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At least 703 records · Page 39Linked to original sources
PubMed2003

Genetic dissection of hybrid incompatibilities between Drosophila simulans and D. mauritiana. I. Differential accumulation of hybrid male sterility effects on the X and autosomes.

The genetic basis of hybrid incompatibility in crosses between Drosophila mauritiana and D. simulans was investigated to gain insight into the evolutionary mechanisms of speciation. In this study, segments of the D. mauritiana third chromosome were introgressed into a D. simulans genetic background and tested as homozygotes for viability, male fertility, and female fertility. The entire third chromosome was covered with partially overlapping segments. Many segments were male sterile, while none were female sterile or lethal, confirming previous reports of the rapid evolution of hybrid male sterility (HMS). A statistical model was developed to quantify the HMS accumulation. In comparison with previous work on the X chromosome, we estimate that the X has approximately 2.5 times the density of HMS factors as the autosomes. We also estimate that the whole genome contains approximately 15 HMS "equivalents"-i.e., 15 times the minimum number of incompatibility factors necessary to cause complete sterility. Although some caveats for the quantitative estimate of a 2.5-fold density difference are described, this study supports the notion that the X chromosome plays a special role in the evolution of reproductive isolation. Possible mechanisms of a "large X" effect include selective fixation of new mutations that are recessive or partially recessive and the evolution of sex-ratio distortion systems.

Animals↗
PubMed1996

Application of molecular biology-based methods to the diagnosis of infectious diseases.

The basis for effective treatment and cure of a patient is the rapid diagnosis of the disease and its causative agent, which is founded on the analysis of the clinical symptoms coupled with laboratory tests. As we approach the 21st century, clinicians are becoming increasingly able to diagnose and treat diseases at the molecular level. The rapid development of new methods and techniques in the area of molecular biology has gained new insights into the genetic and structural features of a considerable number of human pathogens. These results obtained by intensive basic research are currently leading to improved diagnostic procedures. Basically, there are four different possibilities for laboratory diagnosis of infections: 1. direct detection of the pathogens (e.g., microscopy and/or culture), 2. detection of protein components of the pathogens with the help of specific antibodies (e.g., antigen capture ELISA) 3. IgA-, IgM- and IgG-specific detection of antibodies directed against a given pathogen and changes in their corresponding titer, and as the most sensitive method, 4. specific detection of nucleic acids (e.g., PCR) of the pathogens. Here, the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis are serving as examples to review the recent developments as well as the future perspectives in molecular biology-based laboratory diagnosis.

Bacterial Infections↗
PubMed2004

Testing for HER2 in breast cancer.

HER2 is a paradigm of a molecular target whose appropriate assessment is pivotal in the targeting of novel therapies for breast cancer, notably including Herceptin/Trastuzumab. Determining the correct levels requires immunohistochemical and molecular biological skills that are reproducible and measurable, coupled with a knowledge of the appropriate morphological and pathobiological context. Attaining these goals is not easy and laboratories testing for HER2 should maintain a high level of throughput of tests and engage in a recognized external quality assurance scheme. Fluorescence in-situ hybridization testing remains a particular challenge and there is a range of testing strategies. This testing forms the model for the identification of other novel molecular targets. In the future rapid throughput techniques such as real-time quantitative polymerase chain reaction (rqPCR), tissue microarrays or both should bring significant economies of cost and scale.

Breast Neoplasms↗
PubMed2002

Trypsin activity in stool and duodenal aspirate of neonates for differential diagnosis of intestinal obstruction.

The diagnosis of a non-surgical cause of delayed passage of meconium in a neonate may be challenging to the pediatric surgeon. The usefulness of determining trypsin activity (TA) in stool and duodenal aspirate for the diagnosis of cystic fibrosis (CF) and the existence of an entity called transient deficiency of trypsin (TTD) was assessed in 49 neonates over a 14-month period. TA was determined by a gelatin liquefaction technique. An absence of TA was considered if gelatin liquefaction was seen at a dilution of less than 1:100. Neonates with negative activity in both samples were started on supplementary pancreatic enzymes (pancreatin) for 1 month. TA was retested in the stool after stopping pancreatin for 1 week. Neonates with a return of TA were considered to have TTD; those who showed persistent TA deficiency at re-evaluation were investigated for CF by sweat iontophoresis. Twenty-one neonates had negative TA (in 1 only stool was tested); 13 could be re-evaluated (4 died, 4 were lost to follow-up). Nine were found to have TTD as a stool or duodenal sample showed the presence of TA; 3 of 4 patients with persistent negative TA were confirmed to have CF. One patient with normal sweat chloride is awaiting genetic studies. Determination of TA by gelatin liquefaction is a simple, rapid, inexpensive, and reliable (sensitivity 100%, negative predictive value 100%) means to differentiate non-surgical causes of intestinal obstruction such as neonatal and postoperative TTD and CF.

Clinical Enzyme Tests↗
PubMed2002

A bioinformatic strategy to rapidly characterize cDNA libraries.

MOTIVATION: Complementary DNA libraries can define the genetic constituents of specific cells and/or tissues. Their sequencing will illuminate the transcriptome but it is a monumental task requiring considerable resources. RESULTS: We have employed a computational search in conjunction with a microarray-based strategy to alleviate the impediments of deriving a consensus of records that describe testis gene expression. This strategy identified 5681 unique testes-expressed genes of which 3265 were previously portrayed in the UniGene database. Interestingly, a total of 2416 novel testes-expressed genes were identified. This clearly demonstrates that microarrays can be used to rapidly discover a large number of new transcripts.

Adolescent↗
PubMed1996

Molecular biology in ophthalmology. A review of principles and recent advances.

Molecular biology is a young scientific discipline that has already had a profound impact on biomedical science, including basic and clinical eye research. In the coming years, molecular advances will increasingly influence aspects of diagnosis, prognosis, and therapy in clinical ophthalmology. Our current understanding of ocular pathophysiology and classification of eye disease will be advanced and challenged by new discoveries in molecular biology. A knowledge of genotype can clarify apparent phenotype. At the present time, diagnostic tests in ophthalmology for both acquired and inherited diseases are being revolutionized by molecular technology. The molecular genetics of ocular disease is currently the subject of intense investigation using techniques of gene mapping and isolation. Rapid progress in understanding the molecular basis of eye diseases will advance the treatment of these conditions, including the potential for gene therapy.

Amino Acid Sequence↗
PubMed1987

The adaptive significance of sexuality.

The theory predicts that inbred strains of mice are susceptible to tumor viruses that have escaped immune recognition. The theory implies routine evolutionary extinction of asexual species and that existing parthenogenetic species would have to have evolved recently from sexually reproducing precursors. This could be tested by determining the amount of DNA divergence between parthenogenetic and related sexually reproducing species. In mammals and birds genetic substitutions occur at comparable rates, but the AIDS virus evolves about 10 million times more rapidly. This confirms the basic imbalance of rates of evolution between microparasites and metazoan hosts, which is fundamental to the theory. The organization of most eukaryotic genes into exons and introns facilitates the generation of variety of gene products, and the molecular mechanism is similar to the mechanism that generates antibody diversity in the immune response and antigenic variation in trypanosomes. It has been proposed that noncoding 'selfish' DNA is the ultimate sexually transmitted disease. If this were the case, then asexually reproducing species would have an added advantage. An alternative hypothesis is proposed: noncoding DNA could provide insertion sites for retroviruses that would prevent them from being transcribed and replicated and thus moderate their proliferation much as absorber rods moderate proliferation of neutrons in a nuclear reactor. Flowering plants have pollen selection mechanisms that enforce heterozygosity at one or more loci. It has been proposed that analogous sperm selection mechanisms exist in mammals. Such a process would account for observation of a mysterious excess molecular divergence between different strains of inbred mice.

Adaptation, Physiological↗
PubMed2005

TNF but not Fas ligand provides protective anti-L. major immunity in C57BL/6 mice.

The pro-inflammatory cytokine TNF is essential for a protective immune response to some but not all strains of Leishmania major. TNF-deficient mice of a resistant genetic background succumbed rapidly to an infection with L. major BNI. Another member of the TNF superfamily, Fas ligand (FasL), has also been reported to be critical for the immune response to L. major. To test the relative importance of TNF versus FasL for the control of L. major BNI, we infected wildtype C57BL/6 (B6.WT), B6.TNF(-/-), B6.gld and C57BL/6.gld x TNF(-/-) (B6.gld.TNF(-/-)) double-negative mice. Visceral, fatal disease was only observed in B6.TNF(-/-) mice, but not in B6 gld mice. The course of infection and the immune response of B6.gld.TNF(-/-) mice were similar to those of B6.TNF(-/-) mice. B6.gld.TNF(-/-) mice had a high tissue parasite burden and expressed prominent amounts of inducible nitric oxide synthase (iNOS) in the skin, the lymph nodes (LN) and the spleen as previously reported for B6.TNF(-/-) mice, whereas the tissue parasite load and the iNOS expression of B6.gld mice resembled that of B6.WT controls. Neither the TNF- nor the FasL-deficiency exerted a detectable intrinsic effect on the proliferation of T cells. Thus, TNF, but not FasL is essential for the control of L. major BNI. The discrepancy between these and other published data are most likely due to the use of different strains of the pathogen.

Animals↗
PubMed1999

Future scenarios for the prevention and delay of Alzheimer disease onset in high-risk groups. An ethical perspective.

CONTEXT: Alzheimer disease (AD) presents a major scientific and social challenge in our aging society. Strategies to prevent or delay onset of symptoms, as well as to prevent the decline into the advanced stage, are urgently needed. While these strategies do not yet exist in a proven and clinically applicable form, the science is progressing rapidly. OBJECTIVES: The pre-eminent goal is to identify asymptomatic persons at high risk for AD and to then apply pharmacologic and lifestyle interventions that delay onset of disease. In this scenario, genetic susceptibility testing may eventually prove accurate enough to be of use in identifying at-risk individuals decades before probable onset, allowing maximal preventive efforts. Second, an important goal is to delay or prevent the onset of moderate and advanced AD through applying compounds that slow the progression of disease, thereby allowing patients to die of unrelated ailments of old age before they lose their capacities to recognize loved ones and to communicate by speech. CONCLUSIONS: This article provides a discussion of these strategies with attention to a variety of ethical issues that should be of concern to physicians and caregivers. An assessment of the scientific evidence for preventing or delaying AD should be coupled with values analysis.

Age of Onset↗
PubMed1999

Detection of sphingomonads and in situ identification in activated sludge using 16S rRNA-targeted oligonucleotide probes.

The increasing significance of members of the genus Sphingomonas in biotechnological applications has led to an increased interest in the diversity, abundance and ecophysiological potential of this group of Gram-negative bacteria. This general focus provides a challenge to improve means for identification of sphingomonads; eg molecular genetic methods for rapid and specific detection could facilitate screening of new isolates. Here, fluorescently labeled oligonucleotide probes targeted against 16S rRNA were used to typify strains previously assigned to the genus. All 46 sphingomonads tested including type strains of 21 Sphingomonasspecies could be detected with a probe originally designed for the genus and all but one with a probe designed for the alpha-4 subgroup of the Proteobacteria. The two probes are suitable for direct detection of sphingomonads in pure and mixed cultures as well as in environmental samples of unknown composition. The probes were used to identify sphingomonads in situ in activated sludge samples. Sphingomonads were rather abundant accounting for about 5-10% of the total cells in municipal sludges. Distinct patterns in aggregation of the cells suggest that these organisms could be involved in the formation process of sludge flocs.

Journal Article↗
PubMed1999

Desiccation and starvation resistance in Drosophila: patterns of variation at the species, population and intrapopulation levels.

A substantial number of Drosophila studies have investigated variation in desiccation and starvation resistance, providing an opportunity to test for consistent patterns of direct and correlated responses across studies and across the species and population levels. In general, responses to laboratory selection for these traits in D. melanogaster are rapid and indicate abundant genetic variation in populations. However, slower responses to selection for desiccation resistance occur in other species including D. simulans. Clines suggest adaptive divergence although specific selection pressures have not been documented empirically. Drosophila species differ markedly in desiccation and starvation resistance and there is also marked variation within species for desiccation resistance that may be linked to local climatic conditions. Laboratory selection experiments on starvation resistance in D. melanogaster suggest that changes in lipid content are largely responsible for resistance variation but this factor may be less important in explaining variation among species. For desiccation, lines with increased resistance show reduced rates of water loss but no changes in the minimum water content that flies can tolerate. Changes in life history traits are sometimes associated with altered levels of stress resistance. Increased starvation resistance is associated with longer development time and reduced early age reproduction in different studies. However, other associations are inconsistent between studies as in the case of stress resistance changing following selection for longevity. Multiple mechanisms may underlie genetic variation in stress resistance and future studies should address the evolutionary importance of the different mechanisms at the population and species levels.

Animals↗
PubMed2002

Anti-inflammatory interleukin-10 genotype protects dialysis patients from cardiovascular events.

BACKGROUND: Inflammatory processes play an important role for the progression of atherosclerosis. This can be studied particularly well in patients with chronic renal failure who are on hemodialysis, as they show systemic inflammation due to uremia and dialysis while suffering from premature mortality secondary to rapidly progressing atherosclerosis. Interleukin (IL)-10 is a regulatory cytokine that limits inflammatory processes. The quantitative production of IL-10 is subject to genetic variation based on polymorphisms in the promoter of its gene. We tested the hypothesis that the IL-10 genotype, by influencing the capacity to compensate for dialysis-induced systemic inflammation, determines the risk for cardiovascular complications. METHODS: Three hundred chronic hemodialysis patients were genotyped for the polymorphic bases at positions -1082 and -819 of the IL-10 promoter sequence. They were prospectively followed for a mean of 20.2 +/- 7.3 months. End-points of the study were major events related to cardiac, cerebrovascular or peripheral artery disease. RESULTS: The -1082A* allele, which is associated with low production of the cytokine IL-10 and elevated markers of systemic inflammation such as C reactive protein, was predictive for a higher cardiovascular morbidity (relative risk for cardiovascular events 2.76, 95% confidence interval 1.31 to 4.17, P = 0.004) compared to the -1082G* genotype. CONCLUSION: The IL-10 genotype influences the risk for cardiovascular events in hemodialysis patients and allows the definition of a high risk group. The data provide further evidence for a causal role of systemic inflammation for progressive atherosclerosis in dialysis patients.

Aged↗
PubMed1995

Rapid diagnosis of beta-thalassaemia by mutagenically separated polymerase chain reaction (MS-PCR) and its application to prenatal diagnosis.

We have developed a rapid and simple PCR-based method which is modified from the mutagenically separated polymerase chain reaction (MS-PCR) to detect the molecular defects of beta-thalassaemia. We can use this technique to amplify normal and mutant alleles of the beta-globin gene in the same reaction tube, using different-sized allele-specific primers. This mutagenesis separates the amplification reactions of alleles performed in the same tube. Subsequent gel electrophoresis shows at least one of the two allelic products at the same locus or at least two of the several allelic products at different loci. Therefore, in addition to simple handling, MS-PCR provides a within-assay quality control for the exclusion of false negative results. The five most common mutations of beta-thalassaemia and haemoglobin E which occur in the Taiwanese population were tested, and 14 prenatal samples were checked with accurate results. This method is simple, rapid and accurate, and can be used routinely in prenatal diagnosis. The principle used here can also be applied to other genetic diseases.

Base Sequence↗
PubMed2004

Implementation in Australia of molecular diagnostic techniques for the rapid detection of foot and mouth disease virus.

OBJECTIVE: To evaluate and implement rapid molecular diagnostic techniques for the detection of foot and mouth disease virus (FMDV) suitable for use in Australia. DESIGN: Two PCR TaqMan assays targeted to the FMDV internal ribosome entry site or the 3D polymerase coding region for the rapid detection of FMDV were evaluated using non-infectious materials to determine the test most appropriate for implementation as part of Australia's national preparedness for the rapid detection and diagnosis of FMD outbreaks. RESULTS: Two published tests (PCR TaqMan assays targeted to the FMDV IRES region or the FMDV 3D polymerase coding region) were evaluated for their ability to detect FMDV genetic material in non-infectious FMDV ELISA antigen stocks held at Australian Animal Health Laboratory. Both tests were able to detect FMDV genetic material from strains O1 Manisa, O-3039, A22, A24, A Malaysia, C, Asia 1 and SAT 1, 2 and 3. With the exception of Asia 1, the TaqMan assay targeted to the FMD 3D polymerase coding region had Ct values equal to or lower than for the TaqMan assay targeted to the IRES region suggesting that this test may provide broader serotype detection and sensitivity. However, the TaqMan assay directed to the FMDV IRES is the only one to date to have undergone substantial evaluation using clinical samples collected during an outbreak. The greatest differences observed were for O-3039, SAT 1, and 3. CONCLUSION: Given the ease of setting up both tests, AAHL currently runs both tests on highly suspect FMD investigations to provide independent confirmation of the absence of FMDV because the tests are focused on two independent regions of the FMDV genome. These tests add substantially to Australia's preparedness for FMD diagnosis complementing the already well-established virus isolation and antigen capture ELISA tests for index case diagnosis of FMD in Australia.

Animals↗
PubMed2006

Targeting glycogen synthase kinase-3 in the CNS: implications for the development of new treatments for mood disorders.

There exists an immediate need to develop novel medications for the treatment of mood disorders such as bipolar disorder and depression. Initial interest in glycogen synthase kinase-3 (GSK-3) as a target for the treatment of mood disorders arose from the finding that the mood stabilizing drug lithium directly inhibited the enzyme. More recent preclinical evidence implicates the modulation of GSK-3 in either the direct or downstream mechanism of action of many other mood stabilizer and antidepressant medications currently in use. One of the cellular targets of GSK-3, which may mediate some of the effects of lithium and other drugs, is beta-catenin, a transcription factor that is rapidly degraded when GSK-3 is active. Recent rodent behavioral data (both genetic and pharmacological) supports GSK-3 representing a therapeutically relevant target of lithium. This includes antidepressant-like behavior in the forced swim test and antimanic-like response to amphetamine following administration of the GSK-3 inhibitor AR-A014418, a findings that is concomitant with an increase in brain beta-catenin. The evidence described in this review suggests that regulating GSK-3 may represent a target for novel medications to treat mood disorders.

Animals↗
PubMed1987

Recent developments in antiviral chemotherapy.

As can be seen from the preceding brief discussion, the prospects for new antiviral agents for the treatment of viral diseases ranging in severity from the common cold to AIDS appear promising. The latest advances in technologies such as crystallography, genetic engineering, and monoclonal antibodies are all being applied to the discovery of new ways to inhibit virus-specific processes. In addition, the development of diagnostic tests for viral diseases has proceeded at a rapid pace that should facilitate the proper use of the antivirals when they become available. The one lesson that has been learned in the antiviral field over the past decade is that virus-specific inhibitors do exist, and if an essential virus-specific process or protein can be identified, it is likely that a molecule can be found to inhibit or inactivate it.

Antiviral Agents↗