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PubMed1986

Lymphoid and other tissue-specific phenotypes of polyomavirus enhancer recombinants: positive and negative combinational effects on enhancer specificity and activity.

Heterologous enhancer recombinants and deletions of the polyomavirus (Py) noncoding region were constructed and analyzed for tissue specificity of DNA replication and transcription in a number of lymphoid and other cell lines. The simian virus 40 72-base-pair repeat, mouse immunoglobulin heavy-chain enhancer, and Moloney murine leukemia virus enhancer were inserted into the PvuII-D locus (nucleotides 5128 through 5265) of Py. The ability of these recombinants and the parental PvuII-D deletion mutant to replicate in permissive 3T6 cells and MOP-6 cells as well as in nonpermissive mouse B lymphoid, T lymphoid, mastocyte, and embryonal carcinoma cells was determined. Wild-type Py DNA was not permissive for replication in most lymphoid cell lines, except one hybridoma line. Simply deleting the Py PvuII-D region, however, gave Py an expanded host range, allowing high-level replication in some T lymphoid and mastocytoma cell lines, indicating that this element can be a tissue-specific negative as well as positive element. Substitution of the murine leukemia virus enhancer for Py PvuII-D yielded a Py genome which retained the ability to replicate in 3T6 cells but also replicated well in B lymphoid cells. Substitution with the immunoglobulin heavy-chain enhancer allowed replication in B lymphoid cells but interfered with replication in 3T6 cells and mastocytomas. Surprisingly, substitution with the simian virus 40 72-base-pair enhancer repeat gave a recombinant which would not replicate in any cell line tried, including MOP-6 cells, even though other recombinants with this enhancer would replicate. Thus, we observed both cooperation and interference in these combinations between enhancer components and the Py genome and that these combined activities were cell specific. These results are presented as evidence that there may be a positional dependence, or syntax, for the recognition of genetic elements controlling Py tissue specificity.

Animals↗

PubMed1998

The cost of sex revisited: effects of male gamete output of hermaphrodites that are asexual in their female capacity.

The genetic cost of sexual reproduction has been attributed to two causes in mathematical formulations: male function or genome dilution. We develop and analyse a genetic model that shows that both costs occur, depending upon the conditions. The model differs from previous formulations in that the level of output and fertilization success of male gametes produced by hermaphrodites that are asexual in their female function (henceforth "parthenogenetic hermaphrodites") are treated as variables, rather than constants fixed at 0 or 1, as has previously been the case. By expressing the cost of sex in terms of per capita egg loss of sexual individuals and parthenogenetic hermaphrodites, we partition the cost into components due to male function and genome dilution. Which component dominates the cost of sex depends upon the relative male gamete output of the parthenogenetic hermaphrodites. The cost of sex is observed to increase, or remain unchanged in some marginal cases, with increases in (i) frequency of parthenogenetic hermaphrodites, (ii) fertilization success of male gametes produced by parthenogenetic hermaphrodites and (iii) potential eggs lost by diverting resources to male gamete production. In certain situations, parthenogenetic hermaphrodites with an intermediate level of male gamete output have the greatest fitness advantage over sexual individuals. If heritable variation for levels of male gamete output exists among parthenogenetic hermaphrodites, this raises the possibility of the evolution of optimal levels of male gamete production by parthenogenetic hermaphrodites through natural selection, in situations of recurring invasion of asexual populations by propagules from sexual populations, a scenario that is increasingly being appreciated as potentially fairly likely to occur in nature.

Animals↗

PubMed2004

Phenotypic profiles and functional genomics in Alzheimer's disease and in dementia with a vascular component.

Alzheimer's disease (AD) and dementia with vascular component (DVC) are the most prevalent forms of dementia. Both clinical entities share many similarities, but they differ in major phenotypic and genotypic profiles as revealed by structural and functional genomics studies. Comparative phenotypic studies have identified significant differences in 25% of more than 100 parametric variables, including anthropometry, cardiovascular function, aortic atherosclerosis, brain atrophy, blood pressure, blood biochemistry, hematology, thyroid function, folate and vitamin B12 levels, brain hemodynamics and lymphocyte markers. The phenotypic profile of patients with DVC differs from that of AD patients in the following: anthropometric values (weight, height); cardiovascular function (ECG, heart rate); blood pressure; lipid metabolism (HDL-CHO, TGs); uric acid metabolism; peripheral calcium homeostasis; liver function (GOT, GPT, GGT); alkaline phosphatase; lactate dehydrogenase; red and white blood cells; regional brain atrophy (left temporal region, inter-hippocampal distance); and left anterior blood flow velocity. Functional genomics studies incorporating APOE-related changes in biological markers extended the difference between AD and DVC up to 57%. Brain perfusion studies show a severe brain hypoperfusion in dementia associated with enlarged age-dependent arterial perfusion times. Structural genomics studies with AD-related genes, including APP, MAPT, APOE, PS1, PS2, A2M, ACE, AGT, cFOS and PRNP genes, demonstrate different genetic profiles in AD and DVC, with an absolute genetic variation rate ranging from 30% to 80%, depending upon genes and genetic clusters. Single gene analysis identifies relative genetic variations ranging from 0% to 5%. The relative polymorphic variation in genetic clusters integrated by two, three or four genes associated with AD ranges from 1% to 3%. The main phenotypic differences between AD and DVC are genotype-dependent, especially in AD, probably indicating that different genomic factors are determinant for the expression of dementia symptoms which might be accelerated or induced by environmental and/or cerebrovascular factors.

Alzheimer Disease↗

PubMed1999

Conversion of US3-encoded protein kinase gene from pseudorabies virus in a diploid gene located within inverted repeats by genetic recombination between the viral genome isomers.

The pseudorabies virus (PRV) genome consists of two components, long (U(L)) and short (U(S)) regions. The U(S) region is the only one capable of inverting itself relative to the U(L) region during productive infection, generating two equimolecular isomeric forms of viral DNA. Here we describe a recombinant virus (gIp2) generated by genetic recombination between pseudorabies viral isomers. This recombination event was observed in the parental virus gIS8, which was obtained by insertion of the alpha4-TK herpes simplex virus type 1 (HSV1) gene. The growth of gIS8 virus in the presence of 5-bromodeoxyuridine (BrdU) yielded gIp2. This was generated by nonhomologous recombination either between the two viral genomic isomers of gIS8, P and I(U/S), or between the same P isomer using nonhomologous and homologous recombination, with loss of the HSV1 sequences and duplication of the PRV US3-encoded protein kinase gene. Virus gIp2 is negative for TK, gI, gE, 11K and 28K and shows an in vitro replication capacity in neuronal cells approximately 22 times lower than that of parental virus gIS8, and similar to that of the Bartha vaccine virus strain in monkey kidney and human neuronal cells.

Animals↗

PubMedDate not supplied

P53 mutation but not p16/MTS1 mutation occurs in intraductal papillary mucinous tumors of the pancreas.

BACKGROUND/AIMS: Intraductal papillary mucinous tumors of the pancreas are rare lesions, which typically show a benign clinical course. However, some of these tumors have a malignant nature and grow in an invasive manner. The purpose of the study was to determine the prevalence of p53-, p16/MTS1- and K-ras mutations in benign and malignant intraductal papillary mucinous tumors with intent to value their importance for tumor progression. METHODOLOGY: Thirteen different archival tumor specimens were obtained at the Department of Pathology, University of Ulm. Three cases showed an invasive component of the tumor. Genomic DNA was extracted after laser capture microdissection of tumor cells from paraffin-embedded tissue sections. The corresponding sequences of p53 (exon 5, 6, 7, 8) and p16/MTS1 (exon 2) were amplified by polymerase chain reaction and subjected to single strand conformation polymorphism analysis. Codon 12 of K-ras was analyzed by the enrichment polymerase chain reaction-restriction fragment length polymorphism method. Positive samples were further investigated by sequencing. RESULTS: K-ras mutations occurred in benign and malignant intraductal papillary mucinous tumors (4/13), whereas an alteration of the coding p53 gene sequence could only be detected in the intraductal and invasive component of one malignant tumor. None of the tissue specimens revealed mutations in exon 2 of p16/MTS1. CONCLUSIONS: In contrast to K-ras mutations, alterations in the p53 gene may characterize ductal papillary mucinous carcinomas, which could be of major interest for their early diagnosis. The lack of mutations in the p16/MTS1 gene suggests that other genes may be involved in the formation of intraductal papillary mucinous neoplasias.

Biomarkers, Tumor↗

PubMed1991

Fine mapping and characterization of the Syn 6 locus in the herpes simplex virus type 1 genome.

The syncytial mutant of herpes simplex virus type 1 (HSV-1), HSV-1(13) S11, which carries three distinct syncytial mutations, Syn 1, Syn 5 and Syn 6, was described previously. Syn 1 maps to the BamHI L fragment, map units (m.u.) 0.707 to 0.745; Syn 5 is located within the BamHI Q fragment, m.u. 0.296 to 0.317; Syn 6 lies in the junction fragment BamHI SP, m.u. 0.81 to 0.85. Although Syn 1 of HSV-1(13) S11 seems to be homologous to that of HSV-1(MP) and other syncytial mutants, and Syn 5 has been recently characterized, Syn 6 represents a novel syncytial locus which has yet to be characterized. In this paper we report the fine mapping of the Syn 6 locus. This mutation has been mapped, by marker rescue and marker transfer experiments, to the long repeat regions (RL) at both ends of the L component of the HSV genome in a restriction endonuclease fragment of approximately 1.6 kb designated BamHI-SacI C (approximate m.u. 0.01 to 0.02 and 0.81 to 0.82). In the internal copy of RL the sequences containing the Syn 6 mutation were bounded to the left by the 5' end of the alpha gene specifying ICP0 and to the right by the gamma 1 gene encoding ICP34.5.

Animals↗

PubMed2002

Genome-wide profiling of promoter recognition by the two-component response regulator CpxR-P in Escherichia coli.

In Escherichia coli, the two-component Cpx system comprising the CpxA sensor kinase and the CpxR response regulator modulates gene expression in response to a variety of stresses including membrane-protein damage, starvation, and high osmolarity. To date, the few known CpxR-P target operons were mostly identified by genetic screens. To facilitate the discovery of all target operons, we derived a 15-bp weighted matrix for CpxR-P recognition that takes into account the relative base frequency at each nucleotide position. This matrix essentially consists of two tandem 5'-GTAAA-3' motifs separated by a 5-bp linker. All of the 15-bp stretches on both strands of the E. coli MG1655 genome were then scored for their degree of matching with the matrix and classified in statistical deviation groups. The effectiveness of this screening is indicated by the identification of eight new target operons (ung, ompC, psd, mviA, aroK, rpoErseABC, secA, and aer) among eleven candidates tested. Moreover, the matrix score correlates with the likelihood that a site is a true target and with the relative site affinity for CpxR-P in vitro. Our data indicate that some 100 operons are under direct CpxR-P control and that the signal transduction pathway interacts with several other control circuits in manners hitherto unanticipated.

Bacterial Proteins↗

PubMed2026

Oncology nurses' readiness to implement genomics-informed care: A descriptive, cross-sectional study in a Canadian province.

INTRODUCTION: Cancer care providers need to be equipped to support cancer care recipients in evolving care contexts. Genomics is an increasingly common component of cancer care. There is limited understanding of Canadian oncology nurses' readiness to contribute to genomics-informed cancer care. PURPOSE: To describe factors influencing oncology nurses' implementation of genomics in practice in Newfoundland and Labrador (NL; i.e., knowledge, attitudes, confidence, current practices, and social system influences); and identify predictors of their genomic knowledge. METHODS: A cross-sectional online survey was administered between September 2023 to February 2024 to nurses working in cancer care in NL. Variables associated with nurses' implementation of genomics-informed practice were measured using the Genomic Nursing Concept Inventory (GNCI©) and select, modified questions from the Genetics Genomics Nursing Practice Survey (GGNPS). Descriptive and inferential statistics were used to report findings. RESULTS: The survey was completed by 50 NL oncology nurses. While 46% of participants indicated that patients had initiated conversations about genomics with them in the past 3 months, their knowledge levels and reported confidence with genomics practices were low overall. Despite this, participants indicated largely positive attitudes toward the benefits of adopting genomics in practice and a willingness to learn more. CONCLUSION: Findings highlight opportunities to support oncology nurses with practice-based education and resources, to ensure readiness to meet patients' evolving needs and expectations surrounding genomics-informed cancer nursing care.

genomics↗

PubMed2000

De novo RNA synthesis catalyzed by HCV RNA-dependent RNA polymerase.

The 65 kDa RNA-dependent RNA polymerase (NS5B), encoded by the hepatitis C virus (HCV) genome, is a key component involved in viral replication. Here we provide the direct evidence that purified HCV polymerase catalyzed de novo RNA synthesis in a primer-independent manner using homopolymers and HCV RNA as templates. The enzyme could utilize both polyC and polyU as templates for de novo RNA synthesis, suggesting that NS5B specifically recognized pyrimidine bases for initiation. More importantly, NS5B also catalyzed de novo RNA synthesis with an HCV RNA template; the resulting nascent RNA products, smaller than the template used, contained ATP as the first nucleotide. These results indicate that the newly synthesized RNAs did not result from template self-priming and suggest that a replication initiation site in the HCV RNA genome is a uridylate.

3' Untranslated Regions↗

PubMed2005

The ins and outs of HIV replication.

The life cycle of HIV-1 involves a series of steps necessary for the successful infection of human target cells. First the RNA genome enters the cytoplasm after the fusion of the viral membrane and that of the target cell. The RNA genome is then converted to DNA form through the process of reverse transcription. The DNA genome is then integrated into the host cell DNA. Next, viral proteins and more copies of the viral genome are produced. These components assemble to form new virions that are then able to propagate. The cellular proteins involved in HIV-1 entry have been known for more than a decade now and the study of the cellular and viral components involved in HIV-1 entry has led to the development of many therapeutic strategies and drugs designed to block viral replication. Recently, there have been significant advances in the understanding of HIV-1 assembly as a consequence of the identification of the cellular factors that mediate this process. This review will provide a basic outline of the current understanding of HIV-1 entry and exit.

Animals↗

PubMed2024

Relationships between genomic dissipation and de novo SNP evolution.

Patterns of single nucleotide polymorphisms (SNPs) in eukaryotic DNA are traditionally attributed to selective pressure, drift, identity descent, or related factors-without accounting for ways in which bias during de novo SNP formation, itself, might contribute. A functional and phenotypic analysis based on evolutionary resilience of DNA points to decreased numbers of non-synonymous SNPs in human and other genomes, with a predominant component of SNP depletion in the human gene pool caused by robust preferences during de novo SNP formation (rather than selective constraint). Ramifications of these findings are broad, belie a number of concepts regarding human evolution, and point to a novel interpretation of evolving DNA across diverse species.

Polymorphism, Single Nucleotide↗

PubMed1977

Identification of human DNA sequences complementary to chromosomal RNA with an improved RNA/DNA gradient hybridization technique.

Native DNA components in the human genome were identified with an improved RNA/DNA gradient hybridization technique. 3H-Labelled complementary RNA transcribed from total human DNA was hybridized to homologous DNA which had been mildly sheared to generate single-stranded ends. Unhybridized RNA was eliminated from the reaction mixture by column chromatography before the hybrids were subjected to CsCl gradient centrifugation. Nine radioactive peaks representing RNA/DNA hybrids were reproducibly found at buoyant densities of 1.687, 1.693, 1.696, 1.699, 1.702, 1.705, 1.708, 1.711 and 1.715 g/cm3. The technique was also utilized to hybridize I125-labelled human chromosomal RNA to DNA. Three distinct radioactive peaks were found at the heavy buoyant densities of 1.702, 1.705, and 1.708 g/cm3, suggesting a differential enrichment of DNA components with sequences complementary to chromosomal RNA.

Base Sequence↗

PubMed2005

Human XPC-hHR23B interacts with XPA-RPA in the recognition of triplex-directed psoralen DNA interstrand crosslinks.

DNA interstrand crosslinks (ICLs) represent a severe form of damage that blocks DNA metabolic processes and can lead to cell death or carcinogenesis. The repair of DNA ICLs in mammals is not well characterized. We have reported previously that a key protein complex of nucleotide excision repair (NER), XPA-RPA, recognizes DNA ICLs. We now report the use of triplex technology to direct a site-specific psoralen ICL to a target DNA substrate to determine whether the human global genome NER damage recognition complex, XPC-hHR23B, recognizes this lesion. Our results demonstrate that XPC-hHR23B recognizes psoralen ICLs, which have a structure fundamentally different from other lesions that XPC-hHR23B is known to bind, with high affinity and specificity. XPC-hHR23B and XPA-RPA protein complexes were also observed to bind psoralen ICLs simultaneously, demonstrating not only that psoralen ICLs are recognized by XPC-hHR23B alone, but also that XPA-RPA may interact cooperatively with XPC-hHR23B on damaged DNA, forming a multimeric complex. Since XPC-hHR23B and XPA-RPA participate in the recognition and verification of DNA damage, these results support the hypothesis that interplay between components of the global genome repair sub-pathway of NER is critical for the recognition of psoralen DNA ICLs in the mammalian genome.

Cross-Linking Reagents↗

PubMed2001

Genotyping and preparation of the recombinant nucleocapsid protein antigen of hantavirus.

OBJECTIVE: To identify new recombinant antigens with potential for diagnosis of hemorrhagic fever with renal syndrome (HFRS) and establish reverse transcription-polymerase chain reaction-restriction fragments length polymorphism (RT-PCR-RFLP) for genotyping of hantavirus. METHODS: One group of primers was used to clone the full-length S genome segment and the partial S genome segment of the N-terminal. The two cloned genes were both fusionally expressed and non-fusionally expressed in the T7 system. The other group of primers was used to establish a RT-PCR method to detect RNAs in 37 virus isolates, 2 positive standard virus strains of hantavirus and 5 negative controls. The method for typing RFLP was set up by digesting the PCR products of 20 virus isolates with Ras I and Hind III. RESULTS: The non-fusionally expressed products with a working concentration of 1:10,000 by chapping enzyme-linked immunosorbent assay (cELISA), presented good biological activity though yields were lower than that of the fusionally expressed products. The specific component of the hantavirus genome (299 bp or 577 bp) was seen in all viral samples. The genotyping of hantavirus showed that 9 out of the total were Hantann (HTN) viruses, 8 were seoul (SEO) viruses and 3 were not determined. CONCLUSIONS: The good working titrer of expressed recombinant antigen showed that it has the potential to replace the natural antigen for detecting hantavirus antibodies. On comparison with cELISA, the detection rates for these two methods were 100% and 84.6%, and the coincidence rate was 84.6%. The former had a 15.4% higher sensitivity than the latter. The typing efficiency of RT-PCR-RFLP and sero-typing method was 85% (17/20) and 55% (11/20), respectively, showing that the former was 30% higher than the latter, while their results were highly consistent.

Antibodies, Viral↗

PubMed2003

Recent developments in the engineering of zinc finger proteins.

Within the last 20 years, the understanding of the biology of the 'classical' or Cys(2)His(2) zinc finger domain has progressed rapidly from the initial identification of the zinc finger as a repetitive zinc-binding motif in transcription factors to its use in biotechnology. The domain is the most abundant DNA-binding motif in the human genome and is a component of many key eukaryotic transcription factors involved in growth and development. Numerous structures now exist for this domain and its mode of action is known in a variety of zinc finger-DNA complexes. Application of this knowledge has led to the development of 'designer' transcription factors where zinc fingers have been engineered to bind desired DNA sequences. Recently, advances have been made in this field that potentially allow the targeting of any DNA site. Consideration of chromatin structure and the use of effector domains in these 'designer' transcription factors have made possible the regulation of a number of endogenous genes. These advances in the customised regulation of genes will be discussed in detail, as well as the potential to use these proteins in functional genomics and gene therapy applications.

DNA↗

PubMed1998

HIV-1: fifteen proteins and an RNA.

Human immunodeficiency virus type 1 is a complex retrovirus encoding 15 distinct proteins. Substantial progress has been made toward understanding the function of each protein, and three-dimensional structures of many components, including portions of the RNA genome, have been determined. This review describes the function of each component in the context of the viral life cycle: the Gag and Env structural proteins MA (matrix), CA (capsid), NC (nucleocapsid), p6, SU (surface), and TM (transmembrane); the Pol enzymes PR (protease), RT (reverse transcriptase), and IN (integrase); the gene regulatory proteins Tat and Rev; and the accessory proteins Nef, Vif, Vpr, and Vpu. The review highlights recent biochemical and structural studies that help clarify the mechanisms of viral assembly, infection, and replication.

Genes, Viral↗

PubMed2003

Global phenotypic analysis and transcriptional profiling defines the weak acid stress response regulon in Saccharomyces cerevisiae.

Weak organic acids such as sorbate are potent fungistatic agents used in food preservation, but their intracellular targets are poorly understood. We thus searched for potential target genes and signaling components in the yeast genome using contemporary genome-wide functional assays as well as DNA microarray profiling. Phenotypic screening of the EUROSCARF collection revealed the existence of numerous sorbate-sensitive strains. Sorbate hypersensitivity was detected in mutants of the shikimate biosynthesis pathway, strains lacking the PDR12 efflux pump or WAR1, a transcription factor mediating stress induction of PDR12. Using DNA microarrays, we also analyzed the genome-wide response to acute sorbate stress, allowing for the identification of more than 100 genes rapidly induced by weak acid stress. Moreover, a novel War1p- and Msn2p/4p-independent regulon that includes HSP30 was identified. Although induction of the majority of sorbate-induced genes required Msn2p/4p, weak acid tolerance was unaffected by a lack of Msn2p/4p. Ectopic expression of PDR12 from the GAL1-10 promoter fully restored sorbate resistance in a strain lacking War1p, demonstrating that PDR12 is the major target of War1p under sorbic acid stress. Interestingly, comparison of microarray data with results from the phenotypic screening revealed that PDR12 remained as the only gene, which is both stress inducible and required for weak acid resistance. Our results suggest that combining functional assays with transcriptome profiling allows for the identification of key components in large datasets such as those generated by global microarray analysis.

ATP-Binding Cassette Transporters↗

PubMed2005

Analysis of the female gametophyte transcriptome of Arabidopsis by comparative expression profiling.

The extensive data on the transcription of the plant genome are derived primarily from the sporophytic generation. There currently is little information on genes that are expressed during female gametophyte development in angiosperms, and it is not known whether the female gametophyte transcriptome contains a major set of genes that are not expressed in the sporophyte or whether it is primarily a subset of the sporophytic transcriptome. Because the embryo sac is embedded within the maternal ovule tissue, we have utilized the Arabidopsis (Arabidopsis thaliana) mutant sporocyteless that produces ovules without embryo sacs, together with the ATH1 Arabidopsis whole-genome oligonucleotide array, to identify genes that are preferentially or specifically expressed in female gametophyte development. From analysis of the datasets, 225 genes are identified as female gametophyte genes, likely a lower limit as stringent criteria were used for the analysis, eliminating many low expressed genes. Nearly 45% of the identified genes were not previously detected by sporophytic expression profiling, suggesting that the embryo sac transcriptome may contain a significant fraction of transcripts restricted to the gametophyte. Validation of six candidate genes was performed using promoterbeta-glucuronidase fusions, and all of these showed embryo sac-specific expression in the ovule. The unfiltered expression data from this study can be used to evaluate the possibility of female gametophytic expression for any gene in the ATH1 array, and contribute to identification of the functions of the component of the Arabidopsis genome not represented in studies of sporophytic expression and function.

Arabidopsis↗