hyal3 expression was elevated in Hyal1 null mice, suggesting that Hyal3 may compensate in HA degradation in non-skeletal tissues. Overall, the murine MPS IX model displays the key features of the human disease. PMID:18344557

Martin, Dianna C; Atmuri, Vasantha; Hemming, Richard J; Farley, Judith; Mort, John S; Byers, Sharon; Hombach-Klonisch, Sabine; Csoka, Antonei B; Stern, Robert; Triggs-Raine, Barbara L

2008-03-15

81

The utilization of humanized mouse models for the study of human retroviral infections  

PubMed Central

The development of novel techniques and systems to study human infectious diseases in both an in vitro and in vivo settings is always in high demand. Ideally, small animal models are the most efficient method of studying human afflictions. This is especially evident in the study of the human retroviruses, HIV-1 and HTLV-1, in that current simian animal models, though robust, are often expensive and difficult to maintain. Over the past two decades, the construction of humanized animal models through the transplantation and engraftment of human tissues or progenitor cells into immunocompromised mouse strains has allowed for the development of a reconstituted human tissue scaffold in a small animal system. The utilization of small animal models for retroviral studies required expansion of the early CB-17 scid/scid mouse resulting in animals demonstrating improved engraftment efficiency and infectivity. The implantation of uneducated human immune cells and associated tissue provided the basis for the SCID-hu Thy/Liv and hu-PBL-SCID models. Engraftment efficiency of these tissues was further improved through the integration of the non-obese diabetic (NOD) mutation leading to the creation of NODSCID, NOD/Shi-scid IL2r?-/-, and NOD/SCID ?2-microglobulinnull animals. Further efforts at minimizing the response of the innate murine immune system produced the Rag2-/-?c-/- model which marked an important advancement in the use of human CD34+ hematopoietic stem cells. Together, these animal models have revolutionized the investigation of retroviral infections in vivo.

Van Duyne, Rachel; Pedati, Caitlin; Guendel, Irene; Carpio, Lawrence; Kehn-Hall, Kylene; Saifuddin, Mohammed; Kashanchi, Fatah

2009-01-01

82

MOUSE  

NSDL National Science Digital Library

Based in New York City, the MOUSE organization works to empower "underserved students to provide technology support and leadership in their schools, supporting their academic and career success." On their homepage, visitors can learn about their programs, learn about supporting the MOUSE organization, and read up on their resources. In the "Resources" area, visitors can learn about their outreach activities in New York City, Chicago, and California. Visitors working in educational outreach will appreciate the information offered here, including materials on how different groups can receive assistance from the MOUSE organization. Also, visitors can look over the "News" updates to learn about their new programs, their educational seminars, and their outreach activities.

83

Aup1, a novel gene on mouse Chromosome 6 and human Chromosome 2p13  

SciTech Connect

We have cloned a novel mouse cDNA, Aup1, encoding a predicted protein of 410 amino acid residues. The 1.5-kb Aup1 transcript is ubiquitously expressed in mouse tissues. An evolutionary relationship to the Caenorhabditis elegans predicted protein F44b9.5 is indicated by the 35% identity and 53% conservation of the amino acid sequences. Nineteen related human ESTs spanning 80% of the protein have also been identified, with a predicted amino acid sequence identity of 86% between the human and the mouse proteins. The gene has been mapped to a conserved linkage group on human chromosome 2p13 and mouse Chromosome 6. Aup1 was eliminated as a candidate gene for two closely linked disorders, human LGMD2B and mouse mnd2. 15 refs., 2 figs.

Jang, Wonhee; Weber, J.S.; Meisler, M.H. [Univ. of Michigan, Ann Arbor, MI (United States)] [and others

1996-09-01

84

Comparative systems biology of human and mouse as a tool to guide the modeling of human placental pathology  

PubMed Central

Placental abnormalities are associated with two of the most common and serious complications of human pregnancy, maternal preeclampsia (PE) and fetal intrauterine growth restriction (IUGR), each disorder affecting ?5% of all pregnancies. An important question for the use of the mouse as a model for studying human disease is the degree of functional conservation of genetic control pathways from human to mouse. The human and mouse placenta show structural similarities, but there have been no systematic attempts to assess their molecular similarities or differences. We collected protein and mRNA expression data through shot-gun proteomics and microarray expression analysis of the highly vascular exchange region, microdissected from the human and mouse near-term placenta. Over 7000 ortholog genes were detected with 70% co-expressed in both species. Close to 90% agreement was found between our human proteomic results and 1649 genes assayed by immunohistochemistry for expression in the human placenta in the Human Protein Atlas. Interestingly, over 80% of genes known to cause placental phenotypes in mouse are co-expressed in human. Several of these phenotype-associated proteins form a tight protein–protein interaction network involving 15 known and 34 novel candidate proteins also likely important in placental structure and/or function. The entire data are available as a web-accessible database to guide the informed development of mouse models to study human disease.

Cox, Brian; Kotlyar, Max; Evangelou, Andreas I; Ignatchenko, Vladimir; Ignatchenko, Alex; Whiteley, Kathie; Jurisica, Igor; Adamson, S Lee; Rossant, Janet; Kislinger, Thomas

2009-01-01

85

From Mouse to Human: Evolutionary Genomics Analysis of Human Orthologs of Essential Genes  

PubMed Central

Understanding the core set of genes that are necessary for basic developmental functions is one of the central goals in biology. Studies in model organisms identified a significant fraction of essential genes through the analysis of null-mutations that lead to lethality. Recent large-scale next-generation sequencing efforts have provided unprecedented data on genetic variation in human. However, evolutionary and genomic characteristics of human essential genes have never been directly studied on a genome-wide scale. Here we use detailed phenotypic resources available for the mouse and deep genomics sequencing data from human populations to characterize patterns of genetic variation and mutational burden in a set of 2,472 human orthologs of known essential genes in the mouse. Consistent with the action of strong, purifying selection, these genes exhibit comparatively reduced levels of sequence variation, skew in allele frequency towards more rare, and exhibit increased conservation across the primate and rodent lineages relative to the remainder of genes in the genome. In individual genomes we observed ?12 rare mutations within essential genes predicted to be damaging. Consistent with the hypothesis that mutations in essential genes are risk factors for neurodevelopmental disease, we show that de novo variants in patients with Autism Spectrum Disorder are more likely to occur in this collection of genes. While incomplete, our set of human orthologs shows characteristics fully consistent with essential function in human and thus provides a resource to inform and facilitate interpretation of sequence data in studies of human disease.

Georgi, Benjamin; Voight, Benjamin F.; Bucan, Maja

2013-01-01

86

From mouse to human: evolutionary genomics analysis of human orthologs of essential genes.  

PubMed

Understanding the core set of genes that are necessary for basic developmental functions is one of the central goals in biology. Studies in model organisms identified a significant fraction of essential genes through the analysis of null-mutations that lead to lethality. Recent large-scale next-generation sequencing efforts have provided unprecedented data on genetic variation in human. However, evolutionary and genomic characteristics of human essential genes have never been directly studied on a genome-wide scale. Here we use detailed phenotypic resources available for the mouse and deep genomics sequencing data from human populations to characterize patterns of genetic variation and mutational burden in a set of 2,472 human orthologs of known essential genes in the mouse. Consistent with the action of strong, purifying selection, these genes exhibit comparatively reduced levels of sequence variation, skew in allele frequency towards more rare, and exhibit increased conservation across the primate and rodent lineages relative to the remainder of genes in the genome. In individual genomes we observed ~12 rare mutations within essential genes predicted to be damaging. Consistent with the hypothesis that mutations in essential genes are risk factors for neurodevelopmental disease, we show that de novo variants in patients with Autism Spectrum Disorder are more likely to occur in this collection of genes. While incomplete, our set of human orthologs shows characteristics fully consistent with essential function in human and thus provides a resource to inform and facilitate interpretation of sequence data in studies of human disease. PMID:23675308

Georgi, Benjamin; Voight, Benjamin F; Bu?an, Maja

2013-05-09

87

Coronavirus 229E susceptibility in man-mouse hybrids is located on human chromosome 15  

Microsoft Academic Search

Human coronavirus 229E, an enveloped, RNA-containing virus, causes respiratory illness in man and is serologically related to murine coronavirus JHM, which causes acute and chronic demyelination in rodents. 229E displays a species-specific host range restriction whose genetic basis was studied in human-mouse hybrids. 229E replicated in human WI-38 cells but not in three mouse cell lines tested (RAG, LM\\/TK-, and

Alan Y. Sakaguchi; Thomas B. Shows

1982-01-01

88

Human and mouse oligonucleotide-based array CGH  

PubMed Central

Array-based comparative genomic hybridization is a high resolution method for measuring chromosomal copy number changes. Here we present a validated protocol using in-house spotted oligonucleotide libraries for array comparative genomic hybridization (CGH). This oligo array CGH platform yields reproducible results and is capable of detecting single copy gains, multi-copy amplifications as well as homozygous and heterozygous deletions as small as 100 kb with high resolution. A human oligonucleotide library was printed on amine binding slides. Arrays were hybridized using a hybstation and analysed using BlueFuse feature extraction software, with >95% of spots passing quality control. The protocol allows as little as 300 ng of input DNA and a 90% reduction of Cot-1 DNA without compromising quality. High quality results have also been obtained with DNA from archival tissue. Finally, in addition to human oligo arrays, we have applied the protocol successfully to mouse oligo arrays. We believe that this oligo-based platform using ‘off-the-shelf’ oligo libraries provides an easy accessible alternative to BAC arrays for CGH, which is cost-effective, available at high resolution and easily implemented for any sequenced organism without compromising the quality of the results.

van den IJssel, Paul; Tijssen, Marianne; Chin, Suet-Feung; Eijk, Paul; Carvalho, Beatriz; Hopmans, Erik; Holstege, Henne; Bangarusamy, Dhinoth Kumar; Jonkers, Jos; Meijer, Gerrit A.; Caldas, Carlos; Ylstra, Bauke

2005-01-01

89

Isolation of primary myofibroblasts from mouse and human colon tissue.  

PubMed

The myofibroblast is a stromal cell of the gastrointestinal (GI) tract that has been gaining considerable attention for its critical role in many GI functions. While several myofibroblast cell lines are commercially available to study these cells in vitro, research results from a cell line exposed to experimental cell culture conditions have inherent limitations due to the overly reductionist nature of the work. Use of primary myofibroblasts offers a great advantage in terms of confirming experimental findings identified in a cell line. Isolation of primary myofibroblasts from an animal model allows for the study of myofibroblasts under conditions that more closely mimic the disease state being studied. Isolation of primary myofibroblasts from human colon tissue provides arguably the most relevant experimental data, since the cells come directly from patients with the underlying disease. We describe a well-established technique that can be utilized to isolate primary myofibroblasts from both mouse and human colon tissue. These isolated cells have been characterized to be alpha-smooth muscle actin and vimentin-positive, and desmin-negative, consistent with subepithelial intestinal myofibroblasts. Primary myofibroblast cells can be grown in cell culture and used for experimental purposes over a limited number of passages. PMID:24145735

Khalil, Hassan; Nie, Wenxian; Edwards, Robert A; Yoo, James

2013-10-12

90

All kinesin superfamily protein, KIF, genes in mouse and human  

PubMed Central

Intracellular transport is essential for morphogenesis and functioning of the cell. The kinesin superfamily proteins (KIFs) have been shown to transport membranous organelles and protein complexes in a microtubule- and ATP-dependent manner. More than 30 KIFs have been reported in mice. However, the nomenclature of KIFs has not been clearly established, resulting in various designations and redundant names for a single KIF. Here, we report the identification and classification of all KIFs in mouse and human genome transcripts. Previously unidentified murine KIFs were found by a PCR-based search. The identification of all KIFs was confirmed by a database search of the total human genome. As a result, there are a total of 45 KIFs. The nomenclature of all KIFs is presented. To understand the function of KIFs in intracellular transport in a single tissue, we focused on the brain. The expression of 38 KIFs was detected in brain tissue by Northern blotting or PCR using cDNA. The brain, mainly composed of highly differentiated and polarized cells such as neurons and glia, requires a highly complex intracellular transport system as indicated by the increased number of KIFs for their sophisticated functions. It is becoming increasingly clear that the cell uses a number of KIFs and tightly controls the direction, destination, and velocity of transportation of various important functional molecules, including mRNA. This report will set the foundation of KIF and intracellular transport research.

Miki, Harukata; Setou, Mitsutoshi; Kaneshiro, Kiyofumi; Hirokawa, Nobutaka

2001-01-01

91

Genomic cloning of mouse MIF (macrophage inhibitory factor) and genetic mapping of the human and mouse expressed gene and nine mouse pseudogenes  

SciTech Connect

The single functional mouse gene for MIF (macrophage migration inhibitory factor) has been cloned from a P1 library, and its exon/intron structure determined and shown to resemble that of the human gene. The gene was mapped to chromosome 10 using two multilocus crosses between laboratory strains and either Mus musculus or Mus spretus. Nine additional loci containing related sequences, apparently all processed pseudogenes, were also mapped to chromosomes 1, 2, 3, 7, 8, 9, 12, 17, and 19. While most of these pseudogenes were also found in inbred mice and M. spretus, some are species specific. This suggests that there have been active phases of pseudogene formation in Mus both before and after the separation of musculus and spretus. The human gene contains no pseudogene; we assigned the human gene to chromosome 19, consistent with the location of mouse and human functional genes for MIF in a region of conserved linkage. 43 refs., 4 figs., 1 tab.

Kozak, C.A.; Adamson, M.C.; Buckler, C.E. [National Institute of Allergy and Infectious Diseases, Bethesda, MD (United States)] [and others

1995-06-10

92

Continuous delivery of human and mouse erythropoietin in mice by genetically engineered polymer encapsulated myoblasts  

Microsoft Academic Search

The transplantation of polymer encapsulated myoblasts genetically engineered to secrete erythropoietin (Epo) may obviate the need for repeated parenteral administration of recombinant Epo as a treatment for chronic renal failure, cancer or AIDS-associated anemia. To explore this possibility, the human and mouse Epo cDNAs under the control of the housekeeping mouse PGK-1 promoter were transfected into mouse C2C12 myoblasts, which

E Régulier; BL Schneider; N Déglon; Y Beuzard; P Aebischer

1998-01-01

93

Tumorigenicity of Simian Virus 40-Transformed Human Cells and Mouse-Human Hybrids in nude Mice  

Microsoft Academic Search

Four different human cell lines transformed by simian virus 40 (SV40) were tested for their tumorigenicity in athymic nude mice. Two of these lines, W18Va2 and GM52VA, were found to be tumorigenic when inoculated at a concentration of 1 × 107 cells per mouse. The other two cell lines, LN-SV and GM54VA, were found to induce very small tumors only

Hilary Koprowski; Carlo M. Croce

1977-01-01

94

Recommended nomenclature for five mammalian carboxylesterase gene families: human, mouse, and rat genes and proteins  

PubMed Central

Mammalian carboxylesterase (CES or Ces) genes encode enzymes that participate in xenobiotic, drug, and lipid metabolism in the body and are members of at least five gene families. Tandem duplications have added more genes for some families, particularly for mouse and rat genomes, which has caused confusion in naming rodent Ces genes. This article describes a new nomenclature system for human, mouse, and rat carboxylesterase genes that identifies homolog gene families and allocates a unique name for each gene. The guidelines of human, mouse, and rat gene nomenclature committees were followed and “CES” (human) and “Ces” (mouse and rat) root symbols were used followed by the family number (e.g., human CES1). Where multiple genes were identified for a family or where a clash occurred with an existing gene name, a letter was added (e.g., human CES4A; mouse and rat Ces1a) that reflected gene relatedness among rodent species (e.g., mouse and rat Ces1a). Pseudogenes were named by adding “P” and a number to the human gene name (e.g., human CES1P1) or by using a new letter followed by ps for mouse and rat Ces pseudogenes (e.g., Ces2d-ps). Gene transcript isoforms were named by adding the GenBank accession ID to the gene symbol (e.g., human CES1_AB119995 or mouse Ces1e_BC019208). This nomenclature improves our understanding of human, mouse, and rat CES/Ces gene families and facilitates research into the structure, function, and evolution of these gene families. It also serves as a model for naming CES genes from other mammalian species.

Holmes, Roger S.; Wright, Matthew W.; Laulederkind, Stanley J. F.; Cox, Laura A.; Hosokawa, Masakiyo; Imai, Teruko; Ishibashi, Shun; Lehner, Richard; Miyazaki, Masao; Perkins, Everett J.; Potter, Phillip M.; Redinbo, Matthew R.; Robert, Jacques; Satoh, Tetsuo; Yamashita, Tetsuro; Yan, Bingfan; Yokoi, Tsuyoshi; Zechner, Rudolf; Maltais, Lois J.

2011-01-01

95

Chromosomal localization of the gene encoding the human DNA helicase RECQL and its mouse homologue  

SciTech Connect

We have determined the chromosomal location of the human and mouse genes encoding the RECQL protein, a putative DNA helicase homologous to the bacterial DNA helicase, RecQ. RECQL was localized to human chromosome 12 by analysis of human-rodent somatic cell hybrid DNA, fine mapping of RECQL by fluorescence in situ hybridization revealed its chromosomal location to be 12p11-p12. The corresponding mouse gene, Recql, was mapped to the telomeric end of mouse chromosome 6 by analysis of DNA from an interspecific cross. 19 refs., 2 figs.

Puranam, K.L.; Kennington, E.; Blackshear, P.J. [Duke Univ., Durham, NC (United States)] [and others

1995-04-10

96

PPAR?\\/? Expression and Activity in Mouse and Human Melanocytes and Melanoma Cells  

Microsoft Academic Search

Purpose  We examined the expression of PPARs and the effects of PPAR? and PPAR? agonists on growth of mouse and human melanocytes and\\u000a melanoma cells.\\u000a \\u000a \\u000a \\u000a Methods  PPAR?,?, and PPAR? mRNA qualitative expression in melan-a mouse melanocytes, B16 mouse melanoma, human melanocytes, and A375\\u000a and SK-mel28 human melanoma cells was determined by RT-PCR, while quantitative PPAR? mRNA levels were determined by QuantiGene\\u000a assay.

Linda L. Eastham; Caroline N. Mills; Richard M. Niles

2008-01-01

97

DNA synthesis and epigenetic modification during mouse oocyte fertilization by human or hamster sperm injection  

Microsoft Academic Search

Purpose  To evaluate DNA synthesis and epigenetic modification in mouse oocytes during the first cell cycle following the injection\\u000a of human or hamster sperm.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Mouse oocytes following the injection of human and hamster sperm and cultured in M16 medium.\\u000a \\u000a \\u000a \\u000a Results  Male and female pronucleus formation, DNA synthesis, histone protein modification, and heterochromatin formation were similar\\u000a in mouse oocytes injected with human or

Yong-Nan Xu; Xiang-Shun Cui; Jin-Cheol Tae; Yong-Xun Jin; Nam-Hyung Kim

2011-01-01

98

The Mouse Genome Database: Genotypes, Phenotypes, and Models of Human Disease  

PubMed Central

The laboratory mouse is the premier animal model for studying human biology because all life stages can be accessed experimentally, a completely sequenced reference genome is publicly available and there exists a myriad of genomic tools for comparative and experimental research. In the current era of genome scale, data-driven biomedical research, the integration of genetic, genomic and biological data are essential for realizing the full potential of the mouse as an experimental model. The Mouse Genome Database (MGD; http://www.informatics.jax.org), the community model organism database for the laboratory mouse, is designed to facilitate the use of the laboratory mouse as a model system for understanding human biology and disease. To achieve this goal, MGD integrates genetic and genomic data related to the functional and phenotypic characterization of mouse genes and alleles and serves as a comprehensive catalog for mouse models of human disease. Recent enhancements to MGD include the addition of human ortholog details to mouse Gene Detail pages, the inclusion of microRNA knockouts to MGD’s catalog of alleles and phenotypes, the addition of video clips to phenotype images, providing access to genotype and phenotype data associated with quantitative trait loci (QTL) and improvements to the layout and display of Gene Ontology annotations.

Bult, Carol J.; Eppig, Janan T.; Blake, Judith A.; Kadin, James A.; Richardson, Joel E.

2013-01-01

99

Antibody engineering via genetic engineering of the mouse: XenoMouse strains are a vehicle for the facile generation of therapeutic human monoclonal antibodies  

Microsoft Academic Search

The major impediment to the development of murine monoclonal antibodies (mAbs) for therapy in humans has been the difficulty in reducing their potential immunogenicity. XenoMouse™ mice obviate this problem while retaining the relative ease of generating mAbs from a mouse. XenoMouse strains include germline-configured, megabase-sized YACs carrying portions of the human IgH and Ig? loci, including the majority of the

Larry L Green

1999-01-01

100

Difference in substrate specificity between human and mouse lysosomal acid lipase: low affinity for cholesteryl ester in mouse lysosomal acid lipase  

Microsoft Academic Search

Lysosomal acid lipase (LAL) is essential for the intracellular degradation of cholesteryl esters (CE) and triacylglycerols (TG) that are delivered to lysosomes by low density lipoprotein (LDL) receptor mediated endocytosis. We have analysed the difference in the catalytic properties and substrate specificity of human and mouse LALs. LAL activities were measured in human and mouse fibroblasts and in HeLa cells

Johanna E. M. Groener; Wim Bax; Cristiana Stuani; Franco Pagani

2000-01-01

101

Epidermal surface antigen (MS17S1) is highly conserved between mouse and human  

SciTech Connect

A mouse monoclonal antibody ECS-1 raised to human keratinocytes detects a 35-kDa epidermal surface antigen (ESA) and causes keratinocyte dissociation in vitro. ECS-1 stains skin of 16-day mouse embryo and 8- to 9-week human fetus. Mouse Esa cDNA encodes a 379-amino-acid protein that is 99.2% identical to the human, differing at only 3 amino acids. The gene (M17S1) was mapped to mouse chromosome 11, highlighting the conserved linkage synteny existing between human chromosome 17 and mouse chromosome 11. Although the nude locus has been mapped to the same region of chromosome 11, no abnormalities in protein, mRNA, or cDNA or genomic sequences were detected in nude mice. However, both nude and control mice were found to have a second Esa mRNA transcript that conserves amino acid sequence and molecular weight. The mouse and human 5{prime} and 3{prime} untranslated sequences are conserved. Similar RNA folding patterns of the 5{prime} untranslated region are predicted despite a 91-bp insertion in the mouse. These data suggest that both the function and the regulation of ESA protein are of importance and that Esa (M17S1) is not the nude locus gene. 42 refs., 7 figs., 3 tabs.

Cho, Y.J.; Chema, D.; Cho, M. [Univ. of Texas Medical School, Houston, TX (United States)] [and others

1995-05-20

102

Quantifying the relative amount of mouse and human DNA in cancer xenografts using species-specific variation in gene length.  

PubMed

Human cancer cell lines and xenografts are valuable samples for whole-genome sequencing of human cancer. Tumors can be maintained by serial xenografting in athymic (nude) or severe combined immunodeficient (SCID) mice. In the current study, we developed a molecular assay to quantify the relative contributions of human and mouse in mixed DNA samples. The assay was designed based on deletion/insertion variation between human and mouse genomes. The percentage of mouse DNA was calculated according to the relative peak heights of PCR products analyzed by capillary electrophoresis. Three markers from chromosomes 9 and 10 accurately predicted the mouse genome ratio and were combined into a multiplex PCR reaction. We used the assay to quantify the relative DNA amounts of 93 mouse xenografts used for a recently reported integrated genomic analysis of human pancreatic cancer. Of the 93 xenografts, the mean percentage of contaminating mouse DNA was 47%, ranging from 17% to 73%, with 43% of samples having >50% mouse DNA. We then comprehensively compared the human and mouse genomes to identify 370 additional candidate gene loci demonstrating human-mouse length variation. With increasing whole-genome sequencing of human cancers, this assay should be useful to monitor strategies to enrich human cancer cells from mixed human-mouse cell xenografts. Finally, we discuss how contaminating mouse DNA affects next-generation DNA sequencing. PMID:20359302

Lin, Ming-Tseh; Tseng, Li-Hui; Kamiyama, Hirohiko; Kamiyama, Mihoko; Lim, Phillip; Hidalgo, Manuel; Wheelan, Sarah; Eshleman, James

2010-03-01

103

Integrative transcriptional analysis between human and mouse cancer cells provides a common set of transformation associated genes  

Microsoft Academic Search

Mouse functional genomics is largely used to investigate relevant aspects of mammalian physiology and pathology. To which degree mouse models may offer accurate representations of molecular events underlining human diseases such as cancer is not yet fully established. Herein we compare gene expression signatures between a set of human cancer cell lines (NCI-60 cell collection) and a mouse cellular model

C. Balestrieri; M. Vanoni; S. Hautaniemi; L. Alberghina; F. Chiaradonna

104

Effects of exopolysaccharide fraction (EPSF) from a cultivated Cordyceps sinensis fungus on c-Myc, c-Fos, and VEGF expression in B16 melanoma-bearing mice.  

PubMed

The aqueous extract of Cordyceps sinensis (Cs), one of the traditional Chinese medicines, has been used for the treatment of a wide range of disorders for centuries. It is generally accepted that its cultivated Cs fungi possess the same functions as Cs natural herbs. Although polysaccharide from Cs is one of its bioactive compositions, its antitumor ability has not been confirmed. In the present study, we investigated the effects of the exopolysaccharide fraction (EPSF) of a cultivated Cs fungus on c-Myc, c-Fos, and vascular endothelial growth factor (VEGF) expression of tumor-bearing mice. The mice (C57BL/6) were administered three different doses of EPSF peritoneally every 2 days, starting from the day of implantation of B16 melanoma cells through their tail veins for 27 days (14 times). Sections from mouse paraffin-embedded liver and lung tissues were subjected to immunohistochemical analyses. The results of c-Myc, c-Fos, and VEGF expression were analyzed using SimplePCI image analysis software. The c-Myc, c-Fos, and VEGF levels in the lungs and livers of EPSF-treated mice were found to be significantly lower than those of untreated mice (p<0.05). This suggests that EPSF had inhibited tumor growth in the lungs and livers of mice, and that it might be a potential adjuvant in cancer therapy. PMID:16325517

Yang, Jinyu; Zhang, Weiyun; Shi, Peihua; Chen, Jiaping; Han, Xiaodong; Wang, Yong

2005-10-19

105

Pharmacokinetics in melanoma-bearing mice of 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU), a candidate compound for boron neutron capture therapy.  

PubMed Central

Blood pharmacokinetics and tissue distribution of 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU), a boron carrier with postulated melanin-seeking properties for boron neutron capture therapy, were determined in C57/BL mice with subcutaneous pigmented or non-pigmented B16 melanomas. Borocaptate sodium (BSH) was used as a boron compound without melanin-seeking properties in a comparative biodistribution study in the same animal tumour models. Administration of single doses showed that BPTU was retained better in the pigmented B16 tumour than in the non-pigmented variant. BPTU was found in large concentrations in kidney and liver. Brain boron was approximately 10-fold lower than tumour boron. On a molar basis, BPTU demonstrated higher affinity for B16 tumours than BSH. Owing to solubility limits, tumour boron concentrations in this mouse study were too low for effective application of BNCT. However, the high tumour-to-blood and tumour-to-normal tissues ratios indicate that, with appropriate formulation, BPTU could be a promising candidate for clinical BNCT.

Verrijk, R.; Smolders, I. J.; Huiskamp, R.; Gavin, P. R.; Philipp, K. H.; Begg, A. C.

1994-01-01

106

Abundant alkali-sensitive sites in DNA of human and mouse sperm  

SciTech Connect

The DNA of human and mouse sperm cells was analyzed by single-cell microgel electrophoresis, by agarose gel electrophoresis, and by alkaline elution-three techniques that can detect single-strand DNA breaks and/or labile sites. Under these conditions a surprisingly large number of single-strand DNA breaks, approximately 10{sup 6} to 10{sup 7} per genome, were detected in human and mouse sperm but not in human lymphocytes or in mouse bone marrow cells. These breaks were also present in chicken erythrocyte DNA, which is also highly condensed. These breaks were not observed under neutral pH conditions nor under denaturing conditions not involving alkali, suggesting that these sites are alkali-sensitive and do not represent preexisting single-strand breaks. The high frequency of such sites in sperm from healthy mouse and human donors suggest that they represent a functional characteristic of condensed chromatin rather than DNA damage.

Singh, N.P.; Danner, D.B.; McCoy, M.T.; Collins, G.D.; Schneider, E.L. (National Inst. on Aging, Baltimore, MD (United States)); Tice, R.R. (Brookhaven National Lab., NY (United States))

1989-10-01

107

Pre-Clinical Mouse Models of Human Prostate Cancer and their Utility in Drug Discovery  

PubMed Central

In vivo animal experiments are essential to current prostate cancer research, and are particularly critical to studying interactions between tumor cells and their microenvironment. Numerous pre-clinical animal models of prostate cancer are currently available, including transgenic mouse models and human prostate cancer xenograft mouse models. In contrast to transgenic mouse models producing more heterogeneous cohorts of tumors, xenograft mouse models provide more controlled approaches. This unit describes the detailed procedures necessary to establish several distinct pre-clinical mouse models of human prostate cancer, including an orthotopic prostate xenograft model, an orthotopic bone metastasis model, an experimental metastasis model of intra-cardiac injection, and a vossicle model of tumor-bone interaction.

Park, Serk In; Kim, Sun Jin; McCauley, Laurie K.; Gallick, Gary E.

2010-01-01

108

Sense-antisense gene pairs: sequence, transcription, and structure are not conserved between human and mouse  

PubMed Central

Previous efforts to characterize conservation between the human and mouse genomes focused largely on sequence comparisons. These studies are inherently limited because they don't account for gene structure differences, which may exist despite genomic sequence conservation. Recent high-throughput transcriptome studies have revealed widespread and extensive overlaps between genes, and transcripts, encoded on both strands of the genomic sequence. This overlapping gene organization, which produces sense-antisense (SAS) gene pairs, is capable of effecting regulatory cascades through established mechanisms. We present an evolutionary conservation assessment of SAS pairs, on three levels: genomic, transcriptomic, and structural. From a genome-wide dataset of human SAS pairs, we first identified orthologous loci in the mouse genome, then assessed their transcription in the mouse, and finally compared the genomic structures of SAS pairs expressed in both species. We found that approximately half of human SAS loci have single orthologous locations in the mouse genome; however, only half of those orthologous locations have SAS transcriptional activity in the mouse. This suggests that high human-mouse gene conservation overlooks widespread distinctions in SAS pair incidence and expression. We compared gene structures at orthologous SAS loci, finding frequent differences in gene structure between human and orthologous mouse SAS pair members. Our categorization of human SAS pairs with respect to mouse conservation of expression as well as structure points to limitations of mouse models. Gene structure differences, including at SAS loci, may account for some of the phenotypic distinctions between primates and rodents. Genes in non-conserved SAS pairs may contribute to evolutionary lineage-specific regulatory outcomes.

Wood, Emily J.; Chin-Inmanu, Kwanrutai; Jia, Hui; Lipovich, Leonard

2013-01-01

109

Interspecific hybridization between human and mouse somatic cells: Enzyme and linkage studies  

Microsoft Academic Search

Human-mouse somatic cell hybrids have been isolated and examined for enzyme and chromosome constitution. The enzymes assayed were lactate dehydrogenase (LDH), isocitrate dehydrogenase (IDH), NADP-dependent malate dehydrogenase (MDH), glucose 6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), phosphoglucomutase (PGM), and several esterases. Coexpression of mouse and human genomes and formation of heteropolymeric enzymes were observed in seven different hybrid populations for the

Charlotte M. Boone; Frank H. Ruddle

1969-01-01

110

Human and mouse Krüppel-like (MOK2) orthologue genes encode two different zinc finger proteins  

Microsoft Academic Search

We have isolated the human homologue of Mok2 gene encoding a Kriippel-like protein. The identification of three cDNAs and genomic clones reveals that the human protein shows substantial structural differences with the mouse MOK2 protein. The mouse MOK2 protein is composed of seven tandem zinc-finger motifs with five additional amino acids at the COOH-terminal. This structural feature is also present

Michèle Ernoult-Lange; Valérie Arranz; Maryvonne Coniat; Roland Berger; Michel Kress

1995-01-01

111

Rescue of the Friedreich's ataxia knockout mouse by human YAC transgenesis  

Microsoft Academic Search

.   We have generated and characterised transgenic mice that contain the entire Friedreich's ataxia gene (FRDA) within a human\\u000a YAC clone of 370 kb. In an effort to overcome the embryonic lethality of homozygous Frda knockout mice and to study the behaviour\\u000a of human frataxin in a mouse cellular environment, we bred the FRDA YAC transgene onto the null mouse background.

Mark A. Pook; Sahar Al-Mahdawi; Christopher J. Carroll; Mireille Cossée; Hélène Puccio; Lorraine Lawrence; Peter Clark; Margaret B. Lowrie; Jane L. Bradley; Mark J. Cooper; Michel Kœnig; Susan Chamberlain

2001-01-01

112

Comparative Sequence Analysis of the Mouse and Human Lgn1\\/SMA Interval  

Microsoft Academic Search

Human chromosome 5q11.2–q13.3 and its ortholog on mouse chromosome 13 contain candidate genes for an inherited human neurodegenerative disorder called spinal muscular atrophy (SMA) and for an inherited mouse susceptibility to infection with Legionella pneumophila (Lgn1). These homologous genomic regions also have unusual repetitive organizations that create practical difficulties in mapping and raise interesting issues about the evolutionary origin of

Matthew Endrizzi; Sidong Huang; Jeremiah M. Scharf; Arndt-René Kelter; Brunhilde Wirth; Louis M. Kunkel; Webb Miller; William F. Dietrich

1999-01-01

113

Cloning Human Fetal ? Globin and Mouse ? -Type Globin DNA: Preparation and Screening of Shotgun Collections  

NASA Astrophysics Data System (ADS)

Shotgun collections of Charon 3A bacteriophages containing Eco RI fragments of human and mouse DNA were constructed with the use of in vitro packaging. Plaques were screened by hybridization, and globin-specific clones were isolated from both human (Charon 3AHs51.1) and mouse (Charon 3AMm30.5). The fragments cloned were detected in unfractionated genomic DNA by the Southern method of hybridization.

Blattner, Frederick R.; Blechl, Anne E.; Denniston-Thompson, Katherine; Faber, Harvey E.; Richards, Julia E.; Slightom, Jerry L.; Tucker, Philip W.; Smithies, Oliver

1978-12-01

114

Inferring Nonneutral Evolution from Human-Chimp-Mouse Orthologous Gene Trios  

Microsoft Academic Search

Even though human and chimpanzee gene sequences are nearly 99% identical, sequence comparisons can nevertheless be highly informative in identifying biologically important changes that have occurred since our ancestral lineages diverged. We analyzed alignments of 7645 chimpanzee gene sequences to their human and mouse orthologs. These three-species sequence alignments allowed us to identify genes undergoing natural selection along the human

Andrew G. Clark; Stephen Glanowski; Rasmus Nielsen; Paul D. Thomas; Anish Kejariwal; Melissa A. Todd; David M. Tanenbaum; Daniel Civello; Fu Lu; Brian Murphy; Steve Ferriera; Gary Wang; Xianqgun Zheng; Thomas J. White; John J. Sninsky; Mark D. Adams; Michele Cargill

2003-01-01

115

Sequence of a cDNA for mouse thrombomodulin and comparison of the predicted mouse and human amino acid sequences  

SciTech Connect

Thrombomodulin is an endothelial cell surface anticoagulant cofactor for activation of the serum protease protein C. The authors have previously described a complete cDNA for human thrombomodulin, and a partial cDNA for mouse thrombomodulin. They now report the complete cDNA for mouse thrombomodulin, and compare the predicted amino acid sequence to human. The sequence contains a 5{prime} untranslated region of 158 bases, followed by 1,731 bases encoding 577 amino acids, and 1,745 bases of 3{prime} untranslated sequence terminating in a poly A tail (24 bases). The sequence was determined by sequencing both strands of two independent cDNA clones, one encoding bases 1-833, the other 446-3,658.

Dittman, W.A.; Majerus, P.W. (Washington Univ. School of Medicine, St. Louis, MO (USA))

1989-01-25

116

Transcription factor site dependencies in human, mouse and rat genomes  

PubMed Central

Background It is known that transcription factors frequently act together to regulate gene expression in eukaryotes. In this paper we describe a computational analysis of transcription factor site dependencies in human, mouse and rat genomes. Results Our approach for quantifying tendencies of transcription factor binding sites to co-occur is based on a binding site scoring function which incorporates dependencies between positions, the use of information about the structural class of each transcription factor (major/minor groove binder), and also considered the possible implications of varying GC content of the sequences. Significant tendencies (dependencies) have been detected by non-parametric statistical methodology (permutation tests). Evaluation of obtained results has been performed in several ways: reports from literature (many of the significant dependencies between transcription factors have previously been confirmed experimentally); dependencies between transcription factors are not biased due to similarities in their DNA-binding sites; the number of dependent transcription factors that belong to the same functional and structural class is significantly higher than would be expected by chance; supporting evidence from GO clustering of targeting genes. Based on dependencies between two transcription factor binding sites (second-order dependencies), it is possible to construct higher-order dependencies (networks). Moreover results about transcription factor binding sites dependencies can be used for prediction of groups of dependent transcription factors on a given promoter sequence. Our results, as well as a scanning tool for predicting groups of dependent transcription factors binding sites are available on the Internet. Conclusion We show that the computational analysis of transcription factor site dependencies is a valuable complement to experimental approaches for discovering transcription regulatory interactions and networks. Scanning promoter sequences with dependent groups of transcription factor binding sites improve the quality of transcription factor predictions.

Tomovic, Andrija; Stadler, Michael; Oakeley, Edward J

2009-01-01

117

Development of polyclonal antibodies specific to ATP-binding cassette transporters human ABCG4 and mouse Abcg4: site-specific expression of mouse Abcg4 in brain.  

PubMed

In our recent study on seeking new mouse ATP-binding cassette (ABC) transporters of the G subfamily, we succeeded in cloning mouse Abcg4 from a cDNA library of mouse brain, and we characterized the tissue-specific expression and chromosomal localization of the mouse Abcg4 gene. To further characterize the physiological function of mouse Abcg4 protein and to compare its function with that of ABCG2, in the present study, we developed polyclonal antibodies against mouse Abcg4 and established the Abcg4-expression system. To raise antibodies, we selected three different epitope peptides that correspond to the amino acid residues of 46-60, 465-479, and 600-613 in mouse Abcg4 protein. The antibody raised against the epitope encoding the amino acids 46-60 was found to be specific to mouse Abcg4, exhibiting a band with molecular weight of 63,000 on immunoblotting, whereas this band was dose-dependently diminished by adding the corresponding epitope peptide into the immunoblot medium. Use of the antibody for immunoblot detection in mouse normal tissues revealed that the Abcg4 protein is expressed in brain, spleen, and testis. Immunohistochemical studies showed that mouse Abcg4 is site-specifically expressed in the cerebral cortex and medulla of mouse brain. These results suggest that mouse Abcg4 plays a certain physiological role in the brain. It is of importance to note that the sequence of amino acids 46-60 is completely identical between mouse Abcg4 and human ABCG4. Thus, this antibody is applicable to the detection of human ABCG4 as well as mouse Abcg4. PMID:18038765

Koshiba, Shoko; Ito, Takehito; Shiota, Akira; Wakabayashi, Kanako; Ueda, Masatsugu; Ichinose, Hiroshi; Ishikawa, Toshihisa

2007-01-01

118

Web-based access to mouse models of human cancers: the Mouse Tumor Biology (MTB) Database  

Microsoft Academic Search

The Mouse Tumor Biology (MTB) Database serves as a curated, integrated resource for information about tumor genetics and pathology in genetically defined strains of mice (i.e., inbred, transgenic and targeted mutation strains). Sources of information for the database include the published scientific literature and direct data submissions by the scientific community. Researchers access MTB using Web- based query forms and

Carol J. Bult; Debra M. Krupke; Dieter Näf; John P. Sundberg; Janan T. Eppig

2001-01-01

119

Human ?2-glycoprotein I attenuates mouse intestinal ischemia/reperfusion induced injury and inflammation  

PubMed Central

Intestinal ischemia-reperfusion (IR)-induced injury results from a complex cascade of inflammatory components. In the mouse model of intestinal IR, the serum protein, ?2-glycoprotein I (?2-GPI) binds to the cell surface early in the cascade. The bound ?2-GPI undergoes a conformational change which exposes a neoantigen recognized by naturally occurring antibodies and initiates the complement cascade. We hypothesized that providing additional antigen with exogenous ?2-GPI would alter IR-induced tissue injury. Administration of human but not mouse ?2-GPI attenuated IR-induced tissue damage and prostaglandin E2 production indicating a physiological difference between ?2-GPI isolated from the two species. To investigate whether structural features were responsible for this physiological difference, we compared the chemical, physical and biochemical properties of the two proteins. Despite possessing 76% amino acid identity and 86% sequence homology, we found that mouse ?2-GPI differs from the human protein in size, carbohydrate chain location, heterogeneity and secondary structural content. These data suggest that the structural differences result in mouse Ab recognition of soluble human but not mouse ?2-GPI and attenuated IR-induced injury. We conclude that caution should be exercised in interpreting results obtained by using human ?2-GPI in a mouse model.

Tomasi, Maurizio; Hiromasa, Yasuaki; Pope, Michael R.; Gudlur, Sushanth; Tomich, John M.; Fleming, Sherry D.

2012-01-01

120

Mouse LSECtin as a model for a human Ebola virus receptor  

PubMed Central

The biochemical properties of mouse LSECtin, a glycan-binding receptor that is a member of the C-type lectin family found on sinusoidal endothelial cells, have been investigated. The C-type carbohydrate-recognition domain of mouse LSECtin, expressed in bacteria, has been used in solid-phase binding assays, and a tetramerized form has been used to probe a glycan array. In spite of sequence differences near the glycan-binding sites, the mouse receptor closely mimics the properties of the human receptor, showing high affinity binding to glycans bearing terminal GlcNAc?1-2Man motifs. Site-directed mutagenesis has been used to confirm that residues near the binding site that differ between the human and the mouse proteins do not affect this binding specificity. Mouse and human LSECtin have been shown to bind Ebola virus glycoprotein with equivalent affinities, and the GlcNAc?1-2Man disaccharide has been demonstrated to be an effective inhibitor of this interaction. These studies provide a basis for using mouse LSECtin, and knockout mice lacking this receptor, to model the biological properties of the human receptor.

Pipirou, Zoi; Powlesland, Alex S; Steffen, Imke; Pohlmann, Stefan; Taylor, Maureen E; Drickamer, Kurt

2011-01-01

121

Mouse LSECtin as a model for a human Ebola virus receptor.  

PubMed

The biochemical properties of mouse LSECtin, a glycan-binding receptor that is a member of the C-type lectin family found on sinusoidal endothelial cells, have been investigated. The C-type carbohydrate-recognition domain of mouse LSECtin, expressed in bacteria, has been used in solid-phase binding assays, and a tetramerized form has been used to probe a glycan array. In spite of sequence differences near the glycan-binding sites, the mouse receptor closely mimics the properties of the human receptor, showing high affinity binding to glycans bearing terminal GlcNAc?1-2Man motifs. Site-directed mutagenesis has been used to confirm that residues near the binding site that differ between the human and the mouse proteins do not affect this binding specificity. Mouse and human LSECtin have been shown to bind Ebola virus glycoprotein with equivalent affinities, and the GlcNAc?1-2Man disaccharide has been demonstrated to be an effective inhibitor of this interaction. These studies provide a basis for using mouse LSECtin, and knockout mice lacking this receptor, to model the biological properties of the human receptor. PMID:21257728

Pipirou, Zoi; Powlesland, Alex S; Steffen, Imke; Pöhlmann, Stefan; Taylor, Maureen E; Drickamer, Kurt

2011-01-21

122

Structure and chromosomal location of mouse and human CD52 genes.  

PubMed

Human CD52 (CAMPATH-1 antigen) is an abundant surface molecule on lymphocytes and a favoured target for lymphoma therapy and immunosuppression. It comprises a small glycosylphosphatidylinositol (GPI) anchored peptide to which a large carbohydrate moiety is attached. Structurally similar proteins include the proposed mouse homologue, B7 antigen (B7-Ag; not to be confused with the CD28 ligand), and human and mouse CD24. Sequence similarities between CD52 and B7-Ag precursors are concentrated over the signal peptides and the sequences cleaved during GPI attachment. While the short mature peptides are not apparently homologous, the N-linked glycosylation site is retained in both. We describe similarities in exon-intron organisation, syntenic chromosome positions (human CD52, 1p36; mouse B7-Ag, chromosome 4, between Dsil and D4Nds16) and sequence homology in the promoter regions which strongly suggests that B7-Ag is the mouse homologue of CD52. The structure of these genes is also similar to that of mouse CD24, suggesting a common ancestor. Promoter activities and transcription start sites were also analysed. These results suggest that human CD52 and mouse B7-Ag gene expressions are controlled by TATA-less promoters. PMID:10524207

Tone, M; Nolan, K F; Walsh, L A; Tone, Y; Thompson, S A; Waldmann, H

1999-09-01

123

The Mousetrap: What We Can Learn When the Mouse Model Does Not Mimic the Human Disease  

Microsoft Academic Search

In recent years, mouse models for human metabolic diseases have become commonplace because the information gained from in vivo study of biochemical pathways is invaluable, and many metabolic diseases are relatively easy to recreate in mice through gene knockout technology in embryonic stem cells. In certain cases, however, the knockout mice may reproduce only some of the human disease phenotype,

Sarah H. Elsea; Rebecca E. Lucas

2002-01-01

124

Reprogramming within hours following nuclear transfer into mouse but not human zygotes  

Microsoft Academic Search

Fertilized mouse zygotes can reprogram somatic cells to a pluripotent state. Human zygotes might therefore be useful for producing patient-derived pluripotent stem cells. However, logistical, legal and social considerations have limited the availability of human eggs for research. Here we show that a significant number of normal fertilized eggs (zygotes) can be obtained for reprogramming studies. Using these zygotes, we

Dieter Egli; Alice E. Chen; Genevieve Saphier; Justin Ichida; Claire Fitzgerald; Kathryn J. Go; Nicole Acevedo; Jay Patel; Manfred Baetscher; William G. Kearns; Robin Goland; Rudolph L. Leibel; Douglas A. Melton; Kevin Eggan

2011-01-01

125

The NEUROD gene maps to human chromosome 2q32 and mouse chromosome 2  

SciTech Connect

The Neurod gene is a basic-helix-loop-helix gene that regulates neurogenesis and is identical to the hamster beta2 gene that was cloned as a regulator of insulin transcription. Here we report the cloning of human NEUROD and mapping of the gene to human chromosome 2q32 and to mouse chromosome 2. 12 refs., 1 fig.

Tamimi, R.; Dyer-Montgomery, K.; Hernandez, R.; Tapscott, S.J. [Fred Hutchinson Cancer Research Center, Seattle, WA (United States)] [and others

1996-06-15

126

Cell Surface Antigens of Human Malignant Melanoma: Definition of Six Antigenic Systems with Mouse Monoclonal Antibodies  

Microsoft Academic Search

Eighteen mouse monoclonal antibodies were selected for reactivity with cell surface antigens of the immunizing human melanoma cell line SK-MEL-28. Six distinct antigenic systems were defined by direct serological assays and absorption tests with a panel of 41 cell lines derived from normal and malignant human tissues. Biochemical analysis indicated that two of the antigens are glycoproteins with molecular sizes

Wolfgang G. Dippold; Kenneth O. Lloyd; Lucy T. C. Li; Hisami Ikeda; Herbert F. Oettgen; Lloyd J. Old

1980-01-01

127

Comparative sequence analysis of imprinted genes between human and mouse to reveal imprinting signatures  

Microsoft Academic Search

We performed a comparative genomic sequence analysis between human and mouse for 24 imprinted genes on human chromosomes 1, 6, 7, 11, 13, 14, 15, 18, 19, and 20. The MEME program was used to search for motifs within conserved sequences among the imprinted genes and we then used the MAST program to analyze for the presence or absence of

Zhining Wang; Hongtao Fan; Howard H. Yang; Ying Hu; Kenneth H. Buetow; Maxwell P. Lee

2004-01-01

128

A comparison of whole-genome shotgun-derived mouse chromosome 16 and the human genome.  

PubMed

The high degree of similarity between the mouse and human genomes is demonstrated through analysis of the sequence of mouse chromosome 16 (Mmu 16), which was obtained as part of a whole-genome shotgun assembly of the mouse genome. The mouse genome is about 10% smaller than the human genome, owing to a lower repetitive DNA content. Comparison of the structure and protein-coding potential of Mmu 16 with that of the homologous segments of the human genome identifies regions of conserved synteny with human chromosomes (Hsa) 3, 8, 12, 16, 21, and 22. Gene content and order are highly conserved between Mmu 16 and the syntenic blocks of the human genome. Of the 731 predicted genes on Mmu 16, 509 align with orthologs on the corresponding portions of the human genome, 44 are likely paralogous to these genes, and 164 genes have homologs elsewhere in the human genome; there are 14 genes for which we could find no human counterpart. PMID:12040188

Mural, Richard J; Adams, Mark D; Myers, Eugene W; Smith, Hamilton O; Miklos, George L Gabor; Wides, Ron; Halpern, Aaron; Li, Peter W; Sutton, Granger G; Nadeau, Joe; Salzberg, Steven L; Holt, Robert A; Kodira, Chinnappa D; Lu, Fu; Chen, Lin; Deng, Zuoming; Evangelista, Carlos C; Gan, Weiniu; Heiman, Thomas J; Li, Jiayin; Li, Zhenya; Merkulov, Gennady V; Milshina, Natalia V; Naik, Ashwinikumar K; Qi, Rong; Shue, Bixiong Chris; Wang, Aihui; Wang, Jian; Wang, Xin; Yan, Xianghe; Ye, Jane; Yooseph, Shibu; Zhao, Qi; Zheng, Liansheng; Zhu, Shiaoping C; Biddick, Kendra; Bolanos, Randall; Delcher, Arthur L; Dew, Ian M; Fasulo, Daniel; Flanigan, Michael J; Huson, Daniel H; Kravitz, Saul A; Miller, Jason R; Mobarry, Clark M; Reinert, Knut; Remington, Karin A; Zhang, Qing; Zheng, Xiangqun H; Nusskern, Deborah R; Lai, Zhongwu; Lei, Yiding; Zhong, Wenyan; Yao, Alison; Guan, Ping; Ji, Rui-Ru; Gu, Zhiping; Wang, Zhen-Yuan; Zhong, Fei; Xiao, Chunlin; Chiang, Chia-Chien; Yandell, Mark; Wortman, Jennifer R; Amanatides, Peter G; Hladun, Suzanne L; Pratts, Eric C; Johnson, Jeffery E; Dodson, Kristina L; Woodford, Kerry J; Evans, Cheryl A; Gropman, Barry; Rusch, Douglas B; Venter, Eli; Wang, Mei; Smith, Thomas J; Houck, Jarrett T; Tompkins, Donald E; Haynes, Charles; Jacob, Debbie; Chin, Soo H; Allen, David R; Dahlke, Carl E; Sanders, Robert; Li, Kelvin; Liu, Xiangjun; Levitsky, Alexander A; Majoros, William H; Chen, Quan; Xia, Ashley C; Lopez, John R; Donnelly, Michael T; Newman, Matthew H; Glodek, Anna; Kraft, Cheryl L; Nodell, Marc; Ali, Feroze; An, Hui-Jin; Baldwin-Pitts, Danita; Beeson, Karen Y; Cai, Shuang; Carnes, Mark; Carver, Amy; Caulk, Parris M; Center, Angela; Chen, Yen-Hui; Cheng, Ming-Lai; Coyne, My D; Crowder, Michelle; Danaher, Steven; Davenport, Lionel B; Desilets, Raymond; Dietz, Susanne M; Doup, Lisa; Dullaghan, Patrick; Ferriera, Steven; Fosler, Carl R; Gire, Harold C; Gluecksmann, Andres; Gocayne, Jeannine D; Gray, Jonathan; Hart, Brit; Haynes, Jason; Hoover, Jeffery; Howland, Tim; Ibegwam, Chinyere; Jalali, Mena; Johns, David; Kline, Leslie; Ma, Daniel S; MacCawley, Steven; Magoon, Anand; Mann, Felecia; May, David; McIntosh, Tina C; Mehta, Somil; Moy, Linda; Moy, Mee C; Murphy, Brian J; Murphy, Sean D; Nelson, Keith A; Nuri, Zubeda; Parker, Kimberly A; Prudhomme, Alexandre C; Puri, Vinita N; Qureshi, Hina; Raley, John C; Reardon, Matthew S; Regier, Megan A; Rogers, Yu-Hui C; Romblad, Deanna L; Schutz, Jakob; Scott, John L; Scott, Richard; Sitter, Cynthia D; Smallwood, Michella; Sprague, Arlan C; Stewart, Erin; Strong, Renee V; Suh, Ellen; Sylvester, Karena; Thomas, Reginald; Tint, Ni Ni; Tsonis, Christopher; Wang, Gary; Wang, George; Williams, Monica S; Williams, Sherita M; Windsor, Sandra M; Wolfe, Keriellen; Wu, Mitchell M; Zaveri, Jayshree; Chaturvedi, Kabir; Gabrielian, Andrei E; Ke, Zhaoxi; Sun, Jingtao; Subramanian, Gangadharan; Venter, J Craig; Pfannkoch, Cynthia M; Barnstead, Mary; Stephenson, Lisa D

2002-05-31

129

Activity of the human carcinogen MeCCNU in the mouse bone marrow micronucleus assay  

SciTech Connect

The nitrosourea mustard MeCCNU is the most recent organic chemical to be classified as a human carcinogen by IARC. MeCCNU gave a strong positive response when tested in the mouse bone marrow micronucleus assay. Activity was evident using either ip injection or oral gavage of the test chemical. These results further support the correlation between human carcinogens and their genotoxicity.

Tinwell, H.; Ashby, J. (ICI Central Toxicology Lab, Cheshire (England))

1991-01-01

130

Limitations of Hairless Mouse Skin as a Model for In Vitro Permeation Studies Through Human Skin: Hydration Damage  

Microsoft Academic Search

Hairless mouse skin currently provides a popular model membrane for studies in human percutaneous absorption. Although some similarities between the two skin types have been demonstrated, the effects of prolonged hydration on hairless mouse skin have not previously been rigorously examined. We have measured in vitro the effects of hydration at 31°C on the permeabilities of hairless mouse skin and

John Russell Bond; Brian William Barry

1988-01-01

131

Species-Specific and Isoform-Specific RNA Binding of Human and Mouse Fragile X Mental Retardation Proteins  

Microsoft Academic Search

The loss of the fragile X RNA binding protein, FMRP, causes macroorchidism and mental retardation in man. The discovery of a mouse ortholog led to the development of several FMRP knockout mouse strains that recapitulate some features of the disease. As mouse and human FMRPs differ in several amino acids in their RNA binding domains, we compared the RNA binding

Robert B. Denman; Ying Ju Sung

2002-01-01

132

Major Histocompatibility Complex Class II Compartments in Human and Mouse B Lymphoblasts Represent Conventional Endocytic Compartments  

Microsoft Academic Search

In most human and mouse antigen-present- ing cells, the majority of intracellular major histocom- patibility complex (MHC) class II molecules resides in late endocytic MHC class II compartments (MIICs), thought to function in antigen processing and peptide loading. However, in mouse A20 B cells, early en- docytic class II-containing vesicles (CIIVs) have been reported to contain most of the intracellular

Monique J. Kleijmeer; Stanislaw Morkowski; Janice M. Griffith; Alexander Y. Rudensky; Hans J. Geuze

2010-01-01

133

Affinity purification of cytosolic epoxide hydrolase from human, rhesus monkey, baboon, rabbit, rat and mouse liver  

Microsoft Academic Search

An affinity purification system based on elution of cytosolic epoxide hydrolase from a methoxycitronellyl thiol ligand with 4-azidochalcone oxide was applied to a variety of samples including liver from human, monkey, baboon, rabbit, rat and mouse as well as mammary gland from mouse. 2. Hepatic tissues yielded a major 58 kDa band on SDS--PAGE, but the system had to be

MARILYN H. SILVA; BRUCE D. HAMMOCK

1987-01-01

134

Regulatory Role of p27kip1 in the Mouse and Human Testis  

Microsoft Academic Search

p27kip1 is a cyclin-dependent kinase inhibitor that regulates the G1\\/S transition of the cell cycle. Immunohistochemical analysis showed that during mouse testicular development p27kip1 is induced when the fetal germ cells, gonocytes, become quiescent on day 16 postcoitum, suggesting that p27kip1 is an important factor for the G1\\/G0 arrest in gonocytes. In the adult mouse and human testis, in general,

TIM L. BEUMER; HIROAKI KIYOKAWA; HERMIEN L. ROEPERS-GAJADIEN; LINDA A. C. VAN DEN BOS; TYCHO M. T. W. LOCK; IRIS S. GADEMAN; DERK H. RUTGERS; ANDREW KOFF; DIRK G. DE ROOIJ

1999-01-01

135

Identifying novel genes for atherosclerosis through mouse-human comparative genetics.  

PubMed

Susceptibility to atherosclerosis is determined by both environmental and genetic factors. Its genetic determinants have been studied by use of quantitative-trait-locus (QTL) analysis. So far, 21 atherosclerosis QTLs have been identified in the mouse: 7 in a high-fat-diet model only, 9 in a sensitized model (apolipoprotein E- or LDL [low-density lipoprotein] receptor-deficient mice) only, and 5 in both models, suggesting that different gene sets operate in each model and that a subset operates in both. Among the 27 human atherosclerosis QTLs reported, 17 (63%) are located in regions homologous (concordant) to mouse QTLs, suggesting that these mouse and human atherosclerosis QTLs have the same underlying genes. Therefore, genes regulating human atherosclerosis will be found most efficiently by first finding their orthologs in concordant mouse QTLs. Novel mouse QTL genes will be found most efficiently by using a combination of the following strategies: identifying QTLs in new crosses performed with previously unused parental strains; inducing mutations in large-scale, high-throughput mutagenesis screens; and using new genomic and bioinformatics tools. Once QTL genes are identified in mice, they can be tested in human association studies for their relevance in human atherosclerotic disease. PMID:15931593

Wang, Xiaosong; Ishimori, Naoki; Korstanje, Ron; Rollins, Jarod; Paigen, Beverly

2005-05-19

136

Identifying Novel Genes for Atherosclerosis through Mouse-Human Comparative Genetics  

PubMed Central

Susceptibility to atherosclerosis is determined by both environmental and genetic factors. Its genetic determinants have been studied by use of quantitative-trait–locus (QTL) analysis. So far, 21 atherosclerosis QTLs have been identified in the mouse: 7 in a high-fat–diet model only, 9 in a sensitized model (apolipoprotein E– or LDL [low-density lipoprotein] receptor–deficient mice) only, and 5 in both models, suggesting that different gene sets operate in each model and that a subset operates in both. Among the 27 human atherosclerosis QTLs reported, 17 (63%) are located in regions homologous (concordant) to mouse QTLs, suggesting that these mouse and human atherosclerosis QTLs have the same underlying genes. Therefore, genes regulating human atherosclerosis will be found most efficiently by first finding their orthologs in concordant mouse QTLs. Novel mouse QTL genes will be found most efficiently by using a combination of the following strategies: identifying QTLs in new crosses performed with previously unused parental strains; inducing mutations in large-scale, high-throughput mutagenesis screens; and using new genomic and bioinformatics tools. Once QTL genes are identified in mice, they can be tested in human association studies for their relevance in human atherosclerotic disease.

Wang, Xiaosong; Ishimori, Naoki; Korstanje, Ron; Rollins, Jarod; Paigen, Beverly

2005-01-01

137

PhenoHM: human-mouse comparative phenome-genome server  

PubMed Central

PhenoHM is a human–mouse comparative phenome–genome server that facilitates cross-species identification of genes associated with orthologous phenotypes (http://phenome.cchmc.org; full open access, login not required). Combining and extrapolating the knowledge about the roles of individual gene functions in the determination of phenotype across multiple organisms improves our understanding of gene function in normal and perturbed states and offers the opportunity to complement biologically the rapidly expanding strategies in comparative genomics. The Mammalian Phenotype Ontology (MPO), a structured vocabulary of phenotype terms that leverages observations encompassing the consequences of mouse gene knockout studies, is a principal component of mouse phenotype knowledge source. On the other hand, the Unified Medical Language System (UMLS) is a composite collection of various human-centered biomedical terminologies. In the present study, we mapped terms reciprocally from the MPO to human disease concepts such as clinical findings from the UMLS and clinical phenotypes from the Online Mendelian Inheritance in Man knowledgebase. By cross-mapping mouse–human phenotype terms, extracting implicated genes and extrapolating phenotype-gene associations between species PhenoHM provides a resource that enables rapid identification of genes that trigger similar outcomes in human and mouse and facilitates identification of potentially novel disease causal genes. The PhenoHM server can be accessed freely at http://phenome.cchmc.org.

Sardana, Divya; Vasa, Suresh; Vepachedu, Nishanth; Chen, Jing; Gudivada, Ranga Chandra; Aronow, Bruce J.; Jegga, Anil G.

2010-01-01

138

PhenoHM: human-mouse comparative phenome-genome server.  

PubMed

PhenoHM is a human-mouse comparative phenome-genome server that facilitates cross-species identification of genes associated with orthologous phenotypes (http://phenome.cchmc.org; full open access, login not required). Combining and extrapolating the knowledge about the roles of individual gene functions in the determination of phenotype across multiple organisms improves our understanding of gene function in normal and perturbed states and offers the opportunity to complement biologically the rapidly expanding strategies in comparative genomics. The Mammalian Phenotype Ontology (MPO), a structured vocabulary of phenotype terms that leverages observations encompassing the consequences of mouse gene knockout studies, is a principal component of mouse phenotype knowledge source. On the other hand, the Unified Medical Language System (UMLS) is a composite collection of various human-centered biomedical terminologies. In the present study, we mapped terms reciprocally from the MPO to human disease concepts such as clinical findings from the UMLS and clinical phenotypes from the Online Mendelian Inheritance in Man knowledgebase. By cross-mapping mouse-human phenotype terms, extracting implicated genes and extrapolating phenotype-gene associations between species PhenoHM provides a resource that enables rapid identification of genes that trigger similar outcomes in human and mouse and facilitates identification of potentially novel disease causal genes. The PhenoHM server can be accessed freely at http://phenome.cchmc.org. PMID:20507906

Sardana, Divya; Vasa, Suresh; Vepachedu, Nishanth; Chen, Jing; Gudivada, Ranga Chandra; Aronow, Bruce J; Jegga, Anil G

2010-05-27

139

Cell-free entry of human T-cell leukemia virus type 1 to mouse cells.  

PubMed

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia and HTLV-1-associated myelopathy / tropical spastic paraparesis. Recently we infected newborn mice by inoculating HTLV-1-producing human cells, and found that T-cells, B-cells and granulocytes were infected in vivo. To understand the mechanism of viral-cell interaction and the pathogenesis of HTLV-1 using the mouse model, it is important to clarify the cellular tropism using a cell-free HTLV-1 transmission system. We employed a highly transmissible cell-free HTLV-1 produced by a feline kidney cell line, c77, and studied the susceptibility of 9 kinds of mouse cell lines, EL4, RLm1, CTLL-2, J774.1, DA-1, Ba / F3, WEHI-3, NIH3T3 and B1, and two kinds of human cell lines, Molt-4 and Hut78. HTLV-1 proviral sequence was found by PCR in all 9 mouse cell lines as well as in 2 human cell lines and viral entry was blocked with sera from an HTLV-1 carrier and an adult T-cell leukemia patient. Unexpectedly, mouse cell lines EL4 and RLm1 and human cell lines Molt-4 and Hut78 showed similar efficiency for viral entry. These results suggest a wide distribution of HTLV-1 receptor in mouse cells. PMID:11346463

Feng, R; Kabayama, A; Uchida, K; Hoshino, H; Miwa, M

2001-04-01

140

Mechanism of ethylbenzene-induced mouse-specific lung tumor: metabolism of ethylbenzene by rat, mouse, and human liver and lung microsomes.  

PubMed

This study was conducted to determine species differences in the metabolism of ethylbenzene (EB) in liver and lung. EB (0.22-7.0mM) was incubated with mouse, rat and human liver and lung microsomes and the formation of 1-phenylethanol (1PE), acetophenone (AcPh), 2-ethylphenol (2EP), 4-ethylphenol (4EP), 2,5-ethylquinone, and 3,4-ethylquinone were measured. Reactive metabolites (2,5-dihydroxyethylbenzene-GSH [2EP-GSH] and 3,4-dihydroxyethylbenzene-GSH [4EP-GSH]) were monitored via glutathione (GSH) trapping technique. None of the metabolites were formed at detectable levels in incubations with human lung microsomes. Percent conversion of EB to 1PE ranged from 1% (rat lung; 7.0mM EB) to 58% (mouse lung; 0.22 mM EB). More 1PE was formed in mouse lung than in mouse liver microsomes, although formation of 1PE by rat liver and lung microsomes was similar. Metabolism of EB to 1PE was in the order of mouse > rat > human. Formation of AcPh was roughly an order of magnitude lower than 1PE. Conversion of EB to ring-hydroxylated metabolites was much lower (0.0001% [4EP-GSH; rat lung] to 0.6% [2EP-GSH; mouse lung]); 2EP-GSH was typically 10-fold higher than 4EP-GSH. Formation of 2EP-GSH was higher by lung (highest by mouse lung) than liver microsomes and the formation of 2EP-GSH by mouse liver microsomes was higher than rat and human liver microsomes. Increasing concentrations of EB did lead to a decrease in amount of some formed metabolites. This may indicate some level of substrate- or metabolite-mediated inhibition. High concentrations of 2EP and 4EP were incubated with microsomes to further investigate their oxidation to ethylcatechol (ECat) and ethylhydroquinone (EHQ). Conversion of 2EP to EHQ ranged from 6% to 9% by liver (mouse > human > rat) and from 0.1% to 18% by lung microsomes (mouse > rat > human). Conversion of 4EP to ECat ranged from 2% to 4% by liver (mouse > human approximately rat) and from 0.3% to 7% by lung microsomes (mouse > rat > human). Although ring-oxidized metabolites accounted for a relatively small fraction of overall EB metabolism, its selective elevation in mouse lung microsomes is nonetheless consistent with the hypothesized mode of action for observed preferential toxicity of EB to the lung in this species. PMID:19075040

Saghir, Shakil A; Rick, David L; McClymont, E L; Zhang, Fagen; Bartels, Michael J; Bus, James S

2008-12-15

141

Processing of truncated mouse or human rRNA transcribed from ribosomal minigenes transfected into mouse cells.  

PubMed Central

The processing of pre-rRNA in eukaryotic cells involves a complex pattern of nucleolytic reactions taking place in preribosomes with the participation of several nonribosomal proteins and small nuclear RNAs. The mechanism of these reactions remains largely unknown, mainly because of the absence of faithful in vitro assays for most processing steps. We have developed a pre-rRNA processing system using the transient expression of ribosomal minigenes transfected into cultured mouse cells. Truncated mouse or human rRNA genes are faithfully transcribed under the control of mouse promoter and terminator signals. The fate of these transcripts is analyzed by the use of reporter sequences flanking the rRNA gene inserts. Both mouse and human transcripts, containing the 3' end of 18S rRNA-encoding DNA (rDNA), internal transcribed spacer (ITS) 1, 5.8S rDNA, ITS 2, and the 5' end of 28S rDNA, are processed predominantly to molecules coterminal with the natural mature rRNAs plus minor products corresponding to cleavages within ITS 1 and ITS 2. To delineate cis-acting signals in pre-rRNA processing, we studied series of more truncated human-mouse minigenes. A faithful processing at the 18S rRNA/ITS 1 junction can be observed with transcripts containing only the 60 3'-terminal nucleotides of 18S rRNA and the 533 proximal nucleotides of ITS 1. However, further truncation of 18S rRNA (to 8 nucleotides) or of ITS 1 (to 48 nucleotides) abolishes the cleavage of the transcript. Processing at the ITS 2/28S rRNA junction is observed with truncated transcripts lacking the 5.8S rRNA plus a major part of ITS 2 and containing only 502 nucleotides of 28S rRNA. However, further truncation of the 28S rRNA segment to 217 nucleotides abolishes processing. Minigene transcripts containing most internal sequences of either ITS 1 or ITS 2, but devoid of ITS/mature rRNA junctions, are not processed, suggesting that the cleavages in vivo within either ITS segment are dependent on the presence in cis of mature rRNA sequences. These results show that the major cis signals for pre-rRNA processing at the 18S rRNA/ITS 1 or the ITS2/28S rRNA junction involve solely a limited critical length of the respective mature rRNA and adjacent spacer sequences. Images

Hadjiolova, K V; Normann, A; Cavaille, J; Soupene, E; Mazan, S; Hadjiolov, A A; Bachellerie, J P

1994-01-01

142

Integration of Ecogpt and SV40 early region sequences into human chromosome 17: a dominant selection system in whole cell and microcell human-mouse hybrids.  

PubMed

The dominant selectable gene, Ecogpt, has been introduced, by the calcium phosphate precipitation technique, into normal human fibroblasts, along with the SV40 early region genes. In one transfectant clone, integration of these sequences into human chromosome 17 was demonstrated by the construction of human-mouse somatic cell hybrids, selected for by growth in medium containing mycophenolic acid and xanthine. A whole cell hybrid, made between the human transfectant and a mouse L cell, was used as donor of the Ecogpt-carrying human chromosome 17 to 'tribrids' growing in suspension, made by whole cell fusion between a mouse thymoma cell line, and to microcell hybrids made with a mouse teratocarcinoma cell line. Two tribrids contained karyotypically normal human chromosomes 17 and a small number of other human chromosomes, while a third tribrid had a portion of the long arm of chromosome 17 translocated to mouse as its only human genetic material. Two independent microcell hybrids contained a normal chromosome 17 and no other human chromosome on a mouse teratocarcinoma background. These experiments demonstrate the ability to construct human-mouse somatic cell hybrids using a dominant selection system. By applying this approach it should be possible to select for a wide range of different human chromosomes in whole cell and microcell hybrids. In particular, transfer of single human chromosomes to mouse teratocarcinoma cells will allow examination of developmentally regulated human gene sequences after differentiation of such hybrids. PMID:11892815

Tunnacliffe, A; Parkar, M; Povey, S; Bengtsson, B O; Stanley, K; Solomon, E; Goodfellow, P

1983-01-01

143

Integration of Ecogpt and SV40 early region sequences into human chromosome 17: a dominant selection system in whole cell and microcell human-mouse hybrids.  

PubMed Central

The dominant selectable gene, Ecogpt, has been introduced, by the calcium phosphate precipitation technique, into normal human fibroblasts, along with the SV40 early region genes. In one transfectant clone, integration of these sequences into human chromosome 17 was demonstrated by the construction of human-mouse somatic cell hybrids, selected for by growth in medium containing mycophenolic acid and xanthine. A whole cell hybrid, made between the human transfectant and a mouse L cell, was used as donor of the Ecogpt-carrying human chromosome 17 to 'tribrids' growing in suspension, made by whole cell fusion between a mouse thymoma cell line, and to microcell hybrids made with a mouse teratocarcinoma cell line. Two tribrids contained karyotypically normal human chromosomes 17 and a small number of other human chromosomes, while a third tribrid had a portion of the long arm of chromosome 17 translocated to mouse as its only human genetic material. Two independent microcell hybrids contained a normal chromosome 17 and no other human chromosome on a mouse teratocarcinoma background. These experiments demonstrate the ability to construct human-mouse somatic cell hybrids using a dominant selection system. By applying this approach it should be possible to select for a wide range of different human chromosomes in whole cell and microcell hybrids. In particular, transfer of single human chromosomes to mouse teratocarcinoma cells will allow examination of developmentally regulated human gene sequences after differentiation of such hybrids. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. Fig. 5. Fig. 6. Fig. 7.

Tunnacliffe, A; Parkar, M; Povey, S; Bengtsson, B O; Stanley, K; Solomon, E; Goodfellow, P

1983-01-01

144

Novel genetically-humanized mouse model established to evaluate efficacy of therapeutic agents to human interleukin-6 receptor  

PubMed Central

For clinical trials of therapeutic monoclonal antibodies (mAbs) to be successful, their efficacy needs to be adequately evaluated in preclinical experiments. However, in many cases it is difficult to evaluate the candidate mAbs using animal disease models because of lower cross-reactivity to the orthologous target molecules. In this study we have established a novel humanized Castleman's disease mouse model, in which the endogenous interleukin-6 receptor gene is successfully replaced by human IL6R, and human IL6 is overexpressed. We have also demonstrated the therapeutic effects of an antibody that neutralizes human IL6R, tocilizumab, on the symptoms in this mouse model. Plasma levels of human soluble IL6R and human IL6 were elevated after 4-week treatment of tocilizumab in this mouse model similarly to the result previously reported in patients treated with tocilizumab. Our mouse model provides us with a novel means of evaluating the in vivo efficacy of human IL6R-specific therapeutic agents.

Ueda, Otoya; Tateishi, Hiromi; Higuchi, Yoshinobu; Fujii, Etsuko; Kato, Atsuhiko; Kawase, Yosuke; Wada, Naoko A.; Tachibe, Takanori; Kakefuda, Mami; Goto, Chisato; Kawaharada, Makoto; Shimaoka, Shin; Hattori, Kunihiro; Jishage, Kou-ichi

2013-01-01

145

Mapping of Unconventional Myosins in Mouse and Human  

Microsoft Academic Search

Myosins are molecular motors that move along filamentous actin. Seven classes of myosin are expressed in vertebrates: conventional myosin, or myosin-II, as well as the 6 unconventional myosin classes -I, -V, -VI, -VII, -IX, and -X. We have mapped in mouse 22 probes encompassing all known unconventional myosins and, as a result, have identified 16 potential unconventional myosin genes. These

Tama Hasson; Joseph F. Skowron; Debra J. Gilbert; Karen B. Avraham; William L. Perry; William M. Bement; Blake L. Anderson; Elliott H. Sherr; Zheng-Yi Chen; Lloyd A. Greene; David C. Ward; David P. Corey; Mark S. Mooseker; Neal G. Copeland; Nancy A. Jenkins

1996-01-01

146

Transcript profiling identifies iqgap2(-/-) mouse as a model for advanced human hepatocellular carcinoma.  

PubMed

It is broadly accepted that genetically engineered animal models do not always recapitulate human pathobiology. Therefore identifying best-fit mouse models of human cancers that truly reflect the corresponding human disease is of vital importance in elucidating molecular mechanisms of tumorigenesis and developing preventive and therapeutic approaches. A new hepatocellular carcinoma (HCC) mouse model lacking a novel putative tumor suppressor IQGAP2 has been generated by our laboratory. The aim of this study was to obtain the molecular signature of Iqgap2(-/-) HCC tumors and establish the relevance of this model to human disease. Here we report a comprehensive transcriptome analysis of Iqgap2(-/-) livers and a cross-species comparison of human and Iqgap2(-/-) HCC tumors using Significance Analysis of Microarray (SAM) and unsupervised hierarchical clustering analysis. We identified the Wnt/?-catenin signaling pathway as the top canonical pathway dysregulated in Iqgap2(-/-) livers. We also demonstrated that Iqgap2(-/-) hepatic tumors shared genetic signatures with HCC tumors from patients with advanced disease as evidenced by a 78% mouse-to-human microarray data set concordance rate with 117 out of 151 identified ortholog genes having similar expression profiles across the two species. Collectively, these results indicate that the Iqgap2 knockout mouse model closely recapitulates human HCC at the molecular level and supports its further application for the study of this disease. PMID:23951254

Gnatenko, Dmitri V; Xu, Xiao; Zhu, Wei; Schmidt, Valentina A

2013-08-12

147

Divergent cellular phenotypes of human and mouse cells lacking the Werner syndrome RecQ helicase  

PubMed Central

Werner syndrome (WS) is a human autosomal recessive genetic instability and cancer predisposition syndrome with features of premature aging. Several genetically determined mouse models of WS have been generated, however none develops features of premature aging or an elevated risk of neoplasia unless additional genetic perturbations are introduced. In order to determine whether differences in cellular phenotype could explain the discrepant phenotypes of Wrn?/? mice and WRN-deficient humans, we compared the cellular phenotype of newly derived Wrn?/? mouse primary fibroblasts with previous analyses of primary and transformed fibroblasts from WS patients and with newly derived, WRN-depleted human primary fibroblasts. These analyses confirmed previously reported cellular phenotypes of WRN-mutant and WRN-deficient human fibroblasts, and demonstrated that the human WRN-deficient cellular phenotype can be detected in cells grown in 5% or in 20% oxygen. In contrast, we did not identify prominent cellular phenotypes present in WRN-deficient human cells in Wrn?/? mouse fibroblasts. Our results indicate that human and mouse fibroblasts have different functional requirements for WRN protein, and that the absence of a strong cellular phenotype may in part explain the failure of Wrn?/? mice to develop an organismal phenotype resembling Werner syndrome.

Dhillon, Kiranjit K.; Sidorova, Julia M.; Albertson, Tina M.; Anderson, Judith B.; Ladiges, Warren C.; Rabinovitch, Peter S.; Preston, Bradley D.; Monnat, Raymond J.

2009-01-01

148

Mapping of the ARIX homeodomain gene to mouse chromosome 7 and human chromosome 11q13  

SciTech Connect

The recently described homeodomain protein ARIX is expressed specifically in noradreneric cell types of the sympathetic nervous system, brain, and adrenal medulla. ARIX interacts with regulatory elements of the genes encoding the noradrenergic biosynthetic enzymes tyrosine hydroxylase and dopamine {beta}-hydroxylase, suggesting a role for ARIX in expression of the noradrenergic phenotype. In the study described here, the mouse and human ARIX genes are mapped. Using segregation analysis of two panels of mouse backcross DNA, mouse Arix was positioned approximately 50 cM distal to the centromere of chromosome 7, near Hbb. Human ARIX was positioned through analysis of somatic cell hybrids and fluorescence in situ hybridization of human metaphase chromosomes to chromosome 7, near Hbb. Human ARIX was positioned through analysis of somatic cell hybrids and fluorescence in situ hybridization of human metaphase chromosomes to chromosome 11q13.3-q13.4. These map locations extend and further define regions of conserved synteny between mouse and human genomes and identify a new candidate gene for inherited developmental disorders linked to human 11q13.

Johnson, K.R. [Jackson Lab., Bar Harbor, ME (United States); Smith, L.; Rhodes, J. [Oregon Health Sciences Univ., Portland, OR (United States)] [and others

1996-05-01

149

The mouse and human genes encoding the recognition component of the N-end rule pathway  

PubMed Central

The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. The N-end rule pathway is one proteolytic pathway of the ubiquitin system. The recognition component of this pathway, called N-recognin or E3, binds to a destabilizing N-terminal residue of a substrate protein and participates in the formation of a substrate-linked multiubiquitin chain. We report the cloning of the mouse and human Ubr1 cDNAs and genes that encode a mammalian N-recognin called E3?. Mouse UBR1p (E3?) is a 1,757-residue (200-kDa) protein that contains regions of sequence similarity to the 225-kDa Ubr1p of the yeast Saccharomyces cerevisiae. Mouse and human UBR1p have apparent homologs in other eukaryotes as well, thus defining a distinct family of proteins, the UBR family. The residues essential for substrate recognition by the yeast Ubr1p are conserved in the mouse UBR1p. The regions of similarity among the UBR family members include a putative zinc finger and RING-H2 finger, another zinc-binding domain. Ubr1 is located in the middle of mouse chromosome 2 and in the syntenic 15q15-q21.1 region of human chromosome 15. Mouse Ubr1 spans ?120 kilobases of genomic DNA and contains ?50 exons. Ubr1 is ubiquitously expressed in adults, with skeletal muscle and heart being the sites of highest expression. In mouse embryos, the Ubr1 expression is highest in the branchial arches and in the tail and limb buds. The cloning of Ubr1 makes possible the construction of Ubr1-lacking mouse strains, a prerequisite for the functional understanding of the mammalian N-end rule pathway.

Kwon, Yong Tae; Reiss, Yuval; Fried, Victor A.; Hershko, Avram; Yoon, Jeong Kyo; Gonda, David K.; Sangan, Pitchai; Copeland, Neal G.; Jenkins, Nancy A.; Varshavsky, Alexander

1998-01-01

150

Sequence of centromere separation: Separation in a quasi-stable mouse-human somatic cell hybrid  

Microsoft Academic Search

A quasi-stable mouse-human hybrid cell line, HR61, containing between one and ten human chromosomes was analyzed for the sequence of centromere separation. The purpose was to determine which genome of the two initiates centromere separation first. The data clearly indicate that the separation of centromeres of the human genome is not only initiated but is completed before any centromeres from

Baldev K. Vig; Raghbir S. Athwal

1989-01-01

151

The speed of mouse-click as a measure of anxiety during human-computer interaction  

Microsoft Academic Search

The monitoring of the human-computer interaction process is one of the essential aspects in the evaluation and enhancement of both task and affective outcome of human-computer interaction. However, although objective measures exist for task outcome, most affective measures are subjective. This study represented an investigation into the speed of mouse-click as a possible measure in human-computer interaction, and was based

M. Macaulay

2004-01-01

152

Comparative analyses of influenza virus receptor distribution in the human and mouse brains.  

PubMed

Accumulating evidence suggests a potential link between influenza A virus infection and the occurrence of influenza-associated neurological disorders. As influenza infection is mediated by specific receptors on the host cell surface, it is important to understand the distribution patterns of influenza receptors in target organs. We carried out comprehensive experiments to localize influenza receptors in the brains of two different mouse strains and the human brain for comparison using lectin histochemistry. We further compared the brain regions in which influenza receptors were expressed and the regions in which experimental influenza infection was observed. Our results show that the expression patterns for influenza receptors in mouse and human brains are different. In the mouse brain, human influenza virus receptors (HuIV-R) were expressed in part of brainstem and cerebellar white matter while avian influenza virus receptors (AIV-R) were expressed in the cerebellar Purkinje neurons. In contrast, in the human brain, many neurons and glia in widespread regions, including the cerebral cortex, hippocampus, brainstem, and cerebellum, express both AIV-R and HuIV-R. Importantly, vascular endothelial cells, choroid plexus epithelial cells and ependymal cells in both mouse and human brains express high levels of HuIV-R and AIV-R. The regional reciprocity was not observed when comparing regions with influenza receptor expression and the regions of influenza infection within the mouse brain. Our results demonstrate a differential influenza receptor expression pattern in mouse and human brains, and a disparity between influenza receptor distribution and regions with actual influenza infection. PMID:23726946

Kim, Minsoo; Yu, Ji Eun; Lee, Jong-Hwan; Chang, Byung-Joon; Song, Chang-Seon; Lee, Beobyi; Paik, Doo Jin; Nahm, Sang-Soep

2013-05-29

153

Automated whole-genome multiple alignment of rat, mouse, and human  

SciTech Connect

We have built a whole genome multiple alignment of the three currently available mammalian genomes using a fully automated pipeline which combines the local/global approach of the Berkeley Genome Pipeline and the LAGAN program. The strategy is based on progressive alignment, and consists of two main steps: (1) alignment of the mouse and rat genomes; and (2) alignment of human to either the mouse-rat alignments from step 1, or the remaining unaligned mouse and rat sequences. The resulting alignments demonstrate high sensitivity, with 87% of all human gene-coding areas aligned in both mouse and rat. The specificity is also high: <7% of the rat contigs are aligned to multiple places in human and 97% of all alignments with human sequence > 100kb agree with a three-way synteny map built independently using predicted exons in the three genomes. At the nucleotide level <1% of the rat nucleotides are mapped to multiple places in the human sequence in the alignment; and 96.5% of human nucleotides within all alignments agree with the synteny map. The alignments are publicly available online, with visualization through the novel Multi-VISTA browser that we also present.

Brudno, Michael; Poliakov, Alexander; Salamov, Asaf; Cooper, Gregory M.; Sidow, Arend; Rubin, Edward M.; Solovyev, Victor; Batzoglou, Serafim; Dubchak, Inna

2004-07-04

154

Interactions of tumor necrosis factor (TNF) and TNF receptor family members in the mouse and human.  

PubMed

Ligands of the tumor necrosis factor superfamily (TNFSF) (4-1BBL, APRIL, BAFF, CD27L, CD30L, CD40L, EDA1, EDA2, FasL, GITRL, LIGHT, lymphotoxin alpha, lymphotoxin alphabeta, OX40L, RANKL, TL1A, TNF, TWEAK, and TRAIL) bind members of the TNF receptor superfamily (TNFRSF). A comprehensive survey of ligand-receptor interactions was performed using a flow cytometry-based assay. All ligands engaged between one and five receptors, whereas most receptors only bound one to three ligands. The receptors DR6, RELT, TROY, NGFR, and mouse TNFRH3 did not interact with any of the known TNFSF ligands, suggesting that they either bind other types of ligands, function in a ligand-independent manner, or bind ligands that remain to be identified. The study revealed that ligand-receptor pairs are either cross-reactive between human and mouse (e.g. Tweak/Fn14, RANK/RANKL), strictly species-specific (GITR/GITRL), or partially species-specific (e.g. OX40/OX40L, CD40/CD40L). Interestingly, the receptor binding patterns of lymphotoxin alpha and alphabeta are redundant in the human but not in the mouse system. Ligand oligomerization allowed detection of weak interactions, such as that of human TNF with mouse TNFR2. In addition, mouse APRIL exists as two different splice variants differing by a single amino acid. Although human APRIL does not interact with BAFF-R, the shorter variant of mouse APRIL exhibits weak but detectable binding to mouse BAFF-R. PMID:16547002

Bossen, Claudia; Ingold, Karine; Tardivel, Aubry; Bodmer, Jean-Luc; Gaide, Olivier; Hertig, Sylvie; Ambrose, Christine; Tschopp, Jürg; Schneider, Pascal

2006-03-17

155

Toxicity testing of human assisted reproduction devices using the mouse embryo assay.  

PubMed

Systems to assess the toxicity of materials used in human assisted reproduction currently lack efficiency and/or sufficient discriminatory power. The development of 1-cell CBA/B6 F1 hybrid mouse embryos to blastocysts, expressed as blastocyst rate (BR), is used to measure toxicity. The embryos were divided into control and test groups, and were exposed to either control medium or to a potentially toxic test medium. Inferences on toxicity were based on differences in BR between the two groups. The mouse embryo assay followed a stratified (mouse), randomized (embryo), and balanced (equal number of embryos per group and per mouse) design. The number of embryos needed was calculated using power analysis. The basal BR of the hybrid strain was determined in a historical population. Sixty-nine mouse embryos per group were required to detect toxic materials with sufficient sensitivity and to account for the considerable inter-mouse variation in blastocyst development. Fifty-two samples, divided over batches of seven different products were tested before use in the study IVF centre and five of these were found to be toxic. This test system, presented as the Nijmegen mouse embryo assay (NMEA), can be used to detect embryo-toxic materials in daily IVF practice, and this report may provide a starting point for standardization. PMID:19400995

Punt-van der Zalm, J P E M; Hendriks, J C M; Westphal, J R; Kremer, J A M; Teerenstra, S; Wetzels, A M M

2009-04-01

156

NMR HRMAS spectroscopy of lung biopsy samples: Comparison study between human, pig, rat, and mouse metabolomics.  

PubMed

PURPOSE: Using the metabolomics by NMR high-resolution magic angle spinning spectroscopy, we assessed the lung metabolome of various animal species in order to identify the animal model that could be substituted to human lung in studies on fresh lung biopsies. METHODS: The experiments were conducted on intact lung biopsy samples of pig, rat, mouse, and human using a Bruker Advance III 500 spectrometer. Thirty-five to 39 metabolites were identified and 23 metabolites were quantified. Principal component analysis, partial least-squares discriminant analysis, and analysis of variance tests were performed in order to compare the metabolic profiles of each animal lung biopsies to those of the human lung. RESULTS: The metabolic composition between human and pig lung was similar. However, human lung was distinguishable from mouse and rat regarding: Trimethylamine N-oxide and betaïne which were present in rodents but not in human lung, carnitine, and glycerophosphocholine which were present in mouse but not in human lung. Conversely, succinic acid was undetected in rat lung. Furthermore, fatty acids concentration was significantly higher in rodent lungs compared to human lung. CONCLUSION: Using the metabolomics by NMR high-resolution magic angle spinning spectroscopy on lung biopsy, samples allowed to highlight that pig lung seems to be close to human lung as regarding its metabolite composition with more similarities than dissimilarities. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc. PMID:23412987

Benahmed, Malika A; Elbayed, Karim; Daubeuf, François; Santelmo, Nicola; Frossard, Nelly; Namer, Izzie J

2013-02-14

157

Human and mouse switch-like genes share common transcriptional regulatory mechanisms for bimodality  

PubMed Central

Background Gene expression is controlled over a wide range at the transcript level through complex interplay between DNA and regulatory proteins, resulting in profiles of gene expression that can be represented as normal, graded, and bimodal (switch-like) distributions. We have previously performed genome-scale identification and annotation of genes with switch-like expression at the transcript level in mouse, using large microarray datasets for healthy tissue, in order to study the cellular pathways and regulatory mechanisms involving this class of genes. We showed that a large population of bimodal mouse genes encoding for cell membrane and extracellular matrix proteins is involved in communication pathways. This study expands on previous results by annotating human bimodal genes, investigating their correspondence to bimodality in mouse orthologs and exploring possible regulatory mechanisms that contribute to bimodality in gene expression in human and mouse. Results Fourteen percent of the human genes on the HGU133A array (1847 out of 13076) were identified as bimodal or switch-like. More than 40% were found to have bimodal mouse orthologs. KEGG pathways enriched for bimodal genes included ECM-receptor interaction, focal adhesion, and tight junction, showing strong similarity to the results obtained in mouse. Tissue-specific modes of expression of bimodal genes among brain, heart, and skeletal muscle were common between human and mouse. Promoter analysis revealed a higher than average number of transcription start sites per gene within the set of bimodal genes. Moreover, the bimodal gene set had differentially methylated histones compared to the set of the remaining genes in the genome. Conclusion The fact that bimodal genes were enriched within the cell membrane and extracellular environment make these genes as candidates for biomarkers for tissue specificity. The commonality of the important roles bimodal genes play in tissue differentiation in both the human and mouse indicates the potential value of mouse data in providing context for human tissue studies. The regulation motifs enriched in the bimodal gene set (TATA boxes, alternative promoters, methlyation) have known associations with complex diseases, such as cancer, providing further potential for the use of bimodal genes in studying the molecular basis of disease.

Ertel, Adam; Tozeren, Aydin

2008-01-01

158

Localization of the synapsin II (SYN2) gene to human chromosome 3 and mouse chromosome 6  

SciTech Connect

The synapsins are a family of four synaptic vesicle-associated proteins, synapsins Ia, Ib, IIa, and IIb, that have been implicated in modulation of neurotransmitter release and in synaptogenesis . They are products from alternative splicing of two distinct genes, the synapsin I and synapsin II genes. The synapsin I (SYN1) gene has been mapped to the X chromosome in human and mouse. In this study, we have determined the chromosomal location of the synapsin II (SYN2) gene in both and human and mouse. 10 refs., 1 fig.

Lian Li; Lih-Shen Chin; Greengard, P. [Rockefeller Univ., New York, NY (United States)] [and others

1995-07-20

159

Are mouse models of human mycobacterial diseases relevant? Genetics says: 'yes!'  

PubMed Central

Relevance and accuracy of experimental mouse models of tuberculosis (TB) are the subject of constant debate. This article briefly reviews genetic aspects of this problem and provides a few examples of mycobacterial diseases with similar or identical genetic control in mice and humans. The two species display more similarities than differences regarding both genetics of susceptibility/severity of mycobacterial diseases and the networks of protective and pathological immune reactions. In the opinion of the author, refined mouse models of mycobacterial diseases are extremely useful for modelling the corresponding human conditions, if genetic diversity is taken into account.

Apt, Alexander S

2011-01-01

160

In Vivo Ultra-Fast Photoacoustic Flow Cytometry of Circulating Human Melanoma Cells Using Near-Ingrared High-Pulse Rate Lasers  

PubMed Central

The circulating tumor cells (CTCs) appear to be a marker of metastasis development, especially, for highly aggressive and epidemically growing melanoma malignancy that is often metastatic at early stages. Recently, we introduced in vivo photoacoustic (PA) flow cytometry (PAFC) for label-free detection of mouse B16F10 CTCs in melanoma-bearing mice using melanin as an intrinsic marker. Here, we significantly improve the speed of PAFC by using a high pulse repetition rate laser operating at 820 and 1064 nm wavelengths. This platform was used in preclinical studies for label-free PA detection of low pigmented human CTCs. Demonstrated label-free PAFC detection, low level of background signals, and favorable safety standards for near infrared irradiation suggest that a fiber laser operating at 1064 nm at pulse repetition rates up to 0.5 MHz could be a promising source for portable clinical PAFC devices. The possible applications can include early diagnosis of melanoma at the parallel progression of primary tumor and CTCs, detection of cancer recurrence, residual disease, and real-time monitoring of therapy efficiency by counting CTCs before, during and after therapeutic intervention. Herewith, we also address sensitivity of label-free PAFC melanoma CTCs detection and introduce in vivo CTCs targeting by magnetic nanoparticles conjugated with specific antibody and magnetic cells enrichment.

Nedosekin, Dmitry A.; Sarimollaoglu, Mustafa; Ye, John; Galanzha, Ekaterina I.; Zharov, Vladimir P.

2011-01-01

161

In vivo ultra-fast photoacoustic flow cytometry of circulating human melanoma cells using near-infrared high-pulse rate lasers.  

PubMed

The circulating tumor cells (CTCs) appear to be a marker of metastasis development, especially, for highly aggressive and epidemically growing melanoma malignancy that is often metastatic at early stages. Recently, we introduced in vivo photoacoustic (PA) flow cytometry (PAFC) for label-free detection of mouse B16F10 CTCs in melanoma-bearing mice using melanin as an intrinsic marker. Here, we significantly improve the speed of PAFC by using a high-pulse repetition rate laser operating at 820 and 1064 nm wavelengths. This platform was used in preclinical studies for label-free PA detection of low-pigmented human CTCs. Demonstrated label-free PAFC detection, low level of background signals, and favorable safety standards for near-infrared irradiation suggest that a fiber laser operating at 1064 nm at pulse repetition rates up to 0.5 MHz could be a promising source for portable clinical PAFC devices. The possible applications can include early diagnosis of melanoma at the parallel progression of primary tumor and CTCs, detection of cancer recurrence, residual disease and real-time monitoring of therapy efficiency by counting CTCs before, during, and after therapeutic intervention. Herewith, we also address sensitivity of label-free detection of melanoma CTCs and introduce in vivo CTC targeting by magnetic nanoparticles conjugated with specific antibody and magnetic cells enrichment. PMID:21786417

Nedosekin, Dmitry A; Sarimollaoglu, Mustafa; Ye, Jian-Hui; Galanzha, Ekaterina I; Zharov, Vladimir P

2011-07-22

162

The relevance of mouse models for investigating age-related bone loss in humans.  

PubMed

Mice are increasingly used for investigation of the pathophysiology of osteoporosis because their genome is easily manipulated, and their skeleton is similar to that of humans. Unlike the human skeleton, however, the murine skeleton continues to grow slowly after puberty and lacks osteonal remodeling of cortical bone. Yet, like humans, mice exhibit loss of cancellous bone, thinning of cortical bone, and increased cortical porosity with advancing age. Histologic evidence in mice and humans alike indicates that inadequate osteoblast-mediated refilling of resorption cavities created during bone remodeling is responsible. Mouse models of progeria also show bone loss and skeletal defects associated with senescence of early osteoblast progenitors. Additionally, mouse models of atherosclerosis, which often occurs in osteoporotic participants, also suffer bone loss, suggesting that common diseases of aging share pathophysiological pathways. Knowledge of the causes of skeletal fragility in mice should therefore be applicable to humans if inherent limitations are recognized. PMID:23689830

Jilka, Robert L

2013-05-20

163

The Cinderella Effect: Searching for the Best Fit between Mouse Models and Human Diseases.  

PubMed

A recent publication questions the suitability of mice as a model for the human inflammatory response and has fueled the continuing debate about the suitability of mice as models for human disease. We discuss recent advances in disease modeling using mice, and the genetic factors that need to be considered when trying to recapitulate aspects of human disease. Failure to appreciate the important differences between human and mouse biology and genetics underlying attempts to generate faithful models frequently leads to poor outcomes. Closely coordinated human and model organism studies are essential to provide traction for translational research. PMID:23812235

Sundberg, John P; Roopenian, Derry C; Liu, Edison T; Schofield, Paul N

2013-06-27

164

Genetic programs in human and mouse early embryos revealed by single-cell RNA sequencing.  

PubMed

Mammalian pre-implantation development is a complex process involving dramatic changes in the transcriptional architecture. We report here a comprehensive analysis of transcriptome dynamics from oocyte to morula in both human and mouse embryos, using single-cell RNA sequencing. Based on single-nucleotide variants in human blastomere messenger RNAs and paternal-specific single-nucleotide polymorphisms, we identify novel stage-specific monoallelic expression patterns for a significant portion of polymorphic gene transcripts (25?to 53%). By weighted gene co-expression network analysis, we find that each developmental stage can be delineated concisely by a small number of functional modules of co-expressed genes. This result indicates a sequential order of transcriptional changes in pathways of cell cycle, gene regulation, translation and metabolism, acting in a step-wise fashion from cleavage to morula. Cross-species comparisons with mouse pre-implantation embryos reveal that the majority of human stage-specific modules (7?out of?9) are notably preserved, but developmental specificity and timing differ between human and mouse. Furthermore, we identify conserved key members (or hub genes) of the human and mouse networks. These genes represent novel candidates that are likely to be key in driving mammalian pre-implantation development. Together, the results provide a valuable resource to dissect gene regulatory mechanisms underlying progressive development of early mammalian embryos. PMID:23892778

Xue, Zhigang; Huang, Kevin; Cai, Chaochao; Cai, Lingbo; Jiang, Chun-yan; Feng, Yun; Liu, Zhenshan; Zeng, Qiao; Cheng, Liming; Sun, Yi E; Liu, Jia-yin; Horvath, Steve; Fan, Guoping

2013-07-28

165

Gene order is conserved within the human chromosome 21 linkage group on mouse chromosome 10  

SciTech Connect

One hundred progeny from each of two intersubspecific mouse backcrosses were used to construct a comparative genetic map of a region of mouse chromosome 10 (MMU10) that is homologous to the distal tip of the long arm of human chromosome 21 (HSA21). The analysis included five genes and three simple sequence repeat markers, two of which flanked the HSA21-homologous cluster on either side. Analysis of 200 backcross progeny detected at least one crossover between each pair of adjacent genes and demonstrated that the proximal to distal orientation of the cluster was reversed between human and mouse. The order was determined to be Fyn-1-D10Mit20-S100b-Col6a1-Itgb2-Pfk1/D10Mit7-D10Mit11. Comparative mapping supports the order of corresponding markers on HSA21 determined using pulsed-field gel electrophoresis and radiation hybrid line data. However, sequence tagged site content mapping of human yeast artificial chromosomes (YACs) yielded conflicting data on the relative positions of human COL6A1 and S100B on HSA21. This discrepancy was resolved here by demonstrating that several key YACs used in the human contig analysis were mistyped for S100B. The murine map reported here provides a scaffold for construction of physical maps and yeast artificial chromosome contigs that will be useful in the development of mouse models for the study of Down syndrome. 28 refs., 4 figs., 2 tabs.

Irving, N.G.; Cabin, D.E.; Swanson, D.A.; Reeves, R.H. (Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States))

1994-05-01

166

Production of Proinflammatory Mediators by Indoor Air Bacteria and Fungal Spores in Mouse and Human Cell Lines  

Microsoft Academic Search

We compared the inflammatory and cytotoxic responses caused by household mold and bacteria in human and mouse cell lines. We studied the fungi Aspergillus versicolor, Penicillium spinulosum, and Stachybotrys chartarum and the bacteria Bacillus cereus, Pseudomonas fluorescens, and Streptomyces californicus for their cytotoxicity and ability to stimulate the production of inflammatory mediators in mouse RAW264.7 and human 28SC macrophage cell

Kati Huttunen; Anne Hyvärinen; Aino Nevalainen; Hannu Komulainen; Maija-Riitta Hirvonen

2002-01-01

167

RNA folding affects the recruitment of SR proteins by mouse and human polypurinic enhancer elements in the fibronectin EDA exon  

Microsoft Academic Search

In humans, inclusion or exclusion of the fibronectin EDA exon is mainly regulated by a polypurinic enhancer element (exonic splicing enhancer [ESE]) and a nearby silencer element (exonic splicing silencer [ESS]). While human and mouse ESEs behave identically, mutations introduced into the homologous mouse ESS sequence result either in no change in splicing efficiency or in complete exclusion of the

Emanuele Buratti; Andres F. Muro; Maurizio Giombi; Daniel Gherbassi; Alessandra Iaconcig; Francisco E. Baralle

2004-01-01

168

MAMMALIAN CELL CULTURE ASSAY TO QUANTITATE CHEMICALLY INDUCED ANEUPLOIDY: USE OF A MONOCHROMOSOMAL HUMAN/MOUSE CELL HYBRID  

EPA Science Inventory

A short-term assay utilizing a human/mouse monochromosomal hybrid cell line R3-5, to detect chemically induced aneuploidy in mammalian cells is described. A single human chromosome transferred into mouse cells was used as a cytogenetic marker to quantitate abnormal chromosome seg...

169

Introduction of the human pro. cap alpha. 1(I) collagen gene into pro. cap alpha. 1(I)-deficient Mov-13 mouse cells leads to formation of functional mouse-human hybrid type I collagen  

SciTech Connect

The Mov-13 mouse strain carries a retroviral insertion in the pro..cap alpha..1(I) collagen gene that prevents transcription of the gene. Cell lines derived from homozygous embryos do not express type I collagen although normal amounts of pro..cap alpha..2 mRNA are synthesized. The authors have introduced genomic clones of either the human or mouse pro..cap alpha..1(I) collagen gene into homozygous cell lines to assess whether the human or mouse pro..cap alpha..1(I) chains can associate with the endogenous mouse pro..cap alpha..2(I) chain to form stable type I collagen. The human gene under control of the simian virus 40 promoter was efficiently transcribed in the transfected cells. Protein analyses revealed that stable heterotrimers consisting of two human ..cap alpha..1 chains and one mouse ..cap alpha..2 chain were formed and that type I collagen was secreted by the transfected cells at normal rates. However, the electrophoretic migration of both ..cap alpha..1(I) and ..cap alpha..2(I) chains in the human-mouse hybrid molecules were retarded, compared to the ..cap alpha..(I) chains in control mouse cells. Inhibition of the posttranslational hydroxylation of lysine and proline resulted in comigration of human and mouse ..cap alpha..1 and ..cap alpha..2 chains, suggesting that increased posttranslational modification caused the altered electrophoretic migration in the human-mouse hybrid molecules. Amino acid sequence differences between the mouse and human ..cap alpha.. chains may interfere with the normal rate of helix formation and increase the degree of posttranslational modifications similar to those observed in patients with lethal perinatal osteogenesis imperfecta. The Mov-13 mouse system should allow the authors to study the effect specific mutations introduced in transfected pro..cap alpha..1(I) genes have on the synthesis, assembly, and function of collagen I.

Schnieke, A.; Dziadek, M.; Bateman, J.; Mascara, T.; Harbers, K.; Gelinas, R.; Jaenisch, R.

1987-02-01

170

Comparative studies of resistin expression and phylogenomics in human and mouse.  

PubMed

Resistin is a newly identified adipocytokine that has been proposed to be a link between obesity and type 2 diabetes based on animal studies. However, the role of resistin in the pathogenesis of insulin resistance associated with obesity in humans remains unclear. We comparatively and quantitatively studied the tissue distributions of resistin mRNA between human and mouse. The expression level of resistin mRNA in human adipose tissue is extremely low but detectable by real-time PCR and is about 1/250 of that in the mouse. Remarkably, resistin mRNA is abundant in human primary acute leukemia cells and myeloid cell lines U937 and HL60, but not in the Raw264 mouse myeloid cell line. Resistin expression in U937 cells was not affected by lipopolysaccharide (LPS) or by ciglitazone, a PPARgamma ligand. Phylogenomics revealed that the human resistin gene is the ortholog of its murine counterpart and is located in a region of chromosome 19p13.3, which is syntenic to mouse chromosome 8A1. In addition to the resistin-like molecule (RELM) sequences already reported, bioinformatics analysis disclosed another RELM sequence in the vicinity of RELMbeta on human chromosome 3q13.1, but this sequence is unlikely to encode an expressed gene. Therefore, only two RELMs, resistin and RELMbeta, exist in humans, instead of the three RELMs, resistin, RELMalpha, and RELMbeta, that exist in mice. This finding provides a possible answer to the question of why only two RELMs have been cloned in humans and suggests that the RELM family is not well conserved in evolution and may function differently between species. Therefore, caution should be exercised in interpreting resistin as a link between obesity and insulin resistance in humans. The high expression of resistin in human leukemia cells suggests a hitherto unidentified biological function of resistin in leukocytes. PMID:14550293

Yang, Rong-Ze; Huang, Qing; Xu, Aihua; McLenithan, John C; Eisen, Jonathan A; Shuldiner, Alan R; Alkan, Serhan; Gong, Da-Wei; Eison, Jonathan A

2003-10-24

171

The butyrylcholinesterase knockout mouse as a model for human butyrylcholinesterase deficiency.  

PubMed

Butyrylcholinesterase (BChE) is an important enzyme for metabolism of ester drugs. Many humans have partial or complete BChE deficiency due to genetic variation. Our goal was to create a mouse model of BChE deficiency to allow testing of drug toxicity. For this purpose, we created the BChE knockout mouse by gene-targeted deletion of a portion of the BCHE gene (accession number M99492). The BChE(-/-) mouse had no BChE activity in plasma, but it had low residual butyrylthiocholine hydrolase activity in all other tissues attributed to carboxylesterase ES-10. The BChE(-/-) mouse had a normal phenotype except when challenged with drugs. Nicotinic receptor function as indicated by response to nicotine seemed to be normal in BChE(-/-) mice, but muscarinic receptor function as measured by response to oxotremorine and pilocarpine was altered. Heart rate, blood pressure, and respiration, measured in a Vevo imager, were similar in BChE(+/+) and BChE(-/-) mice. Like BChE(-/-) humans, the BChE(-/-) mouse responded to succinylcholine with prolonged respiratory arrest. Bambuterol was not toxic to BChE(-/-) mice, suggesting it is safe in BChE(-/-) humans. Challenge with 150 mg/kg pilocarpine i.p., a muscarinic agonist, or with 50 mg/kg butyrylcholine i.p., induced tonicclonic convulsions and death in BChE(-/-) mice. This suggests that butyrylcholine, like pilocarpine, binds to muscarinic receptors. In conclusion, the BChE(-/-) mouse is a suitable model for human BChE deficiency. PMID:18056867

Li, Bin; Duysen, Ellen G; Carlson, Michaela; Lockridge, Oksana

2007-12-04

172

The mouse QTL map helps interpret human genome-wide association studies for HDL cholesterol[S  

PubMed Central

Genome-wide association (GWA) studies represent a powerful strategy for identifying susceptibility genes for complex diseases in human populations but results must be confirmed and replicated. Because of the close homology between mouse and human genomes, the mouse can be used to add evidence to genes suggested by human studies. We used the mouse quantitative trait loci (QTL) map to interpret results from a GWA study for genes associated with plasma HDL cholesterol levels. We first positioned single nucleotide polymorphisms (SNPs) from a human GWA study on the genomic map for mouse HDL QTL. We then used mouse bioinformatics, sequencing, and expression studies to add evidence for one well-known HDL gene (Abca1) and three newly identified genes (Galnt2, Wwox, and Cdh13), thus supporting the results of the human study. For GWA peaks that occur in human haplotype blocks with multiple genes, we examined the homologous regions in the mouse to prioritize the genes using expression, sequencing, and bioinformatics from the mouse model, showing that some genes were unlikely candidates and adding evidence for candidate genes Mvk and Mmab in one haplotype block and Fads1 and Fads2 in the second haplotype block. Our study highlights the value of mouse genetics for evaluating genes found in human GWA studies.

Leduc, Magalie S.; Lyons, Malcolm; Darvishi, Katayoon; Walsh, Kenneth; Sheehan, Susan; Amend, Sarah; Cox, Allison; Orho-Melander, Marju; Kathiresan, Sekar; Paigen, Beverly; Korstanje, Ron

2011-01-01

173

Frequent detection of infectious xenotropic murine leukemia virus (XMLV) in human cultures established from mouse xenografts  

PubMed Central

Purpose To investigate the frequency of xenotropic murine leukemia virus (MLV) presence in human cell lines established from mouse xenografts and to search for the evidence of horizontal viral spread to other cell lines. Results Six of 23 (26%) mouse DNA free xenograft cultures were strongly positive for MLV and their sequences had greater than 99% homology to known MLV strains. Four of five available supernatant fluids from these viral positive cultures were strongly positive for RT activity. Three of these supernatant fluids were studied to confirm the infectivity of the released virions for other human culture cells. Of the 78 non-xenograft derived cell lines maintained in the xenograft culture-containing facilities, 13 (17%) were positive for MLV, including XMRV, a virus strain first identified in human tissues. By contrast, all 50 cultures maintained in a xenograft culture-free facility were negative for viral sequences. Methodology We examined xenograft tumor cell lines from seven independent laboratories and 128 non-xenografted tumor cell lines. Cell line DNA was examined for mouse DNA contamination, and by 3 Taqman qPCR assays targeting the gag, env or pol regions of MLV. Sequencing was used for viral strain identification. Supernatant fluids were tested for reverse transcriptase (RT) activity. Conclusions Human cultures derived after mouse xenografting frequently contain and release highly infectious xenotropic MLV viruses. Laboratories working with xenograft-derived human cultures should be aware of the risk of contamination with potentially biohazardous human-tropic mouse viruses and their horizontal spread to other cultures.

Zhang, Yu-An; Maitra, Anirban; Hsieh, Jer-Tsong; Rudin, Charles M; Peacock, Craig D; Karikari, Collins; Brekken, Rolf A; Stastny, Victor; Gao, Boning; Girard, Luc; Wistuba, Ignacio; Frenkel, Eugene; Minna, John D

2011-01-01

174

Protein Localization and mRNA Expression of Epimorphin in Mouse and Human Kidneys  

Microsoft Academic Search

Epimorphin is a mesenchymal cell surface protein which induces epithelial branching morphogenesis. However, the role of epimorphin in the kidney has not been addressed. In the present study, the localization of epimorphin protein and the expression of its mRNA were investigated in the developing mouse and adult human kidneys using immunohistochemistry and semiquantitative RT-PCR. The in vitro expression of epimorphin

Satoshi Horikoshi; Mutsuko Yoshikawa; Terumi Shibata; Kaoru Takahashi; Isao Shirato; Yasuhiko Tomino

2001-01-01

175

The Mouse PinkEyed Dilution Gene: Association with Human Prader-Willi and Angelman Syndromes  

Microsoft Academic Search

Complementary DNA clones from the pink-eyed dilution (p) locus of mouse chromosome 7 were isolated from murine melanoma and melanocyte libraries. The transcript from this gene is missing or altered in six independent mutant alleles of the p locus, suggesting that disruption of this gene results in the hypopigmentation phenotype that defines mutant p alleles. Characterization of the human homolog

John M. Gardner; Yoshimichi Nakatsu; Yoichi Gondo; Susan Lee; Mary F. Lyon; Richard A. King; Murray H. Brilliant

1992-01-01

176

INDUCTION OF MICRONUCLEI BY X-RADIATION IN HUMAN, MOUSE, AND RAT PERIPHERAL BLOOD LYMPHOCYTES  

EPA Science Inventory

We compared the radiosensitivity of human, rat, and mouse peripheral blood lymphocytes (PBLs) by analyzing micronuclei (MN) in cytochalasin B-induced binucleated (BN) cells. or each species and dose, 4 ml aliquots of whole blood were X-irradiated to obtain doses of 38, 75, 150, o...

177

FATE OF NON-VIRULENT GROUP A STREPTOCOCCI PHAGOCYTIZED BY HUMAN AND MOUSE NEUTROPHILS  

PubMed Central

The fate of non-virulent group A streptococci phagocytized in vitro has been investigated by destroying the phagocyte with electric current and observing whether the liberated cocci multiply. Human and mouse peripheral blood neutrophils quickly injure ingested cocci, the time required to produce 50 per cent non-survival of chains being 8 and 6¾ minutes, respectively.

Wilson, Armine T.; Wiley, Grove G.; Bruno, Pauline

1957-01-01

178

Cellular functions of genetically imprinted genes in human and mouse as annotated in the gene ontology.  

PubMed

By analyzing the cellular functions of genetically imprinted genes as annotated in the Gene Ontology for human and mouse, we found that imprinted genes are often involved in developmental, transport and regulatory processes. In the human, paternally expressed genes are enriched in GO terms related to the development of organs and of anatomical structures. In the mouse, maternally expressed genes regulate cation transport as well as G-protein signaling processes. Furthermore, we investigated if imprinted genes are regulated by common transcription factors. We identified 25 TF families that showed an enrichment of binding sites in the set of imprinted genes in human and 40 TF families in mouse. In general, maternally and paternally expressed genes are not regulated by different transcription factors. The genes Nnat, Klf14, Blcap, Gnas and Ube3a contribute most to the enrichment of TF families. In the mouse, genes that are maternally expressed in placenta are enriched for AP1 binding sites. In the human, we found that these genes possessed binding sites for both, AP1 and SP1. PMID:23226257

Hamed, Mohamed; Ismael, Siba; Paulsen, Martina; Helms, Volkhard

2012-11-30

179

Cloning and characterization of human and mouse telomerase RNA gene promoter sequences  

Microsoft Academic Search

Variation in telomerase activity is correlated with cellular senescence and tumour progression. However, although the enzymatic activity of telomerase has been well studied, very little is known about how expression of telomerase genes is regulated in mammalian cells. We have therefore cloned the promoter regions of the human (hTR), and mouse, (terc), telomerase RNA genes in order to identify the

Jiang-Qin Zhao; Stacey F Hoare; Robert McFarlane; Sharon Muir; E Kenneth Parkinson; Donald M Black; W Nicol Keith

1998-01-01

180

Isolation and characterization of mouse and human esophageal epithelial cells in 3D organotypic culture  

Microsoft Academic Search

This protocol describes the isolation and characterization of mouse and human esophageal epithelial cells and the application of 3D organotypic culture (OTC), a form of tissue engineering. This model system permits the interrogation of mechanisms underlying epithelial-stromal interactions. We provide guidelines for isolating and cultivating several sources of epithelial cells and fibroblasts, as well as genetic manipulation of these cell

Jiri Kalabis; Gabrielle S Wong; Maria E Vega; Mitsuteru Natsuizaka; Erle S Robertson; Meenhard Herlyn; Hiroshi Nakagawa; Anil K Rustgi

2012-01-01

181

Gene Entropy-Fractal Dimension Informatics with Application to Mouse-Human Translational Medicine  

PubMed Central

DNA informatics represented by Shannon entropy and fractal dimension have been used to form 2D maps of related genes in various mammals. The distance between points on these maps for corresponding mRNA sequences in different species is used to study evolution. By quantifying the similarity of genes between species, this distance might be indicated when studies on one species (mouse) would tend to be valid in the other (human). The hypothesis that a small distance from mouse to human could facilitate mouse to human translational medicine success is supported by the studied ESR-1, LMNA, Myc, and RNF4 sequences. ID1 and PLCZ1 have larger separation. The collinearity of displacement vectors is further analyzed with a regression model, and the ID1 result suggests a mouse-chimp-human translational medicine approach. Further inference was found in the tumor suppression gene, p53, with a new hypothesis of including the bovine PKM2 pathways for targeting the glycolysis preference in many types of cancerous cells, consistent with quantum metabolism models. The distance between mRNA and protein coding CDS is proposed as a measure of the pressure associated with noncoding processes. The Y-chromosome DYS14 in fetal micro chimerism that could offer protection from Alzheimer's disease is given as an example.

Holden, T.; Cheung, E.; Dehipawala, S.; Ye, J.; Tremberger, G.; Lieberman, D.; Cheung, T.

2013-01-01

182

Cell Surface Antigens of Human Bladder Cancer Defined by Mouse Monoclonal Antibodies  

Microsoft Academic Search

Mouse monoclonal antibodies were obtained by immunization with cultured human bladder cancer or lysates of bladder papilloma. They identify 11 distinct antigenic systems as defined by serological analysis of cultured cells and studies of antigen distribution in normal and neoplastic tissues. The most restricted of these antigens, Om5, defines a subset of bladder tumors. Om5 is not detected in normal

Yves Fradet; Carlos Cordon-Cardo; Timothy Thomson; Mary E. Daly; Willet F. Whitmore; Kenneth O. Lloyd; Myron R. Melamed; Lloyd J. Old

1984-01-01

183

Gene entropy-fractal dimension informatics with application to mouse-human translational medicine.  

PubMed

DNA informatics represented by Shannon entropy and fractal dimension have been used to form 2D maps of related genes in various mammals. The distance between points on these maps for corresponding mRNA sequences in different species is used to study evolution. By quantifying the similarity of genes between species, this distance might be indicated when studies on one species (mouse) would tend to be valid in the other (human). The hypothesis that a small distance from mouse to human could facilitate mouse to human translational medicine success is supported by the studied ESR-1, LMNA, Myc, and RNF4 sequences. ID1 and PLCZ1 have larger separation. The collinearity of displacement vectors is further analyzed with a regression model, and the ID1 result suggests a mouse-chimp-human translational medicine approach. Further inference was found in the tumor suppression gene, p53, with a new hypothesis of including the bovine PKM2 pathways for targeting the glycolysis preference in many types of cancerous cells, consistent with quantum metabolism models. The distance between mRNA and protein coding CDS is proposed as a measure of the pressure associated with noncoding processes. The Y-chromosome DYS14 in fetal micro chimerism that could offer protection from Alzheimer's disease is given as an example. PMID:23586047

Holden, T; Cheung, E; Dehipawala, S; Ye, J; Tremberger, G; Lieberman, D; Cheung, T

2013-03-17

184

Characterization and Comparison of the Human and Mouse GLC1A Glaucoma Genes  

PubMed Central

The GLC1A gene (which encodes the protein myocilin) has been associated with the development of primary open angle glaucoma. Bacterial artificial chromosomes containing the human GLC1A gene and its mouse ortholog were subcloned and sequenced to reveal the genomic structure of the genes. Comparison of the coding sequences of the human and mouse GLC1A genes revealed a high degree of amino acid homology (82%) and the presence of several conserved motifs in the predicted GLC1A proteins. The expression of GLC1A was examined by Northern blot analysis of RNA from adult human tissues. GLC1A expression was observed in 17 of 23 tissues tested, suggesting a wider range of expression than was recognized previously. The comparison of the human and mouse GLC1A genes suggests that the mouse may be a useful model organism in studying the molecular pathophysiology of glaucoma. [The sequence data described in this paper have been submitted to the GenBank data library under accession nos. AF049791–AF049796.

Fingert, John H.; Ying, Lihua; Swiderski, Ruth E.; Nystuen, Arne M.; Arbour, Nancy C.; Alward, Wallace L.M.; Sheffield, Val C.; Stone, Edwin M.

1998-01-01

185

Genistein and Daidzein Stimulate Hyaluronic Acid Production in Transformed Human Keratinocyte Culture and Hairless Mouse Skin  

Microsoft Academic Search

We examined the effects of the soy isoflavones genistein (Gen) and daidzein (Dai) on the production of hyaluronic acid (HA) in a transformed human keratinocyte culture and in hairless mouse skin following topical application for 2 weeks. Gen and Dai, but not the glycosides thereof, significantly enhanced the production of HA in vitro and in vivo. Histochemistry using an HA-binding

Kouji Miyazaki; Tomoko Hanamizu; Ryoko Iizuka; Katsuyoshi Chiba

2002-01-01

186

The horse pseudoautosomal region (PAR): characterization and comparison with the human, chimp and mouse PARs  

Microsoft Academic Search

The pseudoautosomal region (PAR) is a genomic segment on mammalian sex chromosomes where sequence homology mimics that seen between autosomal homologues. The region is essential for pairing and proper segregation of sex chromosomes during male meiosis. As yet, only human\\/chimp and mouse PARs have been characterized. The two groups of species differ dramatically in gene content and size of the

T Raudsepp; B. P. Chowdhary

2008-01-01

187

Number of CpG Islands and Genes in Human and Mouse  

Microsoft Academic Search

Estimation of gene number in mammals is difficult due to the high proportion of noncoding DNA within the nucleus. In this study, we provide a direct measurement of the number of genes in human and mouse. We have taken advantage of the fact that many mammalian genes are associated with CpG islands whose distinctive properties allow their physical separation from

Francisco Antequera; Adrian Bird

1993-01-01

188

Maternally transmitted milk containing recombinant human catalase provides protection against oxidation for mouse offspring during lactation  

Microsoft Academic Search

Catalase plays an important role in protecting organisms against oxidative damage caused by reactive oxygen species (ROS) by degrading surplus hydrogen peroxide. Addition of exogenous catalase can alleviate injuries caused by ROS. Thus, production of human catalase through genetic engineering will meet the increasing therapeutic demand for this enzyme. In this study, we successfully expressed the recombinant gene in mouse

Zuyong He; Shengli Yu; Gui Mei; Min Zheng; Meili Wang; Yunping Dai; Bo Tang; Ning Li

2008-01-01

189

Cellular Functions of Genetically Imprinted Genes in Human and Mouse as Annotated in the Gene Ontology  

PubMed Central

By analyzing the cellular functions of genetically imprinted genes as annotated in the Gene Ontology for human and mouse, we found that imprinted genes are often involved in developmental, transport and regulatory processes. In the human, paternally expressed genes are enriched in GO terms related to the development of organs and of anatomical structures. In the mouse, maternally expressed genes regulate cation transport as well as G-protein signaling processes. Furthermore, we investigated if imprinted genes are regulated by common transcription factors. We identified 25 TF families that showed an enrichment of binding sites in the set of imprinted genes in human and 40 TF families in mouse. In general, maternally and paternally expressed genes are not regulated by different transcription factors. The genes Nnat, Klf14, Blcap, Gnas and Ube3a contribute most to the enrichment of TF families. In the mouse, genes that are maternally expressed in placenta are enriched for AP1 binding sites. In the human, we found that these genes possessed binding sites for both, AP1 and SP1.

Hamed, Mohamed; Ismael, Siba; Paulsen, Martina; Helms, Volkhard

2012-01-01

190

An open-access long oligonucleotide microarray resource for analysis of the human and mouse transcriptomes  

PubMed Central

Two collections of oligonucleotides have been designed for preparing pangenomic human and mouse microarrays. A total of 148?993 and 121?703 oligonucleotides were designed against human and mouse transcripts. Quality scores were created in order to select 25?342 human and 24?109 mouse oligonucleotides. They correspond to: (i) a BLAST-specificity score; (ii) the number of expressed sequence tags matching each probe; (iii) the distance to the 3? end of the target mRNA. Scores were also used to compare in silico the two microarrays with commercial microarrays. The sets described here, called RNG/MRC collections, appear at least as specific and sensitive as those from the commercial platforms. The RNG/MRC collections have now been used by an Anglo-French consortium to distribute more than 3500 microarrays to the academic community. Ad hoc identification of tissue-specific transcripts and a ?80% correlation with hybridizations performed on Affymetrix GeneChip™ suggest that the RNG/MRC microarrays perform well. This work provides a comprehensive open resource for investigators working on human and mouse transcriptomes, as well as a generic method to generate new microarray collections in other organisms. All information related to these probes, as well as additional information about commercial microarrays have been stored in a freely-accessible database called MEDIANTE.

Brigand, Kevin Le; Russell, Roslin; Moreilhon, Chimene; Rouillard, Jean-Marie; Jost, Bernard; Amiot, Franck; Magnone, Virginie; Bole-Feysot, Christine; Rostagno, Philippe; Virolle, Virginie; Defamie, Virginie; Dessen, Philippe; Williams, Gary; Lyons, Paul; Rios, Geraldine; Mari, Bernard; Gulari, Erdogan; Kastner, Philippe; Gidrol, Xavier; Freeman, Tom C.; Barbry, Pascal

2006-01-01

191

A mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions  

PubMed Central

Down syndrome (DS) is caused by the presence of an extra copy of human chromosome 21 (Hsa21) and is the most common genetic cause for developmental cognitive disability. The regions on Hsa21 are syntenically conserved with three regions located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. In this report, we describe a new mouse model for DS that carries duplications spanning the entire Hsa21 syntenic regions on all three mouse chromosomes. This mouse mutant exhibits DS-related neurological defects, including impaired cognitive behaviors, reduced hippocampal long-term potentiation and hydrocephalus. These results suggest that when all the mouse orthologs of the Hsa21 genes are triplicated, an abnormal cognitively relevant phenotype is the final outcome of the elevated expressions of these orthologs as well as all the possible functional interactions among themselves and/or with other mouse genes. Because of its desirable genotype and phenotype, this mutant may have the potential to serve as one of the reference models for further understanding the developmental cognitive disability associated with DS and may also be used for developing novel therapeutic interventions for this clinical manifestation of the disorder.

Yu, Tao; Li, Zhongyou; Jia, Zhengping; Clapcote, Steven J.; Liu, Chunhong; Li, Shaomin; Asrar, Suhail; Pao, Annie; Chen, Rongqing; Fan, Ni; Carattini-Rivera, Sandra; Bechard, Allison R.; Spring, Shoshana; Henkelman, R. Mark; Stoica, George; Matsui, Sei-Ichi; Nowak, Norma J.; Roder, John C.; Chen, Chu; Bradley, Allan; Yu, Y. Eugene

2010-01-01

192

Mouse models of cancers: opportunities to address heterogeneity of human cancer and evaluate therapeutic strategies  

PubMed Central

The heterogeneity of human breast cancer has been well described at the morphological, molecular, and genomic levels. This heterogeneity presents one of the greatest obstacles in the effective treatment of breast cancer since the distinct forms of breast cancer that reflect distinct mechanisms of disease will require distinct therapies. Although mouse models of cancer have traditionally been used to simplify the study of human disease, we suggest that there are opportunities to also model the complexity and heterogeneity of human cancer. Here, we illustrate the similarities of mouse models to the human condition in the heterogeneity of both pathologies and gene expression. We then provide an illustration of the potential of gene expression analysis methods when used in conjunction with current treatment options to model individualized therapeutic regimes.

Nevins, Joseph R.

2010-01-01

193

Effectiveness of P-aminobenzoyl-O-phenylenediamine (Goe 1734) against mouse, rat, and human tumour cells.  

PubMed

The new N-phenylbenzamide derivative Goe 1734 was tested for its antitumour effects against mouse, rat, and human tumours. The preparation showed marginal activity against leukaemia L1210, moderate activity against Lewis lung carcinoma, and high activity against osteosarcoma C22LR and Brown Norway myeloid leukaemia. In the subrenal capsule assay the drug was active against four (cisplatin: 2) of nine human tumours. An in vitro clonogenic assay did not reveal any activity of Goe 1734 when mouse osteosarcoma or human tumour cells were exposed for only 1 h. However, continuous exposure led to 70% or greater inhibition of colony formation at concentrations of 0.1-1 microgram/ml (osteosarcoma) or 0.2-2 micrograms/ml (human tumours). PMID:3859382

Lelieveld, P; Middeldorp, R J; van Putten, L M

1985-01-01

194

Constitutive overexpression of human erythropoietin protects the mouse retina against induced but not inherited retinal degeneration.  

PubMed

Elevation of erythropoietin (Epo) concentrations by hypoxic preconditioning or application of recombinant human Epo (huEpo) protects the mouse retina against light-induced degeneration by inhibiting photoreceptor cell apoptosis. Because photoreceptor apoptosis is also the common path to cell loss in retinal dystrophies such as retinitis pigmentosa (RP), we tested whether high levels of huEpo would reduce apoptotic cell death in two mouse models of human RP. We combined the two respective mutant mouse lines with a transgenic line (tg6) that constitutively overexpresses huEpo mainly in neural tissues. Transgenic expression of huEpo caused constitutively high levels of Epo in the retina and protected photoreceptors against light-induced degeneration; however, the presence of high levels of huEpo did not affect the course or the extent of retinal degeneration in a light-independent (rd1) and a light-accelerated (VPP) mouse model of RP. Similarly, repetitive intraperitoneal injections of recombinant huEpo did not protect the retina in the rd1 and the VPP mouse. Lack of neuroprotection by Epo in the two models of inherited retinal degeneration was not caused by adaptational downregulation of Epo receptor. Our results suggest that apoptotic mechanisms during acute, light-induced photoreceptor cell death differ from those in genetically based retinal degeneration. Therapeutic intervention with cell death in inherited retinal degeneration may therefore require different drugs and treatments. PMID:15215287

Grimm, Christian; Wenzel, Andreas; Stanescu, Dinu; Samardzija, Marijana; Hotop, Svenja; Groszer, Mathias; Naash, Muna; Gassmann, Max; Remé, Charlotte

2004-06-23

195

Correction of a mouse model of Menkes disease by the human Menkes gene  

Microsoft Academic Search

The brindled mouse is an accurate model of the fatal human X-linked copper deficiency disorder, Menkes disease. Males carrying the mutant allele of the Menkes gene orthologue Atp7a die in the second week of life. To determine whether the genetic defect in the brindled mice could be corrected by expression of the human Menkes gene, male transgenic mice expressing ATP7A

Roxana M. Llanos; Bi-Xia Ke; Magali Wright; Yolanda Deal; Francois Monty; David R. Kramer; Julian F. B. Mercer

2006-01-01

196

The construction of transgenic and gene knockout\\/knockin mouse models of human disease  

Microsoft Academic Search

The genetic and physiological similarities between mice and humans have focused considerable attention on rodents as potential\\u000a models of human health and disease. Together with the wealth of resources, knowledge, and technologies surrounding the mouse\\u000a as a model system, these similarities have propelled this species to the forefront of biomedical research. The advent of genomic\\u000a manipulation has quickly led to

Alfred Doyle; Michael P. McGarry; Nancy A. Lee; James J. Lee

197

Metastatic MHC class I-negative mouse cells derived by transformation with human papillomavirus type 16  

Microsoft Academic Search

In the endeavour to develop a model for studying gene therapy of cancers associated with human papillomaviruses (HPVs), mouse cells were transformed with the HPV type 16 (HPV16) and activated H-ras oncogenes. This was done by contransfection of plasmid p16HHMo, carrying the HPV16 E6\\/E7 oncogenes, and plasmid pEJ6.6, carrying the gene coding for human H-ras oncoprotein activated by G12V mutation,

M Šmahel; E Sobotková; J Bubeník; J Šímová; R Žák; V Ludvíková; R Hájková; J Kovarv'k; F Jelínek; C Povýšil; J Marinov; V Vonka

2001-01-01

198

Human and mouse orthologs of a new ATP-binding cassette gene, ABCG4  

Microsoft Academic Search

We characterized a new ATP-binding cassette (ABC) transporter gene from human and mouse that is highly expressed in the brain. The gene, ABCG4, produces several transcripts that differ at the 5? end and encode proteins of various lengths. The ABCG4 protein is closely related to the Drosophila white and human ABCG1 genes, and belongs to the ABCG subfamily several members

T. Annilo; J. Tammur; A. Hutchinson; A. Rzhetsky; M. Dean; R. Allikmets

2001-01-01

199

New cell lines from mouse epiblast share defining features with human embryonic stem cells  

Microsoft Academic Search

The application of human embryonic stem (ES) cells in medicine andbiologyhasaninherentrelianceonunderstandingthestarting cellpopulation.HumanEScellsdifferfrommouseEScellsandthe specific embryonic origin of both cell types is unclear. Previous work suggested that mouse ES cells could only be obtained from the embryo before implantation in the uterus1-5. Here we show that cell lines can be derived from the epiblast, a tissue of the post- implantation embryo that

Josh G. Chenoweth; Frances A. Brook; Timothy J. Davies; Edward P. Evans; David L. Mack; Richard L. Gardner; Paul J. Tesar; Ronald D. G. McKay

2007-01-01

200

A TRANSGENIC MOUSE MODEL EXPRESSING EXCLUSIVELY HUMAN HEMOGLOBIN E: INDICATIONS OF A MILD OXIDATIVE STRESS  

PubMed Central

Hemoglobin (Hb) E (?26 Glu? Lys) is the most common abnormal hemoglobin (Hb) variant in the world. Homozygotes for HbE are mildly thalassemic as a result of the alternate splice mutation and present with a benign clinical picture (microcytic and mildly anemic) with rare clinical symptoms. Given that the human red blood cell (RBC) contains both HbE and excess ?-chains along with minor hemoglobins, the consequence of HbE alone on RBC pathophysiology has not been elucidated. This becomes critical for the highly morbid ?E-thalassemia disease. We have generated transgenic mice exclusively expressing human HbE (HbEKO) that exhibit the known aberrant splicing of ?E globin mRNA, but are essentially non-thalassemic as demonstrated by RBC ?/? (human) globin chain synthesis. These mice exhibit hematological characteristics similar to presentations in human EE individuals: microcytic RBC with low MCV and MCH but normal MCHC; target RBC; mild anemia with low Hb, HCT and mildly elevated reticulocyte levels and decreased osmotic fragility, indicating altered RBC surface area to volume ratio. These alterations are correlated with a mild RBC oxidative stress indicated by enhanced membrane lipid peroxidation, elevated zinc protoporphyrin levels, and by small but significant changes in cardiac function. The C57 (background) mouse and full KO mouse models expressing HbE with the presence of HbS or HbA are used as controls. In select cases, the HbA full KO mouse model is compared but found to be limited due to its RBC thalassemic characteristics. Since the HbEKO mouse RBC lacks an abundance of excess ?-chains that would approximate a mouse thalassemia (or a human thalassemia), the results indicate that the observed in vivo RBC mild oxidative stress arises, at least in part, from the molecular consequences of the HbE mutation.

Chen, Qiuying; Fabry, Mary E.; Rybicki, Anne C.; Suzuka, Sandra M.; Balazs, Tatiana C.; Etzion, Zipora; de Jong, Kitty; Akoto, Edna K.; Canterino, Joseph E.; Kaul, Dhananjay K.; Kuypers, Frans A.; Lefer, David; Bouhassira, Eric E.; Hirsch, Rhoda Elison

2012-01-01

201

A transgenic mouse model expressing exclusively human hemoglobin E: indications of a mild oxidative stress.  

PubMed

Hemoglobin (Hb) E (?26 Glu?Lys) is the most common abnormal hemoglobin (Hb) variant in the world. Homozygotes for HbE are mildly thalassemic as a result of the alternate splice mutation and present with a benign clinical picture (microcytic and mildly anemic) with rare clinical symptoms. Given that the human red blood cell (RBC) contains both HbE and excess ?-chains along with minor hemoglobins, the consequence of HbE alone on RBC pathophysiology has not been elucidated. This becomes critical for the highly morbid ?(E)-thalassemia disease. We have generated transgenic mice exclusively expressing human HbE (HbEKO) that exhibit the known aberrant splicing of ?(E) globin mRNA, but are essentially non-thalassemic as demonstrated by RBC ?/? (human) globin chain synthesis. These mice exhibit hematological characteristics similar to presentations in human EE individuals: microcytic RBC with low MCV and MCH but normal MCHC; target RBC; mild anemia with low Hb, HCT and mildly elevated reticulocyte levels and decreased osmotic fragility, indicating altered RBC surface area to volume ratio. These alterations are correlated with a mild RBC oxidative stress indicated by enhanced membrane lipid peroxidation, elevated zinc protoporphyrin levels, and by small but significant changes in cardiac function. The C57 (background) mouse and full KO mouse models expressing HbE with the presence of HbS or HbA are used as controls. In select cases, the HbA full KO mouse model is compared but found to be limited due to its RBC thalassemic characteristics. Since the HbEKO mouse RBC lacks an abundance of excess ?-chains that would approximate a mouse thalassemia (or a human thalassemia), the results indicate that the observed in vivo RBC mild oxidative stress arises, at least in part, from the molecular consequences of the HbE mutation. PMID:22260787

Chen, Qiuying; Fabry, Mary E; Rybicki, Anne C; Suzuka, Sandra M; Balazs, Tatiana C; Etzion, Zipora; de Jong, Kitty; Akoto, Edna K; Canterino, Joseph E; Kaul, Dhananjay K; Kuypers, Frans A; Lefer, David; Bouhassira, Eric E; Hirsch, Rhoda Elison

2012-01-18

202

Gene expression profiling of mouse p53-deficient epidermal carcinoma defines molecular determinants of human cancer malignancy  

PubMed Central

Background The epidermal specific ablation of Trp53 gene leads to the spontaneous development of aggressive tumors in mice through a process that is accelerated by the simultaneous ablation of Rb gene. Since alterations of p53-dependent pathway are common hallmarks of aggressive, poor prognostic human cancers, these mouse models can recapitulate the molecular features of some of these human malignancies. Results To evaluate this possibility, gene expression microarray analysis was performed in mouse samples. The mouse tumors display increased expression of cell cycle and chromosomal instability associated genes. Remarkably, they are also enriched in human embryonic stem cell gene signatures, a characteristic feature of human aggressive tumors. Using cross-species comparison and meta-analytical approaches, we also observed that spontaneous mouse tumors display robust similarities with gene expression profiles of human tumors bearing mutated TP53, or displaying poor prognostic outcome, from multiple body tissues. We have obtained a 20-gene signature whose genes are overexpressed in mouse tumors and can identify human tumors with poor outcome from breast cancer, astrocytoma and multiple myeloma. This signature was consistently overexpressed in additional mouse tumors using microarray analysis. Two of the genes of this signature, AURKA and UBE2C, were validated in human breast and cervical cancer as potential biomarkers of malignancy. Conclusions Our analyses demonstrate that these mouse models are promising preclinical tools aimed to search for malignancy biomarkers and to test targeted therapies of prospective use in human aggressive tumors and/or with p53 mutation or inactivation.

2010-01-01

203

NBCe1 in Mouse and Human Ameloblasts may be Indirectly Regulated by Fluoride  

PubMed Central

Enamel biomineralization results in a release of protons into the enamel matrix, causing an acidification of the local microenvironment. This acidification, which may be enhanced by more rapid mineral deposition in the presence of fluoride, must be neutralized by the overlying ameloblasts. The electrogenic sodium bicarbonate co-transporter NBCe1 has been localized in mouse ameloblasts, and has been proposed to have a role in matrix pH regulation. In this study, transcript analysis by PCR showed NBCe1-A present in human ameloblasts, whereas mouse ameloblasts expressed NBCe1-B. In situ hybridization and qPCR in mouse and fetal human incisors showed that NBCe1 mRNA was up-regulated as ameloblasts differentiated. Ingestion of 50 ppm fluoride resulted in an up-regulation of NBCe1 mRNA in maturation-stage mouse ameloblasts in vivo, as compared with controls. NBCe1 expression was up-regulated by low pH, but not by fluoride, in human ameloblast-lineage cells in vitro. The up-regulation of NBCe1 in vivo as enamel maturation and mineralization progressed provides evidence that NBCe1 participates in pH modulation during enamel formation. Up-regulation of NBCe1 in fluorosed maturation ameloblasts in vivo, with no effect of fluoride in vitro, supports the hypothesis that fluoride-enhanced mineral deposition results in acidification of the mineralizing enamel matrix.

Zheng, L.; Zhang, Y.; He, P.; Kim, J.; Schneider, R.; Bronckers, A.L.; Lyaruu, D.M.; DenBesten, P.K.

2011-01-01

204

Production of a neutralizing mouse-human chimeric antibody against botulinum neurotoxin serotype E.  

PubMed

A mouse-human chimeric antibody that can neutralize botulinum neurotoxin serotype E (BoNT/E) was developed. Variable regions of heavy and light chains obtained using a mouse hybridoma clone (E9-4) cDNA, which was selected on the basis of neutralizing activity against BoNT/E, were fused with the upstream regions of the constant counterparts of human kappa light and gamma 1 heavy chain genes, respectively. CHO-DG44 cells were transfected with these plasmids and a mouse-human chimeric antibody (EC94) was purified to examine binding and neutralizing activity against BoNT/E. EC94 exhibited the same levels of binding activities against BoNT/E as those of a parent mouse monoclonal antibody and neutralized more than 4,000 LD(50)/mg antibody. This chimeric antibody seems to be a useful candidate for infant botulism in which the use of passive immunotherapy is not planned so as to avoid serious events such as anaphylactic shock. We designed shuffling chimeric antibodies with replacement of V(H) or V(L) of EC94 with that of a chimeric antibody (AC24) that possessed neutralizing activity against BoNT/A. These shuffling antibodies did not exhibit neutralizing activity against either BoNT/E or BoNT/A. PMID:23429085

Mukamoto, Masafumi; Maeda, Hiroaki; Kohda, Tomoko; Nozaki, Chikateru; Takahashi, Motohide; Kozaki, Shunji

2013-01-01

205

NOD\\/SCID\\/c null mouse: an excellent recipient mouse model for engraftment of human cells  

Microsoft Academic Search

c null mice and NOD\\/Shi-scid mice. When human CD34 cells from umbilical cord blood were transplanted into this strain, the engraftment rate in the peripheral circulation, spleen, and bone marrow were significantly higher than that in NOD\\/Shi- scid mice treated with anti-asialo GM1 antibody or in the 2-microglobulin- deficient NOD\\/LtSz-scid (NOD\\/SCID\\/ 2mnull) mice, which were as completely defective in NK

Mamoru Ito; Hidefumi Hiramatsu; Kimio Kobayashi; Kazutomo Suzue; Mariko Kawahata; Kyoji Hioki; Yoshito Ueyama; Yoshio Koyanagi; Kazuo Sugamura; Kohichiro Tsuji; Toshio Heike; Tatsutoshi Nakahata

2002-01-01

206

The Pathological Phenotypes of Human TDP-43 Transgenic Mouse Models Are Independent of Downregulation of Mouse Tdp-43  

PubMed Central

Tar DNA binding protein 43 (TDP-43) is the major component of pathological deposits in frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and in amyotrophic lateral sclerosis (ALS). It has been reported that TDP-43 transgenic mouse models expressing human TDP-43 wild-type or ALS-associated mutations recapitulate certain ALS and FTLD pathological phenotypes. Of note, expression of human TDP-43 (hTDP-43) reduces the levels of mouse Tdp-43 (mTdp-43). However, it remained unclear whether the mechanisms through which TDP-43 induces ALS or FTLD-like pathologies resulted from a reduction in mTdp-43, an increase in hTDP-43, or a combination of both. In elucidating the role of mTdp-43 and hTDP-43 in hTDP-43 transgenic mice, we observed that reduction of mTdp-43 in non-transgenic mice by intraventricular brain injection of AAV1-shTardbp leads to a dramatic increase in the levels of splicing variants of mouse sortilin 1 and translin. However, the levels of these two abnormal splicing variants are not increased in hTDP-43 transgenic mice despite significant downregulation of mTdp-43 in these mice. Moreover, further downregulation of mTdp-43 in hTDP-43 hemizygous mice, which are asymptomatic, to the levels equivalent to that of mTdp-43 in hTDP-43 homozygous mice does not induce the pathological phenotypes observed in the homozygous mice. Lastly, the number of dendritic spines and the RNA levels of TDP-43 RNA targets critical for synapse formation and function are significantly decreased in symptomatic homozygous mice. Together, our findings indicate that mTdp-43 downregulation does not lead to a loss of function mechanism or account for the pathological phenotypes observed in hTDP-43 homozygous mice because hTDP-43 compensates for the reduction, and associated functions of mTdp-43. Rather, expression of hTDP-43 beyond a certain threshold leads to abnormal metabolism of TDP-43 RNA targets critical for neuronal structure and function, which might be responsible for the ALS or FTLD-like pathologies observed in homozygous hTDP-43 transgenic mice.

Xu, Ya-Fei; Prudencio, Mercedes; Hubbard, Jaime M.; Tong, Jimei; Whitelaw, Ena C.; Jansen-West, Karen; Stetler, Caroline; Cao, Xiangkun; Song, John; Zhang, Yong-Jie

2013-01-01

207

Cloning Human Fetal ? Globin and Mouse ? -Type Globin DNA: Characterization and Partial Sequencing  

NASA Astrophysics Data System (ADS)

Two globin-related clones isolated from collections of bacteriophages containing unfractionated Eco RI fragments of human and mouse DNA were characterized. Charon3AHs51.1Hb? includes 2.7 kilobase pairs of human DNA containing a large part of a fetal ? globin chain structural gene; Charon 3AMm30.5 includes 4.7 kilobase pairs of mouse DNA related to ? globin. The human fetal ? globin gene has within its coding region two intervening sequences of noncoding DNA, IVS 1 and IVS 2, of approximately 100 and 900 base pairs. Sequence IVS 1 is located at the position of one of the two intervening sequences occurring in adult globin genes; IVS 2 is located at the position of the other.

Smithies, Oliver; Blechl, Ann E.; Denniston-Thompson, Katherine; Newell, Nannette; Richards, Julia E.; Slightom, Jerry L.; Tucker, Phillip W.; Blattner, Frederick R.

1978-12-01

208

A Human-Like Senescence-Associated Secretory Phenotype Is Conserved in Mouse Cells Dependent on Physiological Oxygen  

PubMed Central

Cellular senescence irreversibly arrests cell proliferation in response to oncogenic stimuli. Human cells develop a senescence-associated secretory phenotype (SASP), which increases the secretion of cytokines and other factors that alter the behavior of neighboring cells. We show here that “senescent” mouse fibroblasts, which arrested growth after repeated passage under standard culture conditions (20% oxygen), do not express a human-like SASP, and differ from similarly cultured human cells in other respects. However, when cultured in physiological (3%) oxygen and induced to senesce by radiation, mouse cells more closely resemble human cells, including expression of a robust SASP. We describe two new aspects of the human and mouse SASPs. First, cells from both species upregulated the expression and secretion of several matrix metalloproteinases, which comprise a conserved genomic cluster. Second, for both species, the ability to promote the growth of premalignant epithelial cells was due primarily to the conserved SASP factor CXCL-1/KC/GRO-?. Further, mouse fibroblasts made senescent in 3%, but not 20%, oxygen promoted epithelial tumorigenesis in mouse xenographs. Our findings underscore critical mouse-human differences in oxygen sensitivity, identify conditions to use mouse cells to model human cellular senescence, and reveal novel conserved features of the SASP.

Coppe, Jean-Philippe; Krtolica, Ana; Beausejour, Christian M.; Parrinello, Simona; Hodgson, J. Graeme; Chin, Koei; Desprez, Pierre-Yves; Campisi, Judith

2010-01-01

209

The Construction of Transgenic and Gene Knockout/Knockin Mouse Models of Human Disease  

PubMed Central

The genetic and physiological similarities between mice and humans have focused considerable attention on rodents as potential models of human health and disease. Together with the wealth of resources, knowledge, and technologies surrounding the mouse as a model system, these similarities have propelled this species to the forefront of biomedical research. The advent of genomic manipulation has quickly led to the creation and use of genetically engineered mice as powerful tools for cutting edge studies of human disease research, including the discovery, refinement, and utility of many currently available therapeutic regimes. In particular, the creation of genetically modified mice as models of human disease has remarkably changed our ability to understand the molecular mechanisms and cellular pathways underlying disease states. Moreover, the mouse models resulting from gene transfer technologies have been important components correlating an individual’s gene expression profile to the development of disease pathologies. The objective of this review is to provide physician-scientists with an expansive historical and logistical overview of the creation of mouse models of human disease through gene transfer technologies. Our expectation is that this will facilitate on-going disease research studies and may initiate new areas of translational research leading to enhanced patient care.

Doyle, Alfred; McGarry, Michael P.; Lee, Nancy A.; Lee, James J.

2012-01-01

210

Locations of human and mouse genes encoding the RFX1 and RFX2 transcription factor proteins  

SciTech Connect

RFX transcription factors constitute a highly conserved family of site-specific DNA binding proteins involved in the expression of a variety of cellular and viral genes, including major histocompatibility complex class II genes and genes in human hepatitis B virus. Five members of the RFX gene family have been isolated from human and mouse, and all share a highly characteristic DNA binding domain that is distinct from other known DNA binding motifs. The human RFX1 and RFX2 genes have been assigned by in situ hybridization to chromosome 19p13.1 and 19p13.3, respectively. In this paper, we present data that localize RFX1 and RFX2 precisely within the detailed physical map of human chromosome 19 and genetic data that assign Rfx1 and Rfx2 to homologous regions of mouse chromosomes 8 and 17, respectively. These data define the established relationships between these homologous mouse and human regions in further detail and provide new tools for linking cloned genes to phenotypes in both species. 26 ref., 2 figs.

Doyle, J.; Stubbs, L. [Oak Ridge National Lab., TN (United States); Hoffman, S. [Lawrence Livermore National Lab., CA (United States)] [and others

1996-07-01

211

Use of PC mouse components for continuous measuring of human heartbeat.  

PubMed

A new technology for remote measuring of vibration sources was recently developed for industrial, medical, and security-related applications [Int. Appl. Patent No: PCT/IL2008/001008]. It requires relatively expensive equipment, such as high-speed complementary metal oxide semiconductor (CMOS) sensors and customized optics. In this paper, we demonstrate how the usage of a simple personal computer (PC) mouse as an optical system composed of a low-power laser and a CMOS circuitry on the same integrated circuit package, can be used to monitor heartbeat from the wrist. The method is based on modifying the mouse optical system in such a way that it will recognize temporal change in skin's vibration profile, generated due to the heart pulses, as mouse movement. The tests that were carried out show a very good correlation between the heartbeat rate measured from human skin and the reference values taken manually. PMID:22695566

Beiderman, Yevgeny; Talyosef, Roy; Yeori, Daniel; Garcia, Javier; Mico, Vicente; Zalevsky, Zeev

2012-06-01

212

Human High-Molecular-Weight Melanoma-associated Antigen Mimicry by Mouse Antiidiotypic Monoclonal Antibody TK7-3711  

Microsoft Academic Search

Since the human high-molecular-weight melanoma-associated antigen (HMW-MAA) represents a useful target to implement active specific immunotherapy with mouse antiidiotypic monoclonal antibody (mAh), the present study is aimed at developing and characterizing mouse antiidiotypic inAhs which bear the mirror image of the determinant defined by the anti-HMW-MAA mAb TP61.5. To this end, a BALB\\/c mouse was immunized with the syngeneic mAb

Zhi Jian Chen; Hong Yang; Toshiro Kageshita; Soldano Terrone

213

The LKB1 Tumor Suppressor as a Biomarker in Mouse and Human Tissues  

PubMed Central

Germline mutations in the LKB1 gene (also known as STK11) cause the Peutz-Jeghers Syndrome, and somatic loss of LKB1 has emerged as causal event in a wide range of human malignancies, including melanoma, lung cancer, and cervical cancer. The LKB1 protein is a serine-threonine kinase that phosphorylates AMP-activated protein kinase (AMPK) and other downstream targets. Conditional knockout studies in mouse models have consistently shown that LKB1 loss promotes a highly-metastatic phenotype in diverse tissues, and human studies have demonstrated a strong association between LKB1 inactivation and tumor recurrence. Furthermore, LKB1 deficiency confers sensitivity to distinct classes of anticancer drugs. The ability to reliably identify LKB1-deficient tumors is thus likely to have important prognostic and predictive implications. Previous research studies have employed polyclonal antibodies with limited success, and there is no widely-employed immunohistochemical assay for LKB1. Here we report an assay based on a rabbit monoclonal antibody that can reliably detect endogenous LKB1 protein (and its absence) in mouse and human formalin-fixed, paraffin-embedded tissues. LKB1 protein levels determined through this assay correlated strongly with AMPK phosphorylation both in mouse and human tumors, and with mRNA levels in human tumors. Our studies fully validate this immunohistochemical assay for LKB1 in paraffin-embedded formalin tissue sections. This assay should be broadly useful for research studies employing mouse models and also for the development of human tissue-based assays for LKB1 in diverse clinical settings.

Pena, Christopher G.; Zhang, Song; Zhao, Ni; Bardeesy, Nabeel; Sharpless, Norman E.; Wong, Kwok-Kin; Hayes, D. Neil; Castrillon, Diego H.

2013-01-01

214

The Humanized NOD/SCID Mouse as a Preclinical Model to Study the Fate of Encapsulated Human Islets  

PubMed Central

Despite encouraging results in animal models, the transplantation of microencapsulated islets into humans has not yet reached the therapeutic level. Recent clinical trials using microencapsulated human islets in barium alginate showed the presence of dense fibrotic overgrowth around the microcapsules with no viable islets. The major reason for this is limited understanding of what occurs when encapsulated human islets are allografted. This warrants the need for a suitable small animal model. In this study, we investigated the usefulness of NOD/SCID mice reconstituted with human PBMCs (called humanized NOD/SCID mice) as a preclinical model. In this model, human T cell engraftment could be achieved, and CD45+ cells were observed in the spleen and peripheral blood. Though the engrafted T cells caused a small fibrotic overgrowth around the microencapsulated human islets, this failed to stop the encapsulated islets from functioning in the diabetic recipient mice. The ability of encapsulated islets to survive in this mouse model might partly be attributed to the presence of Th2 cytokines IL-4 and IL-10, which are known to induce graft tolerance. In conclusion, this study showed that the hu-NOD/SCID mouse is not a suitable preclinical model to study the allograft rejection mechanisms of encapsulated human islets. As another result, the maintained viability of transplanted islets on the NOD/SCID background emphasized a critical role of protective mechanisms in autoimmune diabetes transplanted subjects due to specific immunoregulatory effects provided by IL-4 and IL-10.

Vaithilingam, Vijayaganapathy; Oberholzer, Jose; Guillemin, Gilles J.; Tuch, Bernard E.

2010-01-01

215

Development of a Mouse Model of Helicobacter pylori Infection that Mimics Human Disease  

NASA Astrophysics Data System (ADS)

The human pathogen Helicobacter pylori is associated with gastritis, peptic ulcer disease, and gastric cancer. The pathogenesis of H. pylori infection in vivo was studied by adapting fresh clinical isolates of bacteria to colonize the stomachs of mice. A gastric pathology resembling human disease was observed in infections with cytotoxin-producing strains but not with noncytotoxic strains. Oral immunization with purified H. pylori antigens protected mice from bacterial infection. This mouse model will allow the development of therapeutic agents and vaccines against H. pylori infection in humans.

Marchetti, Marta; Arico, Beatrice; Burroni, Daniela; Figura, Natale; Rappuoli, Rino; Ghiara, Paolo

1995-03-01

216

The fibulin-1 gene (FBLN1) is located on human chromosome 22 and on mouse chromosome 15  

SciTech Connect

Fibulin-1 is a calcium-binding glycoprotein present in the extracellular matrix and in the serum. The gene coding for fibulin-1 (FBLN1) was located by in situ hybridization of {sup 3}H-labeled cDNA probes to human and mouse metaphase chromosomes. The gene was assigned to the q13.2-q13.3 region of human chromosome 22 and to the E-F band of mouse chromosome 15. The finding extends the evolutionary conservation between human chromosome 22 and mouse chromosome 15. 11 refs., 2 figs.

Mattei, M.G. [Hopital d`Enfants de la Timone, Marseille (France); Pan, T.C.; Zhang, R.Z. [Thomas Jefferson Univ., Philadelphia, PA (United States)] [and others

1994-07-15

217

Cloning and Characterization of the Mouse and Human Enamelin Genes  

Microsoft Academic Search

Enamelin is likely to be essential for proper dental enamel formation. It is secreted by ameloblasts throughout the secretory stage and can readily be isolated from the enamel matrix of developing teeth. The gene encoding human enamelin is located on the long arm of chromosome 4, in a region previously linked to an autosomal-dominant form of amelogenesis imperfecta (AI). To

J. C.-C. Hu; C. H. Zhang; Y. Yang; C. Kärrman-MÅrdh; K. Forsman-Semb; J. P. Simmer

2001-01-01

218

A mouse model of human repetitive mild traumatic brain injury  

Microsoft Academic Search

A novel method for the study of repetitive mild traumatic brain injury (rmTBI) that models the most common form of head injury in humans is presented. Existing animal models of TBI impart focal, severe damage unlike that seen in repeated and mild concussive injuries, and few are configured for repetitive application. Our model is a modification of the Marmarou weight

Michael J. Kane; Mariana Angoa-Pérez; Denise I. Briggs; David C. Viano; Christian W. Kreipke; Donald M. Kuhn

219

Establishment of a transgenic mouse model of corneal dystrophy overexpressing human BIGH3.  

PubMed

This study aimed to establish a transgenic mouse model of corneal dystrophy (CD) overexpressing the human transforming growth factor, ?-induced, 68 kDa (TGFBI, also known as BIGH3) gene. A purified and linearized recombinant plasmid carrying the expression cassette BIGH3?IRES?EGFP was microinjected into the pronuclei of C57BL/6J mouse fertilized eggs under the control of the phosphoglycerate kinase (PGK) promoter. The expression of human BIGH3 in the transgenic mice was confirmed by PCR using DNA extracted from tail tissue. Four founder transgenic mice were identified by PCR and the increased expression of BIGH3 was observed in the corneas of the transgenic mice by RT?PCR and western blot analysis. The abnormal corneas with central opacity were observed in the transgenic mice by corneal photography. We concluded that the exogenous gene, BIGH3, was integrated successfully into the mouse genome through microinjection. In addition, the phenotype observed in this BIGH3 transgenic mouse model was similar to CD. Therefore, this transgenic model may prove useful in the investigation of the pathogenesis of CD. PMID:24009044

Liao, Xin; Cui, Hongping; Wang, Fang

2013-09-04

220

Automated Construction of High-Density Comparative Maps Between Rat, Human, and Mouse  

PubMed Central

Animal models have been used primarily as surrogates for humans, having similar disease-based phenotypes. Genomic organization also tends to be conserved between species, leading to the generation of comparative genome maps. The emergence of radiation hybrid (RH) maps, coupled with the large numbers of available Expressed Sequence Tags (ESTs), has revolutionized the way comparative maps can be built. We used publicly available rat, mouse, and human data to identify genes and ESTs with interspecies sequence identity (homology), identified their UniGene relationships, and incorporated their RH map positions to build integrated comparative maps with >2100 homologous UniGenes mapped in more than one species (?6% of all mammalian genes). The generation of these maps is iterative and labor intensive; therefore, we developed a series of computer tools (not described here) based on our algorithm that identifies anchors between species and produces printable and on-line clickable comparative maps that link to a wide variety of useful tools and databases. The maps were constructed using sequence-based comparisons, thus creating “hooks” for further sequence-based annotation of human, mouse, and rat sequences. Currently, this map enables investigators to link the physiology of the rat with the genetics of the mouse and the clinical significance of the human.

Kwitek, Anne E.; Tonellato, Peter J.; Chen, Dan; Gullings-Handley, Jo; Cheng, Yongjian Samuel; Twigger, Simon; Scheetz, Todd E.; Casavant, Thomas L.; Stoll, Monika; Nobrega, Marcelo A.; Shiozawa, Masahide; Soares, M. Bento; Sheffield, Val C.; Jacob, Howard J.

2001-01-01

221

The structure and regulation of the human and mouse matrix metalloproteinase-21 gene and protein.  

PubMed Central

Matrix metalloproteinases (MMPs) play key roles in tissue remodelling under normal development and, especially, in diseases ranging from malignancies to stroke. We cloned and thoroughly characterized the novel human and mouse MMP gene encoding MMP-21. MMP-21 is the last uncharacterized MMP coded by the human genome. Human and mouse MMP-21 is the orthologue of Xenopus laevis X-MMP. The latent proenzyme of MMP-21 (569 amino acid residues) consists of the prodomain, the catalytic domain and the haemopexin-like domain, and is potentially capable of being activated in its secretory pathway to the extracellular milieu by furin-like proprotein convertases. Human MMP-21 is the probable target gene of the Wnt pathway. In addition, the expression of MMP-21 is controlled uniquely by Pax and Notch transcription factors known to be critical for organogenesis. MMP-21 is expressed transiently in mouse embryogenesis and increased in embryonic neuronal tissues. Our observations clearly indicate that there is an important specific function for MMP-21 in embryogenesis, especially in neuronal cells.

Marchenko, George N; Marchenko, Natalia D; Strongin, Alex Y

2003-01-01

222

Identification and characterization of human LLGL4 gene and mouse Llgl4 gene in silico.  

PubMed

Drosophila Discs large (Dlg), Scribble (Scrib) and Lethal giant larvae (Lgl) act in concert as regulators of epithelial polarity, and human homologs of Drosophila dlg, scrib, and lgl are cancer-associated genes. LLGL1, LLGL2, and LLGL3/STXBP5 genes, encoding LGL1, LGL2, and LGL3/Tomosyn, respectively, are human homologs of Drosophila lgl gene. Here, we identified and characterized LLGL4 (also known as STXBP5L) gene encoding LGL4 protein, by using bioinformatics. Uncharacterized human KIAA1006 cDNA (AB023223) was derived from human LLGL4 gene. LLGL4 mRNA was expressed in kidney, brain hippocampus, and also in lung carcinoid, and germ cell tumors. LLGL4 gene, consisting of 28 exons, was mapped to human chromosome 3q13.33. Mouse A830015P08Rik cDNA (NM_172440.1) was a 3'-truncated partial Llgl4 cDNA. Nucleotide sequence of full-length mouse Llgl4 cDNA was determined in silico by assembling A830015P08Rik cDNA, BU609516 EST and last two exons of Llgl4 gene within mouse genome clone RP24-174G4 (AC118742.3). Human LGL4 showed 95.8% total-amino-acid identity with mouse Lgl4, and 68.4% total-amino-acid identity with human LGL3. LGLH1 domain (codon 1-11 of LGL4), LGLH2 domain (codon 52-98) and LGLH3 domain (codon 994-1054) were identified as novel conserved regions among LGL family members. LGL1 and LGL2 consist of LGLH1, LGLH2, LGLH3 domains and five WD40 repeats, while LGL3 and LGL4 consist of LGLH1, LGLH2, LGLH3 domains, five WD40 repeats and the C-terminal Syntaxin-binding SNARE domain. This is the first report on identification and characterization of human LLGL4 and mouse Llgl4 genes. PMID:14767561

Katoh, Masuko; Katoh, Masaru

2004-03-01

223

Expression Signature Developed from a Complex Series of Mouse Models Accurately Predicts Human Breast Cancer Survival  

PubMed Central

Purpose The capability of microarray platform to interrogate thousands of genes has led to the development of molecular diagnostic tools for cancer patients. While large-scale comparative studies of clinical samples are often limited by the access of human tissues, expression profiling databases of various human cancer types are publicly available for researchers. Given that mouse models have been instrumental to our current understanding of cancer progression, we aimed to test the hypothesis that novel gene signatures possessing predictability in clinical outcome can be derived by coupling genomic analyses in mouse models of cancer with publicly available human cancer datasets. Experimental Design We established a complex series of syngeneic metastatic animal models using a murine breast cancer cell line. Tumor RNA was hybridized on Affymetrix MouseGenome-430A2.0 GeneChips. With the use of Venn logic, gene signatures that represent metastatic competency were derived and tested against publicly available human breast and lung cancer datasets. Results Survival analyses showed that the spontaneous metastasis gene signature was significantly associated with metastasis-free and overall survival (p<0.0005). Consequently, the six-gene model was determined and demonstrated statistical predictability in predicting survival in breast cancer patients. In addition, the model was able to stratify poor from good prognosis for lung cancer patients in majority of the datasets analyzed. Conclusions Together, our data support that novel gene signature derived from mouse models of cancer can be utilized for predicting human cancer outcome. Our approaches set precedence that similar strategies may be used to decipher novel gene signatures for clinical utility.

He, Mei; Mangiameli, David P.; Kachala, Stefan; Hunter, Kent; Gillespie, John; Bian, Xiaopeng; Shen, H.-C. Jennifer; Libutti, Steven K.

2009-01-01

224

Human-Mouse Gene Identification by Comparative Evidence Integration and Evolutionary Analysis  

PubMed Central

The identification of genes in the human genome remains a challenge, as the actual predictions appear to disagree tremendously and vary dramatically on the basis of the specific gene-finding methodology used. Because the pattern of conservation in coding regions is expected to be different from intronic or intergenic regions, a comparative computational analysis can lead, in principle, to an improved computational identification of genes in the human genome by using a reference, such as mouse genome. However, this comparative methodology critically depends on three important factors: (1) the selection of the most appropriate reference genome. In particular, it is not clear whether the mouse is at the correct evolutionary distance from the human to provide sufficiently distinctive conservation levels in different genomic regions, (2) the selection of comparative features that provide the most benefit to gene recognition, and (3) the selection of evidence integration architecture that effectively interprets the comparative features. We address the first question by a novel evolutionary analysis that allows us to explicitly correlate the performance of the gene recognition system with the evolutionary distance (time) between the two genomes. Our simulation results indicate that there is a wide range of reference genomes at different evolutionary time points that appear to deliver reasonable comparative prediction of human genes. In particular, the evolutionary time between human and mouse generally falls in the region of good performance; however, better accuracy might be achieved with a reference genome further than mouse. To address the second question, we propose several natural comparative measures of conservation for identifying exons and exon boundaries. Finally, we experiment with Bayesian networks for the integration of comparative and compositional evidence.

Zhang, Lingang; Pavlovic, Vladimir; Cantor, Charles R; Kasif, Simon

2003-01-01

225

A rapid method for the determination of human CEA\\/mouse anti-CEA immune complexes in patients undergoing immunoscintigraphy  

Microsoft Academic Search

We report here on a new and quick procedure to isolate human (hu) CEA mouse anti CEA immune complexes of sera from patients admitted for immunoscintigraphy with radiolabeled monoclonal anti CEA antibody. This method employs rabbit anti mouse IgG immune affinity chromatography together with a commercial CEA-IRMA kit for the specific isolation of immune complexes. By applying this procedure we

R. P. Baum; P. Hernaiz Driever; D. Drahovsky; G. Hör

1989-01-01

226

Comparative analysis of the 5â² genomic and promoter regions between the mouse (Hdh) and human Huntington disease (HD) gene  

Microsoft Academic Search

The mouse homologue of the Huntington disease gene (Hdh) has recently been cloned and mapped to a region of synteny with the human, on mouse chromosome 5. The two genes share a high degree of both coding (90% amino acid) and nucleotide (86.2%) identity. We have subsequently performed a detailed comparison of the genomic organization of the 5â² region of

M. Kalchman; B. Lin; J. Nasir

1994-01-01

227

Mutation of the Sry-Related Sox10 Gene in Dominant megacolon, a Mouse Model for Human Hirschsprung Disease  

Microsoft Academic Search

The spontaneous mouse mutant Dominant megacolon (Dom) is a valuable model for the study of human congenital megacolon (Hirschsprung disease). Here we report that the defect in the Dom mouse is caused by mutation of the gene encoding the Sry-related transcription factor Sox10. This assignment is based on (i) colocalization of the Sox10 gene with the Dom mutation on chromosome

Beate Herbarth; Veronique Pingault; Nadege Bondurand; Kirsten Kuhlbrodt; Irm Hermans-Borgmeyer; Aldamaria Puliti; Nicole Lemort; Michel Goossens; Michael Wegner

1998-01-01

228

Isolation and characterization of mouse-human microcell hybrid cell clones permissive for infectious HIV particle release  

PubMed Central

Mouse cells are non-permissive to human immunodeficiency virus type 1 (HIV) in that there is a pronounced post-integration block to viral replication. We have recently demonstrated that mouse-human somatic cell hybrids that contain human chromosome 2 increase both HIV Capsid (CA) production and infectious virus release. Here we report on the isolation of three mouse-human microcell hybrids (MCHs) that behave similarly, starting from a pool of 500 MCH clones. Release of virus was specific to HIV and cell revertants that no longer contained any human chromosome fragments did not release CA or infectious virus. Two of the three cell clones were identical as judged by PCR STS content and fluorescence in situ hybridization (FISH) and contained a single 2-12 human chromosome chimera. The third cell clone only contained human chromosome 12, as determined by PCR, FISH, and microarray analyses. There were no consistent differences in Gag protein and spliced/unspliced viral RNA levels between mouse cell lines. CMV promoter-driven, codon-optimized gag-pol had no effect on infectious HIV release from these mouse cells, despite allowing Gag targeting and increasing CA production. These permissive mouse-human MCHs and their corresponding non-permissive revertants may prove useful for mechanistic studies and also for identifying the responsible gene(s) or factor(s) involved in the production of HIV.

Coskun, Ayse K.; van Maanen, Marc; Janka, David; Stockton, David; Stankiewicz, Pawel; Yatsenko, Svetlana; Sutton, Richard E.

2007-01-01

229

Using the BLT humanized mouse as a stem cell based gene therapy tumor model.  

PubMed

Small animal models such as mice have been extensively used to study human disease and to develop new therapeutic interventions. Despite the wealth of information gained from these studies, the unique characteristics of mouse immunity as well as the species specificity of viral diseases such as human immunodeficiency virus (HIV) infection led to the development of humanized mouse models. The earlier models involved the use of C. B 17 scid/scid mice and the transplantation of human fetal thymus and fetal liver termed thy/liv (SCID-hu) (1, 2) or the adoptive transfer of human peripheral blood leukocytes (SCID-huPBL) (3). Both models were mainly utilized for the study of HIV infection. One of the main limitations of both of these models was the lack of stable reconstitution of human immune cells in the periphery to make them a more physiologically relevant model to study HIV disease. To this end, the BLT humanized mouse model was developed. BLT stands for bone marrow/liver/thymus. In this model, 6 to 8 week old NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) immunocompromised mice receive the thy/liv implant as in the SCID-hu mouse model only to be followed by a second human hematopoietic stem cell transplant (4). The advantage of this system is the full reconstitution of the human immune system in the periphery. This model has been used to study HIV infection and latency (5-8). We have generated a modified version of this model in which we use genetically modified human hematopoietic stem cells (hHSC) to construct the thy/liv implant followed by injection of transduced autologous hHSC (7, 9). This approach results in the generation of genetically modified lineages. More importantly, we adapted this system to examine the potential of generating functional cytotoxic T cells (CTL) expressing a melanoma specific T cell receptor. Using this model we were able to assess the functionality of our transgenic CTL utilizing live positron emission tomography (PET) imaging to determine tumor regression (9). The goal of this protocol is to describe the process of generating these transgenic mice and assessing in vivo efficacy using live PET imaging. As a note, since we use human tissues and lentiviral vectors, our facilities conform to CDC NIH guidelines for Biosafety Level 2 (BSL2) with special precautions (BSL2+). In addition, the NSG mice are severely immunocompromised thus, their housing and maintenance must conform to the highest health standards (http://jaxmice.jax.org/research/immunology/005557-housing.html). PMID:23271478

Vatakis, Dimitrios N; Bristol, Gregory C; Kim, Sohn G; Levin, Bernard; Liu, Wei; Radu, Caius G; Kitchen, Scott G; Zack, Jerome A

2012-12-18

230

Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR)  

Microsoft Academic Search

.   Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate,\\u000a a co-substrate for homocysteine remethylation to methionine. A human cDNA for MTHFR, 2.2 kb in length, has been expressed\\u000a and shown to result in a catalytically active enzyme of approximately 70 kDa. Fifteen mutations have been identified in the\\u000a MTHFR gene: 14 rare mutations associated with severe enzymatic deficiency

Philippe Goyette; Aditya Pai; Renate Milos; Phyllis Frosst; Pamela Tran; Zhoutao Chen; Manuel Chan; Rima Rozen

1998-01-01

231

The human and mouse homologs of the yeast RAD52 gene: cDNA cloning, sequence analysis, assignment to human chromosome 12p12.2-p13, and mRNA expression in mouse tissues.  

PubMed

The yeast Saccharomyces cerevisiae RAD52 gene is involved in DNA double-strand break repair and mitotic/meiotic recombination. The N-terminal amino acid sequence of yeast S. cerevisiae, Schizosaccharomyces pombe, and Kluyveromyces lactis and chicken is highly conserved. Using the technology of mixed oligonucleotide primed amplification of cDNA (MOPAC), two mouse RAD52 homologous cDNA fragments were amplified and sequenced. Subsequently, we have cloned the cDNA of the human and mouse homologs of yeast RAD52 gene by screening cDNA libraries using the identified mouse cDNA fragments. Sequence analysis of cDNA derived amino acid revealed a highly conserved N-terminus among human, mouse, chicken, and yeast RAD52 genes. The human RAD52 gene was assigned to chromosome 12p12.2-p13 by fluorescence in situ hybridization, R-banding, and DNA analysis of somatic cell hybrids. Unlike chicken RAD52 and mouse RAD51, no significant difference in mouse RAD52 mRNA level was found among mouse heart, brain, spleen, lung, liver, skeletal muscle, kidney, and testis. In addition to an approximately 1.9-kb RAD52 mRNA band that is present in all of the tested tissues, an extra mRNA species of approximately 0.85 kb was detectable in mouse testis. PMID:7774919

Shen, Z; Denison, K; Lobb, R; Gatewood, J M; Chen, D J

1995-01-01

232

Genetic Regulation of Pituitary Gland Development in Human and Mouse  

PubMed Central

Normal hypothalamopituitary development is closely related to that of the forebrain and is dependent upon a complex genetic cascade of transcription factors and signaling molecules that may be either intrinsic or extrinsic to the developing Rathke’s pouch. These factors dictate organ commitment, cell differentiation, and cell proliferation within the anterior pituitary. Abnormalities in these processes are associated with congenital hypopituitarism, a spectrum of disorders that includes syndromic disorders such as septo-optic dysplasia, combined pituitary hormone deficiencies, and isolated hormone deficiencies, of which the commonest is GH deficiency. The highly variable clinical phenotypes can now in part be explained due to research performed over the last 20 yr, based mainly on naturally occurring and transgenic animal models. Mutations in genes encoding both signaling molecules and transcription factors have been implicated in the etiology of hypopituitarism, with or without other syndromic features, in mice and humans. To date, mutations in known genes account for a small proportion of cases of hypopituitarism in humans. However, these mutations have led to a greater understanding of the genetic interactions that lead to normal pituitary development. This review attempts to describe the complexity of pituitary development in the rodent, with particular emphasis on those factors that, when mutated, are associated with hypopituitarism in humans.

Kelberman, Daniel; Rizzoti, Karine; Lovell-Badge, Robin; Robinson, Iain C. A. F.; Dattani, Mehul T.

2009-01-01

233

Noise in a Laboratory Animal Facility from the Human and Mouse Perspectives  

PubMed Central

The current study was performed to understand the level of sound produced by ventilated racks, animal transfer stations, and construction equipment that mice in ventilated cages hear relative to what humans would hear in the same environment. Although the ventilated rack and animal transfer station both produced sound pressure levels above the ambient level within the human hearing range, the sound pressure levels within the mouse hearing range did not increase above ambient noise from either noise source. When various types of construction equipment were used 3 ft from the ventilated rack, the sound pressure level within the mouse hearing range was increased but to a lesser degree for each implement than were the sound pressure levels within the human hearing range. At more distant locations within the animal facility, sound pressure levels from the large jackhammer within the mouse hearing range decreased much more rapidly than did those in the human hearing range, indicating that less of the sound is perceived by mice than by humans. The relatively high proportion of low-frequency sound produced by the shot blaster, used without the metal shot that it normally uses to clean concrete, increased the sound pressure level above the ambient level for humans but did not increase sound pressure levels above ambient noise for mice at locations greater than 3 ft from inside of the cage, where sound was measured. This study demonstrates that sound clearly audible to humans in the animal facility may be perceived to a lesser degree or not at all by mice, because of the frequency content of the sound.

Reynolds, Randall P; Kinard, Will L; Degraff, Jesse J; Leverage, Ned; Norton, John N

2010-01-01

234

Metabolism of the anti-tuberculosis drug ethionamide by mouse and human FMO1, FMO2 and FMO3 and mouse and human lung microsomes  

SciTech Connect

Tuberculosis (TB) results from infection with Mycobacterium tuberculosis and remains endemic throughout the world with one-third of the world's population infected. The prevalence of multi-drug resistant strains necessitates the use of more toxic second-line drugs such as ethionamide (ETA), a pro-drug requiring bioactivation to exert toxicity. M. tuberculosis possesses a flavin monooxygenase (EtaA) that oxygenates ETA first to the sulfoxide and then to 2-ethyl-4-amidopyridine, presumably through a second oxygenation involving sulfinic acid. ETA is also a substrate for mammalian flavin-containing monooxygenases (FMOs). We examined activity of expressed human and mouse FMOs toward ETA, as well as liver and lung microsomes. All FMOs converted ETA to the S-oxide (ETASO), the first step in bioactivation. Compared to M. tuberculosis, the second S-oxygenation to the sulfinic acid is slow. Mouse liver and lung microsomes, as well as human lung microsomes from an individual expressing active FMO, oxygenated ETA in the same manner as expressed FMOs, confirming this reaction functions in the major target organs for therapeutics (lung) and toxicity (liver). Inhibition by thiourea, and lack of inhibition by SKF-525A, confirm ETASO formation is primarily via FMO, particularly in lung. ETASO production was attenuated in a concentration-dependent manner by glutathione. FMO3 in human liver may contribute to the toxicity and/or affect efficacy of ETA administration. Additionally, there may be therapeutic implications of efficacy and toxicity in human lung based on the FMO2 genetic polymorphism, though further studies are needed to confirm that suggestion.

Henderson, Marilyn C.; Siddens, Lisbeth K. [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331-7301 (United States); Morre, Jeffrey T. [Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331-7302 (United States); Krueger, Sharon K. [Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-6512 (United States); Williams, David E. [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331-7301 (United States); Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331-7302 (United States); Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-6512 (United States)], E-mail: david.williams@oregonstate.edu

2008-12-15

235

Prostate pathology of genetically engineered mice: definitions and classification. The consensus report from the Bar Harbor meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee  

Microsoft Academic Search

The Pathological Classification of Prostate Lesions in Genetically Engineered Mice (GEM) is the result of a directive from the National Cancer Institute Mouse Models of Human Cancer Consortium Prostate Steering Committee to provide a hierarchical taxonomy of disorders of the mouse prostate to facilitate classification of existing and newly created mouse models and the translation to human prostate pathology. The

Scott B. Shappell; George V. Thomas; Richard L. Roberts; Ron Herbert; Michael M. Ittmann; Mark A. Rubin; Peter A. Humphrey; John P. Sundberg; Nora Rozengurt; Roberto Barrios; Jerrold M. Ward; Robert D. Cardiff

2004-01-01

236

Glucose Metabolism Heterogeneity in Human and Mouse Malignant Glioma Cell Lines  

Microsoft Academic Search

Summary The current study examined specific bioenergetic markers associated with the metabolic phenotype of several human and mouse glioma cell lines. Based on preliminary studies, we hypothesized that glioma cells would express one of at least two different metabolic phenotypes, possibly acquired through progression. The D-54MG and GL261 glioma cell lines displayed an oxidative phosphorylation (OXPHOS)-dependent phenotype, characterized by extremely

Corinne E. Griguer; Claudia R. Oliva; G. Yancey Gillespie

2005-01-01

237

Computational promoter analysis of mouse, rat and human antimicrobial peptide-coding genes  

PubMed Central

Background Mammalian antimicrobial peptides (AMPs) are effectors of the innate immune response. A multitude of signals coming from pathways of mammalian pathogen/pattern recognition receptors and other proteins affect the expression of AMP-coding genes (AMPcgs). For many AMPcgs the promoter elements and transcription factors that control their tissue cell-specific expression have yet to be fully identified and characterized. Results Based upon the RIKEN full-length cDNA and public sequence data derived from human, mouse and rat, we identified 178 candidate AMP transcripts derived from 61 genes belonging to 29 AMP families. However, only for 31 mouse genes belonging to 22 AMP families we were able to determine true orthologous relationships with 30 human and 15 rat sequences. We screened the promoter regions of AMPcgs in the three species for motifs by an ab initio motif finding method and analyzed the derived promoter characteristics. Promoter models were developed for alpha-defensins, penk and zap AMP families. The results suggest a core set of transcription factors (TFs) that regulate the transcription of AMPcg families in mouse, rat and human. The three most frequent core TFs groups include liver-, nervous system-specific and nuclear hormone receptors (NHRs). Out of 440 motifs analyzed, we found that three represent potentially novel TF-binding motifs enriched in promoters of AMPcgs, while the other four motifs appear to be species-specific. Conclusion Our large-scale computational analysis of promoters of 22 families of AMPcgs across three mammalian species suggests that their key transcriptional regulators are likely to be TFs of the liver-, nervous system-specific and NHR groups. The computationally inferred promoter elements and potential TF binding motifs provide a rich resource for targeted experimental validation of TF binding and signaling studies that aim at the regulation of mouse, rat or human AMPcgs.

Brahmachary, Manisha; Schonbach, Christian; Yang, Liang; Huang, Enli; Tan, Sin Lam; Chowdhary, Rajesh; Krishnan, SPT; Lin, Chin-Yo; Hume, David A; Kai, Chikatoshi; Kawai, Jun; Carninci, Piero; Hayashizaki, Yoshihide; Bajic, Vladimir B

2006-01-01

238

Conformational restriction in a series of GPR119 agonists: differences in pharmacology between mouse and human.  

PubMed

A series of conformationally restricted GPR119 agonists were prepared based around a 3,8-diazabicyclo[3.2.1]octane scaffold. Examples were found to have markedly different pharmacology in mouse and human despite similar levels of binding to the receptor. This highlights the large effects on GPCR phamacology that can result from small structural changes in the ligand, together with inter-species differences between receptors. PMID:23628336

Scott, James S; Brocklehurst, Katy J; Brown, Hayley S; Clarke, David S; Coe, Helen; Groombridge, Sam D; Laber, David; MacFaul, Philip A; McKerrecher, Darren; Schofield, Paul

2013-04-10

239

Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia  

Microsoft Academic Search

X-linked hypohidrotic ectodermal dysplasia results in abnormal morphogenesis of teeth, hair and eccrine sweat glands. The gene (ED1) responsible for the disorder has been identified, as well as the analogous X-linked gene (Ta) in the mouse. Autosomal recessive disorders, phenotypically indistinguishable from the X-linked forms, exist in humans and at two separate loci (crinkled, cr, and downless, dl) in mice.

Alex W. Monreal; Denis J. Headon; Paul A. Overbeek; Jonathan Zonana; Betsy M. Ferguson

1999-01-01

240

Ultrastructural differentiation in the nude mouse of transformed cells isolated from the human fetal pituitary gland  

Microsoft Academic Search

Spontaneously transformed human fetal pituitary cells were isolated from first-passage cultures after 3 to 6 months of long- term maintenance in growth medium containing 15% fetal calf serum. The cells, when injected into nude mice, developed into large tumors in 1 to 2 weeks. Attempts to detect growth hormone, prolactin, follicle-stimulating hormone, luteinizing hormone, or thyroid-stimulating hormone from nude mouse

Yew Phew See; Anthony M. Sun; Donna J. McComb; Kaiman Kovacs

1982-01-01

241

Reprogramming of mouse and human somatic cells by high-performance engineered factors  

Microsoft Academic Search

Reprogramming somatic cells to become induced pluripotent stem cells (iPSCs) by using defined factors represents an important breakthrough in biology and medicine, yet remains inefficient and poorly understood. We therefore devised synthetic factors by fusing the VP16 transactivation domain to OCT4 (also known as Pou5f1), NANOG and SOX2, respectively. These synthetic factors could reprogramme both mouse and human fibroblasts with

Yang Wang; Jiekai Chen; Jia-Lei Hu; Xi-Xiao Wei; Dajiang Qin; Juan Gao; Lei Zhang; Jing Jiang; Jin-Song Li; Jing Liu; Ke-Yu Lai; Xia Kuang; Jian Zhang; Duanqing Pei; Guo-Liang Xu

2011-01-01

242

New clinically relevant, orthotopic mouse models of human chondrosarcoma with spontaneous metastasis  

Microsoft Academic Search

BACKGROUND: Chondrosarcoma responds poorly to adjuvant therapy and new, clinically relevant animal models are required to test targeted therapy. METHODS: Two human chondrosarcoma cell lines, JJ012 and FS090, were evaluated for proliferation, colony formation, invasion, angiogenesis and osteoclastogenesis. Cell lines were also investigated for VEGF, MMP-2, MMP-9, and RECK expression. JJ012 and FS090 were injected separately into the mouse tibia

Jonathan CM Clark; Toru Akiyama; Crispin R Dass; Peter FM Choong

2010-01-01

243

Modulation of Mouse and Human Phenobarbital-Responsive Enhancer Module by Nuclear Receptors  

Microsoft Academic Search

The constitutive androstane receptor (CAR) regulates mouse and human CYP2B genes through binding to the direct re- peat-4 (DR4) motifs present in the phenobarbital-responsive enhancer module (PBREM). The preference of PBREM ele- ments for nuclear receptors and the extent of cross-talk be- tween CAR and other nuclear receptors are currently unknown. Our transient transfection and DNA binding experiments indi- cate

J. Makinen; JUKKA GYNTHER; CARSTEN CARLBERG; PAAVO HONKAKOSKI

2002-01-01

244

Methods for detection, isolation and culture of mouse and human invariant NKT cells  

Microsoft Academic Search

This protocol describes methods to identify, purify and culture CD1d restricted invariant natural killer T (iNKT) cells from mouse tissue or human blood samples. The methods for identification and purification of iNKT cells are based on the interaction between iNKT cell receptor and its ligand. The iNKT cell receptor is composed of the invariant V?14J?18\\/V?8.2 in mice or V?24J?18\\/V?11 in

Hiroshi Watarai; Ryusuke Nakagawa; Miyuki Omori-Miyake; Nyambayar Dashtsoodol; Masaru Taniguchi

2007-01-01

245

Assessment of orthologous splicing isoforms in human and mouse orthologous genes  

PubMed Central

Background Recent discoveries have highlighted the fact that alternative splicing and alternative transcripts are the rule, rather than the exception, in metazoan genes. Since multiple transcript and protein variants expressed by the same gene are, by definition, structurally distinct and need not to be functionally equivalent, the concept of gene orthology should be extended to the transcript level in order to describe evolutionary relationships between structurally similar transcript variants. In other words, the identification of true orthology relationships between gene products now should progress beyond primary sequence and "splicing orthology", consisting in ancestrally shared exon-intron structures, is required to define orthologous isoforms at transcript level. Results As a starting step in this direction, in this work we performed a large scale human- mouse gene comparison with a twofold goal: first, to assess if and to which extent traditional gene annotations such as RefSeq capture genuine splicing orthology; second, to provide a more detailed annotation and quantification of true human-mouse orthologous transcripts defined as transcripts of orthologous genes exhibiting the same splicing patterns. Conclusions We observed an identical exon/intron structure for 32% of human and mouse orthologous genes. This figure increases to 87% using less stringent criteria for gene structure similarity, thus implying that for about 13% of the human RefSeq annotated genes (and about 25% of the corresponding transcripts) we could not identify any mouse transcript showing sufficient similarity to be confidently assigned as a splicing ortholog. Our data suggest that current gene and transcript data may still be rather incomplete - with several splicing variants still unknown. The observation that alternative splicing produces large numbers of alternative transcripts and proteins, some of them conserved across species and others truly species-specific, suggests that, still maintaining the conventional definition of gene orthology, a new concept of "splicing orthology" can be defined at transcript level.

2010-01-01

246

Regulation of human protein C gene expression by the mouse WAP promoter  

Microsoft Academic Search

A 4.1 kb mouse whey acidic protein (mWAP) promoter was cloned from a C57BL\\/6 cosmid library. The tissue-specific and developmental pattern of expression of a hybrid gene comprised of the mWAP promoter fragment and the human protein C (HPC) gene was analysed in transgenic mice. The corresponding RNA was detected mainly in the mammary gland, with ‘leakage’ of expression in

Rekha K. Paleyanda; Da-Wei Zhang; Lothar Hennighausen; Robert A. McKnight; Henryk Lubon

1994-01-01

247

Bacterial ?-galactosidase and human dystrophin genes are expressed in mouse skeletal muscle fibers after ballistic transfection  

Microsoft Academic Search

Ballistic transfection, based on cell and tissue bombardment by the tungsten and gold microparticles covered with the gene DNA, was used for the delivery of a bacterial ?-galactosidase and a full-length cDNA copy of the human dystrophin genes into mouse skeletal muscles. CMV-lacZ, SV40-lacZ, LTR-lacZneo and full-length cDNA dystrophin (pDMD-1, approximately 16 kb) in eukaryotic expression vector pJ OMEGA driven

Alexander V. Zelenin; Victor A. Kolesnikov; Olga A. Tarasenko; Ramin A. Shafei; Inessa A. Zelenina; Vyacheslav V. Mikhailov; Maria L. Semenova; Dmitry V. Kovalenko; Olga V. Artemyeva; Tatyana E. Ivaschenko; Oleg V. Evgrafov; George Dickson; Vladislav S. Baranovand

1997-01-01

248

A gene atlas of the mouse and human protein-encoding transcriptomes  

Microsoft Academic Search

The tissue-specific pattern of mRNA expression can indicate important clues about gene function. High-density oligonucleotide arrays offer the opportunity to examine patterns of gene expression on a genome scale. Toward this end, we have designed custom arrays that interrogate the expression of the vast majority of protein-encoding human and mouse genes and have used them to profile a panel of

Andrew I. Su; Tim Wiltshire; Serge Batalov; Hilmar Lapp; Keith A. Ching; David Block; Jie Zhang; Richard Soden; Mimi Hayakawa; Gabriel Kreiman; Michael P. Cooke; John R. Walker; John B. Hogenesch

2004-01-01

249

Validation of a mouse xenograft model system for gene expression analysis of human acute lymphoblastic leukaemia  

Microsoft Academic Search

BACKGROUND: Pre-clinical models that effectively recapitulate human disease are critical for expanding our knowledge of cancer biology and drug resistance mechanisms. For haematological malignancies, the non-obese diabetic\\/severe combined immunodeficient (NOD\\/SCID) mouse is one of the most successful models to study paediatric acute lymphoblastic leukaemia (ALL). However, for this model to be effective for studying engraftment and therapy responses at the

Amy L Samuels; Violet K Peeva; Rachael A Papa; Marin J Firth; Richard W Francis; Alex H Beesley; Richard B Lock; Ursula R Kees

2010-01-01

250

Human Chorionic Gonadotropin Induces Nitric Oxide Synthase mRNA in Mouse Peritoneal Macrophages  

Microsoft Academic Search

We examined the effects of human chorionic gonadotropin (hCG) on the production of nitric oxide (NO) by mouse peritoneal macrophages. hCG had no effect on NO synthesis by itself, whereas recombinant interferon-? (rIFN-?) alone had modest activity. When hCG was used in combination with rIFN-?, there was a marked cooperative induction of NO synthesis in a dose-dependent manner. The optimal

Hyung-Min Kim; Young-Hoe Moon

1996-01-01

251

Distinct response to dioxin in an arylhydrocarbon receptor (AHR)-humanized mouse  

PubMed Central

There are large inter- and intraspecies differences in susceptibility to dioxin-induced toxicities. A critical question in risk assessment of dioxin and related compounds is whether humans are sensitive or resistant to their toxicities. The diverse responses of mammals to dioxin are strongly influenced by functional polymorphisms of the arylhydrocarbon receptor (AHR). To characterize responses mediated by the human AHR (hAHR), we generated a mouse possessing hAHR instead of mouse AHR. Responses of these mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene were compared with the responses of naturally sensitive (C57BL/6J) and resistant (DBA/2) mice. Mice homozygous for hAHR exhibited weaker induction of AHR target genes such as cyp1a1 and cyp1a2 than did C57BL/6J (Ahrb-1/b-1) mice. DBA/2 (Ahrd/d) mice were less responsive to induction of cyp genes than C57BL/6J mice. hAHR and DBA/2 AHR exhibit similar ligand-binding affinities and homozygous hAHR and Ahrd/d mice displayed comparable induction of AHR target genes by 3-methylcholanthrene. However, when TCDD was administered, a greatly diminished response was observed in homozygous hAHR mice compared with Ahrd/d mice, indicating that hAHR expressed in mice is functionally less responsive to TCDD than DBA/2 AHR. After maternal exposure to TCDD, homozygous hAHR fetuses developed embryonic hydronephrosis, but not cleft palate, whereas fetuses possessing Ahrb-1 or Ahrd developed both anomalies. These results suggest that hAHR may define the specificity of the responses to various AHR ligands. Thus, the hAHR knock-in mouse is a humanized model mouse that may better predict the biological effects of bioaccumulative environmental toxicants like TCDD in humans.

Moriguchi, Takashi; Motohashi, Hozumi; Hosoya, Tomonori; Nakajima, Osamu; Takahashi, Satoru; Ohsako, Seiichiroh; Aoki, Yasunobu; Nishimura, Noriko; Tohyama, Chiharu; Fujii-Kuriyama, Yoshiaki; Yamamoto, Masayuki

2003-01-01

252

An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues  

Microsoft Academic Search

MicroRNAs (miRNAs) are a class of small noncoding RNA genes recently found to be abnormally expressed in several types of cancer. Here, we describe a recently developed methodology for miRNA gene expression profiling based on the development of a microchip containing oligonucleotides corresponding to 245 miRNAs from human and mouse genomes. We used these microarrays to obtain highly reproducible results

Chang-Gong Liu; George Adrian Calin; Brian Meloon; Nir Gamliel; Cinzia Sevignani; Manuela Ferracin; Calin Dan Dumitru; Masayoshi Shimizu; Simona Zupo; Mariella Dono; Hansjuerg Alder; Florencia Bullrich; Massimo Negrini; Carlo M. Croce

2004-01-01

253

Identification of the human homolog of the imprinted mouse Air non-coding RNA  

PubMed Central

Genomic imprinting is widely conserved amongst placental mammals. Imprinted expression of IGF2R, however, differs between mice and humans. In mice, Igf2r imprinted expression is seen in all fetal and adult tissues. In humans, adult tissues lack IGF2R imprinted expression, but it is found in fetal tissues and Wilms' tumors where it is polymorphic and only seen in a small proportion of tested samples. Mouse Igf2r imprinted expression is controlled by the Air (Airn) ncRNA whose promoter lies in an intronic maternally-methylated CpG island. The human IGF2R gene carries a homologous intronic maternally-methylated CpG island of unknown function. Here, we use transfection and transgenic studies to show that the human IGF2R intronic CpG island is a ncRNA promoter. We also identify the same ncRNA at the endogenous human locus in 16–40% of Wilms' tumors. Thus, the human IGF2R gene shows evolutionary conservation of key features that control imprinted expression in the mouse.

Yotova, Iveta Y.; Vlatkovic, Irena M.; Pauler, Florian M.; Warczok, Katarzyna E.; Ambros, Peter F.; Oshimura, Mitsuo; Theussl, Hans-Christian; Gessler, Manfred; Wagner, Erwin F.; Barlow, Denise P.

2010-01-01

254

Neovascular Niche for Human Myeloma Cells in Immunodeficient Mouse Bone  

PubMed Central

The interaction with bone marrow (BM) plays a crucial role in pathophysiological features of multiple myeloma (MM), including cell proliferation, chemoresistance, and bone lesion progression. To characterize the MM-BM interactions, we utilized an in vivo experimental model for human MM in which a GFP-expressing human MM cell line is transplanted into NOG mice (the NOG-hMM model). Transplanted MM cells preferentially engrafted at the metaphyseal region of the BM endosteum and formed a complex with osteoblasts and osteoclasts. A subpopulation of MM cells expressed VE-cadherin after transplantation and formed endothelial-like structures in the BM. CD138+ myeloma cells in the BM were reduced by p53-dependent apoptosis following administration of the nitrogen mustard derivative bendamustine to mice in the NOG-hMM model. Bendamustine maintained the osteoblast lining on the bone surface and protected extracellular matrix structures. Furthermore, bendamustine suppressed the growth of osteoclasts and mesenchymal cells in the NOG-hMM model. Since VE-cadherin+ MM cells were chemoresistant, hypoxic, and HIF-2?-positive compared to the VE-cadherin? population, VE-cadherin induction might depend on the oxygenation status. The NOG-hMM model described here is a useful system to analyze the dynamics of MM pathophysiology, interactions of MM cells with other cellular compartments, and the utility of novel anti-MM therapies.

Miyakawa, Yoshitaka; Nakamura-Ishizu, Ayako; Miyauchi, Yoshiteru; Fujita, Nobuyuki; Miyamoto, Kana; Miyamoto, Takeshi; Ikeda, Eiji; Kizaki, Masahiro; Nojima, Yoshihisa; Suda, Toshio

2012-01-01

255

Development of skin-humanized mouse models of pachyonychia congenita.  

PubMed

Molecular characterization and assessment of therapeutic outcomes for inherited cutaneous disorders requires faithful preclinical models. In this study we report the establishment of two different skin-humanized pachyonychia congenita (PC) model systems, based on permanent engraftment of bioengineered skin equivalents generated from patient skin cells onto immunodeficient mice. Using keratinocytes and fibroblasts isolated from unaffected skin biopsies of two PC patients carrying the p.Asn171Lys mutation of the keratin 6a gene (KRT6A), we were able to regenerate PC-derived human skin that appeared phenotypically normal, but developed sustained PC features after the use of an acute hyperproliferative stimulus (i.e., tape stripping). In contrast, the use of keratinocytes from an affected area (i.e., plantar callus) from a different patient carrying the KRT6A mutation p.Asn171Asp led to a full recapitulation of the phenotype that included marked acanthosis and epidermal blistering after minor trauma. The ability to generate large numbers of PC skin-engrafted mice will enable the testing of novel pharmacological or gene-based therapies for this as yet untreatable disease. PMID:21150925

García, Marta; Larcher, Fernando; Hickerson, Robyn P; Baselga, Eulalia; Leachman, Sancy A; Kaspar, Roger L; Del Rio, Marcela

2010-12-09

256

Osmotic and physiological responses of mouse zygotes and human oocytes to mono- and disaccharides.  

PubMed

To survive cryopreservation, oocytes, zygotes and embryos must tolerate a sequence of volumetric contractions and expansions. These result as an egg or an embryo is exposed to a permeating cryoprotective additive, then to an increase followed by a decrease in the osmolality of its extracellular milieu as water freezes during cooling and then melts during warming, and finally to the dilution of the cryoprotective additive solution. Measurements of the extent to which mouse zygotes and human oocytes undergo osmotic contraction have been made by exposing them to solutions of monosaccharides (fructose, galactose, glucose) or disaccharides (maltose, sucrose, trehalose), ranging in concentration from 0.25 to 1.50 M. Mouse zygotes and human oocytes exhibit very similar responses to these solutions. Their volumes contract linearly as a function of 1/(osmolality) of the solutions, yielding estimates of non-osmotic volumes of 13-23%. Mouse zygotes exposed to 1.5 M concentrations of these solutions for 10 min lose 85% of their cell water. Yet > 75% of treated zygotes develop into hatching blastocysts. Human oocytes also appear to survive such extreme dehydration, based on a vital dye assay. These results suggest that solutions of various non-permeating saccharides can serve as osmotic buffers for the recovery of cryopreserved oocytes, zygotes and embryos. PMID:7657759

McWilliams, R B; Gibbons, W E; Leibo, S P

1995-05-01

257

New cell lines from mouse epiblast share defining features with human embryonic stem cells.  

PubMed

The application of human embryonic stem (ES) cells in medicine and biology has an inherent reliance on understanding the starting cell population. Human ES cells differ from mouse ES cells and the specific embryonic origin of both cell types is unclear. Previous work suggested that mouse ES cells could only be obtained from the embryo before implantation in the uterus. Here we show that cell lines can be derived from the epiblast, a tissue of the post-implantation embryo that generates the embryo proper. These cells, which we refer to as EpiSCs (post-implantation epiblast-derived stem cells), express transcription factors known to regulate pluripotency, maintain their genomic integrity, and robustly differentiate into the major somatic cell types as well as primordial germ cells. The EpiSC lines are distinct from mouse ES cells in their epigenetic state and the signals controlling their differentiation. Furthermore, EpiSC and human ES cells share patterns of gene expression and signalling responses that normally function in the epiblast. These results show that epiblast cells can be maintained as stable cell lines and interrogated to understand how pluripotent cells generate distinct fates during early development. PMID:17597760

Tesar, Paul J; Chenoweth, Josh G; Brook, Frances A; Davies, Timothy J; Evans, Edward P; Mack, David L; Gardner, Richard L; McKay, Ronald D G

2007-06-27

258

Organization of human and mouse skeletal myosin heavy chain gene clusters is highly conserved  

PubMed Central

Myosin heavy chains (MyHCs) are highly conserved ubiquitous actin-based motor proteins that drive a wide range of motile processes in eukaryotic cells. MyHC isoforms expressed in skeletal muscles are encoded by a multigene family that is clustered on syntenic regions of human and mouse chromosomes 17 and 11, respectively. In an effort to gain a better understanding of the genomic organization of the skeletal MyHC genes and its effects on the regulation, function, and molecular genetics of this multigene family, we have constructed high-resolution physical maps of both human and mouse loci using PCR-based marker content mapping of P1-artificial chromosome clones. Genes encoding six MyHC isoforms have been mapped with respect to their linear order and transcriptional orientations within a 350-kb region in both human and mouse. These maps reveal that the order, transcriptional orientation, and relative intergenic distances of these genes are remarkably conserved between these species. Unlike many clustered gene families, this order does not reflect the known temporal expression patterns of these genes. However, the conservation of gene organization since the estimated divergence of these species (?75–110 million years ago) suggests that the physical organization of these genes may be significant for their regulation and function.

Weiss, Allison; McDonough, Debra; Wertman, Brett; Acakpo-Satchivi, Leslie; Montgomery, Kate; Kucherlapati, Raju; Leinwand, Leslie; Krauter, Kenneth

1999-01-01

259

The mouse and human Ah receptor differ in recognition of LXXLL motifs  

PubMed Central

The aryl hydrocarbon receptor (AhR) is a ligand inducible transcription factor that exhibits interspecies differences, with the human and mouse AhR C-terminal transactivation domain sharing only 58% amino acid sequence identity. The AhR has a transactivation domain comprised of proline/serine/threonine-rich, glutamine-rich and acidic amino acid subdomains. A truncated mAhR and hAhR containing only the acidic subdomain displayed widely differing transactivation potentials. Whether the glutamine-rich subdomain of the mouse AhR and the human AhR differentially recruit LXXLL-motif coactivators was investigated. Transiently expressed GAL4 DNA binding domain (GAL4DBD)-LXXLL-motif fusion proteins were used to map the critical LXXLL binding sequence of the hAhR to amino acid residues 663-688. Several LXXLL-motif GAL4DBD fusion proteins dramatically differed in their ability to influence the transactivation potential of the mAhR and hAhR. These findings suggest that the human and mouse AhR may display differential recruitment of coactivators and hence may exhibit divergent regulation of target genes.

Flaveny, Colin; Reen, Rashmeet K.; Kusnadi, Ann; Perdew, Gary H.

2008-01-01

260

Comparative hepatotoxicity of deoxynivalenol in rat, mouse and human liver cells in culture.  

PubMed

The present study was undertaken to assess, in vitro, the hepatotoxic potential of the food-borne mycotoxin, deoxynivalenol (DON), using rat (Clone9 and MH1C1), mouse (NBL CL2) and human (WRL68 and HepG2) liver cells in culture. The cells were treated with DON for 24 h at 37 degrees C in 5% CO(2) at concentrations of 0-25 microg ml(-1). Following the treatment period, the cells were assayed for biochemical markers of hepatotoxicity that included three independent cytotoxicity assays, oxidative stress and mitochondrial dysfunction. Concentration-dependent cytotoxicity of DON was observed in each of the five different liver cells derived from three different species (rat, mouse and human) over the entire concentration range studied, beginning at 0.1 microg ml(-1). At these concentrations DON did not induce a biologically significant increase in oxidative stress in these liver cells, and showed a significant decrease in the mitochondrial function only in the rat liver MH1C1 cells compared with the control. The results of this in vitro study suggest that DON is a potential hepatotoxin for the rat, mouse and human liver cells in the concentration range tested in this study. The liver cells used in this study showed distinct endpoint-sensitivity to DON related to the species. PMID:20809545

Sahu, Saura C; O'Donnell, Michael W; Wiesenfeld, Paddy L

2010-08-01

261

Development of a high sensitivity, nested Q-PCR assay for mouse and human aromatase  

PubMed Central

Measurement of breast tissue estradiol levels could provide a powerful method to predict the risk of developing breast cancer but obtaining sufficient amounts of tissue from women is difficult from a practical standpoint. Assessment of aromatase in ductal lavage fluid or fine needle aspirates from breast might provide a surrogate marker for tissue estrogen levels but highly sensitive methods would be required. These considerations prompted us to develop an ultra-sensitive, “nested” PCR assay for aromatase which is up to one million fold more sensitive than standard PCR methods. We initially validated this assay using multiple tissues from the aromatase transgenic mouse and found that coefficients of variation for measurement of replicate samples averaged less than 5%. We demonstrated a 60-fold enhancement in aromatase message in the transgenic versus the wild type mouse breast but surprisingly, levels in the transgenic animals were highly variable, ranging from 0.4 to 27 relative units. The variability of aromatase expression in the transgenic breast did not correlate with the degree of breast development and did not appear to relate to hormonal manipulation of the MMTV promoter but probably related to lack of exhaustive inbreeding and mixed zygocity of transgenic animals. Extensive validation in mouse tissues provided confidence regarding the assay in human tissues, since nearly identical methods were used. The human assay was sufficiently sensitive to detect aromatase in a single human JAR (choriocarcinoma) cell, in all breast biopsies measured, and in 7/23 ductal lavage fluids.

Liu, Giujian; Wu, Yu-sheen; Brenin, David; Yue, Wei; Aiyar, Sarah; Gompel, Anne; Wang, Ji-Ping; Tekmal, Rajeshwar Rao; Santen, Richard J.

2008-01-01

262

Computational analysis of full-length mouse cDNAs compared with human genome sequences.  

PubMed

Although the sequencing of the human genome is complete, identification of encoded genes and determination of their structures remain a major challenge. In this report, we introduce a method that effectively uses full-length mouse cDNAs to complement efforts in carrying out these difficult tasks. A total of 61,227 RIKEN mouse cDNAs (21,076 full-length and 40,151 EST sequences containing certain redundancies) were aligned with the draft human sequences. We found 35,141 non-redundant genomic regions that showed a significant alignment with the mouse cDNAs. We analyzed the structures and compositional properties of the regions detected by the full-length cDNAs, including cross-species comparisons, and noted a systematic bias of GENSCAN against exons of small size and/or low GC-content. Of the cDNAs locating the 35,141 genomic regions, 3,217 did not match any sequences of the known human genes or ESTs. Among those 3,217 cDNAs, 1,141 did not show any significant similarity to any protein sequence in the GenBank non-redundant protein database and thus are candidates for novel genes. PMID:11641714

Kondo, S; Shinagawa, A; Saito, T; Kiyosawa, H; Yamanaka, I; Aizawa, K; Fukuda, S; Hara, A; Itoh, M; Kawai, J; Shibata, K; Hayashizaki, Y

2001-09-01

263

Tissue-Specific Expression of the Gene Encoding a Mouse RNA Binding Protein Homologous to Human HuD Antigen  

Microsoft Academic Search

Abstract We have cloned and sequenced cDNAs encoding amouse ,RNA-binding protein that is homologous to human,HuD antigen. The amino acid sequence deduced from the nucleotide sequence has revealed that the mouse Hu is identical to the human ,counterpart except for two amino-acid substitutions outside the three RNA recognition motifs (RRMs) and,a difference in theN-terminus. The mouse ,HuD gene produces two

Ryoichi Abe; Yutaka Uyeno; Koichi Yamamoto; Hiroshi Sakamoto

1994-01-01

264

Mapping of the NEP receptor tyrosine kinase gene to human chromosome 6p21.3 and mouse chromosome 17C  

SciTech Connect

The mouse receptor tyrosine kinase (RTK) NEP, also called Ptk-3, is widely expressed, with high levels in proliferating neuroepithelia of mouse embryos. The recently described human discoidin domain receptor (DDR) has a predicted amino acid sequence 93% identical to that of murine NEP and may be its human homologue. We have mapped the gene encoding NEP in human and mouse by fluorescence in situ hybridization using a mouse cDNA probe. The NEP/Nep gene maps to human chromosome 6p21.3 and mouse chromosome 17C, respectively. This places the NEP/Nep gene at, or near, the major histocompatibility (MHC) locus-HLA in human and H2 in mouse, respectively. Based on its pattern of expression during development, NEP and Nep represent candidate genes for several MHC-linked developmental abnormalities in human and mouse. 19 refs., 1 fig.

Edelhoff, S.; Disteche, C.M.; Sweetser, D.A. [Univ. of Washington, Seattle, WA (United States)

1995-01-01

265

Physiology of SLC12 transporters: lessons from inherited human genetic mutations and genetically engineered mouse knockouts.  

PubMed

Among the over 300 members of the solute carrier (SLC) group of integral plasma membrane transport proteins are the nine electroneutral cation-chloride cotransporters belonging to the SLC12 gene family. Seven of these transporters have been functionally described as coupling the electrically silent movement of chloride with sodium and/or potassium. Although in silico analysis has identified two additional SLC12 family members, no physiological role has been ascribed to the proteins encoded by either the SLC12A8 or the SLC12A9 genes. Evolutionary conservation of this gene family from protists to humans confirms their importance. A wealth of physiological, immunohistochemical, and biochemical studies have revealed a great deal of information regarding the importance of this gene family to human health and disease. The sequencing of the human genome has provided investigators with the capability to link several human diseases with mutations in the genes encoding these plasma membrane proteins. The availability of bacterial artificial chromosomes, recombination engineering techniques, and the mouse genome sequence has simplified the creation of targeting constructs to manipulate the expression/function of these cation-chloride cotransporters in the mouse in an attempt to recapitulate some of these human pathologies. This review will summarize the three human disorders that have been linked to the mutation/dysfunction of the Na-Cl, Na-K-2Cl, and K-Cl cotransporters (i.e., Bartter's, Gitleman's, and Andermann's syndromes), examine some additional pathologies arising from genetically modified mouse models of these cotransporters including deafness, blood pressure, hyperexcitability, and epithelial transport deficit phenotypes. PMID:23325410

Gagnon, Kenneth B; Delpire, Eric

2013-01-16

266

Species differences in tissue distribution and enzyme activities of arylacetamide deacetylase in human, rat, and mouse.  

PubMed

Human arylacetamide deacetylase (AADAC) is a major esterase responsible for the hydrolysis of clinical drugs such as flutamide, phenacetin, and rifampicin. Thus, AADAC is considered to be a relevant enzyme in preclinical drug development, but there is little information about species differences with AADAC. This study investigated the species differences in the tissue distribution and enzyme activities of AADAC. In human, AADAC mRNA was highly expressed in liver and the gastrointestinal tract, followed by bladder. In rat and mouse, AADAC mRNA was expressed in liver at the highest level, followed by the gastrointestinal tract and kidney. The expression levels in rat tissues were approximately 7- and 10-fold lower than those in human and mouse tissues, respectively. To compare the catalytic efficiency of AADAC among three species, each recombinant AADAC was constructed, and enzyme activities were evaluated by normalizing with the expression levels of AADAC. Flutamide and phenacetin hydrolase activities were detected by the recombinant AADAC of all species. In flutamide hydrolysis, liver microsomes of all species showed similar catalytic efficiencies, despite the lower AADAC mRNA expression in rat liver. In phenacetin hydrolysis, rat liver microsomes showed approximately 4- to 6.5-fold lower activity than human and mouse liver microsomes. High rifampicin hydrolase activity was detected only by recombinant human AADAC and human liver and jejunum microsomes. Taken together, the results of this study clarified the species differences in the tissue distribution and enzyme activities of AADAC and facilitate our understanding of species differences in drug hydrolysis. PMID:22207054

Kobayashi, Yuki; Fukami, Tatsuki; Nakajima, Akinori; Watanabe, Akinobu; Nakajima, Miki; Yokoi, Tsuyoshi

2011-12-29

267

Altered fear learning across development in both mouse and human  

PubMed Central

The only evidence-based behavioral treatment for anxiety and stress-related disorders involves desensitization techniques that rely on principles of extinction learning. However, 40% of patients do not respond to this treatment. Efforts have focused on individual differences in treatment response, but have not examined when, during development, such treatments may be most effective. We examined fear-extinction learning across development in mice and humans. Parallel behavioral studies revealed attenuated extinction learning during adolescence. Probing neural circuitry in mice revealed altered synaptic plasticity of prefrontal cortical regions implicated in suppression of fear responses across development. The results suggest a lack of synaptic plasticity in the prefrontal regions, during adolescence, is associated with blunted regulation of fear extinction. These findings provide insight into optimizing treatment outcomes for when, during development, exposure therapies may be most effective.

Pattwell, Siobhan S.; Duhoux, Stephanie; Hartley, Catherine A.; Johnson, David C.; Jing, Deqiang; Elliott, Mark D.; Ruberry, Erika J.; Powers, Alisa; Mehta, Natasha; Yang, Rui R.; Soliman, Fatima; Glatt, Charles E.; Casey, B. J.; Ninan, Ipe; Lee, Francis S.

2012-01-01

268

Production of a human monoclonal antibody recognising a determinant on mouse IgG2b from a patient receiving mouse monoclonal antibody for diagnostic imaging  

Microsoft Academic Search

Summary The development of human antibodies recognising mouse immunoglobulins represents an obstacle to effective antibody therapy. This study shows that patients produce modest titres of antibodies (predominantly antimouse rather than anti-idiotypic) after a single low-dose injection for immunoscintigraphy, suggesting that repeated imaging with the same or a different antibody could be a problem. Fusion of the lymphocytes from a patient

Lindy G. Durrant; R. Adrian Robins; Kenneth C. Ballantyne; Eric B. Austin; Robert W. Baldwinl

1990-01-01

269

A mouse model of human repetitive mild traumatic brain injury.  

PubMed

A novel method for the study of repetitive mild traumatic brain injury (rmTBI) that models the most common form of head injury in humans is presented. Existing animal models of TBI impart focal, severe damage unlike that seen in repeated and mild concussive injuries, and few are configured for repetitive application. Our model is a modification of the Marmarou weight drop method and allows repeated head impacts to lightly anesthetized mice. A key facet of this method is the delivery of an impact to the cranium of an unrestrained subject allowing rapid acceleration of the free-moving head and torso, an essential characteristic known to be important for concussive injury in humans, and a factor that is missing from existing animal models of TBI. Our method does not require scalp incision, emplacement of protective skull helmets or surgery and the procedure can be completed in 1-2 min. Mice spontaneously recover the righting reflex and show no evidence of seizures, paralysis or impaired behavior. Skull fractures and intracranial bleeding are very rare. Minor deficits in motor coordination and locomotor hyperactivity recover over time. Histological analyses reveal mild astrocytic reactivity (increased expression of GFAP) and increased phospho-tau but a lack of blood-brain-barrier disruption, edema and microglial activation. This new animal model is simple and cost-effective and will facilitate characterization of the neurobiological and behavioral consequences of rmTBI. It is also ideal for high throughput screening of potential new therapies for mild concussive injuries as experienced by athletes and military personnel. PMID:21930157

Kane, Michael J; Angoa-Pérez, Mariana; Briggs, Denise I; Viano, David C; Kreipke, Christian W; Kuhn, Donald M

2011-09-12

270

Screening of maternal sera using a mouse embryo culture assay is not predictive of human embryo development or IVF outcome  

Microsoft Academic Search

Purpose: Maternal serum is commonly added to media used for human IVF but can vary widely in its ability to support the development of human embryos in vitro. The objective of this study was to determine if the screening of maternal serum with a mouse one-cell embryo culture assay would be useful in predicting human embryo development and clinical outcome

Robert N. Clarke; Patricia M. Griffin; John D. Biggers

1995-01-01

271

Cloning of the cDNA and gene encoding mouse lysosomal sialidase and correction of sialidase deficiency in human sialidosis and mouse SM\\/J fibroblasts  

Microsoft Academic Search

Lysosomal sialidase occurs in a multienzyme complex that also contains ?-galactosidase and cathepsin A. We previously cloned the human lysosomal sialidase cDNA and characterized mutations in human sialidosis pa- tients. Here, we report the cloning and expression of the mouse lysosomal sialidase cDNA and gene. The 1.77 kb cDNA encodes an open reading frame of 408 amino acids which shows

Suleiman A. Igdoura; Christopher Gafuik; Carmen Mertineit; Farzad Saberi; Alex V. Pshezhetsky; Michel Potier; Jacquetta M. Trasler; Roy A. Gravel

1998-01-01

272

Characterization of neutralizing mouse-human chimeric and shuffling antibodies against botulinum neurotoxin A.  

PubMed

Mouse-human chimeric monoclonal antibodies that could neutralize botulinum neurotoxins were developed and an attempt was made to establish mouse hybridoma cell clones that produced monoclonal antibodies that neutralized botulinum neurotoxin serotype A (BoNT/A). Four clones (2-4, 2-5, 9-4 and B1) were selected for chimerization on the basis of their neutralizing activity against BoNT/A and the cDNA of the variable regions of their heavy (V(H)) and light chains (V(L)) were fused with the upstream regions of the constant counterparts of human kappa light and gamma 1 heavy chain genes, respectively. CHO-DG44 cells were transfected with these plasmids and mouse-human chimeric antibodies (AC24, AC25, AC94 and ACB1) purified to examine their binding and neutralizing activities. Each chimeric antibody exhibited almost the same capability as each parent mouse mAb to bind and neutralize activities against BoNT/A. From the chimeric antibodies against BoNT/A, shuffling chimeric antibodies designed with replacement of their V(H) or V(L) domains were constructed. A shuffling antibody (AC2494) that derived its V(H) and V(L) domains from chimeric antibodies AC24 and AC94, respectively, showed much higher neutralizing activity than did other shuffling antibodies and parent counterparts. This result indicates that it is possible to build high-potency neutralizing chimeric antibodies by selecting and shuffling V(H) and V(L) domains from a variety of repertoires. A shuffling chimeric antibody might be the best candidate for replacing horse antitoxin for inducing passive immunotherapy against botulism. PMID:22938032

Mukamoto, Masafumi; Maeda, Hiroaki; Kohda, Tomoko; Nozaki, Chikateru; Takahashi, Motohide; Kozaki, Shunji

2012-11-01

273

Conserved CTCF insulator elements flank the mouse and human beta-globin loci.  

PubMed

A binding site for the transcription factor CTCF is responsible for enhancer-blocking activity in a variety of vertebrate insulators, including the insulators at the 5' and 3' chromatin boundaries of the chicken beta-globin locus. To date, no functional domain boundaries have been defined at mammalian beta-globin loci, which are embedded within arrays of functional olfactory receptor genes. In an attempt to define boundary elements that could separate these gene clusters, CTCF-binding sites were searched for at the most distal DNase I-hypersensitive sites (HSs) of the mouse and human beta-globin loci. Conserved CTCF sites were found at 5'HS5 and 3'HS1 of both loci. All of these sites could bind to CTCF in vitro. The sites also functioned as insulators in enhancer-blocking assays at levels correlating with CTCF-binding affinity, although enhancer-blocking activity was weak with the mouse 5'HS5 site. These results show that with respect to enhancer-blocking elements, the architecture of the mouse and human beta-globin loci is similar to that found previously for the chicken beta-globin locus. Unlike the chicken locus, the mouse and human beta-globin loci do not have nearby transitions in chromatin structure but the data suggest that 3'HS1 and 5'HS5 may function as insulators that prevent inappropriate interactions between beta-globin regulatory elements and those of neighboring domains or subdomains, many of which possess strong enhancers. PMID:11997516

Farrell, Catherine M; West, Adam G; Felsenfeld, Gary

2002-06-01

274

Making sense of imprinting the mouse and human IGF2R loci.  

PubMed

The mouse and human IGF2R genes are similar in terms of expression pattern, gene structure and organization. Both genes have features that are common to imprinted genes. These common features are allele-specific methylation and replication asynchrony, plus the ability to restrict expression to one parental allele in diploid cells despite the presence of two functional parental alleles. In inbred laboratory mice Igf2r is initially expressed from both parental chromosomes in preimplantation embryos, it then shows maternal-specific monoallelic expression in all tissues of the postimplantation embryo and adult. The human gene is similarly monoallelically expressed in preterm postimplantation embryonic tissues (preimplantation embryos have not been examined). The behaviour of the human gene then diverges from that observed in inbred mice because it shows biallelic expression in term embryonic tissues and in the adult. An extra difference displayed by the human gene is that monoallelic expression is polymorphic and only occurs in 50% of individuals. The mechanism of IGF2R imprinting will be discussed with relevance to these similarities and differences between the mouse and human genes. PMID:9601022

Wutz, A; Smrzka, O W; Barlow, D P

1998-01-01

275

DRD4 genotype predicts longevity in mouse and human.  

PubMed

Longevity is influenced by genetic and environmental factors. The brain's dopamine system may be particularly relevant, since it modulates traits (e.g., sensitivity to reward, incentive motivation, sustained effort) that impact behavioral responses to the environment. In particular, the dopamine D4 receptor (DRD4) has been shown to moderate the impact of environments on behavior and health. We tested the hypothesis that the DRD4 gene influences longevity and that its impact is mediated through environmental effects. Surviving participants of a 30-year-old population-based health survey (N = 310; age range, 90-109 years; the 90+ Study) were genotyped/resequenced at the DRD4 gene and compared with a European ancestry-matched younger population (N = 2902; age range, 7-45 years). We found that the oldest-old population had a 66% increase in individuals carrying the DRD4 7R allele relative to the younger sample (p = 3.5 × 10(-9)), and that this genotype was strongly correlated with increased levels of physical activity. Consistent with these results, DRD4 knock-out mice, when compared with wild-type and heterozygous mice, displayed a 7-9.7% decrease in lifespan, reduced spontaneous locomotor activity, and no lifespan increase when reared in an enriched environment. These results support the hypothesis that DRD4 gene variants contribute to longevity in humans and in mice, and suggest that this effect is mediated by shaping behavioral responses to the environment. PMID:23283341

Grady, Deborah L; Thanos, Panayotis K; Corrada, Maria M; Barnett, Jeffrey C; Ciobanu, Valentina; Shustarovich, Diana; Napoli, Anthony; Moyzis, Alexandra G; Grandy, David; Rubinstein, Marcelo; Wang, Gene-Jack; Kawas, Claudia H; Chen, Chuansheng; Dong, Qi; Wang, Eric; Volkow, Nora D; Moyzis, Robert K

2013-01-01

276

Human homologue of a gene mutated in the slow Wallerian degeneration (C57BL/Wld(s)) mouse.  

PubMed

The slow Wallerian degeneration mouse (C57BL/Wld(s)) is a mutant strain of mouse, with the unique phenotype of prolonged survival of the distal axon following axotomy. The causative mutation is an 85 kb tandem triplication on distal mouse chromosome 4. The dominant slow Wallerian degeneration phenotype is conferred by a hybrid gene within the triplication, comprising a gene of previously unknown function, D4Cole1e, and the 5' end of ubiquitination factor E4B (Ube4b). It encodes an in-frame fusion protein consisting of the N-terminal 70 amino acids of Ube4b and 303 amino acids derived from the D4Cole1e gene. We have identified the human homologue of D4Cole1e, and mapped it to chromosome 1p36.2. Additional fluorescence in situ hybridisation signals indicate the presence of several homologous human sequences. Northern blot analysis shows two transcripts, widely expressed at varying levels in different human tissues. The human cDNA, which encodes a protein of 279 amino acids, has 80% nucleotide identity with the mouse cDNA. The derived human and mouse protein sequences share 78% amino acid identity and 82% amino acid similarity. The human cDNA and protein sequences are identical to the human nicotinamide mononucleotide adenylyltransferase (NMNAT). We have also determined the intron/exon structure of the gene, which will facilitate the screening of these exons for mutations in human neurodegenerative disorders. PMID:11891043

Fernando, F Shama; Conforti, Laura; Tosi, Sabrina; Smith, A David; Coleman, Michael P

2002-02-01

277

The PanK2 Genes of Mouse and Human Specify Proteins with DistinctSubcellular Locations  

SciTech Connect

Coenzyme A (CoA) biosynthesis is initiated by pantothenatekinase (PanK) and CoA levels are controlled through differentialexpression and feedback regulation of PanK isoforms. PanK2 is amitochondrial protein in humans, but comparative genomics revealed thatacquisition of a mitochondrial targeting signal was limited to primates.Human and mouse PanK2 possessed similar biochemical properties, withinhibition by acetylCoA and activation by palmitoylcarnitine. Mouse PanK2localized in the cytosol, and the expression of PanK2 was higher in humanbrain compared to mouse brain. Differences in expression and subcellularlocalization should be considered in developing a mouse model for humanPanK2 deficiency. (c) 2007 Federation of European Biochemical Societies.Published by Elsevier B.V.

Leonardi, Roberta; Zhang, Yong-Mei; Lydikis, Athanasios; Stevens,Robert D.; Ilkayeva, Olga R.; Wenner, Brett R.; Bain, James R.; Newgard,Christopher B.; Rock, Charles O.; Jackowski, Suzanne

2007-05-01

278

Expression profiling in tuberous sclerosis complex (TSC) knockout mouse astrocytes to characterize human TSC brain pathology.  

PubMed

Individuals with tuberous sclerosis complex (TSC) exhibit a variety of neurologic abnormalities, including mental retardation, epilepsy, and autism. Examination of human TSC brains demonstrate dysplastic astrocytes and neurons, areas of abnormal neuronal migration (tubers), and hamartomatous growths, termed subependymal nodules, which can progress to subependymal giant cell astrocytomas (SEGA). Previous studies have suggested that these neuropathologic features may result from abnormal neuroglial cell differentiation. In an effort to provide support for this hypothesis and to identify specific markers of aberrant neuroglial cell differentiation in TSC, we employed gene expression profiling on Tsc1 conditional knockout (Tsc1(GFAP)CKO) mouse astrocytes. We identified several transcripts implicated in central nervous system development that are differentially expressed in Tsc1(-/-) astrocytes compared to wild-type astrocytes. We validated the differential expression of select transcripts on the protein level both in primary cultures of Tsc1(-/-) astrocytes and in Tsc1(GFAP)CKO mouse brains. Moreover, we show that these markers are also differentially expressed within cortical tubers, but not in adjacent normal tissue from TSC patient brains. This study provides supportive evidence for a developmental defect in neuroglial cell differentiation relevant to the genesis of TSC nervous system pathology and underscores the utility of mouse modeling for understanding the molecular pathogenesis of human disease. PMID:14999811

Ess, Kevin C; Uhlmann, Erik J; Li, Wen; Li, Hongzhen; Declue, Jeffrey E; Crino, Peter B; Gutmann, David H

2004-04-01

279

Splicing-directed therapy in a new mouse model of human accelerated aging.  

PubMed

Hutchinson-Gilford progeria syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates a cryptic donor splice site and yields a truncated form of prelamin A called progerin. Small amounts of progerin are also produced during normal aging. Studies with mouse models of HGPS have allowed the recent development of the first therapeutic approaches for this disease. However, none of these earlier works have addressed the aberrant and pathogenic LMNA splicing observed in HGPS patients because of the lack of an appropriate mouse model. Here, we report a genetically modified mouse strain that carries the HGPS mutation. These mice accumulate progerin, present histological and transcriptional alterations characteristic of progeroid models, and phenocopy the main clinical manifestations of human HGPS, including shortened life span and bone and cardiovascular aberrations. Using this animal model, we have developed an antisense morpholino-based therapy that prevents the pathogenic Lmna splicing, markedly reducing the accumulation of progerin and its associated nuclear defects. Treatment of mutant mice with these morpholinos led to a marked amelioration of their progeroid phenotype and substantially extended their life span, supporting the effectiveness of antisense oligonucleotide-based therapies for treating human diseases of accelerated aging. PMID:22030750

Osorio, Fernando G; Navarro, Claire L; Cadiñanos, Juan; López-Mejía, Isabel C; Quirós, Pedro M; Bartoli, Catherine; Rivera, José; Tazi, Jamal; Guzmán, Gabriela; Varela, Ignacio; Depetris, Danielle; de Carlos, Félix; Cobo, Juan; Andrés, Vicente; De Sandre-Giovannoli, Annachiara; Freije, José M P; Lévy, Nicolas; López-Otín, Carlos

2011-10-26

280

Rat Genome Database: a unique resource for rat, human, and mouse quantitative trait locus data.  

PubMed

The rat has been widely used as a disease model in a laboratory setting, resulting in an abundance of genetic and phenotype data from a wide variety of studies. These data can be found at the Rat Genome Database (RGD, http://rgd.mcw.edu/), which provides a platform for researchers interested in linking genomic variations to phenotypes. Quantitative trait loci (QTLs) form one of the earliest and core datasets, allowing researchers to identify loci harboring genes associated with disease. These QTLs are not only important for those using the rat to identify genes and regions associated with disease, but also for cross-organism analyses of syntenic regions on the mouse and the human genomes to identify potential regions for study in these organisms. Currently, RGD has data on >1,900 rat QTLs that include details about the methods and animals used to determine the respective QTL along with the genomic positions and markers that define the region. RGD also curates human QTLs (>1,900) and houses>4,000 mouse QTLs (imported from Mouse Genome Informatics). Multiple ontologies are used to standardize traits, phenotypes, diseases, and experimental methods to facilitate queries, analyses, and cross-organism comparisons. QTLs are visualized in tools such as GBrowse and GViewer, with additional tools for analysis of gene sets within QTL regions. The QTL data at RGD provide valuable information for the study of mapped phenotypes and identification of candidate genes for disease associations. PMID:23881287

Nigam, Rajni; Laulederkind, Stanley J F; Hayman, G Thomas; Smith, Jennifer R; Wang, Shur-Jen; Lowry, Timothy F; Petri, Victoria; De Pons, Jeff; Tutaj, Marek; Liu, Weisong; Jayaraman, Pushkala; Munzenmaier, Diane H; Worthey, Elizabeth A; Dwinell, Melinda R; Shimoyama, Mary; Jacob, Howard J

2013-07-23

281

Human nerve xenografting in nude mouse: Experimental study of graft revascularization  

SciTech Connect

In the nude mouse, the congenital absence of T lymphocytes makes it possible to implant human nerve grafts without rejection or iatrogenic modifications (by immunosuppression) of human and murine tissues. Medial antebrachial cutaneous nerves were harvested from human cadavers 1-18 hours after death. These nerve grafts were implanted using different techniques in nude mice. All the grafts were macroscopically and microscopically revascularized 3 days after implantation. The modifications in time of this vascularization could be studied with precision through the use of repeated biopsies. The absence of human blood group antigens on the neovessel endothelium suggested a murine origin for angiogenesis. In situ DNA hybridizations with human and mouse DNA confirmed this origin. The topography of the revascularization (maximal in the perineurium and endoneurium) and the almost complete absence of human cells other than Schwann cells in the grafts at the peak of angiogenesis (26 days after grafting) suggested that Schwann cells had a determining role in graft vascularization. The irradiation of the nerve grafts with a dose of 30 grays before implantation did not modify significantly their histologic appearance compared to the control group, whereas an irradiation of 60 grays led to massive lesions. The neurotization of murine axons led to chimerical structures of normal histologic appearance, with vascularization similar to that observed in nonneurotized nerves. Through chimerism (human Schwann cells, murine vessels and axons) this model makes it possible to dissociate the respective role of the host and of the nerve graft in angiogenesis and suggests the existence of growth factors produced by the human Schwann cells.

Duprez, K.; Bour, C.; Merle, M.; Duprez, A. (Hopital Jeanne d'Arc, Dommartin-les-Toul (France))

1991-01-01

282

Apoptosis-associated microRNAs are modulated in mouse, rat and human neural differentiation  

PubMed Central

Background MicroRNAs (miRs or miRNAs) regulate several biological processes in the cell. However, evidence for miRNAs that control the differentiation program of specific neural cell types has been elusive. Recently, we have shown that apoptosis-associated factors, such as p53 and caspases participate in the differentiation process of mouse neural stem (NS) cells. To identify apoptosis-associated miRNAs that might play a role in neuronal development, we performed global miRNA expression profiling experiments in NS cells. Next, we characterized the expression of proapoptotic miRNAs, including miR-16, let-7a and miR-34a in distinct models of neural differentiation, including mouse embryonic stem cells, PC12 and NT2N cells. In addition, the expression of antiapoptotic miR-19a and 20a was also evaluated. Results The expression of miR-16, let-7a and miR-34a was consistently upregulated in neural differentiation models. In contrast, expression of miR-19a and miR-20a was downregulated in mouse NS cell differentiation. Importantly, differential expression of specific apoptosis-related miRNAs was not associated with increased cell death. Overexpression of miR-34a increased the proportion of postmitotic neurons of mouse NS cells. Conclusions In conclusion, the identification of miR-16, let-7a and miR-34a, whose expression patterns are conserved in mouse, rat and human neural differentiation, implicates these specific miRNAs in mammalian neuronal development. The results provide new insights into the regulation of neuronal differentiation by apoptosis-associated miRNAs.

2010-01-01

283

Combined transcriptome analysis of fetal human and mouse cerebral cortex exposed to alcohol.  

PubMed

Fetal exposure to environmental insults increases the susceptibility to late-onset neuropsychiatric disorders. Alcohol is listed as one of such prenatal environmental risk factors and known to exert devastating teratogenetic effects on the developing brain, leading to complex neurological and psychiatric symptoms observed in fetal alcohol spectrum disorder (FASD). Here, we performed a coordinated transcriptome analysis of human and mouse fetal cerebral cortices exposed to ethanol in vitro and in vivo, respectively. Up- and down-regulated genes conserved in the human and mouse models and the biological annotation of their expression profiles included many genes/terms related to neural development, such as cell proliferation, neuronal migration and differentiation, providing a reliable connection between the two species. Our data indicate that use of the combined rodent and human model systems provides an effective strategy to reveal and analyze gene expression changes inflicted by various physical and chemical environmental exposures during prenatal development. It also can potentially provide insight into the pathogenesis of environmentally caused brain disorders in humans. PMID:21368140

Hashimoto-Torii, Kazue; Kawasawa, Yuka Imamura; Kuhn, Alexandre; Rakic, Pasko

2011-02-22

284

Mullerian Inhibiting Substance enhances subclinical doses of chemotherapeutic agents to inhibit human and mouse ovarian cancer.  

PubMed

Mullerian Inhibiting Substance (MIS), a biological modifier that causes regression of Mullerian ducts in male embryos, is effective as a single agent in vitro and in vivo against human and mouse ovarian cancer cell lines expressing MIS type II receptor; however, little is known about how recombinant human MIS (rhMIS), now being scaled for preclinical trials, could be used in combination with cytotoxic or targeted chemotherapeutic agents. Mouse serous and endometrioid ovarian carcinoma cell lines were tested in vitro against rhMIS alone and with doxorubicin, paclitaxel, or cisplatin as agents in clinical use. Because MIS releases FK506 binding protein (FKBP12), which activates the mammalian target of rapamycin (mTOR) downstream of Akt, rhMIS and rapamycin combinations were tested. MIS increases p16 protein levels, and 5'-Aza-2'-deoxycytidine (AzadC) induces p16 mRNA; therefore, they were used in combination in vitro and in vivo with a human ovarian cancer cell line. A paclitaxel-resistant human ovarian cancer cell line and its parental line both respond to rhMIS in vitro. Additivity, synergy, or competition was observed with MIS and rapamycin, AzadC, doxorubicin, cisplatin, and paclitaxel, suggesting that MIS in combination with selective targeted therapies might achieve greater activity against ovarian cancer than the use of each individual agent alone. These assays and statistical analyses could be useful in selecting rhMIS and chemotherapeutic agent combinations that enhance clinical efficacy and reduce toxicity. PMID:17088539

Pieretti-Vanmarcke, Rafael; Donahoe, Patricia K; Pearsall, Lisa A; Dinulescu, Daniela M; Connolly, Denise C; Halpern, Elkan F; Seiden, Michael V; MacLaughlin, David T

2006-11-06

285

Comparative characterization of the human and mouse third ventricle germinal zones.  

PubMed

Recent evidence indicates differences in neural stem cell biology in different brain regions. For example, we demonstrated that neurofibromatosis 1 (NF1) tumor suppressor gene inactivation leads to increased neural stem cell proliferation and gliogenesis in the optic chiasm and brainstem but not in the cerebral cortex. The differential effect of Nf1 inactivation in the optic nerve and brainstem (in which gliomas commonly form in children with NF1) versus the cortex (in which gliomas rarely develop) suggests the existence of distinct ventricular zones for gliomagenesis in children and in adults. Here, we characterized the third ventricle subventricular zone (tv-SVZ) in young and adult mouse and human brains. In children, but not adult humans, the tv-SVZ contains nestin-positive, glial fibrillary acidic protein-positive, brain fatty acid binding protein-positive, and sox2-positive cells with radial processes and prominent cilia. In contrast, the tv-SVZ in young mice contains sox2-positive progenitor cells and ciliated ependymal lining cells but lacks glial fibrillary acidic protein-positive, nestin-positive radial glia. As in the lateral ventricle SVZ, proliferation in the human and murine tv-SVZ decreases with age. The tv-SVZ in adult mice lacks the hypocellular subventricular zone observed in adult human specimens. Collectively, these data indicate the existence of a subventricular zone relevant to our understanding of glioma formation in children and will assist interpretation of genetically engineered mouse glioma models. PMID:21666496

Dahiya, Sonika; Lee, Da Yong; Gutmann, David H

2011-07-01

286

Retroviral-mediated gene transfer and expression of human phenylalanine hydroxylase in primary mouse hepatocytes  

SciTech Connect

Genetic therapy for phenylketonuria (severe phenylalanine hydroxylase deficiency) may require introduction of a normal phenylalanine hydroxylase gene into hepatic cells of patients. The authors report development of a recombinant retrovirus based on the N2 vector for gene transfer and expression of human phenylalanine hydroxylase cDNA in primary mouse hepatocytes. This construct contains an internal promoter of the human {alpha}{sub 1}-antitrypsin gene driving transcription of the phenylalanine hydroxylase cDNA. Primary mouse hepatocytes were isolated from newborn mice, infected with the recombinant virus, and selected for expression of the neomycin-resistance gene. Hepatocytes transformed with the recombinant virus contained high levels of human phenylalanine hydroxylase mRNA transcripts originating from the retroviral and internal promoters. These results demonstrate that the transcriptional regulatory elements of the {alpha}{sub 1} antitrypsin gene retain their tissue-specific function in the recombinant provirus and establish a method for efficient transfer and high-level expression of human phenylalanine hydroxylase in primary hepatocytes.

Peng, H.; Armentano, D.; Mackenzie-Graham, L.; Shen, R.F.; Darlington, G.; Ledley, F.D.; Woo, S.L.C. (Baylor College of Medicine, Houston, TX (USA))

1988-11-01

287

Transcription intermediary factor 1? is a tumor suppressor in mouse and human chronic myelomonocytic leukemia  

PubMed Central

Transcription intermediary factor 1? (TIF1?) was suggested to play a role in erythropoiesis. However, how TIF1? regulates the development of different blood cell lineages and whether TIF1? is involved in human hematological malignancies remain to be determined. Here we have shown that TIF1? was a tumor suppressor in mouse and human chronic myelomonocytic leukemia (CMML). Loss of Tif1g in mouse HSCs favored the expansion of the granulo-monocytic progenitor compartment. Furthermore, Tif1g deletion induced the age-dependent appearance of a cell-autonomous myeloproliferative disorder in mice that recapitulated essential characteristics of human CMML. TIF1? was almost undetectable in leukemic cells of 35% of CMML patients. This downregulation was related to the hypermethylation of CpG sequences and specific histone modifications in the gene promoter. A demethylating agent restored the normal epigenetic status of the TIF1G promoter in human cells, which correlated with a reestablishment of TIF1? expression. Together, these results demonstrate that TIF1G is an epigenetically regulated tumor suppressor gene in hematopoietic cells and suggest that changes in TIF1? expression may be a biomarker of response to demethylating agents in CMML.

Aucagne, Romain; Droin, Nathalie; Paggetti, Jerome; Lagrange, Brice; Largeot, Anne; Hammann, Arlette; Bataille, Amandine; Martin, Laurent; Yan, Kai-Ping; Fenaux, Pierre; Losson, Regine; Solary, Eric; Bastie, Jean-Noel; Delva, Laurent

2011-01-01

288

Role of LIN28A in Mouse and Human Trophoblast Cell Differentiation.  

PubMed

Proper regulation of trophoblast proliferation, differentiation, and function are critical for placenta development and function. The RNA-binding protein, LIN28A, has been well characterized as a potent regulator of differentiation in embryonic stem cells; however, little is known about the function of LIN28A in the placenta. We assessed LIN28A in vitro using mouse trophoblast stem (mTS) cells and human trophoblast cells (ACH-3P). We observed that LIN28A decreased and let-7 miRNA increased when mTS cells were induced to differentiate into mouse trophoblast giant cells (mTGCs) upon the removal of FGF4, heparin and conditioned medium. Similarly, we observed that LIN28A decreased in ACH-3P cells induced to syncytialize with forskolin treatment. To assess LIN28A in vivo we examined Embryonic Day 11.5 mouse placenta and observed abundant LIN28A in the chorioallantoic interface and labyrinth layer, with little LIN28A staining in spongiotrophoblast or differentiated mTGCs. Additionally, shRNA-mediated LIN28A knockdown in ACH-3P cells resulted in increased spontaneous syncytialization, and increased levels of syncytiotrophoblast markers hCG, LGALS13, and ERVW-1 mRNA. Additionally, targeted degradation of LIN28A mRNA increased responsiveness to forskolin-induced differentiation. In contrast, targeted degradation of Lin28a mRNA in mTS cells did not alter cell phenotype when maintained under proliferative culture conditions. Together, these data establish that LIN28A has a functional role in regulating trophoblast differentiation and function, and that loss of LIN28A in human trophoblast is sufficient to induce differentiation, but does not induce differentiation in the mouse. PMID:24006280

Seabrook, Jill L; Cantlon, Jeremy D; Cooney, Austin J; McWhorter, Erin E; Fromme, Brittany A; Bouma, Gerrit J; Anthony, Russell V; Winger, Quinton A

2013-10-24

289

The mouse rumpshaker mutation of the proteolipid protein in human X-linked recessive spastic paraplegia  

SciTech Connect

X-linked recessive spastic paraplegia is a rare neurodegenerative disorder characterized by slowly progressive weakness and spasticity of the lower extremities. We have recently genetically analyzed the original X-linked recessive spastic paraplegia family reported by Johnston and McKusick in 1962. We employed a fluorescent multiplex CA repeat strategy using a 22 locus, 10 cM framework map of the human X chromosome and localized the gene within a 36 cM region of Xq2l.3-q24 which includes the PLP locus. Saugier-Veber et al. recently reported a point mutation (His139Tyr) in exon 3B of the PLP gene in an X-linked recessive spastic paraplegia family (SPG2). This family shows no optic atrophy, in contrast to the family we have studied. This data showed that SPG2 and Pelizaeus-Merzbacher disease were allelic disorders. We investigated the PLP gene as a candidate gene for the original X-linked recessive spastic paraplegia family using SSCP and direct sequencing methods. We found a point mutation (T to C) in exon 4 of affected males which alters the amino-acid (Ile to Thr) at residue 186. This change was absent in the unaffected males of the family and in 40 unrelated control females (80 X chromosomes). Surprisingly, this mutation is identical to the mutation previously identified in the rumpshaker mouse model. The complete homology between both the mouse and human PLP sequence, and the mouse rumpshaker mutation and human spastic paraplegia mutation in our family, permit direct parallels to be drawn with regards to pathophysiology. Our data indicates that the well-documented and striking clinical differences between Pelizaeus-Merzbacher disease and X-linked recessive spastic paraplegia is due to the specific effect of different mutations of the human PLP gene on oligodendrocyte differentiation and development and on later myelin production and maintenance.

Kobayashi, H.; Hoffman, E.P.; Matise, T.C. [and others

1994-09-01

290

Cingulate area 32 homologies in mouse, rat, macaque and human: Cytoarchitecture and receptor architecture.  

PubMed

Homologizing between human and nonhuman area 32 has been impaired since Brodmann said he could not homologize with certainty human area 32 to a specific cortical domain in other species. Human area 32 has four divisions, however, and two can be structurally homologized to nonhuman species with cytoarchitecture and receptor architecture: pregenual (p32) and subgenual (s32) in human and macaque monkey and areas d32 and v32 in rat and mouse. Cytoarchitecture showed that areas d32/p32 have a dysgranular layer IV in all species and that areas v32/s32 have large and dense neurons in layer V, whereas a layer IV is not present in area v32. Areas v32/s32 have the largest neurons in layer Va. Features unique to humans include large layer IIIc pyramids in both divisions, sparse layer Vb in area p32, and elongated neurons in layer VI, with area s32 having the largest layer Va neurons. Receptor fingerprints of both subdivisions of area 32 differed between species in size and shape, although AMPA/GABAA and NMDA/GABAA ratios were comparable among humans, monkeys, and rats and were significantly lower than in mice. Layers I-III of primate and rodent area 32 subdivisions share more similarities in their receptor densities than layers IV-VI. Monkey and human subdivisions of area 32 are more similar to each other than to rat and mouse subdivisions. In combination with intracingulate connections, the location, cytoarchitecture, and ligand binding studies demonstrate critical homologies among the four species. J. Comp. Neurol. 521:4189-4204, 2013. © 2013 Wiley Periodicals, Inc. PMID:23840027

Vogt, Brent A; Hof, Patrick R; Zilles, Karl; Vogt, Leslie J; Herold, Christina; Palomero-Gallagher, Nicola

2013-12-15

291

Isoform specificity of human Na+,K+-ATPase localization and aldosterone regulation in mouse kidney cells  

PubMed Central

Short-term aldosterone coordinately regulates the cell-surface expression of luminal epithelial sodium channels (ENaC) and of basolateral Na+ pumps (Na+, K+-ATPase ?1–?1) in aldosterone-sensitive distal nephron (ASDN) cells. To address the question of whether the subcellular localization of the Na+,K+-ATPase and its regulation by aldosterone depend on subunit isoform-specific structures, we expressed the cardiotonic steroid-sensitive human ? isoforms 1–3 by retroviral transduction in mouse collecting duct mpkCCDc14 cells. Each of the three exogenous human isoforms could be detected by Western blotting. Immunofluorescence indicated that the exogenous ?1 subunit to a large extent localizes to the basolateral membrane or close to it, whereas much of the ?2 subunit remains intracellular. An ouabain-sensitive current carried by exogenous pumps could be detected in apically amphotericin B-permeabilized epithelia expressing human ?1 and ?2 subunits, but not the ?3 subunit. This current displayed a higher apparent Na+ affinity in pumps containing human ?2 subunits (10 mm) than in pumps containing human ?1 (33.2 mm) or endogenous (cardiotonic steroid-resistant) mouse ?1 subunits (mean: 16.3 mm). A very low mRNA level of the Na+,K+-ATPase ? subunit (FXYD2) in mpkCCDc14 cells suggested that this ancillary gene product is not responsible for the relatively low apparent Na+ affinity measured for a1 subunit-containing pumps. Aldosterone increased the pump current carried by endogenous pumps and by pumps containing the human ?1 subunit. In contrast, the current carried by pumps with a human ?2 subunit was not stimulated by the same treatment. In summary, quantitative basolateral localization of the Na+,K+-ATPase and its responsiveness to aldosterone require ?1 subunit-specific sequences that differentiate this isoform from the ?2 and ?3 subunit isoforms.

Summa, Vanessa; Camargo, Simone M R; Bauch, Christian; Zecevic, Marija; Verrey, Francois

2004-01-01

292

Interference by human anti-mouse antibodies in CA 125 assay after immunoscintigraphy: Anti-idiotypic antibodies not neutralized by mouse IgG but removed by chromatography  

SciTech Connect

Falsely increased concentrations of the ovarian carcinoma-associated antigen, CA 125, were measured by a monoclonal antibody (MAb)-based double determinant immunoradiometric assay (IRMA) in patients who developed antibodies to mouse immunoglobulins (IgGs) after receiving injections of the same MAb as is used in the CA 125 IRMA. Addition of undiluted mouse serum or purified mouse IgG to the assay mixture failed to eliminate the falsely increased CA 125 concentrations in most of the samples, owing to the presence of anti-idiotype antibody. Because of their anti-idiotypic nature, the human anti-mouse antibodies (HAMAS) had only little effect on other immunometric assays, and this effect could be completely eliminated by addition of mouse IgG. To eliminate the effect of HAMA on the CA 125 assay, we studied the ability of various chromatographic methods to separate the interfering HAMA from CA 125. For measuring HAMA in serum and chromatographic fractions we developed a time-resolved fluoroimmunoassay. Adequate separation of CA 125 and HAMA was achieved by affinity chromatography of patients' sera with solid-phase Protein A, Protein G, cation-exchange chromatography on Mono S, and gel filtration on Superose 6. These results demonstrate that the interference can effectively be removed by rather simple chromatographic procedures.

Turpeinen, U.; Lehtovirta, P.; Alfthan, H.; Stenman, U.H. (Helsinki Univ. Central Hospital (Finland))

1990-07-01

293

High affinity nuclear and nongenomic estradiol binding sites in the human and mouse lens.  

PubMed

Estrogen is reported to be protective against cataracts in women and animal models. Immunodetection methods have identified the classic estrogen receptors (ER), ER? and ER?, in human lens epithelial cells and their RNAs have been detected in the rat and human lens. To verify that estrogen binding occurs in the lens, sensitive [(125)I]-17?-estradiol binding analyses were performed on subcellular lens fractions from women (ages 39-78 years). The presence of high affinity estradiol binding sites in the nuclear, cytoplasmic, and membrane fractions indicate the lens is able to respond to estrogens, even up to age 78, although fewer binding sites were detected in the postmenopausal women. Additionally, due to the importance of mouse models in estrogen action and lens research, lenses from intact female mice were also analyzed. Both the C57BL/6 and FVB/N mouse strains also possessed high affinity binding sites in all three lens fractions. Furthermore, transcripts for ER?, ER?, and G protein-coupled estrogen receptor (GPER; previously called GPR30) that bind estradiol with high affinity were expressed in the human and mouse lenses. These data provide the first evidence of GPER expression in the lens. Its role, functions, and subcellular location are currently unknown, but a G-shift assay in the membrane fractions of human and mouse lenses did not show evidence that estradiol induced classic G protein-coupled receptor activation. All three receptor transcripts were also detected in the lens capsule region isolated from female C57BL/6 mice, which is mainly comprised of epithelial cells. In contrast, only ER? and GPER were expressed in the cortex/nuclear region, which is primarily composed of differentiating and organelle-free fiber cells. No significant differences in specific estradiol binding and receptor RNA expression were observed in the lenses between male and female C57BL/6 mice. These findings indicate that the lens is an estrogen target tissue in both sexes. The identification of GPER, in addition to ER? and ER?, in the lens also adds to the complexity of possible estrogen responses in the lens. Accordingly, the protective effects of estrogen in women and animals may be mediated by all three estrogen receptors in the lens. In addition, the similarities in binding and receptor RNA expression in the lenses of both species suggest that mice can be used to model estrogen action in the human lens. PMID:23597597

Kirker, M Rachel; Gallagher, Katie M; Witt-Enderby, Paula A; Davis, Vicki L

2013-04-15

294

Complementation of defective translesion synthesis and UV light sensitivity in xeroderma pigmentosum variant cells by human and mouse DNA polymerase ?  

PubMed Central

Defects in the human gene XPV result in the variant form of the genetic disease xeroderma pigmentosum (XP-V). XPV encodes DNA polymerase ?, a novel DNA polymerase that belongs to the UmuC/DinB/Rad30 superfamily. This polymerase catalyzes the efficient and accurate translesion synthesis of DNA past cis-syn cyclobutane di-thymine lesions. In this report we present the cDNA sequence and expression profiles of the mouse XPV gene and demonstrate its ability to complement defective DNA synthesis in XP-V cells. The mouse XPV protein shares 80.3% amino acid identity and 86.9% similarity with the human XPV protein. The recombinant mouse XPV protein corrected the inability of XP-V cell extracts to carry out DNA replication, by bypassing thymine dimers on template DNA. Transfection of the mouse or human XPV cDNA into human XP-V cells corrected UV sensitivity. Northern blot analysis revealed that the mouse XPV gene is expressed ubiquitously, but at a higher level in testis, liver, skin and thymus compared to other tissues. Although the mouse XPV gene was not induced by UV irradiation, its expression was elevated ~4-fold during cell proliferation. These results suggest that DNA polymerase ? plays a role in DNA replication, though the enzyme is not essential for viability.

Yamada, Ayumi; Masutani, Chikahide; Iwai, Shigenori; Hanaoka, Fumio

2000-01-01

295

Human vs. Mouse Eosinophils: "That which we call an eosinophil, by any other name would stain as red"  

PubMed Central

The respective life histories of humans and mice are well defined and describe a unique story of evolutionary conservation extending from sequence identity within the genome to the underpinnings of biochemical, cellular, and physiological pathways. As a consequence, the hematopoietic lineages of both species are invariantly maintained, each with identifiable eosinophils. This canonical presence nonetheless does not preclude disparities between human and mouse eosinophils and/or their effector functions. Indeed, many books and reviews dogmatically highlight differences, providing a rationale to discount the use of mouse models of human eosinophilic diseases. We suggest that this perspective is parochial and ignores the wealth of available studies and the consensus of the literature that overwhelming similarities (and not differences) exist between human and mouse eosinophils. The goal of this review is to summarize this literature and in some cases provide the experimental details, comparing and contrasting eosinophils and eosinophil effector functions in humans vs. mice. In particular, our review will provide a summation and an easy to use reference guide to important studies demonstrating that while differences exist, more often than not their consequences are unknown and do not necessarily reflect inherent disparities in eosinophil function, but instead, species-specific variations. The conclusion from this overview is that despite nominal differences, the vast similarities between human and mouse eosinophils provide important insights as to their roles in health and disease and, in turn, demonstrate the unique utility of mouse-based studies with an expectation of valid extrapolation to the understanding and treatment of patients.

Lee, James J.; Jacobsen, Elizabeth A.; Ochkur, Sergei I; McGarry, Michael P.; Condjella, Rachel M.; Doyle, Alfred D.; Luo, Huijun; Zellner, Katie R.; Protheroe, Cheryl A.; Willetts, Lian; LeSuer, William E.; Colbert, Dana C.; Helmers, Richard A.; Lacy, Paige; Moqbel, Redwan; Lee, Nancy A.

2012-01-01

296

Cytotoxic effects of propiconazole and its metabolites in mouse and human hepatoma cells and primary mouse hepatocytes  

EPA Science Inventory

Abstract: Propiconazole is a triazole-containing fungicide that is used agriculturally on grasses, fruits, grains, seeds, hardwoods, and conifers. Propiconazole is a mouse liver hepatotoxicant and a hepatocarcinogen and has adverse reproductive and developmental toxicities in exp...

297

Human Adipose Derived Stromal Cells Heal Critical Size Mouse Calvarial Defects  

PubMed Central

Background Human adipose-derived stromal cells (hASCs) represent a multipotent cell stromal cell type with proven capacity to differentiate along an osteogenic lineage. This suggests that they may be used to heal defects of the craniofacial or appendicular skeleton. We sought to substantiate the use of undifferentiated hASCs in the regeneration of a non-healing mouse skeletal defect. Methodology/Principal Findings Human ASCs were harvested from female lipoaspirate. Critical-sized (4 mm) calvarial defects were created in the parietal bone of adult male nude mice. Defects were either left empty, treated with an apatite coated PLGA scaffold alone, or a scaffold with human ASCs. MicroCT scans were obtained at stratified time points post-injury. Histology, in situ hybridization, and histomorphometry were performed. Near complete healing was observed among hASC engrafted calvarial defects. This was in comparison to control groups that showed little healing (*P<0.01). Human ASCs once engrafted differentiate down an osteogenic lineage, determined by qRT-PCR and histological co-expression assays using GFP labeled cells. ASCs were shown to persist within a defect site for two weeks (shown by sex chromosome analysis and quantified using Luciferase+ ASCs). Finally, rBMP-2 was observed to increase hASC osteogenesis in vitro and osseous healing in vivo. Conclusions/Significance Human ASCs ossify critical sized mouse calvarial defects without the need for pre-differentiation. Recombinant differentiation factors such as BMP-2 may be used to supplement hASC mediated repair. Interestingly, ASC presence gradually dissipates from the calvarial defect site. This study supports the potential translation for ASC use in the treatment of human skeletal defects.

Levi, Benjamin; James, Aaron W.; Nelson, Emily R.; Vistnes, Dean; Wu, Benjamin; Lee, Min; Gupta, Ankur; Longaker, Michael T.

2010-01-01

298

Biochemical and Morphological Consequences of Human ?-Synuclein Expression in a Mouse ?-Synuclein Null Background  

PubMed Central

A consensus about the functions of human wild-type or mutated ?-synuclein (?SYN) is lacking. Both forms of ?SYN are implicated in Parkinson’s disease, whereas the wild-type form is implicated in substance abuse. Interactions with other cellular proteins and organelles may meditate its functions. We developed a series of congenic mouse lines containing various allele doses or combinations of the human wild type ?SYN (hw?SYN) or a doubly mutated (A30P*A53T) ?SYN (hm2?SYN) in a C57Bl/6J line spontaneously deleted in mouse ?SYN (C57BL/6JOla). Both transgenes had a functional role in the nigrostriatal system, demonstrated by significant elevations in striatal catecholamines, metabolites, and the enzyme tyrosine hydroxylase compared to null-mice without a transgene. Consequences occurred when the transgenes were expressed at a fraction of the endogenous level. Hemizygous congenic mice did not exhibit any change in the number or size of dopaminergic neurons in the ventral midbrain at nine months of age. Human ?SYN was predominantly located in neuronal cell bodies, neurites, synapses, and in intraneuronal/intraneuritic aggregates. The hm2?SYN transgene resulted in more aggregates and dystrophic neurites than did the hw5 transgene. The hw?SYN transgene resulted in higher expression of two striatal proteins, synaptogamin 7 and UCHL1, compared to the levels of the hm2?SYN transgene. These observations suggest that mutations in ?SYN may impair specific functional domains, leaving others intact. These lines may also be useful for exploring interactions between h?SYN and environmental or genetic risk factors in dopamine-related disorders using a mouse model.

Prasad, Kavita; Tarasewicz, Elizabeth; Strickland, Pamela A. Ohman; O'Neill, Michael; Mitchell, Stephen N.; Merchant, Kalpana; Tep, Samnang; Hilton, Kathryn; Datwani, Akash; Buttini, Manuel; Mueller-Steiner, Sarah; Richfield, Eric K.

2011-01-01

299

Biochemical and morphological consequences of human ?-synuclein expression in a mouse ?-synuclein null background.  

PubMed

A consensus about the functions of human wild-type or mutated ?-synuclein (?SYN) is lacking. Both forms of ?SYN are implicated in Parkinson's disease, whereas the wild-type form is implicated in substance abuse. Interactions with other cellular proteins and organelles may meditate its functions. We developed a series of congenic mouse lines containing various allele doses or combinations of the human wild-type ?SYN (hw?SYN) or a doubly mutated (A30P*A53T) ?SYN (hm(2) ?SYN) in a C57Bl/6J line spontaneously deleted in mouse ?SYN (C57BL/6JOla). Both transgenes had a functional role in the nigrostriatal system, demonstrated by significant elevations in striatal catecholamines, metabolites and the enzyme tyrosine hydroxylase compared with null-mice without a transgene. Consequences occurred when the transgenes were expressed at a fraction of the endogenous level. Hemizygous congenic mice did not exhibit any change in the number or size of dopaminergic neurons in the ventral midbrain at 9 months of age. Human ?SYN was predominantly located in neuronal cell bodies, neurites, synapses, and in intraneuronal/intraneuritic aggregates. The hm(2) ?SYN transgene resulted in more aggregates and dystrophic neurites than did the hw5 transgene. The hw?SYN transgene resulted in higher expression of two striatal proteins, synaptogamin 7 and UCHL1, compared with the levels of the hm(2) ?SYN transgene. These observations suggest that mutations in ?SYN may impair specific functional domains, leaving others intact. These lines may be useful for exploring interactions between h?SYN and environmental or genetic risk factors in dopamine-related disorders using a mouse model. PMID:21272100

Prasad, Kavita; Tarasewicz, Elizabeth; Strickland, Pamela A Ohman; O'Neill, Michael; Mitchell, Stephen N; Merchant, Kalpana; Tep, Samnang; Hilton, Kathryn; Datwani, Akash; Buttini, Manuel; Mueller-Steiner, Sarah; Richfield, Eric K

2011-01-28

300

Robust activation of the human but not mouse telomerase gene during the induction of pluripotency  

PubMed Central

Pluripotent stem cells (PSCs) express telomerase and have unlimited proliferative potential. To study telomerase activation during reprogramming, 3 classes of embryonic stem cell (ESC)-like clones were isolated from mouse fibroblasts containing a transgenic hTERT reporter. Class I expressed few pluripotency markers, whereas class II contained many, but not Oct4, Nanog, and Sox2. Neither class of cells differentiated efficiently. Class III cells, the fully reprogrammed induced PSCs (iPSCs), expressed all pluripotency markers, formed teratomas indistinguishable from those of mESCs, and underwent efficient osteogenic differentiation in vitro. Interestingly, whereas the endogenous mTERT gene expression was only moderately increased during reprogramming, the hTERT promoter was strongly activated in class II cells and was further elevated in class III cells. Treatment of class II cells with chemical inhibitors of MEKs and glycogen synthase kinase 3 resulted in their further reprogramming into class III cells, accompanied by a strong activation of hTERT promoter. In reprogrammed human cells, the endogenous telomerase level, although variable among different clones, was dramatically elevated. Only in cells with the highest telomerase were telomeres restored to the lengths in hESCs. Our data, for the first time, demonstrated that the hTERT promoter was strongly activated in discrete steps, revealing a critical difference in human and mouse cell reprogramming. Because telomere elongation is crucial for self-renewal of hPSCs and replicative aging of their differentiated progeny, these findings have important implications in the generation and applications of iPSCs.—Mathew, R., Jia, W., Sharma, A., Zhao, Y., Clarke, L. E., Cheng, X., Wang, H., Salli, U., Vrana, K. E., Robertson, G. P., Zhu, J., Wang, S. Robust activation of the human but not mouse telomerase gene during the induction of pluripotency.

Mathew, Renjith; Jia, Wenwen; Sharma, Arati; Zhao, Yuanjun; Clarke, Loren E.; Cheng, Xiang; Wang, Huayan; Salli, Ugur; Vrana, Kent E.; Robertson, Gavin P.; Zhu, Jiyue; Wang, Shuwen

2010-01-01

301

Localization of a human homolog of the mouse pericentrin gene (PCNT) to chromosome 21qter  

SciTech Connect

Exon trapping was used to identify portions of genes from cosmid DNA of a human chromosome 21-specific library LL21NC02-Q. More than 650 potential exons have been cloned and characterized to date. Among these, 3 trapped {open_quotes}exons{close_quotes} showed strong homology to different regions of the cDNA for the mouse pericentrin (Pcnt) gene, indicating that these 3 exons are portions of a human homolog of the mouse pericentrin gene. With PCR amplification, Southern blot analysis, and FISH, we have mapped this presumed human pericentrin gene (PCNT) to the long arm of chromosome 21 between marker PFKL and 21qter. Pericentrin is a conserved protein component of the filamentous matrix of the centrosome involved in the initial establishment of the organized microtubule array. No candidate hereditary disorder for pericentrin deficiency/abnormality has yet been mapped in the most distal region of 21q; in addition the role of triplication of the pericentrin gene in the pathophysiology or etiology of trisomy 21 is currently unknown. 16 refs., 3 figs.

Chen, Haiming [Univ. of Geneva Medical School (Switzerland); Gos, A.; Morris, M.A. [Cantonal Hospital, Geneva (Switzerland)] [and others

1996-08-01

302

Gastrointestinal cancer studies in the human to nude mouse heterotransplant system.  

PubMed

Human gastrointestinal cancer xenografts were established in the nude mouse. Grafts were accomplished with gastric adenocarcinomas, gastric leiomyosarcoma, histiocytic lymphoma of the stomach and gallbladder, pancreatic tumors, colonic cancers and cell lines of duodenal (HUTU-80) and pancreatic (HS-766-T) cancers, melanoma (SK-Mel-5), and murine metastasizing Lewis lung carcinoma. The rate of successful xenografting of these tumors varied from virtually 100% with colon and duodenal cancer, 50% for a pancreatic cancer (P-1), to only 17% for gastric adenocarcinoma. Pancreas and colon adenocarcinomas have been maintained by successive xenotransplantation over 16 and 19 months, respectively. Human xenografts retained morphological identity with tissues of origin through several transplant generations and shared some of their ultrastructural characteristics but did not metastasize. Rodent xenografts, of heterogenous origin were characterized by differences in the duration of the latent period and in the rate of their initial development as described by the average doubling times and average slopes (B) of their growth curves. Differences between B of the Lewis lung carcinoma and all of the human xenografts and between B of a pancreatic adenocarcinoma and three other neoplasms were significant (P less than 0.05 to 0.04). Labeling indices determined for 14 cancer transplants were in the range of previously reported data for similar neoplasms in patients or other xenograft systems. These findings suggest that the nude mouse model can be used to evaluate endogenous properties of gastrointestinal cancers and their responses to exogenous agents. PMID:321290

Schmidt, M; Deschner, E E; Thaler, H T; Clements, L; Good, R A

1977-05-01

303

Visualizing Human Prostate Cancer Cells in Mouse Skeleton Using Bioconjugated Near-infrared Fluorescent Quantum Dots  

PubMed Central

OBJECTIVES To visualize human prostate cancer cells in mouse bone with bioconjugated near-infrared quantum dot (QD) probes. Near-infrared fluorescent probes using QDs can visualize tumors in deep tissues in vivo. METHODS Human prostate cancer C4-2B xenografts grown in mouse tibia were detected by prostate-specific membrane antigen antibody conjugated with QDs emitting light at the near-infrared range of 800 nm (QD800). Images in culture and in vivo were acquired using the IVIS Imaging System. RESULTS As few as 5000 cells can be detected subcutaneously when tagged with QD800 conjugate and injected directly into mice. QD800 conjugate injected intravenously in mice harboring C4-2B tumors in tibia detected signals from a minimum of 500 000 cells. The maximal light emission was detected 30 minutes after intravenous injection of QD800 conjugate in mice with established C4-2B tumors. CONCLUSIONS Bioconjugated near-infrared QD probes are highly sensitive molecular imaging tools for human prostate cancer micrometastases in mice.

Shi, Chunmeng; Zhu, Ying; Xie, Zhihui; Qian, Weiping; Hsieh, Chia-Ling; Nie, Shuming; Su, Yongping; Zhau, Haiyen E.; Chung, Leland W. K.

2010-01-01

304

Reconstructing the Genomic Architecture of Ancestral Mammals: Lessons From Human, Mouse, and Rat Genomes  

PubMed Central

Recent analysis of genome rearrangements in human and mouse genomes revealed evidence for more rearrangements than thought previously and shed light on previously unknown features of mammalian evolution, like breakpoint reuse and numerous microrearrangements. However, two-way analysis cannot reveal the genomic architecture of ancestral mammals or assign rearrangement events to different lineages. Thus, the “original synteny” problem introduced by Nadeau and Sankoff previously, remains unsolved, as at least three mammalian genomes are required to derive the ancestral mammalian karyotype. We show that availability of the rat genome allows one to reconstruct a putative genomic architecture of the ancestral murid rodent genome. This reconstruction suggests that this ancestral genome retained many previously postulated chromosome associations in the placental ancestor and reveals others that were beyond the resolution of cytogenetic, radiation hybrid mapping, and chromosome painting techniques. Three-way analysis of rearrangements leads to a reliable reconstruction of the genomic architecture of specific regions in the murid ancestor, including the X chromosome, and for the first time allows one to assign major rearrangement events to one of human, mouse, and rat lineages. Our analysis implies that the rate of rearrangements is much higher in murid rodents than in the human lineage and confirms the existence of rearrangement hot-spots in all three lineages.

Bourque, Guillaume; Pevzner, Pavel A.; Tesler, Glenn

2004-01-01

305

Comparative analysis of the nuclear basic proteins in rat, human, guinea pig, mouse and rabbit spermatozoa.  

PubMed

Cysteine-rich protamines (Arg = 47-61%, Cys = 8-16%) were isolated from the sperm of an individual guinea pig, human and rabbit and from pooled samples of mouse and rat sperm. Appreciable concentrations of histones were not found in the sperm nuclei of these species. In addition to the protamines, a substance of relatively low molecular weight, which reacted with the Lowry reagent, appeared in crude acid-soluble extracts of sperm nucleoprotein. This unidentified contaminent was resolved from the protamines by chromatography on Bio-Rex 70. Heterogeneity of human and mouse protamines was revealed by electrophoresis at pH 2.7, in the presence of 2.5 M urea, and confirmed by amino acid analysis, which also suggested the presence of 2 or more species of protamine in the rabbit. By contrast, the guinea pig and rat preparations displayed nearly stoichiometric ratios of amino acid residues, approaching homogeneity by this criterion. The functional consequences of crosslinks between cysteine residues of these proteins and the possible species-specific significance of their differing percentages of histidine are discussed. Potentially analogous functions are suggested for phosphorylated serine and threonine, and for ionized cysteine and tyrosine, within the protamines of developing spermatids. Their amino acid compositions indicate that the protamines of eutherian mammals are coded by a C.G-rich genome which has been unusually susceptible to genetic drift. An especially high rate of G leads to A transitions seems to have occurred in the human protamine genes. PMID:952894

Calvin, H I

1976-06-15

306

Human and mouse orthologs of a new ATP-binding cassette gene, ABCG4.  

PubMed

We characterized a new ATP-binding cassette (ABC) transporter gene from human and mouse that is highly expressed in the brain. The gene, ABCG4, produces several transcripts that differ at the 5' end and encode proteins of various lengths. The ABCG4 protein is closely related to the Drosophila white and human ABCG1 genes, and belongs to the ABCG subfamily several members of which are involved in cholesterol transport. All representatives of this "reverse transporter" subfamily, including ABCG4, have a single ATP-binding domain at the N-terminus and a single C-terminal set of transmembrane segments. ABCG4 maps to human chromosome 11q23, between the markers D11S939 and D11S924, and Abcg4 to a conserved syntenic region on mouse chromosome 9. The abundant expression of this gene in the brain and close evolutionary relationship to the other members of the subfamily suggests a potential role for ABCG4 in cholesterol transport processes in this tissue. PMID:11856881

Annilo, T; Tammur, J; Hutchinson, A; Rzhetsky, A; Dean, M; Allikmets, R

2001-01-01

307

Phosphatidylserine increases IKBKAP levels in a humanized knock-in IKBKAP mouse model.  

PubMed

Familial dysautonomia (FD) is a severe neurodegenerative genetic disorder restricted to the Ashkenazi Jewish population. The most common mutation in FD patients is a T-to-C transition at position 6 of intron 20 of the IKBKAP gene. This mutation causes aberrant skipping of exon 20 in a tissue-specific manner, leading to reduction of the I?B kinase complex-associated protein (IKAP) protein in the nervous system. We established a homozygous humanized mouse strain carrying human exon 20 and its two flanking introns; the 3' intron has the transition observed in the IKBKAP gene of FD patients. Although our FD humanized mouse does not display FD symptoms, the unique, tissue-specific splicing pattern of the IKBKAP in these mice allowed us to evaluate the effect of therapies on gene expression and exon 20 splicing. The FD mice were supplemented with phosphatidylserine (PS), a safe food supplement that increases mRNA and protein levels of IKBKAP in cell lines generated from FD patients. Here we demonstrated that PS treatment increases IKBAKP mRNA and IKAP protein levels in various tissues of FD mice without affecting exon 20 inclusion levels. We also observed that genes associated with transcription regulation and developmental processes were up-regulated in the cerebrum of PS-treated mice. Thus, PS holds promise for the treatment of FD. PMID:23515154

Bochner, Ron; Ziv, Yael; Zeevi, David; Donyo, Maya; Abraham, Lital; Ashery-Padan, Ruth; Ast, Gil

2013-03-20

308

Long-term expression of the glucocerebrosidase gene in mouse and human hematopoietic progenitors.  

PubMed

Gaucher disease (GD), one of the most common inherited metabolic disorders, is an excellent candidate for gene therapy using hematopoietic stem cells as targets. Animal models have demonstrated the feasibility of introducing the human glucocerebrosidase (GC) gene into hematopoietic progenitors with long term expression using a variety of retroviral vectors. We have previously demonstrated the expression and integration of the human GC gene in mouse hematopoietic progenitors and their progeny 4-8 months post transplant in primary recipients using the retroviral vector MFG-GC. We now demonstrate enzyme expression in peripheral blood lymphocytes of secondary recipients more than 12 months post transplantation. We also show a transduction efficiency of up to 95% in colony forming unit-granulocyte macrophage (CFU-GM) colonies generated from transduced CD34+ cells from a variety of sources, using a centrifugation promoted infection protocol. Transduction has also been documented in long term culture initiating cells (LTCIC) from the same transduced CD34+ cells. These data indicate efficient transduction of mouse hematopoietic progenitors as well as human CD34+ cells using the retroviral vector MFG-GC. PMID:7475311

Nimgaonkar, M; Bahnson, A; Kemp, A; Lancia, J; Mannion-Henderson, J; Boggs, S; Mohney, T; Baysal, B; Dunigan, J; Barranger, J A

1995-10-01

309

Differential effect of troglitazone on the human bile acid transporters, MRP2 and BSEP, in the PXB hepatic chimeric mouse.  

PubMed

The aims of this study were to assess the utility of the PXB mouse model of a chimeric human/mouse liver in studying human-specific effects of an important human hepatotoxic drug, the PPAR? agonist, troglitazone. When given orally by gavage for 7 days, at dose levels of 300 and 600 ppm, troglitazone induced specific changes in the human hepatocytes of the chimeric liver without an effect on the murine hepatic portions. The human hepatocytes, in the vehicle-treated PXB mouse, showed an accumulation of electron-dense lipid droplets that appeared as clear vacuoles under the light microscope in H&E-stained sections. Following dosing with troglitazone, there was a loss of the large lipid droplets in the human hepatocytes, a decrease in the amount of lipid as observed in frozen sections of liver stained by Oil-red-O, and a decrease in the expression of two bile acid transporters, BSEP and MRP2. None of these changes were observed in the murine remnants of the chimeric liver. No changes were observed in the expression of three CYPs, CYP 3A2, CYP 1A1, and CYP 2B1, in either the human or murine hepatocytes, even though the baseline expression of the enzymes differed significantly between the two hepatocyte species with the mouse hepatocytes consistently showing increased expression of the protein of all three enzymes. This study has shown that the human hepatocytes, in the PXB chimeric mouse liver, retain an essentially normal phenotype in the mouse liver and, the albeit limited CYP enzymes studied show a more human, rather than a murine, expression pattern. In line with this conclusion, the study has shown a differential response of the human versus the mouse hepatocytes, and the effects observed are highly suggestive of a differential handling of the compound by the two hepatocyte species although the exact reasons are not as yet clear. The PXB chimeric mouse system therefore holds the clear potential to explore human hepatic-specific features, such as metabolism, prior to dosing human subjects, and as such should have considerable utility in drug discovery and development. PMID:22673116

Foster, John R; Jacobsen, Matt; Kenna, Gerry; Schulz-Utermoehl, Timothy; Morikawa, Yoshio; Salmu, Juuso; Wilson, Ian D

2012-06-06

310

Auditory Function in the Tc1 Mouse Model of Down Syndrome Suggests a Limited Region of Human Chromosome 21 Involved in Otitis Media  

Microsoft Academic Search

Down syndrome is one of the most common congenital disorders leading to a wide range of health problems in humans, including frequent otitis media. The Tc1 mouse carries a significant part of human chromosome 21 (Hsa21) in addition to the full set of mouse chromosomes and shares many phenotypes observed in humans affected by Down syndrome with trisomy of chromosome

Stephanie Kuhn; Neil Ingham; Selina Pearson; Susan M. Gribble; Stephen Clayton; Karen P. Steel; Walter Marcotti

2012-01-01

311

Identification and characterization of human MPP7 gene and mouse Mpp7 gene in silico.  

PubMed

Drosophila Crumbs (Crb), Stardust (Sdt), Discs large (Dlg), Scribble (Scrib) and Lethal giant larvae (Lgl) are involved in the establishment and the maintenance of apicobasal polarity in epithelial tissues. Because epithelial polarity is disrupted in tumors, human homologs of Drosophila crb, sdt, dlg, scrib, and lgl are potential cancer-associated genes. MPP1/EMP55, MPP2, MPP3, MPP4, MPP5/PALS1 and MPP6/PALS2 genes are human homologs of Drosoplila sdt. Here, we identified and characterized a novel member of MPP gene family, MPP7, by using bioinformatics. Uncharacterized FLJ32798 cDNAs (BC038105 and AK057360) were derived from human MPP7 gene. BC038105 was a representative MPP7 cDNA, while AK057360 was an aberrant MPP7 cDNA with a frame shift. Human MPP7 mRNA was expressed in placenta, brain, testis as well as in uterus tumor, bladder tumor, and lymphoma. Microsatellite marker D10S588, linked to IDDM and hereditary thrombocytopenia, was located within the MPP7 gene at human chromosome 10p12.1. Nucleotide sequence of mouse Mpp7 cDNA was determined in silico by assembling 3'-truncated cDNA AK078849, genome clone RP24-255J24, and EST AV260217. Human MPP7 showed 92.9% total-amino-acid identity with mouse Mpp7, and 75.7% total-amino-acid identity with zebrafish humpback. MPP7 orthologs were MAGUK proteins with two L27 domains, PDZ domain, SH3 domain, and GuKc domain. MPP7 was most related to MPP3 among MPP family members, functioning as adopter molecules assembling Crb homologs (CRB1, CRB3), Dlt homologs (INADL/PATJ, MPDZ/MUPP1), and Lin-7 homologs (LIN7A, LIN7B, LIN7C). This is the first report on identification and characterization of human MPP7 and mouse Mpp7 genes. PMID:14719143

Katoh, Masuko; Katoh, Masaru

2004-02-01

312

Evolutionary conservation and selection of human disease gene orthologs in the rat and mouse genomes  

PubMed Central

Background Model organisms have contributed substantially to our understanding of the etiology of human disease as well as having assisted with the development of new treatment modalities. The availability of the human, mouse and, most recently, the rat genome sequences now permit the comprehensive investigation of the rodent orthologs of genes associated with human disease. Here, we investigate whether human disease genes differ significantly from their rodent orthologs with respect to their overall levels of conservation and their rates of evolutionary change. Results Human disease genes are unevenly distributed among human chromosomes and are highly represented (99.5%) among human-rodent ortholog sets. Differences are revealed in evolutionary conservation and selection between different categories of human disease genes. Although selection appears not to have greatly discriminated between disease and non-disease genes, synonymous substitution rates are significantly higher for disease genes. In neurological and malformation syndrome disease systems, associated genes have evolved slowly whereas genes of the immune, hematological and pulmonary disease systems have changed more rapidly. Amino-acid substitutions associated with human inherited disease occur at sites that are more highly conserved than the average; nevertheless, 15 substituting amino acids associated with human disease were identified as wild-type amino acids in the rat. Rodent orthologs of human trinucleotide repeat-expansion disease genes were found to contain substantially fewer of such repeats. Six human genes that share the same characteristics as triplet repeat-expansion disease-associated genes were identified; although four of these genes are expressed in the brain, none is currently known to be associated with disease. Conclusions Most human disease genes have been retained in rodent genomes. Synonymous nucleotide substitutions occur at a higher rate in disease genes, a finding that may reflect increased mutation rates in the chromosomal regions in which disease genes are found. Rodent orthologs associated with neurological function exhibit the greatest evolutionary conservation; this suggests that rodent models of human neurological disease are likely to most faithfully represent human disease processes. However, with regard to neurological triplet repeat expansion-associated human disease genes, the contraction, relative to human, of rodent trinucleotide repeats suggests that rodent loci may not achieve a 'critical repeat threshold' necessary to undergo spontaneous pathological repeat expansions. The identification of six genes in this study that have multiple characteristics associated with repeat expansion-disease genes raises the possibility that not all human loci capable of facilitating neurological disease by repeat expansion have as yet been identified.

Huang, Hui; Winter, Eitan E; Wang, Huajun; Weinstock, Keith G; Xing, Heming; Goodstadt, Leo; Stenson, Peter D; Cooper, David N; Smith, Douglas; Alba, M Mar; Ponting, Chris P; Fechtel, Kim

2004-01-01

313

Nuclear Import of the Preintegration Complex Is Blocked upon Infection by Human Immunodeficiency Virus Type 1 in Mouse Cells?  

PubMed Central

Mouse cells do not support human immunodeficiency virus type 1 (HIV-1) replication because of host range barriers at steps including virus entry, transcription, RNA splicing, polyprotein processing, assembly, and release. The exact mechanisms for the suppression, however, are not completely understood. To elucidate further the barriers against HIV-1 replication in mouse cells, we analyzed the replication of the virus in lymphocytes from human CD4/CXCR4 transgenic mice. Although primary splenocytes and thymocytes allowed the entry and reverse transcription of HIV-1, the integration efficiency of the viral DNA was greatly reduced in these cells relative to human peripheral blood mononuclear cells, suggesting an additional block(s) before or at the point of host chromosome integration of the viral DNA. Preintegration processes were further analyzed using HIV-1 pseudotyped viruses. The reverse transcription step of HIV-1 pseudotyped with the envelope of murine leukemia virus or vesicular stomatitis virus glycoprotein was efficiently supported in both human and mouse cells, but nuclear import of the preintegration complex (PIC) of HIV-1 was blocked in mouse cells. We found that green fluorescent protein (GFP)-labeled HIV-1 integrase, which is known to be important in the nuclear localization of the PIC, could not be imported into the nucleus of mouse cells, in contrast to human cells. On the other hand, GFP-Vpr localized exclusively to the nuclei of both mouse and human cells. These observations suggest that, due to the dysfunction of integrase, the nuclear localization of PIC is suppressed in mouse cells.

Tsurutani, Naomi; Yasuda, Jiro; Yamamoto, Naoki; Choi, Byung-Il; Kadoki, Motohiko; Iwakura, Yoichiro

2007-01-01

314

Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer  

PubMed Central

Background The expression of carcino-embryonic antigen by colorectal cancer is an example of oncogenic activation of embryonic gene expression. Hypothesizing that oncogenesis-recapitulating-ontogenesis may represent a broad programmatic commitment, we compared gene expression patterns of human colorectal cancers (CRCs) and mouse colon tumor models to those of mouse colon development embryonic days 13.5-18.5. Results We report here that 39 colon tumors from four independent mouse models and 100 human CRCs encompassing all clinical stages shared a striking recapitulation of embryonic colon gene expression. Compared to normal adult colon, all mouse and human tumors over-expressed a large cluster of genes highly enriched for functional association to the control of cell cycle progression, proliferation, and migration, including those encoding MYC, AKT2, PLK1 and SPARC. Mouse tumors positive for nuclear ?-catenin shifted the shared embryonic pattern to that of early development. Human and mouse tumors differed from normal embryonic colon by their loss of expression modules enriched for tumor suppressors (EDNRB, HSPE, KIT and LSP1). Human CRC adenocarcinomas lost an additional suppressor module (IGFBP4, MAP4K1, PDGFRA, STAB1 and WNT4). Many human tumor samples also gained expression of a coordinately regulated module associated with advanced malignancy (ABCC1, FOXO3A, LIF, PIK3R1, PRNP, TNC, TIMP3 and VEGF). Conclusion Cross-species, developmental, and multi-model gene expression patterning comparisons provide an integrated and versatile framework for definition of transcriptional programs associated with oncogenesis. This approach also provides a general method for identifying pattern-specific biomarkers and therapeutic targets. This delineation and categorization of developmental and non-developmental activator and suppressor gene modules can thus facilitate the formulation of sophisticated hypotheses to evaluate potential synergistic effects of targeting within- and between-modules for next-generation combinatorial therapeutics and improved mouse models.

Kaiser, Sergio; Park, Young-Kyu; Franklin, Jeffrey L; Halberg, Richard B; Yu, Ming; Jessen, Walter J; Freudenberg, Johannes; Chen, Xiaodi; Haigis, Kevin; Jegga, Anil G; Kong, Sue; Sakthivel, Bhuvaneswari; Xu, Huan; Reichling, Timothy; Azhar, Mohammad; Boivin, Gregory P; Roberts, Reade B; Bissahoyo, Anika C; Gonzales, Fausto; Bloom, Greg C; Eschrich, Steven; Carter, Scott L; Aronow, Jeremy E; Kleimeyer, John; Kleimeyer, Michael; Ramaswamy, Vivek; Settle, Stephen H; Boone, Braden; Levy, Shawn; Graff, Jonathan M; Doetschman, Thomas; Groden, Joanna; Dove, William F; Threadgill, David W; Yeatman, Timothy J; Coffey, Robert J; Aronow, Bruce J

2007-01-01

315

An encyclopedia of mouse DNA elements (Mouse ENCODE)  

PubMed Central

To complement the human Encyclopedia of DNA Elements (ENCODE) project and to enable a broad range of mouse genomics efforts, the Mouse ENCODE Consortium is applying the same experimental pipelines developed for human ENCODE to annotate the mouse genome.

2012-01-01

316

Examination of sequence homology between human chromosome 20 and the mouse genome: intense conservation of many genomic elements  

Microsoft Academic Search

The conservation of genomic organization of mammalian species has been of interest for its usefulness in characterizing the genetics of traits and diseases and as one tool for examining evolution. The recent rough draft sequencing of the mouse and human genomes provides the opportunity for more detailed analyses. The current study examines the extent of homology between human chromosome 20 and

Lingxiang Zhu; Gary D. Swergold; Michael F. Seldin

2003-01-01

317

Gene expression profiling of mouse p53-deficient epidermal carcinoma defines molecular determinants of human cancer malignancy  

Microsoft Academic Search

BACKGROUND: The epidermal specific ablation of Trp53 gene leads to the spontaneous development of aggressive tumors in mice through a process that is accelerated by the simultaneous ablation of Rb gene. Since alterations of p53-dependent pathway are common hallmarks of aggressive, poor prognostic human cancers, these mouse models can recapitulate the molecular features of some of these human malignancies. RESULTS:

Ramón García-Escudero; Ana B Martínez-Cruz; Mirentxu Santos; Corina Lorz; Carmen Segrelles; Guillermo Garaulet; Cristina Saiz-Ladera; Clotilde Costa; Águeda Buitrago-Pérez; Marta Dueñas; Jesús M Paramio

2010-01-01

318

Identification of the Gene for Scleroderma in the Tsk/2 Mouse Strain: Implications for Human Scleroderma Pathogenesis and Subset Distinctions.  

National Technical Information Service (NTIS)

We have shown a clear time dependence on the gene expression in the skin of the Tsk2/+ mice. The mouse most resembles human SSc at a narrowly defined time point (4 wks of age) which means studies that use this model as a surrogate for human SSc, must use ...

C. Artlett E. Blankenhorn M. Whitfield

2012-01-01

319

Ultrasound fails to induce proliferation of human brain and mouse endothelial cell lines  

NASA Astrophysics Data System (ADS)

Both in vitro and in vivo studies suggest that ultrasound (US) is capable of inducing angiogenesis. There is no information, however, on whether ultrasound can induce proliferation of brain endothelial cells. We therefore explored the angiogenic potential of ultrasound on a novel immortalised human brain endothelial cell line (hCMEC/D3) and on mouse brain microvascular endothelial cells (bEND3). Ultrasound failed to enhance cell proliferation in both cell lines at all acoustic pressures studied. Endothelial cell damage occurred at 0.24 MPa with significantly slower proliferation. Cells growing in Opticell{trade mark, serif} dishes did not show damage or reduced proliferation at these pressures.

Rodemer, Claus; Jenne, Jürgen; Fatar, Marc; Hennerici, Michael G.; Meairs, Stephen

2012-11-01

320

Expression patterns of mouse and human CYP orthologs (families 1–4) during development and in different adult tissues  

Microsoft Academic Search

The present study compared the relative expression pattern of 10 orthologous CYP forms from families 1–4 in cDNA panels of human and mouse fetal and adult tissues. Except for CYP1A2, all of these CYPs exhibited specific patterns of expression during mouse ontogeny, suggesting possible involvement in development. Cyp1a1 and Cyp2r1 were the only two of the orthologs to be expressed

Dharamainder Choudhary; Ingela Jansson; Ivaylo Stoilov; Mansoor Sarfarazi; John B. Schenkman

2005-01-01

321

Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer  

Microsoft Academic Search

BACKGROUND: The expression of carcino-embryonic antigen by colorectal cancer is an example of oncogenic activation of embryonic gene expression. Hypothesizing that oncogenesis-recapitulating-ontogenesis may represent a broad programmatic commitment, we compared gene expression patterns of human colorectal cancers (CRCs) and mouse colon tumor models to those of mouse colon development embryonic days 13.5-18.5. RESULTS: We report here that 39 colon tumors

Sergio Kaiser; Young-Kyu Park; Jeffrey L Franklin; Richard B Halberg; Ming Yu; Walter J Jessen; Johannes Freudenberg; Xiaodi Chen; Kevin Haigis; Anil G Jegga; Sue Kong; Bhuvaneswari Sakthivel; Huan Xu; Timothy Reichling; Mohammad Azhar; Gregory P Boivin; Reade B Roberts; Anika C Bissahoyo; Fausto Gonzales; Greg C Bloom; Steven Eschrich; Scott L Carter; Jeremy E Aronow; John Kleimeyer; Michael Kleimeyer; Vivek Ramaswamy; Stephen H Settle; Braden Boone; Shawn Levy; Jonathan M Graff; Thomas Doetschman; Joanna Groden; William F Dove; David W Threadgill; Timothy J Yeatman; Robert J Coffey Jr; Bruce J Aronow

2007-01-01

322

Human chromosome 21 determines growth factor dependence in human\\/mouse B-cell hybridomas  

Microsoft Academic Search

Interleukin 6 (IL-6) serves as a growth factor for mouse plasmacyto- mas. As a model for IL-6-mediated growth of plasmacytomas, we study IL-6-dependent B-cell hybridomas, which can be generated through fu sion of B lymphocytes with a plasmacytoma cell line, e.g., SP2\\/0. In the present report, we have investigated the peculiar behavior of B-cell hy bridomas with respect to IL-6

Saskia B. Ebeling; Hanny M. Klaasse Bos; Rosalyn Slater; Wilhelmina J. I. Overkamp; Andrew P. Cuthbert; Robert F. Newbold; Malgorzata Z. Zdzienicka; Lucien A. Aarden

1998-01-01

323

Regional localization of the gene for thyroid peroxidase to human chromosome 2p25 and mouse chromosome 12C  

SciTech Connect

Thyroid peroxidase (TPO) plays a central role in thyroid gland function. The enzyme catalyzes two important reactions of thyroid hormone synthesis, i.e., the iodination of tyrosine residues in thyroglobulin and phenoxy-ester formation between pairs of iodinated tyrosines to generate the thyroid hormones, thyroxine and triiodothyronine. Previously, we isolated the cDNAs encoding human and mouse TPOs and assigned the human TPO gene to the short arm of chromosome 2 by somatic cell hybrid mapping. By a similar analysis of DNA from somatic cell hybrids, the human TPO gene was mapped to 2pter-p12. The mouse TPO gene was localized to chromosome 12 using a rat TPO cDNA as a probe to hybridize with mouse-hamster somatic cell hybrids. In this study, we used fluorescence in situ hybridization (FISH) to confirm the localization of human and mouse TPO genes to human chromosome 2 and mouse chromosome 12 and to assign them regionally to 2p25 and 12C, respectively. 7 refs., 1 fig.

Endo, Yuichi; Onogi, Satoshi; Fujita, Teizo [Fukushima Medical College (Japan)] [and others

1995-02-10

324

Y(4) receptors mediate the inhibitory responses of pancreatic polypeptide in human and mouse colon mucosa.  

PubMed

The antisecretory effects of several Y agonists, including pancreatic polypeptide (PP), indicate the presence of Y(1), Y(2), and Y(4) receptors in mouse and human (h) colon mucosae. Here, we used preparations from human and from wild-type (WT), Y(4), and Y(1) receptor knockout ((-/-)) mice, alongside Y(4) receptor-transfected cells to define the relative functional contribution of the Y(4) receptor. First, rat (r) PP antisecretory responses were lost in murine Y(4)(-/-) preparations, but hPP and Pro(34) peptide YY (PYY) costimulated Y(4) and Y(1) receptors in WT mucosa. The Y(1) antagonist/Y(4) agonist GR231118 [(Ile,Glu,Pro,Dpr,Tyr,Arg,Leu,Arg,Try-NH(2))-2-cyclic(2,4'),(2',4)-diamide] elicited small Y(4)-mediated antisecretory responses in human tissues pretreated with the Y(1) antagonist, BIBO3304 [(R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N(2)-(diphenylacetyl)-argininamide trifluoroacetate)], and attenuated Y(4)-mediated hPP responses in mouse and human mucosa. GR231118 and rPP were also antisecretory in hY(4)-transfected epithelial monolayers but were partial agonists compared with hPP at this receptor. In Y(4)-transfected human embryonic kidney (HEK) 293 cells, Y(4) ligands displaced [(125)I]hPP binding with orders of affinity (pK(i)) at human (hPP = rPP > GR231118 > Pro(34)PYY = PYY) and mouse (rPP = hPP > GR231118 > Pro(34)PYY > PYY) Y(4) receptors. GR231118- and rPP-stimulated guanosine 5'-3-O-(thio)triphosphate binding through hY(4) receptors with significantly lower efficacy than hPP. GR231118 marginally increased basal but abolished further PP-induced hY(4) internalization to recycling (transferrin-labeled) pathways in HEK293 cells. Taken together, these findings show that Y(4) receptors play a definitive role in attenuating colonic anion transport and may be useful targets for novel antidiarrheal agents due to their limited peripheral expression. PMID:16807358

Tough, Iain R; Holliday, Nicholas D; Cox, Helen M

2006-06-28

325

Galactocerebrosidase activity in somatic cell hybrids derived from twitcher mouse/control human fibroblasts is associated with human chromosome 17.  

PubMed Central

Somatic cell hybrids derived from twitcher mouse cells and from control human fibroblasts were selected by two different methods. One method utilized 6-thioguanine-resistant twitcher cells as a parental line and the other used neomycin-resistant control human fibroblasts as a parental line so that hybrid lines could be selected in either HAT or in G-418 medium, respectively. The hybrid lines were analyzed for galactocerebrosidase activity. Since the twitcher cell lines are deficient in galactocerebrosidase activity, the presence of this activity in these hybrid lines depends upon the presence of human chromosome contents. Both galactocerebrosidase-positive and -deficient hybrid lines were analyzed for their human chromosome contents by the use of isozyme markers. In hybrids derived from both selection methods the expression of galactocerebrosidase activity was associated with the presence of human chromosome 17 marker isozymes. This was confirmed cytogenetically by means of trypsin-banded Giemsa staining of intact human chromosome 17 in three galactocerebrosidase-positive hybrid lines. Images Figure 4 Figure 5 Figure 6

Lyerla, T A; Konola, J T; Skiba, M C; Raghavan, S

1989-01-01

326

Human occludin is a hepatitis C virus entry factor required for infection of mouse cells  

PubMed Central

Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. The development of much needed specific antiviral therapies and an effective vaccine has been hampered by the lack of a convenient small animal model. The determinants restricting HCV tropism to human and chimpanzee hosts are unknown. Replication of the viral RNA has been demonstrated in mouse cells1,2, but these cells are not infectable with either lentiviral particles bearing HCV glycoproteins (HCVpp)3 or HCV produced in cell culture (HCVcc)(unpublished data), suggesting a block at the level of entry. Through an iterative cDNA library screening approach we have identified human occludin (OCLN) as an essential HCV cell entry factor that is able to render murine cells infectable with HCVpp. Similarly, OCLN is required for HCV-susceptibility of human cells, since its overexpression in uninfectable cells specifically enhanced HCVpp uptake while its silencing in permissive cells impaired both HCVpp and HCVcc infection. In addition to OCLN, HCVpp infection of murine cells required expression of the previously identified HCV entry factors, CD814, scavenger receptor class B type I (SR-BI)5, and claudin-1 (CLDN1)6. While the mouse versions of SR-BI and CLDN1 function at least as well as the human proteins for promoting HCV entry; both OCLN and CD81, however, must be of human origin to allow efficient infection. The species-specific determinants of OCLN were mapped to its second extracellular loop. The identification of OCLN as a new HCV entry factor further highlights the importance of the tight junction complex in the viral entry process and provides a major advance towards efforts to develop small animal models for HCV.

Ploss, Alexander; Evans, Matthew J.; Gaysinskaya, Valeriya A.; Panis, Maryline; You, Hana; de Jong, Ype P.; Rice, Charles M.

2009-01-01

327

Aberrant splicing induced by missense mutations in BRCA1: clues from a humanized mouse model.  

PubMed

Numerous missense mutations in human BRCA1 gene have been linked to predisposition to breast cancer. However, the functional significance of the majority of these mutations remains unknown. We have examined the molecular basis for three such cancer-causing mutations. The first mutation, a T-->G transversion in codon 64, is predicted to change a conserved cysteine residue to glycine in the RING finger domain of the 1863 amino acid BRCA1 protein. Using a humanized mouse model we demonstrate that this missense mutation actually results in a functionally null protein. This striking result occurs because the single base alteration generates a new 5' splice site in exon 5 and also disrupts a putative exonic splicing enhancer motif. Consequently, the normal splice donor site is disrupted and an internal cryptic splice site is activated. This results in a 22-nucleotide deletion and the aberrant transcript is predicted to encode a severely truncated protein consisting of only 63 amino acids. To identify other missense mutations in BRCA1 that may result in aberrant splicing, we screened various mutations using the Genscan program. We demonstrate that at least two other missense mutations in codons 1495 and 1823 result in aberrant splicing due to the possible disruption of cis-acting splicing regulatory elements. In conclusion, our study demonstrates for the first time the application of a humanized mouse model for functional analysis of human mutations in mice and also shows the need for a careful examination of the functional consequences of single base alterations and single nucleotide polymorphisms identified in human disease-causing genes. PMID:12915465

Yang, Yongping; Swaminathan, Srividya; Martin, Betty K; Sharan, Shyam K

2003-07-08

328

Waardenburg syndrome in man and splotch mutants in the mouse: a paradigm of the usefulness of linkage and synteny homologies in mouse and man for the genetic analysis of human congenital malformations.  

PubMed

The use of chromosomal segments with conserved homologous linkage groups found in different species provides one method of predicting the location of genes causing congenital malformations in man. For example, homology between man and mouse involves 241 homologous autosomal genes spread on 68 homologous chromosomal segments. In addition, the similarities of phenotypic expression of human congenital malformations and mouse mutations indicate the possible involvement of an homologous gene implicated during ontogeny of the two species. The identification of a single gene defect in the mouse and comparative mouse-human gene mapping provides therefore another approach for selecting candidate loci for inborn error of morphogenesis in man. Further molecular studies can then be performed to show that the loci are identical. The human Waardenburg syndrome and the splotch (Sp) mouse mutant represent the first example of the potential of this approach for the understanding of human congenital malformations at the molecular level. PMID:7858167

Delezoide, A L; Vekemans, M

1994-01-01

329

Cloning and expression of MRG receptors in macaque, mouse, and human.  

PubMed

Members of the MRG family of G-protein coupled receptors (GPCRs) are expressed predominately in small diameter sensory neurons of the dorsal root ganglia (DRG) suggesting a possible role in nociception. However, the large expansion of this gene family in rodents, combined with the lack of strict rodent orthologs for many of the human MRG genes, limits the usefulness of rodent models to evaluate human MRG involvement in nociception. Furthermore, the high degree of similarity between related rodent Mrg genes suggests that pharmacological approaches to define the function of individual receptors will prove difficult. The creation of an animal model to examine human MRG function will, therefore, require the identification of human MRG orthologs in a non-rodent species. Here we report the identification of MRGD, MRGE, and several MRGX orthologs in the crab-eating macaque, Macaca fascicularis. Similar to their human counterparts, all isolated macaque genes were expressed in dorsal root ganglia neurons. In the case of macaque MrgX2 and MrgD, expression was co-localized with the known nociceptive neuronal markers, IB4, VR1, and SP. Although expression in DRG neurons was the prominent feature of this family, we also found that MrgE was expressed in numerous brain regions of macaque, mouse, and human. PMID:15710235

Zhang, Lin; Taylor, Noël; Xie, Yuhong; Ford, Roger; Johnson, Jeremy; Paulsen, Janet E; Bates, Brian

2005-02-18

330

Distinct glycosyltransferases synthesize E-selectin ligands in human vs. mouse leukocytes.  

PubMed

The binding of selectins to carbohydrate epitopes expressed on leukocytes is the first step in a multi-step cell adhesion cascade that controls the rate of leukocyte recruitment at sites of inflammation. The glycans that function as selectin-ligands are post-translationally synthesized by the serial action of Golgi resident enzymes called glycosyltransferases (glycoTs). Whereas much of our current knowledge regarding the role of glycoTs in constructing selectin-ligands comes from reconstituted biochemical investigations or murine models, tools to assess the impact of these enzymes on the human ligands are relatively underdeveloped. This is significant since the selectin-ligands, particularly those that bind E-selectin, vary between different leukocyte cell populations and they are also different in humans compared with mice. To address this shortcoming, a recent study by Buffone et al. (2013) outlines a systematic strategy to knockdown upto three glycoTs simultaneously in human leukocytes. The results suggest that the fucosyltransferases (FUTs) regulating selectin-ligand synthesis may be species-specific. In particular, they demonstrate that FUT9 plays a significant role during human, but not mouse, leukocyte-endothelial interactions. Overall, this article discusses the relative roles of the FUTs during human L-, E-, and P-selectin-ligand biosynthesis, and the potential that the knockdown strategy outlined here may assess the role of other glycoTs in human leukocytes also. PMID:23590904

Mondal, Nandini; Buffone, Alexander; Neelamegham, Sriram

2013-04-16

331

Brain homogenates from human tauopathies induce tau inclusions in mouse brain.  

PubMed

Filamentous inclusions made of hyperphosphorylated tau are characteristic of numerous human neurodegenerative diseases, including Alzheimer's disease, tangle-only dementia, Pick disease, argyrophilic grain disease (AGD), progressive supranuclear palsy, and corticobasal degeneration. In Alzheimer's disease and AGD, it has been shown that filamentous tau appears to spread in a stereotypic manner as the disease progresses. We previously demonstrated that the injection of brain extracts from human mutant P301S tau-expressing transgenic mice into the brains of mice transgenic for wild-type human tau (line ALZ17) resulted in the assembly of wild-type human tau into filaments and the spreading of tau inclusions from the injection sites to anatomically connected brain regions. Here we injected brain extracts from humans who had died with various tauopathies into the hippocampus and cerebral cortex of ALZ17 mice. Argyrophilic tau inclusions formed in all cases and following the injection of the corresponding brain extracts, we recapitulated the hallmark lesions of AGD, PSP and CBD. Similar inclusions also formed after intracerebral injection of brain homogenates from human tauopathies into nontransgenic mice. Moreover, the induced formation of tau aggregates could be propagated between mouse brains. These findings suggest that once tau aggregates have formed in discrete brain areas, they become self-propagating and spread in a prion-like manner. PMID:23690619

Clavaguera, Florence; Akatsu, Hiroyasu; Fraser, Graham; Crowther, R Anthony; Frank, Stephan; Hench, Jürgen; Probst, Alphonse; Winkler, David T; Reichwald, Julia; Staufenbiel, Matthias; Ghetti, Bernardino; Goedert, Michel; Tolnay, Markus

2013-05-20

332

Human and Mouse Enamel Phenotypes Resulting from Mutation or Altered Expression of AMEL, ENAM, MMP20 and KLK4  

PubMed Central

Amelogenesis imperfecta (AI) is caused by AMEL, ENAM, MMP20 and KLK4 gene mutations. Mice lacking expression of the AmelX, Enam and Mmp20 genes have been generated. These mouse models provide tools for understanding enamel formation and AI pathogenesis. This study describes the AI phenotypes and relates them to their mouse model counterparts. Human AI phenotypes were determined in a clinical population of AI families and published cases. Human and murine teeth were evaluated using light and electron microscopy. A total of 463 individuals from 54 families were evaluated and mutations in the AMEL, ENAM and KLK4 genes were identified. The majority of human mutations for genes coding enamel nonproteinase proteins (AMEL and ENAM) resulted in variable hypoplasia ranging from local pitting to a marked, generalized enamel thinning. Specific AMEL mutations were associated with abnormal mineralization and maturation defects. Amel and Enam null murine models displayed marked enamel hypoplasia and a complete loss of prism structure. Human mutations in genes coding for the enamel proteinases (MMP20 and KLK4) cause variable degrees of hypomineralization. The murine Mmp20 null mouse exhibits both hypoplastic and hypomineralized defects. The currently available Amel and Enam mouse models for AI exhibit enamel phenotypes (hypoplastic) that are generally similar to those seen in humans. Mmp20 null mice have a greater degree of hypoplasia than humans with MMP20 mutations. Mice lacking expression of the currently known genes associated with the human AI conditions provide useful models for understanding the pathogenesis of these conditions.

Wright, J. Timothy; Hart, Thomas C.; Hart, P. Suzanne; Simmons, Darrin; Suggs, Cynthia; Daley, Bill; Simmer, Jim; Hu, Jan; Bartlett, John D.; Li, Yong; Yuan, Zhi-An; Seow, W. Kim; Gibson, Carolyn W.

2008-01-01

333

Differential Expression and Regulation by Activin of the Neurotrophins BDNF and NT4 During Human and Mouse Ovarian Development  

PubMed Central

The tropomyosin-related kinase (Trk) B neurotrophin receptor is essential for ovarian germ cell survival and primordial follicle formation, but the contributions of its ligands, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4), are unknown. We have investigated their expression and regulation in developing human and mouse ovaries. BDNF expression increased with increasing gestation, expression of human NTF4 and of both Ntf5 and Bdnf in the mouse was unchanged. Bdnf expression was dramatically lower than Ntf5 in the mouse, but levels were comparable in the human. Human fetal ovarian somatic cells expressed BDNF. Activin A selectively regulated BDNF and Ntf5 expression in human and mouse, respectively, identifying an oocyte/somatic signaling pathway which might mediate the pro-survival effects of activin. These data reveal that expression and regulation of the TrkB ligands are differentially controlled in the developing ovaries of humans and mice, and identify BDNF as a potential regulator of germ cell fate in the human fetal ovary. Developmental Dynamics 239:1211–1219, 2010. © 2010 Wiley-Liss, Inc.

Childs, Andrew J; Bayne, Rosemary AL; Murray, Alison A; Martins Da Silva, Sarah J; Collins, Craig S; Spears, Norah; Anderson, Richard A

2010-01-01

334

Comparative Analysis of the  Like Globin Clusters in Mouse, Rat, and Human Chromosomes Indicates a Mechanism Underlying Breaks in Conserved Synteny  

Microsoft Academic Search

We have sequenced and fully annotated a 65,871-bp region of mouse Chromosome 17 including the Hba-ps4 -globin pseudogene. Comparative sequence analysis with the functional -globin loci at human Chromosome 16p13.3 and mouse Chromosome 11 shows that this segment of mouse Chromosome 17 contains a group of three -like pseudogenes (Hba-psm-Hba-ps4-Hba-q3), similar to the duplicated sets found at the functional mouse

Cristina Tufarelli; Ross Hardison; Webb Miller; Jim Hughes; Kevin Clark; Nicki Ventress; Anna Maria Frischauf; Douglas R. Higgs

2004-01-01

335

Cloning and Partial Nucleotide Sequence of Human Immunoglobulin mu Chain cDNA from B Cells and Mouse--Human Hybridomas  

Microsoft Academic Search

Purified mRNAs coding for mu and kappa human immunoglobulin polypeptides were translated in vitro and their products were characterized. The mu -specific mRNAs, derived from both human lymphoblastoid cells (GM607) and from a mouse-human somatic cell hybrid secreting human mu chains (alpha D5-DH11-BC11), were copied into cDNAs and inserted into the plasmid pBR322. Several recombinant cDNAs that were obtained were

Thomas W. Dolby; Joanna Devuono; Carlo M. Croce

1980-01-01

336

Expression of the human Dp 71 (apo-dystrophin 1) gene from a 760 kb reconstructed human distal DMD YAC transferred to mouse cells  

SciTech Connect

In a program to re-introduce and study the 2.5 mb human DMD gene in a mouse background, we have first reconstructed the gene on a single YAC by homologous recombination. We are now testing pilot gene transfer of a 760 kb YAC generated during the process and covering the 3{prime} region of the gene. This YAC contains exons 52-79 and thus includes the internal genes of Dp 71 (apo-dystrophin 1) and Dp 116 (apo-dystrophin 2). To facilitate selection in mammalian cells, the YAC was modified by recombinational insertion (retrofitting) of a neomycin-resistance gene in the right vector-arm. This YAC, yneo(18-25)C, was introduced in mouse LA-9 cells by PEG-mediated cell fusion. G418 resistant transformants were characterized by DMD-exon-PCR and Southern blotting. One of the six clones analyzed accommodated the entire intact YAC-DNA. Expression of the human DMD gene was studied by RT-PCR and revealed expression of the human Dp 71 gene but not of the Dp 116 gene in the full-length clone LA-9/3A. Remarkably, differences were observed in the 3{prime} region of the mouse and the human mRNAs, due to alternative splicing of exons 71 (absent in the human mRNA, present in the mouse mRNA) and 78 (present in the human mRNA, absent in the mouse mRNA). The splicing pattern of the human transcript mirrors that of the major product in human blood cells, suggesting that in this murine cell line processing of the human and the mouse DMD transcripts maintains the exon selectivity of the original species.

Ommen, G.J.B. van; Heikoop, J.C.; Hogervorst, F.B.L. [Leiden Univ. (Netherlands)] [and others

1994-09-01

337

Effects of human interleukin-18 and interleukin-12 treatment on human lymphocyte engraftment in NOD-scid mouse  

PubMed Central

NOD/LtSz-prkdcscid/prkdcscid (non-obese diabetic-severe combine immunodeficiency; NOD-scid) mice grafted with human peripheral blood lymphoid cells have been used as an in vivo humanized mouse model in various studies. However, cytotoxic human T cells are induced in this model during immune responses, which gives misleading results. To assist in grafting of human lymphocytes without the induction of cytotoxic human T cells, we investigated the effects of T helper type 1 (Th1) and Th2 cytokines on human lymphocyte grafting and migration, as well as the production of immunoglobulin deposited in glomeruli and human immunodeficiency virus-1 (HIV-1) infection using NOD-scid mice. Administration of interleukin-18 (IL-18) and IL-12 enhanced the grafting of human CD4+ and CD8+ T cells in the mice, whereas co-administration prevented grafting due to interferon-?-dependent apoptosis. Immunoglobulin A (IgA) deposits were observed in mice treated with IL-18 alone, but not in those given phosphate-buffered saline, IL-12 alone, or IL-18 + IL-12. A high rate of HIV infection was also observed in the IL-18-treated group. Together, these results indicate that IL-18 may be effective for the grafting and migration of CD4+ and CD8+ T cells, except for the induction of apoptosis and regulation of class-switching IgA. IL-18-administered NOD-scid mice provide a useful small humanized model for the study of HIV infection and IgA nephropathy.

Senpuku, Hidenobu; Asano, Toshihiko; Matin, Khairul; Salam, M Abdus; Tsuha, Yuzo; Horibata, Shigeo; Shimazu, Yoshihito; Soeno, Yuichi; Aoba, Takaaki; Sata, Tetsutaro; Hanada, Nobuhiro; Honda, Mitsuo

2002-01-01

338

Introduce a dexamethasone mouse model for monitoring in vivo viability of stored human platelets.  

PubMed

OBJECTIVES: The aim of this study is to establish an available animal model which can evaluate in vivo viability of stored human platelets (HuPLTs). BACKGROUND: The viability in vivo of HuPLTs was usually evaluated by transfusing HuPLTs into animals before clinical trials. It is necessary to develop a method which may slow down rapid clearance of HuPLTs from circulation of the animal. METHODS: Carbon clearance tests were performed by treating mice with dexamethasone (DEX) to determine the phagocytic ability of the mice macrophages. HuPLTs in mice whole blood were detected by flow cytometric analysis with mouse anti-human CD41-fluorescein isothiocyanate monoclonal antibody. Recovery and survival of the HuPLTs stored at 22 °C for 1?day were evaluated after transfusing these HuPLTs into DEX-treated mice, and compared with those either stored at 22 °C for 5?days or at 4 °C for 1?day. RESULTS: Corrected phagocytic indexes of DEX-treated mice decreased significantly compared with those of control mice (P?mouse circulation. And the DEX-treated mouse model was able to evaluate the in vivo viability of stored HuPLTs. PMID:23772863

Xie, R F; Yang, J; Ren, Y N; Fan, H H; Qian, K C

2013-06-18

339

Human embryonic zeta-globin gene expression in mouse-human hybrid erythroid cell lines  

Microsoft Academic Search

Human hemoglobin (Hb) is composed of two pairs of globin chains, each of them contains a heme group. One pair of globin chain is encoded by a gene on the street arm of human chromosome 16 within the ?-globin gene cluster and another pair encoded by a gene on the short arm of human chromosome 11 within the ?-globin gene

Hong Yuan Luo

1993-01-01

340

Human embryonic $\\\\zeta$-globin gene expression in mouse-human hybrid erythroid cell lines  

Microsoft Academic Search

Human hemoglobin (Hb) is composed of two pairs of globin chains, each of them contains a heme group. One pair of globin chains is encoded by a gene on the short arm of human chromosome 16 within the $\\\\alpha$-globin gene cluster and another pair encoded by a gene on the short arm of human chromosome II within the $\\\\beta$-globin gene

Hong Yuan Luo

1994-01-01

341

The differential processing of proenkephalin A in mouse and human breast tumour cell lines.  

PubMed

We have carried out an investigation into the processing of the enkephalin-like immunoreactivity reported in breast tissue using two human breast tumour cell lines and a mouse tumour cell line. A 46 kDa form of proenkephalin (PE) has been observed in the cell lysates of two human breast tumour cell lines (MCF-7, ZR-75-1) and the mouse androgen-responsive Shionogi breast carcinoma cell line (SC115). PE processing in the cell lysates of these cells was assessed by a specific met-enkephalin RIA. The basal levels of processed PE in the MCF-7, ZR-75-1 and SC115 cell lysates were 30, 30 and 76% respectively. The processing enzymes PC1 and PC2, which have been implicated in the differential processing of PE, were detected by immunoblot analysis in these cells. PC1 was found within the cell extracts of all three cell lines. PC2 was only observed in the SC115 cell line, which may account for the higher percentage of processed PE measured. The cDNA of PC2 has been transfected into ZR-75-1 cells and this was accompanied by an increase in the level of processed PE from 30 to 76%. These breast tumour cell lines may provide a useful insight into the function of enkephalin-containing peptides in breast cancer. PMID:10333550

Brar, B K; Lowry, P J

1999-06-01

342

Mitotane reduces human and mouse ACTH-secreting pituitary cell viability and function.  

PubMed

Medical therapy for Cushing's disease (CD) is currently based on agents mainly targeting adrenocortical function. Lately, pituitary-directed drugs have been developed, with limited efficacy. Mitotane, a potent adrenolytic drug, has been recently investigated for the treatment of CD, but the direct pituitary effects have not been clarified so far. The aim of our study was to investigate whether mitotane may affect corticotroph function and cell survival in the mouse pituitary cell line AtT20/D16v-F2 and in the primary cultures of human ACTH-secreting pituitary adenomas, as an in vitro model of pituitary corticotrophs. We found that in the AtT20/D16v-F2 cell line and in primary cultures, mitotane reduces cell viability by inducing caspase-mediated apoptosis and reduces ACTH secretion. In the AtT20/D16v-F2 cell line, mitotane reduces Pomc expression and blocks the stimulatory effects of corticotropin-releasing hormone on cell viability, ACTH secretion, and Pomc expression. These effects were apparent at mitotane doses greater than those usually necessary for reducing cortisol secretion in Cushing's syndrome, but still in the therapeutic window for adrenocortical carcinoma treatment. In conclusion, our results demonstrate that mitotane affects cell viability and function of human and mouse ACTH-secreting pituitary adenoma cells. These data indicate that mitotane could have direct pituitary effects on corticotroph cells. PMID:23814013

Gentilin, Erica; Tagliati, Federico; Terzolo, Massimo; Zoli, Matteo; Lapparelli, Marcello; Minoia, Mariella; Ambrosio, Maria Rosaria; Degli Uberti, Ettore C; Zatelli, Maria Chiara

2013-07-29

343

Hypoxia-inducible factor-1? regulates ? cell function in mouse and human islets  

PubMed Central

Hypoxia-inducible factor-1? (HIF-1?) is a transcription factor that regulates cellular stress responses. While the levels of HIF-1? protein are tightly regulated, recent studies suggest that it can be active under normoxic conditions. We hypothesized that HIF-1? is required for normal ? cell function and reserve and that dysregulation may contribute to the pathogenesis of type 2 diabetes (T2D). Here we show that HIF-1? protein is present at low levels in mouse and human normoxic ? cells and islets. Decreased levels of HIF-1? impaired glucose-stimulated ATP generation and ? cell function. C57BL/6 mice with ? cell–specific Hif1a disruption (referred to herein as ?-Hif1a-null mice) exhibited glucose intolerance, ? cell dysfunction, and developed severe glucose intolerance on a high-fat diet. Increasing HIF-1? levels by inhibiting its degradation through iron chelation markedly improved insulin secretion and glucose tolerance in control mice fed a high-fat diet but not in ?-Hif1a-null mice. Increasing HIF-1? levels markedly increased expression of ARNT and other genes in human T2D islets and improved their function. Further analysis indicated that HIF-1? was bound to the Arnt promoter in a mouse ? cell line, suggesting direct regulation. Taken together, these findings suggest an important role for HIF-1? in ? cell reserve and regulation of ARNT expression and demonstrate that HIF-1? is a potential therapeutic target for the ? cell dysfunction of T2D.

Cheng, Kim; Ho, Kenneth; Stokes, Rebecca; Scott, Christopher; Lau, Sue Mei; Hawthorne, Wayne J.; O'Connell, Philip J.; Loudovaris, Thomas; Kay, Thomas W.; Kulkarni, Rohit N.; Okada, Terumasa; Wang, Xiaohui L.; Yim, Sun Hee; Shah, Yatrik; Grey, Shane T.; Biankin, Andrew V.; Kench, James G.; Laybutt, D. Ross; Gonzalez, Frank J.; Kahn, C. Ronald; Gunton, Jenny E.

2010-01-01

344

Mouse models and the interpretation of human GWAS in type 2 diabetes and obesity  

PubMed Central

Within the last 3 years, genome-wide association studies (GWAS) have had unprecedented success in identifying loci that are involved in common diseases. For example, more than 35 susceptibility loci have been identified for type 2 diabetes and 32 for obesity thus far. However, the causal gene and variant at a specific linkage disequilibrium block is often unclear. Using a combination of different mouse alleles, we can greatly facilitate the understanding of which candidate gene at a particular disease locus is associated with the disease in humans, and also provide functional analysis of variants through an allelic series, including analysis of hypomorph and hypermorph point mutations, and knockout and overexpression alleles. The phenotyping of these alleles for specific traits of interest, in combination with the functional analysis of the genetic variants, may reveal the molecular and cellular mechanism of action of these disease variants, and ultimately lead to the identification of novel therapeutic strategies for common human diseases. In this Commentary, we discuss the progress of GWAS in identifying common disease loci for metabolic disease, and the use of the mouse as a model to confirm candidate genes and provide mechanistic insights.

Cox, Roger D.; Church, Christopher D.

2011-01-01

345

Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis  

PubMed Central

Cooperativity between oncogenic mutations is recognized as a fundamental feature of malignant transformation, and it may be mediated by synergistic regulation of the expression of pro- and antitumorigenic target genes. However, the mechanisms by which oncogenes and tumor suppressors coregulate downstream targets and pathways remain largely unknown. Here, we used ChIP coupled to massively parallel sequencing (ChIP-seq) and gene expression profiling in mouse prostates to identify direct targets of the tumor suppressor Nkx3.1. Further analysis indicated that a substantial fraction of Nkx3.1 target genes are also direct targets of the oncoprotein Myc. We also showed that Nkx3.1 and Myc bound to and crossregulated shared target genes in mouse and human prostate epithelial cells and that Nkx3.1 could oppose the transcriptional activity of Myc. Furthermore, loss of Nkx3.1 cooperated with concurrent overexpression of Myc to promote prostate cancer in transgenic mice. In human prostate cancer patients, dysregulation of shared NKX3.1/MYC target genes was associated with disease relapse. Our results indicate that NKX3.1 and MYC coregulate prostate tumorigenesis by converging on, and crossregulating, a common set of target genes. We propose that coregulation of target gene expression by oncogenic/tumor suppressor transcription factors may represent a general mechanism underlying the cooperativity of oncogenic mutations during tumorigenesis.

Anderson, Philip D.; McKissic, Sydika A.; Logan, Monica; Roh, Meejeon; Franco, Omar E.; Wang, Jie; Doubinskaia, Irina; van Meer, Riet; Hayward, Simon W.; Eischen, Christine M.; Eltoum, Isam-Eldin; Abdulkadir, Sarki A.

2012-01-01

346

The human NPM1 mutation A perturbs megakaryopoiesis in a conditional mouse model.  

PubMed

The NPM1 mutation is the most frequent genetic alteration thus far identified in acute myeloid leukemia (AML). Despite progress in the clinical and biological characterization of NPM1-mutated AML, the role of NPM1 mutation in leukemogenesis in vivo has not been fully elucidated. We report a novel mouse model that conditionally expresses the most common human NPM1 mutation (type A) in the hematopoietic compartment. In Npm1-TCTG/WT;Cre(+) mice, the NPM1 mutant localized in the cytoplasm (NPMc(+)) of bone marrow (BM) cells. The mutant mice developed no AML after 1.5-year follow-up. However, NPMc(+) expression determined a significant platelet count reduction and an expansion of the megakaryocytic compartment in the BM and spleen. Serum thrombopoietin levels overlapped in mutant vs control mice, and BM cells from Npm1-TCTG/WT;Cre(+) mice formed more megakaryocytic colonies in vitro. Moreover, we demonstrated the up-regulation of microRNAs (miRNAs; miR-10a, miR-10b, and miR-20a) inhibiting megakaryocytic differentiation along with increased expression of HOXB genes. Notably, these findings mimic those of human NPM1-mutated AML, which also exhibits a similar miRNA profile and expansion of the megakaryocytic compartment. Our mouse model provides evidence that the NPM1 mutant affects megakaryocytic development, further expanding our knowledge of the role of NPM1 mutant in leukemogenesis. PMID:23435463

Sportoletti, Paolo; Varasano, Emanuela; Rossi, Roberta; Bereshchenko, Oxana; Cecchini, Debora; Gionfriddo, Ilaria; Bolli, Niccolò; Tiacci, Enrico; Intermesoli, Tamara; Zanghì, Pamela; Masciulli, Arianna; Martelli, Maria Paola; Falzetti, Franca; Martelli, Massimo F; Falini, Brunangelo

2013-02-22

347

Modeling tissue-specific structural patterns in human and mouse promoters.  

PubMed

Sets of genes expressed in the same tissue are believed to be under the regulation of a similar set of transcription factors, and can thus be assumed to contain similar structural patterns in their regulatory regions. Here we present a study of the structural patterns in promoters of genes expressed specifically in 26 human and 34 mouse tissues. For each tissue we constructed promoter structure models, taking into account presences of motifs, their positioning to the transcription start site, and pairwise positioning of motifs. We found that 35 out of 60 models (58%) were able to distinguish positive test promoter sequences from control promoter sequences with statistical significance. Models with high performance include those for liver, skeletal muscle, kidney and tongue. Many of the important structural patterns in these models involve transcription factors of known importance in the tissues in question and structural patterns tend to be conserved between human and mouse. In addition to that, promoter models for related tissues tend to have high inter-tissue performance, indicating that their promoters share common structural patterns. Together, these results illustrate the validity of our models, but also indicate that the promoter structures for some tissues are easier to model than those of others. PMID:19850720

Vandenbon, Alexis; Nakai, Kenta

2009-10-22

348

Modeling tissue-specific structural patterns in human and mouse promoters  

PubMed Central

Sets of genes expressed in the same tissue are believed to be under the regulation of a similar set of transcription factors, and can thus be assumed to contain similar structural patterns in their regulatory regions. Here we present a study of the structural patterns in promoters of genes expressed specifically in 26 human and 34 mouse tissues. For each tissue we constructed promoter structure models, taking into account presences of motifs, their positioning to the transcription start site, and pairwise positioning of motifs. We found that 35 out of 60 models (58%) were able to distinguish positive test promoter sequences from control promoter sequences with statistical significance. Models with high performance include those for liver, skeletal muscle, kidney and tongue. Many of the important structural patterns in these models involve transcription factors of known importance in the tissues in question and structural patterns tend to be conserved between human and mouse. In addition to that, promoter models for related tissues tend to have high inter-tissue performance, indicating that their promoters share common structural patterns. Together, these results illustrate the validity of our models, but also indicate that the promoter structures for some tissues are easier to model than those of others.

Vandenbon, Alexis; Nakai, Kenta

2010-01-01

349

The redox state of recombinant human serum albumin and its optimal concentration for mouse embryo culture.  

PubMed

Albumin has multiple physiological functions in embryo culture, such as a chelator of heavy metals, free radical scavenger, pH and osmotic regulator, a stabilizer, growth factor carrier, a surfactant, and a nutrient. However, the commercially available human serum albumin (HSA) products may not be completely safe since they could be contaminated with viruses and prions. Recombinant human serum albumin (rHSA) has been reported to be as efficient as commercial HSA for fertilization and embryo development. Despite the possible benefits of rHSA, it has not been widely used for embryo culture due to its high cost of production. Our objective was to analyze the redox state of different types of HSA products and rHSA to define oxidative status batch variations of HSA and rHSA and to evaluate the optimal concentration of rHSA for mouse embryo culture. The redox state of the HSA and rHSA used in embryo culture media was found to vary widely. Redox variations were found among different HSA batches as well as among rHSA batches. The highest blastocyst development and hatching rates were obtained with rHSA used at a concentration of 0.05 mg/mL. We showed that very low concentrations of rHSA were most favorable for advanced mouse embryo development in culture. PMID:23050831

Otsuki, Junko; Nagai, Yasushi; Matsuyama, Yukie; Terada, Tomoyoshi; Era, Seiichi

2012-10-10

350

EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas  

PubMed Central

Cushing disease is a condition in which the pituitary gland releases excessive adrenocorticotropic hormone (ACTH) as a result of an adenoma arising from the ACTH-secreting cells in the anterior pituitary. ACTH-secreting pituitary adenomas lead to hypercortisolemia and cause significant morbidity and mortality. Pituitary-directed medications are mostly ineffective, and new treatment options are needed. As these tumors express EGFR, we tested whether EGFR might provide a therapeutic target for Cushing disease. Here, we show that in surgically resected human and canine corticotroph cultured tumors, blocking EGFR suppressed expression of proopiomelanocortin (POMC), the ACTH precursor. In mouse corticotroph EGFR transfectants, ACTH secretion was enhanced, and EGF increased Pomc promoter activity, an effect that was dependent on MAPK. Blocking EGFR activity with gefitinib, an EGFR tyrosine kinase inhibitor, attenuated Pomc expression, inhibited corticotroph tumor cell proliferation, and induced apoptosis. As predominantly nuclear EGFR expression was observed in canine and human corticotroph tumors, we preferentially targeted EGFR to mouse corticotroph cell nuclei, which resulted in higher Pomc expression and ACTH secretion, both of which were inhibited by gefitinib. In athymic nude mice, EGFR overexpression enhanced the growth of explanted ACTH-secreting tumors and further elevated serum corticosterone levels. Gefitinib treatment decreased both tumor size and corticosterone levels; it also reversed signs of hypercortisolemia, including elevated glucose levels and excess omental fat. These results indicate that inhibiting EGFR signaling may be a novel strategy for treating Cushing disease.

Fukuoka, Hidenori; Cooper, Odelia; Ben-Shlomo, Anat; Mamelak, Adam; Ren, Song-Guang; Bruyette, Dave; Melmed, Shlomo

2011-01-01

351

Conservation and divergence in the transcriptional programs of the human and mouse immune systems.  

PubMed

Much of the knowledge about cell differentiation and function in the immune system has come from studies in mice, but the relevance to human immunology, diseases, and therapy has been challenged, perhaps more from anecdotal than comprehensive evidence. To this end, we compare two large compendia of transcriptional profiles of human and mouse immune cell types. Global transcription profiles are conserved between corresponding cell lineages. The expression patterns of most orthologous genes are conserved, particularly for lineage-specific genes. However, several hundred genes show clearly divergent expression across the examined cell lineages, and among them, 169 genes did so even with highly stringent criteria. Finally, regulatory mechanisms--reflected by regulators' differential expression or enriched cis-elements--are conserved between the species but to a lower degree, suggesting that distinct regulation may underlie some of the conserved transcriptional responses. PMID:23382184

Shay, Tal; Jojic, Vladimir; Zuk, Or; Rothamel, Katherine; Puyraimond-Zemmour, David; Feng, Ting; Wakamatsu, Ei; Benoist, Christophe; Koller, Daphne; Regev, Aviv

2013-02-04

352

Beige Adipocytes are a Distinct Type of Thermogenic Fat Cell in Mouse and Human  

PubMed Central

Summary Brown fat defends against hypothermia and obesity through thermogenesis mediated by mitochondrial UCP1. Recent data suggest that there are two distinct types of brown fat: classical brown fat derived from a myf-5 cellular lineage and UCP1-positive cells that emerge in white fat from a non-myf-5 lineage. Here we report the cloning of “beige” cells from murine white fat depots. Beige cells resemble white fat cells in having extremely low basal expression of UCP1, but like classical brown fat, they respond to cyclic AMP stimulation with high UCP1 expression and respiration rates. Beige cells have a gene expression pattern distinct from either white or brown fat and are preferentially sensitive to the polypeptide hormone irisin. Finally, we show that deposits of brown fat previously observed in adult humans are composed of beige adipose cells. These data illustrate a new cell type with therapeutic potential in mouse and human.

Wu, Jun; Bostrom, Pontus; Sparks, Lauren M.; Ye, Li; Choi, Jang Hyun; Giang, An-Hoa; Khandekar, Melin; Nuutila, Pirjo; Schaart, Gert; Huang, Kexin; Tu, Hua; van Marken Lichtenbelt, Wouter D.; Hoeks, Joris; Enerback, Sven; Schrauwen, Patrick; Spiegelman, Bruce M.

2012-01-01

353

Conservation and divergence in the transcriptional programs of the human and mouse immune systems  

PubMed Central

Much of the knowledge about cell differentiation and function in the immune system has come from studies in mice, but the relevance to human immunology, diseases, and therapy has been challenged, perhaps more from anecdotal than comprehensive evidence. To this end, we compare two large compendia of transcriptional profiles of human and mouse immune cell types. Global transcription profiles are conserved between corresponding cell lineages. The expression patterns of most orthologous genes are conserved, particularly for lineage-specific genes. However, several hundred genes show clearly divergent expression across the examined cell lineages, and among them, 169 genes did so even with highly stringent criteria. Finally, regulatory mechanisms—reflected by regulators’ differential expression or enriched cis-elements—are conserved between the species but to a lower degree, suggesting that distinct regulation may underlie some of the conserved transcriptional responses.

Shay, Tal; Jojic, Vladimir; Zuk, Or; Rothamel, Katherine; Puyraimond-Zemmour, David; Feng, Ting; Wakamatsu, Ei; Benoist, Christophe; Koller, Daphne; Regev, Aviv

2013-01-01

354

A transgenic mouse model for studying the clearance of blood-borne pathogens via human complement receptor 1 (CR1)  

PubMed Central

Complement receptor 1 (CR1) on the surface of human erythrocytes facilitates intravascular clearance of complement-opsonized pathogens. The need for complement activation can be circumvented by directly coupling the organism to CR1 using a bispecific monoclonal antibody heteropolymer (HP). Lack of a functional homologue to CR1 on mouse erythrocytes has made it difficult to study HP-dependent clearance of pathogens in small animals. We have developed a transgenic mouse that expresses human CR1 on erythrocytes. CR1 antigen is of appropriate size and in a clustered distribution as confirmed by immunoblotting and fluorescence microscopy, respectively. HP that immobilized bacteriophage ?X174 prototype pathogen to erythrocyte CR1 of the transgenic mice increased the rate of clearance of the virus compared with HP that bound bacteriophage, but not CR1. This transgenic mouse model will allow evaluation of different HPs for their in vivo efficacy and potential as human therapeutics.

Repik, A; Pincus, S E; Ghiran, I; Nicholson-Weller, A; Asher, D R; Cerny, A M; Casey, L S; Jones, S M; Jones, S N; Mohamed, N; Klickstein, L B; Spitalny, G; Finberg, R W

2005-01-01

355

Deep-coverage rhesus red blood cell proteome: a first comparison with the human and mouse red blood cell  

PubMed Central

Background. Macaques are the closest evolutionary relatives of humans routinely used in basic and applied biomedical research. Their genetic, physiological, immunological and metabolic similarity to humans, second only to that of the great apes, makes them invaluable models of human disease. These similarities also mean that macaques are often the only experimental models available for evaluating increasingly specific drugs in development, and as a proof-of-concept bridge can help reduce the numbers of compounds that fail in clinical pharmaceutical research. In vertebrates, red blood cells (RBCs) diseases are frequently severe as their role as sole gas transporter makes them indispensable to survival; much research has therefore focused on an in-depth understanding of the functioning of the RBC. RBCs also host malaria, babesia and other parasites. Recently, we presented an in-depth proteome for the human RBC and a comparative human/mouse RBC proteome. Material and methods. Here, we present directly comparable data for the human, mouse and rhesus RBC proteomes. All proteins were identified, validated and categorized in terms of sub-cellular localization, protein family and function and, in comparison with the human and mouse RBC, were classified as orthologues, family-related or unique. Splice isoforms were identified and polypeptides migrating with anomalous apparent molecular weights were grouped into putatively ubiquitinylated or partially degraded complexes. Results and Discussion. Overall there was close concordance between mouse, human and rhesus proteomes, confirming the unexpected RBC complexity. Several novel findings in the human and mouse proteomes have been confirmed here. This comparison sheds light on several open issues in RBC biology and provides a departure point for more comprehensive understanding of RBC function.

Pasini, Erica M.; Kirkegaard, Morten; Mortensen, Peter; Mann, Matthias; Thomas, Alan W.

2010-01-01

356

Enhanced antitumor activity of a combination treatment with a mouse\\/human chimeric anti-MK-1 antibody and lymphokine-activated killer cells in vitro and in a severe combined immunodeficient mouse xenograft model  

Microsoft Academic Search

Mouse monoclonal antibody FU-MK-1, raised against a human gastric adenocarcinoma, recognizes a glycoprotein antigen (termed\\u000a MK-1 antigen) present on most carcinomas and seems to be valuable in immunodiagnosis and immunotherapy of various cancers.\\u000a In a recent study, we constructed a mouse\\/human chimeric antibody, designated Ch FU-MK-1, by fusing the FU-MK-1 VH and V? genes to the human C?1 and C?

Takafumi Yamamoto; Fumiko Arakawa; Ken Nakamura; Tarumi Senba; Yoshihiro Tomita; Seiyo Ikeda; Masahide Kuroki

1999-01-01

357

Novel NG36\\/G9a gene products encoded within the human and mouse MHC class III regions  

Microsoft Academic Search

.   Previous annotation of the Class III region of the human Major Histocompatibility Complex (MHC) depicts NG36 as an independent\\u000a gene, which lies immediately centromeric to the G9a gene. However, data presented in this report show that in human and mouse\\u000a cells the NG36 and G9a genes are predominantly expressed within a single ?3.9-kbp transcript. Thus, the human NG36\\/G9a gene

Stephanie E. Brown; R. Duncan Campbell; Christopher M. Sanderson

2001-01-01

358

Development of Functional Human NK Cells in an Immunodeficient Mouse Model with the Ability to Provide Protection against Tumor Challenge  

Microsoft Academic Search

Studies of human NK cells and their role in tumor suppression have largely been restricted to in vitro experiments which lack the complexity of whole organisms, or mouse models which differ significantly from humans. In this study we showed that, in contrast to C57BL\\/6 Rag2?\\/?\\/?c?\\/? and NOD\\/Scid mice, newborn BALB\\/c Rag2?\\/?\\/?c?\\/? mice can support the development of human NK cells

Amanda Kwant-Mitchell; Elishka A. Pek; Kenneth L. Rosenthal; Ali A. Ashkar; Johan K. Sandberg

2009-01-01

359

Mouse adenovirus (MAV1) expression in primary human endothelial cells and generation of a full-length infectious plasmid  

Microsoft Academic Search

Using RT-PCR, we show that mouse adenovirus type I (MAV-1) is capable of infecting and expressing in various cell types, specifically human endothelial cells. The capability of MAV-1 to infect and express in human endothelial cells makes it a potentially useful alternative to the use of human adenoviruses type 2\\/5 (Ad2\\/5) in virus-based gene therapy, although presently MAV-1 can only

T T Nguyen; J P Nery; S Joseph; C E Rocha; G E Carney; K R Spindler; L P Villarreal

1999-01-01

360

Specificity and rate of human and mouse liver and plasma phosphatidylcholine synthesis analyzed in vivo.  

PubMed

Phosphatidylcholine (PC) synthesis by the direct cytidine diphosphate choline (CDP-choline) pathway in rat liver generates predominantly mono- and di-unsaturated molecular species, while polyunsaturated PC species are synthesized largely by the phosphatidylethanolamine-N-methyltransferase (PEMT) pathway. Although altered PC synthesis has been suggested to contribute to development of hepatocarcinoma and nonalcoholic steatohepatitis, analysis of the specificity of hepatic PC metabolism in human patients has been limited by the lack of sensitive and safe methodologies. Here we incorporated a deuterated methyl-D(9)-labled choline chloride, to quantify biosynthesis fluxes through both of the PC synthetic pathways in vivo in human volunteers and compared these fluxes with those in mice. Rates and molecular specificities of label incorporated into mouse liver and plasma PC were very similar and strongly suggest that label incorporation into human plasma PC can provide a direct measure of hepatic PC synthesis in human subjects. Importantly, we demonstrate for the first time that the PEMT pathway in human liver is selective for polyunsaturated PC species, especially those containing docosahexaenoic acid. Finally, we present a multiple isotopomer distribution analysis approach, based on transfer of deuterated methyl groups to S-adenosylmethionine and subsequent sequential methylations of PE, to quantify absolute flux rates through the PEMT pathway that are applicable to studies of liver dysfunction in clinical studies. PMID:21068006

Pynn, Christopher J; Henderson, Neil G; Clark, Howard; Koster, Grielof; Bernhard, Wolfgang; Postle, Anthony D

2010-11-10

361

Targeted Skipping of Human Dystrophin Exons in Transgenic Mouse Model Systemically for Antisense Drug Development  

PubMed Central

Antisense therapy has recently been demonstrated with great potential for targeted exon skipping and restoration of dystrophin production in cultured muscle cells and in muscles of Duchenne Muscular Dystrophy (DMD) patients. Therapeutic values of exon skipping critically depend on efficacy of the drugs, antisense oligomers (AOs). However, no animal model has been established to test AO targeting human dystrophin exon in vivo systemically. In this study, we applied Vivo-Morpholino to the hDMD/mdx mouse, a transgenic model carrying the full-length human dystrophin gene with mdx background, and achieved for the first time more than 70% efficiency of targeted human dystrophin exon skipping in vivo systemically. We also established a GFP-reporter myoblast culture to screen AOs targeting human dystrophin exon 50. Antisense efficiency for most AOs is consistent between the reporter cells, human myoblasts and in the hDMD/mdx mice in vivo. However, variation in efficiency was also clearly observed. A combination of in vitro cell culture and a Vivo-Morpholino based evaluation in vivo systemically in the hDMD/mdx mice therefore may represent a prudent approach for selecting AO drug and to meet the regulatory requirement.

Lu, Peijuan; Cloer, Caryn; Zillmer, Allen; Shaban, Mona; Lu, Qi Long

2011-01-01

362

Transcription factors link mouse WAP-T mammary tumors with human breast cancer.  

PubMed

Mouse models are important tools to decipher the molecular mechanisms of mammary carcinogenesis and to mimic the respective human disease. Despite sharing common phenotypic and genetic features, the proper translation of murine models to human breast cancer remains a challenging task. In a previous study we showed that in the SV40 transgenic WAP-T mice an active Met-pathway and epithelial-mesenchymal characteristics distinguish low- and high-grade mammary carcinoma. To assign these murine tumors to corresponding human tumors we here incorporated the analysis of expression of transcription factor (TF) coding genes and show that thereby a more accurate interspecies translation can be achieved. We describe a novel cross-species translation procedure and demonstrate that expression of unsupervised selected TFs, such as ELF5, HOXA5 and TFCP2L1, can clearly distinguish between the human molecular breast cancer subtypes--or as, for example, expression of TFAP2B between yet unclassified subgroups. By integrating different levels of information like histology, gene set enrichment, expression of differentiation markers and TFs we conclude that tumors in WAP-T mice exhibit similarities to both, human basal-like and non-basal-like subtypes. We furthermore suggest that the low- and high-grade WAP-T tumor phenotypes might arise from distinct cells of tumor origin. Our results underscore the importance of TFs as common cross-species denominators in the regulatory networks underlying mammary carcinogenesis. PMID:23161608

Otto, Benjamin; Streichert, Thomas; Wegwitz, Florian; Gevensleben, Heidrun; Klätschke, Kristin; Wagener, Christoph; Deppert, Wolfgang; Tolstonog, Genrich V

2012-12-13

363

Chimeric antibody with human constant regions and mouse variable regions directed against carcinoma-associated antigen 17-1A  

SciTech Connect

The authors have cloned the genomic DNA fragments encoding the heavy and light chain variable regions of monoclonal antibody 17-1A, and they have inserted them into mammalian expression vectors containing genomic DNA segments encoding human ..gamma..3 and kappa constant regions. The transfer of these expression vectors containing mouse-human chimeric immunoglobulin genes into Sp2/0 mouse myeloma cells resulted in the production of functional IgG that retained the specific binding to the surface antigen 17-1A expressed on colorectal carcinoma cells.

Sun, L.K.; Curtis, P.; Rakowicz-Szulczynska, E.; Ghrayeb, J.; Chang, N.; Morrison, S.L.; Koprowski, H.

1987-01-01

364

Comparison of chemical-induced changes in proliferation and apoptosis in human and mouse neuroprogenitor cells.  

PubMed

There is a need to develop rapid and efficient models to screen chemicals for their potential to cause developmental neurotoxicity. Use of in vitro neuronal models, including human cells, is one approach that allows for timely, cost-effective toxicity screening. The present study compares the sensitivity of human (ReN CX) and mouse (mCNS) neuroprogenitor cell lines to chemicals using a multiplex assay for proliferation and apoptosis, endpoints that are critical for neural development. Cells were exposed to 0.001-100 ?M concentrations of 11 chemicals (cadmium, chlorpyrifos oxon, dexamethasone, dieldrin, ketamine, lead, maneb, methylmercury, nicotine, trans-retinoic acid, and trimethyltin) reported in the literature to affect proliferation and/or apoptosis, and 5 chemicals (dimethyl pthalate, glyphosate, omeprazole, saccharin, and d-sorbitol) with no reports of effects on either endpoint. High-content screening of markers for proliferation (BrdU incorporation) and apoptosis (activated caspase 3 and p53) was used to assess the effect of chemicals in both cell lines. Of the chemicals tested, methylmercury, cadmium, dieldrin, chlorpyrifos oxon, trans-retinoic acid, and trimethyltin decreased proliferation by at least 50% of control in either the ReN CX or mCNS cells. None of the chemicals tested activated caspase 3 or p53 in the ReN CX cells, while methylmercury, cadmium, dieldrin, chlorpyrifos oxon, trimethyltin, and glyphosate all induced at least a doubling in these apoptotic markers in the mCNS cells. Compared to control, cadmium, trans-retinoic acid, and trimethyltin decreased cell viability (ATP levels) by at least 50% in the ReN CX cells, while cadmium, dieldrin, and methylmercury decreased viability by at least 50% in the mCNS cells. Based on these results, BrdU is an appropriate marker for assessing chemical effects on proliferation, and human cells are more sensitive than mouse cells for this endpoint. By contrast, caspase 3 and p53 were altered by environmental chemicals in mouse, but not in human cells. Therefore, these markers are not appropriate to assess the ability of environmental chemicals to induce apoptosis in the ReN CX cells. PMID:22634143

Culbreth, Megan E; Harrill, Joshua A; Freudenrich, Theresa M; Mundy, William R; Shafer, Timothy J

2012-05-25

365

FGF ligand family mRNA expression profile for mouse preimplantation embryos, early gestation human placenta, and mouse trophoblast stem cells.  

PubMed

Signaling by fibroblast growth factor (FGF) is essential is for trophoblast stem (TS) cells and preimplantation embryos. FGF4 provides essential signaling, but the expression of the complete set of 23 FGF family members has not been analyzed. Here, semi-quantitative RT-PCR and microarray analyses were used to define expression of all FGF ligand mRNA. RT-PCR was done for developmentally important FGF subfamilies, FGF10/FGF22 and FGF8/FGF17/FGF18 as well as FGF11. FGF4 and FGF18 are detected at highest levels by RT-PCR and microarrays. FGF10 was detected at low levels in both assays. FGF11 was detected at moderate levels by microarray, but not by RT-PCR. FGF17 was detected at low levels by array and moderate levels by RT-PCR. FGF8 and FGF22 were detected by RT-PCR, but not by microarrays during late cleavage divisions. FGF8, FGF5, and FGF9 were detected in the oocyte by microarray. FGF2, FGF3, and FGF7 were not detected by RT-PCR or microarrays and FGF13, FGF14, and FGF23 were not detected by microarray. Since a major role of FGF is to maintain TS cells, we tested human and mouse placental cell lines and early gestation human placenta for expression of FGF ligands. Expression in mouse TS cells was compared with preimplantation embryos, and human placental cell line expression was compared with human placenta, to infer which ligands are expressed in placental lineage vs. other cell lineages. The data suggest that human and mouse placenta share FGF18 and its high expression suggests preimplantation and early placental function. PMID:16470835

Zhong, W; Wang, Q T; Sun, T; Wang, F; Liu, J; Leach, R; Johnson, A; Puscheck, E E; Rappolee, D A

2006-05-01

366

Cytotoxic effects of propiconazole and its metabolites in mouse and human hepatoma cells and primary mouse hepatocytes  

Microsoft Academic Search

Propiconazole is a triazole-containing fungicide that is used agriculturally on grasses, fruits, grains, seeds, hardwoods, and conifers. Propiconazole is a mouse liver hepatotoxicant and a hepatocarcinogen that has adverse reproductive and developmental toxicities in experimental animals. The goal of this study was to investigate the cytotoxic responses of propiconazole and its metabolites to determine if metabolism of this agent differentially

Pei-Jen Chen; Tanya Moore; Stephen Nesnow

2008-01-01

367

Isoform specificity of human Na(+), K(+)-ATPase localization and aldosterone regulation in mouse kidney cells.  

PubMed

Short-term aldosterone coordinately regulates the cell-surface expression of luminal epithelial sodium channels (ENaC) and of basolateral Na(+) pumps (Na(+), K(+)-ATPase alpha1-beta1) in aldosterone-sensitive distal nephron (ASDN) cells. To address the question of whether the subcellular localization of the Na(+), K(+)-ATPase and its regulation by aldosterone depend on subunit isoform-specific structures, we expressed the cardiotonic steroid-sensitive human alpha isoforms 1-3 by retroviral transduction in mouse collecting duct mpkCCD(c14) cells. Each of the three exogenous human isoforms could be detected by Western blotting. Immunofluorescence indicated that the exogenous alpha1 subunit to a large extent localizes to the basolateral membrane or close to it, whereas much of the alpha2 subunit remains intracellular. An ouabain-sensitive current carried by exogenous pumps could be detected in apically amphotericin B-permeabilized epithelia expressing human alpha1 and alpha2 subunits, but not the alpha3 subunit. This current displayed a higher apparent Na(+) affinity in pumps containing human alpha2 subunits (10 mM) than in pumps containing human alpha1 (33.2 mM) or endogenous (cardiotonic steroid-resistant) mouse alpha1 subunits (mean: 16.3 mM). A very low mRNA level of the Na(+), K(+)-ATPase gamma subunit (FXYD2) in mpkCCD(c14) cells suggested that this ancillary gene product is not responsible for the relatively low apparent Na(+) affinity measured for a1 subunit-containing pumps. Aldosterone increased the pump current carried by endogenous pumps and by pumps containing the human alpha1 subunit. In contrast, the current carried by pumps with a human alpha2 subunit was not stimulated by the same treatment. In summary, quantitative basolateral localization of the Na(+), K(+)-ATPase and its responsiveness to aldosterone require alpha1 subunit-specific sequences that differentiate this isoform from the alpha2 and alpha3 subunit isoforms. PMID:14694143

Summa, Vanessa; Camargo, Simone M R; Bauch, Christian; Zecevic, Marija; Verrey, François

2003-12-23

368

Comparative mapping on the mouse and human X chromosomes of a human cDNA clone encoding the vasopressin renal-type receptor (AVP2R)  

SciTech Connect

Mutation in the gene for the human renal-type vasopressin receptor (V2R) have recently been identified in patients with nephrogenic diabetes insipidus (NDI). Both V2R and NDI have been independently mapped to Xq28. Using a combination of genetic and physical mapping, we have localized the murine V2r locus to within 100 kb of L1Cam on the mouse X chromosome in a region syntenic with human Xq28. Based on conserved gene order of mouse and human loci in this region, physical mapping using DNA derived form human lymphoblasts has established that the corresponding human loci V2R and L1CAM are linked within 210 kb. The efficiency and precision of genetic mapping of V2r and other loci in the mouse suggest that it might be easier to map additional human genes in the mouse first and infer the corresponding human location. More precise physical mapping in man could then be performed using pulsed-field gel electrophoresis and/or yeast artificial chromosomes. 16 refs., 1 fig. 1 tab.

Faust, C.J.; Gonzales, J.C.; Seibold, A.; Birnbaumer, M.; Herman, G.E. (Baylor College of Medicine, Houston, TX (United States))

1993-02-01

369

Sex and gonadal hormones in mouse models of Alzheimer's disease: what is relevant to the human condition?  

PubMed Central

Biologic sex and gonadal hormones matter in human aging and diseases of aging such as Alzheimer’s – and the importance of studying their influences relates directly to human health. The goal of this article is to review the literature to date on sex and hormones in mouse models of Alzheimer’s disease (AD) with an exclusive focus on interpreting the relevance of findings to the human condition. To this end, we highlight advances in AD and in sex and hormone biology, discuss what these advances mean for merging the two fields, review the current mouse model literature, raise major unresolved questions, and offer a research framework that incorporates human reproductive aging for future studies aimed at translational discoveries in this important area. Unraveling human relevant pathways in sex and hormone-based biology may ultimately pave the way to novel and urgently needed treatments for AD and other neurodegenerative diseases.

2012-01-01

370

Meta-Profiles of Gene Expression during Aging: Limited Similarities between Mouse and Human and an Unexpectedly Decreased Inflammatory Signature  

PubMed Central

Background Skin aging is associated with intrinsic processes that compromise the structure of the extracellular matrix while promoting loss of functional and regenerative capacity. These processes are accompanied by a large-scale shift in gene expression, but underlying mechanisms are not understood and conservation of these mechanisms between humans and mice is uncertain. Results We used genome-wide expression profiling to investigate the aging skin transcriptome. In humans, age-related shifts in gene expression were sex-specific. In females, aging increased expression of transcripts associated with T-cells, B-cells and dendritic cells, and decreased expression of genes in regions with elevated Zeb1, AP-2 and YY1 motif density. In males, however, these effects were contrasting or absent. When age-associated gene expression patterns in human skin were compared to those in tail skin from CB6F1 mice, overall human-mouse correspondence was weak. Moreover, inflammatory gene expression patterns were not induced with aging of mouse tail skin, and well-known aging biomarkers were in fact decreased (e.g., Clec7a, Lyz1 and Lyz2). These unexpected patterns and weak human-mouse correspondence may be due to decreased abundance of antigen presenting cells in mouse tail skin with age. Conclusions Aging is generally associated with a pro-inflammatory state, but we have identified an exception to this pattern with aging of CB6F1 mouse tail skin. Aging therefore does not uniformly heighten inflammatory status across all mouse tissues. Furthermore, we identified both intercellular and intracellular mechanisms of transcriptome aging, including those that are sex- and species-specific.

Swindell, William R.; Johnston, Andrew; Sun, Liou; Xing, Xianying; Fisher, Gary J.; Bulyk, Martha L.; Elder, James T.; Gudjonsson, Johann E.

2012-01-01

371

Evaluation of Depigmenting Activity by 8-Hydroxydaidzein in Mouse B16 Melanoma Cells and Human Volunteers  

PubMed Central

In our previous study, 8-hydroxydaidzein (8-OHDe) was demonstrated to be a potent and unique suicide substrate of mushroom tyrosinase. In this study, the compound was evaluated for in vitro cellular tyrosinase and melanogenesis inhibitory activities in mouse B16 melanoma cells and for in vivo skin-whitening activity in human volunteers. Tyrosinase activity and melanogenesis in the cell culture incubated with 10 ?M of 8-OHDe were decreased to 20.1% and 51.8% of control, respectively, while no obvious cytotoxicity was observed in this concentration. In contrast, a standard tyrosinase inhibitor, kojic acid, showed 69.9% and 71.3% of control in cellular tyrosinase and melanogenesis activity, respectively, at a concentration as high as 100 ?M. Hence, 8-OHDe exhibited more than an inhibitory effects on melanin production in B16 cells 10-fold stronger than kojic acid. In addition, when a cream containing 4% 8-OHDe was applied to human skin in an in vivo study, significant increases in the dL*-values were observed after three weeks. Moreover, the increase in the dL*-values after 8-week treatment with 4% 8-OHDe (from ?0.57 to 1.94) is stronger than those of 2% 8-OHDe treatment (from 0.26 to 0.94) and 2% ascorbic acid-2-glucoside treatment (from 0.07 to 1.54). From the results of the study, it was concluded that 8-OHDe, the potent suicide substrate of mushroom tyrosinase, has depigmenting activities in both mouse melanoma cells and in human volunteers. Thus, the compound has significant potential for use in cosmetics as a skin-whitening ingredient.

Tai, Sorgan Shou-Ku; Lin, Ching-Gong; Wu, Mon-Han; Chang, Te-Sheng

2009-01-01

372

Evaluation of depigmenting activity by 8-hydroxydaidzein in mouse B16 melanoma cells and human volunteers.  

PubMed

In our previous study, 8-hydroxydaidzein (8-OHDe) was demonstrated to be a potent and unique suicide substrate of mushroom tyrosinase. In this study, the compound was evaluated for in vitro cellular tyrosinase and melanogenesis inhibitory activities in mouse B16 melanoma cells and for in vivo skin-whitening activity in human volunteers. Tyrosinase activity and melanogenesis in the cell culture incubated with 10 microM of 8-OHDe were decreased to 20.1% and 51.8% of control, respectively, while no obvious cytotoxicity was observed in this concentration. In contrast, a standard tyrosinase inhibitor, kojic acid, showed 69.9% and 71.3% of control in cellular tyrosinase and melanogenesis activity, respectively, at a concentration as high as 100 microM. Hence, 8-OHDe exhibited more than an inhibitory effects on melanin production in B16 cells 10-fold stronger than kojic acid. In addition, when a cream containing 4% 8-OHDe was applied to human skin in an in vivo study, significant increases in the dL*-values were observed after three weeks. Moreover, the increase in the dL*-values after 8-week treatment with 4% 8-OHDe (from -0.57 to 1.94) is stronger than those of 2% 8-OHDe treatment (from 0.26 to 0.94) and 2% ascorbic acid-2-glucoside treatment (from 0.07 to 1.54). From the results of the study, it was concluded that 8-OHDe, the potent suicide substrate of mushroom tyrosinase, has depigmenting activities in both mouse melanoma cells and in human volunteers. Thus, the compound has significant potential for use in cosmetics as a skin-whitening ingredient. PMID:20057943

Tai, Sorgan Shou-Ku; Lin, Ching-Gong; Wu, Mon-Han; Chang, Te-Sheng

2009-11-20

373

Metastatic MHC class I-negative mouse cells derived by transformation with human papillomavirus type 16  

PubMed Central

In the endeavour to develop a model for studying gene therapy of cancers associated with human papillomaviruses (HPVs), mouse cells were transformed with the HPV type 16 (HPV16) and activated H-ras oncogenes. This was done by contransfection of plasmid p16HHMo, carrying the HPV16 E6/E7 oncogenes, and plasmid pEJ6.6, carrying the gene coding for human H-ras oncoprotein activated by G12V mutation, into secondary C57BL/6 mouse kidney cells. An oncogenic cell line, designated MK16/1/IIIABC, was derived. The epithelial origin of the cells was confirmed by their expression of cytokeratins. No MHC class I and class II molecules were detected on the surface of MK16/1/IIIABC cells. Spontaneous metastases were observed in lymphatic nodes and lungs after prolonged growth of MK16/1/IIIABC-induced subcutaneous tumours. Lethally irradiated MK16/1/IIIABC cells induced protection against challenge with 105homologous cells, but not against a higher cell dose (5 × 105). Plasmids p16HHMo and pEJ6.6 were also used for preventive immunization of mice. In comparison with a control group injected with pBR322, they exhibited moderate protection, in terms of prolonged survival, against MK16/1/IIIABC challenge (P< 0.03). These data suggest that MK16/1/IIIABC cells may serve as a model for studying immune reactions against HPV16-associated human tumours. © 2001 Cancer Research Campaign http://www.bjcancer.com

Smahel, M; Sobotkova, E; Bubenik, J; Simova, J; Zak, R; Ludvikova, V; Hajkova, R; Kovarik, J; Jelinek, F; Povysil, C; Marinov, J; Vonka, V

2001-01-01

374

Different biodistribution of 99mTc-labelled chimeric mouse-human monoclonal antibody between athymic mice model and human.  

PubMed Central

Biodistribution of chimeric mouse/human monoclonal antibody against non-specific cross-reacting antigen (chNCA Ab) was studied in athymic mice and patients with metastatic bone disease. 99mTc-chNCA Ab showed a high labelling efficiency, stability and also a high binding ratio to human granulocytes. Since NCA showed cross-reactivity with carcinoembryonic antigen (CEA), animal experiments showed that 99mTc-chNCA Ab was accumulated in the xenografted tumour which expressed CEA, suggesting the preserved immunoreactivity of labelled materials. In the clinical study, injected 99mTc-chNCA Ab formed a high molecular weight complex immediately after intravenous administration and was trapped mainly in liver. The first-phase plasma half-life was 6.4 +/- 1.1 min. None of the patients showed adverse reaction or human antimurine or anti-chimeric antibody in their serum. 99mTc-chNCA Ab demonstrated remarkably different biodistribution between patients and the animal model and showed different pharmacokinetics from other murine and chimeric Abs reported previously. For safety HPLC analysis should be performed before clinical radioimmunodetection or radioimmunotherapy by incubating radiolabelled MAb with human serum under strict conditions. Images Figure 2 Figure 3 Figure 4

Oriuchi, N.; Watanabe, N.; Sugiyama, S.; Higuchi, T.; Imai, K.; Yamanaka, H.; Hashimoto, M.; Kanda, H.; Endo, K.

1996-01-01

375

Involvement of central opioid systems in human interferon-? induced immobility in the mouse forced swimming test  

PubMed Central

We investigated the mechanism by which human interferon-? (IFN-?) increases the immobility time in a forced swimming test, an animal model of depression.Central administration of IFN-? (0.05–50 IU per mouse, i.cist.) increased the immobility time in the forced swimming test in mice in a dose-dependent manner.Neither IFN-? nor -? possessed any effect under the same experimental conditions.Pre-treatment with an opioid receptor antagonist, naloxone (1?mg?kg?1, s.c.) inhibited the prolonged immobility time induced by IFN-? (60?KIU?kg?1, i.v. or 50 IU per mouse. i.cist.).Peripheral administration of naloxone methiodide (1?mg?kg?1, s.c.), which does not pass the blood–brain barrier, failed to block the effect of IFN-?, while intracisternal administration of naloxone methiodide (1?nmol per mouse) completely blocked.The effect of IFN-? was inhibited by a ?1-specific opioid receptor antagonist, naloxonazine (35?mg?kg?1, s.c.) and a ?1/?2 receptor antagonist, ?-FNA (40?mg?kg?1, s.c.). A selective ?-opioid receptor antagonist, naltrindole (3?mg?kg?1, s.c.) and a ?-opioid receptor antagonist, nor-binaltorphimine (20?mg?kg?1, s.c.), both failed to inhibit the increasing effect of IFN-?.These results suggest that the activator of the central opioid receptors of the ?1-subtype might be related to the prolonged immobility time of IFN-?, but ? and ?-opioid receptors most likely are not involved.

Makino, Mitsuhiro; Kitano, Yutaka; Komiyama, Chika; Hirohashi, Masaaki; Takasuna, Kiyoshi

2000-01-01

376

Ultrastructural and biochemical alterations induced in human, rat and mouse hepatocytes in primary culture exposed to selected carcinogens  

SciTech Connect

Aflatoxin B1 (AFB{sub 1}), dimethylnitrosamine (DMN), 2-acetylaminofluorene (2-AAF) and actinomycin D are all potential human liver carcinogens. In order to investigate carcinogenic susceptibility of human liver to these agents, primary cultures of normal human hepatocytes were exposed to the four carcinogens. In the first series of experiments, human, rat, and mouse hepatocytes in primary culture were exposed to actinomycin D, AFB{sub 1}, and DMN for 24 h and examined for ultrastructural alterations. In an effort to relate the ultrastructural effects with total covalent binding of the carcinogen to DNA, human, rat and mouse hepatocytes were exposed to 2.0 {times} 10{sup {minus}7} M ({sup 3}H)AFB{sub 1} for 24 h. Hepatocytes from male rats had the highest degree of ({sup 3}H)AFB{sub 1}-DNA binding. Human hepatocytes contained the next highest binding level, while hepatocytes from female rats bound 38 pmoles/mg DNA. The AFB{sub 1}-DNA binding level in mouse hepatocytes was 1.4 pmoles/mg DNA. In similar experiments, human, and male and female rat hepatocytes in primary culture were exposed to the carcinogen 2-acetylamino (9-{sup 14}C)fluorene for 24 h. It was determined that male rat hepatocytes had the highest amount of radiolabeled 2-AAF bound to their DNA, female rats contained 0.57 nmoles/mg DNA, while human hepatocytes contained 0.29 nmoles/mg DNA.

Cole, K.H.

1987-01-01

377

Expression and functional properties of mouse B7/BB1 using a fusion protein between mouse CTLA4 and human gamma 1.  

PubMed Central

We report the construction and expression of a fusion protein made from the extracellular portion of the mouse CTLA-4 gene and the constant region of human IgG1. This fusion protein behaves like an antibody to mouse B7/BB1, binding to activated B cells and purified dendritic cells. In addition, we found it to bind to activated T cells. The fusion protein interfered with the ability of antigen-pulsed antigen-presenting cells to induce proliferation of T-cell clones, although the degree of inhibition varied. These findings are discussed in the light of the physiological activation of T cells in secondary lymphoid organs. Images Figure 1

Lane, P; Gerhard, W; Hubele, S; Lanzavecchia, A; McConnell, F

1993-01-01

378

A Human-SCID Mouse Model for Allergic Immune Responses: Bacterial Superantigen Enhances Skin Inflammation and Suppresses IgE Production  

Microsoft Academic Search

Chronic skin colonization with Staphylococcus aureus is a well-known feature in atopic dermatitis. The aim of this study was to develop a human-SCID mouse model to analyze the possible role of bacterial superantigens in human allergic immune responses under in vivo conditions. SCID mice were reconstituted with peripheral blood mononuclear cells (between 2 and 9 × 107 cells per mouse)

Udo Herz; Norbert Schnoy; Siegfried Borelli; Lorenz Weigl; Ulrich Käsbohrer; Angelika Daser; Ulrich Wahn; Eckart Köttgen; Harald Renz

1998-01-01

379

NEUROD2 and NEUROD3 genes map to human chromosomes 17q12 and 5q23-q31 and mouse chromosomes 11 and 13, respectively  

SciTech Connect

NEUROD2 and NEUROD3 are transcription factors involved in neurogenesis that are related to the basic helix-loop-helix protein NEUROD. NEUROD2 maps to human chromosome 17q12 and mouse chromosome 11. NEUROD3 maps to human chromosome 5q23-q31 and mouse chromosome 13. 16 refs., 2 figs.

Tamimi, R.M.; Montgomery-Dyer, K.; Tapscott, S.J. [Fred Hutchinson Cancer Research Center, Seattle, WA (United States)] [and others

1997-03-01

380

The Mouse Hoxd13 spdh Mutation, a Polyalanine Expansion Similar to Human Type II Synpolydactyly (SPD), Disrupts the Function but Not the Expression of Other Hoxd Genes  

Microsoft Academic Search

Polyalanine expansion in the human HOXD13 gene induces synpolydactyly (SPD), an inherited congenital limb malformation. A mouse model was isolated, which showed a spontaneous alanine expansion due to a 21-bp duplication at the corresponding place in the mouse gene. This mutation (synpolydactyly homolog, spdh), when homozygous, causes malformations in mice similar to those seen in affected human patients. We have

Sylvia Bruneau; Kenneth R. Johnson; Masakazu Yamamoto; Atsushi Kuroiwa; Denis Duboule

2001-01-01

381

Primary biliary cirrhosis in the mouse: induction by human mycoplasma-like organisms.  

PubMed Central

Human intraocular and orbital chronic inflammatory disease with autoimmune features has been reported to be caused by mycoplasma-like organisms (MLO). MLO are intracellular cell-wall deficient pathogenic bacteria, closely related to rickettsia, with a characteristic ultrastrural pleomorphic tubulo-spherical and filamentous appearance. No culture system has been developed for MLO and diagnosis of MLO disease is made by detecting these bacteria within infected cells using a transmission electron microscope. In human MLO ocular and orbital disease the organisms are found in parasitized leucocytes at the disease site. Inoculation of human MLO into mouse eyelids produces a high incidence of orbital and introcular disease. MLO disseminate to produce randomly distributed lethal systemic disease with infected leucocytes found in all disease sites and with similar histologic features in all disease sites. Microvasculitis is the initial lesion. Disease progression results in lysis of vascular and parenchymal structures, stromal lymphocytic infiltrates, granulomas, and fibrosis. This report describes the hepatic portal chronic progressive inflammatory disease in 11 of 100 of those mice versus 0 in 200 controls. MLO parasitized portal leucocytes are present in all 11 inflamed livers versus 0 in 5 control livers (P less than 0.05). The resemblance of the animal liver disease induced by MLO to human primary biliary cirrhosis and rifampin treatment of MLO disease are discussed. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8

Johnson, L.; Wirostko, E.; Wirostko, W.

1990-01-01

382

Null mutations in human and mouse orthologs frequently result in different phenotypes  

PubMed Central

One-to-one orthologous genes of relatively closely related species are widely assumed to have similar functions and cause similar phenotypes when deleted from the genome. Although this assumption is the foundation of comparative genomics and the basis for the use of model organisms to study human biology and disease, its validity is known only from anecdotes rather than from systematic examination. Comparing documented phenotypes of null mutations in humans and mice, we find that >20% of human essential genes have nonessential mouse orthologs. These changes of gene essentiality appear to be associated with adaptive evolution at the protein-sequence, but not gene-expression, level. Proteins localized to the vacuole, a cellular compartment for waste management, are highly enriched among essentiality-changing genes. It is probable that the evolution of the prolonged life history in humans required enhanced waste management for proper cellular function until the time of reproduction, which rendered these vacuole proteins essential and generated selective pressures for their improvement. If our gene sample represents the entire genome, our results would mean frequent changes of phenotypic effects of one-to-one orthologous genes even between relatively closely related species, a possibility that should be considered in comparative genomic studies and in making cross-species inferences of gene function and phenotypic effect.

Liao, Ben-Yang; Zhang, Jianzhi

2008-01-01

383

Human endometrial cell coculture reduces the endocrine disruptor toxicity on mouse embryo development  

PubMed Central

Backgrounds Previous studies suggested that endocrine disruptors (ED) are toxic on preimplantation embryos and inhibit development of embryos in vitro culture. However, information about the toxicity of endocrine disruptors on preimplantation development of embryo in human reproductive environment is lacking. Methods Bisphenol A (BPA) and Aroclor 1254 (polychlorinated biphenyls) were used as endocrine disruptors in this study. Mouse 2-cell embryos were cultured in medium alone or vehicle or co-cultured with human endometrial epithelial layers in increasing ED concentrations. Results At 72 hours the percentage of normal blastocyst were decreased by ED in a dose-dependent manner while the co-culture system significantly enhanced the rate and reduced the toxicity of endocrine disruptors on the embryonic development in vitro. Conclusions In conclusion, although EDs have the toxic effect on embryo development, the co-culture with human endometrial cell reduced the preimplantation embryo from it thereby making human reproductive environment protective to preimplantation embryo from the toxicity of endocrine disruptors.

2012-01-01

384

The Human Splice Variant ?16HER2 Induces Rapid Tumor Onset in a Reporter Transgenic Mouse  

PubMed Central

Several transgenic mice models solidly support the hypothesis that HER2 (ERBB2) overexpression or mutation promotes tumorigenesis. Recently, a HER2 splice variant lacking exon-16 (?16HER2) has been detected in human breast carcinomas. This alternative protein, a normal byproduct of HER2, has an increased transforming potency compared to wild-type (wt) HER2 receptors. To examine the ability of ?16HER2 to transform mammary epithelium in vivo and to monitor ?16HER2-driven tumorigenesis in live mice, we generated and characterized a mouse line that transgenically expresses both human ?16HER2 and firefly luciferase under the transcriptional control of the MMTV promoter. All the transgenic females developed multifocal mammary tumors with a rapid onset and an average latency of 15.11 weeks. Immunohistochemical analysis revealed the concurrent expression of luciferase and the human ?16HER2 oncogene only in the mammary gland and in strict correlation with tumor development. Transgenic ?16HER2 expressed on the tumor cell plasma membrane from spontaneous mammary adenocarcinomas formed constitutively active homodimers able to activate the oncogenic signal transduction pathway mediated through Src kinase. These new transgenic animals demonstrate the ability of the human ?16HER2 isoform to transform “per se” mammary epithelium in vivo. The high tumor incidence as well as the short latency strongly suggests that the ?16HER2 splice variant represents the transforming form of the HER2 oncoprotein.

Iezzi, Manuela; Zenobi, Santa; Montani, Maura; Pietrella, Lucia; Kalogris, Cristina; Rossini, Anna; Ciravolo, Valentina; Castagnoli, Lorenzo; Tagliabue, Elda; Pupa, Serenella M.; Musiani, Piero; Monaci, Paolo; Menard, Sylvie; Amici, Augusto

2011-01-01