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PubMed1998

Magnetic field activation of protein-DNA binding.

The mechanisms involved in sensing, signaling, and coordinating changes resulting from magnetic field-induced stress show substantial similarities to those of heat shock, e.g., magnetic field-induced heat shock 70 gene (HSP70) expression involves heat shock factor (HSF) activation and heat shock element binding. However, an additional requirement for transactivation of HSP70 expression by magnetic fields is the binding of Myc protein, indicating that additional elements and/or pathways are involved in the induction of HSP70 expression by magnetic fields. To investigate the possible participation of additional genetic elements in magnetic field-induced HSP70 expression, we examined both magnetic field exposure and heat shock on protein-DNA binding of the transcription factors HSF, AP-1, AP-2, and SP-1 in four human cell lines. The binding sites for these transcription factors are present in the HSP70 promoter. AP-1 binding activity, normally not increased by heat shock, was increased by magnetic fields; heat shock induced an increase only in HSF binding. Although intersecting and converging signaling pathways could account for the multiplicity of elements involved in magnetic field-induced HSP70 transcription, direct interaction of magnetic fields with DNA is also a possible mechanism. Because magnetic fields penetrate the cell, they could well react with conducting electrons present in the stacked bases of the DNA.

Binding, Competitive↗
PubMed2006

SNAP: Combine and Map modules for multilocus population genetic analysis.

We have added two software tools to our Suite of Nucleotide Analysis Programs (SNAP) for working with DNA sequences sampled from populations. SNAP Map collapses DNA sequence data into unique haplotypes, extracts variable sites and manipulates output into multiple formats for input into existing software packages for evolutionary analyses. Map collapses DNA sequence data into unique haplotypes, extracts variable sites and manipulates output into multiple formats for input into existing software packages for evolutionary analyses. Map includes novel features such as recoding insertions or deletions, including or excluding variable sites that violate an infinite-sites model and the option of collapsing sequences with corresponding phenotypic information, important in testing for significant haplotype-phenotype associations. SNAP Combine merges multiple DNA sequence alignments into a single multiple alignment file. The resulting file can be the union or intersection of the input files. SNAP Combine currently reads from and writes to several sequence alignment file formats including both sequential and interleaved formats. Combine also keeps track of the start and end positions of each separate alignment file allowing the user to exclude variable sites or taxa, important in creating input files for multilocus analyses.

Algorithms↗
PubMed2024

Genome-wide copy number variation association study in anorexia nervosa.

This study represents the first large-scale investigation of rare (<1% population frequency) copy number variants (CNVs) in anorexia nervosa (AN). Large, rare CNVs are reported to be causally associated with anthropometric traits, neurodevelopmental disorders, and schizophrenia, yet their role in the genetic basis of AN is unclear. Using genome-wide association study (GWAS) array data from the Anorexia Nervosa Genetics Initiative (ANGI), which included 7414 AN case and 5044 controls, we investigated the association of 67 well-established syndromic CNVs and 178 pleiotropic disease-risk dosage-sensitive CNVs with AN. To identify novel CNV regions (CNVRs) that increase the risk of AN, we conducted genome-wide association studies with a focus on rare CNV-breakpoints (CNV-GWAS). We found no net enrichment of rare CNVs, either deletions or duplications, in AN, and none of the well-established syndromic or pleiotropic CNVs had a significant association with AN status. However, the CNV-GWAS found 21 nominally associated CNVRs that contribute to AN risk, covering protein-coding genes implicated in synaptic function, metabolic/mitochondrial factors, and lipid characteristics, like the CD36 (7q21.11) gene, which transports long-chain fatty acids into cells. CNVRs intersecting genes previously related to neurodevelopmental traits include deletions of NRXN1 intron 5 (2p16.3), IMMP2L (7q31.1), and PTPRD (9p23). Overall, given that our study is well powered to detect the CNV burden level reported for schizophrenia, we can conclude that rare CNVs have a limited role in the etiology of AN, as reported for bipolar disorder. Our nominal associations for the 21 discovered CNVRs are consistent with AN being a metabo-psychiatric trait, as demonstrated by the common genetic architecture of AN, and we provide association results to allow for replication in future research.

Humans↗
PubMed2005

A member of the polymerase beta nucleotidyltransferase superfamily is required for RNA interference in C. elegans.

RNA interference (RNAi) is an ancient, highly conserved mechanism in which small RNA molecules (siRNAs) guide the sequence-specific silencing of gene expression . Several silencing machinery protein components have been identified, including helicases, RNase-related proteins, double- and single-stranded RNA binding proteins, and RNA-dependent RNA polymerase-related proteins . Work on these factors has led to the revelation that RNAi mechanisms intersect with cellular pathways required for development and fertility . Despite rapid progress in understanding key steps in the RNAi pathway, it is clear that many factors required for both RNAi and related developmental mechanisms have not yet been identified. Here, we report the characterization of the C. elegans gene rde-3. Genetic analysis of presumptive null alleles indicates that rde-3 is required for siRNA accumulation and for efficient RNAi in all tissues, and it is essential for fertility and viability at high temperatures. RDE-3 contains conserved domains found in the polymerase beta nucleotidyltransferase superfamily, which includes conventional poly(A) polymerases, 2'-5' oligoadenylate synthetase (OAS), and yeast Trf4p . These findings implicate a new enzymatic modality in RNAi and suggest possible models for the role of RDE-3 in the RNAi mechanism.

Amino Acid Sequence↗
PubMed2000

Combined activities of Gurken and decapentaplegic specify dorsal chorion structures of the Drosophila egg.

During Drosophila oogenesis Gurken, associated with the oocyte nucleus, activates the Drosophila EGF receptor in the follicular epithelium. Gurken first specifies posterior follicle cells, which in turn signal back to the oocyte to induce the migration of the oocyte nucleus from a posterior to an anterior-dorsal position. Here, Gurken signals again to specify dorsal follicle cells, which give rise to dorsal chorion structures including the dorsal appendages. If Gurken signaling is delayed and starts after stage 6 of oogenesis the nucleus remains at the posterior pole of the oocyte. Eggs develop with a posterior ring of dorsal appendage material that is produced by main-body follicle cells expressing the gene Broad-Complex. They encircle terminal follicle cells expressing variable amounts of the TGFbeta homologue, decapentaplegic. By ectopically expressing decapentaplegic and clonal analysis with Mothers against dpp we show that Decapentaplegic signaling is required for Broad-Complex expression. Thus, the specification and positioning of dorsal appendages along the anterior-posterior axis depends on the intersection of both Gurken and Decapentaplegic signaling. This intersection also induces rhomboid expression and thereby initiates the positive feedback loop of EGF receptor activation, which positions the dorsal appendages along the dorsal-ventral egg axis.

Animals↗
PubMed2005

Morphologic and immunophenotypic diversity in Ewing family tumors: a study of 66 genetically confirmed cases.

More than 85% of Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET), or "Ewing family of tumors" (EFTs), have the translocation, t (11;22) (q24;q12), with others having variant translocations. Identification of these by cytogenetic and/or molecular genetic techniques is specific for EFT and is increasingly recognized as the "gold standard" for diagnosis. However, these techniques are not universally available. We therefore studied a large group of genetically confirmed EFTs to more completely understand the morphologic and immunophenotypic spectrum of this rare sarcoma. Sixty-six cytogenetically, FISH or RT-PCR proven-EFTs were retrieved. In 56 cases, immunohistochemistry (IHC) was performed for pan-cytokeratins (PanCK), high molecular weight cytokeratins (HMWCK), desmin (DES), CD99, CD117, and FLI1 protein using heat-induced epitope retrieval and the Dako Envision system. The cases arose chiefly in children and young adults (median 18 years; range, 3-65 years) of both sexes (male, 32; female, 31; unknown, 3) in a variety of bone (N = 39) and soft tissue (N = 27) sites. Histologically, 46 cases (73%) showed only typical features of ES, 9 cases (16%) showed features of PNET, 3 cases (5%) showed "adamantinoma-like" features, 3 cases (5%) corresponded to "atypical Ewing sarcoma," 3 cases (5%) showed principally intersecting fascicles of spindled cells, and 2 cases had abundant hyalinized matrix. IHC results were as follows: PanCK (18 of 56, 32%), HMWCK (3 of 55, 5%), DES (1 of 56, 2%), CD99 (52 of 52, 100%), CD117 (13 of 54, 24%), and FLI1 (44 of 47, 94%). HMWCK was expressed only in "adamantinoma-like" EFTs, none of which expressed DES. In conclusion, most, but not all, EFTs can be accurately diagnosed using time-honored morphologic criteria and ancillary immunohistochemistry. However, genetic confirmation remains essential for the diagnosis of unusual morphologic variants of EFT, including "adamantinoma-like," spindled, sclerosing, and clear cell/anaplastic variants. Therefore, to exclude or confirm the diagnosis of Ewing's sarcoma in round cell sarcomas having a variety of patterns but not specifically conforming to a tumor of known lineage (eg, rhabdomyosarcoma), cytogenetics, and/or molecular analysis is required.

12E7 Antigen↗
PubMed2003

Intersect: identification and visualization of overlaps in database search results.

UNLABELLED: The determination of distant evolutionary relationships remains an important biological problem, and distant homologs often appear in statistically insignificant regions of sequence similarity searches. Intersect is a computer program designed to identify and visualize the overlaps between sets of sequences reported by multiple database searches. This capability extends the usefulness of database search results and aids researchers in identifying the individual sequences that best bridge sequence families and superfamilies. AVAILABILITY: The Intersect program is available from the Babbitt laboratory website at http://www.babbittlab.ucsf.edu/software/intersect

Algorithms↗
PubMed2006

Genome-wide identification of direct targets of the Drosophila retinal determination protein Eyeless.

The discovery of direct downstream targets of transcription factors (TFs) is necessary for understanding the genetic mechanisms underlying complex, highly regulated processes such as development. In this report, we have used a combinatorial strategy to conduct a genome-wide search for novel direct targets of Eyeless (Ey), a key transcription factor controlling early eye development in Drosophila. To overcome the lack of high-quality consensus binding site sequences, phylogenetic shadowing of known Ey binding sites in sine oculis (so) was used to construct a position weight matrix (PWM) of the Ey protein. This PWM was then used for in silico prediction of potential binding sites in the Drosophila melanogaster genome. To reduce the false positive rate, conservation of these potential binding sites was assessed by comparing the genomic sequences from seven Drosophila species. In parallel, microarray analysis of wild-type versus ectopic ey-expressing tissue, followed by microarray-based epistasis experiments in an atonal (ato) mutant background, identified 188 genes induced by ey. Intersection of in silico predicted conserved Ey binding sites with the candidate gene list produced through expression profiling yields a list of 20 putative ey-induced, eye-enriched, ato-independent, direct targets of Ey. The accuracy of this list of genes was confirmed using both in vitro and in vivo methods. Initial analysis reveals three genes, eyes absent, shifted, and Optix, as novel direct targets of Ey. These results suggest that the integrated strategy of computational biology, genomics, and genetics is a powerful approach to identify direct downstream targets for any transcription factor genome-wide.

Animals↗
PubMed2006

Fat and Wingless signaling oppositely regulate epithelial cell-cell adhesion and distal wing development in Drosophila.

Development of organ-specific size and shape demands tight coordination between tissue growth and cell-cell adhesion. Dynamic regulation of cell adhesion proteins thus plays an important role during organogenesis. In Drosophila, the homophilic cell adhesion protein DE-Cadherin (DE-Cad) regulates epithelial cell-cell adhesion at adherens junctions (AJs). Here, we show that along the proximodistal (PD) axis of the developing wing epithelium, apical cell shapes and expression of DE-Cad are graded in response to Wingless (Wg), a morphogen secreted from the dorsoventral (DV) organizer in distal wing, suggesting a PD gradient of cell-cell adhesion. The Fat (Ft) tumor suppressor, by contrast, represses DE-Cad expression. In genetic tests, ft behaves as a suppressor of Wg signaling. Cytoplasmic pool of beta-catenin/Arm, the intracellular transducer of Wg signaling, is negatively correlated with the activity of Ft. Moreover, unlike that of Wg, signaling by Ft negatively regulates the expression of Distalless (Dll) and Vestigial (Vg). Finally, we show that Ft intersects Wnt/Wg signaling, downstream of the Wg ligand. Fat and Wg signaling thus exert opposing regulation to coordinate cell-cell adhesion and patterning along the PD axis of Drosophila wing.

Animals↗
PubMed2025

Ossifying Spindled and Epithelioid Tumor: A Novel Soft Tissue Tumor.

This investigation describes the clinicoradiologic, pathologic, and molecular features of a unique soft tissue tumor characterized by a peripheral shell of bone and composed of bland myoid spindle and epithelioid cells that are keratin-positive. Our study cohort consists of 6 men and 6 women, with a mean age of 32 years. The tumors arose in the extremities (n = 9) and proximal limb girdle (n = 3) and were equally distributed between deep and superficial soft tissues. Patients reported dull painless masses of several months to >10 years duration (mean: 2.9 years). Imaging demonstrated a complete or partial peripheral shell of bone that could extend centrally, and the tumor's mean size was 5.7 cm. Histologically, the tumors were composed of uniform, eosinophilic myoid spindled cells growing in sheets and intersecting fascicles, surrounded by mature lamellar and/or woven bone. Also present was an admixed component of intermediate-sized epithelioid cells with eosinophilic cytoplasm. Mitotic activity was consistently low. Immunohistochemistry showed strong multifocal staining for keratins, and 50% (5/10) showed focal staining for S100; however, all were negative for SMA, desmin, SOX10, ERG, and CD34. Genetic analysis by multiple targeted RNA sequencing panels was negative (n = 10); however, whole transcriptome sequencing (n = 8) revealed a recurrent and novel in-frame SRSF7::NFATC3 fusion in 4 tumors. Dual fluorescence in situ hybridization probes for SRSF7::NFATC3 successfully confirmed this fusion and identified a fifth case, which had not undergone whole transcriptome sequencing but was negative by a targeted RNA fusion panel. Methylation profiling (n = 8) demonstrated a shared epigenetic profile distinct from other entities. Clinical follow-up (n = 11) showed no evidence of recurrence after primary excision with a mean of 41.6 months. In summary, we describe a novel soft tissue tumor designated "ossifying spindled and epithelioid tumor" as a descriptive histologic term that also emphasizes its close radiologic mimic, ossifying fibromyxoid tumor. All cases have behaved in a benign fashion without recurrence following simple excision. Awareness of this entity is important, so that it can be distinguished from other neoplasms that have more aggressive biological potential.

Humans↗
PubMed1981

Genetical variation for enzyme activity in a population of Drosophila melanogaster. VII. Genotype-environment interaction for alcohol dehydrogenase (ADH) activity.

Genotype-environment interaction was detected for ADH activity amongst a set of 18 highly inbred lines of Drosophila melanogaster which had been extracted from the laboratory population, "Texas". The genotype-environment interaction for ADH activity was not wholly associated with genotype-environment interaction for body weight or total protein level. Detailed analyses of the responses of the individual inbred lines in ADH activity in relation to the environmental index, ej and following the procedure of Jinks and Pooni (1979), showed substantial diversity in the form of response. Lines homozygous for the AdhF allele were more environmentally sensitive than AdhS/S lines. Amongst the 16 AdhS/S lines, models of linear, quadratic or two intersecting-straight-lines were used to illustrate the varied responses of genotypes to the environment. The heterogeneity in the response characteristics of the inbred lines was attributed to variations in the conditions of culture media normally present within populations and laboratories. Moreover the non-linear responses shown by some lines to the environment are consistent with a model of genotype-environment interaction for ADH activity mediated by varied genotype-specific sensitivities to different environmental factors.

Alcohol Oxidoreductases↗
PubMed2006

Novel integrative genomics strategies to identify genes for complex traits.

Forward genetics is a common approach to dissecting complex traits like common human diseases. The ultimate aim of this approach was the identification of genes that are causal for disease or other phenotypes of interest. However, the forward genetics approach is by definition restricted to the identification of genes that have incurred mutations over the course of evolution or that incurred mutations as a result of chemical mutagenesis, and that as a result lead to disease or to variations in other phenotypes of interest. Genes that harbour no such mutations, but that play key roles in parts of the biological network that lead to disease, are systematically missed by this class of approaches. Recently, a class of novel integrative genomics approaches has been devised to elucidate the complexity of common human diseases by intersecting genotypic, molecular profiling, and clinical data in segregating populations. These novel approaches take a more holistic view of biological systems and leverage the vast network of gene-gene interactions, in combination with DNA variation data, to establish causal relationships among molecular profiling traits and between molecular profiling and disease (or other classic phenotypes). A number of novel genes for disease phenotypes have been identified as a result of these approaches, highlighting the utility of integrating orthogonal sources of data to get at the underlying causes of disease.

Animals↗
PubMed2005

HYPERSENSITIVE TO RED AND BLUE 1, a ZZ-type zinc finger protein, regulates phytochrome B-mediated red and cryptochrome-mediated blue light responses.

Plant photoreceptors that regulate photomorphogenic development include red/far-red-light-absorbing phytochromes and blue/UV-A-light-absorbing cryptochromes. We have undertaken a genetic screen to identify additional components downstream of the photoreceptors in Arabidopsis thaliana. We identified a short hypocotyl mutant under red and blue light, hypersensitive to red and blue 1 (hrb1). Mutation in HRB1 also enhances the end-of-day far-red light response, inhibits leaf expansion and petiole elongation, and attenuates the expression of CAB3 and CHS. Double mutant analysis indicates that phyB is epistatic to hrb1 under red light, and cry1 cry2 is epistatic to hrb1 under blue light for both hypocotyl growth and light-regulated gene expression responses. HRB1 localizes to the nucleus and belongs to a protein family of Drought induced 19 (Di19). HRB1 and all other family members contain a ZZ-type zinc finger domain, which in other organisms is implicated in protein-protein interactions between dystrophin and calmodulin and between transcriptional adaptors and activators. HRB1 activity is also required for red and blue light-induced expression of PHYTOCHROME INTERACTING FACTOR 4 (PIF4). pif4 shows a very similar hypersensitive response as hrb1 to both red light and blue light and is epistatic to hrb1 in control of light-regulated gene expression responses. Thus, the roles of HRB1 and PIF4 together in regulating both red and blue light responses may represent points where red light signaling and blue light signaling intersect.

Amino Acid Sequence↗
PubMed1996

Longitudinal Gompertzian and Weibull analyses of adult mortality in Spain (Europe), 1900-1992.

Mortality data from Spain, 1900 to 1992, were analyzed using Gompertzian and Weibull functions. Longitudinal Gompertzian analysis demonstrated that annual age-specific mortality rate distributions were determined by a fixed intersection point (in men: 84.3 years, in women: 89.3 years). Two methods of longitudinal Gompertzian analysis were applied. The method based on linear regression indicated that environmental influences upon age-related mortality were constant. The method based on a rough estimate of first derivative suggested that environmental influences have been decreasing. Both of these methods suggested that genetic influence upon age-related mortality is greater for men that for women. Analysis of Spanish mortality data from 1900 to 1992 suggest that the Gompertz function fits age-specific mortality rate distributions in adult men and women better than the Weibull function.

Adult↗
PubMed2002

Local intersection volume: a new 3D descriptor applied to develop a 3D-QSAR pharmacophore model for benzodiazepine receptor ligands.

In this work, we have developed a new descriptor, named local intersection volume (LIV), in order to compose a 3D-QSAR pharmacophore model for benzodiazepine receptor ligands. The LIV can be classified as a 3D local shape descriptor in contraposition to the global shape descriptors. We have selected from the literature 49 non-benzodiazepine compounds as a training data set and the model was obtained and evaluated by genetic algorithms (GA) and partial least-squares (PLS) methods using LIVs as descriptors. The LIV 3D-QSAR model has a good predictive capacity according the cross-validation test by "leave-one-out" procedure (Q(2)=0.72). The developed model was compared to a comprehensive and extensive SAR pharmacophore model, recently proposed by Cook and co-workers, for benzodiazepine receptor ligands [J. Med. Chem. 43 (2000) 71]. It showed a relevant correlation with the pharmacophore groups pointed out in that work. Our LIV 3D-QSAR model was also able to predict affinity values for a series of nine compounds (test data set) that was not included into the training data set.

Algorithms↗
PubMed2004

Reactive nodular fibrous pseudotumors of the gastrointestinal tract: report of 8 cases.

Eight cases of reactive nodular fibrous pseudotumor of the gastrointestinal tract are presented. The patients included 6 males and 2 females between the ages of 1 and 68 years (mean age 41.5 years). Three tumors involved the small intestine, and 5 of the investigated lesions were located in the large bowel. Of these, 2 originated in the sigmoid colon, 1 in the cecum, 1 in the appendix, and 1 in the large bowel not otherwise specified. The tumors' size varied from 3 to 10 cm in the greatest diameter (mean 6.2 cm). Histologically they were composed of stellate or spindle shaped cells resembling fibroblasts arranged haphazardly or in intersecting fascicles, embedded in a collagen-rich stroma, with sparse intralesional mononuclear cells frequently arranged in lymphoid aggregates. Immunohistochemically, the lesions were positive for vimentin (7/7), smooth muscle actin (8/8), muscle-specific actin (5/7), cytokeratins AE1/AE3 (6/7), and CAM 5.2 (1/7), and antigen CD68 (1/7). No case (0/8) reacted positively with antibody to CD117 (c-kit). Genetically no substitutions, deletions, or insertions occurred in exon 11 in all analyzed samples. Likewise, no deletions or insertions in part of exon 9 were observed. Ultrastructurally the tumor cells revealed features typical of myofibroblasts. According to the morphologic, immunohistochemical, and ultrastructural features mentioned above, especially to the positivity of low-molecular-weight cytokeratins, we propose this lesion to be related to a proliferation of multipotential subserosal cells rather than ordinary myofibroblasts or fibroblasts.

Adult↗
PubMed2006

Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription.

Metabolic enzymes rarely regulate informational processes like gene expression. Yeast acetyl-CoA synthetases (Acs1p and 2p) are exceptional, as they are important not only for carbon metabolism but also are shown here to supply the acetyl-CoA for histone acetylation by histone acetyltransferases (HATs). acs2-Ts mutants exhibit global histone deacetylation, transcriptional defects, and synthetic growth defects with HAT mutants at high temperatures. In glycerol with ethanol, Acs1p is an alternate acetyl-CoA source for HATs. Rapid deacetylation after Acs2p inactivation suggests nuclear acetyl-CoA synthesis is rate limiting for histone acetylation. Different histone lysines exhibit distinct deacetylation rates, with N-terminal tail lysines deacetylated rapidly and H3 lysine 56 slowly. Yeast mitochondrial and nucleocytosolic acetyl-CoA pools are biochemically isolated. Thus, acetyl-CoA metabolism is directly linked to chromatin regulation and may affect diverse cellular processes in which acetylation and metabolism intersect, such as disease states and aging.

Acetate-CoA Ligase↗
PubMed2005

GeneKeyDB: a lightweight, gene-centric, relational database to support data mining environments.

BACKGROUND: The analysis of biological data is greatly enhanced by existing or emerging databases. Most existing databases, with few exceptions are not designed to easily support large scale computational analysis, but rather offer exclusively a web interface to the resource. We have recognized the growing need for a database which can be used successfully as a backend to computational analysis tools and pipelines. Such database should be sufficiently versatile to allow easy system integration. RESULTS: GeneKeyDB is a gene-centered relational database developed to enhance data mining in biological data sets. The system provides an underlying data layer for computational analysis tools and visualization tools. GeneKeyDB relies primarily on existing database identifiers derived from community databases (NCBI, GO, Ensembl, et al.) as well as the known relationships among those identifiers. It is a lightweight, portable, and extensible platform for integration with computational tools and analysis environments. CONCLUSION: GeneKeyDB can enable analysis tools and users to manipulate the intersections, unions, and differences among different data sets.

Algorithms↗