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1

Genetically Altered Plant Species  

NASA Technical Reports Server (NTRS)

Researchers in Robert Ferl's lab at the University of Florida in Gainesville, genetically altered this Arabdopsis Thaliana (a brassica species) plant to learn how extreme environments, such as the low atmospheric pressure on Mars, affect plant genes. They inserted green fluorescent protein (GFP) near the on/off switches for anoxia and drought genes. When those genes were turned on after exposure to reduced atmospheric pressure, GFP was turned on as well, causing cells expressing those genes to glow green under a blue light. The natural fluorescence of chlorophyll accounts for the red glow.

2003-01-01

2

Genomewide transcriptional changes associated with genetic alterations and nutritional supplementation affecting tryptophan metabolism in Bacillus subtilis  

PubMed Central

DNA microarrays comprising ?95% of the Bacillus subtilis annotated protein coding ORFs were deployed to generate a series of snapshots of genomewide transcriptional changes that occur when cells are grown under various conditions that are expected to increase or decrease transcription of the trp operon segment of the aromatic supraoperon. Comparisons of global expression patterns were made between cells grown in the presence of indole acrylic acid, a specific inhibitor of tRNATrp charging; cells deficient in expression of the mtrB gene, which encodes the tryptophan-activated negative regulatory protein, TRAP; WT cells grown in the presence or absence of two or three of the aromatic amino acids; and cells harboring a tryptophanyl tRNA synthetase mutation conferring temperature-sensitive tryptophan-dependent growth. Our findings validate expected responses of the tryptophan biosynthetic genes and presumed regulatory interrelationships between genes in the different aromatic amino acid pathways and the histidine biosynthetic pathway. Using a combination of supervised and unsupervised statistical methods we identified ?100 genes whose expression profiles were closely correlated with those of the genes in the trp operon. This finding suggests that expression of these genes is influenced directly or indirectly by regulatory events that affect or are a consequence of altered tryptophan metabolism.

Berka, Randy M.; Cui, Xianju; Yanofsky, Charles

2003-01-01

3

Genetic Alterations in Glioma  

PubMed Central

Gliomas are the most common type of primary brain tumor and have a dismal prognosis. Understanding the genetic alterations that drive glioma formation and progression may help improve patient prognosis by identification of novel treatment targets. Recently, two major studies have performed in-depth mutation analysis of glioblastomas (the most common and aggressive subtype of glioma). This systematic approach revealed three major pathways that are affected in glioblastomas: The receptor tyrosine kinase signaling pathway, the TP53 pathway and the pRB pathway. Apart from frequent mutations in the IDH1/2 gene, much less is known about the causal genetic changes of grade II and III (anaplastic) gliomas. Exceptions include TP53 mutations and fusion genes involving the BRAF gene in astrocytic and pilocytic glioma subtypes, respectively. In this review, we provide an update on all common events involved in the initiation and/or progression across the different subtypes of glioma and provide future directions for research into the genetic changes.

Bralten, Linda B. C.; French, Pim J.

2011-01-01

4

Genetic alterations in breast cancer  

Microsoft Academic Search

The development of neoplasms is the result of the accumulation of genetic alterations. In breast cancer, large efforts have been dedicated to unravel these genetic alterations and to find associations between specific genetic alterations and the clinical and pathological characteristics of the tumour. There has been rapid advancement of the available techniques to identify new genetic alterations; technical advancement will

M. J. van de Vijver

2000-01-01

5

Genetic alterations in gliomas  

Microsoft Academic Search

Conclusion It would seem that distinct genetic changes in different genes, the protein products of which interact in particular growth control mechanism may lead to the same cellular abnormality. This is exemplified in the case of the gliomas by the ways in which p53 and the Rb1 phosphorylation mechanisms may be rendered impotent. It seems likely that many further genetic

V. P. Collins

1995-01-01

6

Stable genetic alterations of ?-catenin and ROR2 regulate the Wnt pathway, affect the fate of MSCs.  

PubMed

The Wnt pathways have been shown to be critical for the fate of mesenchymal stem cells (MSCs) in vitro, but their roles in MSCs in vivo remain poorly characterized due to the lack of stable alterations in their signaling. In the present study, we constructed long-term and stable mMSCs lines with activated and inactivated ?-catenin (the key molecule of the canonical Wnt signaling pathway) or ROR2 (the key molecule of the noncanonical Wnt5a/ROR2 signaling pathway) modifications with lentiviral vectors. We found that the transduction efficiencies mediated by the lentiviral vectors were 92.61-97.04% and were maintained over 20 passages of mMSCs. Transfection by lentiviral vectors not only regulated the mRNA and protein expression of ?-catenin or ROR2 but also regulated nuclear ?-catenin accumulation or the Wnt5a/JNK and Wnt5a/PKC pathways belonging to the canonical Wnt and noncanonical Wnt5a/ROR2 pathways, respectively. ?-Catenin or ROR2 gene overexpression promoted mMSC proliferation, migration and differentiation into osteoblasts, while inhibiting the adipogenic differentiation of mMSCs. In contrast, inactivation of the ?-catenin or ROR2 genes resulted in the opposite effects. Therefore, these results confirm that lentiviral vector transduction can facilitate sustained and efficient gene modification of the Wnt pathway in mMSCs. This study provides a method to investigate the effects of the Wnt pathway on the fate of mMSCs in vivo and for the further improvement of MSC-based therapies. PMID:24590964

Cai, Shi-Xia; Liu, Ai-Ran; He, Hong-Li; Chen, Qi-Hong; Yang, Yi; Guo, Feng-Mei; Huang, Ying-Zi; Liu, Ling; Qiu, Hai-Bo

2014-06-01

7

Poliovirus internal ribosome entry segment structure alterations that specifically affect function in neuronal cells: molecular genetic analysis.  

PubMed

Translation of poliovirus RNA is driven by an internal ribosome entry segment (IRES) present in the 5' noncoding region of the genomic RNA. This IRES is structured into several domains, including domain V, which contains a large lateral bulge-loop whose predicted secondary structure is unclear. The primary sequence of this bulge-loop is strongly conserved within enteroviruses and rhinoviruses: it encompasses two GNAA motifs which could participate in intrabulge base pairing or (in one case) could be presented as a GNRA tetraloop. We have begun to address the question of the significance of the sequence conservation observed among enterovirus reference strains and field isolates by using a comprehensive site-directed mutagenesis program targeted to these two GNAA motifs. Mutants were analyzed functionally in terms of (i) viability and growth kinetics in both HeLa and neuronal cell lines, (ii) structural analyses by biochemical probing of the RNA, and (iii) translation initiation efficiencies in vitro in rabbit reticulocyte lysates supplemented with HeLa or neuronal cell extracts. Phenotypic analyses showed that only viruses with both GNAA motifs destroyed were significantly affected in their growth capacities, which correlated with in vitro translation defects. The phenotypic defects were strongly exacerbated in neuronal cells, where a temperature-sensitive phenotype could be revealed at between 37 and 39.5 degrees C. Biochemical probing of mutated domain V, compared to the wild type, demonstrated that such mutations lead to significant structural perturbations. Interestingly, revertant viruses possessed compensatory mutations which were distant from the primary mutations in terms of sequence and secondary structure, suggesting that intradomain tertiary interactions could exist within domain V of the IRES. PMID:12368304

Malnou, Cécile E; Pöyry, Tuija A A; Jackson, Richard J; Kean, Katherine M

2002-11-01

8

Genetic alterations in gallbladder carcinoma.  

PubMed

Gallbladder carcinoma is an aggressive cancer associated with a poor prognosis. Unfortunately, the precise molecular mechanisms of development and progression of this highly malignant tumor remain unknown. It is still unclear whether loss of heterozygosity (LOH) plays a significant role in gallbladder carcinogenesis, but recent studies have found a high incidence of LOH at several chromosomes in gallbladder carcinoma. In particular, LOH on chromosomes 1p, 3p, 5p, 8p, 9p, 9q, 13q, 16q, and 17p has been highlighted and LOH on 3p, 9p, 13q, 16q, and 17p has been detected in preneoplastic lesions and in the early phase of gallbladder carcinoma during multistep carcinogenesis. The proto-oncogene, K-ras, is the best known genetic alteration in several human neoplasms, including gallbladder carcinoma. The accumulation of these genetic changes leads to a disruption in cell-cycle regulation and also continuous cell proliferation. We present an overview of K-ras alteration and LOH at several chromosome loci in gallbladder carcinoma. Further studies of the molecular mechanism in gallbladder carcinoma and the delineation of the genetic influence involved should promote our understanding of gallbladder carcinogenesis. PMID:15674488

Kuroki, Tamotsu; Tajima, Yoshitsugu; Matsuo, Kei; Kanematsu, Takashi

2005-01-01

9

Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors.  

PubMed

Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome, and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/normal pairs. Two genotypes are evident in rhabdomyosarcoma tumors: those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in rhabdomyosarcoma is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations in NRAS, KRAS, HRAS, FGFR4, PIK3CA, and CTNNB1, we found novel recurrent mutations in FBXW7 and BCOR, providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/RAS/PIK3CA axis affects 93% of cases, providing a framework for genomics-directed therapies that might improve outcomes for patients with rhabdomyosarcoma. Significance: This is the most comprehensive genomic analysis of rhabdomyosarcoma to date. Despite a relatively low mutation rate, multiple genes were recurrently altered, including NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR. In addition, a majority of rhabdomyosarcoma tumors alter the receptor tyrosine kinase/RAS/PIK3CA axis, providing an opportunity for genomics-guided intervention. PMID:24436047

Shern, Jack F; Chen, Li; Chmielecki, Juliann; Wei, Jun S; Patidar, Rajesh; Rosenberg, Mara; Ambrogio, Lauren; Auclair, Daniel; Wang, Jianjun; Song, Young K; Tolman, Catherine; Hurd, Laura; Liao, Hongling; Zhang, Shile; Bogen, Dominik; Brohl, Andrew S; Sindiri, Sivasish; Catchpoole, Daniel; Badgett, Thomas; Getz, Gad; Mora, Jaume; Anderson, James R; Skapek, Stephen X; Barr, Frederic G; Meyerson, Matthew; Hawkins, Douglas S; Khan, Javed

2014-02-01

10

Epigenetic Drivers of Genetic Alterations  

Microsoft Academic Search

DNA methylation plays a key role in the silencing of cancer-related genes, thereby affecting numerous cellular processes, including the cell cycle checkpoint, apoptosis, signal transduction, cell adhesion, and angiogenesis. DNA methylation also affects the expression of genes involved in maintaining the integrity of the genome through DNA repair and detoxification of reactive oxygen species. Here, we discuss how epigenetic changes

Minoru Toyota; Hiromu Suzuki

2010-01-01

11

Distinct Sets of Genetic Alterations in Melanoma  

Microsoft Academic Search

background Exposure to ultraviolet light is a major causative factor in melanoma, although the re- lationship between risk and exposure is complex. We hypothesized that the clinical heterogeneity is explained by genetically distinct types of melanoma with different sus- ceptibility to ultraviolet light. methods We compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF

John A. Curtin; Jane Fridlyand; Toshiro Kageshita; Hetal N. Patel; Klaus J. Busam; Heinz Kutzner; Kwang-Hyun Cho; Setsuya Aiba; Eva-Bettina Bröcker; Philip E. LeBoit; Dan Pinkel; Boris C. Bastian

2010-01-01

12

Gliomagenesis: genetic alterations and mouse models  

Microsoft Academic Search

Glioblastoma multiforme is the most malignant of the primary brain tumours and is almost always fatal. The treatment strategies for this disease have not changed appreciably for many years and most are based on a limited understanding of the biology of the disease. However, in the past decade, characteristic genetic alterations have been identified in gliomas that might underlie the

Eric C. Holland

2001-01-01

13

Effects of energy balance on cancer in genetically altered mice.  

PubMed

Evidence has accumulated from laboratory-based animal experiments and population-based human epidemiological studies that lifestyle factors that affect energy balance, such as caloric intake, nutritional status, and exercise, act in concert with genetic susceptibility to influence cancer development and progression. The use of animal models with specific genetic alterations, in combination with lifestyle modifications that alter overall energy balance, has contributed to a greater understanding of the mechanistic changes occurring during carcinogenesis and to the identification of points of intervention. Studies in our laboratory focusing on the role of energy balance and genetic susceptibility in mice deficient in one (+/-) or both (-/-) alleles of the p53 tumor suppressor gene and mice with a mutant APC allele (APC(Min)) showed that calorie restriction decreases tumor burden, increases tumor latency, and decreases serum insulin-like growth factor (IGF)-1 and leptin levels. Data from our studies, combined with results from other animal and human studies, have established a role for IGF-1 in carcinogenesis. Studies using genetic models of cancer that have been interbred with mice with abnormal levels of IGF-1 will enable the examination of combined effects of energy balance and genetic alterations on the cancer process. Models that integrate lifestyle and genetic effects in a single system provide a physiologically intact system in which combination interventions and therapies for cancer prevention can be tested and validated, thus building a strong preclinical foundation that will inform the development of clinical trials and add perspective to epidemiological studies. PMID:15570044

Patel, Arti C; Nunez, Nomeli P; Perkins, Susan N; Barrett, J Carl; Hursting, Stephen D

2004-12-01

14

Genetic alterations in human pancreatic cancer  

Microsoft Academic Search

Pancreatic cancers, like many other solid tumors in humans, develop and progress toward malignancy through accumulation of\\u000a multiple genetic alterations. Previous studies demonstrated that point mutations of the c-K-ras gene and inactivation of thep53 gene were frequent events in human pancreatic cancers. The high incidence of mutation at codon 12 of the c-K-ras gene, which is detectable even in early

Yoshinori Murakami

1997-01-01

15

Production of Extracellular Nucleic Acids by Genetically Altered Bacteria in Aquatic-Environment Microcosms.  

National Technical Information Service (NTIS)

Factors which affect the production of extracellular DNA by genetically altered strains of escherichia coli, pseudomonas aeruginosa, pseudomonas cepacia, and bradyrhizobium japonicum in aquatic environments were investigated. The presence or absence of th...

J. H. Paul A. W. David

1989-01-01

16

Molecular genetics in affective illness  

SciTech Connect

Genetic transmission in manic depressive illness (MDI) has been explored in twins, adoption, association, and linkage studies. The X-linked transmission hypothesis has been tested by using several markers on chromosome X: Xg blood group, color blindness, glucose-6-phosphate dehydrogenase (G6PD), factor IX (hemophilia B), and DNA probes such as DXS15, DXS52, F8C, ST14. The hypothesis of autosomal transmission has been tested by association studies with the O blood group located on chromosome 9, as well as linkage studies on chromosome 6 with the Human Leucocyte Antigens (HLA) haplotypes and on Chromosome 11 with DNA markers for the following genes: D2 dopamine receptor, tyrosinase, C-Harvey-Ras-A (HRAS) oncogene, insuline (ins), and tyrosine hydroxylase (TH). Although linkage studies support the hypothesis of a major locus for the transmission of MDI in the Xq27-28 region, several factors are limiting the results, and are discussed in the present review. 105 refs., 1 fig., 2 tabs.

Mendlewicz, J.; Sevy, S.; Mendelbaum, K. (Erasme Univ. Hospital, Brussels (Belgium))

1993-01-01

17

Genetic alterations in glioma and medulloblastoma  

Microsoft Academic Search

Multiple genetic changes take place during tumor development and progression. These genetic changes result in inactivation of tumor suppressor genes and activation of proto-oncogenes. Frequent genetic changes observed in gliomas are losses of chromosomal regions on 9p, 10q, 13q, 17p and on 22. Loss of 10q is seen in more than 80% of the glioblastoma multiforme (GBM) tumors suggesting the

B. K. Ahmed Rasheed; Sandra H. Bigner

1991-01-01

18

Molecular genetic alterations in glioblastomas with oligodendroglial component  

Microsoft Academic Search

Glioblastoma multiforme is the most malignant astrocytic glioma and usually resistant to chemotherapy. A small fraction of glioblastomas may contain areas with histological features of oligodendroglial differentiation. To determine the molecular genetic alterations in such \\

Jürgen A. Kraus; Katrin Lamszus; Nicole Glesmann; Martina Beck; Marietta Wolter; Michael Sabel; Dietmar Krex; Thomas Klockgether; Guido Reifenberger; Uwe Schlegel

2001-01-01

19

Genetic alterations in gastric cancers from British patients  

Microsoft Academic Search

Twenty-six gastric carcinoma and matching normal tissue DNAs, which had previously been analyzed for alterations of the APC (adenomatous polyposis coli) and MCC (mutated in colorectal cancer) genes were further investigated for the following genetic alterations: mutation and loss of heterozygosity (LOH) of the p53 gene, replication error (RER) and LOH at 12 microsatellite repeat loci, and mutation of the

Richa Sud; Dagan Wells; Ian C Talbot; Joy D. A Delhanty

2001-01-01

20

Generation of Genetically Altered Mouse Models for Aging Studies  

Microsoft Academic Search

A number of mouse models have been identified and are being used for aging and age-associated disease research. However, the use of the genetically manipulated mouse model is still a relatively untapped resource for the study of the biology of aging. Genetically altered mice can be powerful tools for biology of aging research because gene expression can be controlled and

P. M. Treuting; H. C. Hopkins; C. A. Ware; P. R. Rabinovitch; W. C. Ladiges

2002-01-01

21

Genetic alterations in syndromes with oral manifestations  

PubMed Central

Ever since Gregor Johan Mendel proposed the law of inheritance, genetics has transcended the field of health and has entered all walks of life in its application. Thus, the gene is the pivoting factor for all happenings revolving around it. Knowledge of gene mapping in various diseases would be a valuable tool in prenatally diagnosing the condition and averting the future disability and stigma for the posterity. This article includes an array of genetically determined conditions in patients seen at our college out-patient department with complete manifestation, partial manifestation and array of manifestations not fitting into a particular syndrome.

Anuthama, Krishnamurthy; Prasad, Harikrishnan; Ramani, Pratibha; Premkumar, Priya; Natesan, Anuja; Sherlin, Herald J.

2013-01-01

22

Genetic alterations in syndromes with oral manifestations.  

PubMed

Ever since Gregor Johan Mendel proposed the law of inheritance, genetics has transcended the field of health and has entered all walks of life in its application. Thus, the gene is the pivoting factor for all happenings revolving around it. Knowledge of gene mapping in various diseases would be a valuable tool in prenatally diagnosing the condition and averting the future disability and stigma for the posterity. This article includes an array of genetically determined conditions in patients seen at our college out-patient department with complete manifestation, partial manifestation and array of manifestations not fitting into a particular syndrome. PMID:24379857

Anuthama, Krishnamurthy; Prasad, Harikrishnan; Ramani, Pratibha; Premkumar, Priya; Natesan, Anuja; Sherlin, Herald J

2013-11-01

23

Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer  

Microsoft Academic Search

Lung cancer has become the leading cause of cancer death in many economically well-developed countries. Recent molecular biological studies have revealed that overt lung cancers frequently develop through sequential morphological steps, with the accumulation of multiple genetic and epigenetic alterations affecting both tumor suppressor genes and dominant oncogenes. Cell cycle progression needs to be properly regulated, while cells have built-in

Hirotaka Osada; Takashi Takahashi

2002-01-01

24

Production of extracellular nucleic acids by genetically altered bacteria in aquatic-environment microcosms  

SciTech Connect

Factors which affect the production of extracellular DNA by genetically altered strains of Escherichia coli, Pseudomonas aeruginosa, Pseudomonas cepacia, and Bradyrhizobium japonicum in aquatic environments were investigated. The presence or absence of the ambient microbial community had little effect on the production of extracellular DNA. Results indicate the extracellular-DNA production by genetically altered bacteria released into aquatic environments is more strongly influenced by physiochemical factors than biotic factors; extracellular-DNA production rates are usually greater for organisms released in freshwater than marine environments; and ambient microbial populations can readily utilize materials released by these organisms.

Paul, J.H.; David, A.W.

1989-01-01

25

Targeting genetic alterations in protein methyltransferases for personalized cancer therapeutics  

PubMed Central

The human protein methyltransferases (PMTs) constitute a large enzyme class composed of two families, the protein lysine methyltransferases (PKMTs) and the protein arginine methyltransferases (PRMTs). Examples have been reported of both PKMTs and PRMTs that are genetically altered in specific human cancers, and in several cases these alterations have been demonstrated to confer a unique dependence of the cancer cells on PMT enzymatic activity for the tumorigenic phenotype. Examples of such driver alterations in PMTs will be presented together with a review of current efforts towards the discovery and development of small-molecule inhibitors of these enzymes as personalized cancer therapeutics.

Copeland, R A; Moyer, M P; Richon, V M

2013-01-01

26

Novel ALPL genetic alteration associated with an odontohypophosphatasia phenotype.  

PubMed

Hypophosphatasia (HPP) is an inherited disorder of mineral metabolism caused by mutations in ALPL, encoding tissue non-specific alkaline phosphatase (TNAP). Here, we report the molecular findings from monozygotic twins, clinically diagnosed with tooth-specific odontohypophosphatasia (odonto-HPP). Sequencing of ALPL identified two genetic alterations in the probands, including a heterozygous missense mutation c.454C>T, leading to change of arginine 152 to cysteine (p.R152C), and a novel heterozygous gene deletion c.1318_1320delAAC, leading to the loss of an asparagine residue at codon 440 (p.N440del). Clinical identification of low serum TNAP activity, dental abnormalities, and pedigree data strongly suggests a genotype-phenotype correlation between p.N440del and odonto-HPP in this family. Computational analysis of the p.N440del protein structure revealed an alteration in the tertiary structure affecting the collagen-binding site (loop 422-452), which could potentially impair the mineralization process. Nevertheless, the probands (compound heterozygous: p.[N440del];[R152C]) feature early-onset and severe odonto-HPP phenotype, whereas the father (p.[N440del];[=]) has only moderate symptoms, suggesting p.R152C may contribute or predispose to a more severe dental phenotype in combination with the deletion. These results assist in defining the genotype-phenotype associations for odonto-HPP, and further identify the collagen-binding site as a region of potential structural importance for TNAP function in the biomineralization. PMID:23791648

Martins, Luciane; Rodrigues, Thaisângela L; Ribeiro, Mariana Martins; Saito, Miki Taketomi; Giorgetti, Ana Paula Oliveira; Casati, Márcio Z; Sallum, Enilson A; Foster, Brian L; Somerman, Martha J; Nociti, Francisco H

2013-10-01

27

Selected genetic disorders affecting Ashkenazi Jewish families.  

PubMed

Ashkenazi Jews of Central and Eastern European ancestry have a disproportionately high prevalence of several autosomal recessive genetic disorders. This article describes these 9 disorders and their genetic inheritance patterns: Bloom syndrome; Canavan disease; cystic fibrosis; familial dysautonomia; Fanconi anemia; Gaucher disease; Mucolipidosis IV; Niemann-Pick disease; and Tay-Sachs disease. Genetic testing, counseling, and family planning options for the at-risk population are described. The role of the community health nurse is addressed. PMID:17149032

Weinstein, Lenore B

2007-01-01

28

Genetic and epigenetic alterations in differentiated thyroid carcinoma  

PubMed Central

Abstract Differentiated thyroid carcinoma (DTC) has a favorable prognosis, but it is important to identify those patients who have a high risk of progressive disease and DTC-related death at the time of diagnosis. Analyzing genetic and epigenetic alterations in thyroid cancer may play a role in tumor diagnosis, prognostic and therapeutic strategies.

Brehar, AC; Brehar, FM; Bulgar, AC; Dumitrache, C

2013-01-01

29

Allende Dark Inclusions Affected by Different Degrees of Aqueous Alteration  

NASA Astrophysics Data System (ADS)

A variety of dark inclusions (DIs) have been reported from Allende and other CV3 chondrites [e. g., 1-3]. It has been controversial whether they were formed in the solar nebula [3] or on the meteorite parent body [2]. Recent studies of some DIs [4, 5] revealed evidence suggesting that they experienced intense aqueous alteration and subsequent thermal metamorphism on the meteorite parent body. We here present the results of petrographic and scanning electron microscope studies of two DIs in Allende that are very different in mineralogy and texture from each other. One of the two DIs (16-S-1), which was previously studied by Fruland et al. [1] and Zolensky and Buchanan [6], contains abundant chondrules that are composed mainly of Mg-rich olivine and pyroxene, embedded in a fine-grained matrix. Although the general petrographic feature appears to be common to the CV3 chondrites, 16-S-1 shows several features indicative of secondary alteration. Mesostasis in most chondrules is filled with fine-grained aggregates of Si-, Al-, Ca-rich phases, which were probably formed by replacing glass. Mg-rich olivine and pyroxene, especially those adjacent to mesostasis and matrix, have Fe-rich rims. Fracture-filling veins mainly of Fe-rich olivine occur both in chondrules and matrix. As reported by Zolensky and Buchanan [6], Fe-rich olivine grains in some portions of the matrix and chondrule mesostasis show fibrous to acicular morphology, suggesting that they were produced by dehydration and thermal transformation of phyllosilicate. The textures suggest that 16-S-1 was affected by relatively minor aqueous alteration, so only the chondrule mesostasis and the edges of Mg-rich olivine and pyroxene were affected. The other DI (DN1) lacks chondrules, but instead contains rounded to oval-shaped inclusions (< 600 micrometers, mostly about 150 micrometers in diameter) that are composed mostly of fine grains (<1 to about 20 micrometers in diameter) of homogeneous Fe-rich olivine (Fo(sub)65 to about 68). Olivine grains in the inclusions commonly show fibrous morphology, suggesting pseudomorphs after phyllosilicate. Matrix is also composed mostly of Fe-rich olivine which is similar in composition to that in the inclusions. Fracture-filling veins abundantly occur around relatively large inclusions. The mineralogical and textural features suggest that DN1 was once involved in intense aqueous alteration, so that original chondrules were almost entirely replaced by phyllosilicate. Subsequently, it was dehydrated by mild heating and transformed to a nearly homogeneous aggregate of Fe-rich olivine grains. The present study reveals that both 16-S-1 and DN1 show evidence that they experienced aqueous alteration and subsequent thermal metamorphism on the meteorite parent body, although they are very different in texture and mineralogy. This suggests that such a sequence of secondary process is not unique to the DIs previously studied [4, 5] but is common to other DIs. The differences in mineralogy and texture of DIs are probably explained by different degrees of aqueous alteration in which each DI was involved before thermal metamorphism. The sequence of alteration was probably a common event that occurred near the surfaces of meteorite parent bodies. We believe that systematic studies of DIs would provide a more precise view regarding the evolution of carbonaceous chondrite parent bodies. References: [1] Fruland R. M. et al. (1978) Proc. LPSC 9th, 1305-1329. [2] Bunch T. E. and Chang S. (1983) LPS XIV, 75-76. [3] Bischoff A. et al. (1988) LPS XIX, 88-89. [4] Kojima T. et al. (1993) Meteoritics, 28, 649-658. [5] Kojima T. and Tomeoka K. (1994) Meteoritics, 29, 484. [6] Zolensky M. E. and Buchanan P. C. (1995) LPS XXVI, 1565-1566.

Kojima, T.; Tomeoka, K.

1995-09-01

30

Genetic alterations in HCA-induced tumors.  

PubMed

Accumulating evidence from molecular oncology indicates that carcinogens may induce tumors through characteristic mutations in characteristic genes for each agent. Identification of specific mutations induced by heterocyclic amines (HCAs), food-borne carcinogens, should facilitate risk assessment of HCAs in man. Identification of characteristic genes affected by HCAs will lead to identification of the genes involved in human carcinogenesis. We therefore examined tumors induced by various HCAs from these two viewpoints. With regard to forestomach tumors induced in CDF1 mice by 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), mutations of Ha-ras and p53 were observed in four of eight and two of four tumors, respectively. One papilloma examined had mutations in both Ha-ras and p53, whereas two carcinomas had only one or the other. For Zymbal gland tumors induced in F344 rats by IQ, mutations of Ha- or Ki-ras were observed in both of two papillomas and in 10 of 13 squamous cell carcinomas (SCCs), while p53 mutations were limited to only four of the SCCs. The ras mutation was thus suggested to be an early event, while p53 mutation was more associated with malignancy. In liver tumors induced in F344 rats by 2-amino-3,8-dimethylimidazo[4, 5-f]quinoxaline (MeIQx), mutations of p53 were observed in one of two moderately-differentiated and two of two poorly-differentiated hepatocellular carcinomas (HCCs). No such changes were found in any of nine well-differentiated HCCs, suggesting p53 mutation to be a very late event. In colon tumors induced in F344 rats by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) (nine adenocarcinomas), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) (two adenomas and nine adenocarcinomas), or 2-amino-6-methyldipyrido[1,2-a:3', 2'-d]imidazole (Glu-P-1) (seven adenocarcinomas), a Ki-ras mutation was found in only one Glu-P-1-induced adenocarcinoma. No p53 mutations could be detected. In mammary gland carcinomas induced in F344 rats by PhIP, Ha-ras was activated in three of 17 carcinomas and p53 was mutated in one of 10 carcinomas. We therefore concluded that other genes were involved in colon and mammary carcinomas. G:C base pairs were involved in all 42 positive cases of the present study, and 36 of them were guanine base mutations. This indicates that the changes in IQ, MeIQx, PhIP and Glu-P-1 tumors were mainly caused by non-transcribed strand modifications through their major DNA adducts, N2-(guanin-8-yl)HCAs. Ha-ras mutations in the forestomach tumors induced by MeIQ were all G to T transversions at the second position of codon 13. Mutation sites of p53 did not appear to be specific in the forestomach, Zymbal gland and liver tumors. PMID:8844820

Ushijima, T; Makino, H; Kakiuchi, H; Inoue, R; Sugimura, T; Nagao, M

1995-01-01

31

Genetic Contributions to Altered Callosal Morphology in Schizophrenia  

Microsoft Academic Search

Patients with schizophrenia exhibit abnormalities in midsagittal corpus callosum area, shape, and\\/or displacement. Our goal was to confirm these findings and to establish the genetic and nongenetic contributions to altered callosal morphology in schizophrenia. Relationships between ventricular enlargements potentially contributing to callosal displacements were as- sessed as a secondary goal. High-resolution magnetic reso- nance images were obtained from co-twins of

Katherine L. Narr; Tyrone D. Cannon; Roger P. Woods; Paul M. Thompson; Sharon Kim; Dina Asunction; Theo G. M. van Erp; Veli-Pekka Poutanen; Matti Huttunen; Jouko Lonnqvist; Jaakko Kaprio; John C. Mazziotta; Arthur W. Toga

2002-01-01

32

Genetic alterations of the CHOP gene in gastric cancers  

Microsoft Academic Search

CHOP, a member of the C\\/EBP family of the transcriptional factor, showed a tumor suppressor activity by binding to TCF and\\u000a inhibiting the Wnt signaling pathway. In this study, to determine whether genetic alterations of CHOP gene are involved in the development and\\/or progression of the gastric cancers, we have screened a set of 47 gastric adenoma\\u000a and 81 sporadic

Jae Hwi Song; Jong Kyung Park; Jeong Whan Yoon; Suk Woo Nam; Jung Young Lee; Won Sang Park

2011-01-01

33

Age-Dependent Prognostic Effects of Genetic Alterations in Glioblastoma  

Microsoft Academic Search

Purpose: Although the genetic alterations in glioblas- toma have been well characterized, reports regarding their prognostic effects have been inconsistent. Experimental Design: In this series of 140 consecutive cases of glioblastoma treated at a single center, we analyzed the frequency, age dependency and prognostic effects of TP53 mutation, CDKN2A\\/p16 deletion, EGFR amplification, as well as loss of chromosome 1p, chromosome

Tracy T. Batchelor; Rebecca A. Betensky; J. Matthew Esposito; Loc-Duyen D. Pham; Molly V. Dorfman; Nicole Piscatelli; Sarah Jhung; David Rhee; David N. Louis

2004-01-01

34

Genetic alterations of the KLF6 gene in gastric cancer  

Microsoft Academic Search

The KLF6 is a zinc-finger tumor suppressor that is frequently mutated in several human cancers and broadly involved in differentiation and development, growth-related signal transduction, cell proliferation, apoptosis, and angiogenesis. To determine whether genetic alterations of KLF6 gene are involved in the development and\\/or progression of gastric cancer, we have screened a set of 80 sporadic gastric cancers for mutations

Yong Gu Cho; Chang Jae Kim; Cho Hyun Park; Young Mok Yang; Su Young Kim; Suk Woo Nam; Sug Hyung Lee; Nam Jin Yoo; Jung Young Lee; Won Sang Park

2005-01-01

35

Genetic Alterations in Poorly Differentiated and Undifferentiated Thyroid Carcinomas  

PubMed Central

Thyroid gland presents a wide spectrum of tumours derived from follicular cells that range from well differentiated, papillary and follicular carcinoma (PTC and FTC, respectively), usually carrying a good prognosis, to the clinically aggressive, poorly differentiated (PDTC) and undifferentiated thyroid carcinoma (UTC). It is usually accepted that PDTC and UTC occur either de novo or progress from a pre-existing well differentiated carcinoma through a multistep process of genetic and epigenetic changes that lead to clonal expansion and neoplastic development. Mutations and epigenetic alterations in PDTC and UTC are far from being totally clarified. Assuming that PDTC and UTC may derive from well differentiated thyroid carcinomas (WDTC), it is expected that some PDTC and UTC would harbour genetic alterations that are typical of PTC and FTC. This is the case for some molecular markers (BRAF and NRAS) that are present in WDTC, PDTC and UTC. Other genes, namely P53, are almost exclusively detected in less differentiated and undifferentiated thyroid tumours, supporting a diagnosis of PDTC or, much more often, UTC. Thyroid-specific rearrangements RET/PTC and PAX8/PPAR?, on the other hand, are rarely found in PDTC and UTC, suggesting that these genetic alterations do not predispose cells to dedifferentiation. In the present review we have summarized the molecular changes associated with the two most aggressive types of thyroid cancer.

Soares, Paula; Lima, Jorge; Preto, Ana; Castro, Patricia; Vinagre, Joao; Celestino, Ricardo; Couto, Joana P; Prazeres, Hugo; Eloy, Catarina; Maximo, Valdemar; Sobrinho-Simoes, M

2011-01-01

36

IndividualizedPath: identifying genetic alterations contributing to the dysfunctional pathways in glioblastoma individuals.  

PubMed

Due to the extensive complexity and high genetic heterogeneity of genetic alterations in cancer, comprehensively depicting the molecular mechanisms of cancer remains difficult. Characterizing personalized pathogenesis in cancer individuals can help to reveal new details of the complex mechanisms. In this study, we proposed an integrative method called IndividualizedPath to identify genetic alterations and their downstream risk pathways from the perspective of individuals through combining the DNA copy number, gene expression data and topological structures of biological pathways. By applying the method to TCGA glioblastoma multiforme (GBM) samples, we identified 394 gene-pathway pairs in 252 GBM individuals. We found that genes with copy number alterations showed high heterogeneity across GBM individuals, whereas they affected relatively consistent biological pathways. A global landscape of gene-pathway pairs showed that EGFR linked with multiple cancer-related biological pathways confers the highest risk of GBM. GBM individuals with MET-pathway pairs showed significantly shorter survival times than those with only MET amplification. Importantly, we found that the same risk pathways were affected by different genes in distinct groups of GBM individuals with a significant pattern of mutual exclusivity. Similarly, GBM subtype analysis revealed some subtype-specific gene-pathway pairs. In addition, we found that some rare copy number alterations had a large effect on contribution to numerous cancer-related pathways. In summary, our method offers the possibility to identify personalized cancer mechanisms, which can be applied to other types of cancer through the web server (). PMID:24911613

Ping, Yanyan; Zhang, Hongyi; Deng, Yulan; Wang, Li; Zhao, Hongying; Pang, Lin; Fan, Huihui; Xu, Chaohan; Li, Feng; Zhang, Yong; Gong, Yonghui; Xiao, Yun; Li, Xia

2014-07-01

37

Genetic alterations in the JAG1 gene in Japanese patients with Alagille syndrome  

Microsoft Academic Search

Alagille syndrome (AGS) is a congenital anomaly syndrome that affects liver, heart, pulmonary artery, eyes, face, and skeleton.\\u000a Recently, mutations of the JAG1 gene, which encodes a ligand for the Notch receptor, have been identified in AGS patients. We investigated the JAG1 gene for genetic alterations in eight Japanese AGS patients, using fluorescence in situ hybridization (FISH), single strand\\u000a conformation

Yoshihiro Onouchi; Hiroki Kurahashi; Hitoshi Tajiri; Shinobu Ida; Shintaro Okada; Yusuke Nakamura; Yusuke Nakamura

1999-01-01

38

Detection of genetic alterations in hereditary colorectal cancer screening.  

PubMed

There are two major hereditary colorectal cancer syndromes: Adenomatous Polyposis, secondary to APC germline alterations (FAP, Familial Adenomatous Polyposis) or secondary to MUTYH germline alterations (MAP, MUTYH associated Polyposis), and Lynch syndrome, associated with germline mutations in mismatch repair genes (MLH1, MSH2, MSH6 and PMS2). The elucidation of their genetic basis has depicted an increasingly complex picture that has lead to the implementation of complex diagnostic algorithms that include both tumor profiling and germline analyses. A variety of techniques at the DNA, RNA and protein level are used to screen for molecular alterations both in tumor biopsies (microsatellite instability analysis, mismatch repair protein immunohistochemistry, BRAF-Val600Glu detection and MLH1 promoter hypermethylation analysis) and in the germline (point mutation screening, copy number assessment). Also functional tests are more often used to characterize variants of unknown significance. Methodological issues associated with the techniques analyzed, as well as the algorithms used, are discussed. PMID:19931546

Pineda, Marta; González, Sara; Lázaro, Conxi; Blanco, Ignacio; Capellá, Gabriel

2010-11-10

39

Genetic Alterations in Colorectal Cancer, Comparative Analysis of Deletion Events, and Point Mutations  

Microsoft Academic Search

Although data on genetic alterations leading to the development of colorectal cancer are abundant, no specific genetic alteration, as has been demonstrated for certain rare tumors such as lymphoma, leukemia, or sarcoma, has been shown to be responsible for the development of colorectal carcinomas. The colorectal cancer phenotype undoubtedly originates from an accumulation of different genetic alterations. The nature of

Cecile Ged; Françoise Bonichon; Hubert de Verneuil; Michel Longy

1998-01-01

40

Safety assessment of genetically modified plants with deliberately altered composition.  

PubMed

The development and marketing of 'novel' genetically modified (GM) crops in which composition has been deliberately altered poses a challenge to the European Union (EU)'s risk assessment processes, which are based on the concept of substantial equivalence with a non-GM comparator. This article gives some examples of these novel GM crops and summarizes the conclusions of a report that was commissioned by the European Food Safety Authority on how the EU's risk assessment processes could be adapted to enable their safety to be assessed. PMID:24735114

Halford, Nigel G; Hudson, Elizabeth; Gimson, Amy; Weightman, Richard; Shewry, Peter R; Tompkins, Steven

2014-08-01

41

Genetic and epigenetic alterations after hybridization and genome doubling  

PubMed Central

Hybridization and polyploidization are now recognized as major phenomena in the evolution of plants, promoting genetic diversity, adaptive radiation and speciation. Modern molecular techniques have recently provided evidence that allopolyploidy can induce several types of genetic and epigenetic events that are of critical importance for the evolutionary success of hybrids: (1) chromosomal rearrangements within one or both parental genomes contribute toward proper meiotic pairing and isolation of the hybrid from its progenitors; (2) demethylation and activation of dormant transposable elements may trigger insertional mutagenesis and changes in local patterns of gene expression, facilitating rapid genomic reorganisation; (3) rapid and reproducible loss of low copy DNA sequence appears to result in further differentiation of homoeologous chromosomes; and (4) organ-specific up- or down-regulation of one of the duplicated genes, resulting in unequal expression or silencing one copy. All these alterations also have the potential, while stabilizing allopolyploid genomes, to produce novel expression patterns and new phenotypes, which together with increased heterozygosity and gene redundancy might confer on hybrids an elevated evolutionary potential, with effects at scales ranging from molecular to ecological. Although important advances have been made in understanding genomic responses to allopolyploidization, further insights are still expected to be gained in the near future, such as the direction and nature of the diploidization process, functional relevance of gene expression alterations, molecular mechanisms that result in adaptation to different ecologies/habitats, and ecological and evolutionary implications of recurrent polyploidization.

Paun, Ovidiu; Fay, Michael F.; Soltis, Douglas E.; Chase, Mark W.

2010-01-01

42

Human genetic variation influences vitamin C homeostasis by altering vitamin C transport and antioxidant enzyme function.  

PubMed

New evidence for the regulation of vitamin C homeostasis has emerged from several studies of human genetic variation. Polymorphisms in the genes encoding sodium-dependent vitamin C transport proteins are strongly associated with plasma ascorbate levels and likely impact tissue cellular vitamin C status. Furthermore, genetic variants of proteins that suppress oxidative stress or detoxify oxidatively damaged biomolecules, i.e., haptoglobin, glutathione-S-transferases, and possibly manganese superoxide dismutase, affect ascorbate levels in the human body. There also is limited evidence for a role of glucose transport proteins. In this review, we examine the extent of the variation in these genes, their impact on vitamin C status, and their potential role in altering chronic disease risk. We conclude that future epidemiological studies should take into account genetic variation in order to successfully determine the role of vitamin C nutriture or supplementation in human vitamin C status and chronic disease risk. PMID:23642198

Michels, Alexander J; Hagen, Tory M; Frei, Balz

2013-01-01

43

Altered Sleep and Affect in the Neurotensin Receptor 1 Knockout Mouse  

PubMed Central

Study Objective: Sleep and mood disorders have long been understood to have strong genetic components, and there is considerable comorbidity of sleep abnormalities and mood disorders, suggesting the involvement of common genetic pathways. Here, we examine a candidate gene implicated in the regulation of both sleep and affective behavior using a knockout mouse model. Design: Previously, we identified a quantitative trait locus (QTL) for REM sleep amount, REM sleep bout number, and wake amount in a genetically segregating population of mice. Here, we show that traits mapping to this QTL correlated with an expression QTL for neurotensin receptor 1 (Ntsr1), a receptor for neurotensin, a ligand known to be involved in several psychiatric disorders. We examined sleep as well as behaviors indicative of anxiety and depression in the NTSR1 knockout mouse. Measurements and Results: NTSR1 knockouts had a lower percentage of sleep time spent in REM sleep in the dark phase and a larger diurnal variation in REM sleep duration than wild types under baseline conditions. Following sleep deprivation, NTSR1 knockouts exhibited more wake and less NREM rebound sleep. NTSR1 knockouts also showed increased anxious and despair behaviors. Conclusions: Here we illustrate a link between expression of the Ntsr1 gene and sleep traits previously associated with a particular QTL. We also demonstrate a relationship between Ntsr1 and anxiety and despair behaviors. Given the considerable evidence that anxiety and depression are closely linked with abnormalities in sleep, the data presented here provide further evidence that neurotensin and Ntsr1 may be a component of a pathway involved in both sleep and mood disorders. Citation: Fitzpatrick K; Winrow CJ; Gotter AL; Millstein J; Arbuzova J; Brunner J; Kasarskis A; Vitaterna MH; Renger JJ; Turek FW. Altered sleep and affect in the neurotensin receptor 1 knockout mouse. SLEEP 2012;35(7):949-956.

Fitzpatrick, Karrie; Winrow, Christopher J.; Gotter, Anthony L.; Millstein, Joshua; Arbuzova, Janna; Brunner, Joseph; Kasarskis, Andrew; Vitaterna, Martha H.; Renger, John J.; Turek, Fred W.

2012-01-01

44

Molecular reconstruction of a fungal genetic code alteration.  

PubMed

Fungi of the CTG clade translate the Leu CUG codon as Ser. This genetic code alteration is the only eukaryotic sense-to-sense codon reassignment known to date, is mediated by an ambiguous serine tRNA (tRNACAG(Ser)), exposes unanticipated flexibility of the genetic code and raises major questions about its selection and fixation in this fungal lineage. In particular, the origin of the tRNACAG(Ser) and the evolutionary mechanism of CUG reassignment from Leu to Ser remain poorly understood. In this study, we have traced the origin of the tDNACAG(Ser) gene and studied critical mutations in the tRNACAG(Ser) anticodon-loop that modulated CUG reassignment. Our data show that the tRNACAG(Ser) emerged from insertion of an adenosine in the middle position of the 5'-CGA-3'anticodon of a tRNACGA(Ser) ancestor, producing the 5'-CAG-3' anticodon of the tRNACAG(Ser), without altering its aminoacylation properties. This mutation initiated CUG reassignment while two additional mutations in the anticodon-loop resolved a structural conflict produced by incorporation of the Leu 5'-CAG-3'anticodon in the anticodon-arm of a tRNA(Ser). Expression of the mutant tRNACAG(Ser) in yeast showed that it cannot be expressed at physiological levels and we postulate that such downregulation was essential to maintain Ser misincorporation at sub-lethal levels during the initial stages of CUG reassignment. We demonstrate here that such low level CUG ambiguity is advantageous in specific ecological niches and we propose that misreading tRNAs are targeted for degradation by an unidentified tRNA quality control pathway. PMID:23619021

Mateus, Denisa D; Paredes, João A; Español, Yaiza; Ribas de Pouplana, Lluís; Moura, Gabriela R; Santos, Manuel A S

2013-06-01

45

Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors  

Microsoft Academic Search

Carcinoid tumors and pancreatic endocrine tumors are uncommon neuroendocrine neoplasms, and their genetic alterations are not well characterized. These tumors have site-specific differences in neuroendocrine characteristics, clinical course and genetic alterations. We compared clinicopathological features and loss of heterozygosity of chromosomes 11q, 16q and 18, and BRAF gene mutations in 47 patients with neuroendocrine tumors including 16 with pancreatic endocrine

Gordon G Wang; James C Yao; Samidha Worah; Jill A White; Rene Luna; Tsung-Teh Wu; Asif Rashid

2005-01-01

46

Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions  

Microsoft Academic Search

Until recently, our understanding of the genetic factors contributing to the pathogenesis of acute lymphoblastic leukemia (ALL) has relied on the detection of gross chromosomal alterations and mutational analysis of individual genes. Although these approaches have identified many important abnormalities, they have been unable to identify the full repertoire of genetic alterations in ALL. The advent of high-resolution, microarray-based techniques

C G Mullighan; J R Downing

2009-01-01

47

The Afterlife of Interspecific Indirect Genetic Effects: Genotype Interactions Alter Litter Quality with Consequences for Decomposition and Nutrient Dynamics  

PubMed Central

Aboveground-belowground linkages are recognized as divers of community dynamics and ecosystem processes, but the impacts of plant-neighbor interactions on these linkages are virtually unknown. Plant-neighbor interactions are a type of interspecific indirect genetic effect (IIGE) if the focal plant’s phenotype is altered by the expression of genes in a neighboring heterospecific plant, and IIGEs could persist after plant senescence to affect ecosystem processes. This perspective can provide insight into how plant-neighbor interactions affect evolution, as IIGEs are capable of altering species interactions and community composition over time. Utilizing genotypes of Solidago altissima and Solidago gigantea, we experimentally tested whether IIGEs that had affected living focal plants would affect litter decomposition rate, as well as nitrogen (N) and phosphorous (P) dynamics after the focal plant senesced. We found that species interactions affected N release and genotype interactions affected P immobilization. From a previous study we knew that neighbor genotype influenced patterns of biomass allocation for focal plants. Here we extend those previous results to show that these changes in biomass allocation altered litter quality, that then altered rates of decomposition and nutrient cycling. Our results provide insights into above- and belowground linkages by showing that, through their effects on plant litter quality (e.g., litter lignin:N), IIGEs can have afterlife effects, tying plant-neighbor interactions to ecosystem processes. This holistic approach advances our understanding of decomposition and nutrient cycling by showing that evolutionary processes (i.e., IIGEs) can influence ecosystem functioning after plant senescence. Because plant traits are determined by the combined effects of genetic and environmental influences, and because these traits are known to affect decomposition and nutrient cycling, we suggest that ecosystem processes can be described as gene-less products of genetic interactions among the species comprising ecological communities.

Genung, Mark A.; Bailey, Joseph K.; Schweitzer, Jennifer A.

2013-01-01

48

33 CFR 149.15 - What is the process for submitting alterations and modifications affecting the design and...  

Code of Federal Regulations, 2013 CFR

...alterations and modifications affecting the design and construction of a deepwater port... DEEPWATER PORTS DEEPWATER PORTS: DESIGN, CONSTRUCTION, AND EQUIPMENT General...alterations and modifications affecting the design and construction of a deepwater...

2013-07-01

49

Comparison of Genetic Profiles Between Primary Melanomas and their Metastases Reveals Genetic Alterations and Clonal Evolution During Progression  

Microsoft Academic Search

To examine for the genetic basis of metastatic progression in cutaneous melanoma, we have compared loss of heterozygosity (LOH) of several selected chromosome regions that are implicated in the initiation and progression of melanoma, and alterations of the p16INK4a gene in 14 pairs of primary tumor and synchronous or asynchronous metastasis excised from the same patients. The most frequent genetic

Reiji Morita; Akihide Fujimoto; Naohito Hatta; Kazuhiko Takehara; Minoru Takata

1998-01-01

50

Genetic by environment interactions affect plant-soil linkages  

PubMed Central

The role of plant intraspecific variation in plant–soil linkages is poorly understood, especially in the context of natural environmental variation, but has important implications in evolutionary ecology. We utilized three 18- to 21-year-old common gardens across an elevational gradient, planted with replicates of five Populus angustifolia genotypes each, to address the hypothesis that tree genotype (G), environment (E), and G × E interactions would affect soil carbon and nitrogen dynamics beneath individual trees. We found that soil nitrogen and carbon varied by over 50% and 62%, respectively, across all common garden environments. We found that plant leaf litter (but not root) traits vary by genotype and environment while soil nutrient pools demonstrated genotype, environment, and sometimes G × E interactions, while process rates (net N mineralization and net nitrification) demonstrated G × E interactions. Plasticity in tree growth and litter chemistry was significantly related to the variation in soil nutrient pools and processes across environments, reflecting tight plant–soil linkages. These data overall suggest that plant genetic variation can have differential affects on carbon storage and nitrogen cycling, with implications for understanding the role of genetic variation in plant–soil feedback as well as management plans for conservation and restoration of forest habitats with a changing climate.

Pregitzer, Clara C; Bailey, Joseph K; Schweitzer, Jennifer A

2013-01-01

51

A Comparison of Molecular Alterations in Environmental and Genetic Rat Models of ADHD: a pilot study  

PubMed Central

Attention Deficit Hyperactivity Disorder (ADHD) is the most common neurobehavioral disorder in school-aged children. In addition to genetic factors, environmental influences or gene × environmental interactions also play an important role in ADHD. One example of a well studied environmental risk factor for ADHD is exposure to polychlorinated biphenyls (PCBs). In this study, we investigated whether the well-established genetic model of ADHD based on the Spontaneously Hypertensive Rat (SHR) and a well established PCB-based model of ADHD exhibited similar molecular changes in brain circuits involved in ADHD. The brains from 28 male rats (8 SHR, 8 Sprague-Dawley (SD) controls, 8 Wistar-Kyoto (WKY) controls, and 4 PCB-exposed SD rats) were harvested at postnatal day 55-65 and RNA was isolated from six brain regions of interest. The RNA was analyzed for differences in expression of a set of 308 probe sets interrogating 218 unique genes considered highly relevant to ADHD or epigenetic gene regulation using the Rat RAE 230 2.0 GeneChip (Affymetrix). Selected observations were confirmed by real time quantitative RT-PCR. The results show that the expression levels of genes Gnal, COMT, Adrbk1, Ntrk2, Hk1, Syt11 and Csnk1a1 were altered in both the SHR rats and the PCB-exposed SD rats. Arrb2, Stx12, Aqp6, Syt1, Ddc and Pgk1 expression levels were changed only in the PCB-exposed SD rats. Genes with altered expression only in the SHRs included Oprm1, Calcyon, Calmodulin, Lhx1 and Hes6. The epigenetic genes Crebbp, Mecp2 and Hdac5 are significantly altered in both models. The data provide strong evidence that genes and environment can affect different set of genes in two different models of ADHD and yet result in the similar disease-like symptoms.

DasBanerjee, Tania; Middleton, Frank A.; Berger, David F.; Lombardo, John P.; Sagvolden, Terje; Faraone, Stephen V.

2008-01-01

52

Genetic, epigenetic and stem cell alterations in endometriosis: new insights and potential therapeutic perspectives.  

PubMed

Human endometrium is a highly dynamic tissue, undergoing periodic growth and regression at each menstrual cycle. Endometriosis is a frequent chronic pathological status characterized by endometrial tissue with an ectopic localization, causing pelvic pain and infertility and a variable clinical presentation. In addition, there is well-established evidence that, although endometriosis is considered benign, it is associated with an increased risk of malignant transformation in approximately 1.0% of affected women, with the involvement of multiple pathways of development. Increasing evidence supports a key contribution of different stem/progenitor cell populations not only in the cyclic regeneration of eutopic endometrium, but also in the pathogenesis of at least some types of endometriosis. Evidence has arisen from experiments in animal models of disease through different kinds of assays (including clonogenicity, the label-retaining cell approach, the analysis of undifferentiation markers), as well as from descriptive studies on ectopic and eutopic tissue samples harvested from affected women. Changes in stem cell populations in endometriotic lesions are associated with genetic and epigenetic alterations, including imbalance of miRNA expression, histone and DNA modifications and chromosomal aberrations. The present short review mainly summarizes the latest observations contributing to the current knowledge regarding the presence and the potential contribution of stem/progenitor cells in eutopic endometrium and the aetiology of endometriosis, together with a report of the most recently identified genetic and epigenetic alterations in endometriosis. We also describe the potential advantages of single cell molecular profiling in endometrium and in endometriotic lesions. All these data can have clinical implications and provide a basis for new potential therapeutic applications. PMID:24059589

Forte, Amalia; Cipollaro, Marilena; Galderisi, Umberto

2014-01-01

53

Distinct Effects of Alcohol Consumption and Smoking on Genetic Alterations in Head and Neck Carcinoma  

PubMed Central

Background Tobacco and alcohol consumption are risk factors for head and neck squamous cell carcinoma (HNSCC). Recently, whole-exome sequencing clarified that smoking increased TP53 and other mutations in HNSCC; however, the effects of alcohol consumption on these genetic alterations remain unknown. We explored the association between alcohol consumption and somatic copy-number alterations (SCNAs) across the whole genome in human papillomavirus (HPV)-negative HNSCCs, and compared with the effects of smoking on genetic alterations. Methods SCNA and TP53 mutations in tumor samples were examined by high-resolution comparative genomic hybridization microarray 180K and by direct sequencing, respectively, and statistically analyzed for associations with alcohol consumption and smoking during the 20 years preceding diagnosis of HNSCC. Probes with a corrected p-value (=q-value) less than 0.05 and fold change greater than 1.2 or less than -1.2 were considered statistically significant. Results A total of 248 patients with HNSCC were enrolled. In the HPV-negative patients (n=221), heavy alcohol consumption was significantly associated with SCNAs of oncogenes/oncosuppressors that were previously reported to occur frequently in HNSCCs: CDKN2A (q=0.005), FHIT (q=0.005), 11q13 region including CCND1, FADD and CTTN (q=0.005), ERBB2 (HER2) (q=0.009), 3q25-qter including CCNL1, TP63, DCUN1D1 and PIK3CA (q=0.014), and CSMD1 (q=0.019). But, TP53 mutations were not affected. In contrast, smoking was associated with increased risk of TP53 mutations, but did not induce any significant SCNAs of oncogenes/oncosuppressors. Conclusion These results suggest that both alcohol consumption and smoking had distinct effects on genetic alterations in HNSCCs. Heavy alcohol consumption may trigger previously known and unknown SCNAs, but may not induce TP53 mutation. In contrast, smoking may induce TP53 mutation, but may not trigger any SCNAs.

Urashima, Mitsuyoshi; Hama, Takanori; Suda, Toshihito; Suzuki, Yutaka; Ikegami, Masahiro; Sakanashi, Chikako; Akutsu, Taisuke; Amagaya, Suguru; Horiuchi, Kazuhumi; Imai, Yu; Mezawa, Hidetoshi; Noya, Miki; Nakashima, Akio; Mafune, Aki; Kato, Takakuni; Kojima, Hiromi

2013-01-01

54

Mucinous and Nonmucinous Appendiceal Adenocarcinomas: Different Clinicopathological Features but Similar Genetic Alterations  

Microsoft Academic Search

The genetic alterations of appendiceal carcinomas have not been reported in detail. We studied the clinicopathological factors and genetic alterations including microsatellite instability, p53 overexpression, and mutations of the K-ras proto-oncogene of 30 appendiceal adenocarcinomas, consisting of 23 mucinous and 7 nonmucinous carcinomas. Sixteen (70%) mucinous carcinomas presented with pseudomyxoma peritonei, but 6 of 7 (86%) nonmucinous carcinomas presented with

Wareef Kabbani; Patrick S. Houlihan; Rajayalaksh Luthra; Asif Rashid

2002-01-01

55

The National Toxicology Program Evaluation of Genetically Altered Mice as Predictive Models for Identifying Carcinogens  

Microsoft Academic Search

ABSTRAC~ National Institute of Environmental Health Sciences researchers are exploring the utility of genetically altered mice to study mech- anisms of carcinogenesis. Two of these mouse models, the Tg.AC (carrier of an activated mouse H-ms oncogene) and the p53+ (heterozygous for the wild-type tumor suppressor gene Trp53), have genetic alterations that appear to hasten their expression of chemically induced tumors.

WILLIAM C. EASTIN; JOSEPH K. HASEMAN; JOEL E MAHLER; JOHN R. BUCHER

1998-01-01

56

Genetic background affects induced pluripotent stem cell generation  

PubMed Central

Introduction The influence of genetic background on the ability to generate induced pluripotent stem cells (iPSCs) has the potential to impact future applications, but has yet to be examined in detail. The purpose of this study was to determine if genetic background affects the efficiency of generating iPSCs during early reprograming as well as the pluripotent stability of the iPSCs during later stages of reprograming. Methods Mouse embryonic fibroblasts (MEFs) were isolated from six strains of mice (NON/LtJ; C57BL/6J; DBA/2J; BALB/cJ; 129S1/SvlmJ; CAST/EiJ) that were selected based on genetic diversity and differences in ability to produce embryonic stem cell (ESC) lines. MEFs were reprogramed via doxycycline-inducible lentiviral transduction of murine Oct4, Klf4, Sox2, and c-Myc. Differences in efficiency to generate iPSCs were assessed by comparing the total number of colonies, the percentage of colonies positive for alkaline phosphatase staining and the percentage of cells positive for SSEA1. iPSC colonies were expanded to establish doxycycline-independent cell lines whose pluripotency was then evaluated via ability to form teratomas in NOD.CB17-Prkdcscid/J mice. Proliferation of non-transduced parent MEFs from each strain was also examined over ten days under conditions that simulated reprograming. Results NON/LtJ and CAST/EiJ strains were more efficient than other strains in generating iPSCs for all parameters measured and parent MEFs from these strains were more proliferative than those from other strains. Doxycycline-independent iPSC lines were established using standard conditions for all strains except BALB/cJ, which required a higher concentration (5x) of leukemia inhibitory factor (LIF). iPSCs from all strains were capable of producing teratomas in NOD.CB17-Prkdcscid/J mice. Conclusions The results of this study suggest that genetic background does affect iPSC generation and pluripotent stability. In addition, our results demonstrate that strain differences in efficiency to generate iPSCs during the early stages of reprograming are correlated with those observed in proliferation of parent MEFs. These findings have important implications both for future iPSC applications as well as for future investigation into determining the genes responsible for reprograming efficiency and stability.

2012-01-01

57

Genetic variants in multidrug and toxic compound extrusion-1, hMATE1, alter transport function.  

PubMed

hMATE1 (human multidrug and toxin compound extrusion-1; encoded by SLC47A1) is thought to have an important function in the renal and hepatic elimination of drugs, endogenous compounds and environmental toxins. The goals of this study were to identify genetic variants of hMATE1 and to determine their effects on hMATE1 transport function. We identified four synonymous and six nonsynonymous, coding region variants in DNA samples from 272 individuals (68 Caucasians, 68 African Americans, 68 Asian Americans and 68 Mexican Americans). The overall prevalence of hMATE1 nonsynonymous variants was relatively low with three singleton variants and three variants having allele frequencies > or =2% in a specific ethnic group. The nonsynonymous hMATE1 variants were constructed and stably transfected into HEK-293 cells. Uptake studies using four known hMATE1 substrates (paraquat, metformin, tetraethylammonium and oxaliplatin) were performed in cells transfected with hMATE1 reference or variants. We found that two singleton variants, G64D and V480M, produced a complete loss of function for all four tested substrates whereas three polymorphic variants (allele frequencies > or =2%), L125F, V338I and C497S, significantly altered the transport function in a substrate-dependent manner. Confocal microscopy studies were consistent with functional studies suggesting that the altered function of the variants was due to altered localization to the plasma membrane. These data suggest that nonsynonymous variants in hMATE1 may alter drug disposition and ultimately affect clinical drug response. PMID:19172157

Chen, Ying; Teranishi, Kristen; Li, Shuanglian; Yee, Sook Wah; Hesselson, Stephanie; Stryke, Doug; Johns, Susan J; Ferrin, Thomas E; Kwok, Pui; Giacomini, Kathleen M

2009-04-01

58

Genetic Variants in Multidrug and Toxic Compound Extrusion 1, hMATE1, Alter Transport Function  

PubMed Central

hMATE1 (human multidrug and toxin compound extrusion-1; encoded by SLC47A1) is thought to have an important function in the renal and hepatic elimination of drugs, endogenous compounds and environmental toxins. The goals of this study were to identify genetic variants of hMATE1 and to determine their effects on hMATE1 transport function. We identified four synonymous and six nonsynonymous, coding region variants in DNA samples from 272 individuals (68 Caucasians, 68 African Americans, 68 Asian Americans and 68 Mexican Americans). The overall prevalence of hMATE1 nonsynonymous variants was relatively low with three singleton variants and three variants having allele frequencies ?2% in a specific ethnic group. The nonsynonymous hMATE1 variants were constructed and stably transfected into HEK-293 cells. Uptake studies using four known hMATE1 substrates (paraquat, metformin, tetraethylammonium and oxaliplatin) were performed in cells transfected with hMATE1 reference or variants. We found that two singleton variants, G64D and V480M, produced a complete loss of function for all four tested substrates whereas three polymorphic variants (allele frequencies ?2%), L125F, V338I and C497S, significantly altered the transport function in a substrate-dependent manner. Confocal microscopy studies were consistent with functional studies suggesting that the altered function of the variants was due to altered localization to the plasma membrane. These data suggest that nonsynonymous variants in hMATE1 may alter drug disposition and ultimately affect clinical drug response.

Chen, Ying; Teranishi, Kristen; Li, Shuanglian; Yee, Sook Wah; Hesselson, Stephanie; Stryke, Doug; Johns, Susan J.; Ferrin, Thomas E.; Kwok, Pui; Giacomini, Kathleen M.

2009-01-01

59

Extensive characterization of genetic alterations in a series of human colorectal cancer cell lines  

Microsoft Academic Search

A number of genetic alterations have been described in colorectal cancers. They include allelic losses on specific chromosomal arms, mutations of oncogenes, tumor suppressor genes and mismatch repair genes, microsatellite instability in coding repeat sequences of target genes and methylation defects in gene promoters. Since these alterations have been reported by different groups on different tumors and cell lines, the

Jacqueline Gayet; Xiao-Ping Zhou; Alex Duval; Sandra Rolland; Jean-Marc Hoang; Paul Cottu; Richard Hamelin

2001-01-01

60

Genetic Alterations in Non-Melanoma Skin Cancer  

Microsoft Academic Search

Non-melanoma skin cancer is common and offers unrivaled opportunities to relate genetic changes to clinical and biologic behavior. Recent technical advances in molecular biology render genetic analysis of even the smallest skin cancers possible. In this review I will discuss the role of p53 gene in skin carcinogenesis, the relation between p53 immunostaining and p53 mutation, and recent evidence for

Jonathan Rees

1994-01-01

61

Analysis of Genetic Alterations Associated with DNA Diploidy, Aneuploidy and Multiploidy in Gastric Cancers  

Microsoft Academic Search

Objective: Recent studies have shown a close association between DNA ploidy status (diploidy, aneuploidy and multiploidy) identified by the crypt isolation technique and specific genetic alterations in colorectal carcinomas. However, such an association has not been elucidated for gastric tumors, even though they share common genetic features with colorectal carcinomas. In the present study, we established an association between DNA

Tamotsu Sugai; Wataru Habano; Yu-Fei Jiao; Masamichi Suzuki; Akinori Takagane; Shin-ichi Nakamura

2005-01-01

62

Distinct Responses of Xenografted Gliomas to Different Alkylating Agents Are Related to Histology and Genetic Alterations  

Microsoft Academic Search

A series of 12 human gliomas was established as xenografts in nude mice and used to evaluate the relationship between histology, genetic parameters, and response to alkylating agents. Eight were high-grade oligodendroglial tumors, and four were glioblastoma. They were charac- terized for their genetic alterations, including those considered as \\

Pascal Leuraud; Luc Taillandier; Jacques Medioni; Lucinda Aguirre-Cruz; Emmanuelle Criniere; Yannick Marie; Michele Kujas; Jean-Louis Golmard; Adrien Duprez; Jean-Yves Delattre; Marc Sanson; Marie-France Poupon

63

Genetically altered mice for evaluation of mode-of-action (MOA)  

EPA Science Inventory

Genetically altered mice for evaluation of mode-of-action (MOA). Barbara D. Abbott, Cynthia J. Wolf, Kaberi P. Das, Christopher S. Lau. (Presented by B. Abbott). This presentation provides an example of the use of genetically modified mice to determine the mode-of-action of r...

64

A natural genetic polymorphism affects retroactive interference in Drosophila melanogaster  

PubMed Central

As environments change, animals update their internal representations of the external world. New information about the environment is learned and retained whereas outdated information is disregarded or forgotten. Retroactive interference (RI) occurs when the retrieval of previously learned information is less available owing to the acquisition of recently acquired information. Even though RI is thought to be a major cause of forgetting, its functional significance is still under debate. We find that natural allelic variants of the Drosophila melanogaster foraging gene known to affect rover and sitter behaviour differ in RI. More specifically, rovers who were previously shown to experience greater environmental heterogeneity while foraging display RI whereas sitters do not. Rover responses are biased towards more recent learning events. These results provide an ecological context to investigate the function of forgetting via RI and a suitable genetic model organism to address the evolutionary relevance of cognitive tasks.

Reaume, Christopher J.; Sokolowski, Marla B.; Mery, Frederic

2011-01-01

65

Evidence that disease-induced population decline changes genetic structure and alters dispersal patterns in the Tasmanian devil  

PubMed Central

Infectious disease has been shown to be a major cause of population declines in wild animals. However, there remains little empirical evidence on the genetic consequences of disease-mediated population declines, or how such perturbations might affect demographic processes such as dispersal. Devil facial tumour disease (DFTD) has resulted in the rapid decline of the Tasmanian devil, Sarcophilus harrisii, and threatens to cause extinction. Using 10 microsatellite DNA markers, we compared genetic diversity and structure before and after DFTD outbreaks in three Tasmanian devil populations to assess the genetic consequences of disease-induced population decline. We also used both genetic and demographic data to investigate dispersal patterns in Tasmanian devils along the east coast of Tasmania. We observed a significant increase in inbreeding (FIS pre/post-disease ?0.030/0.012, P<0.05; relatedness pre/post-disease 0.011/0.038, P=0.06) in devil populations after just 2–3 generations of disease arrival, but no detectable change in genetic diversity. Furthermore, although there was no subdivision apparent among pre-disease populations (?=0.005, 95% confidence interval (CI) ?0.003 to 0.017), we found significant genetic differentiation among populations post-disease (?=0.020, 0.010–0.027), apparently driven by a combination of selection and altered dispersal patterns of females in disease-affected populations. We also show that dispersal is male-biased in devils and that dispersal distances follow a typical leptokurtic distribution. Our results show that disease can result in genetic and demographic changes in host populations over few generations and short time scales. Ongoing management of Tasmanian devils must now attempt to maintain genetic variability in this species through actions designed to reverse the detrimental effects of inbreeding and subdivision in disease-affected populations.

Lachish, S; Miller, K J; Storfer, A; Goldizen, A W; Jones, M E

2011-01-01

66

Evidence that disease-induced population decline changes genetic structure and alters dispersal patterns in the Tasmanian devil.  

PubMed

Infectious disease has been shown to be a major cause of population declines in wild animals. However, there remains little empirical evidence on the genetic consequences of disease-mediated population declines, or how such perturbations might affect demographic processes such as dispersal. Devil facial tumour disease (DFTD) has resulted in the rapid decline of the Tasmanian devil, Sarcophilus harrisii, and threatens to cause extinction. Using 10 microsatellite DNA markers, we compared genetic diversity and structure before and after DFTD outbreaks in three Tasmanian devil populations to assess the genetic consequences of disease-induced population decline. We also used both genetic and demographic data to investigate dispersal patterns in Tasmanian devils along the east coast of Tasmania. We observed a significant increase in inbreeding (F(IS) pre/post-disease -0.030/0.012, P<0.05; relatedness pre/post-disease 0.011/0.038, P=0.06) in devil populations after just 2-3 generations of disease arrival, but no detectable change in genetic diversity. Furthermore, although there was no subdivision apparent among pre-disease populations (?=0.005, 95% confidence interval (CI) -0.003 to 0.017), we found significant genetic differentiation among populations post-disease (?=0.020, 0.010-0.027), apparently driven by a combination of selection and altered dispersal patterns of females in disease-affected populations. We also show that dispersal is male-biased in devils and that dispersal distances follow a typical leptokurtic distribution. Our results show that disease can result in genetic and demographic changes in host populations over few generations and short time scales. Ongoing management of Tasmanian devils must now attempt to maintain genetic variability in this species through actions designed to reverse the detrimental effects of inbreeding and subdivision in disease-affected populations. PMID:20216571

Lachish, S; Miller, K J; Storfer, A; Goldizen, A W; Jones, M E

2011-01-01

67

Does bleeding affect fetal Doppler parameters during genetic amniocentesis?  

PubMed Central

Objective The aim of this study was to investigate the relationship between fetal Doppler parameters and bleeding at insertion points during amniocentesis. Material and Methods This prospective study was conducted between July 2010 and February 2011. A total of 215 amniocentesis procedures were performed during this period. Five patients with Down syndrome were excluded from the study. The remaining 210 patients were divided into Group 1 (bleeding at insertion site) and Group 2 as a control group. One needle type was used for all patients. Umbilical artery resistance index (UARI), umbilical artery pulsatility index (UAPI), middle cerebral artery resistance index (MCARI), middle cerebral artery pulsatility index (MCA PI), and middle cerebral artery peak systolic velocity (MCAPSV) were measured immediately and before and after amniocentesis. Results Bleeding at the insertion point during amniocentesis did not significantly change the UARI (34% increase for Group 1 and 46.5% increase for Group 2, p=0.238), the MCARI (52% increase for Group 1 and 45% increase for Group 2, p=0.622), or the MCAPSV (37% increase for Group 1 and 49% increase for Group 2, p=0.199). UARI, MCARI, MCA PI, and MCAPSV were not significantly altered following amniocentesis in Groups 1 and 2. There was a significant increase in UAPI following amniocentesis only in Group 2. Conclusion Bleeding during genetic amniocentesis did not change umbilical artery and middle cerebral artery Doppler parameters.

Iskender, Cantekin; Tar?m, Ebru; Cok, Tayfun; Kalayc?, Hakan; Parlakgumus, Ayse; Yalc?nkaya, Cem

2014-01-01

68

Genetic Evolution of Shape-Altering Programs for Supersonic Aerodynamics  

NASA Technical Reports Server (NTRS)

Two constrained shape optimization problems relevant to aerodynamics are solved by genetic programming, in which a population of computer programs evolves automatically under pressure of fitness-driven reproduction and genetic crossover. Known optimal solutions are recovered using a small, naive set of elementary operations. Effectiveness is improved through use of automatically defined functions, especially when one of them is capable of a variable number of iterations, even though the test problems lack obvious exploitable regularities. An attempt at evolving new elementary operations was only partially successful.

Kennelly, Robert A., Jr.; Bencze, Daniel P. (Technical Monitor)

2002-01-01

69

Does antiepileptogenesis affect sleep in genetic epileptic rats?  

PubMed

Recently it was established that early long lasting treatment with the anti-absence drug ethosuximide (ETX) delays the occurrence of absences and reduces depressive-like symptoms in a genetic model for absence epilepsy, rats of the WAG/Rij strain. Here it is investigated whether anti-epileptogenesis (chronic treatments with ETX for 2 and 4 months) affects REM sleep in this model. Four groups of weaned male WAG/Rij rats were treated with ETX for 4 months, two groups for 2 months (at 2-3 and 4-5 months of age), the fourth group was untreated. Next, the rats were recorded 6 days after the last day of the treatment for 22.5 h. Non-REM sleep and REM sleep parameters and delta power were analyzed in four characteristic and representative hours of the recoding period. Four months treatment with ETX reduced the amount of REM sleep and REM sleep as percentage of total sleep time. Other sleep parameters were not affected by the treatment. Clear differences between the various hours of the light-dark phase in amounts of non-REM and REM sleep and delta power were found, in line with commonly reported circadian sleep patterns. It can be concluded that the reduction of REM sleep is unique for the early and long lasting chronic treatment. The outcomes may explain our earlier finding that a reduction of REM sleep might alleviate depressive like symptoms. PMID:21946343

van Luijtelaar, Gilles; Wilde, Matthias; Citraro, Rita; Scicchitano, Francesca; van Rijn, Clementina

2012-07-01

70

Genetic alterations in pediatric high-grade astrocytomas  

Microsoft Academic Search

High-grade astrocytomas are tumors that are uncommon in children. Relatively few studies have been performed on their molecular properties and so it is not certain whether they follow different genetic pathways from those described in adult diffuse astrocytomas. In this study, we evaluated 24 pediatric high-grade astrocytomas (11 anaplastic astrocytomas and 13 glioblastomas) all of which were sporadic and primary.

Yue Cheng; Ho-Keung Ng; Shang-Fu Zhang; Min Ding; Jesse Chung-Sean Pang; Jian Zheng; Wai-Sang Poon

1999-01-01

71

Genetic alterations in lobular breast cancer by comparative genomic hybridization  

Microsoft Academic Search

Infiltrating lobular carcinoma (ILC) and infiltrating ductal carcinoma (IDC) are distinguished by their histopathological appearance. However, little is known about the differences in genetic changes between lobular cancers and ductal cancers. We used comparative genomic hybridization (CGH) and compared aberrations in 19 ILCs and 46 IDCs. The total number of aberrations was lower in ILC than in IDC. While the

Takafumi Nishizaki; Karen Chew; Lisa Chu; Jorma Isola; Anne Kallioniemi; Noel Weidner; Frederic M. Waldman

1997-01-01

72

Colorectal cancer and genetic alterations in the Wnt pathway  

Microsoft Academic Search

In colorectal tumours, Wnt pathway genetics continues to be dominated by mutations in the adenomatous polyposis coli (APC) gene. Germline mutations cause familial adenomatous polyposis and at least two-thirds of sporadic colorectal tumours also acquire APC mutations, quite possibly as the initiating events in tumorigenesis. These mutations almost always cause loss of the C-terminal functions of the APC protein –

S Segditsas; I Tomlinson

2006-01-01

73

Genetic alterations in medullary thyroid cancer: diagnostic and prognostic markers.  

PubMed

Medullary thyroid carcinoma (MTC) is a rare calcitonin producing neuroendocrine tumour that originates from the parafollicular C-cells of the thyroid gland. The RET proto-oncogene encodes the RET receptor tyrosine kinase, with consequently essential roles in cell survival, differentiation and proliferation. Somatic or germline mutations of the RET gene play an important role in this neoplasm in development of sporadic and familial forms, respectively. Genetic diagnosis has an important role in differentiating sporadic from familiar MTC. Furthermore, depending on the location of the mutation, patients can be classified into risk classes. Therefore, genetic screening of the RET gene plays a critical role not only in diagnosis but also in assessing the prognosis and course of MTC. PMID:22654561

A, Taccaliti; F, Silvetti; G, Palmonella; M, Boscaro

2011-12-01

74

Genetic Alterations in Medullary Thyroid Cancer: Diagnostic and Prognostic Markers  

PubMed Central

Medullary thyroid carcinoma (MTC) is a rare calcitonin producing neuroendocrine tumour that originates from the parafollicular C-cells of the thyroid gland. The RET proto-oncogene encodes the RET receptor tyrosine kinase, with consequently essential roles in cell survival, differentiation and proliferation. Somatic or germline mutations of the RET gene play an important role in this neoplasm in development of sporadic and familial forms, respectively. Genetic diagnosis has an important role in differentiating sporadic from familiar MTC. Furthermore, depending on the location of the mutation, patients can be classified into risk classes. Therefore, genetic screening of the RET gene plays a critical role not only in diagnosis but also in assessing the prognosis and course of MTC.

A, Taccaliti; F, Silvetti; G, Palmonella; M, Boscaro

2011-01-01

75

Genetic alteration of Zymomonas mobilis for ethanol production  

SciTech Connect

Strain improvement by mutagenesis with UV resulted in Zymomonas mobilis strains which were highly EtOH and temperature tolerant and which were able to produce more than 100 g EtOH /h at EtOH concentrations of 80-90 g/L. Genetic engineering has the potential of producing strains with the ability to ferment starch and cellulose directly to EtOH.

Skotnicki, M.L.; Lee, K.J.; Tribe, D.E.; Rogers, P.L.

1982-01-01

76

Clinical implications of DNA repair genetic alterations in cancer  

Microsoft Academic Search

Summary  The overall prognosis of advanced cancer remains poor. Whilst accumulation of genetic mutations drives the cancerous phenotype,\\u000a it is well known that DNA damaging lesions that lead to such mutations are predominantly monitored and repaired by the highly\\u000a conserved DNA repair machinery in cells. Though chemotherapy as well as radiotherapy remains the mainstay of treatment, it\\u000a is clear that the

L. Gossage; M. Mohammed; S. Madhusudan

2009-01-01

77

Clinicopathologic significance of genetic alterations in hepatocellular carcinoma  

Microsoft Academic Search

Hepatocarcinogenesis may involve multiple mutations with distinctive pathogenetic and clinicopathologic significance. To test this hypothesis, 68 cases of hepatocellular carcinoma (HCC) were studied prospectively for genetic–clinicopathologic correlation. Ten pathologic characteristics were evaluated. TP53 (alias p53) gene mutation was studied by a polymerase chain reaction (PCR)–single-strand conformation polymorphism–sequencing; CDKN2B (alias p15) and CDKN2A (alias p16) gene methylation by methylation-specific PCR; and

A. Pang; I. O. Ng; S. T. Fan; Y. L. Kwong

2003-01-01

78

GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings.  

PubMed

GM1 gangliosidosis and Morquio B syndrome, both arising from beta-galactosidase (GLB1) deficiency, are very rare lysosomal storage diseases with an incidence of about 1:100,000-1:200,000 live births worldwide. Here we report the beta-galactosidase gene (GLB1) mutation analysis of 21 unrelated GM1 gangliosidosis patients, and of 4 Morquio B patients, of whom two are brothers. Clinical features of the patients were collected and compared with those in literature. In silico analyses were performed by standard alignments tools and by an improved version of GLB1 three-dimensional models. The analysed cohort includes remarkable cases. One patient with GM1 gangliosidosis had a triple X syndrome. One patient with juvenile GM1 gangliosidosis was homozygous for a mutation previously identified in Morquio type B. A patient with infantile GM1 gangliosidosis carried a complex GLB1 allele harbouring two genetic variants leading to p.R68W and p.R109W amino acid changes, in trans with the known p.R148C mutation. Molecular analysis showed 27 mutations, 9 of which are new: 5 missense, 3 microdeletions and a nonsense mutation. We also identified four new genetic variants with a predicted polymorphic nature that was further investigated by in silico analyses. Three-dimensional structural analysis of GLB1 homology models including the new missense mutations and the p.R68W and p.R109W amino acid changes showed that all the amino acid replacements affected the resulting protein structures in different ways, from changes in polarity to folding alterations. Genetic and clinical associations led us to undertake a critical review of the classifications of late-onset GM1 gangliosidosis and Morquio B disease. PMID:21497194

Caciotti, Anna; Garman, Scott C; Rivera-Colón, Yadilette; Procopio, Elena; Catarzi, Serena; Ferri, Lorenzo; Guido, Carmen; Martelli, Paola; Parini, Rossella; Antuzzi, Daniela; Battini, Roberta; Sibilio, Michela; Simonati, Alessandro; Fontana, Elena; Salviati, Alessandro; Akinci, Gulcin; Cereda, Cristina; Dionisi-Vici, Carlo; Deodato, Francesca; d'Amico, Adele; d'Azzo, Alessandra; Bertini, Enrico; Filocamo, Mirella; Scarpa, Maurizio; di Rocco, Maja; Tifft, Cynthia J; Ciani, Federica; Gasperini, Serena; Pasquini, Elisabetta; Guerrini, Renzo; Donati, Maria Alice; Morrone, Amelia

2011-07-01

79

GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings  

PubMed Central

GM1 gangliosidosis and Morquio B syndrome, both arising from beta-galactosidase (GLB1) deficiency, are very rare lysosomal storage diseases with an incidence of about 1:100,000– 1:200,000 live births worldwide. Here we report the beta-galactosidase gene (GLB1) mutation analysis of 21 unrelated GM1 gangliosidosis patients, and of 4 Morquio B patients, of whom two are brothers. Clinical features of the patients were collected and compared with those in literature. In silico analyses were performed by standard alignments tools and by an improved version of GLB1 three-dimensional models. The analysed cohort includes remarkable cases. One patient with GM1 gangliosidosis had a triple X syndrome. One patient with juvenile GM1 gangliosidosis was homozygous for a mutation previously identified in Morquio type B. A patient with infantile GM1 gangliosidosis carried a complex GLB1 allele harbouring two genetic variants leading to p.R68W and p.R109W amino acid changes, in trans with the known p.R148C mutation. Molecular analysis showed 27 mutations, 9 of which are new: 5 missense, 3 microdeletions and a nonsense mutation. We also identified four new genetic variants with a predicted polymorphic nature that was further investigated by in silico analyses. Three-dimensional structural analysis of GLB1 homology models including the new missense mutations and the p.R68W and p.R109W amino acid changes, showed that all the amino acids replacements affected the resulting protein structures in different ways, from changes in polarity to folding alterations. Genetic and clinical associations led us to undertake a critical review of the classifications of late-onset GM1 gangliosidosis and Morquio B disease.

Caciotti, Anna; Garman, Scott C; Rivera-Colon, Yadilette; Procopio, Elena; Catarzi, Serena; Ferri, Lorenzo; Guido, Carmen; Martelli, Paola; Parini, Rossella; Antuzzi, Daniela; Battini, Roberta; Sibilio, Michela; Simonati, Alessandro; Fontana, Elena; Salviati, Alessandro; Akinci, Gulcin; Cereda, Cristina; Dionisi-Vici, Carlo; Deodato, Francesca; d'Amico, Adele; d'Azzo, Alessandra; Bertini, Enrico; Filocamo, Mirella; Scarpa, Maurizio; di Rocco, Maja; Tifft, Cynthia J; Ciani, Federica; Gasperini, Serena; Pasquini, Elisabetta; Guerrini, Renzo; Donati, Maria Alice; Morrone, Amelia

2011-01-01

80

CYP4F2 genetic variant alters required warfarin dose  

PubMed Central

Warfarin is an effective, commonly prescribed anticoagulant used to treat and prevent thrombotic events. Because of historically high rates of drug-associated adverse events, warfarin remains underprescribed. Further, interindividual variability in therapeutic dose mandates frequent monitoring until target anticoagulation is achieved. Genetic polymorphisms involved in warfarin metabolism and sensitivity have been implicated in variability of dose. Here, we describe a novel variant that influences warfarin requirements. To identify additional genetic variants that contribute to warfarin requirements, screening of DNA variants in additional genes that code for drug-metabolizing enzymes and drug transport proteins was undertaken using the Affymetrix drug-metabolizing enzymes and transporters panel. A DNA variant (rs2108622; V433M) in cytochrome P450?4F2 (CYP4F2) was associated with warfarin dose in 3 independent white cohorts of patients stabilized on warfarin representing diverse geographic regions in the United States and accounted for a difference in warfarin dose of approximately 1 mg/day between CC and TT subjects. Genetic variation of CYP4F2 was associated with a clinically relevant effect on warfarin requirement.

Caldwell, Michael D.; Awad, Tarif; Johnson, Julie A.; Gage, Brian F.; Falkowski, Mat; Gardina, Paul; Hubbard, Jason; Turpaz, Yaron; Langaee, Taimour Y.; Eby, Charles; King, Cristi R.; Brower, Amy; Schmelzer, John R.; Glurich, Ingrid; Vidaillet, Humberto J.; Yale, Steven H.; Qi Zhang, Kai; Berg, Richard L.

2008-01-01

81

Lack of association between genetic polymorphisms affecting sympathetic activity and tilt-induced vasovagal syncope.  

PubMed

Although the pathophysiology of vasovagal syncope is not completely understood, the involvement of sympathetic nervous system alterations has been suggested. Since predisposition to fainting during orthostatic challenge may be associated with genetic variations, we sought to explore the role of genetic polymorphisms affecting sympathetic nervous system function in the susceptibility to tilt-induced vasovagal syncope. We genotyped 129 subjects with recurrent unexplained syncope who underwent tilt testing, and investigated the recurrence of syncope. The analysed polymorphisms were Arg492Cys (ADRA1A gene), Ser49Gly and Arg389Gly (ADRB1), Arg16Gly and Gln27Glu (ADRB2), 825C/T (GNB3), -1021C/T (DBH) and S/L (SLC6A4). No association of the aforementioned genetic variants with both tilt test outcomes and new syncopal episodes during follow-up was found. None of the considered polymorphisms influencing sympathetic activity is a major risk factor for vasovagal syncope in Italian patients. PMID:20129829

Sorrentino, Sandro; Forleo, Cinzia; Iacoviello, Massimo; Guida, Pietro; D'Andria, Valentina; Favale, Stefano

2010-06-24

82

Early neonatal inflammation affects adult pain reactivity and anxiety related traits in mice: genetic background counts.  

PubMed

Protracted or recurrent pain and inflammation in the early neonatal period may cause long-lasting changes in central neural function. However, more research is necessary to better characterize the long-term behavioral sequelae of such exposure in the neonatal period. Objectives: (1) to study whether timing of postnatal exposure to persistent inflammation alters responsiveness to thermal pain in the adult animal; (2) to assess whether animals experiencing early postnatal chronic inflammation display altered anxiety related behavior; (3) to study the importance of genetic background. Newborn mice (outbred strain, CD1 and F1 hybrid strain, B6C3F1) received an injection of Complete Freund's Adjuvant (CFA) or saline on either postnatal day 1 or 14 (PND1; PND14) into the left hind paw. Pain to radiant heat and anxiety were examined in 12-week-old adult animals. Adult baseline PWL was significantly decreased in CD1 mice exposed to CFA on PND 1 and 14 as compared to their saline treated counterparts. B6C3F1 mice exposed to CFA on PND14 showed markedly reduced baseline PWL compared to the PND14 saline group. Persistent inflammation experienced by B6C3F1 mice on PND1 failed to affect baseline adult thermal responsiveness. Adult mice, CD1 and B6C3F1, displayed low anxiety traits only if they had been exposed to persistent inflammation on PND1 and not on PND14. Our research suggests a role for genetic background in modulating long-term behavioral consequences of neonatal persistent inflammation: the data support the hypothesis that pain experienced very early in life differentially affects adult behavioral and emotional responsiveness in outbred (CD1) and hybrid mice (B6C3F1). PMID:19665540

Benatti, Cristina; Alboni, Silvia; Capone, Giacomo; Corsini, Daniela; Caggia, Federica; Brunello, Nicoletta; Tascedda, Fabio; Blom, Joan M C

2009-11-01

83

Genetic Alterations in ERBB2-amplified Breast Carcinomas1,2  

Microsoft Academic Search

Amplification of the ERBB2 oncogene has recently re- ceived attention as a target for antibody-based therapies and as a predictor of response to adjuvant chemotherapy. Mod- ification of treatment strategies based on ERBB2 status has led to further interest in the genetic alterations that accom- pany ERBB2 gene amplification or overexpression. In this study, chromosome alterations that are associated with

Jorma Isola; Lisa Chu; Sandy DeVries; Kouji Matsumura; Karen Chew; Britt Marie Ljung; Frederic M. Waldman

1999-01-01

84

Molecular Detection of Genetic Alterations in the Serum of Colorectal Cancer Patients1  

Microsoft Academic Search

We have searched for the presence of genetic alterations in serum DNA obtained from 44 colorectal cancer patients. Microsatellite analysis using highly polymorphic markers revealed loss of heterozygosity and\\/or microsat ellite instability in 35 of 44 (80%) primary tumors. No alterations were detected in the paired serum DNA. We next used an oligonucleotide-mediated mismatch ligatíon assay to detect tumor specific

Kenji Hibi; C. Rahj Robinson; Susan Booker; Li Wu; David Sidransky; Jin Jen

1998-01-01

85

Melanoma: From Melanocyte to Genetic Alterations and Clinical Options  

PubMed Central

Metastatic melanoma remained for decades without any effective treatment and was thus considered as a paradigm of cancer resistance. Recent progress with understanding of the molecular mechanisms underlying melanoma initiation and progression revealed that melanomas are genetically and phenotypically heterogeneous tumors. This recent progress has allowed for the development of treatment able to improve for the first time the overall disease-free survival of metastatic melanoma patients. However, clinical responses are still either too transient or limited to restricted patient subsets. The complete cure of metastatic melanoma therefore remains a challenge in the clinic. This review aims to present the recent knowledge and discoveries of the molecular mechanisms involved in melanoma pathogenesis and their exploitation into clinic that have recently facilitated bench to bedside advances.

Bertolotto, Corine

2013-01-01

86

Geographical mapping of a multifocal thyroid tumour using genetic alteration analysis & miRNA profiling  

Microsoft Academic Search

BACKGROUND: Papillary thyroid carcinoma (PTC) frequently presents as multiple tumour-foci within a single thyroid gland or pluriform, with synchronous tumours comprising different histological variants, raising questions regarding its clonality. Among the genetic aberrations described in PTC, the BRAF V600E mutation and ret\\/PTC activation occur most commonly. Several studies have investigated the genetic alteration status of multifocal thyroid tumours, with discordant

Sinéad T Aherne; Paul C Smyth; Richard J Flavin; Susan M Russell; Karen M Denning; Jing Huan Li; Simone M Guenther; John J O'Leary; Orla M Sheils

2008-01-01

87

Complex layers of genetic alteration in the generation of antibody diversity  

Microsoft Academic Search

The diversity of the immune system is known to be somatically amplified by various genetic alteration mechanisms including V(D)J recombination, somatic hypermutation (SH) and class switch recombination (CSR). Recent findings that both CSR and SH are abolished by mutations of mouse and human AID, a member of the RNA-editing cytidine deaminase family, suggest that at least dual layers of genetic

Masamichi Muramatsu; Tasuku Honjo

2001-01-01

88

Genetic alterations in ovarian carcinoma: with specific reference to histological subtypes  

Microsoft Academic Search

Multiple genetic changes including activation of proto-oncogenes and inactivation of tumor suppressor gene are involved in the development of human ovarian cancer. We describe such genetic alterations with specific reference to histological subtypes. K-ras activation is specific for mucinous tumors including adenomas. Borderline tumors and carcinomas, suggesting that K-ras activation may be associated with the mucinous differentiation rather than malignant

Masami Fujita; Takayuki Enomoto; Yuji Murata

2003-01-01

89

Genetic Alterations of p16 INK4a and p53Genes in Sporadic Dysplastic Nevus  

Microsoft Academic Search

It is still unclear whether the sporadic form of dysplastic nevi (SDN) represents a premalignant lesion of malignant melanoma and whether genetic alterations are involved in the development of SDN. To determine whetherp16INK4aandp53genetic abnormalities could be associated with development of SDN, nevus cell nests were procured selectively from H & E-stained slide sections by using a modified microdissection technique and

Jung Young Lee; Seung Myung Dong; Min Sun Shin; Su Young Kim; Sug Hyung Lee; Seok Jin Kang; Jung Duk Lee; Choo Soung Kim; Sang Ho Kim; Nam Jin Yoo

1997-01-01

90

Genetic and Epigenetic Somatic Alterations in Head and Neck Squamous Cell Carcinomas Are Globally Coordinated but Not Locally Targeted  

PubMed Central

Background Solid tumors, including head and neck squamous cell carcinomas (HNSCC), arise as a result of genetic and epigenetic alterations in a sustained stress environment. Little work has been done that simultaneously examines the spectrum of both types of changes in human tumors on a genome-wide scale and results so far have been limited and mixed. Since it has been hypothesized that epigenetic alterations may act by providing the second carcinogenic hit in gene silencing, we sought to identify genome-wide DNA copy number alterations and CpG dinucleotide methylation events and examine the global/local relationships between these types of alterations in HNSCC. Methodology/Principal Findings We have extended a prior analysis of 1,413 cancer-associated loci for epigenetic changes in HNSCC by integrating DNA copy number alterations, measured at 500,000 polymorphic loci, in a case series of 19 primary HNSCC tumors. We have previously demonstrated that local copy number does not bias methylation measurements in this array platform. Importantly, we found that the global pattern of copy number alterations in these tumors was significantly associated with tumor methylation profiles (p<0.002). However at the local level, gene promoter regions did not exhibit a correlation between copy number and methylation (lowest q?=?0.3), and the spectrum of genes affected by each type of alteration was unique. Conclusion/Significance This work, using a novel and robust statistical approach demonstrates that, although a “second hit” mechanism is not likely the predominant mode of action for epigenetic dysregulation in cancer, the patterns of methylation events are associated with the patterns of allele loss. Our work further highlights the utility of integrative genomics approaches in exploring the driving somatic alterations in solid tumors.

Poage, Graham M.; Christensen, Brock C.; Houseman, E. Andres; McClean, Michael D.; Wiencke, John K.; Posner, Marshall R.; Clark, John R.; Nelson, Heather H.; Marsit, Carmen J.; Kelsey, Karl T.

2010-01-01

91

Genetic Determinants of Altered Virulence of Taiwanese Foot-and-Mouth Disease Virus  

Microsoft Academic Search

In 1997, a devastating outbreak of foot-and-mouth disease (FMD) in Taiwan was caused by a serotype O virus (referred to here as OTai) with atypical virulence. It produced high morbidity and mortality in swine but did not affect cattle. We have defined the genetic basis of the species specificity of OTai by evaluating the properties of genetically engineered chimeric viruses

CLAYTON W. BEARD; PETER W. MASON

2000-01-01

92

Genetics and personality affect visual perspective in autobiographical memory  

Microsoft Academic Search

Major depression is associated with a decrease of 1st person (versus 3rd person) visual perspective in autobiographical memory, even after full remission. This study aimed to examine visual perspective in healthy never-depressed subjects presenting with either genetic or psychological vulnerability for depression. Sixty healthy participants performed the Autobiographical Memory Test with an assessment of visual perspective. Genetic vulnerability was defined

Cédric Lemogne; Loretxu Bergouignan; Claudette Boni; Philip Gorwood; Antoine Pélissolo; Philippe Fossati

2009-01-01

93

Genetically based trait in a dominant tree affects ecosystem processes  

Microsoft Academic Search

Fundamental links between genes and ecosystem processes have remained elusive, although they have the potential to place ecosystem sciences within a genetic and evolutionary framework. Utilizing common gardens with cottonwood trees of known genotype, we found that the concentration of condensed tannins is genetically based and is the best predictor of ecosystem-level processes. Condensed tannin inputs from foliage explained 55-65%

Jennifer A. Schweitzer; Joseph K. Bailey; Brian J. Rehill; Gregory D. Martinsen; Stephen C. Hart; Richard L. Lindroth; Paul Keim; Thomas G. Whitham

2004-01-01

94

Epimutations and genetic aberration adversely affect ART outcome  

Microsoft Academic Search

Summary In the last decade the advent of ART has proven to be a boon for the infertile couple. In a large number of infertile couples there may be a genetic basis. Such couples who harbor genetic abnormalities need to be provided comprehensive counseling prior to opting for ART. Despite state of art technology and professional expertise, the carry home

Dada R; Kumar R; Shamsi MB; Singh H

2007-01-01

95

Altered gene dosage confirms the genetic interaction between FIAT and ?NAC.  

PubMed

Factor inhibiting ATF4-mediated transcription (FIAT) interacts with Nascent polypeptide associated complex and coregulator alpha (?NAC). In cultured osteoblastic cells, this interaction contributes to maximal FIAT-mediated inhibition of Osteocalcin (Ocn) gene transcription. We set out to demonstrate the physiological relevance of this interaction by altering gene dosage in compound Fiat and Naca (encoding ?NAC) heterozygous mice. Compound Naca(+/-); Fiat(+/-) heterozygous animals were viable, developed normally, and exhibited no significant difference in body weight compared with control littermate genotypes. Animals with a single Fiat allele had reduced Fiat mRNA expression without changes in the expression of related family members. Expression of the osteocyte differentiation marker Dmp1 was elevated in compound heterozygotes. Static histomorphometry parameters were assessed at 8weeks of age using microcomputed tomography (?CT). Trabecular measurements were not different between genotypes. Cortical thickness and area were not affected by gene dosage, but we measured a significant increase in cortical porosity in compound heterozygous mice, without changes in biomechanical parameters. The bone phenotype of compound Naca(+/-); Fiat(+/-) heterozygotes confirms that FIAT and ?NAC are part of a common genetic pathway and support a role for the FIAT/?NAC interaction in normal bone physiology. PMID:24440290

Hekmatnejad, Bahareh; Mandic, Vice; Yu, Vionnie W C; Akhouayri, Omar; Arabian, Alice; St-Arnaud, René

2014-04-01

96

Distinct association between aberrant methylation of Wnt inhibitors and genetic alterations in acute myeloid leukaemia  

PubMed Central

Background: Aberrant activation of Wnt signalling through hypermethylation of Wnt inhibitor genes is involved in several human malignancies, including acute myeloid leukaemia (AML). It remains unclear whether hypermethylation of Wnt inhibitors is associated with molecular gene mutations in the development of AML. Methods: We investigated the association of the promoter hypermethylation of six Wnt inhibitors (Wif-1, SFRP1, SFRR2, SFRP4, SFRP5, and DKK1) with gene aberrations in the leukaemogenesis of 269 AML patients. Results: In total, 166 patients (61.7%) had hypermethylation of at least one Wnt inhibitor. The majority (68.5%) of patients with Wnt inhibitor hypermethylation had concurrent Class II gene mutations that affect transcription factors or cofactors. There was a close association of Wif-1 hypermethylation with t(15;17) (P=0.0005) and CEBPA mutation (P<0.0001), DKK1 hypermethylation with t(8;21) (P<0.0001) and ASXL1 mutation (P=0.0078), SFRP-1 hypermethylation with t(8;21) (P<0.0001), SFRP-2 hypermethylation with AML1/RUNX1 mutation (P=0.0012), and SFRP-5 hypermethylation with MLL/PTD (P=0.0505). On the other side, hypermethylation of Wnt inhibitors was always negatively associated with NPM1 mutation and FLT3/ITD. Conclusion: There was distinct association between hypermethylation of individual Wnt inhibitors and specific gene aberrations, especially Class II mutations. The Wnt inhibitor hypermethylation might interact with genetic alterations in the leukaemogenesis.

Hou, H-A; Kuo, Y-Y; Liu, C-Y; Lee, M C; Tang, J-L; Chen, C-Y; Chou, W-C; Huang, C-F; Lee, F-Y; Liu, M-C; Yao, M; Tien, H-F

2011-01-01

97

Genetic Alterations in Barrett Esophagus and Adenocarcinomas of the Esophagus and Esophagogastric Junction Region  

Microsoft Academic Search

The incidence of esophageal adenocarcinoma has in- creased markedly in the past two decades, but the genetic alterations in this cancer and its precursor, Barrett mucosa, have not been characterized exten- sively. DNA replication errors and allelic losses of chromosomes 17p, 18q, and 5q were studied in 36 resected adenocarcinomas arising in the esophagus and esophagogastric junction, 56 Barrett adenocarci-

Tsung-Teh Wu; Toshiaki Watanabe; Richard Heitmiller; Marianna Zahurak; Arlene A. Forastiere

1998-01-01

98

Genetic alterations linked with bladder cancer risk, recurrence, progression, and patient survival  

Cancer.gov

A new analysis by researchers from the University of Texas MD Anderson Cancer Center in Houston has found that genetic alterations in a particular cellular pathway are linked with bladder cancer risk, recurrence, disease progression, and patient survival. Published early online in CANCER, a peer- reviewed journal of the American Cancer Society, the findings could help improve bladder cancer screening and treatment.

99

High prevalence of p16 genetic alterations in head and neck tumours  

Microsoft Academic Search

Inactivation of the p16 gene is believed to contribute to the tumorigenic process of several neoplasms, including head and neck tumours. In the present study, DNA samples from paired tumour and adjacent normal tissue from 47 patients with squamous cell carcinoma of the head and neck were investigated for the occurrence of p16 genetic alterations. Single-strand conformation polymorphism and direct

E C Miracca; L P Kowalski; M A Nagai

1999-01-01

100

Genetic alterations in sporadic and Crohn's-associated adenocarcinomas of the small intestine  

Microsoft Academic Search

BACKGROUND & AIMS: Small intestinal carcinomas are rare but occur with increased incidence in Crohn's disease. The aim of this study was to elucidate the genetic alterations. METHODS: Mutations and deletions involved in colorectal carcinoma were studied in sporadic and Crohn's- associated intestinal carcinomas and precursors. RESULTS: c-K-ras mutations were present in all four sporadic carcinomas with contiguous adenomas, in

A Rashid

1997-01-01

101

Accumulation of genetic alterations and their significance in each primary human cancer and cell line  

Microsoft Academic Search

Analyses of multiple genetic alterations accumulated in each cancer cell is expected to provide useful information to elucidate the molecular mechanisms involved in tumorigenesis. Here, we summarized the results of studies on aberrations of oncogenes and tumor suppressor genes by ourselves and other groups. DNAs analyzed were from particular sets of surgical specimens from human tumors and cancer cell lines

Yoshinori Murakami; Takao Sekiya

1998-01-01

102

Genetic alterations detected on chromosomes 13 and 14 in Chinese non-small cell lung carcinomas  

Microsoft Academic Search

Genetic alterations in 28 non-small cell lung carcinoma patients were detected on chromosomes 13q and 14q with microsatellite markers by polymerase chain reaction techniques. Loss of heterozygosity of up to 50% was detected with chromosome 13 markers and of up to 37% for chromosome 14. Microsatellite instability was as high as 30% on chromosome 13 and up to 19% on

Fung Mei Kwong; Po Shan Wong; Maria Li Lung

2003-01-01

103

Genetic alterations detected by comparative genomic hybridization and recurrence rate in epithelial ovarian carcinoma  

Microsoft Academic Search

To assess the putative correlation between comparative genomic hybridization (CGH)-detectable genetic alterations in epithelial ovarian cancer and disease recurrence, conventional CGH was performed on 45 epithelial ovarian cancers: 26 tumors from sporadic, BRCA mutation noncarriers and 11 and 8 tumors from BRCA1 and BRCA2 mutation carriers, respectively. Relevant clinical data, including histology, grade, stage, size of residual tumor, recurrence, and

Ilan Bruchim; Ofir Israeli; Salaheddin M. Mahmud; Ayala Aviram-Goldring; Shlomit Rienstein; Eitan Friedman; Gilad Ben-Baruch; Walter H. Gotlieb

2009-01-01

104

Genetic alterations on chromosome 17 in human breast cancer: relationships to clinical features and DNA ploidy  

Microsoft Academic Search

We analyzed DNA from 105 primary breast cancers to assess amplification of the ERBB2 gene and loss of heterozygosity (LOH) on chromosome 17 using 4 polymorphic markers, and investigated the relationships of these genetic alterations to clinicopathological characteristics including DNA ploidy. Amplification of the ERBB2 gene was observed in 28% of the tumors. ERBB2 was amplified in tumors of all

Masahiro Watatani; Koichi Nagayama; Yukio Imanishi; Kazuyoshi Kurooka; Tomio Wada; Hiroki Inui; Kyoko Hirai; Masatoshi Ozaki; Masayuki Yasutomi

1993-01-01

105

Genetic alterations in bladder cancer and their clinical applications in molecular tumor staging  

Microsoft Academic Search

Molecular biology is expected to provide new tools and approaches to assess the prognosis of patients with bladder cancer, by providing information on the risks of tumor recurrence and progression from superficial bladder cancer to an invasive phenotype. Genetic and epigenetic alterations have been closely associated with bladder carcinogenesis and progression, although most of these are still under investigation in

Kokichi Sugano; Tadao Kakizoe

2006-01-01

106

Genetic and expression alterations in association with the sarcomatous change of cholangiocarcinoma cells  

Microsoft Academic Search

Cholangiocarcinoma (CC) is an intrahepatic bile duct carcinoma with a high mortality rate and a poor prog- nosis. Sarcomatous change\\/epithelial mesenchymal transition (EMT) of CC frequently leads to aggressive intrahepatic spread and metastasis. The aim of this study was to identify the genetic alterations and gene expression pattern that might be associated with the sarcomatous change in CC. Previously, we

Hee-Jung Yoo; Bo-Ra Yun; Jung-Hee Kwon; Hyuk-Soo Ahn; Min-A Seol; Mi-Jin Lee; Goung-Ran Yu; Hee-Chul Yu; BeeHak Hong; KwanYong Choi; Dae-Ghon Kim

2009-01-01

107

DNA fingerprinting techniques for the analysis of genetic and epigenetic alterations in colorectal cancer.  

PubMed

Genetic somatic alterations are fundamental hallmarks of cancer. In addition to point and other small mutations targeting cancer genes, solid tumors often exhibit aneuploidy as well as multiple chromosomal rearrangements of large fragments of the genome. Whether somatic chromosomal alterations and aneuploidy are a driving force or a mere consequence of tumorigenesis remains controversial. Recently it became apparent that not only genetic but also epigenetic alterations play a major role in carcinogenesis. Epigenetic regulation mechanisms underlie the maintenance of cell identity crucial for development and differentiation. These epigenetic regulatory mechanisms have been found substantially altered during cancer development and progression. In this review, we discuss approaches designed to analyze genetic and epigenetic alterations in colorectal cancer, especially DNA fingerprinting approaches to detect changes in DNA copy number and methylation. DNA fingerprinting techniques, despite their modest throughput, played a pivotal role in significant discoveries in the molecular basis of colorectal cancer. The aim of this review is to revisit the fingerprinting technologies employed and the oncogenic processes that they unveiled. PMID:20851135

Samuelsson, Johanna K; Alonso, Sergio; Yamamoto, Fumiichiro; Perucho, Manuel

2010-11-10

108

Genetic alterations in prostate cancer cell lines detected by comparative genomic hybridization  

Microsoft Academic Search

Recent studies have identified several chromosomal regions that are altered in prostate cancer. However, the specific genes affected are, in most of the cases, not known. Cancer cell lines could provide a valuable resource for cloning of genes that are commonly affected in cancer. The first step in the identification of such genes is the detection of chromosomal aberrations. Here,

Nina N. Nupponen; Eija R. Hyytinen; Anne H. Kallioniemi; Tapio Visakorpi

1998-01-01

109

Altered acquisition and extinction of amphetamine-paired context conditioning in genetic mouse models of altered NMDA receptor function.  

PubMed

Repeated intermittent exposure to amphetamine (AMPH) results in the development of persistent behavioral and neurological changes. When drug exposure is paired with a specific environment, contextual cues can control conditioned responses, context-specific sensitization, and alterations in dendritic morphology in the nucleus accumbens (NAc). Intact N-methyl-D-aspartate (NMDA) glutamate receptor signaling is thought to be required for associative learning. The acquisition of context-specific behavioral sensitization to AMPH and extinction of conditioned hyperactivity have been investigated in two genetically modified mouse strains: the serine racemase homozygous knockout (SR-/-) and glycine transporter 1 heterozygous mutant (GlyT1-/+). These strains have reciprocally altered NMDA receptor co-agonists, D-serine and glycine, levels that result in decreased (SR-/-) or increased (GlyT1-/+) NMDA receptor signaling. AMPH-induced changes in dendritic morphology in the NAc were also examined. SR-/- mice showed reduced expression of context-specific sensitization and conditioned hyperactivity. However, the conditioned hyperactivity in these mice is completely resistant to extinction. Extinction reversed AMPH-induced increased in NAc spine density in wild-type but not SR-/- mice. GlyT1 -/+ mice showed a more rapid acquisition of sensitization, but no alteration in the extinction of conditioned hyperactivity. The SR-/- data demonstrate that a genetic model of NMDA receptor hypofunction displays a reduced ability to extinguish conditioned responses to drug-associated stimuli. Findings also demonstrate that the morphological changes in the NAc encode conditioned responses that are sensitive to extinction and reduced NMDA receptor activity. NMDA receptor hypofunction may contribute to the comorbidity of substance abuse in schizophrenia. PMID:22763616

Benneyworth, Michael A; Coyle, Joseph T

2012-10-01

110

Altered Acquisition and Extinction of Amphetamine-Paired Context Conditioning in Genetic Mouse Models of Altered NMDA Receptor Function  

PubMed Central

Repeated intermittent exposure to amphetamine (AMPH) results in the development of persistent behavioral and neurological changes. When drug exposure is paired with a specific environment, contextual cues can control conditioned responses, context-specific sensitization, and alterations in dendritic morphology in the nucleus accumbens (NAc). Intact N-methyl-D-aspartate (NMDA) glutamate receptor signaling is thought to be required for associative learning. The acquisition of context-specific behavioral sensitization to AMPH and extinction of conditioned hyperactivity have been investigated in two genetically modified mouse strains: the serine racemase homozygous knockout (SR?/?) and glycine transporter 1 heterozygous mutant (GlyT1?/+). These strains have reciprocally altered NMDA receptor co-agonists, D-serine and glycine, levels that result in decreased (SR?/?) or increased (GlyT1?/+) NMDA receptor signaling. AMPH-induced changes in dendritic morphology in the NAc were also examined. SR?/? mice showed reduced expression of context-specific sensitization and conditioned hyperactivity. However, the conditioned hyperactivity in these mice is completely resistant to extinction. Extinction reversed AMPH-induced increased in NAc spine density in wild-type but not SR?/? mice. GlyT1 ?/+ mice showed a more rapid acquisition of sensitization, but no alteration in the extinction of conditioned hyperactivity. The SR?/? data demonstrate that a genetic model of NMDA receptor hypofunction displays a reduced ability to extinguish conditioned responses to drug-associated stimuli. Findings also demonstrate that the morphological changes in the NAc encode conditioned responses that are sensitive to extinction and reduced NMDA receptor activity. NMDA receptor hypofunction may contribute to the comorbidity of substance abuse in schizophrenia.

Benneyworth, Michael A; Coyle, Joseph T

2012-01-01

111

Torn at the Genes One Family's Debate Over Genetically Altered Plants  

NSDL National Science Digital Library

The setting for this case is the family dinner table, where a heated discussion about genetically altered foods is taking place. Marsha Cumberland’s brother-in-law has joined the family for dinner. Ed is an industry official whose job it is to decide whether or not new products need pre-market approval by the FDA. He has just returned from a conference on transgenic foods.  When it turns out that some of the food on the dinner table is genetically modified, a debate ensues with different members of the family at different ends of the spectrum. Written for an introductory biology course, the case considers the scientific and ethical issues of genetically altered plants.

Nelson, Jennifer; Herreid, Clyde F.

2000-01-01

112

Dim light at night interacts with intermittent hypoxia to alter cognitive and affective responses  

PubMed Central

Obstructive sleep apnea (OSA) and dim light at night (dLAN) have both been independently associated with alterations in mood and cognition. We aimed to determine whether dLAN would interact with intermittent hypoxia (IH), a condition characteristic of OSA, to alter the behavioral, cognitive, and affective responses. Adult male mice were housed in either standard lighting conditions (14:10-h light-dark cycle; 150 lux:0 lux) or dLAN (150 lux:5 lux). Mice were then exposed to IH (15 cycles/h, 8 h/day, FiO2 nadir of 5%) for 3 wk, then tested in assays of affective and cognitive responses; brains were collected for dendritic morphology and PCR analysis. Exposure to dLAN and IH increased anxiety-like behaviors, as assessed in the open field, elevated plus maze, and the light/dark box. dLAN and IH increased depressive-like behaviors in the forced swim test. IH impaired learning and memory performance in the passive avoidance task; however, no differences were observed in spatial working memory, as assessed by y-maze or object recognition. IH combined with dLAN decreased cell body area in the CA1 and CA3 regions of the hippocampus. Overall, IH decreased apical spine density in the CA3, whereas dLAN decreased spine density in the CA1 of the hippocampus. TNF-? gene expression was not altered by IH or lighting condition, whereas VEGF expression was increased by dLAN. The combination of IH and dLAN provokes negative effects on hippocampal dendritic morphology, affect, and cognition, suggesting that limiting nighttime exposure to light in combination with other established treatments may be of benefit to patients with OSA.

Weil, Zachary M.; Magalang, Ulysses J.; Nelson, Randy J.

2013-01-01

113

Genetic background affects susceptibility to tumoral stem cell reprogramming  

PubMed Central

The latest studies of the interactions between oncogenes and its target cell have shown that certain oncogenes may act as passengers to reprogram tissue-specific stem/progenitor cell into a malignant cancer stem cell state. In this study, we show that the genetic background influences this tumoral stem cell reprogramming capacity of the oncogenes using as a model the Sca1-BCRABLp210 mice, where the type of tumor they develop, chronic myeloid leukemia (CML), is a function of tumoral stem cell reprogramming. Sca1-BCRABLp210 mice containing FVB genetic components were significantly more resistant to CML. However, pure Sca1-BCRABLp210 FVB mice developed thymomas that were not seen in the Sca1-BCRABLp210 mice into the B6 background. Collectively, our results demonstrate for the first time that tumoral stem cell reprogramming fate is subject to polymorphic genetic control.

Garcia-Ramirez, Idoia; Ruiz-Roca, Lucia; Martin-Lorenzo, Alberto; Blanco, Oscar; Garcia-Cenador, Maria Begona; Garcia-Criado, Francisco Javier; Vicente-Duenas, Carolina; Sanchez-Garcia, Isidro

2013-01-01

114

Altering SARS Coronavirus Frameshift Efficiency Affects Genomic and Subgenomic RNA Production  

PubMed Central

In previous studies, differences in the amount of genomic and subgenomic RNA produced by coronaviruses with mutations in the programmed ribosomal frameshift signal of ORF1a/b were observed. It was not clear if these differences were due to changes in genomic sequence, the protein sequence or the frequency of frameshifting. Here, viruses with synonymous codon changes are shown to produce different ratios of genomic and subgenomic RNA. These findings demonstrate that the protein sequence is not the primary cause of altered genomic and subgenomic RNA production. The synonymous codon changes affect both the structure of the frameshift signal and frameshifting efficiency. Small differences in frameshifting efficiency result in dramatic differences in genomic RNA production and TCID50 suggesting that the frameshifting frequency must stay above a certain threshold for optimal virus production. The data suggest that either the RNA sequence or the ratio of viral proteins resulting from different levels of frameshifting affects viral replication.

Plant, Ewan P.; Sims, Amy C.; Baric, Ralph S.; Dinman, Jonathan D.; Taylor, Deborah R.

2013-01-01

115

Commentary on Zohar's "Prospects for 'genetic therapy' -- can a person benefit from being altered?  

PubMed

In his paper on the effects of Prenatal Genetic Intervention (PGI) on personal identity, Noam Zohar comes to a conclusion about genetic makeup and the uses of gene therapy quite different from the one I reach in another piece in this issue. Zohar's argument rests on the contention that personal identity changes with alteration of the genome, following what I have identified as the "constitutive" view. To see that this is the pillar supporting the weight of his argument, consider the following. Questions of identity aside, how can it be that altering the genome of children suffering from Lesch-Nyhan syndrome or Tay-Sachs disease so that they now produce the enzyme that they formerly lacked does not benefit them? Clearly, if their identities were not changed, such individuals would in fact realize great benefit from PGI, since the devastating bad effects of the genetic flaw would be avoided. Such a change would certainly make the altered individuals better off, that is, it would benefit them. On this, Zohar and I do not disagree. Persistence of identity through such genetic change is the sticking point. PMID:11653951

Kahn, Jeffrey P

1991-10-01

116

Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves  

PubMed Central

BACE1 is a promising therapeutic and preventive target for Alzheimer’s disease because it is essential for amyloid deposition. However, the recent demonstration of BACE1 in modulating developmental myelination in both peripheral and central nervous systems raises a concern of its effect on myelin maintenance or remyelination, and inhibition of these processes will potentially be detrimental to the BACE1 inhibitor users who are susceptible to myelination diseases such as adult peripheral nerve injury or multiple sclerosis. In this report, we investigated the role of BACE1 during peripheral nerve remyelination in wild-type (WT) and BACE1-null mice. We show here that genetic deletion of BACE1 affects sciatic nerve remyelination. The impaired remyelination appears to stem from the loss of neuregulin-1 cleavage by BACE1. To demonstrate a direct cleavage of neuregulin-1 by BACE1, we have identified a BACE1 cleavage site that turns out be highly conserved among neuregulin-1 paralogues. Moreover, we show that neuregulin-1 family member neuregulin-3 is also cleavable by BACE1. We hypothesize that the BACE1-cleaved extracellular domain of axonal neuregulin-1, perhaps neuregulin-3 as well, binds to Schwann cell ErbB receptors, which in turn regulate remyelination. Pharmacological inhibition of BACE1 should be carefully monitored to avoid alteration of signaling pathway that regulates remyelination.—Hu, X., He, W., Diaconu, C., Tang, X., Kidd, G. J., Macklin, W. B., Trapp, B. D., Yan, R. Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves.

Hu, Xiangyou; He, Wanxia; Diaconu, Claudiu; Tang, Xiaoying; Kidd, Grahame J.; Macklin, Wendy B.; Trapp, Bruce D.; Yan, Riqiang

2008-01-01

117

Newly Identified Genetic Variations May Affect Breast Cancer Risk  

Cancer.gov

Researchers have identified genetic variations in a region of DNA that may be associated with risk for breast cancer. Women with the variation have a 1.4 times greater risk of developing breast cancer compared to those without this variation.

118

Genetic diversity of a dominant C4 grass is altered with increased precipitation variability.  

PubMed

Climate change has the potential to alter the genetic diversity of plant populations with consequences for community dynamics and ecosystem processes. Recent research focused on changes in climatic means has found evidence of decreased precipitation amounts reducing genetic diversity. However, increased variability in climatic regimes is also predicted with climate change, but the effects of this aspect of climate change on genetic diversity have yet to be investigated. After 10 years of experimentally increased intra-annual variability in growing season precipitation regimes, we report that the number of genotypes of the dominant C(4) grass, Andropogon gerardii Vitman, has been significantly reduced in native tallgrass prairie compared with unmanipulated prairie. However, individuals showed a different pattern of genomic similarity with increased precipitation variability resulting in greater genome dissimilarity among individuals when compared to unmanipulated prairie. Further, we found that genomic dissimilarity was positively correlated with aboveground productivity in this system. The increased genomic dissimilarity among individuals in the altered treatment alongside evidence for a positive correlation of genomic dissimilarity with phenotypic variation suggests ecological sorting of genotypes may be occurring via niche differentiation. Overall, we found effects of more variable precipitation regimes on population-level genetic diversity were complex, emphasizing the need to look beyond genotype numbers for understanding the impacts of climate change on genetic diversity. Recognition that future climate change may alter aspects of genetic diversity in different ways suggests possible mechanisms by which plant populations may be able to retain a diversity of traits in the face of declining biodiversity. PMID:22907523

Avolio, Meghan L; Beaulieu, Jeremy M; Smith, Melinda D

2013-02-01

119

Campylobacter jejuni pdxA affects flagellum-mediated motility to alter host colonization.  

PubMed

Vitamin B6 (pyridoxal-5'-phosphate, PLP) is linked to a variety of biological functions in prokaryotes. Here, we report that the pdxA (putative 4-hydroxy-L-threonine phosphate dehydrogenase) gene plays a pivotal role in the PLP-dependent regulation of flagellar motility, thereby altering host colonization in a leading foodborne pathogen, Campylobacter jejuni. A C. jejuni pdxA mutant failed to produce PLP and exhibited a coincident loss of flagellar motility. Mass spectrometric analyses showed a 3-fold reduction in the main flagellar glycan pseudaminic acid (Pse) associated with the disruption of pdxA. The pdxA mutant also exhibited reduced growth rates compared with the WT strain. Comparative metabolomic analyses revealed differences in respiratory/energy metabolism between WT C. jejuni and the pdxA mutant, providing a possible explanation for the differential growth fitness between the two strains. Consistent with the lack of flagellar motility, the pdxA mutant showed impaired motility-mediated responses (bacterial adhesion, ERK1/2 activation, and IL-8 production) in INT407 cells and reduced colonization of chickens compared with the WT strain. Overall, this study demonstrated that the pdxA gene affects the PLP-mediated flagellar motility function, mainly through alteration of Pse modification, and the disruption of this gene also alters the respiratory/energy metabolisms to potentially affect host colonization. Our data therefore present novel implications regarding the utility of PLP and its dependent enzymes as potent target(s) for the control of this pathogen in the poultry host. PMID:23936426

Asakura, Hiroshi; Hashii, Noritaka; Uema, Masashi; Kawasaki, Nana; Sugita-Konishi, Yoshiko; Igimi, Shizunobu; Yamamoto, Shigeki

2013-01-01

120

Altered Expression of MGMT in High-Grade Gliomas Results from the Combined Effect of Epigenetic and Genetic Aberrations  

PubMed Central

MGMT downregulation in high-grade gliomas (HGG) has been mostly attributed to aberrant promoter methylation and is associated with increased sensitivity to alkylating agent-based chemotherapy. However, HGG harboring 10q deletions also benefit from treatment with alkylating agents. Because the MGMT gene is mapped at 10q26, we hypothesized that both epigenetic and genetic alterations might affect its expression and predict response to chemotherapy. To test this hypothesis, promoter methylation and mRNA levels of MGMT were determined by quantitative methylation-specific PCR (qMSP) or methylation-specific multiplex ligation dependent probe amplification (MS-MLPA) and quantitative RT-PCR, respectively, in a retrospective series of 61 HGG. MGMT/chromosome 10 copy number variations were determined by FISH or MS-MLPA analysis. Molecular findings were correlated with clinical parameters to assess their predictive value. Overall, MGMT methylation ratios assessed by qMSP and MS-MLPA were inversely correlated with mRNA expression levels (best coefficient value obtained with MS-MLPA). By FISH analysis in 68.3% of the cases there was loss of 10q26.1 and in 15% of the cases polysomy was demonstrated; the latter displayed the highest levels of transcript. When genetic and epigenetic data were combined, cases with MGMT promoter methylation and MGMT loss depicted the lowest transcript levels, although an impact in response to alkylating agent chemotherapy was not apparent. Cooperation between epigenetic (promoter methylation) and genetic (monosomy, locus deletion) changes affecting MGMT in HGG is required for effective MGMT silencing. Hence, evaluation of copy number alterations might add relevant prognostic and predictive information concerning response to alkylating agent-based chemotherapy.

Ramalho-Carvalho, Joao; Pires, Malini; Lisboa, Susana; Graca, Ines; Rocha, Patricia; Barros-Silva, Joao Diogo; Savva-Bordalo, Joana; Mauricio, Joaquina; Resende, Mario; Teixeira, Manuel R.; Honavar, Mrinalini; Henrique, Rui; Jeronimo, Carmen

2013-01-01

121

Altered expression of MGMT in high-grade gliomas results from the combined effect of epigenetic and genetic aberrations.  

PubMed

MGMT downregulation in high-grade gliomas (HGG) has been mostly attributed to aberrant promoter methylation and is associated with increased sensitivity to alkylating agent-based chemotherapy. However, HGG harboring 10q deletions also benefit from treatment with alkylating agents. Because the MGMT gene is mapped at 10q26, we hypothesized that both epigenetic and genetic alterations might affect its expression and predict response to chemotherapy. To test this hypothesis, promoter methylation and mRNA levels of MGMT were determined by quantitative methylation-specific PCR (qMSP) or methylation-specific multiplex ligation dependent probe amplification (MS-MLPA) and quantitative RT-PCR, respectively, in a retrospective series of 61 HGG. MGMT/chromosome 10 copy number variations were determined by FISH or MS-MLPA analysis. Molecular findings were correlated with clinical parameters to assess their predictive value. Overall, MGMT methylation ratios assessed by qMSP and MS-MLPA were inversely correlated with mRNA expression levels (best coefficient value obtained with MS-MLPA). By FISH analysis in 68.3% of the cases there was loss of 10q26.1 and in 15% of the cases polysomy was demonstrated; the latter displayed the highest levels of transcript. When genetic and epigenetic data were combined, cases with MGMT promoter methylation and MGMT loss depicted the lowest transcript levels, although an impact in response to alkylating agent chemotherapy was not apparent. Cooperation between epigenetic (promoter methylation) and genetic (monosomy, locus deletion) changes affecting MGMT in HGG is required for effective MGMT silencing. Hence, evaluation of copy number alterations might add relevant prognostic and predictive information concerning response to alkylating agent-based chemotherapy. PMID:23505468

Ramalho-Carvalho, João; Pires, Malini; Lisboa, Susana; Graça, Inês; Rocha, Patrícia; Barros-Silva, João Diogo; Savva-Bordalo, Joana; Maurício, Joaquina; Resende, Mário; Teixeira, Manuel R; Honavar, Mrinalini; Henrique, Rui; Jerónimo, Carmen

2013-01-01

122

Tissue culture-induced genetic and epigenetic alterations in rice pure-lines, F1 hybrids and polyploids  

PubMed Central

Background Genetic and epigenetic alterations can be invoked by plant tissue culture, which may result in heritable changes in phenotypes, a phenomenon collectively termed somaclonal variation. Although extensive studies have been conducted on the molecular nature and spectrum of tissue culture-induced genomic alterations, the issue of whether and to what extent distinct plant genotypes, e.g., pure-lines, hybrids and polyploids, may respond differentially to the tissue culture condition remains poorly understood. Results We investigated tissue culture-induced genetic and epigenetic alterations in a set of rice genotypes including two pure-lines (different subspecies), a pair of reciprocal F1 hybrids parented by the two pure-lines, and a pair of reciprocal tetraploids resulted from the hybrids. Using two molecular markers, amplified fragment length polymorphism (AFLP) and methylation-sensitive amplified polymorphism (MSAP), both genetic and DNA methylation alterations were detected in calli and regenerants from all six genotypes, but genetic alteration is more prominent than epigenetic alteration. While significant genotypic difference was observed in frequencies of both types of alterations, only genetic alteration showed distinctive features among the three types of genomes, with one hybrid (N/9) being exceptionally labile. Surprisingly, difference in genetic alteration frequencies between the pair of reciprocal F1 hybrids is much greater than that between the two pure-line subspecies. Difference also exists in the pair of reciprocal tetraploids, but is to a less extent than that between the hybrids. The steady-state transcript abundance of genes involved in DNA repair and DNA methylation was significantly altered in both calli and regenerants, and some of which were correlated with the genetic and/or epigenetic alterations. Conclusions Our results, based on molecular marker analysis of ca. 1,000 genomic loci, document that genetic alteration is the major cause of somaclonal variation in rice, which is concomitant with epigenetic alterations. Perturbed expression by tissue culture of a set of 41 genes encoding for enzymes involved in DNA repair and DNA methylation is associated with both genetic and epigenetic alterations. There exist fundamental differences among distinct genotypes, pure-lines, hybrids and tetraploids, in propensities of generating both genetic and epigenetic alterations under the tissue culture condition. Parent-of-origin has a conspicuous effect on the alteration frequencies.

2013-01-01

123

Genetic diversity affects colony survivorship in commercial honey bee colonies.  

PubMed

Honey bee (Apis mellifera) queens mate with unusually high numbers of males (average of approximately 12 drones), although there is much variation among queens. One main consequence of such extreme polyandry is an increased diversity of worker genotypes within a colony, which has been shown empirically to confer significant adaptive advantages that result in higher colony productivity and survival. Moreover, honey bees are the primary insect pollinators used in modern commercial production agriculture, and their populations have been in decline worldwide. Here, we compare the mating frequencies of queens, and therefore, intracolony genetic diversity, in three commercial beekeeping operations to determine how they correlate with various measures of colony health and productivity, particularly the likelihood of queen supersedure and colony survival in functional, intensively managed beehives. We found the average effective paternity frequency (m e ) of this population of honey bee queens to be 13.6?±?6.76, which was not significantly different between colonies that superseded their queen and those that did not. However, colonies that were less genetically diverse (headed by queens with m e ???7.0) were 2.86 times more likely to die by the end of the study when compared to colonies that were more genetically diverse (headed by queens with m e ?>?7.0). The stark contrast in colony survival based on increased genetic diversity suggests that there are important tangible benefits of increased queen mating number in managed honey bees, although the exact mechanism(s) that govern these benefits have not been fully elucidated. PMID:23728203

Tarpy, David R; Vanengelsdorp, Dennis; Pettis, Jeffrey S

2013-08-01

124

A Transposon-Based Genetic Screen in Mice Identifies Genes Altered in Colorectal Cancer*  

PubMed Central

Human colorectal cancers (CRCs) display a large number of genetic and epigenetic alterations, some of which are causally involved in tumorigenesis (drivers) and others that have little functional impact (passengers). To help distinguish between these two classes of alterations, we used a transposon-based genetic screen in mice to identify candidate genes for CRC. Mice harboring mutagenic Sleeping Beauty (SB) transposons were crossed to mice expressing SB transposase in gastrointestinal tract epithelium. Most of the offspring developed intestinal lesions including intraepithelial neoplasia, adenomas, and adenocarcinomas. Analysis of over 16,000 transposon insertions identified 77 candidate CRC genes, 60 of which are mutated and/or dysregulated in human CRC and thus are most likely to drive tumorigenesis. These genes include APC, PTEN and SMAD4. The screen also identified 17 new candidate genes that had not previously been implicated in CRC, including POLI, PTPRK, and RSPO2.

Starr, Timothy K.; Allaei, Raha; Silverstein, Kevin A. T.; Staggs, Rodney A.; Sarver, Aaron L.; Bergemann, Tracy L.; Gupta, Mihir; O'Sullivan, M. Gerard; Matise, Ilze; Dupuy, Adam J.; Collier, Lara S.; Powers, Scott; Oberg, Ann L.; Asmann, Yan W.; Thibodeau, Stephen N.; Tessarollo, Lino; Copeland, Neal G.; Jenkins, Nancy A.; Cormier, Robert T.; Largaespada, David A.

2009-01-01

125

Genetic Alterations of the Transforming Growth Factor ß Receptor Genes in Pancreatic and Biliary Adenocarcinomas1  

Microsoft Academic Search

Transforming growth factor ß (TGF-ß)is an extracellular ligand that binds to a heterodimeric receptor, initiating signals that regulate growth, differentiation, and apoptosis. Many cancers, including pancreatic cancer, harbor defects in TGF-\\/3 signaling and are resistant to H.1 -\\/{-mediated growth suppression. Genetic alterations of DPC4, which encodes a DNA binding protein that is a downstream component of the pathway, most frequently

Michael Coggins; Manu Shekher; Kenan Turnacioglu; Charles J. Yeo; Ralph H. Hruban; Scott E. Kern

126

Genetic alterations associated with the evolution and progression of astrocytic brain tumours  

Microsoft Academic Search

Diffusely infiltrating low-grade astrocytomas (WHO grade II) have an intrinsic tendency for progression to anaplastic astrocytoma (WHO grade III) and glioblastoma (WHO grade IV). This change is due to the sequential acquisition of genetic alterations, several of which have recently been identified. In low-grade astrocytomas, p53 mutations with or without loss of heterozygosity on chromosome 17p are the principal detectable

H. Ohgaki; P. Kleihues; B. Schäuble; A. Hausen; K. Ammon

1995-01-01

127

Genetic alterations of the NRP\\/B gene are associated with human brain tumors  

Microsoft Academic Search

Nearly all brain tumors develop following the progressive accumulation of genetic alterations of oncogenes and tumor suppressor genes (such as p53 and retinoblastoma protein). Furthermore, aberrations in the nuclear matrix often contribute to genomic instabilities and the development of cancer. We have previously shown that nuclear-restricted protein\\/brain (NRP\\/B), a member of the BTB\\/Kelch repeat family, is a nuclear matrix protein

Xing-Qun Liang; Hava Karsenty Avraham; Shuxian Jiang; Shalom Avraham

2004-01-01

128

Heterogeneous genetic alterations in ovarian mucinous tumors: Application and usefulness of laser capture microdissection  

Microsoft Academic Search

Histologic observation of ovarian mucinous tumors suggests that there is a multistep transition through the accumulation of genetic alterations. We analyzed loss of heterozygosity (LOH) and replication error (RER) on TP53 and D17S855 as well as K-ras point mutations of the heterogeneous histologic areas of the same tumor in 26 cases of ovarian mucinous tumor. The laser capture microdissection (LCM)

Yukio Takeshima; Vishwa Jeet Amatya; Yutaka Daimaru; Fumio Nakayori; Tomohiro Nakano; Kouki Inai

2001-01-01

129

Infrequent genetic alterations of the PTEN gene in Japanese patients with sporadic prostate cancer  

Microsoft Academic Search

Prostate cancer is a major cause of cancer death among elderly men in America, Europe, and Japan. However, the molecular\\u000a mechanism of carcinogenesis is not yet well characterized. Frequent loss of heterozygosity (LOH) on chromosome 10q was reported\\u000a in prostate cancer, and a candidate tumor suppressor gene, PTEN, was isolated on chromosome band 10q23.3. To investigate the genetic alterations of

Kazuhiko Orikasa; Shin-ichi Fukushige; Senji Hoshi; Seiichi Orikasa; Keiichi Kondo; Yasuhide Miyoshi; Yoshinobu Kubota; Akira Horii

1998-01-01

130

Malignant transformation of endometriosis and genetic alterations of K-ras and microsatellite instability  

Microsoft Academic Search

Objectives: To clarify the role of specific genetic alterations in the multi-step process of malignant transformation of endometriosis. Methods: In cases of ovarian endometrioid carcinoma, we separated regions of normal endometriosis, atypical endometriosis and ovarian endometrioid carcinoma by laser microdissection, and examined K-ras mutation and microsatellite instability in each separated tissue sample. Results: We detected K-ras mutation and microsatellite instability

S. Amemiya; A. Sekizawa; J. Otsuka; T. Tachikawa; H. Saito; T. Okai

2004-01-01

131

Genetic alterations of APC , K -ras , p53 , MSI, and MAGE in Korean colorectal cancer patients  

Microsoft Academic Search

Background and aim  Colorectal cancer (CRC) is one of the most rapidly increasing cancers in Korea, but no comprehensive analysis has been performed\\u000a to speculate the genetic basis of CRC development. We investigated the presence of adenomatous polyposis coli gene (APC), Kirsten-ras (K-ras), p53, microsatellite instability (MSI), and melanoma antigen gene (MAGE) alterations in CRC and correlated the results obtained with

Chang-Ho Jeon; Han-IL Lee; Im-Hee Shin; Jong-Wook Park

2008-01-01

132

Pathological features and genetic alterations in colorectal carcinomas with characteristics of nonpolypoid growth  

Microsoft Academic Search

We sought to clarify pathological features and genetic alterations in colorectal carcinomas with characteristics of nonpolypoid growth. Colorectal carcinomas resected at Showa University Hospital in Tokyo included 86 with characteristics of polypoid growth (PG) and 21 with those of nonpolypoid growth (NPG). Mutations of APC, Ki-ras, and p53 genes, as well as microsatellite instability (MSI), were analysed using fluorescence-based polymerase

K Kaneko; T Kurahashi; R Makino; K Konishi; H Ito; A Katagiri; Y Kumekawa; Y Hirayama; K Yoneyama; M Kushima; M Kusano; H Tajiri; B J Rembacken; K Mitamura; M Imawari

2004-01-01

133

Genetic Alterations in Goblet Cell Carcinoids of the Vermiform Appendix and Comparison with Gastrointestinal Carcinoid Tumors  

Microsoft Academic Search

Goblet cell carcinoid is a relatively rare neuroendocrine tumor of the vermiform appendix with poorly understood molecular pathogenesis. We studied the clinicopathologic features and genetic alterations, including allelic loss of chromosomes 11q, 16q, and 18q; sequencing of the K-ras, ?-catenin, and DPC4 (SMAD4) genes; and p53 overexpression and loss of DPC4 by immunohistochemistry; in 16 goblet cell carcinoids. We compared

Mirela Stancu; Tsung-Teh Wu; Charita Wallace; Patrick S Houlihan; Asif Rashid

2003-01-01

134

Benign Breast Disease: Absence of Genetic Alterations at Several Loci Implicated in Breast Cancer Malignancy1  

Microsoft Academic Search

Benign breast disease (li Iti »is a heterogeneous group of benign breast problems that has been associated with breast cancer risk by several investigators. Genetic alterations have been described in breast carcino mas under the headings of loss of heterozygosity (Ip, 3p, 7q, lip, 17p, 17 and 18q), mutations (p53, c-H-ras-1), and\\/or gene amplifications (C-\\/HVC, int-2\\/FGF3, and c-erbB-2\\/neu). In an

Sarab Lizard-Nacol; Rosette Lidereau; Muriel Arnal; Lyse Hahnel; Patrick Roignot; Jean Cuisenier; Jacques Guerrin

1995-01-01

135

Genetic Alterations of Candidate Tumor Suppressor ING1 in Human Esophageal Squamous Cell Cancer1  

Microsoft Academic Search

Overexpression of ING1, a candidate tumor suppressor gene, efficiently blocks cell growth or induces apoptosis in different experimental systems. ING1 maps to chromosome 13q33-34, and because loss of the terminal region of chromosome 13q has been implicated in esophageal squamous cell cancer (ESCC), we examined ESCC for genetic alterations of ING1. Among 31 informative cases of ESCC, 58.9% of the

Lisheng Chen; Nagahide Matsubara; Tadashi Yoshino; Takeshi Nagasaka; Naoko Hoshizima; Yasuhiro Shirakawa; Yoshio Naomoto; Hiroshi Isozaki; Karl Riabowol; Noriaki Tanaka

2001-01-01

136

Are DNA mismatch repair deficiencies responsible for accumulation of genetic alterations in epithelial ovarian cancers?  

Microsoft Academic Search

To investigate the association of DNA mismatch repair deficiencies in the development and\\/or progression of epithelial ovarian cancers, the relationship between replication errors (RERs) and genetic alterations in three genes (p53, c-erbB2, K-ras) and loss of heterozygosity (LOH) on 6q27 was investigated in 70 patients with epithelial ovarian cancers. The presence of RERs was examined by PCR using five microsatellite

Mitsuaki Suzuki; Michitaka Ohwada; Yasushi Saga; Susumu Saito; Ikuo Sato

2001-01-01

137

Different genetic alterations in rat forestomach tumors induced by genotoxic and non-genotoxic carcinogens  

Microsoft Academic Search

Human beings are exposed to a multitude of carcinogens in their environment, and most cancers are considered to be chemically induced. Here we examined differences in genetic alterations in rat forestomach tumors induced by repeated exposure to a genotoxic carcinogen, N-methyl-N- nitro-N-nitrosoguanidine (MNNG) or N-methylnitroso- urethane (MNUR), and chronic treatment with a non- genotoxic carcinogen, butylated hydroxyanisole (BHA) or caffeic

Masahiro Kaneko; Keiichirou Morimura; Takayuki Nishikawa; Hideki Wanibuchi; Nobuyasu Takada; Harushi Osugi; Hiroaki Kinoshita; Shoji Fukushima

138

Comparison of Epigenetic and Genetic Alterations in Mucinous Cystic Neoplasm and Serous Microcystic Adenoma of Pancreas  

Microsoft Academic Search

Mucinous cystic neoplasms and serous microcystic adenomas account for the majority of cystic tumors of pancreas. Mucinous cystic neoplasms and serous microcystic adenomas have different frequencies of progression to malignancy. The genetic and epigenetic alterations of these tumors have not been studied in detail. In this study, we compared methylation status of p16, p14, VHL, and ppENK genes by methylation-specific

Sang Geol Kim; Tsung-Teh Wu; Jae Hyuk Lee; Young Kook Yun; Jean-Pierre Issa; Asif Rashid

2003-01-01

139

Use of Genetically Altered Stem Cells for the Treatment of Huntington's Disease  

PubMed Central

Transplantation of stem cells for the treatment of Huntington’s disease (HD) garnered much attention prior to the turn of the century. Several studies using mesenchymal stem cells (MSCs) have indicated that these cells have enormous therapeutic potential in HD and other disorders. Advantages of using MSCs for cell therapies include their ease of isolation, rapid propagation in culture, and favorable immunomodulatory profiles. However, the lack of consistent neuronal differentiation of transplanted MSCs has limited their therapeutic efficacy to slowing the progression of HD-like symptoms in animal models of HD. The use of MSCs which have been genetically altered to overexpress brain derived neurotrophic factor to enhance support of surviving cells in a rodent model of HD provides proof-of-principle that these cells may provide such prophylactic benefits. New techniques that may prove useful for cell replacement therapies in HD include the use of genetically altering fate-restricted cells to produce induced pluripotent stem cells (iPSCs). These iPSCs appear to have certain advantages over the use of embryonic stem cells, including being readily available, easy to obtain, less evidence of tumor formation, and a reduced immune response following their transplantation. Recently, transplants of iPSCs have shown to differentiate into region-specific neurons in an animal model of HD. The overall successes of using genetically altered stem cells for reducing neuropathological and behavioral deficits in rodent models of HD suggest that these approaches have considerable potential for clinical use. However, the choice of what type of genetically altered stem cell to use for transplantation is dependent on the stage of HD and whether the end-goal is preserving endogenous neurons in early-stage HD, or replacing the lost neurons in late-stage HD. This review will discuss the current state of stem cell technology for treating the different stages of HD and possible future directions for stem-cell therapy in HD.

Crane, Andrew T.; Rossignol, Julien; Dunbar, Gary L.

2014-01-01

140

Use of Genetically Altered Stem Cells for the Treatment of Huntington's Disease.  

PubMed

Transplantation of stem cells for the treatment of Huntington's disease (HD) garnered much attention prior to the turn of the century. Several studies using mesenchymal stem cells (MSCs) have indicated that these cells have enormous therapeutic potential in HD and other disorders. Advantages of using MSCs for cell therapies include their ease of isolation, rapid propagation in culture, and favorable immunomodulatory profiles. However, the lack of consistent neuronal differentiation of transplanted MSCs has limited their therapeutic efficacy to slowing the progression of HD-like symptoms in animal models of HD. The use of MSCs which have been genetically altered to overexpress brain derived neurotrophic factor to enhance support of surviving cells in a rodent model of HD provides proof-of-principle that these cells may provide such prophylactic benefits. New techniques that may prove useful for cell replacement therapies in HD include the use of genetically altering fate-restricted cells to produce induced pluripotent stem cells (iPSCs). These iPSCs appear to have certain advantages over the use of embryonic stem cells, including being readily available, easy to obtain, less evidence of tumor formation, and a reduced immune response following their transplantation. Recently, transplants of iPSCs have shown to differentiate into region-specific neurons in an animal model of HD. The overall successes of using genetically altered stem cells for reducing neuropathological and behavioral deficits in rodent models of HD suggest that these approaches have considerable potential for clinical use. However, the choice of what type of genetically altered stem cell to use for transplantation is dependent on the stage of HD and whether the end-goal is preserving endogenous neurons in early-stage HD, or replacing the lost neurons in late-stage HD. This review will discuss the current state of stem cell technology for treating the different stages of HD and possible future directions for stem-cell therapy in HD. PMID:24961705

Crane, Andrew T; Rossignol, Julien; Dunbar, Gary L

2014-01-01

141

Deficient NRG1-ERBB signaling alters social approach: relevance to genetic mouse models of schizophrenia  

Microsoft Academic Search

Growth factor Neuregulin 1 (NRG1) plays an essential role in development and organization of the cerebral cortex. NRG1 and\\u000a its receptors, ERBB3 and ERBB4, have been implicated in genetic susceptibility for schizophrenia. Disease symptoms include\\u000a asociality and altered social interaction. To investigate the role of NRG1-ERBB signaling in social behavior, mice heterozygous\\u000a for an Nrg1 null allele (Nrg1+\\/?), and mice

Sheryl S. Moy; H. Troy Ghashghaei; Randal J. Nonneman; Jill M. Weimer; Yukako Yokota; Daekee Lee; Cary Lai; David W. Threadgill; E. S. Anton

2009-01-01

142

Genetic Alterations and Expression Pattern of CEACAM1 in Colorectal Adenomas and Cancers  

Microsoft Academic Search

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed on epithelial cells throughout the intestinal\\u000a tract and is a negative regulator of tumor cell growth, suggesting that it may function as a tumor suppressor. In this study,\\u000a to determine whether the CEACAM1 is involved in colorectal tumorigenesis, we have investigated the genetic alterations, including\\u000a mutations and allelic loss, of the

Jae Hwi Song; Zhang Cao; Jung Hwan Yoon; Suk Woo Nam; Su Young Kim; Jung Young Lee; Won Sang Park

2011-01-01

143

Genetic variations alter production and behavioral responses following heat stress in 2 strains of laying hens.  

PubMed

Genetic differences alter the type and degree of hens' responses and their ability to adapt to a stressor. This study examined the effects of genotypic variations on the productivity and behavior of laying hens following heat stress (HS). Two strains of White Leghorn hens were used: DXL (Dekalb XL), a commercial strain individually selected for egg production and KGB (kind, gentle bird), a strain selected for high group productivity and survivability. Ninety hens (48 DXL and 42 KGB) at 28 wk of age were randomly assigned to either a hot (H: mean = 32.6°C) or control (C: mean = 24.3°C) treatment and housed in pairs by strain for 9 d. Egg production and quality, behavior, body and organ weights, and circulating hormone concentrations were measured. Heat-stressed hens had lower egg production [adjusted (adj) P < 0.001] than their respective controls. Among H-DXL hens, egg weight tended to be reduced at d 1 and was reduced at d 9 (adj P = 0.007), but was reduced only at d 9 among H-KGB hens (adj P = 0.007). Eggshell thickness was also reduced among H hens at d 9 (adj P = 0.007), especially among H-KGB hens (adj P = 0.01). Plasma triiodothyronine concentration was reduced among H-hens (adj P = 0.01), especially among H-DXL hens (adj P = 0.01). Neither temperature nor strain affected the plasma thyroxine and plasma and yolk corticosterone concentrations. Heat-stressed hens spent less time walking (adj P = 0.001) and more time drinking (adj P = 0.007) and resting (adj P = 0.001) than C-hens. The results indicate that although HS reduced production and caused behavioral changes among hens from both strains, the responses differed by genotype. The data provide evidence that genetic selection is a useful strategy for reducing HS response in laying hens. The results provide insights for conducting future studies to develop heat-resistant strains to improve hen well-being, especially under the current commercial conditions. PMID:23300291

Mack, L A; Felver-Gant, J N; Dennis, R L; Cheng, H W

2013-02-01

144

Warming and altered precipitation affect litter decomposition and nitrogen dynamics in a mixed-grass prairie  

NASA Astrophysics Data System (ADS)

Litter decomposition and nitrogen dynamics are important processes in ecosystems and how they respond to climate changes is a global concern. In order to explore the effects of warming and altered precipitation on litter decomposition and nitrogen dynamics, we conducted a field decomposition experiment with warming (+3°C) and altered precipitation (half and double) in a mixed-grass prairie in Oklahoma, USA, using litter bags with dominant C3 and C4 grasses since June, 2012. Litter bags were collected every month in the first six months and subsequently every three month thereafter. Remaining litter biomass as well as element concentration were measured in the lab. Warming significantly decreased the litter decomposition rate (k) by 25.4% for C3 grasses and 25.0% for C4 grasses. Doubled precipitation significantly increased the litter decomposition rate by 23.3% for C3 grasses and 30.1% for C4 grasses while half precipitation showed no significant effects. Soil temperature and soil moisture, controlled by warming and altered precipitation, are found to be the most important factors in regulating litter decomposition rate. Warming also decreased N concentration in C3 grasses while doubled precipitation increased N concentration in C4 grasses after one year of field decomposition. During that time, N concentration showed an average increase of 99.6% in C3 grass while only 68.1% in C4 grass. Other elements such as P and K were not much affected by these treatments although there were significant differences between C3 and C4 grasses. Our results suggest that climate change has significant impact on litter decomposition rate, which could influence the carbon balance of the ecosystem. Nutrient dynamics, especially nitrogen, were shown to be specific to plant types under altered climatic conditions. Our results show that conclusion derived from single-factor climate change experiments should be treated with caution due to interactive effects of warming with altered precipitation and differential responses of C3 and C4 plants.

Chen, X.; Luo, Y.; Xu, X.; Li, D.; Niu, S.

2013-12-01

145

Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia  

PubMed Central

SUMMARY Genomic profiling has identified a subtype of high-risk B-progenitor acute lymphoblastic leukemia (B-ALL) with alteration of IKZF1, a gene expression profile similar to BCR-ABL1-positive ALL and poor outcome (Ph-like ALL). The genetic alterations that activate kinase signaling in Ph-like ALL are poorly understood. We performed transcriptome and whole genome sequencing on 15 cases of Ph-like ALL, and identified rearrangements involving ABL1, JAK2, PDGFRB, CRLF2 and EPOR, activating mutations of IL7R and FLT3, and deletion of SH2B3, which encodes the JAK2 negative regulator LNK. Importantly, several of these alterations induce transformation that is attenuated with tyrosine kinase inhibitors, suggesting the treatment outcome of these patients may be improved with targeted therapy.

Roberts, Kathryn G.; Morin, Ryan D.; Zhang, Jinghui; Hirst, Martin; Zhao, Yongjun; Su, Xiaoping; Chen, Shann-Ching; Payne-Turner, Debbie; Churchman, Michelle; Harvey, Richard C.; Chen, Xiang; Kasap, Corynn; Yan, Chunhua; Becksfort, Jared; Finney, Richard P.; Teachey, David T.; Maude, Shannon L.; Tse, Kane; Moore, Richard; Jones, Steven; Mungall, Karen; Birol, Inanc; Edmonson, Michael N.; Hu, Ying; Buetow, Kenneth E.; Chen, I-Ming; Carroll, William L.; Wei, Lei; Ma, Jing; Kleppe, Maria; Levine, Ross L.; Garcia-Manero, Guillermo; Larsen, Eric; Shah, Neil P.; Devidas, Meenakshi; Reaman, Gregory; Smith, Malcolm; Paugh, Steven W.; Evans, William E.; Grupp, Stephan A.; Jeha, Sima; Pui, Ching-Hon; Gerhard, Daniela S.; Downing, James R.; Willman, Cheryl L.; Loh, Mignon; Hunger, Stephen P.; Marra, Marco; Mullighan, Charles G.

2012-01-01

146

Progress in detecting genetic alterations and their association with human disease.  

PubMed

The completion of the Human Genome Project provided a reference sequence to which researchers could compare sequences from individual patients in the hope of identifying disease-causing mutations. However, this still necessitated candidate gene testing or a very limited screen of multiple genes using Sanger sequencing. With the advent of high-throughput Sanger sequencing, it became possible to screen hundreds of patients for alterations in hundreds of genes. This process was time consuming and limited to a few locations/institutions that had the space to house tens of sequencing equipment. The development of next generation sequencing revolutionized the process. It is now feasible to sequence the entire exome of multiple individuals in about 10 days. However, this meant that a massive amount of data needed to be filtered to identify the relevant alteration. This is presently the rate-limiting step in providing a convincing association between a genetic alteration and a human disorder. PMID:23876707

Schwartz, Charles E; Chen, Chin-Fu

2013-11-01

147

Genetic effects in Drosophila on the potency of diverse general anesthetics: a distinctive pattern of altered sensitivity  

PubMed Central

Mutations that influence the sensitivity of an organism to a volatile general anesthetic can be divided into two classes. In one, sensitivity to all other volatile agents is affected to a similar degree. Although this class may contain mutations of interest for understanding anesthesia, it is also likely to contain mutations that merely alter general health. In the second class, mutations confer non-uniform effects on potency (NEP), i.e., larger effects for some volatile anesthetics than for others. Members of this class are of special interest for studies of arousal and its pharmacological suppression because they not only avoid the pitfall of effects on global health, they imply the existence of drug targets that are preferentially affected by particular agents. In this work we provide the first systematic investigation of the relative frequency and diversity of NEP mutations in Drosophila. As a first step we isolated and characterized a set of P element insertion mutations that confer altered sensitivity of the fruit fly to the clinical anesthetic halothane. Then we tested the members of this collection for their effect on the sensitivity of flies to five other volatile agents. Not only do we find that most of the mutations show non-uniform effects, they share a characteristic arrangement of altered potencies (halothane >>desflurane ? enflurane ? isoflurane ? methoxyflurane > sevoflurane). From this result, although we do not know how direct or indirect are the effects of the mutations, we infer the existence of a biologically relevant target for anesthetic action that has a distinct preference for halothane over other agents. Intriguingly, P element insertions that co-map with several NEP loci have been shown to alter the fly’s response to cocaine and ethanol, suggesting that common genetic elements are involved in the response to all three drugs.

Campbell, Joseph L.; Gu, Qun; Guo, Dongyu; Nash, Howard A.

2009-01-01

148

Identification of Novel Genetic Alterations in Samples of Malignant Glioma Patients  

PubMed Central

Glioblastoma is the most frequent and malignant human brain tumor. High level of genomic instability detected in glioma cells implies that numerous genetic alterations accumulate during glioma pathogenesis. We investigated alterations in AP-PCR DNA profiles of 30 glioma patients, and detected specific changes in 11 genes not previously associated with this disease: LHFPL3, SGCG, HTR4, ITGB1, CPS1, PROS1, GP2, KCNG2, PDE4D, KIR3DL3, and INPP5A. Further correlations revealed that 8 genes might play important role in pathogenesis of glial tumors, while changes in GP2, KCNG2 and KIR3DL3 should be considered as passenger mutations, consequence of high level of genomic instability. Identified genes have a significant role in signal transduction or cell adhesion, which are important processes for cancer development and progression. According to our results, LHFPL3 might be characteristic of primary glioblastoma, SGCG, HTR4, ITGB1, CPS1, PROS1 and INPP5A were detected predominantly in anaplastic astrocytoma, suggesting their role in progression of secondary glioblastoma, while alterations of PDE4D seem to have important role in development of both glioblastoma subtypes. Some of the identified genes showed significant association with p53, p16, and EGFR, but there was no significant correlation between loss of PTEN and any of identified genes. In conclusion our study revealed genetic alterations that were not previously associated with glioma pathogenesis and could be potentially used as molecular markers of different glioblastoma subtypes.

Milinkovic, Vedrana; Bankovic, Jasna; Rakic, Miodrag; Stankovic, Tijana; Skender-Gazibara, Milica; Ruzdijic, Sabera; Tanic, Nikola

2013-01-01

149

Identification of novel genetic alterations in samples of malignant glioma patients.  

PubMed

Glioblastoma is the most frequent and malignant human brain tumor. High level of genomic instability detected in glioma cells implies that numerous genetic alterations accumulate during glioma pathogenesis. We investigated alterations in AP-PCR DNA profiles of 30 glioma patients, and detected specific changes in 11 genes not previously associated with this disease: LHFPL3, SGCG, HTR4, ITGB1, CPS1, PROS1, GP2, KCNG2, PDE4D, KIR3DL3, and INPP5A. Further correlations revealed that 8 genes might play important role in pathogenesis of glial tumors, while changes in GP2, KCNG2 and KIR3DL3 should be considered as passenger mutations, consequence of high level of genomic instability. Identified genes have a significant role in signal transduction or cell adhesion, which are important processes for cancer development and progression. According to our results, LHFPL3 might be characteristic of primary glioblastoma, SGCG, HTR4, ITGB1, CPS1, PROS1 and INPP5A were detected predominantly in anaplastic astrocytoma, suggesting their role in progression of secondary glioblastoma, while alterations of PDE4D seem to have important role in development of both glioblastoma subtypes. Some of the identified genes showed significant association with p53, p16, and EGFR, but there was no significant correlation between loss of PTEN and any of identified genes. In conclusion our study revealed genetic alterations that were not previously associated with glioma pathogenesis and could be potentially used as molecular markers of different glioblastoma subtypes. PMID:24358143

Milinkovic, Vedrana; Bankovic, Jasna; Rakic, Miodrag; Stankovic, Tijana; Skender-Gazibara, Milica; Ruzdijic, Sabera; Tanic, Nikola

2013-01-01

150

Factors Affecting for Genetic Merit Calculation and Use of Conversion Equations of Dairy Bulls  

Microsoft Academic Search

Factors affecting calculation and use of conversion equations were reviewed. Methods of expressing reliability of con- verted evaluations were surveyed. Of 16 countries responding, 6 did not calculate reliability for converted evaluations, 5 accepted reliability from the exporting country, and 5 assumed genetic correla- tions of .6 to 1.0 with the US. Genetic correlations between the US and 8 other

R. L POWELL; R. WIGGANS; P. M. VanRADEN

1994-01-01

151

Population genetic dynamics of three-spined sticklebacks (Gasterosteus aculeatus) in anthropogenic altered habitats  

PubMed Central

In industrialized and/or agriculturally used landscapes, inhabiting species are exposed to a variety of anthropogenic changes in their environments. Genetic diversity may be reduced if populations encounter founder events, bottlenecks, or isolation. Conversely, genetic diversity may increase if populations adapt to changes in selective regimes in newly created habitats. With the present study, genetic variability of 918 sticklebacks from 43 samplings (21.3 ± 3.8 per sample) at 36 locations from cultivated landscapes in Northwest Germany was analyzed at nine neutral microsatellite loci. To test if differentiation is influenced by habitat alterations, sticklebacks were collected from ancient running waters and adjacent artificial stagnant waters, from brooks with salt water inflow of anthropogenic and natural origin and adjacent freshwater sites. Overall population structure was dominated by isolation by distance (IBD), which was significant across all populations, and analysis of molecular variance (AMOVA) revealed that 10.6% of the variation was explained by river catchment area. Populations in anthropogenic modified habitats deviated from the general IBD structure and in the AMOVA, grouping by habitat type running/stagnant water explained 4.9% of variation and 1.4% of the variation was explained by salt-/freshwater habitat. Sticklebacks in salt-polluted water systems seem to exhibit elevated migratory activity between fresh- and saltwater habitats, reducing IBD. In other situations, populations showed distinct signs of genetic isolation, which in some locations was attributed to mechanical migration barriers, but in others to potential anthropogenic induced bottleneck or founder effects. The present study shows that anthropogenic habitat alterations may have diverse effects on the population genetic structure of inhabiting species. Depending on the type of habitat change, increased genetic differentiation, diversification, or isolation are possible consequences.

Scharsack, Joern P; Schweyen, Hannah; Schmidt, Alexander M; Dittmar, Janine; Reusch, Thorsten BH; Kurtz, Joachim

2012-01-01

152

Genetic alterations of RD(INK4/ARF) enhancer in human cancer cells.  

PubMed

Recent identification of an enhancer element, RD(INK4/ARF) (RD), in the prominent INK4/ARF locus provides a novel mechanism to simultaneously regulate the transcription of p15(INK4B) (p15), p14(ARF) , and p16(INK4A) (p16) tumor suppressor genes. While genetic inactivation of p15, p14(ARF) , and p16 in human tumors has been extensively studied, little is known about genetic alterations of RD and its impact on p15, p14(ARF) , and p16 in human cancer. The purpose of this study was to investigate the potential existence of genetic alterations of RD in human cancer cells. DNAs extracted from 17 different cancer cell lines and 31 primary pheochromocytoma tumors were analyzed for deletion and mutation of RD using real-time PCR and direct DNA sequencing. We found that RD was deleted in human cancer cell lines and pheochromocytoma tumors at frequencies of 41.2% (7/17) and 13.0% (4/31), respectively. While some of these RD deletion events occurred along with deletions of the entire INK4/ARF locus, other RD deletion events were independent of genetic alterations in p15, p14(ARF) , and p16. Furthermore, the status of RD was poorly associated with the expression of p15, p14(ARF) , and p16 in tested cancer cell lines and tumors. This study demonstrates for the first time that deletion of the RD enhancer is a prevalent event in human cancer cells. Its implication in carcinogenesis remains to be further explored. PMID:23065809

Li, Junan; Knobloch, Thomas J; Poi, Ming J; Zhang, Zhaoxia; Davis, Andrew T; Muscarella, Peter; Weghorst, Christopher M

2014-03-01

153

Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia.  

PubMed

Hereditary spastic paraplegia (HSP) is considered one of the most heterogeneous groups of neurological disorders, both clinically and genetically. The disease comprises pure and complex forms that clinically include slowly progressive lower-limb spasticity resulting from degeneration of the corticospinal tract. At least 48 loci accounting for these diseases have been mapped to date, and mutations have been identified in 22 genes, most of which play a role in intracellular trafficking. Here, we identified mutations in two functionally related genes (DDHD1 and CYP2U1) in individuals with autosomal-recessive forms of HSP by using either the classical positional cloning or a combination of whole-genome linkage mapping and next-generation sequencing. Interestingly, three subjects with CYP2U1 mutations presented with a thin corpus callosum, white-matter abnormalities, and/or calcification of the basal ganglia. These genes code for two enzymes involved in fatty-acid metabolism, and we have demonstrated in human cells that the HSP pathophysiology includes alteration of mitochondrial architecture and bioenergetics with increased oxidative stress. Our combined results focus attention on lipid metabolism as a critical HSP pathway with a deleterious impact on mitochondrial bioenergetic function. PMID:23176821

Tesson, Christelle; Nawara, Magdalena; Salih, Mustafa A M; Rossignol, Rodrigue; Zaki, Maha S; Al Balwi, Mohammed; Schule, Rebecca; Mignot, Cyril; Obre, Emilie; Bouhouche, Ahmed; Santorelli, Filippo M; Durand, Christelle M; Oteyza, Andrés Caballero; El-Hachimi, Khalid H; Al Drees, Abdulmajeed; Bouslam, Naima; Lamari, Foudil; Elmalik, Salah A; Kabiraj, Mohammad M; Seidahmed, Mohammed Z; Esteves, Typhaine; Gaussen, Marion; Monin, Marie-Lorraine; Gyapay, Gabor; Lechner, Doris; Gonzalez, Michael; Depienne, Christel; Mochel, Fanny; Lavie, Julie; Schols, Ludger; Lacombe, Didier; Yahyaoui, Mohamed; Al Abdulkareem, Ibrahim; Zuchner, Stephan; Yamashita, Atsushi; Benomar, Ali; Goizet, Cyril; Durr, Alexandra; Gleeson, Joseph G; Darios, Frederic; Brice, Alexis; Stevanin, Giovanni

2012-12-01

154

Attitudes toward prenatal genetic testing for Treacher Collins syndrome among affected individuals and families.  

PubMed

Treacher Collins syndrome (TCS) is a craniofacial syndrome that is both phenotypically variable and heterogeneous, caused by mutations in the TCOF1, POLR1C, and POLR1D genes. We examined attitudes towards TCS prenatal genetic testing among affected families using a telephone questionnaire. Participants were 31 affected adults and relatives recruited primarily through families cared for in the mid-Atlantic region. Nineteen participants (65%) reported that they would take a TCS prenatal genetic test which could not predict degree of disease severity. Interest in TCS genetic testing was associated with higher income, higher concern about having a child with TCS, lower religiosity, lower concern about genetic testing procedures, and having a sporadic rather than familial mutation. Over half reported that their decision to have TCS genetic testing would be influenced a great deal by their desire to relieve anxiety and attitudes toward abortion. Ten participants (32%) reported that they would be likely to end the pregnancy upon receiving a positive test result; this was lower amongst TCS affected individuals and higher amongst participants with children with TCS. Genetics healthcare providers need to be aware of affected individuals' and families' attitudes and interest in prenatal genetic testing for TCS, and the possible implications for other craniofacial disorders, so that patients' information needs can be met. PMID:22628272

Wu, Rebecca L; Lawson, Cathleen S; Jabs, Ethylin Wang; Sanderson, Saskia C

2012-07-01

155

Frequent genetic alterations in EGFR- and HER2-driven pathways in breast cancer brain metastases.  

PubMed

Current standard systemic therapies for treating breast cancer patients with brain metastases are inefficient. Targeted therapies against human epidermal growth factor receptors are of clinical interest because of their alteration in a subset of breast cancers (BCs). We analyzed copy number, mutation status, and protein expression of epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), phosphatase and tensin homologue (PTEN), and PI3K catalytic subunit (PIK3CA) in 110 ductal carcinoma in situ, primary tumor, and metastatic BC samples. Alterations in EGFR, HER2, and PTEN, alone or in combination, were found in a significantly larger fraction of breast cancer brain metastases tumor tissue compared with samples from primary tumors with good prognosis, bone relapse, or other distant metastases (all P < 0.05). Primary tumor patients with a subsequent brain relapse showed almost equally high frequencies of especially EGFR and PTEN alteration as the breast cancer brain metastases patients. PIK3CA was not associated with an increased risk of brain metastases. Genetic alterations in both EGFR and PTEN were especially common in triple-negative breast cancer patients and rarely were seen among HER2-positive patients. In conclusion, we identified two independent high-risk primary BC subgroups for developing brain metastases, represented by genetic alterations in either HER2 or EGFR/PTEN-driven pathways. In contrast, none of these pathways was associated with an increased risk of bone metastasis. These findings highlight the importance of both pathways as possible targets in the treatment of brain metastases in breast cancer. PMID:23665199

Hohensee, Ina; Lamszus, Katrin; Riethdorf, Sabine; Meyer-Staeckling, Sönke; Glatzel, Markus; Matschke, Jakob; Witzel, Isabell; Westphal, Manfred; Brandt, Burkhard; Müller, Volkmar; Pantel, Klaus; Wikman, Harriet

2013-07-01

156

Genetic Background Affects Properties of Satellite Cells and mdx Phenotypes  

PubMed Central

Duchenne muscular dystrophy (DMD) is the most common lethal genetic disorder of children. The mdx (C57BL/10 background, C57BL/10-mdx) mouse is a widely used model of DMD, but the histopathological hallmarks of DMD, such as the smaller number of myofibers, accumulation of fat and fibrosis, and insufficient regeneration of myofibers, are not observed in adult C57BL/10-mdx except for in the diaphragm. In this study, we showed that DBA/2 mice exhibited decreased muscle weight, as well as lower myofiber numbers after repeated degeneration–regeneration cycles. Furthermore, the self-renewal efficiency of satellite cells of DBA/2 is lower than that of C57BL/6. Therefore, we produced a DBA/2-mdx strain by crossing DBA/2 and C57BL/10-mdx. The hind limb muscles of DBA/2-mdx mice exhibited lower muscle weight, fewer myofibers, and increased fat and fibrosis, in comparison with C57BL/10-mdx. Moreover, remarkable muscle weakness was observed in DBA/2-mdx. These results indicate that the DBA/2-mdx mouse is a more suitable model for DMD studies, and the efficient satellite cell self-renewal ability of C57BL/10-mdx might explain the difference in pathologies between humans and mice.

Fukada, So-ichiro; Morikawa, Daisuke; Yamamoto, Yukiko; Yoshida, Tokuyuki; Sumie, Noriaki; Yamaguchi, Masahiko; Ito, Takahito; Miyagoe-Suzuki, Yuko; Takeda, Shin'ichi; Tsujikawa, Kazutake; Yamamoto, Hiroshi

2010-01-01

157

Tumor derived mutations of protein tyrosine phosphatase receptor type k affect its function and alter sensitivity to chemotherapeutics in glioma.  

PubMed

Poor prognosis and resistance to therapy in malignant gliomas is mainly due to the highly dispersive nature of glioma cells. This dispersive characteristic results from genetic alterations in key regulators of cell migration and diffusion. A better understanding of these regulatory signals holds promise to improve overall survival and response to therapy. Using mapping arrays to screen for genomic alterations in gliomas, we recently identified alterations of the protein tyrosine phosphatase receptor type kappa gene (PTPRK) that correlate to patient outcomes. These PTPRK alterations are very relevant to glioma biology as PTPRK can directly sense cell-cell contact and is a dephosphorylation regulator of tyrosine phosphorylation signaling, which is a major driving force behind tumor development and progression. Subsequent sequencing of the full length PTPRK transcripts revealed novel PTPRK gene deletion and missense mutations in numerous glioma biopsies. PTPRK mutations were cloned and expressed in PTPRK-null malignant glioma cells. The effect of these mutations on PTPRK anti-oncogenic function and their association with response to anti-glioma therapeutics, such as temozolomide and tyrosine kinase inhibitors, was subsequently analyzed using in vitro cell-based assays. These genetic variations altered PTPRK activity and its post-translational processing. Reconstitution of wild-type PTPRK in malignant glioma cell lines suppressed cell growth and migration by inhibiting EGFR and ?-catenin signaling and improved the effect of conventional therapies for glioma. However, PTPRK mutations abrogated tumor suppressive effects of wild-type PTPRK and altered sensitivity of glioma cells to chemotherapy. PMID:23696788

Agarwal, Supreet; Al-Keilani, Maha S; Alqudah, Mohammad A Y; Sibenaller, Zita A; Ryken, Timothy C; Assem, Mahfoud

2013-01-01

158

Tumor Derived Mutations of Protein Tyrosine Phosphatase Receptor Type K Affect Its Function and Alter Sensitivity to Chemotherapeutics in Glioma  

PubMed Central

Poor prognosis and resistance to therapy in malignant gliomas is mainly due to the highly dispersive nature of glioma cells. This dispersive characteristic results from genetic alterations in key regulators of cell migration and diffusion. A better understanding of these regulatory signals holds promise to improve overall survival and response to therapy. Using mapping arrays to screen for genomic alterations in gliomas, we recently identified alterations of the protein tyrosine phosphatase receptor type kappa gene (PTPRK) that correlate to patient outcomes. These PTPRK alterations are very relevant to glioma biology as PTPRK can directly sense cell–cell contact and is a dephosphorylation regulator of tyrosine phosphorylation signaling, which is a major driving force behind tumor development and progression. Subsequent sequencing of the full length PTPRK transcripts revealed novel PTPRK gene deletion and missense mutations in numerous glioma biopsies. PTPRK mutations were cloned and expressed in PTPRK-null malignant glioma cells. The effect of these mutations on PTPRK anti-oncogenic function and their association with response to anti-glioma therapeutics, such as temozolomide and tyrosine kinase inhibitors, was subsequently analyzed using in vitro cell-based assays. These genetic variations altered PTPRK activity and its post-translational processing. Reconstitution of wild-type PTPRK in malignant glioma cell lines suppressed cell growth and migration by inhibiting EGFR and ?-catenin signaling and improved the effect of conventional therapies for glioma. However, PTPRK mutations abrogated tumor suppressive effects of wild-type PTPRK and altered sensitivity of glioma cells to chemotherapy.

Agarwal, Supreet; Al-Keilani, Maha S.; Alqudah, Mohammad A. Y.; Sibenaller, Zita A.; Ryken, Timothy C.; Assem, Mahfoud

2013-01-01

159

Genetic locus in Rhizobium japonicum (fredii) affecting soybean root nodule differentiation.  

PubMed Central

A genetic locus in fast-growing Rhizobium japonicum (fredii) USDA 191 (Fix+ on several contemporary soybean cultivars) was identified by random Tn5 mutagenesis as affecting the development and differentiation of root nodules. This mutant (MU042) is prototrophic and shows no apparent alterations in its surface properties. It induces aberrant nodules, arrested at the same early level of differentiation, on all its host plants. An 8.1-kilobase EcoRI fragment containing Tn5 was cloned from MU042. In USDA 191 as well as another fast-growing strain, USDA 201, the affected locus was found to be unlinked to the large symbiotic plasmid and appears to be chromosomal. An analogous sequence has been shown to be present in Bradyrhizobium japonicum (J. Stanley, G.G. Brown, and D.P.S. Verma, J. Bacteriol. 163:148-154, 1985) as well as in R. trifolii and R. meliloti. MU042 was complemented for effective nodulation of soybean by a cosmid clone from USDA 201, and the complementing locus was delimited to a 6-kilobase EcoRI subfragment. An R. trifolii strain (MU225), whose indigenous symbiotic plasmid was replaced by that of strain USDA 191, induced more highly differentiated nodules on soybean than did MU042. This suggests that the mutation in MU042 can be functionally substituted by similar loci of other fast-growing rhizobia. Leghemoglobin and nodulin-35 (uricase II) were present in the differentiated Fix- nodules induced by MU225, whereas both were absent in MU042-induced pseudonodule structures. Images

Stanley, J; Longtin, D; Madrzak, C; Verma, D P

1986-01-01

160

Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas  

PubMed Central

The commonest pediatric brain tumors are low-grade gliomas (LGGs). We utilized whole genome sequencing to discover multiple novel genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24/39 (62%) tumors. Intragenic duplications of the FGFR1 tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes containing TKD-duplicated FGFR1 into brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. TKD-duplicated FGFR1 induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs/LGGNTs.

Zhang, Jinghui; Wu, Gang; Miller, Claudia P.; Tatevossian, Ruth G.; Dalton, James D.; Tang, Bo; Orisme, Wilda; Punchihewa, Chandanamali; Parker, Matthew; Qaddoumi, Ibrahim; Boop, Fredrick A.; Lu, Charles; Kandoth, Cyriac; Ding, Li; Lee, Ryan; Huether, Robert; Chen, Xiang; Hedlund, Erin; Nagahawatte, Panduka; Rusch, Michael; Boggs, Kristy; Cheng, Jinjun; Becksfort, Jared; Ma, Jing; Song, Guangchun; Li, Yongjin; Wei, Lei; Wang, Jianmin; Shurtleff, Sheila; Easton, John; Zhao, David; Fulton, Robert S.; Fulton, Lucinda L.; Dooling, David J.; Vadodaria, Bhavin; Mulder, Heather L.; Tang, Chunlao; Ochoa, Kerri; Mullighan, Charles G.; Gajjar, Amar; Kriwacki, Richard; Sheer, Denise; Gilbertson, Richard J.; Mardis, Elaine R.; Wilson, Richard K.; Downing, James R.; Baker, Suzanne J.; Ellison, David W.

2013-01-01

161

Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas.  

PubMed

The most common pediatric brain tumors are low-grade gliomas (LGGs). We used whole-genome sequencing to identify multiple new genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24 of 39 (62%) tumors. Intragenic duplications of the portion of FGFR1 encoding the tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes expressing FGFR1 with the duplication involving the TKD into the brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. FGFR1 with the duplication induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs and LGGNTs. PMID:23583981

Zhang, Jinghui; Wu, Gang; Miller, Claudia P; Tatevossian, Ruth G; Dalton, James D; Tang, Bo; Orisme, Wilda; Punchihewa, Chandanamali; Parker, Matthew; Qaddoumi, Ibrahim; Boop, Fredrick A; Lu, Charles; Kandoth, Cyriac; Ding, Li; Lee, Ryan; Huether, Robert; Chen, Xiang; Hedlund, Erin; Nagahawatte, Panduka; Rusch, Michael; Boggs, Kristy; Cheng, Jinjun; Becksfort, Jared; Ma, Jing; Song, Guangchun; Li, Yongjin; Wei, Lei; Wang, Jianmin; Shurtleff, Sheila; Easton, John; Zhao, David; Fulton, Robert S; Fulton, Lucinda L; Dooling, David J; Vadodaria, Bhavin; Mulder, Heather L; Tang, Chunlao; Ochoa, Kerri; Mullighan, Charles G; Gajjar, Amar; Kriwacki, Richard; Sheer, Denise; Gilbertson, Richard J; Mardis, Elaine R; Wilson, Richard K; Downing, James R; Baker, Suzanne J; Ellison, David W

2013-06-01

162

A genetic algorithms approach for altering the membership functions in fuzzy logic controllers  

NASA Technical Reports Server (NTRS)

Through previous work, a fuzzy control system was developed to perform translational and rotational control of a space vehicle. This problem was then re-examined to determine the effectiveness of genetic algorithms on fine tuning the controller. This paper explains the problems associated with the design of this fuzzy controller and offers a technique for tuning fuzzy logic controllers. A fuzzy logic controller is a rule-based system that uses fuzzy linguistic variables to model human rule-of-thumb approaches to control actions within a given system. This 'fuzzy expert system' features rules that direct the decision process and membership functions that convert the linguistic variables into the precise numeric values used for system control. Defining the fuzzy membership functions is the most time consuming aspect of the controller design. One single change in the membership functions could significantly alter the performance of the controller. This membership function definition can be accomplished by using a trial and error technique to alter the membership functions creating a highly tuned controller. This approach can be time consuming and requires a great deal of knowledge from human experts. In order to shorten development time, an iterative procedure for altering the membership functions to create a tuned set that used a minimal amount of fuel for velocity vector approach and station-keep maneuvers was developed. Genetic algorithms, search techniques used for optimization, were utilized to solve this problem.

Shehadeh, Hana; Lea, Robert N.

1992-01-01

163

Association of genetic alterations on chromosome 17 and loss of hormone receptors in breast cancer.  

PubMed Central

To investigate possible relationships between genetic alterations and hormonal deregulation during breast cancer development and/or progression, we examined 616 primary breast cancers for loss of heterozygosity (LOH) at chromosomal regions 16q24, 17p13.3 and 17q21, and for amplifications of the ERBB2 and c-MYC loci. A comparison of oestrogen receptor (ER) and progesterone receptor (PgR) status in tumour cells with data concerning these genetic alterations revealed that LOH at 17q21 was significantly correlated with absence of oestrogen receptors (ER) (P < 0.0003) or progesterone receptors (PgR) (P < 0.0001), and with the absence of both (P < 0.0001). Similarly, a significant association was observed between amplification of ERBB2 and the absence of either ER or PgR. LOH at 17p13.3 was associated with the absence of PgR (P < 0.01). These data suggest a possible relationship between specific genetic changes on chromosome 17 and hormonal deregulation in the progression of breast cancer. Images Figure 1

Ito, I.; Yoshimoto, M.; Iwase, T.; Watanabe, S.; Katagiri, T.; Harada, Y.; Kasumi, F.; Yasuda, S.; Mitomi, T.; Emi, M.

1995-01-01

164

Y chromosome microdeletions and alterations of spermatogenesis, patient approach and genetic counseling.  

PubMed

Infertility affects 15% of couples at reproductive age and human male infertility appears frequently idiopathic. The main genetic causes of spermatogenesis defect responsible for non-obstructive azoospermia and severe oligozoospermia are constitutional chromosomal abnormalities and microdeletions in the azoospermia factor region of the Y chromosome. The improvement of the Yq microdeletion screening method gave new insights in the mechanism responsible for the genesis of Yq microdeletions and for the consequences of the management of male infertility and genetic counselling in case of assisted reproductive technology. PMID:24786699

Rives, Nathalie

2014-05-01

165

Process-induced extracellular matrix alterations affect the mechanisms of soft tissue repair and regeneration  

PubMed Central

Extracellular matrices derived from animal tissues for human tissue repairs are processed by various methods of physical, chemical, or enzymatic decellularization, viral inactivation, and terminal sterilization. The mechanisms of action in tissue repair vary among bioscaffolds and are suggested to be associated with process-induced extracellular matrix modifications. We compared three non-cross-linked, commercially available extracellular matrix scaffolds (Strattice, Veritas, and XenMatrix), and correlated extracellular matrix alterations to in vivo biological responses upon implantation in non-human primates. Structural evaluation showed significant differences in retaining native tissue extracellular matrix histology and ultrastructural features among bioscaffolds. Tissue processing may cause both the condensation of collagen fibers and fragmentation or separation of collagen bundles. Calorimetric analysis showed significant differences in the stability of bioscaffolds. The intrinsic denaturation temperature was measured to be 51°C, 38°C, and 44°C for Strattice, Veritas, and XenMatrix, respectively, demonstrating more extracellular matrix modifications in the Veritas and XenMatrix scaffolds. Consequently, the susceptibility to collagenase degradation was increased in Veritas and XenMatrix when compared to their respective source tissues. Using a non-human primate model, three bioscaffolds were found to elicit different biological responses, have distinct mechanisms of action, and yield various outcomes of tissue repair. Strattice permitted cell repopulation and was remodeled over 6 months. Veritas was unstable at body temperature, resulting in rapid absorption with moderate inflammation. XenMatrix caused severe inflammation and sustained immune reactions. This study demonstrates that extracellular matrix alterations significantly affect biological responses in soft tissue repair and regeneration. The data offer useful insights into the rational design of extracellular matrix products and bioscaffolds of tissue engineering.

Xu, Hui; Sandor, Maryellen; Lombardi, Jared

2013-01-01

166

Copy Number Variation Affecting the Photoperiod-B1 and Vernalization-A1 Genes Is Associated with Altered Flowering Time in Wheat (Triticum aestivum)  

PubMed Central

The timing of flowering during the year is an important adaptive character affecting reproductive success in plants and is critical to crop yield. Flowering time has been extensively manipulated in crops such as wheat (Triticum aestivum L.) during domestication, and this enables them to grow productively in a wide range of environments. Several major genes controlling flowering time have been identified in wheat with mutant alleles having sequence changes such as insertions, deletions or point mutations. We investigated genetic variants in commercial varieties of wheat that regulate flowering by altering photoperiod response (Ppd-B1 alleles) or vernalization requirement (Vrn-A1 alleles) and for which no candidate mutation was found within the gene sequence. Genetic and genomic approaches showed that in both cases alleles conferring altered flowering time had an increased copy number of the gene and altered gene expression. Alleles with an increased copy number of Ppd-B1 confer an early flowering day neutral phenotype and have arisen independently at least twice. Plants with an increased copy number of Vrn-A1 have an increased requirement for vernalization so that longer periods of cold are required to potentiate flowering. The results suggest that copy number variation (CNV) plays a significant role in wheat adaptation.

Isaac, Peter; Laurie, David A.

2012-01-01

167

Genetically Determined Dosage of Follicle-Stimulating Hormone (FSH) Affects Male Reproductive Parameters  

PubMed Central

Context: The detailed role of FSH in contributing to male testicular function and fertility has been debated. We have previously identified the association between the T-allele of the FSHB promoter polymorphism (rs10835638; G/T, ?211 bp from the mRNA start) and significantly reduced male serum FSH. Objective: In the current study, the T-allele carriers of the FSHB ?211 G/T single nucleotide polymorphism represented a natural model for documenting downstream phenotypic consequences of insufficient FSH action. Design and Subjects: We genotyped rs10835638 in the population-based Baltic cohort of young men (n = 1054; GG carriers, n = 796; GT carriers, n = 244; TT carriers, n = 14) recruited by Andrology Centres in Tartu, Estonia; Riga, Latvia; and Kaunas, Lithuania. Marker-trait association testing was performed using linear regression (additive, recessive models) adjusted by age, body mass index, smoking, and recruitment center. Results: Serum hormones directly correlated with the T-allele dosage of rs10835638 included FSH (additive model, P = 1.11 × 10?6; T-allele effect, ?0.41 IU/liter), inhibin-B (P = 2.16 × 10?3; T-allele effect, ?14.67 pg/ml), and total testosterone (P = 9.30 × 10?3; T-allele effect, ?1.46 nmol/liter). Parameters altered only among TT homozygotes were reduced testicular volume (recessive model, P = 1.19 × 10?4; TT genotype effect, ?9.47 ml) and increased serum LH (P = 2.25 × 10?2; TT genotype effect, 1.07 IU/liter). The carrier status of rs10835638 alternative genotypes did not affect sperm motility and morphology, calculated free testosterone, serum SHBG, and estradiol concentrations. Conclusion: We showed for the first time that genetically determined low FSH may have wider downstream effects on the male reproductive system, including impaired testes development, altered testicular hormone levels (inhibin-B, total testosterone, LH), and affected male reproductive potential.

Grigorova, Marina; Punab, Margus; Zilaitiene, Birute; Erenpreiss, Juris; Ausmees, Kristo; Matulevicius, Valentinas; Tsarev, Igor; J?rgensen, Niels

2011-01-01

168

Aeromonas proteolyrica bacteria in aerospace environments. [possible genetic alterations and effects on man  

NASA Technical Reports Server (NTRS)

Preflight studies on Aeromonas proteolytica are reported to investigate the possibility of genetic alterations resulting in increased proteolysis in spacecraft environments. This organism may be present on human tissue and could pose medical problems if its endopeptidase and a hemolysin were to be produced in ususually high quantities or altered in such a way as to be more effective in their activities. Considered are: (1) Development of a nutrative holding medium for suspension of organisms; (2) the establishment of baseline information for the standardization of the assay for endopeptidase levels and hemolytic titers; (3) formulation of a method by which intracutaneous hemorrhage could be quantitated in guinea pig tissue; and (4) the responses of these organisms to parameters of spaceflight and experimentation.

Foster, B. G.

1974-01-01

169

Genetic Alterations in Cancer Knowledge System: Analysis of Gene Mutations in Mouse and Human Liver and Lung Tumors  

Microsoft Academic Search

Mutational incidence and spectra for genes examined in both human and mouse lung and liver tumors were analyzed using the National Institute of Environmental Health Sciences (NIEHS) Genetic Alterations in Cancer (GAC) knowledge system. GAC is a publicly available, web-based system for evaluating data ob- tained from peer-reviewed studies of genetic changes in tumors associated with exposure to chemical, physical,

Marcus A. Jackson; Isabel Lea; Asif Rashid; Shyamal D. Peddada; June K. Dunnick

2005-01-01

170

Macro-environment of breast carcinoma: frequent genetic alterations in the normal appearing skins of patients with breast cancer  

Microsoft Academic Search

Genetic abnormalities in microenvironmental tissues with subsequent alterations of reciprocal interactions between epithelial and mesenchymal cells play a key role in the breast carcinogenesis. Although a few reports have demonstrated abnormal fibroblastic functions in normal-appearing fibroblasts taken from the skins of breast cancer patients, the genetic basis of this phenomenon and its implication for carcinogenesis are unexplored. We analyzed 12

Farid Moinfar; Alfred Beham; Gerhard Friedrich; Alexander Deutsch; Andelko Hrzenjak; Gero Luschin; Fattaneh A Tavassoli

2008-01-01

171

Accumulation of genetic alterations in a human hepatoma cell line transfected with hepatitis B virus  

Microsoft Academic Search

Chromosome and molecular analyses of the hepatitis B virus (HBV)-transfected HepG2T14.1 variant of the HepG2 cell line was conducted. In HepG2T14.1 cells several genetic alterations such as de novo aberrations of chromosomes 9, 14, 15, and 20 were identified that are not present in the parental HepG2 cell line. Furthermore, HepG2T14.1 cells showed loss of heterozygosity (LOH) in the q

Kristin W Livezey; Daniela Simon

1997-01-01

172

Phytoplasmal infection derails genetically preprogrammed meristem fate and alters plant architecture  

PubMed Central

In the life cycle of higher plants, it is the fate of meristem cells that determines the pattern of growth and development, and therefore plant morphotype and fertility. Floral transition, the turning point from vegetative growth to reproductive development, is achieved via genetically programmed sequential changes in meristem fate from vegetative to inflorescence, and to floral, leading to flower formation and eventual seed production. The transition is rarely reversible once initiated. In this communication, we report that a bacterial infection can derail the genetically programmed fate of meristem cells, thereby drastically altering the growth pattern of the host plant. We identified four characteristic symptoms in tomato plants infected with a cell wall-less bacterium, phytoplasma. The symptoms are a manifestation of the pathogen-induced alterations of growth pattern, whereas each symptom corresponds to a distinct phase in the derailment of shoot apical meristem fate. The phases include premature floral meristem termination, suppressed floral meristem initiation, delayed conversion of vegetative meristem to inflorescence meristem, and repetitive initiation and outgrowth of lateral vegetative meristems. We further found that the pathogen-induced alterations of growth pattern were correlated with transcriptional reprogramming of key meristem switching genes. Our findings open an avenue toward understanding pathological alterations in patterns of plant growth and development, thus aiding identification of molecular targets for disease control and symptom alleviation. The findings also provide insights for understanding stem cell pluripotency and raise a tantalizing possibility for using phytoplasma as a tool to dissect the course of normal plant development and to modify plant morphogenesis by manipulating meristem fate.

Wei, Wei; Davis, Robert Edward; Nuss, Donald L.; Zhao, Yan

2013-01-01

173

Urbanization affects stream ecosystem function by altering hydrology, chemistry, and biotic richness.  

PubMed

Catchment urbanization can alter physical, chemical, and biological attributes of stream ecosystems. In particular, changes in land use may affect the dynamics of organic matter decomposition, a measure of ecosystem function. We examined leaf-litter decomposition in 18 tributaries of the St. Johns River, Florida, USA. Land use in all 18 catchments ranged from 0% to 93% urban which translated to 0% to 66% total impervious area (TIA). Using a litter-bag technique, we measured mass loss, fungal biomass, and macroinvertebrate biomass for two leaf species (red maple [Acer rubrum] and sweetgum [Liquidambar styraciflua]). Rates of litter mass loss, which ranged from 0.01 to 0.05 per day for red maple and 0.006 to 0.018 per day for sweetgum, increased with impervious catchment area to levels of approximately 30-40% TIA and then decreased as impervious catchment area exceeded 40% TIA. Fungal biomass was also highest in streams draining catchments with intermediate levels of TIA. Macroinvertebrate biomass ranged from 17 to 354 mg/bag for red maple and from 15 to 399 mg/bag for sweetgum. Snail biomass and snail and total invertebrate richness were strongly related to breakdown rates among streams regardless of leaf species. Land-use and physical, chemical, and biological variables were highly intercorrelated. Principal-components analysis was therefore used to reduce the variables into several orthogonal axes. Using stepwise regression, we found that flow regime, snail biomass, snail and total invertebrate richness, and metal and nutrient content (which varied in a nonlinear manner with impervious surface area) were likely factors affecting litter breakdown rates in these streams. PMID:17069372

Chadwick, Michael A; Dobberfuhl, Dean R; Benke, Arthur C; Huryn, Alexander D; Suberkropp, Keller; Thiele, John E

2006-10-01

174

Alterations in welding process voltage affect the generation of ultrafine particles, fume composition, and pulmonary toxicity.  

PubMed

The goal was to determine if increasing welding voltage changes the physico-chemical properties of the fume and influences lung responses. Rats inhaled 40 mg/m³ (3 h/day × 3 days) of stainless steel (SS) welding fume generated at a standard voltage setting of 25 V (regular SS) or at a higher voltage (high voltage SS) of 30 V. Particle morphology, size and composition were characterized. Bronchoalveolar lavage was performed at different times after exposures to assess lung injury. Fumes collected from either of the welding conditions appeared as chain-like agglomerates of nanometer-sized primary particles. High voltage SS welding produced a greater number of ultrafine-sized particles. Fume generated by high voltage SS welding was higher in manganese. Pulmonary toxicity was more substantial and persisted longer after exposure to the regular SS fume. In summary, a modest raise in welding voltage affected fume size and elemental composition and altered the temporal lung toxicity profile. PMID:21281223

Antonini, James M; Keane, Michael; Chen, Bean T; Stone, Samuel; Roberts, Jenny R; Schwegler-Berry, Diane; Andrews, Ronnee N; Frazer, David G; Sriram, Krishnan

2011-12-01

175

Chemosensory cues affect amygdaloid neurogenesis and alter behaviors in the socially monogamous prairie vole.  

PubMed

The current study examined the effects of pheromonal exposure on adult neurogenesis and revealed the role of the olfactory pathways on adult neurogenesis and behavior in the socially monogamous prairie vole (Microtus ochrogaster). Subjects were injected with a cell proliferation marker [5-bromo-2'-deoxyuridine (BrdU)] and then exposed to their own soiled bedding or bedding soiled by a same- or opposite-sex conspecific. Exposure to opposite-sex bedding increased BrdU labeling in the amygdala (AMY), but not the dentate gyrus (DG), of female, but not male, voles, indicating a sex-, stimulus-, and brain region-specific effect. The removal of the main olfactory bulbs or lesioning of the vomeronasal organ (VNOX) in females reduced BrdU labeling in the AMY and DG, and inhibited the male bedding-induced BrdU labeling in the AMY, revealing the importance of an intact olfactory pathway for amygdaloid neurogenesis. VNOX increased anxiety-like behavior and altered social preference, but it did not affect social recognition memory in female voles. VNOX also reduced the percentage of BrdU-labeled cells that co-expressed the neuronal marker TuJ1 in the AMY, but not the DG. Together, our data indicate the importance of the olfactory pathway in mediating brain plasticity in the limbic system as well as its role in behavior. PMID:24641515

Liu, Y; Lieberwirth, C; Jia, X; Curtis, J T; Meredith, M; Wang, Z X

2014-05-01

176

Altering the Axial Light Gradient Affects Photomorphogenesis in Emerging Seedlings of Zea mays L. 1  

PubMed Central

The axial (longitudinal) red-light gradient (632 nanometers) of 4 day old dark-grown maize seedlings is increased by staining the peripheral cells of the coleoptile. The magnitude of increase in the light gradient is dependent solely on the light-absorbing qualities of the stain used. Metanil yellow has no effect on the axial red-light gradient, while methylene blue causes a large increase in this light gradient. These stains did not affect growth in darkness or the sensitivity of mesocotyl elongation to red light. However, mesocotyl elongation was altered for the dark-grown seedlings stained with methylene blue when these seedlings were transplanted, covered with soil, and permitted to emerge under natural lighting conditions. These observations are consistent with the idea that there is a single perceptive site below the coleoptilar node, and suggest that this perceptive site receives the actinic light which has traveled downward through the length of the shoot from an entry point in the plant tip region.

Parks, Brian M.; Poff, Kenneth L.

1986-01-01

177

Human genetics. The genetics of Mexico recapitulates Native American substructure and affects biomedical traits.  

PubMed

Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between subcontinental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide. PMID:24926019

Moreno-Estrada, Andrés; Gignoux, Christopher R; Fernández-López, Juan Carlos; Zakharia, Fouad; Sikora, Martin; Contreras, Alejandra V; Acuña-Alonzo, Victor; Sandoval, Karla; Eng, Celeste; Romero-Hidalgo, Sandra; Ortiz-Tello, Patricia; Robles, Victoria; Kenny, Eimear E; Nuño-Arana, Ismael; Barquera-Lozano, Rodrigo; Macín-Pérez, Gastón; Granados-Arriola, Julio; Huntsman, Scott; Galanter, Joshua M; Via, Marc; Ford, Jean G; Chapela, Rocío; Rodriguez-Cintron, William; Rodríguez-Santana, Jose R; Romieu, Isabelle; Sienra-Monge, Juan José; del Rio Navarro, Blanca; London, Stephanie J; Ruiz-Linares, Andrés; Garcia-Herrera, Rodrigo; Estrada, Karol; Hidalgo-Miranda, Alfredo; Jimenez-Sanchez, Gerardo; Carnevale, Alessandra; Soberón, Xavier; Canizales-Quinteros, Samuel; Rangel-Villalobos, Héctor; Silva-Zolezzi, Irma; Burchard, Esteban Gonzalez; Bustamante, Carlos D

2014-06-13

178

Genetic Exchange in an Arbuscular Mycorrhizal Fungus Results in Increased Rice Growth and Altered Mycorrhiza-Specific Gene Transcription?†  

PubMed Central

Arbuscular mycorrhizal fungi (AMF) are obligate symbionts with most terrestrial plants. They improve plant nutrition, particularly phosphate acquisition, and thus are able to improve plant growth. In exchange, the fungi obtain photosynthetically fixed carbon. AMF are coenocytic, meaning that many nuclei coexist in a common cytoplasm. Genetic exchange recently has been demonstrated in the AMF Glomus intraradices, allowing nuclei of different Glomus intraradices strains to mix. Such genetic exchange was shown previously to have negative effects on plant growth and to alter fungal colonization. However, no attempt was made to detect whether genetic exchange in AMF can alter plant gene expression and if this effect was time dependent. Here, we show that genetic exchange in AMF also can be beneficial for rice growth, and that symbiosis-specific gene transcription is altered by genetic exchange. Moreover, our results show that genetic exchange can change the dynamics of the colonization of the fungus in the plant. Our results demonstrate that the simple manipulation of the genetics of AMF can have important consequences for their symbiotic effects on plants such as rice, which is considered the most important crop in the world. Exploiting natural AMF genetic variation by generating novel AMF genotypes through genetic exchange is a potentially useful tool in the development of AMF inocula that are more beneficial for crop growth.

Colard, Alexandre; Angelard, Caroline; Sanders, Ian R.

2011-01-01

179

Genetic compatibility affects division of labor in the Argentine ant Linepithema humile.  

PubMed

Division of labor is central to the organization of insect societies. Within-colony comparisons between subfamilies of workers (patrilines or matrilines) revealed genetic effects on division of labor in many social insect species. Although this has been taken as evidence for additive genetic effects on division of labor, it has never been experimentally tested. To determine the relative roles of additive and nonadditive genetic effects (e.g., genetic compatibility, epistasis, and parent-of-origin imprinting effects) on worker behavior, we performed controlled crosses using the Argentine ant Linepithema humile. Three of the measured behaviors (the efficiency to collect pupae, the foraging propensity, and the distance between non-brood-tenders and brood) were affected by the maternal genetic background and the two others (the efficiency to feed larvae and the distance between brood-tenders and brood) by the paternal genetic background. Moreover, there were significant interactions between the maternal and paternal genetic backgrounds for three of the five behaviors. These results are most consistent with parent-of-origin and genetic compatibility effects on division of labor. The finding of nonadditive genetic effects is in strong contrast with the current view and has important consequences for our understanding of division of labor in insect societies. PMID:23356622

Libbrecht, Romain; Keller, Laurent

2013-02-01

180

NS Reassortment of an H7-Type Highly Pathogenic Avian Influenza Virus Affects Its Propagation by Altering the Regulation of Viral RNA Production and Antiviral Host Response? †  

PubMed Central

Highly pathogenic avian influenza viruses (HPAIV) with reassorted NS segments from H5- and H7-type avian virus strains placed in the genetic background of the A/FPV/Rostock/34 HPAIV (FPV; H7N1) were generated by reverse genetics. Virological characterizations demonstrated that the growth kinetics of the reassortant viruses differed from that of wild-type (wt) FPV and depended on whether cells were of mammalian or avian origin. Surprisingly, molecular analysis revealed that the different reassortant NS segments were not only responsible for alterations in the antiviral host response but also affected viral genome replication and transcription as well as nuclear ribonucleoprotein (RNP) export. RNP reconstitution experiments demonstrated that the effects on accumulation levels of viral RNA species were dependent on the specific NS segment as well as on the genetic background of the RNA-dependent RNA polymerase (RdRp). Beta interferon (IFN-?) expression and the induction of apoptosis were found to be inversely correlated with the magnitude of viral growth, while the NS allele, virus subtype, and nonstructural protein NS1 expression levels showed no correlation. Thus, these results demonstrate that the origin of the NS segment can have a dramatic effect on the replication efficiency and host range of HPAIV. Overall, our data suggest that the propagation of NS reassortant influenza viruses is affected at multiple steps of the viral life cycle as a result of the different effects of the NS1 protein on multiple viral and host functions.

Wang, Zhongfang; Robb, Nicole C.; Lenz, Eva; Wolff, Thorsten; Fodor, Ervin; Pleschka, Stephan

2010-01-01

181

Life history influences how fire affects genetic diversity in two lizard species.  

PubMed

'Fire mosaics' are often maintained in landscapes to promote successional diversity in vegetation with little understanding of how this will affect ecological processes in animal populations such as dispersal, social organization and re-establishment. To investigate these processes, we conducted a replicated, spatiotemporal landscape genetics study of two Australian woodland lizard species [Amphibolurus norrisi (Agamidae) and Ctenotus atlas (Scincidae)]. Agamids have a more complex social and territory structure than skinks, so fire might have a greater impact on their population structure and thus genetic diversity. Genetic diversity increased with time since fire in C. atlas and decreased with time since fire in A. norrisi. For C. atlas, this might reflect its increasing population size after fire, but we could not detect increased gene flow that would reduce the loss of genetic diversity through genetic drift. Using landscape resistance analyses, we found no evidence that postfire habitat succession or topography affected gene flow in either species and we were unable to distinguish between survival and immigration as modes of postfire re-establishment. In A. norrisi, we detected female-biased dispersal, likely reflecting its territorial social structure and polygynous mating system. The increased genetic diversity in A. norrisi in recently burnt habitat might reflect a temporary disruption of its territoriality and increased male dispersal, a hypothesis that was supported with a simulation experiment. Our results suggest that the effects of disturbance on genetic diversity will be stronger for species with territorial social organization. PMID:24750427

Smith, Annabel L; Bull, C Michael; Gardner, Michael G; Driscoll, Don A

2014-05-01

182

Genetic and Biochemical Alterations in Non-Small Cell Lung Cancer  

PubMed Central

Despite significant advances in the detection and treatment of lung cancer, it causes the highest number of cancer-related mortality. Recent advances in the detection of genetic alterations in patient samples along with physiologically relevant animal models has yielded a new understanding of the molecular etiology of lung cancer. This has facilitated the development of potent and specific targeted therapies, based on the genetic and biochemical alterations present in the tumor, especially non-small-cell lung cancer (NSCLC). It is now clear that heterogeneous cell signaling pathways are disrupted to promote NSCLC, including mutations in critical growth regulatory proteins (K-Ras, EGFR, B-RAF, MEK-1, HER2, MET, EML-4-ALK, KIF5B-RET, and NKX2.1) and inactivation of growth inhibitory pathways (TP53, PTEN, p16, and LKB-1). How these pathways differ between smokers and non-smokers is also important for clinical treatment strategies and development of targeted therapies. This paper describes these molecular targets in NSCLC, and describes the biological significance of each mutation and their potential to act as a therapeutic target.

Johnson, Jackie L.; Pillai, Smitha; Chellappan, Srikumar P.

2012-01-01

183

Molecular Genetic Alteration of Plant Respiration (Silencing and Overexpression of Alternative Oxidase in Transgenic Tobacco).  

PubMed Central

The alternative oxidase (AOX) of plant mitochondria is encoded by the nuclear gene Aox1. Sense and antisense DNA constructs of Nicotiana tabacum Aox1 were introduced into tobacco, and transgenic plants with both increased and decreased levels of mitochondrial AOX protein were identified. Suspension cells derived from wild-type and transgenic plants were grown in heterotrophic batch culture. Transgenic cells with increased AOX protein had an increased capacity for cyanide-resistant, salicylhydroxamic acid-sensitive respiration compared to wild-type cells, whereas transgenic cells with decreased AOX protein had a decreased capacity for such respiration. Thus, genetic alteration of the level of AOX protein was sufficient to alter the capacity for electron transport through the alternative pathway. Under our standard growth conditions, "antisense" cells with dramatically reduced levels of AOX protein had growth and respiration rates similar to the wild type. However, whereas wild-type cells were able to grow under conditions that severely suppressed cytochrome pathway activity, antisense cells could not survive this treatment. This suggests that a critical function of AOX may be to support respiration when the cytochrome pathway is impaired. The much higher level of AOX protein in "sense" cells compared to the wild type did not appreciably alter the steady-state partitioning of electrons between the cytochrome path and the alternative pathway in vivo, suggesting that this partitioning may be subject to additional regulatory factors.

Vanlerberghe, G. C.; Vanlerberghe, A. E.; McIntosh, L.

1994-01-01

184

Micronucleus test and observation of nuclear alterations in erythrocytes of Nile tilapia exposed to waters affected by refinery effluent  

Microsoft Academic Search

Micronuclei and nuclear alterations tests were performed on erythrocytes of Oreochromis niloticus (Perciformes, Cichlidae) in order to evaluate the water quality from Paraíba do Sul river, in an area affected by effluents from an oil shale processing plant, located in the city of São José dos Campos, Brazil-SP. Water samples were collected on 2004 May and August (dry season) and

Tatiana da Silva Souza; Carmem S. Fontanetti

2006-01-01

185

Delineation of Behavioral Phenotypes in Genetic Syndromes: Characteristics of Autism Spectrum Disorder, Affect and Hyperactivity  

ERIC Educational Resources Information Center

We investigated autism spectrum disorder (ASD) symptomatology, hyperactivity and affect in seven genetic syndromes; Angelman (AS; n = 104), Cri du Chat (CdCS; 58), Cornelia de Lange (CdLS; 101), Fragile X (FXS; 191), Prader-Willi (PWS; 189), Smith-Magenis (SMS; 42) and Lowe (LS; 56) syndromes (age range 4-51). ASD symptomatology was heightened in…

Oliver, Chris; Berg, Katy; Moss, Jo; Arron, Kate; Burbidge, Cheryl

2011-01-01

186

Genetic linkage analysis of bipolar affective disorder in an Old Order Amish pedigree  

Microsoft Academic Search

We have used genetic linkage analysis in an effort to identify a gene responsible for bipolar affective disorder (BAD) in an Old Order Amish pedigree. The initial study of this pedigree showed strong evidence for linkage of the chromosome 11p15 markers HRAS1 and the insulin gene (INS) to BAD, whereas a second report found no evidence for linkage. We have

Adam Law; Charles W. Richard; Robert W. Cottingham; G. Mark Lathrop; David R. Cox; Richard M. Myers

1992-01-01

187

Genetic Transmission of Major Affective Disorders: Quantitative Models and Linkage Analyses  

Microsoft Academic Search

We comprehensively reviewed 2 types of studies aimed at specifying the mode of inheritance of major affective disorders: quantitative models and linkage analyses. Quantitative models attempt to represent the genetic mechanism responsible for the familial distribution of a disorder. Despite efforts to refine models by incorporating the bipolar–unipolar distinction or the sex effect, consistent support for a specific mode of

Stephen V. Faraone; William S. Kremen; Ming T. Tsuang

1990-01-01

188

Genetic predisposition to chikungunya – a blood group study in chikungunya affected families  

Microsoft Academic Search

Chikungunya fever is a viral disease transmitted to humans by the bite of CHIKV virus infected Aedes mosquitoes. During monsoon outbreak of chikungunya fever, we carried out the genetic predisposition to chikungunya in disease affected 100 families by doing blood group (ABO) tests by focusing on individuals who were likely to have a risk of chikungunya and identified the blood

Sudarsanareddy Lokireddy; Vemula Sarojamma; Vadde Ramakrishna

2009-01-01

189

Collecting Duct Carcinomas Represent a Unique Tumor Entity Based on Genetic Alterations  

PubMed Central

Collecting duct carcinoma (CDC) is a rare renal neoplasm that is associated with poor prognosis due to its highly aggressive course and limited response to immuno- or chemotherapy. Histologically, CDC is defined as a subtype of renal cell carcinomas, but in some cases, it is difficult to differentiate from urothelial carcinomas (UC). Therefore the aim of this study was to determine genetic alterations of CDC in comparison to that of urothelial carcinomas of the upper urinary tract (UUT-UC) to clarify the histological origin of this rare tumor entity. Twenty-nine CDC samples were obtained from seven different German centers and compared with twenty-six urothelial carcinomas of the upper urinary tract. Comparative genomic hybridization (CGH) was used to investigate the genetic composition of patients’ tumors and allowed the detection of losses and gains of DNA copy numbers throughout the entire genome. The clinical data were correlated with CGH results. CGH analysis of CDC revealed DNA aberrations in many chromosomes. DNA losses were more frequently observed than gains, while high-level amplifications were not detected. The mean frequency of CDC chromosomal aberrations (4.9/case) was slightly lower than that in UUT-UC (5.4/case). Recurrent CDC DNA losses occurred at 8p (n=9/29), 16p (9/29), 1p (n=7/29) and 9p (n=7/29), and gains occurred in 13q (n=9/29). In contrast to CDC, the most frequently detected UUT-UC DNA aberration was a loss at 9q (n=13/26). DNA losses at 9q, 13q and 8q as well as gains at 8p showed significant variations in UUT-UC compared to CDC. There was no correlation between the patients’ clinical course and the presence or absence of these recurrent genetic alterations. CDCs are characterized by a different genetic pattern compared to UUT-UC. Regarding the published data on renal cell carcinoma, we conclude that CDC appears to be a unique entity among kidney carcinomas.

Parr, Martin; Hartmann, Arndt; Fussel, Susanne; Toma, Marieta; Grobholz, Rainer; Pflugmann, Thomas; Wullich, Bernd; Strauss, Arne; Behnes, Carl Ludwig; Otto, Wolfgang; Stockle, Michael; Jung, Volker

2013-01-01

190

Functional and gel characteristics of liquid whole egg as affected by pH alteration  

Microsoft Academic Search

Studies were conducted to evaluate the effect of pH alteration of liquid whole egg (LWE) from newly laid shell eggs on their functional and gel characteristics. The pH of LWE was altered either with 1 N NaOH or 1 N HCl to 6.5, 7.0, 7.5, 8.0, 8.5, and 9.0 and tested for their foaming capacities (FCs), foam stabilities (FSs), and

Y. I Chang; T. C Chen

2000-01-01

191

Drug-induced and Genetic Alterations in Stress-Responsive Systems: Implications for Specific Addictive Diseases  

PubMed Central

From the earliest work in our laboratory, we hypothesized, and with studies conducted in both clinical research and animal models, we have shown that drugs of abuse, administered or self-administered, on a chronic basis, profoundly alter stress-responsive systems. Alterations of expression of specific genes involved in stress responsivity, with increases or decreases in mRNA levels, receptor and neuropeptide levels, and resultant changes in hormone levels, have been documented to occur after chronic intermittent exposure to heroin, morphine, other opiates, cocaine, other stimulants and alcohol in animal models and in human molecular genetics. The best studied of the stress-responsive systems in humans and mammalian species in general is undoubtedly the HPA axis. In addition, there are stress-responsive systems in other parts in the brain itself, and some of these include components of the HPA axis, such as CRF and CRF receptors, along with POMC gene and gene products. Several other stress-responsive systems are known to influence the HPA axis, such as the vasopressin-vasopressin receptor system. Orexin-hypocretin, acting at its receptors, may effect changes which suggest that it should be properly categorized as a stress-responsive system. However, less is known about the interactions and connectivity of some of these different neuropeptide and receptor systems, and in particular, about the possible connectivity of fast-acting (e.g., glutamate and GABA) and slow-acting (including dopamine, serotonin and norepinephrine) neurotransmitters with each of these stress-responsive components and the resultant impact, especially in the setting of chronic exposure to drugs of abuse. Several of these stress-responsive systems and components, primarily based on our laboratory-based and human molecular genetics research of addictive diseases, will be briefly discussed in this review.

Zhou, Yan; Proudnikov, Dmitri; Yuferov, Vadim; Kreek, Mary Jeanne

2009-01-01

192

Genetic alterations and expression pattern of CEACAM1 in colorectal adenomas and cancers.  

PubMed

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed on epithelial cells throughout the intestinal tract and is a negative regulator of tumor cell growth, suggesting that it may function as a tumor suppressor. In this study, to determine whether the CEACAM1 is involved in colorectal tumorigenesis, we have investigated the genetic alterations, including mutations and allelic loss, of the CEACAM1 gene in 17 colonic adenomas and 123 sporadic colorectal cancers. In addition, the expression pattern of the CEACAM1 protein was examined in 60 colonic adenomas and 123 sporadic colorectal adenocarcinomas. No mutation was found in colonic adenomas, but four somatic missense mutations, L36F, T312I, V398I and A445V, were detected in colorectal cancers. Interestingly, all of the mutations were found in left-side colon cancers of the patients with clinical stage III. In LOH analysis, nine adenomas were informative for at least one of the markers and five (55.6%) showed allelic loss. Thirty-eight cancers were informative at D19S211 and D19S872 markers and 21 (56.3%) showed LOH at these markers. Statistically, the frequency of allelic loss at the CEACAM1 locus was not associated with clinicopathologic parameters (P > 0.05). In immunohistochemical analysis, loss of expression of CEACAM1 protein was detected in nine (15.0%) and 30 (24.4%) of 60 colorectal adenomas and 123 colorectal cancers. Statistically, there was no significant relationship between loss of CEACAM1 expression and clinicopathologic parameters, including clinical stage, tumor location, tumor size, lymph node metastasis and 5-year survival (P > 0.05). These data suggest that genetic alteration and loss of expression of the CEACAM1 may contribute to the development of colorectal cancers, as an early event. PMID:20524097

Song, Jae Hwi; Cao, Zhang; Yoon, Jung Hwan; Nam, Suk Woo; Kim, Su Young; Lee, Jung Young; Park, Won Sang

2011-03-01

193

ICLAS Working Group on Harmonization: international guidance concerning the production care and use of genetically-altered animals.  

PubMed

Replacement, Reduction and Refinement, the ‘Three Rs’ of Russell & Burch, are accepted worldwide as fundamental to the ethics of animal experimentation. The production, care and use of genetically-altered animals can pose particular challenges to the implementation of the Three Rs,1 necessitating additional considerations by those responsible for overseeing the ethical use and appropriate care of animals involved in science. The International Council for Laboratory Animal Science brings representatives of the international laboratory animal science community together to recommend acceptance of guidance documents.The harmonization of guidance concerning genetically-altered animals was seen as a priority because of the increasing globalization of research involving these animals. PMID:23563121

Rose, M; Everitt, J; Hedrich, H; Schofield, J; Dennis, M; Scott, E; Griffin, G

2013-07-01

194

Molecular genetics alterations and tumor behavior of sporadic vestibular schwannoma from the People’s Republic of China  

Microsoft Academic Search

Objectives: To analyze the molecular genetic alteration of sporadic vestibular schwannomas from the People’s Republic of China and to correlate these alterations with the tumor behaviors. Methods: Four highly polymorphic microsatellite DNA markers were used to observe the frequency of loss of heterozygosity (LOH) in chromosome 22. The NF2 gene mutations were detected by Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP)

Liu-Guan Bian; Wuttipong Tirakotai; Qing-Fang Sun; Wei-Guo Zhao; Jian-Kang Shen; Qi-Zhong Luo

2005-01-01

195

Genetic alterations in quadruple malignancies of a patient with multiple sclerosis: their role in malignancy development and response to therapy  

PubMed Central

Multiple cancers represent 2.42% of all human cancers and are mainly double or triple cancers. Many possible causes of multiple malignancies have been reported such as genetic alterations, exposure to anti-cancer chemotherapy, radiotherapy, immunosuppressive therapy and reduced immunologic response. We report a female patient with multiple sclerosis and quadruple cancers of different embryological origin. Patient was diagnosed with stage III (T3, N1a, MO) medullary thyroid carcinoma (MTC), multicentric micropapillary thyroid carcinoma, scapular and lumbar melanomas (Clark II, Breslow II), and lobular invasive breast carcinoma (T1a, NO, MO). All tumors present in our patient except micropapillary thyroid carcinomas were investigated for gene alterations known to have a key role in cancer promotion and progression. Tumor samples were screened for the p16 alterations (loss of heterozygosity and homozygous deletions), loss of heterozygosity of PTEN, p53 alterations (mutational status and loss of heterozygosity) and mutational status of RET, HRAS and KRAS. Each type of tumor investigated had specific pattern of analyzed genetic alterations. The most prominent genetic changes were mutual alterations in PTEN and p53 tumor suppressors present in breast cancer and two melanomas. These co-alterations could be crucial for promoting development of multiple malignancies. Moreover the insertion in 4th codon of HRAS gene was common for all tumor types investigated. It represents frameshift mutation introducing stop codon at position 5 which prevents synthesis of a full-length protein. Since the inactivated RAS enhances sensitivity to tamoxifen and radiotherapy this genetic alteration could be considered as a good prognostic factor for this patient.

Milosevic, Zorica; Tanic, Nikola; Bankovic, Jasna; Stankovic, Tijana; Buta, Marko; Lavrnic, Dragana; Milovanovic, Zorka; Pupic, Gordana; Stojkovic, Sonja; Milinkovic, Vedrana; Ito, Yasuhiro; Dzodic, Radan

2014-01-01

196

Histopathologic and genetic alterations as predictors of response to treatment and survival in lung cancer: A review of published data  

Microsoft Academic Search

Lung carcinogenesis is considered to be the result of composite environmental, genetic and epigenetic changes. Despite the fact that many of the genetic alterations, including loss of heterozygocity in the 3p chromosome locus and point mutations in the tumor-suppressor genes TP53 and retinoblastoma (RB1), occur in nearly all histopathologic types of lung cancer, the frequency and the “timing” of their

Giannis Mountzios; Meletios-Athanassios Dimopoulos; Jean-Charles Soria; Despina Sanoudou; Christos A. Papadimitriou

2010-01-01

197

Dioecy, more than monoecy, affects plant spatial genetic structure: the case study of Ficus  

PubMed Central

In this analysis, we attempt to understand how monoecy and dioecy drive spatial genetic structure (SGS) in plant populations. For this purpose, plants of the genus Ficus were used as a comparative model due to their particular characteristics, including high species diversity, variation in life histories, and sexual systems. One of the main issues we assessed is whether dioecious fig tree populations are more spatially genetically structured than monoecious populations. Using the Sp statistic, which allows for quantitative comparisons among different studies, we compared the extent of SGS between monoecious and dioecious Ficus species. To broaden our conclusions we used published data on an additional 27 monoecious and dioecious plant species. Furthermore, genetic diversity analyses were performed for two monoecious Ficus species using 12 microsatellite markers in order to strengthen our conclusions about SGS. Our results show that dioecy, more than monoecy, significantly contributes to SGS in plant populations. On average, the estimate of Sp was six times higher for dioecious Ficus species than monoecious Ficus species and it was two times higher in dioecious than monoecious plant species. Considering these results, we emphasize that the long-distance pollen dispersal mechanism in monoecious Ficus species seems to be the dominant factor in determining weak spatial genetic structure, high levels of genetic diversity, and lack of inbreeding. Although Ficus constitute a model species to study SGS, a more general comparison encompassing a wider range of plants is required in order to better understand how sexual systems affect genetic structure.

Nazareno, Alison G; Alzate-Marin, Ana L; Pereira, Rodrigo Augusto S

2013-01-01

198

Genetic and epigenetic alterations in primary-progressive paired oligodendroglial tumors.  

PubMed

The aim of the present study was to identify genetic and epigenetic alterations involved in the progression of oligodendroglial tumors. We characterized 21 paired, World Health Organization (WHO) grade II and III oligodendroglial tumors from patients who received craniotomies for the partial or complete resection of primary and secondary oligodendroglial tumors. Tumor DNA was analyzed for alterations in selected genetic loci (1p36, 9p22, 10q23-24, 17p13, 19q13, 22q12), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2) and the CpG island methylation status of critical tumor-related genes (MGMT, P16, DAPK, PTEN, RASSF1A, Rb1). Alterations of these markers were common early in the tumorigenesis. In the primary tumors we identified 12 patients (57.1%) with 1p36 deletions, 17 (81.0%) with 19q13 deletions, 9 (42.9%) with 1p36/19q13 codeletions, 11 (52.3%) with 9p22 deletions, and 12 (57.1%) with IDH1 mutation. Epigenetic analysis detected promoter methylation of the MGMT, P16, DAPK, PTEN, RASSF1A, and Rb1 genes in 38.1%, 19.0%, 38.1%, 33.3%, 66.7%, and 14.3% of primary tumors, respectively. After progression, additional losses of 1p, 9p, 10q, 17p, 19q and 22q were observed in 3 (14.3%), 1 (4.8%), 3 (14.3%), 2 (9.5%), 1 (4.8%) and 3 (14.3%) cases, respectively. Additional methylations of the MGMT, P16, DAPK, PTEN, RASSF1A, and RB1 promoters was observed in 4 (19.0%), 2 (9.5%), 0 (0%), 6 (28.6%), 2(9.5%) and 3 (14.3%) cases, respectively. The status of IDH1 mutation remained unchanged in all tumors after progression. The primary tumors of three patients with subsequent progression to high-grade astrocytomas, all had 9p deletion, intact 1p, intact 10q and unmethylated MGMT. Whether this may represent a molecular signature of patients at-risk for the development of aggressive astrocytomas needs further investigation. PMID:23826216

Kuo, Lu-Ting; Tsai, Shao-Yu; Chang, Cheng-Chi; Kuo, Kuang-Ting; Huang, Abel Po-Hao; Tsai, Jui-Chang; Tseng, Ham-Min; Kuo, Meng-Fai; Tu, Yong-Kwang

2013-01-01

199

Genetic and Epigenetic Alterations in Primary-Progressive Paired Oligodendroglial Tumors  

PubMed Central

The aim of the present study was to identify genetic and epigenetic alterations involved in the progression of oligodendroglial tumors. We characterized 21 paired, World Health Organization (WHO) grade II and III oligodendroglial tumors from patients who received craniotomies for the partial or complete resection of primary and secondary oligodendroglial tumors. Tumor DNA was analyzed for alterations in selected genetic loci (1p36, 9p22, 10q23–24, 17p13, 19q13, 22q12), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2) and the CpG island methylation status of critical tumor-related genes (MGMT, P16, DAPK, PTEN, RASSF1A, Rb1). Alterations of these markers were common early in the tumorigenesis. In the primary tumors we identified 12 patients (57.1%) with 1p36 deletions, 17 (81.0%) with 19q13 deletions, 9 (42.9%) with 1p36/19q13 codeletions, 11 (52.3%) with 9p22 deletions, and 12 (57.1%) with IDH1 mutation. Epigenetic analysis detected promoter methylation of the MGMT, P16, DAPK, PTEN, RASSF1A, and Rb1 genes in 38.1%, 19.0%, 38.1%, 33.3%, 66.7%, and 14.3% of primary tumors, respectively. After progression, additional losses of 1p, 9p, 10q, 17p, 19q and 22q were observed in 3 (14.3%), 1 (4.8%), 3 (14.3%), 2 (9.5%), 1 (4.8%) and 3 (14.3%) cases, respectively. Additional methylations of the MGMT, P16, DAPK, PTEN, RASSF1A, and RB1 promoters was observed in 4 (19.0%), 2 (9.5%), 0 (0%), 6 (28.6%), 2(9.5%) and 3 (14.3%) cases, respectively. The status of IDH1 mutation remained unchanged in all tumors after progression. The primary tumors of three patients with subsequent progression to high-grade astrocytomas, all had 9p deletion, intact 1p, intact 10q and unmethylated MGMT. Whether this may represent a molecular signature of patients at-risk for the development of aggressive astrocytomas needs further investigation.

Kuo, Lu-Ting; Tsai, Shao-Yu; Chang, Cheng-Chi; Kuo, Kuang-Ting; Huang, Abel Po-Hao; Tsai, Jui-Chang; Tseng, Ham-Min; Kuo, Meng-Fai; Tu, Yong-Kwang

2013-01-01

200

The experience of altered states of consciousness in shamanic ritual: the role of pre-existing beliefs and affective factors.  

PubMed

Much attention has been paid recently to the role of anomalous experiences in the aetiology of certain types of psychopathology, e.g. in the formation of delusions. We examine, instead, the top-down influence of pre-existing beliefs and affective factors in shaping an individual's characterisation of anomalous sensory experiences. Specifically we investigated the effects of paranormal beliefs and alexithymia in determining the intensity and quality of an altered state of consciousness (ASC). Fifty five participants took part in a sweat lodge ceremony, a traditional shamanic ritual which was unfamiliar to them. Participants reported significant alterations in their state of consciousness, quantified using the 'APZ' questionnaire, a standardized measure of ASC experience. Participants endorsing paranormal beliefs compatible with shamanic mythology, and those showing difficulty identifying feelings scored higher on positive dimensions of ASC experience. Our findings demonstrate that variation in an individual's characterisation of anomalous experiences is nuanced by pre-existing beliefs and affective factors. PMID:20558090

Polito, Vince; Langdon, Robyn; Brown, Jac

2010-12-01

201

Neonatal Phytoestrogen Exposure Alters Oviduct Mucosal Immune Response to Pregnancy and Affects Preimplantation Embryo Development in the Mouse1  

PubMed Central

ABSTRACT Treatment of neonatal mice with the phytoestrogen genistein (50 mg/kg/day) results in complete female infertility caused in part by preimplantation embryo loss in the oviduct between Days 2 and 3 of pregnancy. We previously demonstrated that oviducts of genistein-treated mice are “posteriorized” as compared to control mouse oviducts because they express numerous genes normally restricted to posterior regions of the female reproductive tract (FRT), the cervix and vagina. We report here that neonatal genistein treatment resulted in substantial changes in oviduct expression of genes important for the FRT mucosal immune response, including immunoglobulins, antimicrobials, and chemokines. Some of the altered immune response genes were chronically altered beginning at the time of neonatal genistein treatment, indicating that these alterations were a result of the posteriorization phenotype. Other alterations in oviduct gene expression were observed only in early pregnancy, immediately after the FRT was exposed to inflammatory or antigenic stimuli from ovulation and mating. The oviduct changes affected development of the surviving embryos by increasing the rate of cleavage and decreasing the trophectoderm-to-inner cell mass cell ratio at the blastocyst stage. We conclude that both altered immune responses to pregnancy and deficits in oviduct support for preimplantation embryo development in the neonatal genistein model are likely to contribute to infertility phenotype.

Jefferson, Wendy N.; Padilla-Banks, Elizabeth; Phelps, Jazma Y.; Cantor, Amy M.; Williams, Carmen J.

2012-01-01

202

Altered Expression of SPINDLY Affects Gibberellin Response and Plant Development1  

Microsoft Academic Search

Gibberellins (GAs) are plant hormones with diverse roles in plant growth and development. SPINDLY (SPY) is one of several genes identified in Arabidopsis that are involved in GA response and it is thought to encode an O-GlcNAc transferase. Genetic analysis suggests that SPY negatively regulates GA response. To test the hypothesis that SPY acts specifically as a negatively acting component

Stephen M. Swain; Tong-seung Tseng; Neil E. Olszewski

2001-01-01

203

Genetic Analysis of 63 Mutations Affecting Maize Kernel Development Isolated from Mutator Stocks  

PubMed Central

Sixty-three mutations affecting development of the maize kernel were isolated from active Robertson's Mutator (Mu) stocks. At least 14 previously undescribed maize gene loci were defined by mutations in this collection. Genetic mapping located 53 of these defective kernel (dek) mutations to particular chromosome arms, and more precise map determinations were made for 21 of the mutations. Genetic analyses identified 20 instances of allelism between one of the novel mutations and a previously described dek mutation, or between new dek mutations identified in this study; phenotypic variability was observed in three of the allelic series. Viability testing of homozygous mutant kernels identified numerous dek mutations with various pleiotropic effects on seedling and plant development. The mutations described here presumably arose by insertion of a Mu transposon within a dek gene; thus, many of the affected loci are expected to be accessible to molecular cloning via transposon-tagging.

Scanlon, M. J.; Stinard, P. S.; James, M. G.; Myers, A. M.; Robertson, D. S.

1994-01-01

204

Frequent Genetic Alterations at the Microsatellite Level in Cytologic Sputum Samples of Patients with Idiopathic Pulmonary Fibrosis  

Microsoft Academic Search

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiol- ogy associated with DNA damage and malignancy. Bronchogenic carcinoma is the cause of death in 10% to 13% of IPF patients. Mi- crosatellite instability (MSI) and loss of heterozygosity (LOH) are frequently detected in cancers. If these genetic alterations could be observed in IPF, they might explain the higher relative

DIMITRIS A. VASSILAKIS; GEORGE SOURVINOS; DEMETRIOS A. SPANDIDOS; NIKOLAOS M. SIAFAKAS; DEMOSTHENES BOUROS

2000-01-01

205

Genetic alterations in hepatocellular carcinomas: association between loss of chromosome 4q and p53 gene mutations  

Microsoft Academic Search

The major risk factors for hepatocellular carcinomas (HCC) in high incidence areas include infection with hepatitis B and C viruses (HBV, HCV) and exposure to aflatoxin. Genetic alterations in 24 liver resection specimens from Shanghai and Qidong were studied. Hepatitis B virus was integrated in all patient samples, and a null phenotype for the GSTM1 enzyme was present in 63%

A Rashid; J-S Wang; G-S Qian; B-X Lu; S R Hamilton; J D Groopman

1999-01-01

206

Malignant transformation of endometriosis: application of laser microdissection for analysis of genetic alterations according to pathological changes  

Microsoft Academic Search

Endometriosis is considered to be a possible precancerous disease. Pathologically, we observed malignant transformation of endometriosis to clear cell carcinoma or endometriotic carcinoma of the ovary, via the step of atypical endometriosis. Pathological changes reflected genetic alterations. In cases of clear cell carcinoma, we assessed K- ras mutations in regions of normal endometriosis, atypical endometriosis, and clear cell carcinoma, and

Akihiko Sekizawa; Satoshi Amemiya; Junko Otsuka; Hiroshi Saito; Antonio Farina; Takashi Okai; Tetsuhiko Tachikawa

2004-01-01

207

Epigenetic and genetic alterations of APC and CDH1 genes in lobular breast cancer: relationships with abnormal E-cadherin and catenin expression and microsatellite instability.  

PubMed

The causes and functional consequences of E-cadherin (E-CD) loss in breast cancer are poorly understood. E-CD loss might act in concert with alterations in the APC/beta-catenin pathway to permit oncogenic beta-catenin signaling. To test this hypothesis, we have analyzed the presence of genetic and epigenetic alterations affecting E-CD (CDH1), APC and beta-catenin (CTNNB1) genes and the immunohistochemical expression of E-CD, beta- and gamma-catenin in a series of 46 infiltrating lobular breast carcinomas (ILCs). Since 80% of ILCs featured complete loss of E-CD expression, we analyzed the molecular alterations responsible for E-CD inactivation in these tumors. We found that 10 of 46 (22%) cases harbored mutations in CDH1, including 1 case with 2 different mutations (1 of which was germline). CDH1 was also inactivated by loss of heterozygosity (LOH; 30/41, 73%) and promoter hypermethylation (19/46, 41%). Interestingly, LOH and mutations were also detected in the corresponding in situ lesions of the ILCs, implying that these alterations are early events in lobular cancer tumorogenesis. Additionally, the presence of a polymorphism in the CDH1 promoter was found to be inversely correlated with CDH1 mutations, but not with E-CD levels. We next examined whether alterations in the APC/beta-catenin pathway also occurred in the same series of ILCs. Although no CTNNB1 or APC mutations were detected, promoter methylation (25/46, 52%) and LOH (7/30, 23%) of APC were found. Moreover, methylation of APC and CDH1 occurred concordantly. However, beta- and gamma-catenin were severely reduced or absent in 90% of these tumors, implying that alterations in CDH1 and APC genes do not promote beta-catenin accumulation in ILC. These molecular alterations were not associated with microsatellite instability. In summary, several different mechanisms (mutations, LOH, methylation) are involved in the frequent CDH1 inactivation in invasive and in situ lobular breast cancer. The same tumors also show genetic and epigenetic alterations of APC gene. However, altered CDH1 and APC genes do not promote beta-catenin accumulation in this tumor type. PMID:12800196

Sarrió, David; Moreno-Bueno, Gema; Hardisson, David; Sánchez-Estévez, Carolina; Guo, Mingzhou; Herman, James G; Gamallo, Carlos; Esteller, Manel; Palacios, José

2003-08-20

208

Alterations in Cortical Excitation and Inhibition in Genetic Mouse Models of Huntington's Disease  

PubMed Central

Previously, we identified progressive alterations in spontaneous excitatory (EPSCs) and inhibitory (IPSCs) postsynaptic currents in the striatum of the R6/2 mouse model of Huntington’s disease (HD). Medium-sized spiny neurons (MSNs) from these mice displayed a lower frequency of EPSCs and a population of cells exhibited an increased frequency of IPSCs beginning at about 40 days, a time point when the overt behavioral phenotype begins. The cortex provides the major excitatory drive to the striatum and is affected during disease progression. We examined spontaneous EPSCs and IPSCs of somatosensory cortical pyramidal neurons in layers II/III in slices from three different mouse models of HD, the R6/2, the YAC128 and the CAG140 knock-in. Results revealed that spontaneous EPSCs occurred at a higher frequency and evoked EPSCs were larger in behaviorally phenotypic mice while spontaneous IPSCs were initially increased in frequency in all models and subsequently decreased in R6/2 mice after they displayed the typical R6/2 overt behavioral phenotype. Changes in miniature IPSCs and evoked IPSC paired-pulse ratios suggested altered probability of GABA release. Also, in R6/2 mice, blockade of GABAA receptors induced complex discharges in slices and seizures in vivo at all ages. In conclusion, altered excitatory and inhibitory inputs to pyramidal neurons in the cortex in HD appear to be a prevailing deficit throughout the development of the disease. Furthermore, the differences between synaptic phenotypes in cortex and striatum are important for the development of future therapeutic approaches, which may need to be targeted early in the development of the phenotype.

Cummings, Damian M.; Andre, Veronique M.; Uzgil, Besim O.; Gee, Steven M.; Fisher, Yvette E.; Cepeda, Carlos; Levine, Michael S.

2009-01-01

209

Alteration of poly(ADP-ribose) metabolism affects murine sperm nuclear architecture by impairing pericentric heterochromatin condensation.  

PubMed

The mammalian sperm nucleus is characterized by unique properties that are important for fertilization. Sperm DNA retains only small numbers of histones in distinct positions, and the majority of the genome is protamine associated, which allows for extreme condensation and protection of the genetic material. Furthermore, sperm nuclei display a highly ordered architecture that is characterized by a centrally located chromocenter comprising the pericentromeric chromosome regions and peripherally positioned telomeres. Establishment of this unique and well-conserved nuclear organization during spermiogenesis is not well understood. Utilizing fluorescence in situ hybridization (FISH), we show that a large fraction of the histone-associated sperm genome is repetitive in nature, while a smaller fraction is associated with unique DNA sequences. Coordinated activity of poly(ADP-ribose) (PAR) polymerase and topoisomerase II beta has been shown to facilitate DNA relaxation and histone to protamine transition during spermatid condensation, and altered PAR metabolism is associated with an increase in sperm histone content. Combining FISH with three-dimensional laser scanning microscopy technology, we further show that altered PAR metabolism by genetic or pharmacological intervention leads to a disturbance of the overall sperm nuclear architecture with a lower degree of organization and condensation of the chromocenters formed by chromosomal pericentromeric heterochromatin. PMID:23729169

Meyer-Ficca, Mirella L; Lonchar, Julia D; Ihara, Motomasa; Bader, Jessica J; Meyer, Ralph G

2013-08-01

210

Integrative Analysis Reveals Relationships of Genetic and Epigenetic Alterations in Osteosarcoma  

PubMed Central

Background Osteosarcomas are the most common non-haematological primary malignant tumours of bone, and all conventional osteosarcomas are high-grade tumours showing complex genomic aberrations. We have integrated genome-wide genetic and epigenetic profiles from the EuroBoNeT panel of 19 human osteosarcoma cell lines based on microarray technologies. Principal Findings The cell lines showed complex patterns of DNA copy number changes, where genomic copy number gains were significantly associated with gene-rich regions and losses with gene-poor regions. By integrating the datasets, 350 genes were identified as having two types of aberrations (gain/over-expression, hypo-methylation/over-expression, loss/under-expression or hyper-methylation/under-expression) using a recurrence threshold of 6/19 (>30%) cell lines. The genes showed in general alterations in either DNA copy number or DNA methylation, both within individual samples and across the sample panel. These 350 genes are involved in embryonic skeletal system development and morphogenesis, as well as remodelling of extracellular matrix. The aberrations of three selected genes, CXCL5, DLX5 and RUNX2, were validated in five cell lines and five tumour samples using PCR techniques. Several genes were hyper-methylated and under-expressed compared to normal osteoblasts, and expression could be reactivated by demethylation using 5-Aza-2?-deoxycytidine treatment for four genes tested; AKAP12, CXCL5, EFEMP1 and IL11RA. Globally, there was as expected a significant positive association between gain and over-expression, loss and under-expression as well as hyper-methylation and under-expression, but gain was also associated with hyper-methylation and under-expression, suggesting that hyper-methylation may oppose the effects of increased copy number for detrimental genes. Conclusions Integrative analysis of genome-wide genetic and epigenetic alterations identified dependencies and relationships between DNA copy number, DNA methylation and mRNA expression in osteosarcomas, contributing to better understanding of osteosarcoma biology.

Skarn, Magne; Naml?s, Heidi M.; Barragan-Polania, Ana H.; Cleton-Jansen, Anne-Marie; Serra, Massimo; Liest?l, Knut; Hogendoorn, Pancras C. W.; Hovig, Eivind; Myklebost, Ola; Meza-Zepeda, Leonardo A.

2012-01-01

211

Genetic and epigenetic alterations of the APC gene in malignant melanoma.  

PubMed

High levels of beta-catenin and activating mutations in the beta-catenin gene (CTNNB1) have been demonstrated in malignant melanomas, implicating dysregulated Wnt signalling in the pathogenesis of this malignancy. We systematically examined melanoma cell lines for activating CTNNB1 mutations as well as genetic and epigenetic alterations of the adenomatous polyposis coli gene (APC), another key component of the Wnt signalling transduction pathway. Of 40 cell lines tested, one carried a truncating APC mutation and loss of the corresponding wild-type allele, and one carried a CTNNB1 missense mutation. Hypermethylation of APC promoter 1A was present in five of the cell lines (13%) and in nine of 54 melanoma biopsies (17%). Cells with truncating APC or activating CTNNB1 mutations showed increased transcription from endogenous and ectopic beta-catenin/T-cell factor (Tcf)-responsive target genes, consistent with the known effects of these alterations on beta-catenin stability and Tcf transactivation. In contrast, cell lines with APC promoter 1A hypermethylation did not show increased Wnt signalling, probably due to residual APC activity expressed from promoter 1B. Suppression of APC transcripts in melanoma cells by stable expression of short hairpin RNAs led to a Wnt signalling-independent increase in cell proliferation, but also reduced the invasive growth in collagen type I. Collectively, our data suggest that the tumour-suppressive function of APC in melanocytic cells is dose dependent. We propose that epigenetic silencing of promoter 1A may contribute to the development of malignant melanoma by reducing the expression of APC to a level that promotes cell proliferation without compromising the invasive capacity. PMID:15133491

Worm, Jesper; Christensen, Claus; Grønbaek, Kirsten; Tulchinsky, Eugene; Guldberg, Per

2004-07-01

212

Genetic manipulation of intraspinal plasticity after spinal cord injury alters the severity of autonomic dysreflexia  

PubMed Central

Severe spinal cord injuries above mid-thoracic levels can lead to a potentially life-threatening hypertensive condition termed autonomic dysreflexia that is often triggered by painful distension of pelvic viscera (bladder or bowel) and consequent sensory fiber activation, including nociceptive C-fibers. Interruption of tonically active medullo-spinal pathways after injury causes disinhibition of thoracolumbar sympathetic preganglionic neurons, and intraspinal sprouting of nerve growth factor (NGF)-responsive primary afferent fibers is thought to contribute to their hyperactivity. We investigated spinal levels that are critical for eliciting autonomic dysreflexia using a model of noxious colorectal distension (CRD) after complete spinal transection at the 4th thoracic segment in rats. Post-traumatic sprouting of calcitonin gene-related peptide (CGRP)-immunoreactive primary afferent fibers was selectively altered at specific spinal levels caudal to the injury with bilateral microinjections of adenovirus encoding the growth-promoting NGF or growth-inhibitory semaphorin 3A (Sema3a) compared to control green fluorescent protein (GFP). Two weeks later, cardio-physiological responses to CRD were assessed among treatment groups prior to histological analysis of afferent fiber density at the injection sites. Dysreflexic hypertension was significantly higher with NGF over-expression in lumboscral segments compared to GFP, whereas similar over-expression of Sema3a significantly reduced noxious CRD-evoked hypertension. Quantitative analysis of CGRP immunostaining in the spinal dorsal horns showed a significant correlation between the extent of fiber sprouting into the spinal segments injected and the severity of autonomic dysreflexia. These results demonstrate that site-directed genetic manipulation of axon guidance molecules after complete spinal cord injury can alter endogenous circuitry in order to modulate plasticity-induced autonomic pathophysiology.

Cameron, Adrian A.; Smith, George M.; Randall, David C.; Brown, David R.; Rabchevsky, Alexander G.

2012-01-01

213

Genetic modification of iron metabolism in mice affects the gut microbiota.  

PubMed

The composition of the gut microbiota is affected by environmental factors as well as host genetics. Iron is one of the important elements essential for bacterial growth, thus we hypothesized that changes in host iron homeostasis, may affect the luminal iron content of the gut and thereby the composition of intestinal bacteria. The iron regulatory protein 2 (Irp2) and one of the genes mutated in hereditary hemochromatosis Hfe , are both proteins involved in the regulation of systemic iron homeostasis. To test our hypothesis, fecal metal content and a selected spectrum of the fecal microbiota were analyzed from Hfe-/-, Irp2-/- and their wild type control mice. Elevated levels of iron as well as other minerals in feces of Irp2-/- mice compared to wild type and Hfe-/- mice were observed. Interestingly significant variation in the general fecal-bacterial population-patterns was observed between Irp2-/- and Hfe-/- mice. Furthermore the relative abundance of five species, mainly lactic acid bacteria, was significantly different among the mouse lines. Lactobacillus (L.) murinus and L. intestinalis were highly abundant in Irp2-/- mice, Enterococcus faecium species cluster and a species most similar to Olsenella were highly abundant in Hfe-/- mice and L. johnsonii was highly abundant in the wild type mice. These results suggest that deletion of iron metabolism genes in the mouse host affects the composition of its intestinal bacteria. Further studying the relationship between gut microbiota and genetic mutations affecting systemic iron metabolism in human should lead to clinical implications. PMID:22580926

Buhnik-Rosenblau, Keren; Moshe-Belizowski, Shirly; Danin-Poleg, Yael; Meyron-Holtz, Esther G

2012-10-01

214

Morphological alterations in the tympanic membrane affected by tympanosclerosis: ultrastructural study.  

PubMed

The ultrastructure of tympanoslerotic tissue, surgically excised from patients, has been studied with particular reference to the morphological changes of the connective tissue components and mineralization. Detailed analysis revealed the combination of degenerative and fibroplastic alterations, especially in the circular fibrous layer of the thickened lamina propria. In the biological material in this study the authors recognized different stages of calcium plaque development with discrete, moderate, and severe degree of mineralization. Extracellular matrix vesicles, with or without calcareous deposits, released by degenerating fibroblasts were prominent. In these biopsies no distinct morphological features of an inflammatory reaction were seen. PMID:24134073

Tukaj, Cecylia; Kuczkowski, Jerzy; Sakowicz-Burkiewicz, Monika; Gulida, Gra?yna; Tretiakow, Dymitry; Mionskowski, Tomasz; Pawe?czyk, Tadeusz

2014-04-01

215

Pharmacological profiles of alpha 2 adrenergic receptor agonists identified using genetically altered mice and isobolographic analysis.  

PubMed

Endogenous, descending noradrenergic fibers impose analgesic control over spinal afferent circuitry mediating the rostrad transmission of pain signals. These fibers target alpha 2 adrenergic receptors (alpha(2)ARs) on both primary afferent terminals and secondary neurons, and their activation mediates substantial inhibitory control over this transmission, rivaling that of opioid receptors which share a similar pattern of distribution. The terminals of primary afferent nociceptive neurons and secondary spinal dorsal horn neurons express alpha(2A)AR and alpha(2C)AR subtypes, respectively. Spinal delivery of these agents serves to reduce their side effects, which are mediated largely at supraspinal sites, by concentrating the drugs at the spinal level. Targeting these spinal alpha(2)ARs with one of five selective therapeutic agonists, clonidine, dexmedetomidine, brimonidine, ST91 and moxonidine, produces significant antinociception that can work in concert with opioid agonists to yield synergistic antinociception. Application of several genetically altered mouse lines had facilitated identification of the primary receptor subtypes that likely mediate the antinociceptive effects of these agents. This review provides first an anatomical description of the localization of the three subtypes in the central nervous system, second a detailed account of the pharmacological history of each of the six primary agonists, and finally a comprehensive report of the specific interactions of other GPCR agonists with each of the six principal alpha(2)AR agonists featured. PMID:19393691

Fairbanks, Carolyn A; Stone, Laura S; Wilcox, George L

2009-08-01

216

Genetic and epigenetic alterations of steroidogenic factor?1 in ovarian tumors.  

PubMed

Steroidogenic factor-1 (SF?1), the product of the NR5A1 gene, is an essential transcription factor that is known to regulate steroidogenesis in ovarian epithelia, including the synthesis of progesterone, a suppressor of ovarian cancer. Expression of the SF?1 protein, a potential ovarian tumor suppressor, has been demonstrated in normal OSE cells, but is lost in most ovarian tumors and ovarian tumor cell lines. We examined loss of heterozygosity (LOH) and promoter methylation as potential mechanisms that may explain the loss of SF?1 protein in ovarian tumor tissues. Genotyping of three NR5A1 SNPs in matched tumor/normal tissues identified LOH in 16/36 (44%) of the ovarian tumors successfully analyzed, and somatic mutations (gain of allele) in 10% of the tumors. Furthermore, a methylation-sensitive restriction enzyme method was used to demonstrate statistically significant (p<0.0001) increase in the frequency of NR5A1 gene methylation in ovarian tumors (36/46; 78%) versus normal ovaries (1/11; 9%). These data suggest that the SF?1 encoding gene exhibits frequent genetic (LOH/base substitution) and epigenetic (methylation) somatic alterations in ovarian tumors. These data also present novel molecular mechanisms that may explain the loss of SF?1 protein in ovarian tumors, and its potential role in ovarian carcinogenesis. PMID:23291911

Miller, Sarah; Bhasin, Nobel; Urrego, Heather; Moroz, Krzysztof; Rowan, Brian G; Ramayya, Meera S; Makridakis, Nick M

2013-02-01

217

Detection of complex genetic alterations in human glioblastoma multiforme using comparative genomic hybridization  

SciTech Connect

The aim of the present study was to detect complex genetic alterations in human glioblastoma multiforme (GBM) by comparative genomic in situ hybridization (CGH). Of the 24 GBM that were examined, increased fluorescence intensities indicating chromosomal polysomy of chromosome 7 and gene amplification at chromosome 7p were found in 42% of the tumors. In addition, signal enhancement of chromosome 19 was present in 29% and at 12q13-15 in 21% of the tumors. We also detected reduction of fluorescence intensities indicating gross deletions on chromosomes 10 (58%), 9p (46%), and 13 (29%). There was a close correlation of CGH results when compared with Southern analysis of the EGFR gene localized on chromosome 7 and loss of heterozygosity detection of chromosome 9 and 10 by microsatellite PCR. A close correlation was also observed between copy number changes of chromosome 7 and deletions of chromosome 10. Amplification of chromosome 12q and deletions of chromosomes 9p and 13 seemed to be complementary in the tumors investigated in the present study. 44 refs., 3 figs., 1 tab.

Schlegel, J.; Stumm, G. [Universitaet Marburg (Germany); Scherthan, H.; Arens, N. [Universitaet Kaiderlautern (Germany)] [and others

1996-01-01

218

Altered response to metabolic challenges in mice with genetically targeted deletions of galanin-like peptide  

PubMed Central

Galanin-like peptide (GALP) is expressed in the arcuate nucleus and is implicated in the neuroendocrine regulation of metabolism and reproduction. To investigate the physiological significance of GALP, we generated and characterized a strain of mice with a genetically targeted deletion in the GALP gene [GALP knockout (KO) mice]. We report that GALP KO mice have a subtle, but notable, metabolic phenotype that becomes apparent during adaptation to changes in nutrition. GALP KO mice are indistinguishable from wild-type (WT) controls in virtually all aspects of growth, sexual development, body weight, food and water consumption, and motor behaviors, when they are allowed unlimited access to standard rodent chow. However, GALP KO mice have an altered response to changes in diet. 1) Male GALP KO mice consumed less food during refeeding after a fast than WT controls (P < 0.01). 2) GALP KO mice of both sexes gained less weight on a high-fat diet than WT controls (P < 0.01), despite both genotypes having consumed equal amounts of food. We conclude that although GALP signaling may not be essential for the maintenance of energy homeostasis under steady-state nutritional conditions, GALP may play a role in readjusting energy balance under changing nutritional circumstances.

Dungan Lemko, Heather M.; Clifton, Donald K.; Steiner, Robert A.; Fraley, Gregory S.

2008-01-01

219

Genetic and epigenetic alterations of steroidogenic factor-1 in ovarian tumors  

PubMed Central

Steroidogenic factor-1 (SF-1), the product of the NR5A1 gene, is an essential transcription factor that is known to regulate steroidogenesis in ovarian epithelia, including the synthesis of progesterone, a suppressor of ovarian cancer. Expression of the SF-1 protein, a potential ovarian tumor suppressor, has been demonstrated in normal OSE cells, but is lost in most ovarian tumors and ovarian tumor cell lines. We examined loss of heterozygosity (LOH) and promoter methylation as potential mechanisms that may explain the loss of SF-1 protein in ovarian tumor tissues. Genotyping of three NR5A1 SNPs in matched tumor/normal tissues identified LOH in 16/36 (44%) of the ovarian tumors successfully analyzed, and somatic mutations (gain of allele) in 10% of the tumors. Furthermore, a methylation-sensitive restriction enzyme method was used to demonstrate statistically significant (p<0.0001) increase in the frequency of NR5A1 gene methylation in ovarian tumors (36/46; 78%) versus normal ovaries (1/11; 9%). These data suggest that the SF-1 encoding gene exhibits frequent genetic (LOH/base substitution) and epigenetic (methylation) somatic alterations in ovarian tumors. These data also present novel molecular mechanisms that may explain the loss of SF-1 protein in ovarian tumors, and its potential role in ovarian carcinogenesis.

MILLER, SARAH; BHASIN, NOBEL; URREGO, HEATHER; MOROZ, KRZYSZTOF; ROWAN, BRIAN G.; RAMAYYA, MEERA S.; MAKRIDAKIS, NICK M.

2013-01-01

220

Delineation of behavioral phenotypes in genetic syndromes: characteristics of autism spectrum disorder, affect and hyperactivity.  

PubMed

We investigated autism spectrum disorder (ASD) symptomatology, hyperactivity and affect in seven genetic syndromes; Angelman (AS; n = 104), Cri du Chat (CdCS; 58), Cornelia de Lange (CdLS; 101), Fragile X (FXS; 191), Prader-Willi (PWS; 189), Smith-Magenis (SMS; 42) and Lowe (LS; 56) syndromes (age range 4-51). ASD symptomatology was heightened in CdLS and FXS. High levels of impulsivity were seen in SMS, AS, CdCS, FXS and adults with CdLS. Negative affect was prominent in adults with CdLS, while positive affect was prominent in adults with AS and FXS. Heightened levels of overactivity and impulsivity were identified in FXS, AS and SMS while low levels were identified in PWS. These findings confirm and extend previously reported behavioral phenotypes. PMID:21080217

Oliver, Chris; Berg, Katy; Moss, Jo; Arron, Kate; Burbidge, Cheryl

2011-08-01

221

Alterations in affective processing of attack images following September 11, 2001.  

PubMed

The events of September 11, 2001 created unprecedented uncertainty about safety in the United States and created an aftermath with significant psychological impact across the world. This study examined emotional information encoding in 31 healthy individuals whose stress response symptoms ranged from none to a moderate level shortly after the attacks as assessed by the Impact of Event Scale-Revised. Participants viewed attack-related, negative (but attack-irrelevant), and neutral images while their event-related brain potentials (ERPs) were recorded. Attack images elicited enhanced P300 relative to negative and neutral images, and emotional images prompted larger slow waves than neutral images did. Total symptoms were correlated with altered N2, P300, and slow wave responses during valence processing. Specifically, hyperarousal and intrusion symptoms were associated with diminished stimulus discrimination between neutral and unpleasant images; avoidance symptoms were associated with hypervigilance, as suggested by reduced P300 difference between attack and other images and reduced appraisal of attack images as indicated by attenuated slow wave. The findings in this minimally symptomatic sample are compatible with the alterations in cognition in the posttraumatic stress disorder (PTSD) literature and are consistent with a dimensional model of PTSD. PMID:21882249

Tso, Ivy F; Chiu, Pearl H; King-Casas, Brooks R; Deldin, Patricia J

2011-10-01

222

Early Experiences Can Alter Gene Expression and Affect Long-Term Development. Working Paper #10  

ERIC Educational Resources Information Center

New scientific research shows that environmental influences can actually affect whether and how genes are expressed. Thus, the old ideas that genes are "set in stone" or that they alone determine development have been disproven. In fact, scientists have discovered that early experiences can determine how genes are turned on and off and even…

National Scientific Council on the Developing Child, 2010

2010-01-01

223

Frequent codeletion of p16\\/MTS1 and p15\\/MTS2 and genetic alterations in p16\\/MTS1 in pancreatic tumors  

Microsoft Academic Search

BACKGROUND & AIMS: Cell-cycle inhibitor and tumor-suppressor gene p16\\/MTS1 was found to be altered in a variety of human tumors. To directly investigate genetic alterations and expression of p16\\/MTS1 and p15\\/MTS2, this study surveyed pancreatic tumors. METHODS: Cell-cycle inhibitors were analyzed for genetic alterations and expression by polymerase chain reaction, DNA sequencing, reverse-transcription polymerase chain reaction, and Western blotting. RESULTS:

M Naumann; N Savitskaia; C Eilert; A Schramm; H Kalthoff; W Schmiegel

1996-01-01

224

Genetic alterations of chromosome band 9p21 – 22 in head and neck cancer are not restricted to p16INK4a  

Microsoft Academic Search

Although genetic alterations of chromosome band 9p21 – 22 occur frequently in head and neck squamous cell carcinoma (HNSCC) cell lines, alterations of the cyclin-dependent kinase inhibitor p16INK4a located in this region are less common in corresponding primary tumors. To further investigate genetic alterations at 9p21 – 22 and p16INK4a in primary HNSCC, a paired set of 21 tumors and

Pamela Waber; Sandra Dlugosz; Qin-Chang Cheng; John Truelson; Perry D Nisen

1997-01-01

225

The future in clinical genetics: affective forecasting biases in patient and clinician decision making.  

PubMed

When clinicians facilitate and patients make decisions about predictive genetic testing, they often base their choices on the predicted emotional consequences of positive and negative test results. Research from psychology and decision making suggests that such predictions may often be biased. Work on affective forecasting-predicting one's future emotional states-shows that people tend to overestimate the impact of (especially negative) emotional events on their well-being; a phenomenon termed the impact bias. In this article, we review the causes and consequences of the impact bias in medical decision making, with a focus on applying such findings to predictive testing in clinical genetics. We also recommend strategies for reducing the impact bias and consider the ethical and practical implications of doing so. PMID:23952534

Peters, S A; Laham, S M; Pachter, N; Winship, I M

2014-04-01

226

Plant hybrid zones affect biodiversity: Tools for a genetic-based understanding of community structure  

SciTech Connect

Plant hybrid zones are dynamic centers of ecological and evolutionary processes for plants and their associated communities. Studies in the wild and in gardens with synthetic crosses showed that hybrid eucalypts supports the greatest species richness and abundances of insect and fungal taxa. In an updated review of 152 case studies of taxa associated with diverse hybridizing systems, there were 43 (28%) cases of hybrids being more susceptible than their parent species, 7 (5%) resistant, 35 (23%) additive, 35 (23%) dominant, and 32 (21%) showed no response to hybridization. Thus, most taxa respond to hybrids in ways that result in equal or greater abundance, and hybrids tend to accumulate the taxa of their parent species. These studies suggest that genetic-based plant traits affect the distribution of many species and that the variation in hybrids can be used as tools to examine the genetic components of community structure and biodiversity.

Whitham, T.G.; Martinsen, G.D.; Keim, P. [Northern Arizona Univ., Flagstaff, AZ (United States); Floate, K.D. [Agriculture and Agri-Food Canada, Lethbridge, Alberta (Canada); Dungey, H.S. [Univ. of Tasmania, Hobart, Tasmania (Australia)]|[Queensland Forest Research Inst., Gympie, Queensland (Australia); Potts, B.M. [Univ. of Tasmania, Hobart, Tasmania (Australia)

1999-03-01

227

Hypothyroidism affects D2 receptor-mediated breathing without altering D2 receptor expression.  

PubMed

Bromocriptine depressed ventilation in air and D2 receptor expression in the nucleus tractus solitaries (NTS) in male hypothyroid hamsters. Here we postulated that in age-matched hypothyroid female hamsters, the pattern of D2 receptor modulation of breathing and D2 receptor expression would differ from those reported in hypothyroid males. In females hypothyroidism did not affect D2 receptor protein levels in the NTS, carotid bodies or striatum. Bromocriptine, but not carmoxirole (a peripheral D2 receptor agonist), increased oxygen consumption and body temperature in awake air-exposed hypothyroid female hamsters and stimulated their ventilation before and following exposure to hypoxia. Carmoxirole depressed frequency of breathing in euthyroid hamsters prior to, during and following hypoxia exposures and stimulated it in the hypothyroid hamsters following hypoxia. Although hypothyroidism did not affect expression of D2 receptors, it influenced central D2 modulation of breathing in a disparate manner relative to euthyroid hamsters. PMID:24434437

Schlenker, Evelyn H; Del Rio, Rodrigo; Schultz, Harold D

2014-03-01

228

Altered Cohesin Gene Dosage Affects Mammalian Meiotic Chromosome Structure and Behavior  

PubMed Central

Based on studies in mice and humans, cohesin loss from chromosomes during the period of protracted meiotic arrest appears to play a major role in chromosome segregation errors during female meiosis. In mice, mutations in meiosis-specific cohesin genes cause meiotic disturbances and infertility. However, the more clinically relevant situation, heterozygosity for mutations in these genes, has not been evaluated. We report here evidence from the mouse that partial loss of gene function for either Smc1b or Rec8 causes perturbations in the formation of the synaptonemal complex (SC) and affects both synapsis and recombination between homologs during meiotic prophase. Importantly, these defects increase the frequency of chromosomally abnormal eggs in the adult female. These findings have important implications for humans: they suggest that women who carry mutations or variants that affect cohesin function have an elevated risk of aneuploid pregnancies and may even be at increased risk of transmitting structural chromosome abnormalities.

Stevense, Michelle; Smith, Helen; Nagaoka, So; Hassold, Terry; McKay, Michael; Xu, Huiling; Fu, Jun; Revenkova, Ekaterina; Jessberger, Rolf; Hunt, Patricia

2013-01-01

229

Haplotype structure strongly affects recombination in a maize genetic interval polymorphic for Helitron and retrotransposon insertions  

PubMed Central

We have asked here how the remarkable variation in maize haplotype structure affects recombination. We compared recombination across a genetic interval of 9S in 2 highly dissimilar heterozygotes that shared 1 parent. The genetic interval in the common haplotype is ?100 kb long and contains 6 genes interspersed with gene-fragment-bearing Helitrons and retrotransposons that, together, comprise 70% of its length. In one heterozygote, most intergenic insertions are homozygous, although polymorphic, enabling us to determine whether any recombination junctions fall within them. In the other, most intergenic insertions are hemizygous and, thus, incapable of homologous recombination. Our analysis of the frequency and distribution of recombination in the interval revealed that: (i) Most junctions were circumscribed to the gene space, where they showed a highly nonuniform distribution. In both heterozygotes, more than half of the junctions fell in the stc1 gene, making it a clear recombination hotspot in the region. However, the genetic size of stc1 was 2-fold lower when flanked by a hemizygous 25-kb retrotransposon cluster. (ii) No junctions fell in the hypro1 gene in either heterozygote, making it a genic recombination coldspot. (iii) No recombination occurred within the gene fragments borne on Helitrons nor within retrotransposons, so neither insertion class contributes to the interval's genetic length. (iv) Unexpectedly, several junctions fell in an intergenic region not shared by all 3 haplotypes. (v) In general, the ability of a sequence to recombine correlated inversely with its methylation status. Our results show that haplotypic structural variability strongly affects the frequency and distribution of recombination events in maize.

He, Limei; Dooner, Hugo K.

2009-01-01

230

Natural Selection Affects Multiple Aspects of Genetic Variation at Putatively Neutral Sites across the Human Genome  

PubMed Central

A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries of genetic variation, like allele frequencies, are also correlated with recombination rate and whether these correlations can be explained solely by negative selection against deleterious mutations or whether positive selection acting on favorable alleles is also required. Here we attempt to address these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination and that human diversity, human-chimp divergence, and average minor allele frequency are reduced near genes. Population genetic simulations show that either positive natural selection acting on favorable mutations or negative natural selection acting against deleterious mutations can explain these correlations. However, models with strong positive selection on nonsynonymous mutations and little negative selection predict a stronger negative correlation between neutral diversity and nonsynonymous divergence than observed in the actual data, supporting the importance of negative, rather than positive, selection throughout the genome. Further, we show that the widespread presence of weakly deleterious alleles, rather than a small number of strongly positively selected mutations, is responsible for the correlation between neutral genetic diversity and recombination rate. This work suggests that natural selection has affected multiple aspects of linked neutral variation throughout the human genome and that positive selection is not required to explain these observations.

Lohmueller, Kirk E.; Albrechtsen, Anders; Li, Yingrui; Kim, Su Yeon; Korneliussen, Thorfinn; Vinckenbosch, Nicolas; Tian, Geng; Huerta-Sanchez, Emilia; Feder, Alison F.; Grarup, Niels; J?rgensen, Torben; Jiang, Tao; Witte, Daniel R.; Sandbaek, Annelli; Hellmann, Ines; Lauritzen, Torsten; Hansen, Torben

2011-01-01

231

Altered cellular response to UV irradiation in a patient affected by premature ageing.  

PubMed

An abnormal response to UV-irradiation was found in a patient affected by precocious senescence. A decreased level of unscheduled DNA synthesis (UDS) was present in 60% of Go lymphocytes and in fibroblasts after the fifth culture passage. Hypersensitivity of lymphocytes to UV-light was indicated also by a decreased rate of DNA synthesis after mitogen stimulation. The results of this study indicate that the defect which determines the premature ageing influences the capacity to repair UV-induced DNA damage. PMID:3089902

Stefanini, M; Orecchia, G; Rabbiosi, G; Nuzzo, F

1986-07-01

232

Genetic Deletion of Mst1 Alters T Cell Function and Protects against Autoimmunity  

PubMed Central

Mammalian sterile 20-like kinase 1 (Mst1) is a MAPK kinase kinase kinase which is involved in a wide range of cellular responses, including apoptosis, lymphocyte adhesion and trafficking. The contribution of Mst1 to Ag-specific immune responses and autoimmunity has not been well defined. In this study, we provide evidence for the essential role of Mst1 in T cell differentiation and autoimmunity, using both genetic and pharmacologic approaches. Absence of Mst1 in mice reduced T cell proliferation and IL-2 production in vitro, blocked cell cycle progression, and elevated activation-induced cell death in Th1 cells. Mst1 deficiency led to a CD4+ T cell development path that was biased toward Th2 and immunoregulatory cytokine production with suppressed Th1 responses. In addition, Mst1?/? B cells showed decreased stimulation to B cell mitogens in vitro and deficient Ag-specific Ig production in vivo. Consistent with altered lymphocyte function, deletion of Mst1 reduced the severity of experimental autoimmune encephalomyelitis (EAE) and protected against collagen-induced arthritis development. Mst1?/? CD4+ T cells displayed an intrinsic defect in their ability to respond to encephalitogenic antigens and deletion of Mst1 in the CD4+ T cell compartment was sufficient to alleviate CNS inflammation during EAE. These findings have prompted the discovery of novel compounds that are potent inhibitors of Mst1 and exhibit desirable pharmacokinetic properties. In conclusion, this report implicates Mst1 as a critical regulator of adaptive immune responses, Th1/Th2-dependent cytokine production, and as a potential therapeutic target for immune disorders.

Salojin, Konstantin V.; Hamman, Brian D.; Chang, Wei Chun; Jhaver, Kanchan G.; Al-Shami, Amin; Crisostomo, Jeannette; Wilkins, Carrie; Digeorge-Foushee, Ann Marie; Allen, Jason; Patel, Nita; Gopinathan, Suma; Zhou, Julia; Nouraldeen, Amr; Jessop, Theodore C.; Bagdanoff, Jeffrey T.; Augeri, David J.; Read, Robert; Vogel, Peter; Swaffield, Jonathan; Wilson, Alan; Platt, Kenneth A.; Carson, Kenneth G.; Main, Alan; Zambrowicz, Brian P.; Oravecz, Tamas

2014-01-01

233

Altering n-3 to n-6 polyunsaturated fatty acid ratios affects prostaglandin production by ovine uterine endometrium.  

PubMed

Consumption of n-3 polyunsaturated fatty acids (PUFAs) is considered beneficial to health but effects on fertility remain uncertain. This study investigated the effect of n-3 PUFA supplementation on endometrial prostaglandin (PG) production. Ovine uterine endometrial cells were cultured to confluence in DMEM/F12 medium containing 10% foetal bovine serum. Stromal and epithelial cell populations were confirmed by immunocytochemistry. Cultures were supplemented with 0, 20 or 100 ?M of ?-linolenic acid (ALA), stearidonic acid (SDA), eicosapentaenoic acid (EPA) with lipopolysaccharide (LPS) at 0 and 0.1 ?g/ml, or different combinations of EPA with arachidonic acid (AA) in serum-free medium for 24h. PGs were quantified using radioimmunoassay and PG-endoperoxide synthase (PTGS) isoforms, PGE and PGF synthase (microsomal PGES1 and PGFS) mRNAs by qPCR. LPS increased PGE2 production significantly without changing PGF2? production, causing increased PGE2:PGF2? ratios. ALA and SDA increased PGE2, PGF2? and PGE2:PGF2? ratios (P<0.05-0.01) while EPA alone did not affect PG generation. AA significantly stimulated PTGS1 and PTGS2 mRNA expression and PGE2 and PGF2? production (P<0.01). The stimulatory effect of AA was attenuated by up to 80% (P<0.05) when AA was combined with EPA. The PGE2:PGF2? ratio was not affected by AA or EPA alone, but increased when these two PUFAs were combined (P<0.05). SDA and EPA decreased PTGS1 mRNA expression (P<0.05) but did not alter PTGS2 expression. EPA and AA up-regulated mPGES1 expression (P<0.05) without affecting PGFS expression. Since AA is preferentially incorporated in uterine endometrium to produce 2-series PGs, alteration of PG production by EPA may affect many reproductive processes. PMID:24287151

Cheng, Zhangrui; Abayasekara, D Robert E; Ward, Freya; Preece, Daniel M W; Raheem, Kabir A; Wathes, D Claire

2013-12-01

234

Examination of Genetic Alterations in Preneoplastic and Neoplastic Lesions of the Lung From Uranium Miners. Final Technical Report  

SciTech Connect

Lung cancer is one of the leading causes of death in the United States and in Western Europe. The incidence of lung cancer in developing countries is rising as their cigarette smoking habits increase. The objectives of this proposed research are to analyze genetic alterations associated with the development and progression on non-small cell lung carcinoma (MSCLC). Endpoints that may be realized from this proposed research are: (1) detection of early genetic and/or cellular alterations which ultimately could lead to diagnostic modalities for the early detection of lung cancer; and (2) detection of novel tumor suppressor genes on chromosome 9p. This proposal will analyze both tumor specimens and sputum samples.

Anderson, Marshall

2000-07-12

235

Nuclear DNA content affects the productivity of conifer forests by altering hydraulic architecture  

NASA Astrophysics Data System (ADS)

Predictions of future global climate rely on feedbacks between terrestrial vegetation and the global carbon cycle, but the exact mechanisms underlying this relationship are still being discussed. One of the key knowledge gaps lies on the scaling of cellular processes to the ecosystem level. Here we examine whether an under-explored plant trait, inter-specific variation in the bulk amount of DNA in unreplicated somatic cells (2C DNA content), can explain inter-specific variation in the maximum productivity of conifer forests. We expected 2C DNA content to be negatively related to conifer productivity because: 1) it is positively correlated with cell volume (which, in turn, potentially affects structural features such as leaf mass area, a strong predictor of photosynthetic capacity); 2) it is positively correlated with stomatal size (with larger stomata leading to lower overall stomatal conductance and, by extension, lower CO2 uptake); and 3) larger genome sizes may reduce P availability in RNA (which has been hypothesized to slow growth). We present the results of regression and independent contrasts in different monospecific forests encompassing a 52º latitudinal gradient, each being dominated by 1 of 35 different conifer species. Contrary to expectations, we observed a positive correlation between genome size and maximum Gross Primary Productivity (R2 = 0.47) and also between genome size maximum tree height (R2 = 0.27). This correlation was apparently driven by the effects of genome size on stem hydraulics, since 2C DNA was positively correlated with wood density (R2 = 0.40) and also with resistance to cavitation (P50, R2 = 0.28). That is, increased genome sizes have a positive effect on the productivity of conifer forests by affecting the vascular tissues to increase their capacity for water transport. Our results shed a new light on the evolution of the vascular system of conifer forests and how they affect ecosystem productivity, and indicate the potential to further explore the trait of genome size for understanding global patterns of forest productivity.

Alday, Josu; Resco de Dios, Víctor

2014-05-01

236

CTP:phosphocholine cytidylyltransferase ? (CCT?) and lamins alter nuclear membrane structure without affecting phosphatidylcholine synthesis.  

PubMed

CTP:phosphocholine cytidylyltransferase ? (CCT?) is a nuclear enzyme that catalyzes the rate-limiting step in the CDP-choline pathway for phosphatidylcholine (PC) synthesis. Lipid activation of CCT? results in its translocation to the nuclear envelope and expansion of an intranuclear membrane network termed the nucleoplasmic reticulum (NR) by a mechanism involving membrane deformation. Nuclear lamins are also required for stability and proliferation of the NR, but whether this unique structure, or the nuclear lamina in general, is required for PC synthesis is not known. To examine this relationship, the nuclear lamina was depleted by RNAi or disrupted by expression of the Hutchinson-Gilford progeria syndrome (HGPS) mutant lamin A (progerin), and the effect on CCT? and choline metabolism was analyzed. siRNA-mediated silencing of lamin A/C or lamin B1 in CHO cells to diminish the NR had no effect on PC synthesis, while double knockdown non-specifically inhibited the pathway. Confirming this minor role in PC synthesis, only 10% of transiently overexpressed choline/ethanolamine phosphotransferase was detected in the NR. In CHO cells, CCT? was nucleoplasmic and co-localized with GFP-progerin in nuclear folds and invaginations; however, HGPS fibroblasts displayed an abnormal distribution of CCT? in the cytoplasm and nuclear envelope that was accompanied by a 2-fold reduction in PC synthesis. In spite of its altered localization, choline-labeling experiments showed that CCT activity was unaffected, and inhibition of PC synthesis was traced to reduced activity of a hemicholinium-sensitive choline transporter. We conclude that CCT? and lamins specifically cooperate to form the NR, but the overall structure of the nuclear envelope has a minimal impact on CCT activity and PC synthesis. PMID:21504799

Gehrig, Karsten; Ridgway, Neale D

2011-06-01

237

Genetic Alterations That Inhibit In Vivo Pressure-Overload Hypertrophy Prevent Cardiac Dysfunction Despite Increased Wall Stress  

Microsoft Academic Search

Background—A long-standing hypothesis has been that hypertrophy is compensatory and by normalizing wall stress acts to maintain normal cardiac function. Epidemiological data, however, have shown that cardiac hypertrophy is associated with increased mortality, thus casting doubt on the validity of this hypothesis. Methods and Results—To determine whether cardiac hypertrophy is necessary to preserve cardiac function, we used 2 genetically altered

Giovanni Esposito; Antonio Rapacciuolo; Sathyamangla V. Naga Prasad; Hideyuki Takaoka; Steven A. Thomas; Walter J. Koch; Howard A. Rockman

238

Allele-specific Hras Mutations and Genetic Alterations at Tumor Susceptibility Loci in Skin Carcinomas from Interspecific Hybrid Mice1  

Microsoft Academic Search

We have investigated the effects of germ-line variants that influence skin tumor susceptibility loci on the patterns of somatic genetic alterations in mouse skin cancers. Using a two-stage skin carcinogenesis model, we previ- ously identified at least 13 skin tumor susceptibility ( Skts) loci in a large interspecific F1 backcross ((NIH\\/Ola M. spretus) NIH\\/Ola) study. In this report, we describe

Hiroki Nagase; Jian-Hua Mao; Allan Balmain

2003-01-01

239

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene  

PubMed Central

A large body of evidence strongly suggests that the p53 tumor suppressor pathway is central in reducing cancer frequency in vertebrates. The protein product of the haploinsufficient mouse double minute 2 (MDM2) oncogene binds to and inhibits the p53 protein. Recent studies of human genetic variants in p53 and MDM2 have shown that single nucleotide polymorphisms (SNPs) can affect p53 signaling, confer cancer risk, and suggest that the pathway is under evolutionary selective pressure (1–4). In this report, we analyze the haplotype structure of MDM4, a structural homolog of MDM2, in several different human populations. Unusual patterns of linkage disequilibrium (LD) in the haplotype distribution of MDM4 indicate the presence of candidate SNPs that may also modify the efficacy of the p53 pathway. Association studies in 5 different patient populations reveal that these SNPs in MDM4 confer an increased risk for, or early onset of, human breast and ovarian cancers in Ashkenazi Jewish and European cohorts, respectively. This report not only implicates MDM4 as a key regulator of tumorigenesis in the human breast and ovary, but also exploits for the first time evolutionary driven linkage disequilibrium as a means to select SNPs of p53 pathway genes that might be clinically relevant.

Atwal, Gurinder Singh; Kirchhoff, Tomas; Bond, Elisabeth E.; Montagna, Marco; Menin, Chiara; Bertorelle, Roberta; Scaini, Maria Chiara; Bartel, Frank; Bohnke, Anja; Pempe, Christina; Gradhand, Elise; Hauptmann, Steffen; Offit, Kenneth; Levine, Arnold J.; Bond, Gareth L.

2009-01-01

240

Production of extracellular nucleic acids by genetically altered bacteria in aquatic-environment microcosms. [Escherichia coli, Pseudomonas aeroginosa, Pseudomonas cepacia, Bradyrhizobium japonicum  

SciTech Connect

The factors which affect the production of extracellular DNA by genetically altered strains of Escherichia coli, Pseudomonas aeruginosa, Pseudomonas cepacia, and Bradyrhizobium japonicum in aquatic environments were investigated. Cellular nucleic acids were labeled in vivo by incubation with ({sup 3}H)thymidine or ({sup 3}H)adenine, and production of extracellular DNA in marine waters, artificial seawater, or minimal salts media was determined by detecting radiolabeled macromolecules in incubation filtrates. The presence or absence of the ambient microbial community had little effect on the production of extracellular DNA. Three of four organisms produced the greatest amounts of extracellular nucleic acids when incubated in low-salinity media (2% artificial seawater) rather than high-salinity media (10 to 50% artificial seawater). The greatest production of extracellular nucleic acids by P. cepacia occurred at pH 7 and 37{degree}C, suggesting that extracellular-DNA production may be a normal physiologic function of the cell. Incubation of labeled P. cepacia cells in water from Bimini Harbor, Bahamas, resulted in labeling of macromolecules of the ambient microbial population. Collectively these results indicate that (i) extracellular-DNA production by genetically altered bacteria released into aquatic environments is more strongly influenced by physicochemical factors than biotic factors, (ii) extracellular-DNA production rates are usually greater for organisms released in freshwater than marine environments, and (iii) ambient microbial populations can readily utilize materials released by these organisms.

Paul, J.H.; David, A.W. (Univ. of South Florida, St. Petersburg (USA))

1989-08-01

241

Genetic loci that affect aristolochic acid-induced nephrotoxicity in the mouse  

PubMed Central

Aristolochic acids (AA) are plant-derived nephrotoxins and carcinogens found in traditional medicines and herbal remedies. AA causes aristolochic acid nephropathy (AAN) and is a suspected environmental agent in Balkan endemic nephropathy (BEN) and its associated upper urothelial cancer. Approximately 5–10% of individuals exposed to AA develop renal insufficiency and/or cancer; thus a genetic predisposition to AA sensitivity has been proposed. The mouse is an established animal model of AAN, and inbred murine strains vary in AA sensitivity, confirming the genetic predisposition. We mapped quantitative trait loci (QTL) correlated with proximal tubule dysfunction after exposure to AA in an F2 population of mice, derived from breeding an AA-resistant strain (C57BL/6J) and an AA-sensitive strain (DBA/2J). A single main QTL was identified on chromosome 4 (Aanq1); three other interacting QTLs, (Aanq2–4) also were detected. The Aanq1 region was also detected in untreated mice, raising the possibility that preexisting differences in proximal tubule function may affect the severity of AA-elicited toxicity. This study lays the groundwork for identifying the genetic pathways contributing to AA sensitivity in the mouse and will further our understanding of human susceptibility to AA found widely in traditional medicines.

2011-01-01

242

Does originating from a genetic isolate affect the level of cognitive impairments in schizophrenia families?  

PubMed

Earlier studies have detected differences in the prevalence, symptomatology and genetic risk variants of schizophrenia between a north-eastern Finnish genetic isolate and the rest of Finland. This study compared a population-based isolate sample (145 persons with schizophrenia, 304 first-degree relatives and 32 controls) with a rest of Finland sample (73 persons with schizophrenia, 100 first-degree relatives and 80 controls) in cognitive functioning. Persons from the isolate outperformed persons in the rest of Finland sample in verbal learning, verbal ability and cognitive flexibility in the schizophrenia groups and in verbal learning, speeded processing and attentional control in the relatives groups. The differences between the subsamples remained significant after taking into account an intragenic Reelin STR allele, previously associated with cognitive impairments and almost absent from the isolate, in addition to disorder characteristics and familial loading. In control groups, we observed no differences between the isolate and the rest of Finland. In conclusion, cognitive impairments were milder in schizophrenia patients and their first-degree relatives within than outside the isolate. An absence of differences between the control samples suggests that the differences in schizophrenia families may relate to genetic background, possibly to partly distinct variants affecting the liability inside and outside the isolate. PMID:23083916

Torniainen, Minna; Wedenoja, Juho; Varilo, Teppo; Partonen, Timo; Suokas, Jaana; Häkkinen, Laura; Lönnqvist, Jouko; Suvisaari, Jaana; Tuulio-Henriksson, Annamari

2013-07-30

243

A genetic screen for zygotic embryonic lethal mutations affecting cuticular morphology in the wasp Nasonia vitripennis.  

PubMed Central

We have screened for zygotic embryonic lethal mutations affecting cuticular morphology in Nasonia vitripennis (Hymenoptera; Chalcidoidea). Our broad goal was to investigate the use of Nasonia for genetically surveying conservation and change in regulatory gene systems, as a means to understand the diversity of developmental strategies that have arisen during the course of evolution. Specifically, we aim to compare anteroposterior patterning gene functions in two long germ band insects, Nasonia and Drosophila. In Nasonia, unfertilized eggs develop as haploid males while fertilized eggs develop as diploid females, so the entire genome can be screened for recessive zygotic mutations by examining the progeny of F1 females. We describe 74 of >100 lines with embryonic cuticular mutant phenotypes, including representatives of coordinate, gap, pair-rule, segment polarity, homeotic, and Polycomb group functions, as well as mutants with novel phenotypes not directly comparable to those of known Drosophila genes. We conclude that Nasonia is a tractable experimental organism for comparative developmental genetic study. The mutants isolated here have begun to outline the extent of conservation and change in the genetic programs controlling embryonic patterning in Nasonia and Drosophila.

Pultz, M A; Zimmerman, K K; Alto, N M; Kaeberlein, M; Lange, S K; Pitt, J N; Reeves, N L; Zehrung, D L

2000-01-01

244

Usefulness of combined genetic data in Hungarian families affected by autosomal dominant polycystic kidney disease.  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary diseases. Mutations of two known genetic loci (PKD1: 16p13.3 and PKD2: 4q21.2) can lead to bilateral renal cysts. The PKD1 locus is the more common ( approximately 85%), with a more severe phenotype. Because of the genetic complexity of ADPKD and the size and complexity of the PKD1 gene, pedigree-based linkage analysis is a useful tool for the genetic diagnosis in families with more than one subject affected. We tested linkage or non-linkage to the closely linked DNA markers flanking the PKD1 (D16S663 and D16S291) and one intragenic D16S3252 and PKD2 (D4S1563 and D4S2462) in 30 ADPKD-affected families, to determine the distributions of alleles and the degree of microsatellite polymorphisms (in 91 patients and 125 healthy subjects). To characterize the markers, used heterozygosity levels, polymorphism information content and LOD scores were calculated. The D16S663 marker included 12 kinds of alleles, while D16S291 had 10 alleles and D16S3252 had 8. D4S1563 had 12 alleles and D4S2462 had 11. In a search for a common ancestral relationship, we considered the patients' alleles with the same repeat number. Only one haplotype was detected in more than one (2) unrelated families. The calculated two-point LOD scores indicated a linkage to PKD1 in 22 families (74%). In four families (13%) with a linkage to PKD2, the patients reached the end-stage renal disease after the age of 65years. One family was linked to neither gene (3%), and in three families (10%) a linkage to both genes was possible. In the latter three families, the numbers of analyzed subjects were small (4-5), and/or some markers were only partially or non-informative. However, the elderly affected family members exhibited the clinical signs of the PKD1 form in these cases. The new Hungarian population genetic information was compared with available data on other populations. PMID:19056484

Endreffy, Emoke; Maróti, Zoltán; Bereczki, Csaba; Túri, Sándor

2009-02-01

245

Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2  

PubMed Central

Chronic neuropathic pain is affected by specifics of the precipitating neural pathology, psychosocial factors, and by genetic predisposition. Little is known about the identity of predisposing genes. Using an integrative approach, we discovered that CACNG2 significantly affects susceptibility to chronic pain following nerve injury. CACNG2 encodes for stargazin, a protein intimately involved in the trafficking of glutamatergic AMPA receptors. The protein might also be a Ca2+ channel subunit. CACNG2 has previously been implicated in epilepsy. Initially, using two fine-mapping strategies in a mouse model (recombinant progeny testing [RPT] and recombinant inbred segregation test [RIST]), we mapped a pain-related quantitative trait locus (QTL) (Pain1) into a 4.2-Mb interval on chromosome 15. This interval includes 155 genes. Subsequently, bioinformatics and whole-genome microarray expression analysis were used to narrow the list of candidates and ultimately to pinpoint Cacng2 as a likely candidate. Analysis of stargazer mice, a Cacng2 hypomorphic mutant, provided electrophysiological and behavioral evidence for the gene's functional role in pain processing. Finally, we showed that human CACNG2 polymorphisms are associated with chronic pain in a cohort of cancer patients who underwent breast surgery. Our findings provide novel information on the genetic basis of neuropathic pain and new insights into pain physiology that may ultimately enable better treatments.

Nissenbaum, Jonathan; Devor, Marshall; Seltzer, Ze'ev; Gebauer, Mathias; Michaelis, Martin; Tal, Michael; Dorfman, Ruslan; Abitbul-Yarkoni, Merav; Lu, Yan; Elahipanah, Tina; delCanho, Sonia; Minert, Anne; Fried, Kaj; Persson, Anna-Karin; Shpigler, Hagai; Shabo, Erez; Yakir, Benjamin; Pisante, Anne; Darvasi, Ariel

2010-01-01

246

Mutant huntingtin affects endocytosis in striatal cells by altering the binding of AP-2 to membranes.  

PubMed

Clathrin-mediated endocytosis plays an important role in the maintenance of neuronal integrity in the synaptic terminals. Here we studied the effect of anomalous polyglutamine expansion in huntingtin on the interaction of coat proteins with membranes, in areas of mouse brain or in cultured striatal cells. We observed that this anomaly induces a redistribution of AP-2, but not other coat proteins, from the membrane to the cytosol in the striatum, and in the cultured striatal cells. It was also noted that huntingtin associates with AP-2, and that this association decreases due to the mutation in huntingtin. This decreased receptor-mediated endocytosis, measured by the internalization of transferrin in the mutated cells. It was also confirmed that huntingtin mutation made the cells more vulnerable to the action of quinolinic acid, with an increasing degradation of the AP-2 alpha subunits. On the basis of these results, we conclude that abnormal polyglutamine expansion in huntingtin affects clathrin-mediated endocytosis, and may be one of the pathogenic mechanisms of neurodegeneration. PMID:23219902

Borgonovo, Janina E; Troncoso, Mariana; Lucas, José J; Sosa, Miguel A

2013-03-01

247

Intentional social distance regulation alters affective responses towards victims of violence: an FMRI study.  

PubMed

We used functional magnetic resonance imaging (fMRI) to investigate brain processes underlying control of emotional responses towards a person in distress by cognitive social distance modulation. fMRI and peripheral physiological responses (startle response and electrodermal activity) were recorded from 24 women while they watched victim-offender scenes and modulated their social distance to the victim by cognitive reappraisal. We found that emotional responses, including startle eyeblink and amygdala responses, can effectively be modulated by social distance modulation. Furthermore, our data provide evidence that activity in the dorsomedial prefrontal cortex (dmPFC) and the anterior paracingulate cortex (aPCC), two brain regions that have previously been associated with brain processes related to distant and close others, is differentially modulated by intentional social distance modulation: activity in the dmPFC increased with increasing disengagement from the victim and activity in the aPCC increased with increasing engagement with the victim. We suggest that these two regions play opposing roles in cognitive modulation of social distance and affective responses towards persons in distress that enable the adaptive and flexible social behavior observed in humans. PMID:21998031

Leiberg, Susanne; Eippert, Falk; Veit, Ralf; Anders, Silke

2012-10-01

248

THE ESTROGENIC AND ANTIANDROGENIC PESTICIDE METHOXYCHLOR ALTERS THE REPRODUCTIVE TRACT AND BEHAVIOR WITHOUT AFFECTING PITUITARY SIZE OR LH AND PROLACTIN SECRETION IN MALE RATS  

EPA Science Inventory

The estrogenic and antiandrogenic pesticide methoxychlor alters the reproductive tract and behavior without affecting pituitary size or LH and prolactin secretion in male rats. Gray LE Jr, Ostby J, Cooper RL, Kelce WR. Endocrinology Branch, United States Environment...

249

Prevalence and specificity of LKB1 genetic alterations in lung cancers  

Microsoft Academic Search

Germline LKB1 mutations cause Peutz–Jeghers syndrome, a hereditary disorder that predisposes to gastrointestinal hamartomatous polyposis and several types of malignant tumors. Somatic LKB1 alterations are rare in sporadic cancers, however, a few reports showed the presence of somatic alterations in a considerable fraction of lung cancers. To determine the prevalence and the specificity of LKB1 alterations in lung cancers, we

S Matsumoto; R Iwakawa; K Takahashi; T Kohno; Y Nakanishi; Y Matsuno; K Suzuki; M Nakamoto; E Shimizu; J D Minna; J Yokota

2007-01-01

250

Targeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumors  

PubMed Central

Background Human papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) is an emerging disease, representing a distinct clinical and epidemiological entity. Understanding the genetic basis of this specific subtype of cancer could allow therapeutic targeting of affected pathways for a stratified medicine approach. Methods Twenty HPV+ and 20 HPV- laser-capture microdissected oropharyngeal carcinomas were used for paired-end sequencing of hybrid-captured DNA, targeting 3,230 exons in 182 genes often mutated in cancer. Copy number alteration (CNA) profiling, Sequenom MassArray sequencing and immunohistochemistry were used to further validate findings. Results HPV+ and HPV- oropharyngeal carcinomas cluster into two distinct subgroups. TP53 mutations are detected in 100% of HPV negative cases and abrogation of the G1/S checkpoint by CDKN2A/B deletion and/or CCND1 amplification occurs in the majority of HPV- tumors. Conclusion These findings strongly support a causal role for HPV, acting via p53 and RB pathway inhibition, in the pathogenesis of a subset of oropharyngeal cancers and suggest that studies of CDK inhibitors in HPV- disease may be warranted. Mutation and copy number alteration of PI3 kinase (PI3K) pathway components appears particularly prevalent in HPV+ tumors and assessment of these alterations may aid in the interpretation of current clinical trials of PI3K, AKT, and mTOR inhibitors in HNSCC.

2013-01-01

251

Interest in Genetic Testing Among Affected Men from Hereditary Prostate Cancer (HPC) Families and their Unaffected Male Relatives  

PubMed Central

PURPOSE The objective of this study was to evaluate potential sociodemographic, medical, psychosocial, and behavioral correlates of interest in genetic testing in men from hereditary prostate cancer families (HPC). METHODS Family members affected with prostate cancer (n=559) and their unaffected male relatives (n=370) completed a mailed survey. Multivariable logistic regression models were used to examine the association between potential correlates and interest in genetic testing for prostate cancer. RESULTS Forty-five percent of affected and 56% of unaffected men reported that they definitely would take a genetic test for prostate cancer. More affected men reported high levels of familiarity with genetic testing than unaffected men (46% vs. 25%). There were several variables that were significantly correlated with interest in either affected or unaffected men but only age and familiarity with genetics were significant in both groups. After controlling for confounding variables, only familiarity remained a significant correlate in both groups. CONCLUSIONS The contrast between low levels of familiarity with genetics and high test interest among unaffected men highlights the need for increased educational efforts targeting HPC families. Overall, results illuminated several novel characteristics of men from HPC families that should be considered when developing future informed consent procedures or educational materials for prostate cancer genetic testing.

Harris, Julie N.; Bowen, Deborah J.; Kuniyuki, Alan; McIntosh, Laura; FitzGerald, Liesel M.; Ostrander, Elaine A.; Stanford, Janet L.

2009-01-01

252

Genetic analysis of an Indian family with members affected with Waardenburg syndrome and Duchenne muscular dystrophy  

PubMed Central

Purpose Waardenburg syndrome (WS) is characterized by sensorineural hearing loss and pigmentation defects of the eye, skin, and hair. It is caused by mutations in one of the following genes: PAX3 (paired box 3), MITF (microphthalmia-associated transcription factor), EDNRB (endothelin receptor type B), EDN3 (endothelin 3), SNAI2 (snail homolog 2, Drosophila) and SOX10 (SRY-box containing gene 10). Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the DMD gene. The purpose of this study was to identify the genetic causes of WS and DMD in an Indian family with two patients: one affected with WS and DMD, and another one affected with only WS. Methods Blood samples were collected from individuals for genomic DNA isolation. To determine the linkage of this family to the eight known WS loci, microsatellite markers were selected from the candidate regions and used to genotype the family. Exon-specific intronic primers for EDN3 were used to amplify and sequence DNA samples from affected individuals to detect mutations. A mutation in DMD was identified by multiplex PCR and multiplex ligation-dependent probe amplification method using exon-specific probes. Results Pedigree analysis suggested segregation of WS as an autosomal recessive trait in the family. Haplotype analysis suggested linkage of the family to the WS4B (EDN3) locus. DNA sequencing identified a novel missense mutation p.T98M in EDN3. A deletion mutation was identified in DMD. Conclusions This study reports a novel missense mutation in EDN3 and a deletion mutation in DMD in the same Indian family. The present study will be helpful in genetic diagnosis of this family and increases the mutation spectrum of EDN3.

Kapoor, Saketh; Bindu, Parayil Sankaran; Taly, Arun B.; Sinha, Sanjib; Gayathri, Narayanappa; Rani, S. Vasantha; Chandak, Giriraj Ratan

2012-01-01

253

Cytoplasmic genome substitution in wheat affects the nuclear-cytoplasmic cross-talk leading to transcript and metabolite alterations  

PubMed Central

Background Alloplasmic lines provide a unique tool to study nuclear-cytoplasmic interactions. Three alloplasmic lines, with nuclear genomes from Triticum aestivum and harboring cytoplasm from Aegilops uniaristata, Aegilops tauschii and Hordeum chilense, were investigated by transcript and metabolite profiling to identify the effects of cytoplasmic substitution on nuclear-cytoplasmic signaling mechanisms. Results In combining the wheat nuclear genome with a cytoplasm of H. chilense, 540 genes were significantly altered, whereas 11 and 28 genes were significantly changed in the alloplasmic lines carrying the cytoplasm of Ae. uniaristata or Ae. tauschii, respectively. We identified the RNA maturation-related process as one of the most sensitive to a perturbation of the nuclear-cytoplasmic interaction. Several key components of the ROS chloroplast retrograde signaling, together with the up-regulation of the ROS scavenging system, showed that changes in the chloroplast genome have a direct impact on nuclear-cytoplasmic cross-talk. Remarkably, the H. chilense alloplasmic line down-regulated some genes involved in the determination of cytoplasmic male sterility without expressing the male sterility phenotype. Metabolic profiling showed a comparable response of the central metabolism of the alloplasmic and euplasmic lines to light, while exposing larger metabolite alterations in the H. chilense alloplasmic line as compared with the Aegilops lines, in agreement with the transcriptomic data. Several stress-related metabolites, remarkably raffinose, were altered in content in the H. chilense alloplasmic line when exposed to high light, while amino acids, as well as organic acids were significantly decreased. Alterations in the levels of transcript, related to raffinose, and the photorespiration-related metabolisms were associated with changes in the level of related metabolites. Conclusion The replacement of a wheat cytoplasm with the cytoplasm of a related species affects the nuclear-cytoplasmic cross-talk leading to transcript and metabolite alterations. The extent of these modifications was limited in the alloplasmic lines with Aegilops cytoplasm, and more evident in the alloplasmic line with H. chilense cytoplasm. We consider that, this finding might be linked to the phylogenetic distance of the genomes.

2013-01-01

254

Environmental stress alters genetic regulation of novelty seeking in vervet monkeys.  

PubMed

Considerable attention has been paid to identifying genetic influences and gene-environment interactions that increase vulnerability to environmental stressors, with promising but inconsistent results. A nonhuman primate model is presented here that allows assessment of genetic influences in response to a stressful life event for a behavioural trait with relevance for psychopathology. Genetic and environmental influences on free-choice novelty seeking behaviour were assessed in a pedigreed colony of vervet monkeys before and after relocation from a low stress to a higher stress environment. Heritability of novelty seeking scores, and genetic correlations within and between environments were conducted using variance components analysis. The results showed that novelty seeking was markedly inhibited in the higher stress environment, with effects persisting across a 2-year period for adults but not for juveniles. There were significant genetic contributions to novelty seeking scores in each year (h(2) = 0.35-0.43), with high genetic correlations within each environment (rhoG > 0.80) and a lower genetic correlation (rhoG = 0.35, non-significant) between environments. There were also significant genetic contributions to individual change scores from before to after the move (h(2) = 0.48). These results indicate that genetic regulation of novelty seeking was modified by the level of environmental stress, and they support a role for gene-environment interactions in a behavioural trait with relevance for mental health. PMID:21631727

Fairbanks, L A; Bailey, J N; Breidenthal, S E; Laudenslager, M L; Kaplan, J R; Jorgensen, M J

2011-08-01

255

Environmental stress alters genetic regulation of novelty seeking in vervet monkeys  

PubMed Central

Considerable attention has been paid to identifying genetic influences and gene–environment interactions that increase vulnerability to environmental stressors, with promising but inconsistent results. A nonhuman primate model is presented here that allows assessment of genetic influences in response to a stressful life event for a behavioural trait with relevance for psychopathology. Genetic and environmental influences on free-choice novelty seeking behaviour were assessed in a pedigreed colony of vervet monkeys before and after relocation from a low stress to a higher stress environment. Heritability of novelty seeking scores, and genetic correlations within and between environments were conducted using variance components analysis. The results showed that novelty seeking was markedly inhibited in the higher stress environment, with effects persisting across a 2-year period for adults but not for juveniles. There were significant genetic contributions to novelty seeking scores in each year (h2 = 0.35–0.43), with high genetic correlations within each environment (rhoG > 0.80) and a lower genetic correlation (rhoG = 0.35, non-significant) between environments. There were also significant genetic contributions to individual change scores from before to after the move (h2 = 0.48). These results indicate that genetic regulation of novelty seeking was modified by the level of environmental stress, and they support a role for gene–environment interactions in a behavioural trait with relevance for mental health.

Fairbanks, L A; Bailey, J N; Breidenthal, S E; Laudenslager, M L; Kaplan, J R; Jorgensen, M J

2011-01-01

256

Seismic properties of rocks affected by hydrothermal alteration: a case study from the Lalor Lake VMS mining camp  

NASA Astrophysics Data System (ADS)

Global demand of base metals, uranium, diamonds, and precious metals has been pushing technological barrier to find and extract minerals at higher depth, which was not feasible in just a few decades ago. Seismic properties of rocks containing and surrounding ore bodies have been useful in characterizing and modeling geologic structures, and mapping high-resolution images of ore bodies. Although seismic surveys and drill hole sonic and density logs are essential for mineral exploration at depth, limited availability of seismic logs to link rock properties of different ore forming geologic structure is a hindrance to seismic interpretations. Volcanogenic Massive Sulphides (VMS) are rich in minerals and of primary interests among geologists and mining industries alike. VMS deposits occur due to focused discharge of metal-enriched fluids associated in the hydrothermal alteration process, and are rich in Zn, Cu, Pb, Ag, Au, etc. Alteration halos surrounding ore deposits can be widespread, and their locations are easier to determine than the deposits within them. Physical rock properties affected by alteration can provide clues on type and potentially size of ore deposits in the surrounding area. In this context, variations in seismic properties of rocks due to hydrothermal alteration near the deposits can help in improving modeling accuracy, and better interpretation of seismic data for economic mineral exploration. While reflection seismic techniques can resolve ore bodies at higher depths than other conventional geophysical techniques, they are relatively expensive both in terms of field data acquisition and post-processing, especially for high-resolution 3D surveys. Acoustic impedance contrasts of ore lenses with their hosting rock environment; geometry, size and spatial location relative to the surface affect their detection with seismic data. Therefore, apriori knowledge of seismic rock properties from drill hole logs and core samples in the potential survey area are essential to determine whether any 2D/3D active survey would be worth conducting. In situ density and velocity logs, and thus, acoustic impedance provide first order control on reflectivity of various lithologies. In this abstract, we analyzed well logs from 12 drill holes geographically located in the northern Manitoba, Canada, in an attempt to characterize lithologies based on their seismic properties. Velocities, density, acoustic impedance and Poisson's ratio of major lithologies were compared among each other. Massive sulphide and Diorite have higher average acoustic impedance than the others. Our quantitative analysis suggests that alteration has considerable effect on overall acoustic impedance of Argillite, Felsic Volcanic and Stringer Sulphide rocks. This can be useful in selecting values of model parameters for seismic wave propagation simulation, which can be used to compare with seismic survey data. In addition, core sample analysis from the same drill holes aided our understanding of mineralization, alteration, and overall composition of different rocks under consideration.

Miah, K.; Bellefleur, G.; Schetselaar, E.

2013-12-01

257

How does altered precipitation and annual grass invasion affect plant N uptake in a native semi-arid shrub community?  

NASA Astrophysics Data System (ADS)

Climate change is expected to alter precipitation patterns, which will change the timing and amount of plant resources. Precipitation patterns determine water and nitrogen (N) availability, because water stimulates microbial N turnover and N transport. In order for plants to utilize water and N, they must coincide with the phenology and meet physiological requirements of the plant. As resource supply shifts, differences in species' ability to acquire resources will affect plant community composition. Semiarid ecosystems, such as shrublands in Southern California, are particularly sensitive to shifts in precipitation because they are severely water limited. This study takes advantage of the altered phenology and resource demands presented by invasive annual grasses in a native semiarid shrubland. The goal is to understand how altered precipitation patterns affect plant N uptake. Rainfall levels were manipulated to 50% and 150% of ambient levels. It is expected that higher rainfall levels promote annual grass invasion because grasses have higher water and N requirements and begin to grow earlier in the season than shrubs. A 15N tracer was added with the first rain event and plant samples were collected regularly to track the movement of N into the plants. Net soil N accumulation was determined using resin bags. Invasive grasses altered the timing and amount of N uptake but amount of rainfall had less effect on N distribution. 15N was detected sooner and at higher level in grasses than shrubs. 24hours after the first rain event 15N was detectable in grasses, 15N accumulated rapidly and peaked 2 months earlier than shrubs. Shrub 15N levels remained at pre-rain event levels for the first 2 months and began to increase at the beginning of spring, peak mid-spring and decline as the shrubs entered summer dormancy. One year later 15N levels in annual grass litter remained high, while 15N levels in shrubs returned to initial background levels as a result of resorption. 15N concentrations are more variable in grasses which could indicate higher plasticity in grass N uptake compared to shrubs. Resin N supports the 15N patterns. Resin N declined more rapidly under grasses and was lower than under shrubs, presumably due to high grass N uptake. Resin N was particularly high under shrubs in wetter conditions indicating that shrubs could not take advantage of high N supply. Together the 15N and resin N patterns indicate that grasses accumulate more N and begin N uptake earlier in the season than shrubs. Although 15N did not differ in response to rainfall, invasion alters the distribution of N in the system. Rain was only manipulated for one growing season; multiple years of altered precipitation may yield significant differences. Early season N uptake by grasses, the low variability in shrub 15N and low shrub 15N in wetter conditions, despite high resin N, indicates that N competition between invasive grasses and native shrubs is weak. If N supply is sufficient for shrub demands, invasive grasses and shrubs could coexist. This study contributes to a broader understanding of how changes in resource supply, plant phenology and functional type interact and respond to climate change.

Mauritz, M.; Lipson, D.; Cleland, E. E.

2012-12-01

258

Genetic mapping of quantitative trait loci affecting growth and carcass traits in F2 intercross chickens.  

PubMed

We constructed a chicken F(2) resource population to facilitate the genetic improvement of economically important traits, particularly growth and carcass traits. An F(2) population comprising 240 chickens obtained by crossing a Shamo (lean, lightweight Japanese native breed) male and White Plymouth Rock breed (fat, heavyweight broiler) females was measured for BW, carcass weight (CW), abdominal fat weight (AFW), breast muscle weight (BMW), and thigh muscle weight (TMW) and was used for genome-wide linkage and QTL analysis, using a total of 240 microsatellite markers. A total of 14 QTL were detected at a 5% chromosome-wide level, and 7 QTL were significant at a 5% experiment-wide level for the traits evaluated in the F(2) population. For growth traits, significant and suggestive QTL affecting BW (measured at 6 and 9 wk) and average daily gain were identified on similar regions of chromosomes 1 and 3. For carcass traits, the QTL effects on CW were detected on chromosomes 1 and 3, with the greatest F-ratio of 15.0 being obtained for CW on chromosome 3. Quantitative trait loci positions affecting BMW and TMW were not detected at the same loci as those detected for BMW percentage of CW and TMW percentage of CW. For AFW, QTL positions were detected at the same loci as those detected for AFW percentage of CW. The present study identified significant QTL affecting BW, CW, and AFW. PMID:19211515

Uemoto, Y; Sato, S; Odawara, S; Nokata, H; Oyamada, Y; Taguchi, Y; Yanai, S; Sasaki, O; Takahashi, H; Nirasawa, K; Kobayashi, E

2009-03-01

259

Recurrent genetic alterations in 26 colorectal carcinomas and 21 adenomas from Chinese patients  

Microsoft Academic Search

Colorectal cancer (CRC) is one of the most common malignancies worldwide. The incidence of CRC in the Chinese population has increased dramatically during the last two decades; however, nonrandom chromosomal alterations in Chinese patients have not been described. In the present study, comparative genomic hybridization (CGH) was applied to detect recurrent chromosome alterations in 26 primary colorectal carcinomas and 21

Qiao-Jie He; Wei-Fen Zeng; Jonathan S. T Sham; Dan Xie; Xing-Wu Yang; Han-Liang Lin; Wen-Hua Zhan; Feng Lin; Sui-De Zeng; Daping Nie; Lin-Fei Ma; Chu-Jun Li; Shen Lu; Xin-Yuan Guan

2003-01-01

260

Micronucleus test and observation of nuclear alterations in erythrocytes of Nile tilapia exposed to waters affected by refinery effluent.  

PubMed

Micronuclei and nuclear alterations tests were performed on erythrocytes of Oreochromis niloticus (Perciformes, Cichlidae) in order to evaluate the water quality from Paraíba do Sul river, in an area affected by effluents from an oil shale processing plant, located in the city of São José dos Campos, Brazil-SP. Water samples were collected on 2004 May and August (dry season) and on 2004 November and 2005 January (rain season), in three distinct sites, comprising 12 samples. It was possible to detect substances of clastogenic and/or aneugenic potential, as well as cytotoxic substances, chiefly at the point corresponding to the drainage of oil shale plant wastes along the river. The highest incidence of micronuclei and nuclear alterations was detected during May and August, whereas the results obtained in November and January were insignificant. This work shows that the effluent treatment provided by the oil shale plant was not fully efficient to minimize the effect of cytotoxic and mutagenic substances in the test organism surveyed. PMID:16678473

da Silva Souza, Tatiana; Fontanetti, Carmem S

2006-06-16

261

Altered Mucus Glycosylation in Core 1 O-Glycan-Deficient Mice Affects Microbiota Composition and Intestinal Architecture  

PubMed Central

A functional mucus layer is a key requirement for gastrointestinal health as it serves as a barrier against bacterial invasion and subsequent inflammation. Recent findings suggest that mucus composition may pose an important selection pressure on the gut microbiota and that altered mucus thickness or properties such as glycosylation lead to intestinal inflammation dependent on bacteria. Here we used TM-IEC C1galt-/- mice, which carry an inducible deficiency of core 1-derived O-glycans in intestinal epithelial cells, to investigate the effects of mucus glycosylation on susceptibility to intestinal inflammation, gut microbial ecology and host physiology. We found that TM-IEC C1galt-/- mice did not develop spontaneous colitis, but they were more susceptible to dextran sodium sulphate-induced colitis. Furthermore, loss of core 1-derived O-glycans induced inverse shifts in the abundance of the phyla Bacteroidetes and Firmicutes. We also found that mucus glycosylation impacts intestinal architecture as TM-IEC C1galt-/- mice had an elongated gastrointestinal tract with deeper ileal crypts, a small increase in the number of proliferative epithelial cells and thicker circular muscle layers in both the ileum and colon. Alterations in the length of the gastrointestinal tract were partly dependent on the microbiota. Thus, the mucus layer plays a role in the regulation of gut microbiota composition, balancing intestinal inflammation, and affects gut architecture.

Sommer, Felix; Adam, Nina; Johansson, Malin E. V.; Xia, Lijun; Hansson, Gunnar C.; Backhed, Fredrik

2014-01-01

262

Conservation of Genetic Alterations in Recurrent Melanoma Supports the Melanoma Stem Cell Hypothesis  

Microsoft Academic Search

It is generally accepted that human cancers derive from a mutated single cell. However, the genetic steps characterizing various stages of progression remain unclear. Studying a unique case of metastatic melanoma, we observed that cell lines derived from metachronous metastases arising over a decade retained a central core of genetic stability in spite of divergent phenotypes. In the present study,

Marianna Sabatino; Yingdong Zhao; Sonia Voiculescu; Alessandro Monaco; Paul Robbins; Laszlo Karai; Brian J. Nickoloff; Michele Maio; Silvia Selleri; Francesco M. Marincola; Ena Wang

2008-01-01

263

Toward Altering Milk Composition by Genetic Manipulation: Current Status and Challenges  

Microsoft Academic Search

The implementation of large-scale genome map- ping and sequencing has improved the understanding of animal genetics. A large number of gene sequences are now available to serve as regulatory elements or genes of interest. Although the central thrust of this work is focused on understanding disease states, the manipulation of normal metabolic processes is feasi- ble. To date, the genetic

Costas N. Karatzas; Jeffrey D. Turner

1997-01-01

264

Genetic associations with clinical characteristics in bipolar affective disorder and recurrent unipolar depressive disorder.  

PubMed

Genetic factors may be associated with disease subtype as well as susceptibility. We have therefore typed polymorphisms at the serotonin transporter, dopamine receptor, tryptophan hydroxylase, tyrosine hydoxylase, and monoamine oxidase A (MAOA) loci in 139 unipolar and 131 bipolar patients and investigated associations with gender, number of episodes, age of onset, history of psychotic symptoms, history of suicidal behavior, and history of substance abuse. In bipolar subjects, the promoter variable number tandem repeat (VNTR) allele 132 of MAOA was associated with history of suicide attempts, P = 0.029, particularly in females, P = 0.006. The Fnu4HI allele 1 of MAOA was also associated with history of suicide attempts in females, P = 0.0162. The serotonin transporter promoter allele 2 was associated with increasing number of manic episodes, P = 0.02, and history of psychotic symptoms, P = 0.0243. One significant association was found in the unipolar group: dopamine D2 receptor promoter allele 2 with history of psychotic symptoms, P = 0. 0165. We have tested multiple loci for a variety of different clinical variables and performed 228 tests of significance in total. It is possible that these preliminary findings are type 1 errors, because one would expect 11 of the 228 tests to reach a nominal significance level of P < 0.05 by chance alone if all the tests were independent. The associations with the MAOA and serotonin transporter loci are consistent with previous data suggesting associations with susceptibility to bipolar affective disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:36-42, 2000 PMID:10686549

Ho, L W; Furlong, R A; Rubinsztein, J S; Walsh, C; Paykel, E S; Rubinsztein, D C

2000-02-01

265

Genetic alterations of the TGF-? signaling pathway in colorectal cancer cell lines: A novel mutation in Smad3 associated with the inactivation of TGF-?-induced transcriptional activation  

Microsoft Academic Search

To investigate genetic alterations involved in the TGF-? signaling pathway in colorectal cancer, we assayed DNA synthesis rates after treating TGF-? and checked for genetic alterations in TGF-?RII, TGF-?RI, Smad2, Smad3, and Smad4 in 12 colorectal cancer cell lines. Eleven lines, except SNU-61, show no significant change in DNA synthesis rate after TGF-? treatment. In these 11 lines, several mutations

Ja-Lok Ku; Seok-Hee Park; Kyong-Ah Yoon; Young-Kyoung Shin; Kyung-Hee Kim; Jin-Sung Choi; Hio-Chung Kang; Il-Jin Kim; Inn-Oc Han; Jae-Gahb Park

2007-01-01

266

A genome-wide scan in affected sibling pairs with idiopathic recurrent miscarriage suggests genetic linkage.  

PubMed

Previously, siblings of patients with idiopathic recurrent miscarriage (IRM) have been shown to have a higher risk of miscarriage. This study comprises two parts: (i) an epidemiological part, in which we introduce data on the frequency of miscarriage among 268 siblings of 244 patients with IRM and (ii) a genetic part presenting data from a genome-wide linkage study of 38 affected sibling pairs with IRM. All IRM patients (probands) had experienced three or more miscarriages and affected siblings two or more miscarriages. The sibling pairs were genotyped by the Affymetrix GeneChip 50K XbaI platform and non-parametric linkage analysis was performed via the software package Merlin. We find that siblings of IRM patients exhibit a higher frequency of miscarriage than population controls regardless of age at the time of pregnancy. We identify chromosomal regions with LOD scores between 2.5 and 3.0 in subgroups of affected sibling pairs. Maximum LOD scores were identified in four occurrences: for rs10514716 (3p14.2) when analyzing sister-pairs only; for rs10511668 (9p22.1) and rs341048 (11q13.4) when only analyzing families where the probands have had four or more miscarriages; and for rs10485275 (6q16.3) when analyzing one sibling pair from each family only. We identify no founder mutations. Concluding, our results imply that IRM patients and their siblings share factors which increase the risk of miscarriage. In this first genome-wide linkage study of affected sibling pairs with IRM, we identify regions on chromosomes 3, 6, 9 and 11 which warrant further investigation in order to elucidate their putative roles in the genesis of IRM. PMID:21257601

Kolte, A M; Nielsen, H S; Moltke, I; Degn, B; Pedersen, B; Sunde, L; Nielsen, F C; Christiansen, O B

2011-06-01

267

Alterations in Seed Development Gene Expression Affect Size and Oil Content of Arabidopsis Seeds1[C][W][OPEN  

PubMed Central

Seed endosperm development in Arabidopsis (Arabidopsis thaliana) is under control of the polycomb group complex, which includes Fertilization Independent Endosperm (FIE). The polycomb group complex regulates downstream factors, e.g. Pheres1 (PHE1), by genomic imprinting. In heterozygous fie mutants, an endosperm develops in ovules carrying a maternal fie allele without fertilization, finally leading to abortion. Another endosperm development pathway depends on MINISEED3 (a WRKY10 transcription factor) and HAIKU2 (a leucine-rich repeat kinase). While the role of seed development genes in the embryo and endosperm establishment has been studied in detail, their impact on metabolism and oil accumulation remained unclear. Analysis of oil, protein, and sucrose accumulation in mutants and overexpression plants of the four seed development genes revealed that (1) seeds carrying a maternal fie allele accumulate low oil with an altered composition of triacylglycerol molecular species; (2) homozygous mutant seeds of phe1, mini3, and iku2, which are smaller, accumulate less oil and slightly less protein, and starch, which accumulates early during seed development, remains elevated in mutant seeds; (3) embryo-specific overexpression of FIE, PHE1, and MINI3 has no influence on seed size and weight, nor on oil, protein, or sucrose content; and (4) overexpression of IKU2 results in seeds with increased size and weight, and oil content of overexpressed IKU2 seeds is increased by 35%. Thus, IKU2 overexpression represents a novel strategy for the genetic manipulation of the oil content in seeds.

Fatihi, Abdelhak; Zbierzak, Anna Maria; Dormann, Peter

2013-01-01

268

Rare Mutations of CACNB2 Found in Autism Spectrum Disease-Affected Families Alter Calcium Channel Function  

PubMed Central

Autism Spectrum Disorders (ASD) are complex neurodevelopmental diseases clinically defined by dysfunction of social interaction. Dysregulation of cellular calcium homeostasis might be involved in ASD pathogenesis, and genes coding for the L-type calcium channel subunits CaV1.2 (CACNA1C) and CaV?2 (CACNB2) were recently identified as risk loci for psychiatric diseases. Here, we present three rare missense mutations of CACNB2 (G167S, S197F, and F240L) found in ASD-affected families, two of them described here for the first time (G167S and F240L). All these mutations affect highly conserved regions while being absent in a sample of ethnically matched controls. We suggest the mutations to be of physiological relevance since they modulate whole-cell Ba2+ currents through calcium channels when expressed in a recombinant system (HEK-293 cells). Two mutations displayed significantly decelerated time-dependent inactivation as well as increased sensitivity of voltage-dependent inactivation. In contrast, the third mutation (F240L) showed significantly accelerated time-dependent inactivation. By altering the kinetic parameters, the mutations are reminiscent of the CACNA1C mutation causing Timothy Syndrome, a Mendelian disease presenting with ASD. In conclusion, the results of our first-time biophysical characterization of these three rare CACNB2 missense mutations identified in ASD patients support the hypothesis that calcium channel dysfunction may contribute to autism.

Breitenkamp, Alexandra F. S.; Matthes, Jan; Nass, Robert Daniel; Sinzig, Judith; Lehmkuhl, Gerd; Nurnberg, Peter; Herzig, Stefan

2014-01-01

269

Specific Serotonergic Denervation Affects tau Pathology and Cognition without Altering Senile Plaques Deposition in APP/PS1 Mice  

PubMed Central

Senile plaques and neurofibrillary tangles are major neuropathological features of Alzheimer's Disease (AD), however neuronal loss is the alteration that best correlates with cognitive impairment in AD patients. Underlying neurotoxic mechanisms are not completely understood although specific neurotransmission deficiencies have been observed in AD patients and, in animal models, cholinergic and noradrenergic denervation may increase amyloid-beta deposition and tau phosphorylation in denervated areas. On the other hand brainstem neurodegeneration has been suggested as an initial event in AD, and serotonergic dysfunction, as well as reductions in raphe neurones density, have been reported in AD patients. In this study we addressed whether specific serotonergic denervation, by administering 5,7-dihydroxitriptamine (5,7-DHT) in the raphe nuclei, could also worsen central pathology in APPswe/PS1dE9 mice or interfere with learning and memory activities. In our hands specific serotonergic denervation increased tau phosphorylation in denervated cortex, without affecting amyloid-beta (A?) pathology. We also observed that APPswe/PS1dE9 mice lesioned with 5,7-DHT were impaired in the Morris water maze test, supporting a synergistic effect of the serotonergic denervation and the presence of APP/PS1 transgenes on learning and memory impairment. Altogether our data suggest that serotonergic denervation may interfere with some pathological aspects observed in AD, including tau phosphorylation or cognitive impairment, without affecting A? pathology, supporting a differential role of specific neurotransmitter systems in AD.

Ramos-Rodriguez, Juan Jose; Molina-Gil, Sara; Rey-Brea, Raquel; Berrocoso, Esther; Garcia-Alloza, Monica

2013-01-01

270

Factors affecting performance of prenatal genetic testing by Israeli Jewish women.  

PubMed

The number of prenatal genetic tests that are being offered to women is constantly increasing. However, there is little national data as to who is performing the tests and the reasons for doing or not doing so. This study evaluated the proportion of Jewish women in Israel who perform the various prenatal genetic tests and the factors affecting the performance of these tests. It was found that 60.9% of the women performed the triple test, 50.8% of women older than 35 years performed amniocentesis, while 63.3 and 24.3% of women performed Tay-Sachs and fragile-X carrier testing respectively. Ninety-six percent of the secular women compared to only 6.7% of the ultrareligious women performed the triple test. It was also found that94.4% of the secular women, 36.4% of the religious, and none of the ultrareligious women older than 35 years performed amniocentesis. In the stepwise regression analysis, being secular, having a higher income, fewer children, and being of Ashkenazi origin remained significant factors in determining performance of Tay-Sachs carrier testing. As regards fragile-X carrier testing, being secular, having fewer than four children, and having a higher income and a supplementary medical insurance remained significant factors. The main reason reported by the women for not performing amniocentesis or the triple test was for religious or moral grounds (53.3 and 67% respectively). The main reason given for not performing Tay-Sachs or fragile-X testing was that they were not referred for the tests (76 and 82% respectively). Consideration should be given to providing first trimester prenatal diagnosis to the ultrareligious group, including state subsidized fragile-X testing and educating the primary care givers about the importance of prenatal genetic testing. The information from the present study is vital for the planning of an equitable prenatal genetic service and provides guidelines for the implementation of such services in other countries. PMID:12838566

Sher, Carron; Romano-Zelekha, Orly; Green, Manfred S; Shohat, Tamy

2003-07-30

271

Recurrent genetic alterations in 26 colorectal carcinomas and 21 adenomas from Chinese patients.  

PubMed

Colorectal cancer (CRC) is one of the most common malignancies worldwide. The incidence of CRC in the Chinese population has increased dramatically during the last two decades; however, nonrandom chromosomal alterations in Chinese patients have not been described. In the present study, comparative genomic hybridization (CGH) was applied to detect recurrent chromosome alterations in 26 primary colorectal carcinomas and 21 colorectal adenomas from Chinese patients. In CRC, several recurrent chromosomal changes were found, including gains of 8q (14/26 cases, 54%), 20q (54%), 3q (50%), 13q (50%), 5p (46%), 7p (42%), 7q (42%), and 12p (38%) and losses of 18q (65%) and 17p (42%). From comparison with previous CGH studies, the frequent gains of 3q and 12p might be distinctive occurrences in Chinese patients. The distribution of frequently found chromosomal alterations in different locations was studied. The gain of 20q was more frequently found in colon cancer (P<0.01) and the gain of 12p was more frequently found in rectal cancer. Chromosomal alterations were found in 19/21 of adenomas; the most frequent chromosomal alteration was the loss of 18q (9/21 cases, 43%). These recurrent alterations provide several starting points for the isolation of candidate oncogenes and tumor suppressor genes. PMID:12850373

He, Qiao-Jie; Zeng, Wei-Fen; Sham, Jonathan S T; Xie, Dan; Yang, Xing-Wu; Lin, Han-Liang; Zhan, Wen-Hua; Lin, Feng; Zeng, Sui-De; Nie, Daping; Ma, Lin-Fei; Li, Chu-Jun; Lu, Shen; Guan, Xin-Yuan

2003-07-15

272

Exome Capture Sequencing of Adenoma Reveals Genetic Alterations in Multiple Cellular Pathways at the Early Stage of Colorectal Tumorigenesis  

PubMed Central

Most of colorectal adenocarcinomas are believed to arise from adenomas, which are premalignant lesions. Sequencing the whole exome of the adenoma will help identifying molecular biomarkers that can predict the occurrence of adenocarcinoma more precisely and help understanding the molecular pathways underlying the initial stage of colorectal tumorigenesis. We performed the exome capture sequencing of the normal mucosa, adenoma and adenocarcinoma tissues from the same patient and sequenced the identified mutations in additional 73 adenomas and 288 adenocarcinomas. Somatic single nucleotide variations (SNVs) were identified in both the adenoma and adenocarcinoma by comparing with the normal control from the same patient. We identified 12 nonsynonymous somatic SNVs in the adenoma and 42 nonsynonymous somatic SNVs in the adenocarcinoma. Most of these mutations including OR6X1, SLC15A3, KRTHB4, RBFOX1, LAMA3, CDH20, BIRC6, NMBR, GLCCI1, EFR3A, and FTHL17 were newly reported in colorectal adenomas. Functional annotation of these mutated genes showed that multiple cellular pathways including Wnt, cell adhesion and ubiquitin mediated proteolysis pathways were altered genetically in the adenoma and that the genetic alterations in the same pathways persist in the adenocarcinoma. CDH20 and LAMA3 were mutated in the adenoma while NRXN3 and COL4A6 were mutated in the adenocarcinoma from the same patient, suggesting for the first time that genetic alterations in the cell adhesion pathway occur as early as in the adenoma. Thus, the comparison of genomic mutations between adenoma and adenocarcinoma provides us a new insight into the molecular events governing the early step of colorectal tumorigenesis.

Zheng, Liangtao; Ge, Weiting; Li, Dan; Zhang, Yong; Hu, Xueda; Gao, Zhibo; Xu, Jinghong; Huang, Yanqin; Hu, Hanguang; Zhang, Hang; Zhang, Hao; Liu, Mingming; Yang, Huanming; Zheng, Lei; Zheng, Shu

2013-01-01

273

Genetic variation in the serotonin receptor gene affects immune responses in rheumatoid arthritis  

PubMed Central

Many genetic variants associate with the risk of developing rheumatoid arthritis (RA); however, their functional roles are largely unknown. Here, we aimed to investigate whether the RA-associated serotonin receptor 2A (HTR2A) haplotype affects T-cell and monocyte functions. Patients with established RA (n=379) were genotyped for two single-nucleotide polymorphisms (SNPs) in the HTR2A locus, rs6314 and rs1328674, to define presence of the risk haplotype for each individual. Patients with and without the RA-associated TC haplotype were selected and T-cell and monocyte function was monitored following in vitro stimulations with staphylococcal enterotoxin B and lipopolysaccharide (LPS) using multiparameter flow cytometry. Within the cohort, 44 patients were heterozygous for the TC haplotype (11.6%) while none were homozygous. Upon stimulation, T cells from TC-carrier patients produced more proinflammatory cytokines (tumor necrosis factor alpha (TNF-?), interleukin-17 (IL-17) and interferon gamma (IFN-?)) and monocytes produced higher levels of TNF-? compared with patients carrying the non-TC haplotype (P<0.05 and 0.01, respectively). Such cytokine production could be inhibited in the presence of the selective 5-HT2 receptor agonist (2,5-Dimethoxy-4-iodoamphetamine, DOI); interestingly, this effect was more pronounced in TC carriers. Our data demonstrate that association of RA with a distinct serotonin receptor haplotype has functional impact by affecting the immunological phenotype of T cells and monocytes.

Snir, O; Hesselberg, E; Amoudruz, P; Klareskog, L; Zarea-Ganji, I; Catrina, A I; Padyukov, L; Malmstrom, V; Seddighzadeh, M

2013-01-01

274

Intermediate-Type Vancomycin Resistance (VISA) in Genetically-Distinct Staphylococcus aureus Isolates Is Linked to Specific, Reversible Metabolic Alterations  

PubMed Central

Intermediate (VISA-type) vancomycin resistance in Staphylococcus aureus has been associated with a range of physiologic and genetic alterations. Previous work described the emergence of VISA-type resistance in two clonally-distinct series of isolates. In both series (the first belonging to MRSA clone ST8-USA300, and the second to ST5-USA100), resistance was conferred by a single mutation in yvqF (a negative regulator of the vraSR two-component system associated with vancomycin resistance). In the USA300 series, resistance was reversed by a secondary mutation in vraSR. In this study, we combined systems-level metabolomic profiling with statistical modeling techniques to discover specific, reversible metabolic alterations associated with the VISA phenotype.

Alexander, Elizabeth L.; Gardete, Susana; Bar, Haim Y.; Wells, Martin T.; Tomasz, Alexander; Rhee, Kyu Y.

2014-01-01

275

Genetic Alterations in Primary Bladder Cancers and Their Métastases1  

Microsoft Academic Search

Bladder cancer progression is thought to be associated with sequential genetic events. To search for the specific genetic changes associated with the metastatic process, comparative genomic hybridization was performed on 22 primary tumors and 24 métastases (10 distant and 14 nodal métas tases) from 17 patients with stage p I 2-4 bladder cancer. There was a striking similarity between the

Regina M. Hovey; Lisa Chu; Margit Balazs; Sandy DeVries; Dan Moore; Guido Sauter; Peter R. Carroll; Frederic M. Waldman

276

Tg.AC Genetically Altered Mouse: Assay Working Group Overview of Available Data  

Microsoft Academic Search

In aGovernment\\/Industry\\/Academicpartnershiptoevaluatealternativeapproachestocarcinogenicity testing,21pharmaceuticalagentsrepresenting avariety ofchemical and pharmacological classes and possessing known human and or rodent carcinogenicpotential wereselected forstudy in several rodent models. The studies from this partnership project, coordinated by the International Life Sciences Institute, provide additional data to better understand themodels' limitationsand sensitivity in identifying carcinogens. Theresultsof these alternativemodelstudieswerereviewed by members ofAssayWorkingGroups (AWG)composedofscientistsfromgovernmentand industrywith expertiseintoxicology,genetics,statistics,andpathology. The Tg.AC genetically manipulated

WILLIAM C. EASTIN; JOHN H. MENNEAR; RAY W. TENNANT; RAY E. STOLL; DAN G. BRANSTETTER; JOHN R. BUCHER; Bruce McCullough; ROBERT L. BINDER; JUDSON W. SPALDING; JOEL F. MAHLER

2001-01-01

277

Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations  

PubMed Central

Even though hematopoietic stem cell (HSC) dysfunction is presumed in myelodysplastic syndrome (MDS), the exact nature of quantitative and qualitative alterations is unknown. We conducted a study of phenotypic and molecular alterations in highly fractionated stem and progenitor populations in a variety of MDS subtypes. We observed an expansion of the phenotypically primitive long-term HSCs (lineage?/CD34+/CD38?/CD90+) in MDS, which was most pronounced in higher-risk cases. These MDS HSCs demonstrated dysplastic clonogenic activity. Examination of progenitors revealed that lower-risk MDS is characterized by expansion of phenotypic common myeloid progenitors, whereas higher-risk cases revealed expansion of granulocyte-monocyte progenitors. Genome-wide analysis of sorted MDS HSCs revealed widespread methylomic and transcriptomic alterations. STAT3 was an aberrantly hypomethylated and overexpressed target that was validated in an independent cohort and found to be functionally relevant in MDS HSCs. FISH analysis demonstrated that a very high percentage of MDS HSC (92% ± 4%) carry cytogenetic abnormalities. Longitudinal analysis in a patient treated with 5-azacytidine revealed that karyotypically abnormal HSCs persist even during complete morphologic remission and that expansion of clonotypic HSCs precedes clinical relapse. This study demonstrates that stem and progenitor cells in MDS are characterized by stage-specific expansions and contain epigenetic and genetic alterations.

Will, Britta; Zhou, Li; Vogler, Thomas O.; Ben-Neriah, Susanna; Schinke, Carolina; Tamari, Roni; Yu, Yiting; Bhagat, Tushar D.; Bhattacharyya, Sanchari; Barreyro, Laura; Heuck, Christoph; Mo, Yonkai; Parekh, Samir; McMahon, Christine; Pellagatti, Andrea; Boultwood, Jacqueline; Montagna, Cristina; Silverman, Lewis; Maciejewski, Jaroslaw; Greally, John M.; Ye, B. Hilda; List, Alan F.; Steidl, Christian

2012-01-01

278

Genetic alterations within the retinoblastoma locus in colorectal carcinomas. Relation to DNA ploidy pattern studied by flow cytometric analysis.  

PubMed Central

Alterations within the retinoblastoma (Rb) gene, as detected by the VNTR probe p68RS2.0, and flow cytometric DNA pattern have been analysed in 255 colorectal carcinomas. A total of 35.3% of the tumours had alterations within the Rb gene. Amplification of one allele was demonstrated in 29.5% of the tumours, and loss of heterozygosity was found in 11.5%. No association was found between amplification within the Rb gene and clinicopathological characteristics of the patients. The high frequency of alterations demonstrated within the Rb gene, suggests that this gene is involved in colorectal carcinogenesis with amplification as by far the most abundant genetic alteration. This may imply that the Rb gene has an oncogene-like function in colorectal carcinomas, rather than acting as a tumour suppressor gene. Sixty-three per cent of the carcinomas were DNA aneuploid, and a significant association was demonstrated between amplification within the Rb gene and DNA aneuploidy (P less than 0.01). Two other chromosome loci were analysed, on chromosome 1p (probe pYNZ2) and on chromosome 2p (probe pYNH24), respectively. On chromosome 1p, heterozygous loss was found in 22.2% of the tumours, indicating an involvement of this chromosome in a subset of colorectal carcinomas. Images Figure 1

Meling, G. I.; Lothe, R. A.; B?rresen, A. L.; Hauge, S.; Graue, C.; Clausen, O. P.; Rognum, T. O.

1991-01-01

279

Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations.  

PubMed

Even though hematopoietic stem cell (HSC) dysfunction is presumed in myelodysplastic syndrome (MDS), the exact nature of quantitative and qualitative alterations is unknown. We conducted a study of phenotypic and molecular alterations in highly fractionated stem and progenitor populations in a variety of MDS subtypes. We observed an expansion of the phenotypically primitive long-term HSCs (lineage(-)/CD34(+)/CD38(-)/CD90(+)) in MDS, which was most pronounced in higher-risk cases. These MDS HSCs demonstrated dysplastic clonogenic activity. Examination of progenitors revealed that lower-risk MDS is characterized by expansion of phenotypic common myeloid progenitors, whereas higher-risk cases revealed expansion of granulocyte-monocyte progenitors. Genome-wide analysis of sorted MDS HSCs revealed widespread methylomic and transcriptomic alterations. STAT3 was an aberrantly hypomethylated and overexpressed target that was validated in an independent cohort and found to be functionally relevant in MDS HSCs. FISH analysis demonstrated that a very high percentage of MDS HSC (92% ± 4%) carry cytogenetic abnormalities. Longitudinal analysis in a patient treated with 5-azacytidine revealed that karyotypically abnormal HSCs persist even during complete morphologic remission and that expansion of clonotypic HSCs precedes clinical relapse. This study demonstrates that stem and progenitor cells in MDS are characterized by stage-specific expansions and contain epigenetic and genetic alterations. PMID:22753872

Will, Britta; Zhou, Li; Vogler, Thomas O; Ben-Neriah, Susanna; Schinke, Carolina; Tamari, Roni; Yu, Yiting; Bhagat, Tushar D; Bhattacharyya, Sanchari; Barreyro, Laura; Heuck, Christoph; Mo, Yonkai; Parekh, Samir; McMahon, Christine; Pellagatti, Andrea; Boultwood, Jacqueline; Montagna, Cristina; Silverman, Lewis; Maciejewski, Jaroslaw; Greally, John M; Ye, B Hilda; List, Alan F; Steidl, Christian; Steidl, Ulrich; Verma, Amit

2012-09-01

280

Genetic alterations and growth pattern in biliary duct carcinomas: loss of heterozygosity at chromosome 5q bears a close relation with polypoid growth  

Microsoft Academic Search

Biliary duct carcinomas (BDCs) are relatively rare and the carcinogenic mechanisms underlying their induction are poorly understood. There are two growth patterns, polypoid and non-polypoid infiltrative type, but little information is available concerning the relation between growth pattern and genetic alterations. A comparative study was therefore conducted to clarify if differences in genetic changes, including loss of heterozygosity (LOH) at

E Hidaka; A Yanagisawa; M Seki; T Setoguchi; Y Kato

2001-01-01

281

A herpesvirus genetic element which affects translation in the absence of the viral GADD34 function.  

PubMed Central

Novel suppressor variants of conditionally lethal HSV-1 gamma34.5 deletion mutants have been isolated which exhibit restored ability to grow on neoplastic neuronal cells. Deletion of the viral gamma34.5 genes, whose products share functional similarity with the cellular GADD34 gene, renders the virus non-neurovirulent and imposes a block to viral replication in neuronal cells. Protein synthesis ceases at late times post-infection and the translation initiation factor eIF2alpha is phosphorylated by the cellular PKR kinase [Chou et al. (1990) Science, 252, 1262-1266; (1995) Proc. Natl Acad. Sci. USA, 92, 10516-10520]. The suppressor mutants have overcome the translational block imposed by PKR. Multiple, independent isolates all contain rearrangements within a 595 bp element in the HSV-1 genome where the unique short component joins the terminal repeats. This alteration, which affects the production of the viral mRNA and protein from the Us11 and Us12 genes, is both necessary and sufficient to confer the suppressor phenotype on gamma34.5 mutant viruses. HSV-1 thus encodes a specific element which inhibits ongoing protein synthesis in the absence of the viral GADD34-like function. Since this inhibition involves the accumulation of phosphorylated eIF2alpha, the element identified by the suppressor mutations may be a discrete PKR activator. Activation of the PKR kinase thus does not proceed through a general, cellular 'antiviral' sensing mechanism. Instead, the virus deliberately activates PKR and encodes a separate function which selectively prevents the phosphorylation of at least one PKR target, eIF2alpha. The nature of this potential activator element, and how analogous cellular elements could affect PKR pathways which affect growth arrest and differentiation are discussed. Images

Mohr, I; Gluzman, Y

1996-01-01

282

Modulation of polyamine metabolic flux in adipose tissue alters the accumulation of body fat by affecting glucose homeostasis.  

PubMed

The continued rise in obesity despite public education, awareness and policies indicates the need for mechanism-based therapeutic approaches to help control the disease. Our data, in conjunction with other studies, suggest an unexpected role for the polyamine catabolic enzyme spermidine/spermine-N1-acetyltransferase (SSAT) in fat homeostasis. Our previous studies showed that deletion of SSAT greatly exaggerates weight gain and that the transgenic overexpression suppresses weight gain in mice on a high-fat diet. This discovery is substantial but the underlying molecular linkages are only vaguely understood. Here, we used a comprehensive systems biology approach, on white adipose tissue (WAT), to discover that the partition of acetyl-CoA towards polyamine catabolism alters glucose homeostasis and hence, fat accumulation. Comparative proteomics and antibody-based expression studies of WAT in SSAT knockout, wild type and transgenic mice identified nine proteins with an increasing gradient across the genotypes, all of which correlate with acetyl-CoA consumption in polyamine acetylation. Adipose-specific SSAT knockout mice and global SSAT knockout mice on a high-fat diet exhibited similar growth curves and proteomic patterns in their WAT, confirming that attenuated consumption of acetyl-CoA in acetylation of polyamines in adipose tissue drives the obese phenotype of these mice. Analysis of protein expression indicated that the identified changes in the levels of proteins regulating acetyl-CoA consumption occur via the AMP-activated protein kinase pathway. Together, our data suggest that differential expression of SSAT markedly alters acetyl-CoA levels, which in turn trigger a global shift in glucose metabolism in adipose tissue, thus affecting the accumulation of body fat. PMID:23881108

Liu, Chunli; Perez-Leal, Oscar; Barrero, Carlos; Zahedi, Kamyar; Soleimani, Manoocher; Porter, Carl; Merali, Salim

2014-03-01

283

Genetic risk for Parkinson's disease correlates with alterations in neuronal manganese sensitivity between two human subjects.  

PubMed

Manganese (Mn) is an environmental risk factor for Parkinson's disease (PD). Recessive inheritance of PARK2 mutations is strongly associated with early onset PD (EOPD). It is widely assumed that the influence of PD environmental risk factors may be enhanced by the presence of PD genetic risk factors in the genetic background of individuals. However, such interactions may be difficult to predict owing to the complexities of genetic and environmental interactions. Here we examine the potential of human induced pluripotent stem (iPS) cell-derived early neural progenitor cells (NPCs) to model differences in Mn neurotoxicity between a control subject (CA) with no known PD genetic risk factors and a subject (SM) with biallelic loss-of-function mutations in PARK2 and family history of PD but no evidence of PD by neurological exam. Human iPS cells were generated from primary dermal fibroblasts of both subjects. We assessed several outcome measures associated with Mn toxicity and PD. No difference in sensitivity to Mn cytotoxicity or mitochondrial fragmentation was observed between SM and CA NPCs. However, we found that Mn exposure was associated with significantly higher reactive oxygen species (ROS) generation in SM compared to CA NPCs despite significantly less intracellular Mn accumulation. Thus, this report offers the first example of human subject-specific differences in PD-relevant environmental health related phenotypes that are consistent with pathogenic interactions between known genetic and environmental risk factors for PD. PMID:23099318

Aboud, Asad A; Tidball, Andrew M; Kumar, Kevin K; Neely, M Diana; Ess, Kevin C; Erikson, Keith M; Bowman, Aaron B

2012-12-01

284

History of oilseed rape cropping and geographic origin affect the genetic structure of Plasmodiophora brassicae populations.  

PubMed

The soilborne pathogen Plasmodiophora brassicae causes clubroot on Brassica crops, a common disease in many oilseed rape growing regions. Here, we investigate genetic diversity and geographic differentiation of P. brassicae populations from different regions in Germany. We compared three regions that differ in oilseed rape cropping history, oilseed rape acreage, and incidence of clubroot. These regions were either spatially separated or separated by the former inner German border. Plasmodiophora isolates were collected from 59 fields (29, 17, and 13 fields per region, respectively) and 174 amplified fragment length polymorphism (AFLP) markers were analyzed. Every field isolate showed a unique genotype pattern; that is, no genotype was shared among the regions and different fields. The mean gene diversity was 0.27, suggesting that P. brassicae is a genetically diverse species. The comparison of indexes (gene diversity, genotypic diversity, and linkage disequilibrium) between the regions does not support our hypotheses that cropping history, oilseed rape acreage, and incidence of clubroot affect these estimates. Principal component analysis (PCA), fixation index (FST), and generalized linear model (GLM) were suitable to specify regional differences. PCA revealed two clusters of isolates based on the geographic origin of the isolates and FST showed that these clusters were highly differentiated. Hypotheses about association of genotypes with different spatial scales were tested with GLM: the region, reflecting the cropping history, and the individual field had a significant effect on the AFLP pattern. We propose that individual field isolates represent a discrete population and that geographic differentiation results from low levels of gene flow due to the limited dispersal of this soilborne pathogen and from localized selection pressure as unifying force on the genotypes. PMID:24261407

Strehlow, Becke; de Mol, Friederike; Struck, Christine

2014-05-01

285

Genetic background alters the spectrum of tumors that develop in p53-deficient mice  

Microsoft Academic Search

ABSTRACT,Using,gene,targeting,in embryonic,stem cells, we have generated mice with one or two null pSS germ,line alleles. Mice with both p53 alleles inactivated are,developmentally,normal,but highly susceptible to the early development,of spontaneous,tumors. Initial studies were,performed,in mice,with,a mixed,inbred,genetic background,(75% C57BL\\/6 and,25% 129\\/Sv) (Done- hower et al., Nature (London) 356, 215-221, 1992). To study the effect of genetic background,on tumorigenesis in p53-deficient mice, we have

LAWRENCE A. DONEHOWER; UUMMUNIUAI IUNS

286

Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome  

PubMed Central

Recently, mutations of the additional sex comb-like 1 (ASXL1) gene were identified in patients with myelodysplastic syndrome (MDS), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, ASXL1 mutations were identified in 106 (22.7%) of the 466 patients with primary MDS based on the French-American-British (FAB) classification and 62 (17.1%) of the 362 patients based on the World Health Organization (WHO) classification. ASXL1 mutation was closely associated with trisomy 8 and mutations of RUNX1, EZH2, IDH, NRAS, JAK2, SETBP1 and SRSF2, but was negatively associated with SF3B1 mutation. Most ASXL1-mutated patients (85%) had concurrent other gene mutations at diagnosis. ASXL1 mutation was an independent poor prognostic factor for survival. Sequential studies showed that the original ASXL1 mutation remained unchanged at disease progression in all 32 ASXL1-mutated patients but were frequently accompanied with acquisition of mutations of other genes, including RUNX1, NRAS, KRAS, SF3B1, SETBP1 and chromosomal evolution. On the other side, among the 80 ASXL1-wild patients, only one acquired ASXL1 mutation at leukemia transformation. In conclusion, ASXL1 mutations in association with other genetic alterations may have a role in the development of MDS but contribute little to disease progression.

Chen, T-C; Hou, H-A; Chou, W-C; Tang, J-L; Kuo, Y-Y; Chen, C-Y; Tseng, M-H; Huang, C-F; Lai, Y-J; Chiang, Y-C; Lee, F-Y; Liu, M-C; Liu, C-W; Liu, C-Y; Yao, M; Huang, S-Y; Ko, B-S; Hsu, S-C; Wu, S-J; Tsay, W; Chen, Y-C; Tien, H-F

2014-01-01

287

Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome.  

PubMed

Recently, mutations of the additional sex comb-like 1 (ASXL1) gene were identified in patients with myelodysplastic syndrome (MDS), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, ASXL1 mutations were identified in 106 (22.7%) of the 466 patients with primary MDS based on the French-American-British (FAB) classification and 62 (17.1%) of the 362 patients based on the World Health Organization (WHO) classification. ASXL1 mutation was closely associated with trisomy 8 and mutations of RUNX1, EZH2, IDH, NRAS, JAK2, SETBP1 and SRSF2, but was negatively associated with SF3B1 mutation. Most ASXL1-mutated patients (85%) had concurrent other gene mutations at diagnosis. ASXL1 mutation was an independent poor prognostic factor for survival. Sequential studies showed that the original ASXL1 mutation remained unchanged at disease progression in all 32 ASXL1-mutated patients but were frequently accompanied with acquisition of mutations of other genes, including RUNX1, NRAS, KRAS, SF3B1, SETBP1 and chromosomal evolution. On the other side, among the 80 ASXL1-wild patients, only one acquired ASXL1 mutation at leukemia transformation. In conclusion, ASXL1 mutations in association with other genetic alterations may have a role in the development of MDS but contribute little to disease progression. PMID:24442206

Chen, T-C; Hou, H-A; Chou, W-C; Tang, J-L; Kuo, Y-Y; Chen, C-Y; Tseng, M-H; Huang, C-F; Lai, Y-J; Chiang, Y-C; Lee, F-Y; Liu, M-C; Liu, C-W; Liu, C-Y; Yao, M; Huang, S-Y; Ko, B-S; Hsu, S-C; Wu, S-J; Tsay, W; Chen, Y-C; Tien, H-F

2014-01-01

288

Does Wheat Genetically Modified for Disease Resistance Affect Root-Colonizing Pseudomonads and Arbuscular Mycorrhizal Fungi?  

PubMed Central

This study aimed to evaluate the impact of genetically modified (GM) wheat with introduced pm3b mildew resistance transgene, on two types of root-colonizing microorganisms, namely pseudomonads and arbuscular mycorrhizal fungi (AMF). Our investigations were carried out in field trials over three field seasons and at two locations. Serial dilution in selective King's B medium and microscopy were used to assess the abundance of cultivable pseudomonads and AMF, respectively. We developed a denaturing gradient gel electrophoresis (DGGE) method to characterize the diversity of the pqqC gene, which is involved in Pseudomonas phosphate solubilization. A major result was that in the first field season Pseudomonas abundances and diversity on roots of GM pm3b lines, but also on non-GM sister lines were different from those of the parental lines and conventional wheat cultivars. This indicates a strong effect of the procedures by which these plants were created, as GM and sister lines were generated via tissue cultures and propagated in the greenhouse. Moreover, Pseudomonas population sizes and DGGE profiles varied considerably between individual GM lines with different genomic locations of the pm3b transgene. At individual time points, differences in Pseudomonas and AMF accumulation between GM and control lines were detected, but they were not consistent and much less pronounced than differences detected between young and old plants, different conventional wheat cultivars or at different locations and field seasons. Thus, we conclude that impacts of GM wheat on plant-beneficial root-colonizing microorganisms are minor and not of ecological importance. The cultivation-independent pqqC-DGGE approach proved to be a useful tool for monitoring the dynamics of Pseudomonas populations in a wheat field and even sensitive enough for detecting population responses to altered plant physiology.

Foetzki, Andrea; Luginbuhl, Carolin; Winzeler, Michael; Kneubuhler, Yvan; Matasci, Caterina; Mascher-Frutschi, Fabio; Kalinina, Olena; Boller, Thomas; Keel, Christoph; Maurhofer, Monika

2013-01-01

289

Array comparative genomic hybridization-based characterization of genetic alterations in pulmonary neuroendocrine tumors  

PubMed Central

The goal of this study was to characterize and classify pulmonary neuroendocrine tumors based on array comparative genomic hybridization (aCGH). Using aCGH, we performed karyotype analysis of 33 small cell lung cancer (SCLC) tumors, 13 SCLC cell lines, 19 bronchial carcinoids, and 9 gastrointestinal carcinoids. In contrast to the relatively conserved karyotypes of carcinoid tumors, the karyotypes of SCLC tumors and cell lines were highly aberrant. High copy number (CN) gains were detected in SCLC tumors and cell lines in cytogenetic bands encoding JAK2, FGFR1, and MYC family members. In some of those samples, the CN of these genes exceeded 100, suggesting that they could represent driver alterations and potential drug targets in subgroups of SCLC patients. In SCLC tumors, as well as bronchial carcinoids and carcinoids of gastrointestinal origin, recurrent CN alterations were observed in 203 genes, including the RB1 gene and 59 microRNAs of which 51 locate in the DLK1-DIO3 domain. These findings suggest the existence of partially shared CN alterations in these tumor types. In contrast, CN alterations of the TP53 gene and the MYC family members were predominantly observed in SCLC. Furthermore, we demonstrated that the aCGH profile of SCLC cell lines highly resembles that of clinical SCLC specimens. Finally, by analyzing potential drug targets, we provide a genomics-based rationale for targeting the AKT-mTOR and apoptosis pathways in SCLC.

Voortman, Johannes; Lee, Jih-Hsiang; Killian, Jonathan Keith; Suuriniemi, Miia; Wang, Yonghong; Lucchi, Marco; Smith, William I.; Meltzer, Paul; Wang, Yisong; Giaccone, Giuseppe

2010-01-01

290

Altered sucrose synthase and invertase expression affects the local and systemic sugar metabolism of nematode-infected Arabidopsis thaliana plants  

PubMed Central

Sedentary endoparasitic nematodes of plants induce highly specific feeding cells in the root central cylinder. From these, the obligate parasites withdraw all required nutrients. The feeding cells were described as sink tissues in the plant’s circulation system that are supplied with phloem-derived solutes such as sugars. Currently, there are several publications describing mechanisms of sugar import into the feeding cells. However, sugar processing has not been studied so far. Thus, in the present work, the roles of the sucrose-cleaving enzymes sucrose synthases (SUS) and invertases (INV) in the development of Heterodera schachtii were studied. Gene expression analyses indicate that both enzymes are regulated transcriptionally. Nematode development was enhanced on multiple INV and SUS mutants. Syncytia of these mutants were characterized by altered enzyme activity and changing sugar pool sizes. Further, the analyses revealed systemically affected sugar levels and enzyme activities in the shoots of the tested mutants, suggesting changes in the source–sink relationship. Finally, the development of the root-knot nematode Meloidogyne javanica was studied in different INV and SUS mutants and wild-type Arabidopsis plants. Similar effects on the development of both sedentary endoparasitic nematode species (root-knot and cyst nematode) were observed, suggesting a more general role of sucrose-degrading enzymes during plant–nematode interactions.

Hofmann, Julia

2014-01-01

291

Altered sucrose synthase and invertase expression affects the local and systemic sugar metabolism of nematode-infected Arabidopsis thaliana plants.  

PubMed

Sedentary endoparasitic nematodes of plants induce highly specific feeding cells in the root central cylinder. From these, the obligate parasites withdraw all required nutrients. The feeding cells were described as sink tissues in the plant's circulation system that are supplied with phloem-derived solutes such as sugars. Currently, there are several publications describing mechanisms of sugar import into the feeding cells. However, sugar processing has not been studied so far. Thus, in the present work, the roles of the sucrose-cleaving enzymes sucrose synthases (SUS) and invertases (INV) in the development of Heterodera schachtii were studied. Gene expression analyses indicate that both enzymes are regulated transcriptionally. Nematode development was enhanced on multiple INV and SUS mutants. Syncytia of these mutants were characterized by altered enzyme activity and changing sugar pool sizes. Further, the analyses revealed systemically affected sugar levels and enzyme activities in the shoots of the tested mutants, suggesting changes in the source-sink relationship. Finally, the development of the root-knot nematode Meloidogyne javanica was studied in different INV and SUS mutants and wild-type Arabidopsis plants. Similar effects on the development of both sedentary endoparasitic nematode species (root-knot and cyst nematode) were observed, suggesting a more general role of sucrose-degrading enzymes during plant-nematode interactions. PMID:24187419

Cabello, Susana; Lorenz, Cindy; Crespo, Sara; Cabrera, Javier; Ludwig, Roland; Escobar, Carolina; Hofmann, Julia

2014-01-01

292

Paraoxonase-1 is not affected in polycystic ovary syndrome without metabolic syndrome and insulin resistance, but oxidative stress is altered.  

PubMed

Paraoxonase-1 (PON1) activity is decreased in polycystic ovary syndrome (PCOS) having metabolic syndrome (MetS) or insulin resistance (IR). We aimed to assess PON1 activity and oxidative stress in PCOS without MetS or IR. Metabolic and hormonal parameters, high-sensitive C-reactive protein (hs-CRP), oxidative stress parameters (total antioxidant status (TAS), total oxidative stress (TOS), oxidative stress index (OSI), lipid hydroperoxide (LOOH), total free sulfhydryl (--SH) groups), PON and arylesterase were analyzed in 30 normal weighed patients with PCOS without MetS or IR and 20 normal controls. Hs-CRP, PON, arylesterase, and TAS levels of PCOS and control groups were similar. LOOH, TOS, and OSI of PCOS group were higher than in the controls (p < 0.05; p < 0.001, and p < 0.001, respectively). - SH group levels showed a positive correlation with free testosterone (fT). TOS positively correlated with free androgen index (FAI), body mass index (BMI), waist-to-hip ratio (WHR), LOOH, and OSI. This study showed that oxidative stress is increased in PCOS even in the absence of MetS or IR. PON1 activity appears not to be affected in PCOS without MetS and IR. Several metabolic and antropometric risk factors may aggravate this altered oxidative state in PCOS. PMID:21557696

Torun, Ayse Nur; Vural, Mehmet; Cece, Hasan; Camuzcuoglu, Hakan; Toy, Harun; Aksoy, Nurten

2011-12-01

293

Detection of Genetic Alterations in Breast Sentinel Lymph Node by Array- CGH.  

National Technical Information Service (NTIS)

The sentinel lymph node (SLN) is the first node in the mammary gland to harbor malignant cells in breast tumors with metastasis, and SLN positivity is an indication for axillary lymph node dissection. The purpose of our study is to identify specific genet...

L. R. Cavalli

2006-01-01

294

Homeostasis of Synaptic Transmission in Drosophila with Genetically Altered Nerve Terminal Morphology  

Microsoft Academic Search

We present a new test of the hypothesis that synaptic strength is directly related to nerve terminal morphology through analy- sis of synaptic transmission at Drosophila neuromuscular junc- tions with a genetically reduced number of nerve terminal var- icosities. Synaptic transmission would decrease in target cells with fewer varicosities if there is a relationship between the number of varicosities and

Bryan A. Stewart; Christoph M. Schuster; Corey S. Goodman; Harold L. Atwood

1996-01-01

295

Comparison of genetic alterations in colonic adenoma and ulcerative colitis-associated dysplasia and carcinoma  

Microsoft Academic Search

Carcinoma is an important complication of ulcerative colitis (UC) and develops from dysplastic precursor lesions. Genetic changes involved in the malignant transformation have not been fully characterized. We studied 19 cases of UC with high-grade dysplasia (HGD) and eight samples of associated carcinoma (CA). Microdissection of normal epithelium, epithelium at the site of chronic inflammation, HGD, and CA was performed.

Franz Fogt; Alexander O Vortmeyer; Harvey Goldman; Thomas J Giordano; Maria J Merino; Zhengping Zhuang

1998-01-01

296

Alterations in Homocysteine Metabolism Among Alcohol Dependent Patients - Clinical, Pathobiochemical and Genetic Aspects  

Microsoft Academic Search

Addiction research focusing on homocysteine metabolism and its association with aspects of alcohol dependence has revealed important findings. Recent literature on this topic has been taken into account for the review provided. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the homocysteine metabolism. Plasma homocysteine levels are influenced by the single-nucleotide polymorphism (SNP) MTHFR C677T. Besides genetic factors, environ- mental

Ulrich C. Lutz

2008-01-01

297

Functional and Structural Alterations of the Intraparietal Sulcus in a Developmental Dyscalculia of Genetic Origin  

Microsoft Academic Search

Cognitive theories of numerical representation suggest that understanding of numerical quantities is driven by a magnitude representation associated with the intraparietal sulcus and possibly under genetic control. The aim of this study was to investigate, using fMRI and structural imaging, the interaction between the abnormal development of numerical representation in an X-linked condition, Turner syndrome (TS), and the development of

Nicolas Molko; Arnaud Cachia; Denis Rivière; Jean-François Mangin; Marie Bruandet; Denis Le Bihan; Laurent Cohen; Stanislas Dehaene

2003-01-01

298

The hyperactive syndrome: Metanalysis of genetic alterations, pharmacological treatments and brain lesions which increase locomotor activity  

Microsoft Academic Search

The large number of transgenic mice realized thus far with different purposes allows addressing new questions, such as which animals, over the entire set of transgenic animals, show a specific behavioural abnormality. In the present study, we have used a metanalytical approach to organize a database of genetic modifications, brain lesions and pharmacological interventions that increase locomotor activity in animal

Davide Viggiano

2008-01-01

299

Detection of Genetic Alterations in Breast Sentinel Lymph Node by Array- CGH.  

National Technical Information Service (NTIS)

The sentinel lymph node (SLN) is the first node in the mammary gland to harbor malignant cells in breast tumors with metastasis, and SLN positivity is an indication for axillary lymph node dissection. The purpose of our study is to identify specific genet...

L. R. Cavalli

2005-01-01

300

Host plant genetics affect hidden ecological players: links among Populus , condensed tannins, and fungal endophyte infection  

Microsoft Academic Search

Recent studies have shown effects of host plant genetics on community and ecosystem processes, which makes understanding the impacts of genetically based traits on hidden or non-apparent organisms more important. Here we examined links among genetic variation in hybrid cottonwoods, plant phytochemistry, and twig fungal endophytes (i.e., a common hidden organism). We found three major patterns: (1) twig fungal endophyte

Joseph K. Bailey; Ron Deckert; Jennifer A. Schweitzer; Brian J. Rehill; Richard L. Lindroth; Catherine Gehring; Thomas G. Whitham

2005-01-01

301

PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context.  

PubMed

There has been increasing interest in the use of isoform-selective inhibitors of phosphatidylinositide-3-kinase (PI3K) in cancer therapy. Using conditional deletion of the p110 catalytic isoforms of PI3K to predict sensitivity of cancer types to such inhibitors, we and others have demonstrated that tumors deficient of the phosphatase and tensin homolog (PTEN) are often dependent on the p110? isoform of PI3K. Because human cancers usually arise due to multiple genetic events, determining whether other genetic alterations might alter the p110 isoform requirements of PTEN-null tumors becomes a critical question. To investigate further the roles of p110 isoforms in PTEN-deficient tumors, we used a mouse model of ovarian endometrioid adenocarcinoma driven by concomitant activation of the rat sarcoma protein Kras, which is known to activate p110?, and loss of PTEN. In this model, ablation of p110? had no effect on tumor growth, whereas p110? ablation blocked tumor formation. Because ablation of PTEN alone is often p110? dependent, we wondered if the same held true in the ovary. Because PTEN loss alone in the ovary did not result in tumor formation, we tested PI3K isoform dependence in ovarian surface epithelium (OSE) cells deficient in both PTEN and p53. These cells were indeed p110? dependent, whereas OSEs expressing activated Kras with or without PTEN loss were p110? dependent. Furthermore, isoform-selective inhibitors showed a similar pattern of the isoform dependence in established Kras(G12D)/PTEN-deficient tumors. Taken together, our data suggest that, whereas in some tissues PTEN-null tumors appear to inherently depend on p110?, the p110 isoform reliance of PTEN-deficient tumors may be altered by concurrent mutations that activate p110?. PMID:24737887

Schmit, Fabienne; Utermark, Tamara; Zhang, Sen; Wang, Qi; Von, Thanh; Roberts, Thomas M; Zhao, Jean J

2014-04-29

302

Genetic background affects susceptibility to mammary hyperplasias and carcinomas in Apc(min)/+ mice.  

PubMed

Treatment of female C57BL/6J (B6) mice carrying the mutant Min allele of the adenomatous polyposis coli (Apc) gene with ethylnitrosourea (ENU) results in approximately 90% of mice developing an average of three mammary tumors within 65 days. As a first step in the identification of loci modifying susceptibility to ENU-induced mammary tumors and hyperplasias, we have tested ENU-treated Apc(Min)/+ (Min/+) mice on several hybrid backgrounds for susceptibility to mammary and intestinal tumors. C57BR/cdJxB6 (BRB6) Min/+ mice were more sensitive to development of mammary squamous cell carcinomas than B6 Min/+ mice. In contrast, Min/+ hybrids between B6 and FVB/NTac (FVB), 129X1/SvJ (129X1), and 129S6/SvEvTac (129S6) were all significantly more resistant to mammary carcinoma development. However, mice from these three crosses developed more focal mammary hyperplasias than did the B6 or BRB6 Min/+ mice. Susceptibility to intestinal tumors was independent of mammary tumor susceptibility in most hybrids. These results indicate that genetic background can affect independently the phenotypes conferred by the Min allele of APC: PMID:11309311

Moser, A R; Hegge, L F; Cardiff, R D

2001-04-15

303

A logistic regression mixture model for interval mapping of genetic trait loci affecting binary phenotypes.  

PubMed

Often in genetic research, presence or absence of a disease is affected by not only the trait locus genotypes but also some covariates. The finite logistic regression mixture models and the methods under the models are developed for detection of a binary trait locus (BTL) through an interval-mapping procedure. The maximum-likelihood estimates (MLEs) of the logistic regression parameters are asymptotically unbiased. The null asymptotic distributions of the likelihood-ratio test (LRT) statistics for detection of a BTL are found to be given by the supremum of a chi2-process. The limiting null distributions are free of the null model parameters and are determined explicitly through only four (backcross case) or nine (intercross case) independent standard normal random variables. Therefore a threshold for detecting a BTL in a flanking marker interval can be approximated easily by using a Monte Carlo method. It is pointed out that use of a threshold incorrectly determined by reading off a chi2-probability table can result in an excessive false BTL detection rate much more severely than many researchers might anticipate. Simulation results show that the BTL detection procedures based on the thresholds determined by the limiting distributions perform quite well when the sample sizes are moderately large. PMID:16272416

Deng, Weiping; Chen, Hanfeng; Li, Zhaohai

2006-02-01

304

Mutants in three genes affecting transport of magnesium in Escherichia coli: genetics and physiology.  

PubMed Central

Mutants in three genes affecting two Mg2+ transport systems are described. System I, for which Co2+, Mn2+, and Mg2+ are substrates, is inactive in corA mutants corB mutants express system I after growth on high (10 mM) Mg2+ but not low (0.1 mM) Mg2+. Both corA and corB mutants are resistant to Co2+ or Mn2+. corA mutants are sensitive to CA2+. Transport system II is specific for Mg2+ and is repressed by growth on 10 mM Mg2+. mgt mutations inactivate system II. Growth on mgt mutants in normal except on very low (1 muM) concentrations of Mg2+, corA mgt strains exhibit no high-affinity, energy-dependent transport of Mg2+ and require 10 mM Mg2+ for optimal growth. The three genes are not linked. The corA locus is contransducible with ilv at 75 min, corB is cotransducible with pyrB at 85 min, and mgt is cotransducible with malB and mel at 81 min on the genetic map.

Park, M H; Wong, B B; Lusk, J E

1976-01-01

305

Mitochondrial genetic analyses suggest selection against maternal lineages in bipolar affective disorder.  

PubMed Central

Previous reports of preferential transmission of bipolar affective disorder (BP) from the maternal versus the paternal lines in families suggested that this disorder may be caused by mitochondrial DNA mutations. We have sequenced the mitochondrial genome in 25 BP patients with family histories of psychiatric disorder that suggest matrilineal inheritance. No polymorphism identified more than once in this sequencing showed any significant association with BP in association studies using 94 cases and 94 controls. To determine whether our BP sample showed evidence of selection against the maternal lineage, we determined genetic distances between all possible pairwise comparisons within the BP and control groups, based on multilocus mitochondrial polymorphism haplotypes. These analyses revealed fewer closely related haplotypes in the BP group than in the matched control group, suggesting selection against maternal lineages in this disease. Such selection is compatible with recurrent mitochondrial mutations, which are associated with slightly decreased fitness. Although such mismatch distribution comparisons have been used previously for analyses of population histories, this is, as far as we are aware, the first report of this method being used to study disease.

Kirk, R; Furlong, R A; Amos, W; Cooper, G; Rubinsztein, J S; Walsh, C; Paykel, E S; Rubinsztein, D C

1999-01-01

306

Citrus Leaf Volatiles as Affected by Developmental Stage and Genetic Type  

PubMed Central

Major volatiles from young and mature leaves of different citrus types were analyzed by headspace-solid phase microextraction (HS-SPME)-GC-MS. A total of 123 components were identified form nine citrus cultivars, including nine aldehydes, 19 monoterpene hydrocarbons, 27 oxygenated monoterpenes, 43 sesquiterpene hydrocarbons, eight oxygenated sesquiterpenes, two ketones, six esters and nine miscellaneous. Young leaves produced higher amounts of volatiles than mature leaves in most cultivars. The percentage of aldehyde and monoterpene hydrocarbons increased, whilst oxygenated monoterpenes and sesquiterpenes compounds decreased during leaf development. Linalool was the most abundant compound in young leaves, whereas limonene was the chief component in mature ones. Notably, linalool content decreased, while limonene increased, during leaf development in most cultivars. Leaf volatiles were also affected by genetic types. A most abundant volatile in one or several genotypes can be absent in another one(s), such as limonene in young leaves of lemon vs. Satsuma mandarin and ?-terpinene in mature leaves of three genotypes vs. the other four. Compositional data was subjected to multivariate statistical analysis, and variations in leaf volatiles were identified and clustered into six groups. This research determining the relationship between production of major volatiles from different citrus varieties and leaf stages could be of use for industrial and culinary purposes.

Azam, Muhammad; Jiang, Qian; Zhang, Bo; Xu, Changjie; Chen, Kunsong

2013-01-01

307

Statistics of Scientific Procedures on Living Animals 2012: another increase in experimentation - genetically-altered animals dominate again.  

PubMed

The Annual Statistics of Scientific Procedures on Living Animals Great Britain 2012 reveal that the level of animal experimentation in Great Britain continues to rise, with just over 4.1 million procedures being started in that year. Despite the previous year's indication that the dominance of the production and use of genetically-altered (GA, i.e. genetically-modified animals plus animals with harmful genetic defects) animal might be abating, it returned with a vengeance in 2012. Breeding increased from 43% to 48% of all procedures, and GA animals were involved in 59% of all the procedures. Indeed, if the breeding of these animals were removed from the statistics, the total number of procedures would actually decline by 2%. In order to honour their pledge to reduce animal use in science, the Coalition Government will have to address this issue. The general trends in the species used, and the numbers and types of procedures, are also reviewed. Finally, forthcoming changes to the statistics are discussed. PMID:24168136

Hudson-Shore, Michelle

2013-09-01

308

Genetic Alterations of the p53 Gene Are a Feature of Malignant Mesotheliomas1  

Microsoft Academic Search

A putative tumor suppressor gene, p53, has been shown to be altered in a variety of human tumor types. The primary mechanism of p53 inactivation is believed to be mutation of one alíele followed by loss of the second alíele.Malignant mesothelioma is a tumor that has been highly associated with exposure to asbestos fibers, which are known to cause chromosomal

Richard J. Cote; Suresh C. Jhanwar; Steve Novick; Angel Pellicer

1991-01-01

309

Genetic Alteration of the c-myc Protooncogene (MYC) in Human Primary Breast Carcinomas  

Microsoft Academic Search

We have studied the genomic organization of the c-myc locus (MYC) from 121 human primary breast carcinomas. Two types of alterations were observed: (i) the c-myc protooncogene appeared to be amplified 2- to 15-fold in 38 (32%) of the carcinoma DNAs and (ii) a non-germ-line c-myc-related fragment of variable size was detected in 5 primary breast carcinoma DNAs. With three

Chantal Escot; Charles Theillet; Rosette Lidereau; Frederique Spyratos; Marie-Helene Champeme; Jean Gest; Robert Callahan

1986-01-01

310

Transgenerational carcinogenesis: induction and transmission of genetic alterations and mechanisms of carcinogenesis  

Microsoft Academic Search

Parental exposure, i.e. germ cell exposure to radiation and chemicals, increased the incidence of tumors and malformations in the offspring, and the germ-line alterations that cause cancer are transmissible to further generations. However, tumor incidences were 100-fold higher than those of ordinary mouse mutations and there were apparent strain differences in the types of induced tumors. In human, higher risk

Taisei Nomura

2003-01-01

311

Genetic Variants of the Vitamin D Receptor Gene Alter Risk of Cutaneous Melanoma  

Microsoft Academic Search

Sunlight causes DNA damage but also induces production of vitamin D whose metabolite 1,25-(OH)2D3 has antiproliferative and pro-differentiative effects in both melanocytes and cutaneous melanoma (CM) cells mediated through the vitamin D receptor (VDR). We hypothesized that genetic polymorphisms of VDR are associated with risk of CM. In a hospital-based case–control study of 602 non-Hispanic white CM patients and 603

Chunying Li; Zhensheng Liu; Zhengdong Zhang; Sara S Strom; Jeffrey E Gershenwald; Victor G Prieto; Jeffrey E Lee; Merrick I Ross; Paul F Mansfield; Janice N Cormier; Madeleine Duvic; Elizabeth A Grimm; Qingyi Wei

2007-01-01

312

Genetic variants in multidrug and toxic compound extrusion-1, hMATE1, alter transport function  

Microsoft Academic Search

hMATE1 (human multidrug and toxin compound extrusion-1; encoded by SLC47A1) is thought to have an important function in the renal and hepatic elimination of drugs, endogenous compounds and environmental toxins. The goals of this study were to identify genetic variants of hMATE1 and to determine their effects on hMATE1 transport function. We identified four synonymous and six nonsynonymous, coding region

Ying Chen; Kristen Teranishi; Shuanglian Li; Sook Wah Yee; Stephanie Hesselson; Doug Stryke; Susan J Johns; Thomas E Ferrin; Pui Kwok; Kathleen M Giacomini

2009-01-01

313

Genetic variants of human organic anion transporter 4 demonstrate altered transport of endogenous substrates  

PubMed Central

Apical reabsorption from the urine has been shown to be important for such processes as the maintenance of critical metabolites in the blood and the excretion of nephrotoxic compounds. The solute carrier (SLC) transporter OAT4 (SLC22A11) is expressed on the apical membrane of renal proximal tubule cells and is known to mediate the transport of a variety of xenobiotic and endogenous organic anions. Functional characterization of genetic variants of apical transporters thought to mediate reabsorption, such as OAT4, may provide insight into the genetic factors influencing the complex pathways involved in drug elimination and metabolite reclamation occurring in the kidney. Naturally occurring genetic variants of OAT4 were identified in public databases and by resequencing DNA samples from 272 individuals comprising 4 distinct ethnic groups. Nine total nonsynonymous variants were identified and functionally assessed using uptake of three radiolabeled substrates. A nonsense variant, R48Stop, and three other variants (R121C, V155G, and V155M) were found at frequencies of at least 2% in an ethnic group specific fashion. The L29P, R48Stop, and H469R variants displayed a complete loss of function, and kinetic analysis identified a reduced Vmax in the common nonsynonymous variants. Plasma membrane levels of OAT4 protein were absent or reduced in the nonfunctional variants, providing a mechanistic reason for the observed loss of function. Characterization of the genetic variants of reabsorptive transporters such as OAT4 is an important step in understanding variability in tubular reabsorption with important implications in innate homeostatic processes and drug disposition.

Shima, James E.; Komori, Takafumi; Taylor, Travis R.; Stryke, Doug; Kawamoto, Michiko; Johns, Susan J.; Carlson, Elaine J.; Ferrin, Thomas E.

2010-01-01

314

Adaptive and genetic alterations of the renin angiotensin system in cardiac hypertrophy and failure.  

PubMed

The risk to suffer from cardiovascular events may be modulated, in part, by neurohormonal systems. Neurohormones such as angiotensin II or aldosterone may be activated secondary to congestive heart failure or in the course of an acute myocardial infarction. These systems, if activated, will subject the failing heart to increased hemodynamic load and, thus, further compromise cardiac function. In addition, structural changes of the heart and vessels occurring with pressure or volume overload may be amplified by the growth promoting effects of these agents. Taken together, the interaction of underlying cardiovascular disease and activated neurohormones may often determine clinical symptoms and prognosis. More recently, growing evidence suggests that the basal, genetically determined, activity of the renin angiotensin aldosterone system may relate to the development of cardiovascular disease as well. In particular, variants of the angiotensinogen and angiotensin converting enzyme genes have been associated with essential hypertension, myocardial infarction, or left ventricular hypertrophy. In this regard, the data suggest that the renin angiotensin aldosterone system may be one of the primary causes, rather than only a secondary co-factor, in the pathogenesis of these most important cardiovascular disorders. In light of the various options of pharmacological intervention, it seems important that ongoing clinical and molecular-genetic research will further define the role of the renin angiotensin system in clinical conditions or genetic risk profiles. PMID:8957547

Holmer, S R; Schunkert, H

1996-01-01

315

Development of a certified reference material for genetically modified potato with altered starch composition.  

PubMed

The presence of genetically modified organisms (GMOs) in food and feed products is subject to regulation in the European Union (EU) and elsewhere. As part of the EU authorization procedure for GMOs intended for food and feed use, reference materials must be produced for the quality control of measurements to quantify the GMOs. Certified reference materials (CRMs) are available for a range of herbicide- and insect-resistant genetically modified crops such as corn, soybean, and cotton. Here the development of the first CRM for a GMO that differs from its non-GMO counterpart in a major compositional constituent, that is, starch, is described. It is shown that the modification of the starch composition of potato (Solanum tuberosum L.) tubers, together with other characteristics of the delivered materials, have important consequences for the certification strategy. Moreover, the processing and characterization of the EH92-527-1 potato material required both new and modified procedures, different from those used routinely for CRMs produced from genetically modified seeds. PMID:17508757

Broothaerts, Wim; Corbisier, Philippe; Emons, Hendrik; Emteborg, Håkan; Linsinger, Thomas P J; Trapmann, Stefanie

2007-06-13

316

Genetic Alterations in the PI3K/Akt Signaling Pathway Confer Sensitivity of Thyroid Cancer Cells to Therapeutic Targeting of Akt and mTOR  

PubMed Central

We investigated the genotype-dependent therapeutic potential of targeting the PI3K/Akt pathway for thyroid cancer. Proliferation of TPC1, Hth7, FTC133, OCUT1, K1, and BCPAP cells that harbored PI3K/Akt-activating genetic alterations was potently inhibited by the Akt inhibitor perifosine whereas SW1736, Hth74, WRO, KAT18, and TAD2 cells that harbored no genetic alterations had no or only modest responses. Inhibition of Akt phosphorylation by perifosine was seen in these cells. Genetic-dependent apoptosis was induced by perifosine in cells selectively tested. Similarly, potent inhibition of cell proliferation by the mTOR inhibitor temsirolimus occurred in virtually all the cells harboring genetic alterations whereas modest inhibition was seen in some of the cells not harboring genetic alterations. Temsirolimus inhibited the phosphorylation of p70S6K, a substrate of mTOR. Knockdown of Akt1/2 or mTOR by shRNA approach inhibited the proliferation and colony formation of FTC133 and OCUT1 cells that harbored genetic alterations in the PI3K/Akt pathway but had no effect on SW1736 and KAT18 cells that did not. Transfection with PIK3CA mutants greatly sensitized SW1736 cells to perifosine and temsirolimus. Growth of xenograft tumors derived from FTC133 cells but not SW1736 cells in nude mice was dramatically inhibited by perifosine. Thus, this work for the first time demonstrates that genetic alterations in the PI3K/Akt pathway confer thyroid cancer cells addiction to this pathway and their sensitivity to inhibition by targeting Akt and mTOR. This genotype-based targeting of the PI3K/Akt pathway using Akt and mTOR inhibitors may offer an effective therapeutic strategy for thyroid cancer and warrants further studies.

Liu, Dingxie; Hou, Peng; Liu, Zhi; Wu, Guojun; Xing, Mingzhao

2009-01-01

317

Genetic alterations in the phosphoinositide 3-kinase/Akt signaling pathway confer sensitivity of thyroid cancer cells to therapeutic targeting of Akt and mammalian target of rapamycin.  

PubMed

We investigated the genotype-dependent therapeutic potential of targeting the phosphoinositide 3-kinase (PI3K)/Akt pathway for thyroid cancer. Proliferation of TPC1, Hth7, FTC133, OCUT1, K1, and BCPAP cells that harbored PI3K/Akt-activating genetic alterations was potently inhibited by the Akt inhibitor perifosine, whereas SW1736, Hth74, WRO, KAT18, and TAD2 cells that harbored no genetic alterations had no or only modest responses. Inhibition of Akt phosphorylation by perifosine was seen in these cells. Genetic-dependent apoptosis was induced by perifosine in cells selectively tested. Similarly, potent inhibition of cell proliferation by the mammalian target of rapamycin (mTOR) inhibitor temsirolimus occurred in virtually all the cells harboring genetic alterations, whereas modest inhibition was seen in some of the cells not harboring genetic alterations. Temsirolimus inhibited the phosphorylation of p70S6K, a substrate of mTOR. Knockdown of Akt1/2 or mTOR by shRNA approach inhibited the proliferation and colony formation of FTC133 and OCUT1 cells that harbored genetic alterations in the PI3K/Akt pathway but had no effect on SW1736 and KAT18 cells that did not. Transfection with PIK3CA mutants greatly sensitized SW1736 cells to perifosine and temsirolimus. Growth of xenograft tumors derived from FTC133 cells but not SW1736 cells in nude mice was dramatically inhibited by perifosine. Thus, this work for the first time shows that genetic alterations in the PI3K/Akt pathway confer thyroid cancer cells addiction to this pathway and their sensitivity to inhibition by targeting Akt and mTOR. This genotype-based targeting of the PI3K/Akt pathway using Akt and mTOR inhibitors may offer an effective therapeutic strategy for thyroid cancer and warrants further studies. PMID:19706758

Liu, Dingxie; Hou, Peng; Liu, Zhi; Wu, Guojun; Xing, Mingzhao

2009-09-15

318

Comparative xenobiotic metabolism between Tg.AC and p53+/- genetically altered mice and their respective wild types.  

PubMed

The use of transgenic animals, such as v-Ha-ras activated (TG:AC) and p53+/- mice, offers great promise for a rapid and more sensitive assay for chemical carcinogenicity. Some carcinogens are metabolically activated; therefore, it is critical that the altered genome of either of these model systems does not compromise their capability and capacity for metabolism of xenobiotics. The present work tests the generally held assumption that xenobiotic metabolism in the TG:AC and p53+/- mouse is not inherently different from that of the respective wild type, the FVB/N and C57BL/6 mouse, by comparing each genotype's ability to metabolize benzene, ethoxyquin, or methacrylonitrile. Use of these representative substrates offers the opportunity to examine arene oxide formation, aromatic ring opening, hydroxylation, epoxidation, O-deethylation, and a number of conjugation reactions. Mice were treated by gavage with (14)C-labeled parent compound, excreta were collected, and elimination routes and rates, as well as (14)C-derived metabolite profiles in urine, were compared between relevant treatment groups. Results of this study indicated that metabolism of the 3 parent compounds was not appreciably altered between either FVB/N and TG:AC mice or C57BL/6 and p53+/- mice. Further, expression of CYP1A2, CYP2E1, CYP3A, and GST-alpha in liver of naive genetically altered mice was similar to that of corresponding wild-type mice. Thus, these results suggest that the inherent ability of TG:AC and p53+/- mice to metabolize xenobiotics is not compromised by their altered genomes and would not be a factor in data interpretation of toxicity studies using either transgenic mouse line. PMID:11294974

Sanders, J M; Burka, L T; Chanas, B; Matthews, H B

2001-05-01

319

QTL mapping reveals the genetic architecture of loci affecting pre- and post-zygotic isolating barriers in Louisiana Iris  

PubMed Central

Background Hybridization among Louisiana Irises has been well established and the genetic architecture of reproductive isolation is known to affect the potential for and the directionality of introgression between taxa. Here we use co-dominant markers to identify regions where QTL are located both within and between backcross maps to compare the genetic architecture of reproductive isolation and fitness traits across treatments and years. Results QTL mapping was used to elucidate the genetic architecture of reproductive isolation between Iris fulva and Iris brevicaulis. Homologous co-dominant EST-SSR markers scored in two backcross populations between I. fulva and I. brevicaulis were used to generate genetic linkage maps. These were used as the framework for mapping QTL associated with variation in 11 phenotypic traits likely responsible for reproductive isolation and fitness. QTL were dispersed throughout the genome, with the exception of one region of a single linkage group (LG) where QTL for flowering time, sterility, and fruit production clustered. In most cases, homologous QTL were not identified in both backcross populations, however, homologous QTL for flowering time, number of growth points per rhizome, number of nodes per inflorescence, and number of flowers per node were identified on several linkage groups. Conclusions Two different traits affecting reproductive isolation, flowering time and sterility, exhibit different genetic architectures, with numerous QTL across the Iris genome controlling flowering time and fewer, less distributed QTL affecting sterility. QTL for traits affecting fitness are largely distributed across the genome with occasional overlap, especially on LG 4, where several QTL increasing fitness and decreasing sterility cluster. Given the distribution and effect direction of QTL affecting reproductive isolation and fitness, we have predicted genomic regions where introgression may be more likely to occur (those regions associated with an increase in fitness and unlinked to loci controlling reproductive isolation) and those that are less likely to exhibit introgression (those regions linked to traits decreasing fitness and reproductive isolation).

2012-01-01

320

Modifying metabolically sensitive histone marks by inhibiting glutamine metabolism affects gene expression and alters cancer cell phenotype  

PubMed Central

The interplay of metabolism and epigenetic regulatory mechanisms has become a focal point for a better understanding of cancer development and progression. In this study, we have acquired data supporting previous observations that demonstrate glutamine metabolism affects histone modifications in human breast cancer cell lines. Treatment of non-invasive epithelial (T-47D and MDA-MB-361) and invasive mesenchymal (MDA-MB-231 and Hs-578T) breast cancer cell lines with the glutaminase inhibitor, Compound 968, resulted in cytotoxicity in all cell lines, with the greatest effect being observed in MDA-MB-231 breast cancer cells. Compound 968-treatment induced significant downregulation of 20 critical cancer-related genes, the majority of which are anti-apoptotic and/or promote metastasis, including AKT, BCL2, BCL2L1, CCND1, CDKN3, ERBB2, ETS1, E2F1, JUN, KITLG, MYB, and MYC. Histone H3K4me3, a mark of transcriptional activation, was reduced at the promoters of all but one of these critical cancer genes. The decrease in histone H3K4me3 at global and gene-specific levels correlated with reduced expression of SETD1 and ASH2L, genes encoding the histone H3K4 methyltransferase complex. Further, the expression of other epigenetic regulatory genes, known to be downregulated during apoptosis (e.g., DNMT1, DNMT3B, SETD1 and SIRT1), was also downregulated by Compound 968. These changes in gene expression and histone modifications were accompanied by the activation of apoptosis, and decreased invasiveness and resistance of MDA-MB-231 cells to chemotherapeutic drug doxorubicin. The results of this study provide evidence to a link between cytotoxicity caused by inhibiting glutamine metabolism with alterations of the epigenome of breast cancer cells and suggest that modification of intracellular metabolism may enhance the efficiency of epigenetic therapy.

Simpson, Natalie E.; Tryndyak, Volodymyr P.; Pogribna, Marta; Beland, Frederick A.; Pogribny, Igor P.

2012-01-01

321

Genetic alterations following ionizing radiation in human ovarian cancer?derived endothelial cells.  

PubMed

Recent studies have focused on the role of endothelial cells during tumor radiotherapy, and the majority of studies have found that the rate of endothelial cell apoptosis determines the response of the tumor to ionizing radiation treatment. However, gene expression changes in human ovarian cancer?derived endothelial cells in response to X?ray radiation remains poorly understood. The present study was conducted to investigate the radiation?induced gene alterations in human ovarian cancer?derived endothelial cells and to provide novel potential targets for combined anti?angiogenesis and radiation therapy for the treatment of human ovarian cancer. Ovarian cancer?derived endothelial cells, which were harvested from six human ovarian epithelial carcinomas prior to and 4 h after 400 cGy X?ray irradiation, were analyzed using cDNA microarray technology. Significant genes were selected to corroborate the microarray experiments using a quantitative polymerase chain reaction (qPCR). A total of 28 genes common to all the cDNA microarray results were identified, of which 22 genes were found to be consistently upregulated or downregulated. Thirteen genes were upregulated persistently and nine genes downregulated persistently following irradiation with 400 cGy X?ray in comparison with the matched group. The majority of the significantly altered genes (?2?fold change in expression) were found to have a role in vasculogenesis, cell cycle regulation, inflammation and the immune response, cell growth and apoptosis, nicotinamide metabolism, cell signaling, chemokines and cell adhesion. Eight randomly selected genes were corroborated using qPCR technology. Radiation?induced gene alterations in ovarian cancer?derived endothelial cells and gene?related pathways were associated with vasculogenesis and the radiosensitivity of human ovarian cancer, and may provide promising biomarkers for radiation and anti?angiogenesis treatments against ovarian carcinoma. PMID:24691555

Liu, Ting; Du, Xuelian; Sheng, Xiugui

2014-06-01

322

Next-generation sequencing analysis of lung and colon carcinomas reveals a variety of genetic alterations.  

PubMed

The development of targeted therapies in cancer has accelerated the development of molecular diagnosis. This new cancer discipline is booming, with an increasing number of gene alterations to analyze in a growing number of patients. To deal with this fast-developing activity, current analysis techniques (Sanger sequencing, allelic discrimination and high resolution melting) take more and more time. In recent years, next generation sequencing (NGS) technologies have appeared and given new perspectives in oncology. In this study, we analyzed FFPE lung and colon carcinomas using the Truseq Cancer Panel, which analyzes the mutation hotspots of 48 genes. We also tested the use of whole-genome amplification before NGS analysis. NGS results were compared with the data obtained from routine diagnosis. All of the alterations routinely observed were identified by NGS. Moreover, NGS revealed mutations in the KRAS and EGFR genes in patients diagnosed as wild-type by routine techniques. NGS also identified concomitant mutations in EGFR and KRAS or BRAF mutations, and a 15-nt deletion in exon 19 of EGFR in colon carcinomas. The study of the other genes sequenced in the Panel revealed 14 genes altered by 27 different mutations and three SNP with a possible role in cancer susceptibility or in the response to treatment. In conclusion, this study showed that NGS analysis could be used for the analysis of gDNA extracted from FFPE tissues. However, given the high sensitivity of this technology, high-throughput clinical trials are needed to confirm its reliability for the molecular diagnosis of cancer. PMID:24990411

Chevrier, Sandy; Arnould, Laurent; Ghiringhelli, François; Coudert, Bruno; Fumoleau, Pierre; Boidot, Romain

2014-09-01

323

Population-based study on incidence, survival rates, and genetic alterations of low-grade diffuse astrocytomas and oligodendrogliomas.  

PubMed

We carried out a population-based study on low-grade diffuse gliomas in the Canton of Zurich, Switzerland (population 1.16 million). From 1980 to 1994, 987 astrocytic and oligodendroglial tumors were diagnosed, of which 122 (12.4%) were low-grade (WHO grade II). The incidence rates adjusted to the World Standard Population, per million population per year, were 2.28 for low-grade diffuse astrocytomas, 0.89 for oligoastrocytomas, and 2.45 for oligodendrogliomas. The survival rate (mean follow-up 7.5+/-4.8 years) was highest for patients with oligodendroglioma (78% at 5 years, 51% at 10 years), followed by those with oligoastrocytoma (70% at 5 years, 49% at 10 years) and fibrillary astrocytoma (65% at 5 years, 31% at 10 years). Survival of patients with gemistocytic astrocytoma was poor, with survival rates of 16% at 5 years and 0% at 10 years. Younger patients (<50 years) survived significantly longer than older patients (>50 years; P=0.013). DNA sequencing, performed in 84% of cases, revealed that TP53 mutations were most frequent in gemistocytic astrocytomas (88%), followed by fibrillary astrocytomas (53%) and oligoastrocytomas (44%), but were infrequent (13%) in oligodendrogliomas. The presence of TP53 mutations was associated with shorter survival of patients with low-grade diffuse gliomas (log-rank test; P=0.047), but when each histological type was analyzed separately, an association was observed only for oligoastrocytoma ( P=0.05). Loss on 1p and 19q were assessed by quantitative microsatellite analysis in 67% of cases. These alterations were frequent in oligodendrogliomas (1p, 57%; 19q, 69%), less common in oligoastrocytomas (1p, 27%; 19q, 45%), rare in fibrillary astrocytomas (1p, 7%; 19q, 7%), and absent in gemistocytic astrocytomas. None of these alterations were predictive of survival. These results establish the frequency of key genetic alterations in low-grade diffuse gliomas at a population-based level. Multivariate Cox's regression analysis indicates that only age and histological type, but not genetic alterations, are significant predictive factors. PMID:15118874

Okamoto, Yoshikazu; Di Patre, Pier-Luigi; Burkhard, Christoph; Horstmann, Sonja; Jourde, Benjamin; Fahey, Michael; Schüler, Danielle; Probst-Hensch, Nicole M; Yasargil, M Gazi; Yonekawa, Yasuhiro; Lütolf, Urs M; Kleihues, Paul; Ohgaki, Hiroko

2004-07-01

324

Genetic alterations of chromosomes, p53 and p16 genes in low- and high-grade bladder cancer  

PubMed Central

A majority of patients with bladder cancer present with superficial disease and subsequently, some patients show progression to muscle invasive or metastatic disease. Bladder cancer has a complex genetic process and identification of the genetic alterations which occur during progression may lead to the understanding of the nature of the disease and provide the possibility of early treatment. The aim of the present study was to compare the structural and numerical chromosomal differences and changes in the p16 and p53 genes between low-grade (LG) and high-grade (HG) bladder cancer (BC) using cytogenetic and molecular cytogenetic methods. Between March 2009 and March 2010, cytogenetic analyses were carried out on tumor and blood samples in 34 patients with transitional cell type BC, and on blood samples of 34 healthy patients as a control group. Fluorescence in situ hybridization probes for the p16 and p53 genes were also used to screen the alterations in these genes in 32 patients with BC. The patients were divided into two groups (LG and HG) and the findings were compared. A total of 11 (32.3%) patients exhibited LGBC, 22 (64.7%) exhibited HGBC and one (3%) patient exhibited carcinoma in situ. There were no differences between the LGBC and HGBC groups according to the number of chromosomal aberrations (P=0.714); however, differences between alterations of the p16 and p53 genes were significant (P=0.002 and P=0.039). Almost all structural abnormalities were found to be located to the 1q21, 1q32, 3p21 and 5q31 regions in patients with HG tumors. In conclusion, the p16 and p53 genes were altered more prominently in patients with HG tumors compared with LG tumors. The structural abnormalities in the 1q21, 1q32, 3p21 and 5q31 regions were observed more frequently in patients with HG tumors. These regions may play significant roles in the progression of BC, but further studies are required to find candidate genes for a panel of BC.

ABAT, DENIZ; DEMIRHAN, OSMAN; INANDIKLIOGLU, NIHAL; TUNC, ERDAL; ERDOGAN, SEYDA; TASTEMIR, DENIZ; USLU, INAYET NUR; TANSUG, ZUHTU

2014-01-01

325

Impact of pathognomonic genetic alterations on the prognosis of papillary thyroid carcinoma  

Microsoft Academic Search

Introduction  BRAF mutations and RET or NTRK1 rearrangements were identified as causing events that drive the malignant transformation of\\u000a the thyroid follicular cell. The impact of these alterations on the course of papillary thyroid carcinoma (PTC) is still unsettled.\\u000a \\u000a \\u000a \\u000a \\u000a Patients and methods  Tumor tissues of 290 (98 male, 192 female) patients were intra-operatively snap frozen or harvested from archival paraffin-embedded\\u000a blocks and

Thomas J. Musholt; Sonja Schönefeld; Christina H. Schwarz; Felix M. Watzka; Petra B. Musholt; Christian Fottner; Matthias M. Weber; Erik Springer; Arno Schad

2010-01-01

326

Region-Specific Genetic Alterations in the Aging Hippocampus: Implications For Cognitive Aging  

PubMed Central

Aging is associated with cognitive decline in both humans and animals and of all brain regions, the hippocampus appears to be particularly vulnerable to senescence. Age-related spatial learning deficits result from alterations in hippocampal connectivity and plasticity. These changes are differentially expressed in each of the hippocampal fields known as cornu ammonis 1 (CA1), cornu ammonis 3 (CA3), and the dentate gyrus. Each sub-region displays varying degrees of susceptibility to aging. For example, the CA1 region is particularly susceptible in Alzheimer's disease while the CA3 region shows vulnerability to stress and glucocorticoids. Further, in animals, aging is the main factor associated with the decline in adult neurogenesis in the dentate gyrus. This review discusses the relationship between region-specific hippocampal connectivity, morphology, and gene expression alterations and the cognitive deficits associated with senescence. In particular, data are reviewed that illustrate how the molecular changes observed in the CA1, CA3, and dentate regions are associated with age-related learning deficits. This topic is of importance because increased understanding of how gene expression patterns reflect individual differences in cognitive performance is critical to the process of identifying new and clinically useful biomarkers for cognitive aging.

Burger, Corinna

2010-01-01

327

Aneuploidy facilitates oncogenic transformation via specific genetic alterations, including Twist2 upregulation.  

PubMed

Aneuploidy, deviation from the normal chromosome number, and other chromosomal aberrations are commonly observed in cancer. Integrin-mediated adhesion and dynamic turnover of adhesion sites are required for successful cytokinesis of normal adherent cells and impaired cell division can lead to the generation of cells with abnormal chromosome contents. We find that repeated cytokinesis failure, due to impaired integrin traffic alone, is sufficient to induce chromosome aberrations resulting in the generation of aneuploid cells with malignant properties. Here, we have compared isogenic aneuploid and euploid cell lines with unravel aneuploidy-induced changes in cellular signaling. Euploid, non-transformed, and aneuploid, transformed, cell lines were investigated using genome-wide gene expression profiling, analysis of deregulated biological pathways and array-comparative genomic hybridization. We find that aneuploidy drives malignancy via inducing marked changes in gene and micro RNA expression profiles and thus imposing specific growth and survival promoting alterations in cellular signaling. Importantly, we identify Twist2 as a key regulator of survival, invasion and anchorage-independent growth in the aneuploid cells. In addition, alterations in lipid biosynthetic pathways and miR-10b upregulation are likely contributors to the malignant phenotype. PMID:23689353

Högnäs, Gunilla; Hämälistö, Saara; Rilla, Kirsi; Laine, Jukka O; Vilkki, Vesa; Murumägi, Astrid; Edgren, Henrik; Kallioniemi, Olli; Ivaska, Johanna

2013-09-01

328

Polluted water concentrates: Induction of genetic alterations in Saccharomyces cerevisiae D7 strain  

SciTech Connect

In a previous paper the authors showed that samples of raw water obtained from the Riachuelo (a heavily polluted watercourse) induced genetic effects in Saccharomyces cerevisiae D7 strain. In those tests the raw water samples were assayed within 24 hr and only the mutagenic activity of the non-volatile, water soluble constituents could be detected. The detection and quantitation of genetic toxicity in the organic water-insoluble fraction becomes much more difficult. This organic material consists of thousands of unidentified compounds in dilute mixtures which are not amenable to current analytical technology. Consequently, concentration of organic compounds is required before performance of biological tests. The development of analytical methods involving XAD resins for the isolation and identification of pesticides and other compounds led to the use of XAD resins in the concentration of organics in water. In the experiments reported here the genotoxic potential of XAD2 concentrates, obtained from samples of a heavily polluted stream, were evaluated by the induction of gene conversion and point mutation in Saccharomyces cerevisiae D7 strain.

Moretton, J.; Baro, P.; Zelazny, A.; D'Aquino, M.D. (School of Pharmacy and Biochemistry, Buenos Aires (Argentina))

1991-02-01

329

Detection of Genetic Alterations in Bladder Tumors by Comparative Genomic Hybridization and Cytogenetic Analysis  

Microsoft Academic Search

Comparative genomic hybridization (CGH) and conventional cytogenetic karyotyping were used to screen for losses and gains of DNA sequences along all chromosome arms in 16 bladder tumors. Cytogenetic results were highly complex. The most frequently affected chromosomes were 5, 8, 9, 21, and Y as determined by karyotyping. There was close correlation between the CGH data and cytogenetic results in

Sun Hoe Koo; Kye Chul Kwon; Chun Hwa Ihm; Young Mi Jeon; Jong Woo Park; Chong Koo Sul

1999-01-01

330

Growth Hormone Secretion Is Differently Affected in Genetically Obese Male and Female Rats  

Microsoft Academic Search

Growth hormone (GH) secretion is markedly blunted in obesity. Reportedly, genetically obese Zucker rats show a reduced GH secretion due to an impaired function of hypothalamic neurons producing the GH-releasing hormone (GHRH). The aim of this work was: (1) to compare the in vitro GH responsiveness to GHRH in genetically obese female versus male Zucker rats and, (2) to evaluate

Daniela Cocchi; Marco Parenti; Lorena Cattaneo; V. De Gennaro Colonna; Andrea Zocchetti; Eugenio E. Müller

1993-01-01

331

Prenatal genetic testing: an investigation of determining factors affecting the decision-making process.  

PubMed

Despite the increase in popularity of prenatal genetic testing, relatively little is known about the role psychological factors play in the decision-making process. In this analogue study, a sample of Italian female university students was used to investigate determining factors that predict the intention of undergoing prenatal genetic testing. Structural Equation Modelling was used to describe the dynamic interplay between knowledge, beliefs, attitudes and health-related behaviour such as prenatal genetic testing. Following the Theory of Reasoned Action, three dimensions predicted the intention to undergo prenatal genetic testing: the need for more scientific information, a positive attitude towards genetic testing, and the inclination to terminate pregnancy after receiving a positive test result. Results showed that less religious women tended to be more in favour of prenatal tests and in undertaking such tests. This preliminary study provides genetic counsellors and policy makers with a clearer picture of their clients' motives and attitudes behind the decision-making process of prenatal genetic testing, contributing to improving both the communication process between counsellors and their clients and the organization of genetic services. PMID:22477148

Pivetti, Monica; Melotti, Giannino

2013-02-01

332

DNA ALTERATIONS  

EPA Science Inventory

The exposure of an organism to genotoxic chemicals may induce a cascade of genetic events. nitially, structural alterations to DNA are formed. ext, the DNA damage is processed and subsequently expressed in mutant gene products. inally, diseases result from the genetic damage. he ...

333

Genetic and epigenetic alterations are involved in the regulation of TPM1 in cholangiocarcinoma.  

PubMed

Cholangiocarcinoma is a malignant tumor originating from biliary epithelial cells. The tumor suppressor gene tropomyosin 1 (TPM1) is downregulated in several human cancer types; however, its expression status in cholangiocarcinoma is still unknown. We elucidated TPM1 expression and its regulation mechanism in cholangiocarcinoma. Real-time (RT)-PCR, western blot analysis and immunohistochemistry were performed to examine TPM1 expression levels in cholangiocarcinoma cell lines and tumor tissues. Cell lines were treated with lentiviral vector containing the miR-21 knockdown and inhibitors of genetic and epigenetic mechanisms (manumycin A, LY294002, U0126, DAC and TSA), and the TPM1 expression change was observed by RT-PCR and western blot analyses. Cell proliferation, apoptosis and migration were evaluated by water-soluble tetrazolium salt (WST-1) assay, flow cytometry and wound healing experiments, respectively. TPM1 was downregulated in the intrahepatic cholangiocarcinoma cells (HuCCT1) and upregulated in the extrahepatic cholangiocarcinoma cells (QBC939) compared with normal intrahepatic biliary epithelial cells (HIBEC). TPM1 stained negative in the intrahepatic cholangiocarcinoma tissues, as revealed by immunohistochemistry, although there was no significant difference in staining of the intrahepatic cholangiocarcinoma tissues and adjacent non-cancer tissues. RAS and two important downstream signaling pathways (RAS/PI3K/AKT and RAS/MEK/ERK) were involved in TPM1 regulation and inhibition of the epigenetic mechanisms such as DNA methylation, histone deacetylation and miR-21 upregulation upregulated TPM1 expression. Inhibitors of genetic and epigenetic mechanisms (manumycin A, LY294002, U0126, DAC and TSA) inhibited cell proliferation and migration and induced apoptosis. These data indicated that TPM1 is downregulated in HuCCT1 cells and that the Ras signaling pathway as well as DNA methylation, histone deacetylation and miR-21 upregulation play important roles in the suppression of TPM1 expression in HuCCT1 cells. Thus, compounds that inhibit genetic and epigenetic mechanisms may be promising agents in treating cholangiocarcinoma. PMID:23254774

Yang, Wei; Wang, Xiaoyuan; Zheng, Wei; Li, Kedong; Liu, Haofeng; Sun, Yueming

2013-02-01

334

Genetic and molecular alterations in pancreatic cancer: Implications for personalized medicine  

PubMed Central

Recent advances in human genomics and biotechnologies have profound impacts on medical research and clinical practice. Individual genomic information, including DNA sequences and gene expression profiles, can be used for prediction, prevention, diagnosis, and treatment for many complex diseases. Personalized medicine attempts to tailor medical care to individual patients by incorporating their genomic information. In a case of pancreatic cancer, the fourth leading cause of cancer death in the United States, alteration in many genes as well as molecular profiles in blood, pancreas tissue, and pancreas juice has recently been discovered to be closely associated with tumorigenesis or prognosis of the cancer. This review aims to summarize recent advances of important genes, proteins, and microRNAs that play a critical role in the pathogenesis of pancreatic cancer, and to provide implications for personalized medicine in pancreatic cancer.

Fang, Yantian; Yao, Qizhi; Chen, Zongyou; Xiang, Jianbin; William, Fisher E.; Gibbs, Richard A.; Chen, Changyi

2013-01-01

335

Detecting somatic genetic alterations in tumor specimens by exon capture and massively parallel sequencing.  

PubMed

Efforts to detect and investigate key oncogenic mutations have proven valuable to facilitate the appropriate treatment for cancer patients. The establishment of high-throughput, massively parallel "next-generation" sequencing has aided the discovery of many such mutations. To enhance the clinical and translational utility of this technology, platforms must be high-throughput, cost-effective, and compatible with formalin-fixed paraffin embedded (FFPE) tissue samples that may yield small amounts of degraded or damaged DNA. Here, we describe the preparation of barcoded and multiplexed DNA libraries followed by hybridization-based capture of targeted exons for the detection of cancer-associated mutations in fresh frozen and FFPE tumors by massively parallel sequencing. This method enables the identification of sequence mutations, copy number alterations, and select structural rearrangements involving all targeted genes. Targeted exon sequencing offers the benefits of high throughput, low cost, and deep sequence coverage, thus conferring high sensitivity for detecting low frequency mutations. PMID:24192750

Won, Helen H; Scott, Sasinya N; Brannon, A Rose; Shah, Ronak H; Berger, Michael F

2013-01-01

336

Anxiety and affective disorder comorbidity related to serotonin and other neurotransmitter systems: obsessive-compulsive disorder as an example of overlapping clinical and genetic heterogeneity  

PubMed Central

Individuals with obsessive–compulsive disorder (OCD) have also been shown to have comorbid lifetime diagnoses of major depressive disorder (MDD; rates greater than 70%), bipolar disorder (rates greater than 10%) and other anxiety disorders (e.g. panic disorder, post-traumatic stress disorder (PTSD)). In addition, overlap exists in some common genetic variants (e.g. the serotonin transporter gene (SLC6A4), the brain-derived neurotrophic factor (BDNF) gene), and rare variants in genes/chromosomal abnormalities (e.g. the 22q11 microdeletion syndrome) found across the affective/anxiety disorder spectrums. OCD has been proposed as a possible independent entity for DSM-5, but by others thought best retained as an anxiety disorder subtype (its current designation in DSM-IV), and yet by others considered best in the affective disorder spectrum. This review focuses on OCD, a well-studied but still puzzling heterogeneous disorder, regarding alterations in serotonergic, dopaminergic and glutamatergic neurotransmission in addition to other systems involved, and how related genes may be involved in the comorbidity of anxiety and affective disorders. OCD resembles disorders such as depression, in which gene × gene interactions, gene × environment interactions and stress elements coalesce to yield OC symptoms and, in some individuals, full-blown OCD with multiple comorbid disorders.

Murphy, Dennis L.; Moya, Pablo R.; Fox, Meredith A.; Rubenstein, Liza M.; Wendland, Jens R.; Timpano, Kiara R.

2013-01-01

337

Indirect genetic effects and inbreeding: consequences of BLUP selection for socially affected traits on rate of inbreeding  

PubMed Central

Background Social interactions often occur among living organisms, including aquatic animals. There is empirical evidence showing that social interactions may genetically affect phenotypes of individuals and their group mates. In this context, the heritable effect of an individual on the phenotype of another individual is known as an Indirect Genetic Effect (IGE). Selection for socially affected traits may increase response to artificial selection, but also affect rate of inbreeding. Methods A simulation study was conducted to examine the effect of Best Linear Unbiased Prediction (BLUP) selection for socially affected traits on the rate of inbreeding. A base scenario without IGE and three alternative scenarios with different magnitudes of IGE were simulated. In each generation, 25 sires and 50 dams were mated, producing eight progeny per dam. The population was selected for 20 generations using BLUP. Individuals were randomly assigned to groups of eight members in each generation, with two families per group, each contributing four individuals. “Heritabilities” (for both direct and indirect genetic effects) were equal to 0.1, 0.3 or 0.5, and direct–indirect genetic correlations were ?0.8, ?0.4, 0, 0.4, or 0.8. The rate of inbreeding was calculated from generation 10 to 20. Results For the base scenario, the rates of inbreeding were 4.09, 2.80 and 1.95% for “heritabilities” of 0.1, 0.3 and 0.5, respectively. Overall, rates of inbreeding for the three scenarios with IGE ranged from 2.21 to 5.76% and were greater than for the base scenarios. The results show that social interaction within groups of two families increases the resemblance between estimated breeding values of relatives, which, in turn, increases the rate of inbreeding. Conclusion BLUP selection for socially affected traits increased the rate of inbreeding. To maintain inbreeding at an acceptable rate, a selection algorithm that restricts the increase in mean kinship, such as optimum contribution selection, is required.

2014-01-01

338

Progressive increase of genetic alteration in urinary bladder cancer by combined allelotyping analysis and comparative genomic hybridization.  

PubMed

Bladder cancer is the ninth most common cancer in the world. Urothelial carcinoma (formerly known as transitional cell carcinoma) comprises the majority of bladder cancers. In order to decipher the genetic alteration leading to the carcinogenesis of urothelial cancer, we performed genome-wide allelotyping analysis using 384 microsatellite markers spanning 22 autosomes together with comparative genomic hybridization (CGH) in 21 urothelial cancer. High frequency of allelic imbalance was observed in chromosome arm 1q (61.9%), 3p (61.9%), 4q (66.67%), 8p (57.14%), 9p (76.2%) and 9q (66.67%). Allelic imbalance with frequency above average was also observed in chromosome arm 2q, 10p, 10q, 11p, 11q, 12q, 13q, 15q, 17p and 19q. The allelic imbalance of each case and fractional allelic loss for each chromosome was associated with higher tumor grade and stage (P<0.05). We have also delineated several minimal deletion regions on chromosome 3p, 4q, 8p, 9p, 9q, 11p, 13q, 16q and 17p. By CGH analysis, common chromosomal alterations included gain of 1p, 1q, 12q, 16p, 17q and 19p as well as loss of 4q and 9p in most of the cases. Our findings may provide valuable information to locate putative oncogenes and tumor suppressor genes in the carcinogenesis of bladder cancer in this locality. PMID:19287953

Chan, Michael W Y; Hui, Angela Bik-Yu; Yip, Sidney Kam-Hung; Ng, Chi-Fai; Lo, Kwok-Wai; Tong, Joanna H M; Chan, Anthony W H; Cheung, Ho Y; Wong, Wai S; Chan, Peter S F; Lai, Fernand M M; To, Ka-Fai

2009-04-01

339

Transcriptome Profiling of Human Ulcerative Colitis Mucosa Reveals Altered Expression of Pathways Enriched in Genetic Susceptibility Loci  

PubMed Central

Human colonic mucosa altered by inflammation due to ulcerative colitis (UC) displays a drastically altered pattern of gene expression compared with healthy tissue. We aimed to understand the underlying molecular pathways influencing these differences by analyzing three publically-available, independently-generated microarray datasets of gene expression from endoscopic biopsies of the colon. Gene set enrichment analysis (GSEA) revealed that all three datasets share 87 gene sets upregulated in UC lesions and 8 gene sets downregulated (false discovery rate <0.05). The upregulated pathways were dominated by gene sets involved in immune function and signaling, as well as the control of mitosis. We applied pathway analysis to genotype data derived from genome-wide association studies (GWAS) of UC, consisting of 5,584 cases and 11,587 controls assembled from eight European-ancestry cohorts. The upregulated pathways derived from the gene expression data showed a highly significant overlap with pathways derived from the genotype data (33 of 56 gene sets, hypergeometric P?=?1.49×10–19). This study supports the hypothesis that heritable variation in gene expression as measured by GWAS signals can influence key pathways in the development of disease, and that comparison of genetic susceptibility loci with gene expression signatures can differentiate key drivers of inflammation from secondary effects on gene expression of the inflammatory process.

Li, Jin; Zhu, Junfei; Gu, Mengnan; Baldassano, Robert N.; Grant, Struan F. A.; Hakonarson, Hakon

2014-01-01

340

Variation in chlorobenzoate catabolism by Pseudomonas putida P111 as a consequence of genetic alterations  

SciTech Connect

Chlorobenzoates are key intermediates in the degradative pathways of polychlorinated biphenyls and benzoate herbicides. Bacteria that cometabolize these pollutants generally accumulate chlorobenzoates because they are not able to grow on them. Special interest has been focused on ortho-chlorobenzoates because they are more refractory to biodegradation. In all of these studies the enzyme responsible for the first attack on the ortho-chlorobenzoates possesses minimal or negligible activity with meta- or para-chlorobenzoates. This study reports evidence for the existence of two separate benzoate dioxygenases in Pseudomonas putida P111 and for the transpostional nature of the clc operon, on the basis of genetic investigations of different phenotypic variants of this strain. 42 refs., 4 figs., 1 tab.

Brenner, V.; Focht, D.D. (Univ. of California, Riverside, CA (United States)); Hernandez, B.S. (Univ. of Panama (Panama))

1993-09-01

341

Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain  

Microsoft Academic Search

CYP2B6 metabolizes drugs such as nicotine and bupropion, and many toxins and carcinogens. Nicotine induces CYP2B1 in rat brain and in humans polymorphic variation in CYP2B6 affects smoking cessation rates. The aim of this study was to compare CYP2B6 expression in brains of human smokers and non-smokers and alcoholics and non-alcoholics (n=26). CYP2B6 expression was brain region-specific, and was observed

Sharon Miksys; Caryn Lerman; Peter G. Shields; Deborah C. Mash; Rachel F. Tyndale

2003-01-01

342

Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence.  

PubMed

Alcohol dependence frequently co-occurs with cigarette smoking, another common addictive behavior. Evidence from genetic studies demonstrates that alcohol dependence and smoking cluster in families and have shared genetic vulnerability. Recently a candidate gene study in nicotine dependent cases and nondependent smoking controls reported strong associations between a missense mutation (rs16969968) in exon 5 of the CHRNA5 gene and a variant in the 3'-UTR of the CHRNA3 gene and nicotine dependence. In this study we performed a comprehensive association analysis of the CHRNA5-CHRNA3-CHRNB4 gene cluster in the Collaborative Study on the Genetics of Alcoholism (COGA) families to investigate the role of genetic variants in risk for alcohol dependence. Using the family-based association test, we observed that a different group of polymorphisms, spanning CHRNA5-CHRNA3, demonstrate association with alcohol dependence defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV) criteria. Using logistic regression we replicated this finding in an independent case-control series from the family study of cocaine dependence. These variants show low linkage disequilibrium with the SNPs previously reported to be associated with nicotine dependence and therefore represent an independent observation. Functional studies in human brain reveal that the variants associated with alcohol dependence are also associated with altered steady-state levels of CHRNA5 mRNA. PMID:18414406

Wang, J C; Grucza, R; Cruchaga, C; Hinrichs, A L; Bertelsen, S; Budde, J P; Fox, L; Goldstein, E; Reyes, O; Saccone, N; Saccone, S; Xuei, X; Bucholz, K; Kuperman, S; Nurnberger, J; Rice, J P; Schuckit, M; Tischfield, J; Hesselbrock, V; Porjesz, B; Edenberg, H J; Bierut, L J; Goate, A M

2009-05-01

343

Genetically-induced Estrogen Receptor Alpha mRNA (Esr1) Overexpression Does Not Adversely Affect Fertility or Penile Development in Male Mice  

PubMed Central

Previously, we reported that estrogen receptor alpha mRNA (Esr1) or protein (ESR1) overexpression resulting from neonatal exposure to estrogens in rats was associated with infertility and mal-developed penis characterized by reduced length and weight and abnormal accumulation of fat cells. The objective of this study was to determine if mutant male mice overexpressing Esr1 are naturally infertile or have reduced fertility and/or develop abnormal penis. The fertility parameters, including fertility and fecundity indices, numbers of days from the day of cohabitation to the day of delivery, and numbers of pups per female, were not altered from controls, as a result of Esr1 overexpression. Likewise, penile morphology, including the length, weight, and diameter and os penis development, was not altered from controls. Conversely, weights of the seminal vesicles and bulbospongiosus and levator ani (BS/LA) muscles were significantly (P < 0.05) lower as compared to controls; however, the weight of the testis, the morphology of the testis and epididymis, and the plasma and testicular testosterone concentration were not different from controls. Hence, the genetically-induced Esr1 overexpression alone, without an exogenous estrogen exposure during the neonatal period, is unable to adversely affect the development of the penis as well as other male reproductive organs, except limited, but significant, reductions in weights of the seminal vesicles and BS/LA muscles.

Heath, John; Abdelmageed, Yazeed; Braden, Tim D.; Williams, Carol S.; Williams, John W.; Paulose, Tessie; Hernandez-Ochoa, Isabel; Gupta, Rupesh; Flaws, Jodi A.; Goyal, Hari O.

2011-01-01

344

Search and insights into novel genetic alterations leading to classical and atypical Werner syndrome.  

PubMed

Segmental progeroid syndromes are a group of disorders with multiple features resembling accelerated aging. Adult-onset Werner syndrome (WS) and childhood-onset Hutchinson-Gilford progeria syndrome are the best known examples. The discovery of genes responsible for such syndromes has facilitated our understanding of the basic mechanisms of aging as well as the pathogenesis of other common, age-related diseases. Our International Registry of Werner Syndrome accesses progeroid pedigrees from all over the world, including those for whom we have ruled out a mutation at the WRN locus. Cases without WRN mutations are operationally categorized as 'atypical WS' (AWS). In 2003, we identified LMNA mutations among a subset of AWS cases using a candidate gene approach. As of 2013, the Registry has 142 WS patients with WRN mutations, 11 AWS patients with LMNA mutations, and 49 AWS patients that have neither WRN nor LMNA mutations. Efforts are underway to identify the responsible genes for AWS with unknown genetic causes. While WS and AWS are rare disorders, the causative genes have been shown to have much wider implications for cancer, cardiovascular disease and the biology of aging. Remarkably, centenarian studies revealed WRN and LMNA polymorphic variants among those who have escaped various geriatric disorders. PMID:24401204

Oshima, Junko; Hisama, Fuki M

2014-01-01

345

Genetically altered mouse models: the good, the bad, and the ugly.  

PubMed

Targeted gene disruption in mice is a powerful tool for generating murine models for human development and disease. While the human genome program has helped to generate numerous candidate genes, few genes have been characterized for their precise in vivo functions. Gene targeting has had an enormous impact on our ability to delineate the functional roles of these genes. Many gene knockout mouse models faithfully mimic the phenotypes of the human diseases. Because some models display an unexpected or no phenotype, controversy has arisen about the value of gene-targeting strategies. We argue in favor of gene-targeting strategies, provided they are used with caution, particularly in interpreting phenotypes in craniofacial and oral biology, where many genes have pleiotropic roles. The potential pitfalls are outweighed by the unique opportunities for developing and testing different therapeutic strategies before they are introduced into the clinic. In the future, we believe that genetically engineered animal models will be indispensable for gaining important insights into the molecular mechanisms underlying development, as well as disease pathogenesis, diagnosis, prevention, and treatment. PMID:12799320

Thyagarajan, Tamizchelvi; Totey, Satish; Danton, Mary Jo S; Kulkarni, Ashok B

2003-01-01

346

Pleiotropy of Segregating Genetic Variants that Affect Honey Bee Worker Life Expectancy  

PubMed Central

In contrast to many other complex traits, the natural genetic architecture of life expectancy has not been intensely studied, particularly in non-model organisms, such as the honey bee (Apis mellifera L.). Multiple factors that determine honey bee worker lifespan have been identified and genetic analyses have been performed on some of those traits. Several of the traits are included in a suite of correlated traits that form the pollen hoarding syndrome, which was named after the behavior to store surplus pollen in the nest and is tied to social evolution. Here, seven quantitative trait loci that had previously been identified for their effects on different aspects of the pollen hoarding syndrome were studied for their genetic influence on the survival of adult honey bee workers. To gain a more comprehensive understanding of the genetic architecture of worker longevity, a panel of 280 additional SNP markers distributed across the genome was also tested. Allelic distributions were compared between young and old bees in two backcross populations of the bi-directionally selected high- and low-pollen hoarding strain. Our results suggest a pleiotropic effect of at least one of the behavioral quantitative trait loci on worker longevity and one significant and several other putative genetic effects in other genomic regions. At least one locus showed evidence for strong antagonistic pleiotropy and several others suggested genetic factors that influence pre-emergence survival of worker honey bees. Thus, the predicted association between worker lifespan and the pollen hoarding syndrome was supported at the genetic level and the magnitude of the identified effects also strengthened the view that naturally segregating genetic variation can have major effects on age-specific survival probability in the wild.

Dixon, Luke R.; McQuage, Michelle R.; Lonon, Ellen J.; Buehler, Dominique; Seck, Oumar; Rueppell, Olav

2012-01-01

347

Sampling Issues Affecting Accuracy of Likelihood-based Classification Using Genetical Data  

Microsoft Academic Search

We demonstrate the effectiveness of a genetic algorithm for discovering multi-locus combinations that provide accurate individual\\u000a assignment decisions and estimates of mixture composition based on likelihood classification. Using simulated data representing\\u000a different levels of inter-population differentiation (Fst? 0.01 and 0.10), genetic diversities (four or eight alleles per locus), and population sizes (20, 40, 100 individuals in\\u000a baseline populations), we show

B. Guinand; K. T. Scribner; A. Topchy; K. S. Page; W. Punch; M. K. Burnham-Curtis

2004-01-01

348

Deregulation of Wnt/?-catenin signaling through genetic or epigenetic alterations in human neuroendocrine tumors  

PubMed Central

Carcinoid tumors are rare neuroendocrine tumors (NETs) that are increasing in incidence. Mutation and altered expression of Wnt/?-catenin signaling components have been described in many tumors but have not been well-studied in NETs. Here, we observed accumulation of ?-catenin in the cytoplasm and/or nucleus in 25% of clinical NET tissues. By mutational analysis, the mutations of ?-catenin (I35S) and APC (E1317Q, T1493T) were identified in NET cells and the tissues. Expression of representative Wnt inhibitors was absent or markedly decreased in BON, a human pancreatic carcinoid cell line; treatment with 5-aza-2?-deoxycytidine (5-aza-CdR) increased expression levels of the Wnt inhibitors. Methylation analyses demonstrated that CpG islands of SFRP-1 and Axin-2 were methylated, whereas the promoters of DKK-1, DKK-3 and WIF-1 were unmethylated in four NET cells. Aberrant methylation of SFRP-1 was particularly observed in most of clinical NET tissues. In addition, the repression of these unmethylated genes was associated with histone H3 lysine 9 dimethylation (H3K9me2) in BON cells. Together, 5-aza-CdR treatment inhibited cell proliferation and decreased the protein levels of H3K9me2 and G9a. Moreover, a novel G9a inhibitor, UNC0638, suppressed BON cell proliferation through inhibition of Wnt/?-catenin pathway. Overexpression of the inhibitory genes, particularly SFRP-1 and WIF-1 in BON cells, resulted in suppression of anchorage-independent growth and inhibition of tumor growth in mice. Our findings suggest that aberrant Wnt/?-catenin signaling, through either mutations or epigenetic silencing of Wnt antagonists, contributes to the pathogenesis and growth of NETs and have important clinical implications for the prognosis and treatment of NETs.

Evers, B.Mark

2013-01-01

349

Spinocerebellar Ataxia: Patient and Health Professional Perspectives on Whether and How Patents Affect Access to Clinical Genetic Testing  

PubMed Central

Genetic testing for spinocerebellar ataxia (SCA) is used in diagnosis of rare movement disorders. Such testing generally does not affect treatment, but confirmation of mutations in a known gene can confirm diagnosis and end an often years-long quest for the cause of distressing and disabling symptoms. Through interviews and a web forum hosted by the National Ataxia Foundation, patients and health professionals related their experiences with patents’ impact on access to genetic testing for SCA. In the United States, Athena Diagnostics holds either a patent or an exclusive license to a patent in the case of 6 SCA variants (SCA1-3 & 6-8) and two other hereditary ataxias (Friedreich’s Ataxia and Early Onset Ataxia). Athena has enforced its exclusive rights to SCA-related patents by sending cease and desist letters to multiple laboratories offering genetic testing for inherited neurological conditions, including SCA. Roughly half of web forum respondents had decided not to get genetic tests. Price, coverage and reimbursement by insurers and health plans, and fear of genetic discrimination were the main reasons cited for deciding not to get tested. Price was cited as an access concern by the physicians, and as sole US provider, coverage and reimbursement depend on having payment agreements between Athena and payers. In cases where payers do not reimburse, the patient is responsible for payment, although some patients can apply to the voluntary Athena Access and Patient Protection Programs offered by the company.

Powell, Ashton; Chandrasekharan, Subhashini; Cook-Deegan, Robert

2011-01-01

350

Titanium Mass-balance Analysis of Paso Robles Soils: Elemental Gains and Losses as Affected by Acid Alteration Fluids  

NASA Technical Reports Server (NTRS)

The Columbia Hills soils have been exposed to aqueous alteration in alkaline [1] as well as acid conditions [2,3]. The Paso Robles class soils are bright soils that possess the highest S concentration of any soil measured on Mars [2]. Ferric-sulfate detection by Moessbauer analysis indicated that acid solutions were involved in forming these soils [4]. These soils are proposed to have formed by alteration of nearby rock by volcanic hydrothermal or fumarolic activity. The Paso Robles soils consist of the original Paso Robles-disturbed-Pasadena (PR-dist), Paso Robles- PasoLight (PR-PL), Arad-Samra, Arad-Hula, Tyrone- Berker Island1 and Tyrone-MountDarwin [2 ,3. ]Chemical characteristics indicate that the PR-dist and PR-PL soils could be derived from acid weathering of local Wishstone rocks while the Samra and Hula soils are likely derived from local Algonquin-Iroquet rock [3]. The Paso Robles soils were exposed to acidic sulfur bearing fluids; however, little else is known about the chemistry of the alteration fluid and its effects on the alteration of the proposed parent materials. The objectives of this work are to conduct titanium normalized mass-balance analysis to1) assess elemental gains and losses from the parent materials in the formation of the Paso Robles soils and 2) utilize this information to indicate the chemical nature of the alteration fluids.

Sutter, Brad; Ming, Douglas W.

2010-01-01

351

Glutamate receptor composition of the post-synaptic density is altered in genetic mouse models of NMDA receptor hypo- and hyperfunction.  

PubMed

The N-methyl-d-aspartate receptor (NMDAR) and ?-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) are ionotropic glutamate receptors responsible for excitatory neurotransmission in the brain. These excitatory synapses are found on dendritic spines, with the abundance of receptors concentrated at the postsynaptic density (PSD). We utilized two genetic mouse models, the serine racemase knockout (SR-/-) and the glycine transporter subtype 1 heterozygote mutant (GlyT1+/-), to determine how constitutive NMDAR hypo- and hyperfunction, respectively, affect the glutamate receptor composition of the PSD in the hippocampus and prefrontal cortex (PFC). Using cellular fractionation, we found that SR-/- mice had elevated protein levels of NR1 and NR2A NMDAR subunits specifically in the PSD-enriched fraction from the hippocampus, but not from the PFC. There were no changes in the amounts of AMPAR subunits (GluR1, GluR2), or PSD protein of 95 kDa (PSD95) in either brain region. GlyT1+/- mice also had elevated protein expression of NR1 and NR2A subunits in the PSD, as well as an increase in total protein. Moreover, GlyT1+/- mice had elevated amounts of GluR1 and GluR2 in the PSD, and higher total amounts of GluR1. Similar to SR-/- mice, there were no protein changes observed in the PFC. These findings illustrate the complexity of synaptic adaptation to altered NMDAR function. PMID:21443867

Balu, Darrick T; Coyle, Joseph T

2011-05-25

352

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis  

PubMed Central

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07.

Whitcomb, David C.; LaRusch, Jessica; Krasinskas, Alyssa M.; Klei, Lambertus; Smith, Jill P.; Brand, Randall E.; Neoptolemos, John P.; Lerch, Markus M.; Tector, Matt; Sandhu, Bimaljit S.; Guda, Nalini M.; Orlichenko, Lidiya; Alkaade, Samer; Amann, Stephen T.; Anderson, Michelle A.; Baillie, John; Banks, Peter A.; Conwell, Darwin; Cote, Gregory A.; Cotton, Peter B.; DiSario, James; Farrer, Lindsay A.; Forsmark, Chris E.; Johnstone, Marianne; Gardner, Timothy B.; Gelrud, Andres; Greenhalf, William; Haines, Jonathan L.; Hartman, Douglas J.; Hawes, Robert A.; Lawrence, Christopher; Lewis, Michele; Mayerle, Julia; Mayeux, Richard; Melhem, Nadine M.; Money, Mary E.; Muniraj, Thiruvengadam; Papachristou, Georgios I.; Pericak-Vance, Margaret A.; Romagnuolo, Joseph; Schellenberg, Gerard D.; Sherman, Stuart; Simon, Peter; Singh, Vijay K.; Slivka, Adam; Stolz, Donna; Sutton, Robert; Weiss, Frank Ulrich; Wilcox, C. Mel; Zarnescu, Narcis Octavian; Wisniewski, Stephen R.; O'Connell, Michael R.; Kienholz, Michelle L.; Roeder, Kathryn; Barmada, M. Michael; Yadav, Dhiraj; Devlin, Bernie; Albert, Marilyn S.; Albin, Roger L.; Apostolova, Liana G.; Arnold, Steven E.; Baldwin, Clinton T.; Barber, Robert; Barnes, Lisa L.; Beach, Thomas G.; Beecham, Gary W.; Beekly, Duane; Bennett, David A.; Bigio, Eileen H.; Bird, Thomas D.; Blacker, Deborah; Boxer, Adam; Burke, James R.; Buxbaum, Joseph D.; Cairns, Nigel J.; Cantwell, Laura B.; Cao, Chuanhai; Carney, Regina M.; Carroll, Steven L.; Chui, Helena C.; Clark, David G.; Cribbs, David H.; Crocco, Elizabeth A.; Cruchaga, Carlos; DeCarli, Charles; Demirci, F. Yesim; Dick, Malcolm; Dickson, Dennis W.; Duara, Ranjan; Ertekin-Taner, Nilufer; Faber, Kelley M.; Fallon, Kenneth B.; Farlow, Martin R.; Ferris, Steven; Foroud, Tatiana M.; Frosch, Matthew P.; Galasko, Douglas R.; Ganguli, Mary; Gearing, Marla; Geschwind, Daniel H.; Ghetti, Bernardino; Gilbert, John R.; Gilman, Sid; Glass, Jonathan D.; Goate, Alison M.; Graff-Radford, Neill R.; Green, Robert C.; Growdon, John H.; Hakonarson, Hakon; Hamilton-Nelson, Kara L.; Hamilton, Ronald L.; Harrell, Lindy E.; Head, Elizabeth; Honig, Lawrence S.; Hulette, Christine M.; Hyman, Bradley T.; Jicha, Gregory A.; Jin, Lee-Way; Jun, Gyungah; Kamboh, M. Ilyas; Karydas, Anna; Kaye, Jeffrey A.; Kim, Ronald; Koo, Edward H.; Kowall, Neil W.; Kramer, Joel H.; Kramer, Patricia; Kukull, Walter A.; LaFerla, Frank M.; Lah, James J.; Leverenz, James B.; Levey, Allan I.; Li, Ge; Lin, Chiao-Feng; Lieberman, Andrew P.; Lopez, Oscar L.; Lunetta, Kathryn L.; Lyketsos, Constantine G.; Mack, Wendy J.; Marson, Daniel C.; Martin, Eden R.; Martiniuk, Frank; Mash, Deborah C.; Masliah, Eliezer; McKee, Ann C.; Mesulam, Marsel; Miller, Bruce L.; Miller, Carol A.; Miller, Joshua W.; Montine, Thomas J.; Morris, John C.; Murrell, Jill R.; Naj, Adam C.; Olichney, John M.; Parisi, Joseph E.; Peskind, Elaine; Petersen, Ronald C.; Pierce, Aimee; Poon, Wayne W.; Potter, Huntington; Quinn, Joseph F.; Raj, Ashok; Raskind, Murray; Reiman, Eric M.; Reisberg, Barry; Reitz, Christiane; Ringman, John M.; Roberson, Erik D.; Rosen, Howard J.; Rosenberg, Roger N.; Sano, Mary; Saykin, Andrew J.; Schneider, Julie A.; Schneider, Lon S.; Seeley, William W.; Smith, Amanda G.; Sonnen, Joshua A.; Spina, Salvatore; Stern, Robert A.; Tanzi, Rudolph E.; Trojanowski, John Q.; Troncoso, Juan C.; Tsuang, Debby W.; Valladares, Otto; Van Deerlin, Vivianna M.; Van Eldik, Linda J.; Vardarajan, Badri N.; Vinters, Harry V.; Vonsattel, Jean Paul; Wang, Li-San; Weintraub, Sandra; Welsh-Bohmer, Kathleen A.; Williamson, Jennifer; Woltjer, Randall L.; Wright, Clinton B.; Younkin, Steven G.; Yu, Chang-En; Yu, Lei

2012-01-01

353

Genetic Background Alters the Severity and Onset of Neuromuscular Disease Caused by the Loss of Ubiquitin-Specific Protease 14 (Usp14)  

PubMed Central

In this study, we identified and characterized an N-ethyl-N-nitrosourea (ENU) induced mutation in Usp14 (nmf375) that leads to adult-onset neurological disease. The nmf375 mutation causes aberrant splicing of Usp14 mRNA, resulting in a 95% reduction in USP14. We previously showed that loss of USP14 in ataxia (axJ) mice results in reduced ubiquitin levels, motor endplate disease, Purkinje cell axonal dystrophy and decreased hippocampal paired pulse facilitation (PPF) during the first 4-6 weeks of life, and early postnatal lethality by two months of age. Although the loss of USP14 is comparable between the nmf375 and axJ mice, the nmf375 mice did not exhibit these axJ developmental abnormalities. However, by 12 weeks of age the nmf375 mutants present with ubiquitin depletion and motor endplate disease, indicating a continual role for USP14-mediated regulation of ubiquitin pools and neuromuscular junction (NMJ) structure in adult mice. The observation that motor endplate disease was only seen after ubiquitin depletion suggests that the preservation of NMJ structure requires the stable maintenance of synaptic ubiquitin pools. Differences in genetic background were shown to affect ubiquitin expression and dramatically alter the phenotypes caused by USP14 deficiency.

Hallengren, Jada J.; Walters, Brandon J.; Dobrunz, Lynn E.; Francillon, Ludwig; Wilson, Julie A.; Phillips, Scott E.; Wilson, Scott M.

2013-01-01

354

Genetic variation in APOJ, LPL, and TNFRSF10B affects plasma fatty acid distribution in Alaskan Eskimos123  

PubMed Central

Background: Alterations in plasma fatty acid distribution are linked to metabolic abnormalities related to type 2 diabetes and cardiovascular disease. Objective: The aim of this study was to investigate genetic factors influencing plasma fatty acid distribution in Alaskan Eskimos from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study. Design: Fatty acids in plasma were measured by gas chromatography in 761 related individuals (>35 y of age). Results: Quantitative genetic analyses showed that fatty acid distribution is significantly heritable (P < 0.001), with heritabilities ranging from 0.33 to 0.55. A genome-wide scan for plasma fatty acids identified a 20-cM region on chromosome 8 (p12–p21) with a quantitative trait locus for monounsaturated fatty acids (logarithm of odds score = 3.8). The same region had a quantitative trait locus for polyunsaturated fatty acids (logarithm of odds score = 2.6). We genotyped single nucleotide polymorphisms (SNPs) in candidate genes in 8p12–p21 and found a significant association between fatty acids and SNPs in apolipoprotein J (APOJ), lipoprotein lipase (LPL), macrophage scavenger receptor 1 (MSR1), and tumor necrosis factor receptor superfamily member 10b (TNFRSF10B). A Bayesian quantitative trait nucleotide analysis based on a measured genotype model showed that SNPs in LPL, TNFRSF10B, and APOJ had strong statistical evidence of a functional effect (posterior probability ?75%) on plasma fatty acid distribution. Conclusions: The results indicate that there is strong genetic influence on plasma fatty acid distribution and that genetic variation in APOJ, LPL, and TNFRSF10B may play a role. The GOCADAN study was registered at www.clinicaltrials.gov as NCT00006192.

Voruganti, V Saroja; Cole, Shelley A; Ebbesson, Sven OE; Goring, Harald HH; Haack, Karin; Laston, Sandra; Wenger, Charlotte R; Tejero, M Elizabeth; Devereux, Richard B; Fabsitz, Richard R; MacCluer, Jean W; Umans, Jason G; Howard, Barbara V; Comuzzie, Anthony G

2010-01-01

355

A genetic interpretation of heightened risk of BSE in offspring of affected dams.  

PubMed Central

An analysis is presented of the results of a cohort study designed to test whether or not the aetiological agent of bovine spongiform encephalopathy (BSE) in cattle can be transmitted maternally (vertically) from dam offspring. Various genetic models are fitted to the data under the assumption that the results could be explained entirely by genetic predisposition to disease (as opposed to maternal transmission) given exposure of offspring of diseased and unaffected dams to contaminated cattle feed. The analyses suggest that the results could be explained by the hypothesis of genetic predisposition, provided a large difference exists in the susceptibility of resistant and susceptible hosts, and explore the range of genotypic parameters and frequencies consistent with the limited currently available data. The results presented are broadly robust, even under the scenario that a portion of the observed maternally enhanced risk of BSE is due to a low level of maternal transmission in late incubation stage dams.

Ferguson, N M; Donnelly, C A; Woolhouse, M E; Anderson, R M

1997-01-01

356

Genetic disorders of simple sphingolipid metabolism.  

PubMed

A better understanding of the functions sphingolipids play in living organisms can be achieved by analyzing the biochemical and physiological changes that result from genetic alterations of sphingolipid metabolism. This review summarizes the current knowledge gained from studies both on human patients and mutant animals (mice, cats, dogs, and cattle) with genetic disorders of sphingolipid metabolism. Genetic alterations affecting the biosynthesis, transport, or degradation of simple sphingolipids are discussed. PMID:23579453

Albinet, Virginie; Bats, Marie-Lise; Bedia, Carmen; Sabourdy, Frédérique; Garcia, Virginie; Ségui, Bruno; Andrieu-Abadie, Nathalie; Hornemann, Thorsten; Levade, Thierry

2013-01-01

357

Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia.  

PubMed

Despite risk-adapted treatment, survival of children with relapse of acute lymphoblastic leukemia (ALL) remains poor compared with that of patients with initial diagnosis of ALL. Leukemia-associated genetic alterations may provide novel prognostic factors to refine present relapse treatment strategies. Therefore, we investigated the clinical relevance of 13 recurrent genetic alterations in 204 children treated uniformly for relapsed B-cell precursor ALL according to the ALL-REZ BFM 2002 protocol. The most common alterations were deletions of CDKN2A/2B, IKZF1, PAX5, ETV6, fusion of ETV6-RUNX1 and deletions and/or mutations of TP53. Multivariate analysis identified IKZF1 deletion and TP53 alteration as independent predictors of inferior outcome (P=0.002 and P=0.001). Next, we investigated how both alterations can improve the established risk stratification in relapsed ALL. Intermediate-risk relapse patients with low minimal residual disease are currently considered to have a good prognosis. In this group, deletion of IKZF1 and alteration of TP53 identify patients with significantly inferior outcome (P<0.001). In high-risk relapse patients, deletion of IKZF1 is strongly predictive of a second relapse after stem cell transplantation (P<0.001). We conclude that IKZF1 and TP53 represent relevant prognostic factors that should be considered in future risk assessment of children with relapsed ALL to indicate treatment intensification or intervention. PMID:22699455

Krentz, S; Hof, J; Mendioroz, A; Vaggopoulou, R; Dörge, P; Lottaz, C; Engelmann, J C; Groeneveld, T W L; Körner, G; Seeger, K; Hagemeier, C; Henze, G; Eckert, C; von Stackelberg, A; Kirschner-Schwabe, R

2013-02-01

358

Genetic modifiers interact with Cpefat to affect body weight, adiposity, and hyperglycemia  

Microsoft Academic Search

Obesity and Type II diabetes are complex diseases in the human population. The existence of a large number of contributing loci and gene-gene as well as gene-environment interactions make it difficult to identify the disease genes underlying these complex traits. In mouse models of obesity and Type II diabetes such as the murine fat mutation, genetic crosses can be used

Gayle B. Collin; Terry P. Maddatu; Saunak Sen; Jurgen K. Naggert

2005-01-01

359

The Genetic Map of Artemisia annua L. Identifies Loci Affecting Yield of the Antimalarial Drug Artemisinin  

Microsoft Academic Search

Artemisinin is a plant natural product produced by Artemisia annua and the active ingredient in the most effective treatment for malaria. Efforts to eradicate malaria are increasing demand for an affordable, high-quality, robust supply of artemisinin. We performed deep sequencing on the transcriptome of A. annua to identify genes and markers for fast-track breeding. Extensive genetic variation enabled us to

Ian A. Graham; Katrin Besser; Susan Blumer; Caroline A. Branigan; Tomasz Czechowski; Luisa Elias; Inna Guterman; David Harvey; Peter G. Isaac; Awais M. Khan; Tony R. Larson; Yi Li; Tanya Pawson; Teresa Penfield; Anne M. Rae; Deborah A. Rathbone; Sonja Reid; Joe Ross; Margaret F. Smallwood; Vincent Segura; Theresa Townsend; Darshna Vyas; Thilo Winzer; Dianna Bowles

2010-01-01

360

Environmental, Management, and Genetic Factors Affecting Semen Production in Holstein Bulls  

Microsoft Academic Search

The objective of this study was to evaluate the importance of environment, management, physiologi- cal status, and genetics on semen quality (volume of the ejaculate, sperm concentration, sperm motility, number of sperm, and number of motile spermatozoa per ejaculate) of Canadian Holstein bulls. For this purpose, semen production data from 198 bulls were analyzed using mixed linear models. Young bulls

M. Mathevon; M. M. Buhr; J. C. M. Dekkers

1998-01-01

361

Alterations in lignin content and phenylpropanoids pathway in date palm (Phoenix dactylifera L.) tissues affected by brittle leaf disease.  

PubMed

Brittle leaf disease or Maladie de la Feuille Cassante (MFC) is a lethal disorder of date palm that has assumed epidemic proportions in the oases of Tunisia and Algeria. No pathogen could ever be associated with the disease, while leaflets of affected palms have been previously shown to be deficient in manganese. The work reported here aims to understand the biochemical basis of the date palm response to this disorder. Since the typical disease symptom is the leaf fragility, we have investigated lignin content in leaves and roots. Strong decrease in total lignin content was observed in affected leaves, while lignin content increased in affected roots. Histochemical analyses showed hyperlignification thicker suberin layer in roots cortical cells. The phenylpropanoids pathway was also disrupted in leaves and roots, cinnamoyl-CoA reductase and cinnamyl-alcohol dehydrogenase gene expression was affected by the disease which severely affects the cell wall integrity. PMID:23987806

Saidi, Mohammed Najib; Bouaziz, Donia; Hammami, Ines; Namsi, Ahmed; Drira, Noureddine; Gargouri-Bouzid, Radhia

2013-10-01

362

Negative Affect Shares Genetic and Environmental Influences with Symptoms of Childhood Internalizing and Externalizing Disorders  

ERIC Educational Resources Information Center

The co-occurrence of internalizing and externalizing disorders suggests that they may have common underlying vulnerability factors. Research has shown that negative affect is moderately positively correlated with both internalizing and externalizing disorders in children. The present study is the first to provide an examination of negative affect

Mikolajewski, Amy J.; Allan, Nicholas P.; Hart, Sara A.; Lonigan, Christopher J.; Taylor, Jeanette

2013-01-01

363

The Genetics and Biology of True Love: Prosocial Biological Affects and the Left Hemisphere  

Microsoft Academic Search

J. R. Gray (2002) questioned the conceptual basis and empirical support for prosocial biological affects and was skeptical whether the distinction between selfish versus prosocial biological affects can contribute to the discussion regarding hemispheric differences. In reply, hemispheric differences in emotional experience and expression are considered, with the suggestion that the individualist-prosocial distinction may indeed provide a useful addition to

Ross Buck

2002-01-01

364

The genetics and biology of true love: Prosocial biological affects and the left hemisphere  

Microsoft Academic Search

Jeremy R. Gray (2002) has reviewed my developmental- interactionist theory of affect (Buck, 1999) and has raised inter- esting and important questions and concerns. Gray questioned the conceptual basis and empirical support for the notion of prosocial biological affects, and he was skeptical whether the distinction between individualist or, colloquially, \\

Ross Buck

2002-01-01

365

Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau  

PubMed Central

Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P = 0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (odds ratio = 1.69, P = 8.2×10?5) and greater survival in SCC cases (hazard ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggest that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners.

Belinsky, Steven A.

2013-01-01

366

Loss of heterozygosity and microsatellite instability in breast hyperplasia. No obligate correlation of these genetic alterations with subsequent malignancy.  

PubMed Central

Loss of heterozygosity and microsatellite instability have been often reported in breast cancer and seldom in proliferative breast disease (PBD). DNA samples from microdissected PBD lesions, including papillomas (25 lesions), from 8 women were analyzed by polymerase chain reaction for loss of heterozygosity and microsatellite instability at 10 loci including INT-2 oncogene locus, D17S796 (the p53 gene region), and D17S579 (in the region of the BRCA-1 gene). In a patient, five loci with microsatellite instability and two loci with loss of heterozygosity were identified in one papilloma with florid hyperplasia and atypia, and 10 other PBD lesions were negative for genetic alteration (GA) and atypia. Three loci with microsatellite instability were identified in another PBD lesion without atypia, whereas another lesion from this second patient had minimal atypia without GAs. These two patients have been well for more than 20 years. No other patient, including a woman developing cancer, had GAs. We detected GAs in PBD (25% of women, 8% of lesions). Incomplete correlation between GAs and anatomic atypia was suggested. It seems evident that several GAs in PBD lesions may not indicate clinically meaningful premalignancy for remaining breast. Images Figure 1 Figure 2 Figure 3

Kasami, M.; Vnencak-Jones, C. L.; Manning, S.; Dupont, W. D.; Page, D. L.

1997-01-01

367

Analysis of protein gene products in cells with altered chromosome sets for the purpose of genetic mapping  

SciTech Connect

Two-dimensional electrophoresis was used for analyzing proteins in hybrid cells that contained single human chromosomes (chromosome 5, chromosome 21, or chromosomes 5 and 21) against the background of the mouse genome. By comparing the protein patterns of hybrid and parent cells (about 1000 protein fractions for each kind of cell), five fractions among proteins of hybrid cells were supposedly identified as human proteins. The genes of two of them are probably located on chromosome 5, and those of the other three on chromosome 21. Moreover, analysis of proteins in fibroblasts of patients with the cri-du-chat syndrome (5p-) revealed a decrease in the content of two proteins as compared with those in preparations of diploid fibroblasts. This fact was regarded as evidence that two corresponding genes are located on the short arm of chromosome 5. Methodological problems associated with the use of protein pattern analysis in cells with altered chromosome sets for the purposes of genetic mapping are discussed.

Shishkin, S.S.; Zakharov, S.F.; Gromov, P.S.; Shcheglova, M.V.; Kukharenko, V.I.; Shilov, A.G.; Matveeva, N.M.; Zhdanova, N.S.; Efimochkin, A.S.; Krokhina, T.B. [Medical Genetic Research Center, Moscow (Russian Federation)]|[Institute of Cytology and Genetics, Novosibirsk (Russian Federation)

1994-12-01

368

Spinal cord injury markedly altered protein expression patterns in the affected rat urinary bladder during healing stages.  

PubMed

The influence of spinal cord injury (SCI) on protein expression in the rat urinary bladder was assessed by proteomic analysis at different time intervals post-injury. After contusion SCI between T9 and T10, bladder tissues were processed by 2-DE and MALDI-TOF/MS at 6 hr to 28 days after SCI to identify proteins involved in the healing process of SCI-induced neurogenic bladder. Approximately 1,000 spots from the bladder of SCI and sham groups were visualized and identified. At one day after SCI, the expression levels of three protein were increased, and seven spots were down-regulated, including heat shock protein 27 (Hsp27) and heat shock protein 20 (Hsp20). Fifteen spots such as S100-A11 were differentially expressed seven days post-injury, and seven proteins including transgelin had altered expression patterns 28 days after injury. Of the proteins with altered expression levels, transgelin, S100-A11, Hsp27 and Hsp20 were continuously and variably expressed throughout the entire post-SCI recovery of the bladder. The identified proteins at each time point belong to eight functional categories. The altered expression patterns identified by 2-DE of transgelin and S100-A11 were verified by Western blot. Transgelin and protein S100-A11 may be candidates for protein biomarkers in the bladder healing process after SCI. PMID:21655070

Lee, Ji-Young; Kim, Bong Jo; Sim, Gyujin; Kim, Gyu-Tae; Kang, Dawon; Jung, Jae Hun; Hwa, Jeong Seok; Kwak, Yeon Ju; Choi, Yeon Jin; Park, Young Sook; Han, Jaehee; Lee, Cheol Soon; Kang, Kee Ryeon

2011-06-01

369

Genetic changes from artificial propagation of Pacific salmon affect the productivity and viability of supplemented populations  

USGS Publications Warehouse

Although several studies have shown genetic differences between hatchery and wild anadromous Pacific salmon (Oncorhynchus spp.), none has provided compelling evidence that artificial propagation poses a genetic threat to conservation of naturally spawning populations. When the published studies and three studies in progress are considered collectively, however, they provide strong evidence that the fitness for natural spawning and rearing can be rapidly and substantially reduced by artificial propagation. This issue takes on great importance in the Pacific Northwest where supplementation of wild salmon populations with hatchery fish has been identified as an important tool for restoring these populations. Recognition of negative aspects may lead to restricted use of supplementation, and better conservation, better evaluation, and greater benefits when supplementation is used.

Reisenbichler, R. R.; Rubin, S. P.

1999-01-01

370

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.  

PubMed

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection. PMID:21051598

Pereyra, Florencia; Jia, Xiaoming; McLaren, Paul J; Telenti, Amalio; de Bakker, Paul I W; Walker, Bruce D; Ripke, Stephan; Brumme, Chanson J; Pulit, Sara L; Carrington, Mary; Kadie, Carl M; Carlson, Jonathan M; Heckerman, David; Graham, Robert R; Plenge, Robert M; Deeks, Steven G; Gianniny, Lauren; Crawford, Gabriel; Sullivan, Jordan; Gonzalez, Elena; Davies, Leela; Camargo, Amy; Moore, Jamie M; Beattie, Nicole; Gupta, Supriya; Crenshaw, Andrew; Burtt, Noël P; Guiducci, Candace; Gupta, Namrata; Gao, Xiaojiang; Qi, Ying; Yuki, Yuko; Piechocka-Trocha, Alicja; Cutrell, Emily; Rosenberg, Rachel; Moss, Kristin L; Lemay, Paul; O'Leary, Jessica; Schaefer, Todd; Verma, Pranshu; Toth, Ildiko; Block, Brian; Baker, Brett; Rothchild, Alissa; Lian, Jeffrey; Proudfoot, Jacqueline; Alvino, Donna Marie L; Vine, Seanna; Addo, Marylyn M; Allen, Todd M; Altfeld, Marcus; Henn, Matthew R; Le Gall, Sylvie; Streeck, Hendrik; Haas, David W; Kuritzkes, Daniel R; Robbins, Gregory K; Shafer, Robert W; Gulick, Roy M; Shikuma, Cecilia M; Haubrich, Richard; Riddler, Sharon; Sax, Paul E; Daar, Eric S; Ribaudo, Heather J; Agan, Brian; Agarwal, Shanu; Ahern, Richard L; Allen, Brady L; Altidor, Sherly; Altschuler, Eric L; Ambardar, Sujata; Anastos, Kathryn; Anderson, Ben; Anderson, Val; Andrady, Ushan; Antoniskis, Diana; Bangsberg, David; Barbaro, Daniel; Barrie, William; Bartczak, J; Barton, Simon; Basden, Patricia; Basgoz, Nesli; Bazner, Suzane; Bellos, Nicholaos C; Benson, Anne M; Berger, Judith; Bernard, Nicole F; Bernard, Annette M; Birch, Christopher; Bodner, Stanley J; Bolan, Robert K; Boudreaux, Emilie T; Bradley, Meg; Braun, James F; Brndjar, Jon E; Brown, Stephen J; Brown, Katherine; Brown, Sheldon T; Burack, Jedidiah; Bush, Larry M; Cafaro, Virginia; Campbell, Omobolaji; Campbell, John; Carlson, Robert H; Carmichael, J Kevin; Casey, Kathleen K; Cavacuiti, Chris; Celestin, Gregory; Chambers, Steven T; Chez, Nancy; Chirch, Lisa M; Cimoch, Paul J; Cohen, Daniel; Cohn, Lillian E; Conway, Brian; Cooper, David A; Cornelson, Brian; Cox, David T; Cristofano, Michael V; Cuchural, George; Czartoski, Julie L; Dahman, Joseph M; Daly, Jennifer S; Davis, Benjamin T; Davis, Kristine; Davod, Sheila M; DeJesus, Edwin; Dietz, Craig A; Dunham, Eleanor; Dunn, Michael E; Ellerin, Todd B; Eron, Joseph J; Fangman, John J W; Farel, Claire E; Ferlazzo, Helen; Fidler, Sarah; Fleenor-Ford, Anita; Frankel, Renee; Freedberg, Kenneth A; French, Neel K; Fuchs, Jonathan D; Fuller, Jon D; Gaberman, Jonna; Gallant, Joel E; Gandhi, Rajesh T; Garcia, Efrain; Garmon, Donald; Gathe, Joseph C; Gaultier, Cyril R; Gebre, Wondwoosen; Gilman, Frank D; Gilson, Ian; Goepfert, Paul A; Gottlieb, Michael S; Goulston, Claudia; Groger, Richard K; Gurley, T Douglas; Haber, Stuart; Hardwicke, Robin; Hardy, W David; Harrigan, P Richard; Hawkins, Trevor N; Heath, Sonya; Hecht, Frederick M; Henry, W Keith; Hladek, Melissa; Hoffman, Robert P; Horton, James M; Hsu, Ricky K; Huhn, Gregory D; Hunt, Peter; Hupert, Mark J; Illeman, Mark L; Jaeger, Hans; Jellinger, Robert M; John, Mina; Johnson, Jennifer A; Johnson, Kristin L; Johnson, Heather; Johnson, Kay; Joly, Jennifer; Jordan, Wilbert C; Kauffman, Carol A; Khanlou, Homayoon; Killian, Robert K; Kim, Arthur Y; Kim, David D; Kinder, Clifford A; Kirchner, Jeffrey T; Kogelman, Laura; Kojic, Erna Milunka; Korthuis, P Todd; Kurisu, Wayne; Kwon, Douglas S; LaMar, Melissa; Lampiris, Harry; Lanzafame, Massimiliano; Lederman, Michael M; Lee, David M; Lee, Jean M L; Lee, Marah J; Lee, Edward T Y; Lemoine, Janice; Levy, Jay A; Llibre, Josep M; Liguori, Michael A; Little, Susan J; Liu, Anne Y; Lopez, Alvaro J; Loutfy, Mono R; Loy, Dawn; Mohammed, Debbie Y; Man, Alan; Mansour, Michael K; Marconi, Vincent C; Markowitz, Martin; Marques, Rui; Martin, Jeffrey N; Martin, Harold L; Mayer, Kenneth Hugh; McElrath, M Juliana; McGhee, Theresa A; McGovern, Barbara H; McGowan, Katherine; McIntyre, Dawn; Mcleod, Gavin X; Menezes, Prema; Mesa, Greg; Metroka, Craig E; Meyer-Olson, Dirk; Miller, Andy O; Montgomery, Kate; Mounzer, Karam C; Nagami, Ellen H; Nagin, Iris; Nahass, Ronald G; Nelson, Margret O; Nielsen, Craig; Norene, David L; O'Connor, David H; Ojikutu, Bisola O; Okulicz, Jason; Oladehin, Olakunle O; Oldfield, Edward C; Olender, Susan A; Ostrowski, Mario; Owen, William F; Pae, Eunice; Parsonnet, Jeffrey; Pavlatos, Andrew M; Perlmutter, Aaron M; Pierce, Michael N; Pincus, Jonathan M; Pisani, Leandro; Price, Lawrence Jay; Proia, Laurie; Prokesch, Richard C; Pujet, Heather Calderon; Ramgopal, Moti; Rathod, Almas; Rausch, Michael; Ravishankar, J; Rhame, Frank S

2010-12-10

371

Genetic modifiers affecting severity of epilepsy caused by mutation of sodium channel Scn2a  

Microsoft Academic Search

Mutations in the voltage-gated sodium channels SCN1A and SCN2A are responsible for several types of human epilepsy. Variable expressivity among family members is a common feature of these inherited epilepsies, suggesting that genetic modifiers may influence the clinical manifestation of epilepsy. The transgenic mouse model Scn2aQ54 has an epilepsy phenotype as a result of a mutation in Scn2a that slows

Sarah K. Bergren; Shu Chen; Andrzej Galecki; Jennifer A. Kearney

2005-01-01

372

Genetic mapping of QTLs affecting tree growth and architecture in Populus: implication for ideotype breeding  

Microsoft Academic Search

A segregated F2 progeny derived from two highly divergent poplar species, Populus trichocarpa and P. deltoides, was used to evaluate the genetic basis of canopy structure and function in a clonally replicated plantation. The QTLs of\\u000a large effect on growth, branch, and leaf traits were identified using the Populus linkage map constructed by 343 molecular markers. Stem height and harvest

R. L. Wu

1998-01-01

373

Genetic variation in immunoglobulin g receptor affects survival after lung transplantation.  

PubMed

Chronic rejection remains the most important complication after lung transplantation (LTx). There is mounting evidence that both rheumatoid arthritis and chronic rejection share similar inflammatory mechanisms. As genetic variants in the FCGR2A gene that encodes the immunoglobulin gamma receptor (IgGR) have been identified in rheumatoid arthritis, we investigated the relationship between a genetic variant in the IgGR gene and chronic rejection and mortality after LTx. Recipient DNA from blood or explant lung tissue of 418 LTx recipients was evaluated for the IgGR (rs12746613) polymorphism. Multivariate analysis was carried out, correcting for several co-variants. In total, 216 patients had the CC-genotype (52%), 137 had the CT-genotype (33%) and 65 had the TT-genotype (15%). Univariate analysis demonstrated higher mortality in the TT-genotype compared with both other genotypes (p?genetic variant in the IgGR is associated with higher mortality and more respiratory infections, although not with increased prevalence of chronic rejection, after LTx. PMID:24802006

Ruttens, D; Verleden, S E; Goeminne, P C; Vandermeulen, E; Wauters, E; Cox, B; Vos, R; Van Raemdonck, D E; Lambrechts, D; Vanaudenaerde, B M; Verleden, G M

2014-07-01

374

Genetic interactions affecting human gene expression identified by variance association mapping  

PubMed Central

Non-additive interaction between genetic variants, or epistasis, is a possible explanation for the gap between heritability of complex traits and the variation explained by identified genetic loci. Interactions give rise to genotype dependent variance, and therefore the identification of variance quantitative trait loci can be an intermediate step to discover both epistasis and gene by environment effects (GxE). Using RNA-sequence data from lymphoblastoid cell lines (LCLs) from the TwinsUK cohort, we identify a candidate set of 508 variance associated SNPs. Exploiting the twin design we show that GxE plays a role in ?70% of these associations. Further investigation of these loci reveals 57 epistatic interactions that replicated in a smaller dataset, explaining on average 4.3% of phenotypic variance. In 24 cases, more variance is explained by the interaction than their additive contributions. Using molecular phenotypes in this way may provide a route to uncovering genetic interactions underlying more complex traits. DOI: http://dx.doi.org/10.7554/eLife.01381.001

Brown, Andrew Anand; Buil, Alfonso; Vinuela, Ana; Lappalainen, Tuuli; Zheng, Hou-Feng; Richards, J Brent; Small, Kerrin S; Spector, Timothy D; Dermitzakis, Emmanouil T; Durbin, Richard

2014-01-01

375

Genetic and environmental factors affecting bone mineral density in large families.  

PubMed Central

This study assessed whether relatives with low bone mineral density (BMD) could be identified in five large families using historical, biochemical, and genetic markers for osteoporosis. Fifty of 65 relatives had their bone density and bone turnover markers measured, together with an assessment of their risk factors for osteoporosis. Only 33% (5/15) of siblings, 50% (6/12) of children and 43% (10/23) of nephews and nieces had entirely normal BMD. There was no difference in life-style risk factors for osteoporosis, history of previous fractures or body mass index between normal subjects and those with osteopenia or osteoporosis. Osteopenic individuals had a significantly higher than normal osteocalcin value. Within families, there was no clear association between BMD and any of the genetic markers (vitamin D receptor gene polymorphisms, COL 1A1 and COL 1A2 polymorphisms of the collagen gene), either alone or in combination. The addition of genetic markers to the other risk factors for low BMD did not improve the prediction of BMD. In conclusion, we suggest that the presence of osteoporosis in a first degree relative should be one of the clinical indications for bone density measurement as the individuals at risk would not be picked up by other methods.

Yeap, S. S.; Beaumont, M.; Bennett, A.; Keating, N. A.; White, D. A.; Hosking, D. J.

1998-01-01

376

Genetic and environmental factors affecting cryptic variations in gene regulatory networks  

PubMed Central

Background Cryptic genetic variation (CGV) is considered to facilitate phenotypic evolution by producing visible variations in response to changes in the internal and/or external environment. Several mechanisms enabling the accumulation and release of CGVs have been proposed. In this study, we focused on gene regulatory networks (GRNs) as an important mechanism for producing CGVs, and examined how interactions between GRNs and the environment influence the number of CGVs by using individual-based simulations. Results Populations of GRNs were allowed to evolve under various stabilizing selections, and we then measured the number of genetic and phenotypic variations that had arisen. Our results showed that CGVs were not depleted irrespective of the strength of the stabilizing selection for each phenotype, whereas the visible fraction of genetic variation in a population decreased with increasing strength of selection. On the other hand, increasing the number of different environments that individuals encountered within their lifetime (i.e., entailing plastic responses to multiple environments) suppressed the accumulation of CGVs, whereas the GRNs with more genes and interactions were favored in such heterogeneous environments. Conclusions Given the findings that the number of CGVs in a population was largely determined by the size (order) of GRNs, we propose that expansion of GRNs and adaptation to novel environments are mutually facilitating and sustainable sources of evolvability and hence the origins of biological diversity and complexity.

2013-01-01

377

Genetic Influences on the Dynamics of Pain and Affect in Fibromyalgia  

PubMed Central

Objective The purpose of the present investigation was to determine if variation in the catechol-O-methyltransferase (COMT) and mu-opioid receptor (OPRM1) genes is associated with pain-related positive affective regulation in fibromyalgia (FM). Design Forty-six female FM patients completed an electronic diary that included daily assessments of positive affect and pain. Between- and within-person analyses were conducted with multilevel modeling. Main Outcome Measure Daily positive affect was the primary outcome measure. Results Analyses revealed a significant gene × experience interaction for COMT, such that individuals with met/met genotype experienced a greater decline in positive affect on days when pain was elevated than did either val/met or val/val individuals. This finding supports a role for catecholamines in positive affective reactivity to FM pain. A gene × experience interaction for OPRM1 also emerged, indicating that individuals with at least one asp40 allele maintained greater positive affect despite elevations in daily pain than those homozygous for the asn40 allele. This finding may be explained by the asp40 allele’s role in reward processing. Conclusions Together, the findings offer researchers ample reason to further investigate the contribution of the catecholamine and opioid systems, and their associated genomic variants, to the still poorly understood experience of FM.

Finan, Patrick H.; Zautra, Alex J.; Davis, Mary C.; Lemery-Chalfant, Kathryn

2011-01-01

378

Genetics  

MedlinePLUS

... Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers ... The chromosomes are made up of strands of genetic information called DNA. Genes are sections of DNA. ...

379

TRIB3 R84 variant affects glucose homeostasis by altering the interplay between insulin sensitivity and secretion  

Microsoft Academic Search

Aims\\/hypothesis  The results of studies on the genetics of complex traits need to be replicated and to reach robust statistical significance\\u000a before they can be considered as established. We here tried to replicate the previously reported association between the TRIB3 Q84R polymorphism (rs2295490) and glucose homeostasis.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Three samples of Europeans with fasting glucose n?=?791), the association between TRIB3 Q84R and impaired

S. Prudente; R. Baratta; F. Andreozzi; E. Morini; M. G. Farina; A. Nigro; M. Copetti; F. Pellegrini; E. Succurro; L. Di Pietrantonio; C. Brufani; F. Barbetti; B. Dallapiccola; G. Sesti; V. Trischitta; L. Frittitta

2010-01-01

380

The Role of Genetic Sex in Affect Regulation and Expression of GABA-Related Genes Across Species.  

PubMed

Although circulating hormones and inhibitory gamma-aminobutyric acid (GABA)-related factors are known to affect mood, considerable knowledge gaps persist for biological mechanisms underlying the female bias in mood disorders. Here, we combine human and mouse studies to investigate sexual dimorphism in the GABA system in the context of major depressive disorder (MDD) and then use a genetic model to dissect the role of sex-related factors in GABA-related gene expression and anxiety-/depressive-like behaviors in mice. First, using meta-analysis of gene array data in human postmortem brain (N?=?51 MDD subjects, 50 controls), we show that the previously reported down-regulation in MDD of somatostatin (SST), a marker of a GABA neuron subtype, is significantly greater in women with MDD. Second, using gene co-expression network analysis in control human subjects (N?=?214; two frontal cortex regions) and expression quantitative trait loci mapping (N?=?170 subjects), we show that expression of SST and the GABA-synthesizing enzymes glutamate decarboxylase 67 (GAD67) and GAD65 are tightly co-regulated and influenced by X-chromosome genetic polymorphisms. Third, using a rodent genetic model [Four Core Genotypes (FCG) mice], in which genetic and gonadal sex are artificially dissociated (N???12/group), we show that genetic sex (i.e., X/Y-chromosome) influences both gene expression (lower Sst, Gad67, Gad65 in XY mice) and anxiety-like behaviors (higher in XY mice). This suggests that in an intact male animal, the observed behavior represents the outcomes of male genetic sex increasing and male-like testosterone decreasing anxiety-like behaviors. Gonadal sex was the only factor influencing depressive-like behavior (gonadal males?genetic sex) on GABA-related genes and anxiety-like behaviors. PMID:24062698

Seney, Marianne L; Chang, Lun-Ching; Oh, Hyunjung; Wang, Xingbin; Tseng, George C; Lewis, David A; Sibille, Etienne

2013-01-01

381

Genetic investigations on 8 patients affected by ring 20 chromosome syndrome  

PubMed Central

Background Mosaic Chromosome 20 ring [r(20)] is a chromosomal disorder associated with a rare syndrome characterized by a typical seizure phenotype, a particular electroclinical pattern, cognitive impairment, behavioural problems and absence of a consistent pattern of dysmorphology. The pathogenic mechanism underlying seizures disorders in r(20) syndrome is still unknown. We performed a detailed clinical and genetic study on 8 patients with r(20) chromosome, aimed at detecting the genetic mechanism underlying r(20) syndrome. Methods We submitted 8 subjects with a previous diagnosis of ring 20 chromosome mosaicism to a clinical re-evaluation, followed by cytogenetic, FISH, array-CGH and molecular analyses. The genetic study was also extended to their available parents. Results FISH and array-CGH experiments indicate that cryptic deletions on chromosome 20 are not the cause of the r(20) chromosome associated disease. Moreover, no evidence of chromosome 20 uniparental disomy was found. Analysis of FISH signals given by variant in size alphoid tandem repeats probes on the normal chromosome 20 and the r(20) chromosome in the mosaic carriers suggests that the r(20) chromosome is the same chromosome not circularized in the "normal" cell line. Conclusions Higher percentages of r(20) chromosome cells were observed to be related with precocious age at seizure onset and with resistance to antiepileptic drug treatment. Behavioural problems also seem to be associated with higher percentages of r(20) chromosome cells. Our results suggest that an epigenetic mechanism perturbing the expression of genes close to the telomeric regions, rather than deletion of genes located at the distal 20p and/or 20q regions, may underlie the manifestation of r(20) syndrome.

2010-01-01

382

The Genetics of Common Variation affecting Platelet Development, Function and Pharmaceutical Targeting  

PubMed Central

Summary Common variant effects on human platelet function and response to anti-platelet treatment have traditionally been studied using candidate gene approaches involving a limited number of variants and genes. These studies have often been undertaken in clinically defined cohorts. More recently, studies have applied genome-wide scans in larger population samples than prior candidate studies, in some cases scanning relatively healthy individuals. These studies demonstrate synergy with some prior candidate gene findings (e.g., GP6, ADRA2A) but also uncover novel loci involved in platelet function. Here, I summarise findings on common genetic variation influencing platelet development, function and therapeutics. Taken together, candidate gene and genome-wide studies begin to account for common variation in platelet function and provide information that may ultimately be useful in pharmacogenetic applications in the clinic. More than 50 loci have been identified with consistent associations with platelet phenotypes in ?2 populations. Several variants are under further study in clinical trials relating to anti-platelet therapies. In order to have useful clinical applications, variants must have large effects on a modifiable outcome. Regardless of clinical applications, studies of common genetic influences, even of small effect, offer additional insights into platelet biology including the importance of intracellular signalling and novel receptors. Understanding of common platelet-related genetics remains behind parallel fields (e.g., lipids, blood pressure) due to challenges in phenotype ascertainment. Further work is necessary to discover and characterise loci for platelet function, and to assess whether these loci contribute to disease aetiologies or response to therapeutics.

Johnson, Andrew D.

2011-01-01

383

Synergistic ablation does not affect atrophy or altered myosin heavy chain expression in the non-weight bearing soleus muscle  

NASA Technical Reports Server (NTRS)

The purpose of this study was to investigate whether the soleus muscle undergoes atrophy and alterations in myosin heavy chain (MHC) composition during non-weight bearing in the absence of synergists. Thirty-two female rats were randomly assigned to four groups: control (C), synergistic ablation (ABL) of the gastrocnemius and plantaris muscles to overload the soleus muscle, hindlimb suspension (HLS), or a combination of synergistic ablation and hindlimb suspension (HLS-ABL). After 28 days of hindlimb suspension, soleus atrophy was more pronounced in HLS (58%) than in HLS-ABL (43%) rats. Compared to C rats, non-weight bearing decreased mixed and myofibrillar protein contents and Type I MHC 49%, 45%, and 7%, respectively, in HLS animals. In addition, de novo expression of fast Type IIx and Type IIb MHC (5% and 2%, respectively) was observed in HLS animals. Similarly, when compared to C rats, mixed and myofibrillar protein contents and Type I MHC decreased 43%, 46%, and 4%, respectively, in HLS-ABL animals. Also, de novo expression of Type IIx (4%) and IIb (1%) MHC was observed. Collectively, these data indicate that the loss of muscle protein and Type I MHC, and the de novo expression of Type IIx and Type IIb MHC in the rat soleus occur independently of the presence of synergists during non-weight bearing. Furthermore, these results confirm the contention that soleus mass and MHC expression are highly sensitive to alterations in mechanical load.

Linderman, J. K.; Talmadge, R. J.; Gosselink, K. L.; Tri, P. N.; Roy, R. R.; Grindeland, R. E.

1996-01-01

384

Polybrominated diphenyl ethers do not affect metamorphosis but alter the proteome of the invasive slipper limpet Crepidula onyx.  

PubMed

Man-made polybrominated diphenyl ethers (PBDEs) used as flame retardants in various consumer products may be harmful to marine organisms. Larvae of some marine invertebrates, especially invasive species, can develop resistance to PBDEs through altered protein expression patterns or proteome plasticity. This is the first report of a proteomics approach to study BDE-47 induced molecular changes in the invasive limpet Crepidula onyx. Larvae of C. onyx were cultured for 5 days (hatching to metamorphosis) in the presence of BDE-47 (1 ?g L(-1)). Using a 2-DE proteomics approach with triple quadrupole and high-resolution TOF-MS, we showed that BDE-47 altered the proteome structure but not the growth or metamorphosis of C. onyx larvae. We found eight significant differentially expressed proteins in response to BDE-47, deemed the protein expression signature, consisting of cytoskeletal, stress tolerance, metabolism and energy production related proteins. Our data suggest C. onyx larvae have adequate proteome plasticity to tolerate BDE-47 toxicity. PMID:23743271

Mukherjee, Joy; Po, Beverly H K; Chiu, Jill M Y; Wu, Rudolf S S; Qian, Pei-Yuan; Thiyagarajan, Vengatesen

2013-08-15

385

Genetic variation in pro-melanin-concentrating hormone gene affects carcass traits in cattle  

US Patent & Trademark Office Database

An A-to-T single nucleotide polymorphism (SNP) identified at position -134 relative to the ATG start codon, in the Pro-Melanin-Concentrating Hormone (PMCH) gene of Bos taurus and Bos indicus animals of both British and Continental type, is associated with changes in the average fat and grade fat. The A allele occurred in 67% of cattle examined and was associated with higher average fat and grade fat levels. The cattle industry may make use of these findings to genetically select for, and/or sort, cattle using this SNP.

2011-08-30

386

Sampling issues affecting accuracy of likelihood-based classification using genetical data  

USGS Publications Warehouse

We demonstrate the effectiveness of a genetic algorithm for discovering multi-locus combinations that provide accurate individual assignment decisions and estimates of mixture composition based on likelihood classification. Using simulated data representing different levels of inter-population differentiation (Fst ~ 0.01 and 0.10), genetic diversities (four or eight alleles per locus), and population sizes (20, 40, 100 individuals in baseline populations), we show that subsets of loci can be identified that provide comparable levels of accuracy in classification decisions relative to entire multi-locus data sets, where 5, 10, or 20 loci were considered. Microsatellite data sets from hatchery strains of lake trout, Salvelinus namaycush, representing a comparable range of inter-population levels of differentiation in allele frequencies confirmed simulation results. For both simulated and empirical data sets, assignment accuracy was achieved using fewer loci (e.g., three or four loci out of eight for empirical lake trout studies). Simulation results were used to investigate properties of the 'leave-one-out' (L1O) method for estimating assignment error rates. Accuracy of population assignments based on L1O methods should be viewed with caution under certain conditions, particularly when baseline population sample sizes are low (<50).

Guinand, B.; Scribner, K. T.; Topchy, A.; Page, K. S.; Punch, W.; Burnham-Curtis, M. K.

2004-01-01

387

Specific alterations in complement protein activity of little brown myotis (Myotis lucifugus) hibernating in white-nose syndrome affected sites.  

PubMed

White-nose syndrome (WNS) is the most devastating condition ever reported for hibernating bats, causing widespread mortality in the northeastern United States. The syndrome is characterized by cutaneous lesions caused by a recently identified psychrophilic and keratinophylic fungus (Geomyces destructans), depleted fat reserves, atypical behavior, and damage to wings; however, the proximate cause of mortality is still uncertain. To assess relative levels of immunocompetence in bats hibernating in WNS-affected sites compared with levels in unaffected bats, we describe blood plasma complement protein activity in hibernating little brown myotis (Myotis lucifugus) based on microbicidal competence assays using Escherichia coli, Staphylococcus aureus and Candida albicans. Blood plasma from bats collected during mid-hibernation at WNS-affected sites had higher bactericidal ability against E. coli and S. aureus, but lower fungicidal ability against C. albicans when compared with blood plasma from bats collected at unaffected sites. Within affected sites during mid-hibernation, we observed no difference in microbicidal ability between bats displaying obvious fungal infections compared to those without. Bactericidal ability against E. coli decreased significantly as hibernation progressed in bats collected from an affected site. Bactericidal ability against E. coli and fungicidal ability against C. albicans were positively correlated with body mass index (BMI) during late hibernation. We also compared complement activity against the three microbes within individuals and found that the ability of blood plasma from hibernating M. lucifugus to lyse microbial cells differed as follows: E. coli>S. aureus>C. albicans. Overall, bats affected by WNS experience both relatively elevated and reduced innate immune responses depending on the microbe tested, although the cause of observed immunological changes remains unknown. Additionally, considerable trade-offs may exist between energy conservation and immunological responses. Relationships between immune activity and torpor, including associated energy expenditure, are likely critical components in the development of WNS. PMID:22140440

Moore, Marianne S; Reichard, Jonathan D; Murtha, Timothy D; Zahedi, Bita; Fallier, Renee M; Kunz, Thomas H

2011-01-01

388

Specific Alterations in Complement Protein Activity of Little Brown Myotis (Myotis lucifugus) Hibernating in White-Nose Syndrome Affected Sites  

PubMed Central

White-nose syndrome (WNS) is the most devastating condition ever reported for hibernating bats, causing widespread mortality in the northeastern United States. The syndrome is characterized by cutaneous lesions caused by a recently identified psychrophilic and keratinophylic fungus (Geomyces destructans), depleted fat reserves, atypical behavior, and damage to wings; however, the proximate cause of mortality is still uncertain. To assess relative levels of immunocompetence in bats hibernating in WNS-affected sites compared with levels in unaffected bats, we describe blood plasma complement protein activity in hibernating little brown myotis (Myotis lucifugus) based on microbicidal competence assays using Escherichia coli, Staphylococcus aureus and Candida albicans. Blood plasma from bats collected during mid-hibernation at WNS-affected sites had higher bactericidal ability against E. coli and S. aureus, but lower fungicidal ability against C. albicans when compared with blood plasma from bats collected at unaffected sites. Within affected sites during mid-hibernation, we observed no difference in microbicidal ability between bats displaying obvious fungal infections compared to those without. Bactericidal ability against E. coli decreased significantly as hibernation progressed in bats collected from an affected site. Bactericidal ability against E. coli and fungicidal ability against C. albicans were positively correlated with body mass index (BMI) during late hibernation. We also compared complement activity against the three microbes within individuals and found that the ability of blood plasma from hibernating M. lucifugus to lyse microbial cells differed as follows: