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At least 469 records · Page 26Linked to original sources
PubMed1996

Cancer genetics and cell and molecular biology. Is this the way forward?

Lung cancer, the most prevalent cancer in the western world, is predominantly caused by smoking and thus perceived as a "self-inflicted" disease. Nevertheless, only 20% of smokers develop lung cancer. This review examines the concept of high-risk populations and screening. It looks at developments in the molecular epidemiology of the disease that shed new light on genetic changes that may predispose individuals to malignancy. Improvements in existing drug therapy are discussed as well as important new therapeutic developments, including antigrowth factors (antagonists G and D), antimetastatic agents (matrix metalloproteinase inhibitors), and natural products, arising from a greater understanding of signal transduction pathways and the process of cell metastasis.

Antihypertensive Agents↗
PubMed1978

Determination of radiation equivalence of ethyl methanesulphonate (EMS) for induction of gene conversion in diploid yeast.

A unit Rad-Equivalent Chemical (REC) has been suggested for purposes of quantitating the mutagenic hazards of chemicals. The usefulness of this approach is demonstrated by the establishment of a constant relationship between the forward mutation frequency and haploid genome size in various organisms for both radiation and chemical EMS. However, it is necessary to determine the radiation equivalence of chemicals in as many organisms and for as many end-points as possible. For end-points we are limited to forward mutations. Another relevant genetic end-point of interest in this regard is gene conversion which can also monitor any kind of DNA damage in a suitable diploid system. Hence, we have determined the REC value for EMS in diploid yeast with gene conversion as the end-point. This agrees well with the REC values estimated in a number of organisms with forward mutation as the end-point. This finding further underlines the generality of the REC concept.

Alleles↗
PubMed1984

Methodologies for the determination of various genetic effects in permeable strains of E. coli K-12 differing in DNA repair capacity. Quantification of DNA adduct formation, experiments with organ homogenates and hepatocytes, and animal-mediated assays.

Derivatives of E. coli K-12 strain 343/113 differing in DNA repair capacity, in permeability to large molecules, and in some metabolizing activities (nitroreductase, glutathione), were constructed for the quantitative determination of the induction of various genetic effects, such as forward and back mutations, lysogenic induction of prophage lambda, and repairable DNA damage. These E. coli strains can be used in assay procedures which allow variation and control over several experimental conditions, such as oxygen tension, time, pH, temperature of incubation and growth phase of the indicator cells. Methods are described for the simultaneous determination of genetic effects and of DNA-adduct formation during mutagen treatment, i.e. by using radio-labeled compounds or by means of an enzyme-linked immunosorbent assay (ELISA). Mammalian biotransformation of xenobiotics can be investigated by including various fractions of mammalian organs in the system. Examples of the relative effectiveness of the activating potential of S9, S100 and isolated hepatocytes for dialkylnitrosamines and other carcinogens are presented. Host-mediated assays, finally, are described which, in addition to gene mutations, can also be used for the determination of repairable DNA damage in bacteria present in different organs, including the liver, spleen, lungs, kidneys, pancreas, and the blood stream of chemically treated mice. It is concluded that quantitative tests in vitro for assessment of induced mutagenic spectrum and genotoxic potency, combined with the host-mediated assay as a monitor, in vivo, of genotoxic factors present in various organs of animals, may become useful in the assessment of genotoxic (and possibly tumor-initiating) properties of chemicals for which long-term in-vivo mutagenicity and/or carcinogenicity data are not yet available.

Alkylation↗
PubMed1990

Genetic exchange in African trypanosomes.

African trypanosomes are important pathogens of humans and domestic animals, but little was known, until recently, of the genetic system of these parasites. Recent results demonstrate the existence of nonobligatory genetic exchange between different stocks of T. brucei. A number of models have been put forward for the mechanism of genetic exchange, including a fusion model with subsequent random loss of chromosomes and a more conventional mendelian system.

Animals↗
PubMed2005

Novel integrative approaches to the identification of candidate genes in hypertension.

Hypertension, diabetes, and obesity are common diseases that are genetically expressed as complex traits. The clinical expression of these diseases, which run in families but have no clear pattern of inheritance, has been attributed to the interaction between multiple genes and the environment. Identifying the underlying genes, a crucial step in understanding the molecular pathogenesis of complex diseases, has had limited success so far, stressing the need for novel strategies to move this process forward. Innovative integrative genetic-genomic approaches have been proposed recently for the identification of new high-priority candidate genes. These strategies, which combine expression profiling with genetic linkage in different ways, may represent a breakthrough in the search for the genes involved in complex diseases.

Animals↗
PubMed2002

Effect of forward and reverse selection for ethanol-induced locomotor response on other measures of ethanol sensitivity.

BACKGROUND: Ethanol sensitivity may be a predictor of genetic predisposition to ethanol abuse. To examine ethanol sensitivity in rodents, two lines of mice were bred in replicate for high (FAST-1 and -2) and low (SLOW-1 and -2) locomotor stimulant responses to ethanol. After large differences between the lines developed and further response to selection seemed to have arrested, reverse selection was initiated by breeding the slowest FAST mice with each other and the fastest SLOW mice with each other. The reverse-selected lines, named r-FAST and r-SLOW, were virtually equally sensitive to the stimulant effects of the selection dose of ethanol after 16 generations of reverse selection. METHODS: These experiments used this unique genetic model to examine two responses, putatively genetically correlated with sensitivity to ethanol stimulation: handling-induced convulsions during chronic ethanol withdrawal, and ethanol-induced hypothermia. Ethanol clearance, for which a small difference was previously found between the FAST and SLOW lines, was also examined. RESULTS: Handling-induced convulsions during chronic ethanol withdrawal were significantly greater in both FAST lines compared with both SLOW lines. Reverse selection eliminated the difference between the replicate 1 lines but did not alter the difference between the replicate 2 lines. Ethanol-induced hypothermia was greater in both SLOW lines compared with the FAST lines. This difference was significantly reduced by reverse selection in r-SLOW mice only. Ethanol clearance rates were similar among all lines and replicates. CONCLUSIONS: These data demonstrate the usefulness of reverse-selected lines for examining putatively genetically correlated traits. Changes in the correlated traits demonstrated the existence of persistent trait-relevant genetic heterogeneity and some genetic overlap between the correlated traits and the selection trait. Absence of a change after reverse selection suggests that trait-relevant genetic heterogeneity was eliminated by forward selection or, alternatively, that the trait was not influenced by genes associated with successful reverse selection.

Animals↗
PubMedDate not supplied

An alkylsilyl-tethered, high-capacity solid support amenable to diversity-oriented synthesis for one-bead, one-stock solution chemical genetics.

The synthesis and use of an alkylsilyl-tethered large (500-600 microm) polystyrene resin (1) are disclosed. An optimized Suzuki coupling of bromine-functionalized polystyrene and a silicon-functionalized alkylborane generates the silicon-substituted polystyrene 1 in large scale (>100 g). Resin loading is accomplished by activation as the silyl triflate, which can accommodate even sterically encumbered secondary alcohols and phenols. Treatment with HF/pyridine for linker cleavage is mild, efficient, and amenable to an automated, large-scale distribution system. This platform delivers, minimally, 50 nmol of each small molecule derived from a diversity-oriented, split-pool synthesis on a per bead basis for use in both forward and reverse chemical genetic assays. This technology satisfies many requirements of a one bead-one stock solution approach to chemical genetics.

Alkynes↗
PubMedDate not supplied

Genetic effects of ozone: induction of point mutation and genetic recombination in Saccharomyces cerevisiae.

The mutagenicity and recombinogenicity of the atmospheric pollutant, ozone, were investigated in several strains of Saccharomyces cerevisiae. It was observed that ozone induced a variety of genetic events, such as forward and reverse mutations as well as gene conversion and mitotic crossing-over. However, when compared to known mutagens like ultraviolet light, X-rays and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), ozone appeared to be a weak mutagen.

Mutagenicity Tests↗
PubMed1997

An overview of clinical molecular genetics.

Clinical molecular genetics has recently become recognized as a diagnostic discipline. This article covers the evolution, structure, and possible forward development of clinical molecular genetics. Topics covered include general test categories, introducing new tests, laboratory facilities, staffing and training, and overview of quality issues.

Genetic Testing↗
PubMed2005

Ephrin signaling in vivo: look both ways.

Eph receptors and ephrins have captured the interest of the developmental biology community in recent years for their pleiotropic functions during embryogenesis. Loss-of-function studies using various animal models have demonstrated the involvement of Ephs and ephrins in many aspects of embryogenesis including segmentation, neural crest cells migration, angiogenesis, and axon guidance. An essential property of this signaling pathway is the ability of both Ephs and ephrins to behave as receptors or ligands and their consequent cell autonomous and nonautonomous mode of action. While many reports did not discriminate between Eph autonomous signaling (forward) and ephrin autonomous signaling (reverse), recent genetic and in vivo studies have shown that both forward and reverse signaling play important roles during embryogenesis.

Animals↗
PubMed2006

Bladder cancer, a two phased disease?

The processes of intraepithelial migration, intraluminal seeding, and field cancerization as models for initiation, spread, and recurrences of urothelial cell carcinoma (UCC) are reviewed in light of recent molecular investigations. The accumulated molecular data on synchronous and metachronous tumors indicate that the majority of recurrent and multiple tumors are monoclonal. Molecular data has also shown the presence of chromosomal and genetic changes in precursor lesions as well as in normal urothelial cells. Genetic-histological mapping of cystectomized bladders has shown that overt tumors occur as local events in areas of genetically altered urothelium. A model is put forward in which the tumor process is initiated by genetically altered but histologically normal cells that produce fields of altered cells by intraepithelial displacement. By the accumulation of further genetic changes the fields of altered urothelium reaches a state of criticality, which locally may produce frank tumors.

Carcinoma↗
PubMed2002

Development of the locomotor network in zebrafish.

The zebrafish is a leading model for studies of vertebrate development and genetics. Its embryonic motor behaviors are easy to assess (e.g. for mutagenic screens), the embryos develop rapidly (hatching as larvae at 2 days) and are transparent, permitting calcium imaging and patch clamp recording in vivo. We review primarily the recent advances in understanding the cellular basis for the development of motor activities in the developing zebrafish. The motor activities are generated largely in the spinal cord and hindbrain. In the embryo these segmented structures possess a relatively small number of repeating sets of identifiable neurons. Many types of neurons as well as the two types of muscle cells have been classified based on their morphologies. Some of the molecular signals for cellular differentiation have been identified recently and mutations affecting cell development have been isolated. Embryonic motor behaviors appear in sequence and consist of an early period of transient spontaneous coiling contractions, followed by the emergence of twitching responses to touch, and later by the ability to swim. Coiling contractions are generated by an electrically coupled network of a subset of spinal neurons whereas a chemical (glutamatergic and glycinergic) synaptic drive underlies touch responses and swimming. Swimming becomes sustained in larvae once the neuromodulatory serotonergic system develops. These results indicate many similarities between developing zebrafish and other vertebrates in the properties of the synaptic drive underlying locomotion. Therefore, the zebrafish is a useful preparation for gaining new insights into the development of the neural control of vertebrate locomotion. As the types of neurons, transmitters, receptors and channels used in the locomotor network are being defined, this opens the possibility of combining cellular neurophysiology with forward and reverse molecular genetics to understand the principles of locomotor network assembly and function.

Animals↗
PubMed2002

Reduced amplification efficiency of KIAA0027/MLC1 alleles: implications for the molecular diagnosis of megalencephalic leukoencephalopathy with subcortical cysts.

Autosomal recessive megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare childhood-onset spongiform leukodystrophy with macrocephaly and slowly progressive deterioration of motor functions. Mutations in KIAA0027/MLC1 have recently been found associated with MLC, and a high degree of allelic heterogeneity has been observed. In addition, initial reports suggested that a rare variant in exon 11 (L309M) is involved in the etiology of schizophrenia, but recent studies have brought forward compelling arguments that genetic variants of MLC1 are not associated with schizophrenia. Using DHPLC-analysis, reproduction of previous findings on L309M revealed homoduplex resolution patterns among individuals, who had been described to be heterozygous for the variant, which was further confirmed by sequencing the respective PCR products. Cumulative effects of high GC content, secondary folding structures due to incomplete intronic tandem-repeats, and a complicated insertion polymorphism at the 3-end of exon 11 may be the cause of preferential amplification of specific alleles of exon 11. Consistent amplification was obtained only when we employed exonic primers directly adjacent to the L309M variant. For mutational screening, we propose a two-step test: (1) testing for the 33 bp insertion polymorphism of exon 11, and (2) amplification of the exon using different primer sets depending on the presence or absence of the insertion.

Alleles↗
PubMed2006

Reconstructing and deconstructing agonist-induced activation of integrin alphaIIbbeta3.

BACKGROUND: Integrin receptors, composed of transmembrane alpha and beta subunits, are essential for the development and functioning of multicellular animals. Agonist stimulation leads cells to regulate integrin affinity ("activation"), thus controlling cell adhesion and migration, controlling extracellular-matrix assembly, and contributing to angiogenesis, tumor cell metastasis, inflammation, the immune response, and hemostasis. A final step in integrin activation is the binding of talin, a cytoskeletal protein, to integrin beta cytoplasmic domains. Many different signaling molecules that regulate integrin affinity have been described, but a pathway that connects agonist stimulation to talin binding and activation has not been mapped. RESULTS: We used forward, reverse, and synthetic genetics to engineer and order an integrin activation pathway in cells expressing a prototype activatable integrin, platelet alphaIIbbeta3. Phorbol myristate acetate (PMA) activated alphaIIbbeta3 only after the increased expression of both recombinant protein kinase Calpha (PKCalpha) and talin to levels approximating those in platelets. Inhibition of Rap1 GTPase reduced alphaIIbbeta3 activation, whereas activated Rap1A(G12V) bypassed the requirement for PKC, establishing that Rap1 is downstream of PKC. Talin binding to integrins mediates Rap1-induced activation because Rap1A(G12V) failed to activate alphaIIbbeta3 in cells expressing integrin binding-defective talin (W359A). Rap1 activated integrins by forming an integrin-associated complex containing talin in combination with the Rap effector, RIAM. Furthermore, siRNA-mediated knockdown of RIAM blocked integrin activation. CONCLUSIONS: We have, for the first time, ordered a pathway from agonist stimulation to integrin activation and established the Rap1-induced formation of an "integrin activation complex," containing RIAM and talin, that binds to and activates the integrin.

Animals↗
PubMed2004

Lipid species profiling: a high-throughput approach to identify lipid compositional changes and determine the function of genes involved in lipid metabolism and signaling.

The development of electrospray ionization mass spectrometry has provided the foundation for the development of strategies to identify and quantify complex lipids from unfractionated extracts of small biological samples. In the 1990s, the feasibility of detailed lipid profiling was demonstrated; in the past two years, analytical strategies have been extended to include classes of lipids that are unique to plants. High-throughput lipid profiling by electrospray ionization tandem mass spectrometry, in combination with forward- or reverse-genetics approaches, has recently been utilized to identify lipid metabolic pathways that are involved in plant development and stress responses, to specify the roles of particular genes and enzymes in plant responses to environmental cues, to determine the lipid species that serve as the substrates and products of specific enzymes, and to identify lipid-metabolizing enzymes that are involved in varied plant processes.

Genes, Plant↗
PubMed2001

Phenotypes of Drosophila homologs of human XPF and XPG to chemically-induced DNA modifications.

DmXPF (mei9) and DmXPG (mus201) mutants are Drosophila homologs of the mammalian XPF and XPG genes, respectively. For Drosophila germ cells, causal correlations exist between the magnitude of a potentiating effect of a deficiency in these functions, measured as the M(NER-)/M(NER+) mutability ratio, and the type of DNA modification. M(NER-)/M(NER+) mutability ratios may vary with time interval between DNA adduct formation and repair, mutagen dose and depend also on the genetic endpoint measured. For forward mutations, there is no indication of any differential response of DmXPF compared to DmXPG. Subtle features appeared from a class-by-class comparison: (i) Methylating agents always produce higher M(NER-)/M(NER+) ratios than their ethylating analogs; (ii) M(NER-)/M(NER+) mutability ratios are significantly enhanced for cross-linking N-mustards, aziridine and di-epoxide compounds, but not for cross-linking nitrosoureas. The low hypermutability effects with bifunctional nitrogen mustards, aziridine and epoxide compounds are attributed to unrepaired mono-alkyl adducts; (iii) The efficient repair of mono-alkyl-adducts at ring nitrogens in wild-type germ cells is evident from the absence of a dose-response relationship for ethylene oxide, propylene imine and methyl methanesulfonate (MMS). These chemicals become powerful germline mutagens when the NER system is disrupted. Systematic studies of the type performed on germ cells are not available for somatic cells of Drosophila. The sparse data available show large differences in the response of germ cells and somatic cells. The bifunctional agent mechlorethamine (MEC) but not the monofunctional MMS or 2-chloroethylamine cause in NER(-) XXfemale symbol the highest potentiating effect on mitotic recombination. The causes of the discrepancy between the extraordinarily high activity of MEC in mus201 somatic cells and its low potentiating effect in germ cells is unknown at present.

Animals↗
PubMed2000

Knowing left from right: the molecular basis of laterality defects.

The apparent symmetry of the vertebrate body conceals profound asymmetries in the development and placement of internal organs. Asymmetric organ development is controlled in part by genes expressed asymmetrically in the early embryo, and alterations in the activities of these genes can result in severe defects during organogenesis. Recently, data from different vertebrates have allowed researchers to put forward a model of genetic interactions that explains how asymmetric patterns of gene expression in the early embryo are translated into spatial patterns of asymmetric organ development. This model helps us to understand the molecular basis of a number of congenital malformations in humans.

Animals↗
PubMedDate not supplied

Quantitative structure-activity relationship studies of progesterone receptor binding steroids.

The selection of appropriate descriptors is an important step in the successful formulation of quantitative structure-activity relationships (QSARs). This paper compares a number of feature selection routines and mapping methods that are in current use. They include forward stepping regression (FSR), genetic function approximation (GFA), generalized simulated annealing (GSA), and genetic neural network (GNN). On the basis of a data set of steroids of known in vitro binding affinity to the progsterone receptor, a number of QSAR models are constructed. A comparison of the predictive qualities for both training and test compounds demonstrates that the GNN protocol achieves the best results among the 2D QSAR that are considered. Analysis of the choice of descriptors by the GNN method shows that the results are consistent with established SARs on this series of compounds.

Neural Networks, Computer↗