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PubMed2004

Genetic variation in bovine mononuclear leukocyte responses to dexamethasone.

The objective of this study was to determine whether bovine mononuclear leukocytes exhibit genetic variability prior to and after a glucocorticoid hormone challenge in vivo. Test animals included 60 pedigreed Holstein bulls treated on 3 consecutive days with dexamethasone and 5 untreated control bulls. Eight indicator traits of leukocyte responsiveness to dexamethasone included the percentages of circulating B cells, T cells (CD4, CD8, and workshop cluster 1 molecule expressed by bovine gammadelta T cell), major histocompatibility complex (MHC) I and II expressing cells, and mean expressions of surface MHC I and MHC II on circulating cells. Blood for this work was collected from each test bull 10 times before, during, and after dexamethasone administration, with corresponding samples taken for control bulls. Random regression models with treatment-specific serial correlation were applied to the leukocyte data sets to estimate genetic and nongenetic sources of variation in baseline and recovery aspects of the traits. All traits responded predictably to glucocorticoid challenge. Genetic variation was observed in baseline measurements of all traits, with heritability estimates ranging from 0.21 +/- 0.03 to 0.60 +/- 0.06. Genetic variation in linear recovery from nadir values following dexamethasone administration was significant only for percentage CD4, percentage CD8, and for surface expression of MHC II. The genetic covariance between basal and linear recovery was positive and significant for percentage CD4, percentage CD8, and MHC II expression. The bovine lymphocyte antigen DRB3.2 locus accounted for significant proportions of total variation in percentage MHC II cells and MHC I expression. These results suggest that genetic variability exists for important basal and glucocorticoid-modified phenotypes of bovine mononuclear leukocytes, implying that immunocompetence traits impacted by this stress hormone may be enhanced by genetic selection.

Animals↗
PubMed2000

Mild preconditioning and low-level engraftment confer methotrexate resistance in mice transplanted with marrow expressing drug-resistant dihydrofolate reductase activity.

Effective engraftment of hematopoietic cells targeted for gene transfer is facilitated by cytoreductive preconditioning such as high-dose total body irradiation (TBI). To minimize the adverse side effects associated with TBI, experiments were conducted to determine whether sublethal doses of TBI would allow sufficient engraftment of MTX-resistant hematopoietic cells to confer survival on recipient mice administered MTX. FVB/N animals were administered 1, 2, or 4 Gy TBI (lethal dose, 8.5 Gy), transplanted with 10(7) FVB/N transgenic marrow cells expressing an MTX-resistant dihydrofolate reductase (DHFR) transgene, and then administered MTX daily for 60 days. Control mice administered 1 Gy with or without subsequent transplantation of normal marrow cells succumbed to MTX toxicity by day 45. In contrast, nearly all animals transplanted with transgenic marrow survived MTX administration, regardless of the TBI dose used for preconditioning. The donor DHFR transgenic marrow engraftment level was proportional to the preconditioning dose of TBI but was surprisingly reduced in animals given 2 or 4 Gy TBI and subsequently administered MTX when compared with control animals administered phosphate-buffered saline. Animals preconditioned with 1 Gy were also protected from MTX toxicity when transplanted with reduced amounts (5 x 10(6) and 1 x 10(6) cells) of DHFR transgenic donor marrow, resulting in low-level (approximately 1%) engraftment. In conclusion, very mild preconditioning allows sufficient low-level engraftment of genetically modified stem cells for in vivo manifestation of the modified phenotype, suggesting the usefulness of mild preconditioning regimens in human gene therapy trials targeting hematopoietic stem cells. (Blood. 2000;96:1334-1341)

Animals↗
PubMedDate not supplied

[Distribution of single nucleotide polymorphisms of IL-10 gene in patients with mucoviscidosis].

Distribution of interleukin-10 promoter-1082 G-->A single nucleotide polimorphism (SNP) in the group of cystic fibrosis (CF) patients has been studied. As a whole 42 CF patients and 73 persons of the control group were genotyped for IL-10 promoter-1082 G-->A SNP. The frequences of IL-10-1082 G-allele and GG high expression genotype increased significantly in CF patients in comparison to the control group. In addition, study of IL-10-1082 SNP distribution in the separate CF groups showed statistically significant increasing of the G-allele and GG-genotype frequencies in the subgroup of homozygous delF508 cariers. The possible role of IL-10 promoter SNP as a phenotype modifiers at different CF genotypes is examined.

Child↗
PubMedDate not supplied

Different susceptibility of lung cell lines to inhibitors of tumor promotion and inducers of differentiation.

Histologically distinct lung tumor and normal cell lines were treated with a variety of potential inhibitors of cell growth such as inducers of cell differentiation, inhibitors of protein kinase C and inhibitors of tumor promotion. The response was assessed by 3H thymidine incorporation and cloning efficiency. Both phorbol retinoate acetate and mezerein stimulated growth in lung normal cell lines (human fibroblastic PEH cells and rat epithelial TP9 cells) while inhibiting growth in lung tumor cell lines (human small-cell cancer-derived cell line IRSC-10M and adenocarcinoma-derived cell line A549). Likewise, the hydrophobic peptide melittin did not inhibit growth and cloning efficiency of normal cells at 1 microM, a concentration which prevented proliferation in tumor cells. Protein kinase C inhibitors, chlorpromazine, trifluoperazine and 1-(5 isoquinolinylsulfonyl) 2-methylpiperazine, were much more effective on proliferation of IRSC-1OM than of A549 cells. In contrast, the latter cells were more susceptible to anti-promoters such as glycyrrhetic acid, an anti-inflammatory agent, and 3,4',2', 4'-tetrahydroxychalcone or 2,3,5-trimethyl-6 (12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone, two inhibitors of lipoxygenase, a key enzyme in arachidonate metabolism. Our results provide evidence that small-cell carcinoma-derived cells, in contrast with adenocarcinoma-derived cells, are growth-inhibited by protein kinase C inhibitors and poorly dependent on the arachidonate metabolism. This difference in responsiveness suggests that different growth signalling pathways are preferentially triggered in these histologically distinct lung tumor cell lines. As a consequence, the proper susceptibility of tumor cells to phenotype modifiers has to be taken into account in cancer therapy.

Arachidonic Acid↗
PubMed1991

Platelet-derived growth factor-BB and transforming growth factor beta 1 selectively modulate glycosaminoglycans, collagen, and myofibroblasts in excisional wounds.

Recombinant platelet-derived growth factor (PDGF) and transforming growth factor beta 1 (TGF-beta 1) influence the rate of extracellular matrix formed in treated incisional wounds. Because incisional healing processes are difficult to quantify, a full-thickness excisional wound model in the rabbit ear was developed to permit detailed analyses of growth-factor-mediated tissue repair. In the present studies, quantitative and qualitative differences in acute inflammatory cell influx, glycosaminoglycan (GAG) deposition, collagen formation, and myofibroblast generation in PDGF-BB (BB homodimer)- and TGF-beta 1-treated wounds were detected when analyzed histochemically and ultrastructurally. Although both growth factors significantly augmented extracellular matrix formation and healing in 10-day wounds compared with controls (P less than 0.002). PDGF-BB markedly increased macrophage influx and GAG deposition, whereas TGF-beta 1 selectively induced significantly more mature collagen bundles at the leading edge of new granulation tissue (P = 0.007). Transforming growth factor-beta 1-treated wound fibroblasts demonstrated active collagen fibrillogenesis and accretion of subfibrils at the ultrastructural level. Myofibroblasts, phenotypically modified fibroblasts considered responsible for wound contraction, were observed in control, but were absent in early growth-factor-treated granulating wounds. These results provide important insights into the mechanisms of soft tissue repair and indicate that 1) PDGF-BB induces an inflammatory response and provisional matrix synthesis within wounds that is qualitatively similar but quantitatively increased compared with normal wounds; 2) TGF-beta 1 preferentially triggers synthesis and more rapid maturation of collagen within early wounds; and 3) both growth factors inhibit the differentiation of fibroblasts into myofibroblasts, perhaps because wound contraction is not required, due to increased extracellular matrix synthesis.

Animals↗
PubMed1991

Molecular biology of vascular hypertrophy.

In chronic models of hypertension such as the spontaneously hypertensive rat (SHR), thickening of the media of large arteries occurs mainly through smooth muscle cell (SMC) hypertrophy accompanied by DNA replication resulting in large polyploid cells. In resistance vessels of SHR, medial hypertrophy occurs through a hyperplastic response. It has been suggested that this hyperplasia is due to mitogens such as platelet-derived growth factor (PDGF), while the hypertrophied polyploid cells occur from stimulation by angiotensin II from within the vessel wall. Angiotensin II activates many of the same cellular pathways as PDGF, including stimulation of phospholipase C, mobilization of intracellular calcium and activation of Na+/H+ exchange. Both induce transient increases in the proto-oncogenes c-fos and c-myc. However, a possible explanation for the difference in SMC response may be involvement of an intracellular pathway stimulated by PDGF (but not by angiotensin II), such as stimulation of JE (a cytokine-like molecule), which may activate transcriptional events necessary for mitogenesis. In atherosclerosis vascular hypertrophy occurs in the form of focal intimal thickening and results from hyperplasia of diploid SMC and their greatly increased production of extracellular matrix, (particularly collagen) and the accumulation of intra- and extracellular lipid. The SMC involved in atherogenesis are phenotypically modified compared with the SMC of undiseased regions, and amongst other features have a lower volume fraction of myofilaments (Vvmyo). Associated with modulation to a low Vvmyo are increases in SMC expression of mRNA for collagens type I (alpha 1 and alpha 2) and type III (alpha 1), elastin, fibronectin, as well as massive increases in collagen protein (26- to 45-fold), glycosaminoglycans (5-fold), and lipid accumulation (7-fold).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Improvement of dental development in osteopetrotic mice by maternal vitamin D3 sulfate administration.

Utilizing the microphthalamic mouse, (mi/mi) as a model of osteopetrosis, vitamin D3 (cholecalciferol) was administered prenatally and postnatally to study its effects on tooth development and subsequent eruption. It has previously been reported that vitamin D3 crosses the placental barrier and is absorbed into mammary gland milk. Fifteen heterozygotes (+/mi) were used as breeders. There were three study groups: A) 5.0 ng/gm cholecalciferol sulfate; B) 2.5 ng/gm cholecalciferol sulfate; and C) no therapy. Intraperitoneal injections were administered three times per week, beginning when pregnancy was evident, and continuing for 4 additional weeks during lactation. Approximately half of the 59 offspring were sacrificed at age 1 day and the other half at 4 weeks. The former group was studied for crown development, and the latter group was studied for root development and eruption. When the osteopetrotic offspring of group A were compared with osteopetrotic offspring of group C, crown development and tooth eruption were substantially more advanced. Parameters examined were maturity of the ameloblasts and odontoblasts, dentin and enamel formation, root sheath development, status of eruption, and degree of apex closure. It was concluded that cholecalciferol sulfate significantly improves tooth development and subsequent eruption in the osteopetrotic mouse. A genetic disease has had its phenotype modified by vitamin therapy during gestation.

Animals↗
PubMed1986

Ontogeny of MHC-linked, T cell-mediated suppression is regulated by the T cell genotype.

Regulation of T cell effector functions by major histocompatibility complex (MHC) gene products has been extensively researched. Investigations in this area have established several important concepts of immunobiology. First, genes within the I-region of the MHC profoundly affect development of immune responses through their effects on cell-cell interactions. In the course of analyzing antigen-induced T cell activation, investigators identified specific Ir-genes by demonstrating that certain strains of mice were unable to develop immunity to defined antigens. It is now accepted that immune response defects in murine species are potentiated by cell surface molecules encoded within the I-subregion of the MHC, called Ia. Those molecules coded within the I-A subregion have the potential to be expressed by many different cell types. Second, induction of helper T cell effector function requires recognition of antigen in association with I-region encoded, cell surface molecules. For example, only a single structural combination of antigenic determinant and Ia molecule can deliver the inductive signal(s) to potential helper T cells. This fundamental aspect of helper T cell activation, now documented in numerous experimental systems, is referred to as MHC- or I-region restricted, antigen recognition. MHC-restriction is a characteristic of T cells mediating delayed-type hypersensitivity, help, and cytotoxicity. Third, several lines of evidence have established that T cell recognition of self-MHC molecules is a modifiable phenotype; conferred by a receptor having both variable and constant regions and not encoded by genes in the MHC. The development of both thymic grafted homozygous nu/nu mice and irradiation-induced bone marrow chimeras as experimental models resulted in a better understanding of the mechanism of MHC-restricted, antigen recognition. It was observed that expression of MHC gene products by the host is sufficient to select a new immune response phenotype for cellular interactions. The selection process takes place during T cell maturation, in the absence of antigen and under the dominant influence of the thymus, even though there is ample evidence for selective pressure in the extrathymic environment. For example, the self-MHC recognition repertoire of T cells in P----F1 chimeras undergoes an initial expansion which results in an F1 immune response phenotype. This expansion is followed by an apparent contraction back to the immune response phenotype of the parental donor. The contraction is time dependent and reflects accessory cell turnover in the irradiated host.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Lethal vaccinia infection in cyclophosphamide-suppressed mice is associated with decreased expression of Thy-1, Lyt-2 and L3T4 and diminished IL-2 production in surviving T cells.

Prior treatment of C57BL/6J mice with 300 mg/kg of cyclophosphamide (Cy) converts a subclinical infection with vaccinia virus to a lethal disease. This is accompanied by a loss of more than 80% of spleen cells and a decreased capacity, on a cell-for-cell basis, to develop virus-immune cytotoxic T lymphocytes (CTL), although the frequency of CTL precursors among surviving T cells is not greatly modified. Phenotypically, the surviving T cells express low levels of cell-surface Thy-1, Lyt-2 and L3T4 and, upon stimulation, are less able to produce IL-2 for more than 1 week following Cy treatment. The defect in capacity to generate CTL effectors both in vitro and in vivo can be corrected by providing an exogenous source of IL-2. These experiments indicate that a single dose of Cy induces changes in T cells that persist throughout the development of an immune response. Such effects are in accordance with the known property of Cy to mediate DNA damage.

Animals↗
PubMedDate not supplied

[The comparative identification of Campylobacter strains by traditional enzymatic tests and the gene amplification reaction].

39 strains of Campylobacter isolated from 153 diarrhoeal children (0-3 years) were comparatively identified by the traditional enzymatic tests and by the Polymerase Chain reaction (PCR). The hippurate hydrolysis test appreciated 27 strains as Campylobacter jejuni (69.2%) and 12 strains as Campylobacter coli (30.8%). The P.C.R. realised in France has appreciated 29 strains as Campylobacter jejuni (74.4%) and 10 strains as Campylobacter coli (25.6%). The analysis of the results discrepancy permitted to reveal 4 strains appreciated by two methods as different ones. The supplementary examinations of dubious strains by API-Campy test systems permitted to confirm the PCR results and to explain their divergence in contrast to hippurate hydrolysis test results. Two results were appreciated as false ones for hippurate test (5.1%). Other two errors were due to two hippurate-negative Campylobacter jejuni strains. The PCR results were exact, without errors and not influenced by modified phenotypical characters of Campylobacter strains. Thus, the efficiency of the identification by the hippurate hydrolysis test was only 89.7% in comparison to 100% efficiency of PCR (p<0.05). The discrepant cases indicated the necessity of supplementary differentiation of hippurate-negative Campylobacter strains including genetical methods in order to define the species exactly and to prevent the grave consequences especially characteristic of Campylobacter jejuni.

Bacteriological Techniques↗
PubMed2003

MC1R mutations modify the classic phenotype of oculocutaneous albinism type 2 (OCA2).

The heterogeneous group of disorders known as oculocutaneous albinism (OCA) shares cutaneous and ocular hypopigmentation associated with common developmental abnormalities of the eye. Mutations of at least 11 loci produce this phenotype. The majority of affected individuals develop some cutaneous melanin; this is predominantly seen as yellow/blond hair, whereas fewer have brown hair. The OCA phenotype is dependent on the constitutional pigmentation background of the family, with more OCA pigmentation found in families with darker constitutional pigmentation, which indicates that other genes may modify the OCA phenotype. Sequence variation in the melanocortin-1 receptor (MC1R) gene is associated with red hair in the normal population, but red hair is unusual in OCA. We identified eight probands with OCA who had red hair at birth. Mutations in the P gene were responsible for classic phenotype of oculocutaneous albinism type 2 (OCA2) in all eight, and mutations in the MC1R gene were responsible for the red (rather than yellow/blond) hair in the six of eight who continued to have red hair after birth. This is the first demonstration of a gene modifying the OCA phenotype in humans.

Adolescent↗
PubMed1966

Genetic modifiers of the phenotypic level of deoxyribonucleic acid-conferred novobiocin resistance in Haemophilus.

Leidy, Grace (Columbia University, New York, N.Y.), Iris Jaffee, and Hattie E. Alexander. Genetic modifiers of the phenotypic level of deoxyribonucleic acid-conferred novobiocin resistance in Haemophilus. J. Bacteriol. 92:1464-1468. 1966.-An apparent increase in novobiocin resistance in Haemophilus aegyptius after a second exposure to a particular H. influenzae transforming deoxyribonucleic acid was shown to be the result not of multi-step transformation but of the action of a gene functioning as an enhancement modifier. The modifier is very closely linked to a streptomycin resistance gene (which is linked to a novobiocin resistance marker); it affects the natural degree of resistance to both novobiocin and kanamycin to a measurable degree. Evidence of a repressor of the enhancement modifier is reported.

DNA, Bacterial↗
PubMed1991

Modified immunoblotting technique for phenotyping lipoprotein(a).

We describe a modified immunoblotting method for phenotyping lipoprotein(a) [Lp(a)]. This immunoblotting procedure uses commercially available reagents that have a long shelf life. The method is sensitive and takes only 18 microL of sera. Lp(a) phenotyping can be performed on sera stored at 4 degrees C for as much as a week or at -80 degrees C for as long as a year. In a study of 145 unrelated healthy subjects, we found Lp(a) allelic frequencies of LpF = 1.8%, LpB = 2.6%, LpS1 = 5.1%, LpS2 = 14.8%, LpS3 = 35.9%, LpS4 = 11.6%, and LpO = 28.0%.

Alleles↗
PubMed2001

A systematic screen for dominant second-site modifiers of Merlin/NF2 phenotypes reveals an interaction with blistered/DSRF and scribbler.

Merlin, the Drosophila homologue of the human tumor suppressor gene Neurofibromatosis 2 (NF2), is required for the regulation of cell proliferation and differentiation. To better understand the cellular functions of the NF2 gene product, Merlin, recent work has concentrated on identifying proteins with which it interacts either physically or functionally. In this article, we describe genetic screens designed to isolate second-site modifiers of Merlin phenotypes from which we have identified five multiallelic complementation groups that modify both loss-of-function and dominant-negative Merlin phenotypes. Three of these groups, Group IIa/scribbler (also known as brakeless), Group IIc/blistered, and Group IId/net, are known genes, while two appear to be novel. In addition, two genes, Group IIa/scribbler and Group IIc/blistered, alter Merlin subcellular localization in epithelial and neuronal tissues, suggesting that they regulate Merlin trafficking or function. Furthermore, we show that mutations in scribbler and blistered display second-site noncomplementation with one another. These results suggest that Merlin, blistered, and scribbler function together in a common pathway to regulate Drosophila wing epithelial development.

Alleles↗
PubMed2000

Partial rescue of the ocular retardation phenotype by genetic modifiers.

The or(J) allele of the murine ocular retardation mutation is caused by a premature stop codon in the homeodomain of the Chx10 gene. When expressed on an inbred 129/Sv strain, the or(J) phenotype is characterized by microphthalmia and a thin, poorly differentiated retina in which the peripheral portion is affected to a greater extent than the central portion. Such mutant retinae lack differentiated bipolar cells and the optic nerve typically fails to form, leading to blindness. Here, we show that progeny from an outcrossed backcross between 129/Sv-or(J) /or(J) and Mus musculus castaneus produce animals that are homozygous for the or(J) mutation and exhibit a much ameliorated eye phenotype. Although not of normal size, such modified or(J) eyes are significantly larger than those in 129/Sv-or(J) /or(J) mice, and contain a better organized retina which includes bipolar cells. Furthermore, optic nerves are frequently present, and the eyes show a degree of function as reflected by electroretinogram and pupillary response. As in 129/Sv-or(J) /or(J) mice, however, modified or(J) eyes show incomplete growth and a lack of cell differentiation in the periphery of the retina. The selective, and apparently nonmodifiable, effect of the ocular retardation phenotype on the periphery of the retina indicates that Chx10 plays an important role in the central-to-peripheral gradient of retinal development. These findings demonstrate that the ocular retardation phenotype can be greatly modified by the genetic background, and help to define a role for Chx10 in ocular development.

Animals↗
PubMed2003

Cardiovascular and renal phenotyping of genetically modified mice: a challenge for traditional physiology.

1. The advent of techniques to genetically modify experimental animals and produce directed mutations in both a conditional and tissue-specific manner has dramatically opened up new fields for physiologists in cardiovascular and renal research. 2. A consequence of altering the genetic background of mice is the difficulty in predicting the phenotypic outcome of the genetic mutation. We therefore suggest that physiologists may need to change their current experimental paradigms to face this new era. Hence, our aim is to propose a complementary research philosophy for physiologists working in the post-genomic era. That is, instead of using strictly hypothesis-driven research philosophies, one will have to perform screening studies of mutant mice, within a field of interest, to find valuable phenotypes. Once a relevant phenotype is found, in-depth studies of the underlying mechanisms should be performed. These follow-up studies should be performed using a traditional hypothesis-driven research philosophy. 3. The rapidly increasing availability of mutated mouse models of human disease also necessitates the development of techniques to characterize these various mouse phenotypes. In particular, the miniaturization and refinement of techniques currently used to study the renal and cardiovascular system in larger animals will be discussed in the present review. Hence, we aim to outline what techniques are currently available and should be present in a laboratory to screen and study renal and cardiovascular phenotypes in genetically modified mice, with particular emphasis on methodologies used in the intact, conscious animal.

Animals↗
PubMed1996

Adenovirus-mediated p16/CDKN2 gene transfer induces growth arrest and modifies the transformed phenotype of glioma cells.

The p16 (MTS1/CDKN2) gene localized at the 9p21 chromosomal region encodes for a cell cycle inhibitor protein and is altered in many human cancers. The frequency of p16 alterations in gliomas exceeds 50%. To restore the missing wild-type p16 gene efficiently in glioma cells an adenovirus vector carrying the full length coding sequence of the wild-type p16 cDNA, Ad5RSV-p16, was constructed. Three human glioma cell lines, U251 MG, U-87 MG and D54 MG, that did not express endogenous p16/CDKN2 gene and were easily infected with adenovirus vectors were selected for these experiments. Introduction of the Ad5RSV-p16 in these malignant glioma cell lines directed the biosynthesis of functional p16 protein in the majority of the exposed cells, significantly inhibited cell growth, influenced cell morphology and modified the transformed phenotype of cells including the ability to form colonies in soft agar. Flow cytometric studies revealed that the majority of the Ad5RSV-p16 infected glioma cells were arrested in the G0-G1 phases of the cell cycle. These results suggest that p16/CDKN2 inactivation is a significant factor in the genesis and progression of gliomas and that the restoration of the wild-type p16 protein could have clinical and therapeutic utility.

Adenoviridae↗