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PubMed2005

Data mining for protein-protein interactions in invertebrate model organisms.

Well-annotated genome databases are available for many invertebrate species, notably the fruitfly, Drosophila melanogaster, and the nematode, Caenorhabditis elegans. An adequate interpretation of this information at the biological level requires the exploration of the interactions between the gene products. Knowledge of protein interactions and the components of cell signalling pathways in the fly and worm are particularly valuable as hypotheses can be rapidly tested using the powerful genetic toolkits available. Invertebrates offer additional experimental advantages when attempting to characterise protein-protein interactions (PPIs). Their relatively small genome size compared to mammals helps to reduce missed interactions due to redundancy, and their function can be addressed using forward (mutants) and reverse (RNA interference) genetics. However, the researcher looking for evidence of PPIs for a protein of interest is faced with the challenge of extracting interaction data from sources that are highly varied, such as the results of microarray experiments in the unstructured text of research papers. This challenge is greatly reduced by a range of public databases of curated information, as well as publicly available, enhanced search engines, which can provide either direct experimental evidence for a PPI, or valuable clues for generating new hypotheses.

Animals↗
PubMed1998

[Experimental genetic modifications in the renin-angiotensin and kallikrein-kinin systems: significance for understanding cardiovascular regulation and study of genetic determinism of human diseases].

The precise role of the different proteins that constitute the renin-angiotensin and kallikrein-kinin systems in the development of hypertension and some cardiac and renal diseases remains unclear. Genetic manipulations in animals is a powerful approach that provide the opportunity to explore the role of each of these proteins in vivo. Indeed it is possible in the rat and in the mouse to manipulate a specific gene without modifying the other genetic and environmental factors. A causal link can thus be established between the gene and a physiologic or pathologic alteration. The possibilities are either the overexpression of the gene in all or in specific tissues (transgenesis), or the modification (often the inactivation) of the endogenous gene by homologous recombination. The second technique has the advantage to be more specific but it can be used only in the mouse; it is performed by transfecting totipotent embryonic stem cells with a vector harboring identical sequences to those of the gene to be targeted. The embryonic stem cells are then injected into embryos in which they will participate in the generation of the different organs including the gonads. The resulting chimeric animals can therefore transmit the mutation to their offspring creating a new genetically modified mouse strain. Many strains targeted in the different components of the renin-angiotensin and kallikrein-kinin systems have been generated in this way. These animal models should allow to test many physiopathological hypotheses that have been put forward from the results of human genetics and clinical studies, and also to raise new ones.

Animals↗
PubMed2004

The role of marriage rules in the structure of genetic relatedness.

In this work, we take a forward in time approach to compute the probabilities of non-identity by descent for a population consisting of n sections obeying one of a class of marriage rules that is invariant under cyclical relabeling of sections. A perturbation method allows for exact asymptotics using the reciprocal of the section population as a small parameter. The analysis yields relatedness measures that generalize Wright's F-statistics.

Algorithms↗
PubMed2001

Using genetic variation to study human disease.

The generation of a draft sequence of the human genome has spawned a unique opportunity to investigate the role of genetic variation in human diseases. The difference between any two human genomes has been estimated to be less than 0.1% overall, but still, this means that there are at least several million nucleotide differences per individual. The study of single nucleotide polymorphisms (SNPs), the most common type of variant, is likely to contribute substantially to deciphering genetic determinants of common and rare diseases. The effort to identify SNPs has been accelerated by three developments: the availability of sequence data from the genome project, improved informatic tools for searching the former and high-throughput genotype platforms. With these new tools in hand, dissecting the genetics of disease will rapidly move forward, although a number of formidable challenges will have to be met to see its promise realized in clinical medicine.

Genetic Predisposition to Disease↗
PubMedDate not supplied

New developments in genetic testing and screening.

Genetic testing and screening is moving forward with a range of new developments. Nurses need to be aware of progress in this area to be able to advise patients and refer them for help and counselling.

Counseling↗
PubMed1990

Genotoxicity of bergapten and bergamot oil in Saccharomyces cerevisiae.

In order to determine the genotoxic potential of bergapten (5-methoxypsoralen (5-MOP] and bergamot oil (BO), the genetic effects of 5-MOP and BO (containing equivalent amounts of 5-MOP) were studied in haploid and diploid yeast (Saccharomyces cerevisiae) using solar simulated radiation (SSR). At equal doses of SSR, equal concentrations of 5-MOP alone or 5-MOP in BO have a similar influence on survival and on the induction of cytoplasmic "petite" mutations, reverse and forward mutations, mitotic gene conversion and genetically aberrant colonies including mitotic crossing over. No reciprocity is found between SSR dose and 5-MOP concentration for cytotoxic, mutagenic and recombinogenic effects. In the presence of chemical filters (Parsol 1789, a UVA filter, and Parsol MCX, a cinnamate derivative acting as a UVB filter) considerable protection is observed against the induction of genetic effects by 5-MOP and BO containing 5-MOP in haploid and diploid cells. As indicated by the lower induction kinetics, the protection is higher than expected from the light-absorbing properties, suggesting photochemical interaction. The protection is slightly higher for BO than for 5-MOP. The induction of genetic effects by 5-MOP alone or BO containing 5-MOP is independent of oxygen. Experiments on suction blister fluids taken from patients after topical treatment with BO containing 5-MOP indicate that in comparison with water the bioavailability and thus the genotoxic effects of the compounds are decreased. Moreover, in addition to the filtering effect against the photoinduced genotoxic effects of BO, the presence of chemical filters apparently reduces the penetration of BO containing 5-MOP and provides a reduction in biological effectiveness.

5-Methoxypsoralen↗
PubMed2004

A new cell-based assay for measuring the forward mutation rate of HIV-1.

Over 20 years into the ever-worsening AIDS pandemic, genetic variation remains the greatest obstacle for treating and preventing HIV-1 infection. Mutation rate assays for HIV-1 have been reported; however, none measure directly the forward mutation rate during replication of the virus in cell culture while still retaining the ability to propagate and further study mutant proviruses. Therefore, the objective of the current study was to develop such a phenotypic cell-based assay for measuring the forward mutation rate of HIV-1. Conventional recombinant DNA techniques and polymerase chain reaction were used to create a replication defective HIV-1 vector, pNL4-3Delta+cass, which is based on the NL4-3 strain and contains the thymidine kinase gene from human herpes virus type 1 as the mutational target. A series of transfection and infection steps were used to introduce the vector into 143B cells, which are negative for thymidine kinase function, and produce vector virus for a single cycle of replication. Viral titers were measured by counting the number of drug resistant colonies on the assay plates, and forward mutation rates were calculated from the viral titers. Mutant proviruses were sequenced to determine the types of genetic alterations that occurred. The average forward mutation rate for HIV-1 was 2.2 x 10(-5)mutations/base/cycle. The majority of mutations were base substitutions, including high frequencies of C-->U and G-->A transitions. Single adenosine insertions were also observed frequently. The new assay is economical and provides a direct measurement of the mutation rate during a single cycle of viral replication. Target cells containing mutant proviruses survive the drug selection process and may be propagated for further analysis. The new assay is novel and has many advantages over previous mutation rate assays and thus will be very useful in future studies on genetic variation of HIV-1.

Cell Line↗
PubMed1975

Survival of the genetically incompatible fetal allograft.

A hypothesis is put forward to account for the non-rejection of the fetal allograft, based on shared surface-repellent molecules (S.R.M.s) which prevent close apposition of maternal and fetal immunocompetent cells. This hypothesis is shown to be compatible with the major theoretical requirements of the immune system. Thus it provides possible explanations for the self/not-self recognition process, tolerance to organ transplants, the development of autoimmune disease, and high and low zone tolerance. It is also argued that the recognition of self is important with reference to cellular antigens, but may not be essential for humoral antigens.

Antibody Formation↗
PubMed2004

Identifying environmental contributions to autism: provocative clues and false leads.

The potential role of environmental factors in autism spectrum disorders (ASD) is an area of emerging interest within the public and scientific communities. The high degree of heritability of ASD suggests that environmental influences are likely to operate through their interaction with genetic susceptibility during vulnerable periods of development. Evaluation of the plausibility of specific neurotoxicants as etiological agents in ASD should be guided by toxicological principles, including dose-effect dependency and pharmacokinetic parameters. Clinical and epidemiological investigations require the use of sufficiently powered study designs with appropriate control groups and unbiased case ascertainment and exposure assessment. Although much of the existing data that have been used to implicate environmental agents in ASD are limited by methodological shortcomings, a number of efforts are underway that will allow more rigorous evaluation of the role of environmental exposures in the etiology and/or phenotypic expression of the disorder. Surveillance systems are now in place that will provide reliable prevalence estimates going forward in time. Anticipated discoveries in genetics, brain pathology, and the molecular/cellular basis of functional impairment in ASD are likely to provide new opportunities to explore environmental aspects of this disorder.

Autistic Disorder↗
PubMed1984

Theory of epigenetic coding.

The logic of genetic control of development may be based on a binary epigenetic code. This paper revises the author's previous scheme dealing with the numerology of annelid metamerism in these terms. Certain features of the code had been deduced to be combinatorial, others not. This paradoxical contrast is resolved here by the interpretation that these features relate to different operations of the code; the combinatiorial to coding identity of units, the non-combinatorial to coding production of units. Consideration of a second paradox in the theory of epigenetic coding leads to a new solution which further provides a basis for epimorphic regeneration, and may in particular throw light on the "regeneration-duplication" phenomenon. A possible test of the model is also put forward.

Animals↗
PubMed1978

Genetical studies on revertants to sensitivity from a cycloheximide resistant strain of Schizosaccharomyces pombe.

Six UV induced cycloheximide-sensitive revertants were isolated from the cyh1-C7 strain of Schizosaccharomyces pombe which is resistant to cycloheximide. In all cases reversion to sensitivity was due to a forward mutation in a second suppressor gene. Genetical analysis showed that at least two genes, designated scr1 and scr2 (scr=suppression of cycloheximide resistance) were involved. Both scr1 and scr2 suppressed the resistance of six independently isolated alleles at the cyh1 locus. They had no effect on two known nonsense mutations in the ade7 locus. The cyh1-C7 strain has an altered 60S ribosomal protein which can be detected by two-dimensional polyacrylamide gel electrophoresis. In two suppressed strains, cyh1-C7 scr1 and cyh1-C7 scr2, the original altered protein was present. However no further ribosomal protein differences were observed which could be correlated with the presence of the scr genes. Both scr mutations conferred cold sensitivity on the organism indicating that they were of the missense type. Hence it seems certain that scr1 and scr2 are not mutations in tRNA genes leading to either nonsense or missense suppression. There is however no direct evidence that they code for ribosomal proteins and exert their effect on cyh1-C7 at the ribosomal level.

Cycloheximide↗
PubMed1999

Quantitative genetics of intraspecies hybrids.

Quantitative genetics generally is based on the properties of the randomly fertilized (RF) population or inbred derivatives of it. Simple hybrids and hybrid swarms do not conform to this model; and only some properties of hybrid means appear to have been available. In this paper, several genetical properties are derived, including genotype and allele frequencies, genotypic variance, broad-sense heritability, and outbreeding coefficient. The earlier mean is confirmed, and hybrid vigour is examined critically. These results make it possible to evaluate quantitatively both natural selection and forward selection (in plant breeding) from hybrids. An important finding is that hybrids with maximum hybrid vigour do not maximize genetic advance from forward selection, i.e. evolution is unlikely to enhance hybrid vigour. Another finding is that the concepts of additive genetic variance and narrow-sense heritability are inappropriate for hybrids, owing to the genetic disequilibrium inherent from their origin, and to the ephemeral nature of their population structure.

Alleles↗
PubMed2004

An indirect test of the new mutation hypothesis associating advanced paternal age with the etiology of schizophrenia.

Two studies by Malaspina et al. [2001: Arch Gen Psychiatr 58:361-367]; [2002: Am J Med Genet 114:299-303] have put forward the hypothesis that advanced paternal age with concomitant mutations in the male germ line is associated with sporadic schizophrenia in offspring. The hypothesis was supported by an observation of a monotonic increase in the risk for schizophrenia with increased paternal age, and a second observation in a separate sample of greater paternal mean age at birth among cases of apparent sporadic schizophrenia. The present study did not test the association of the risk of schizophrenia with advanced paternal age, but repeated the test of paternal age at birth among sporadic versus familial schizophrenic probands. We also examined the risk of schizophrenia, psychosis, and broad psychosis among paternal 1st and 2nd degree relatives of schizophrenic probands as a function of paternal age at birth of the proband, reasoning that if probands born to older fathers are more likely to be sporadic cases, the risk of schizophrenia (or psychosis) should be lower on the paternal side of the family. Results indicate a lack of support for the previous finding that sporadic probands tend to have older fathers at birth than familial probands. Results also failed to support the related hypothesis that increased paternal age is associated with the lower risk of schizophrenia (or psychosis) in the relatives of schizophrenic probands. The failure to support the paternal age hypothesis may be a function of heterogeneous samples, but calls for further research in the context of family studies.

Family Health↗
PubMed1976

Early orthopedic treatment for class III skeletal patterns.

Early short-term use of the chin cup resulted in the following significant findings in Class III skeletal problems: 1. A decrease in the gonial, mandibular, and SNB angles. 2. An increase in posterior facial height as a result of increased ramal height. 3. A faster and more pronounced result in the younger patients. 4. Correction of the Class III malocclusion. These findings negate the idea that Class III traction simply repositions the condyle within the fossa. When tracings are superimposed, it is obvious that these changes are not that of a rigid body. It is believed that the change is due to remodeling of the mandible itself. The shape changes as a result of the extrinsic mechanical forces plus the intrinsic functional requirements of the newly determined position. The question as to what degree the new functional homeostatic relationship can overcome the genetic aberration of a more forward-growing mandible. This conflict will probably vary with each individual and may be predictable in the near future. However, should the aberrant growth manifest itself, it would simply require renewed force application.

Child↗
PubMed2006

Functional imaging in clinical oncology: magnetic resonance imaging- and computerised tomography-based techniques.

Over recent years, advances in cellular biology, molecular biology and genetics have led to a leap forward in our understanding of the biological basis of cancer. Some of these developments have revealed processes and targets that can be visualised and measured by new functional imaging techniques. The resulting images have the potential to improve cancer staging, prognosis and risk assessment, guide radiotherapy planning, direct treatment schedules, improve response assessment and provide new end points for clinical trials. In this review, we have outlined the magnetic resonance imaging- and computerised tomography-based functional techniques and provide evidence for their use.

Humans↗
PubMed2005

Chemical complementation: a definitive phenotypic strategy for identifying small molecule inhibitors of elusive cellular targets.

Forward Pharmacology seeks to identify small or large molecules that modulate a normal or abnormal biological process in living cells or whole organisms and historically has been responsible for the discovery of many clinically used drugs. Forward Pharmacology approaches have become particularly attractive because advances in combinatorial chemistry and laboratory automation have made it possible to generate and interrogate large compound collections in a short period of time. Because many drug discovery efforts are now directed against specific biochemical targets, however, the utility of Forward Pharmacology is limited by the fact that assays to investigate compounds in biological systems are often phenotypic rather than target specific. We discuss here a novel strategy to discover target-based small molecules in intact cells using contemporary Forward Pharmacology in cells with specific genetic manipulations. The method, which we have termed "chemical complementation", is defined as the ability of small molecules to reverse a genetically induced phenotypic change in intact cells. Chemical complementation represents an extension of the commonly used genetic complementation approach, where cDNA libraries are used to investigate the function of genes based on their ability to rescue a specific genetic defect. We present examples of how chemical complementation has been used to identify and credential cell-active, small molecule inhibitors of 2 dual-specificity phosphatases, Cdc25A and MKP-3, which heretofore have eluded small molecule drug discovery efforts.

Animals↗
PubMed2024

Dissecting the association between blood pressure traits, hypertension, antihypertensive medications and epilepsy: A Mendelian randomization study.

BACKGROUND: Observational studies suggest that hypertension and epilepsy have a high co-occurrence, and antihypertensive medications may have impacts on the prevention and treatment of epilepsy. However, the directionality of causation between them is elusive. METHOD: By leveraging genome-wide association studies (GWAS) summary data of each trait, we firstly performed bidirectional univariate Mendelian randomization (UVMR) to assess the strength and direction of the associations between pairs of traits, then multivariate MR (MVMR) was conducted to adjust for potential confounders in causalities. Cochran's Q statistics, leave-one-out analysis, MR-Egger regression and MR-Pleiotropy Residual Sum and Outlier methods (MR-PRESSO) were employed to evaluate the robustness of the results. Drug target MR was proceeded to assess the association between five classes of first-line antihypertensive medications and epilepsy. Specifically, single nucleotide polymorphisms (SNPs) extracted from GWAS data on systolic blood pressure (SBP)/diastolic blood pressure (DBP), along with expression quantitative trait loci (eQTL) were utilized as proxies for antihypertensive medications, respectively. RESULTS: Forward UVMR results provided evidence that genetically predicted blood pressure traits and hypertension have causal effects on epilepsy, while reverse UVMR indicated no causal impacts of epilepsy on blood pressure traits or hypertension. The sensitivity analysis results were robust. The causalities between DBP, hypertension and epilepsy remained remarkable after adjustment by MVMR. Inverse-variance-weighted MR (IVW-MR) yielded evidence of positive association only between Beta-Blockers target genes based on DBP GWAS screening and epilepsy. Summary-data-based MR (SMR) identified a positive correlation between Beta-Blockers target gene ADRA1D and epilepsy risk. CONCLUSIONS: Hypertension has a causal effect on epilepsy and managing DBP in patients with hypertension through Beta-Blockers may help prevent epilepsy.

Humans↗
PubMed1999

Too late for the midwife toad: stress, variability and Hsp90.

In the 1940s and 1950s, Waddington put forward his theories of canalization and genetic assimilation. These provided a genetic basis to account for the inheritance of some apparently 'acquired' characters. Rutherford and Lindquist have now provided a molecular framework for these theories. Their results are also relevant to observations from the 1950s concerning homozygosity and variability, with a bearing on current views concerning the use of inbred strains.

Animals↗