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PubMed1994

Mapping and genetic organization of pTiChry5, a novel Ti plasmid from a highly virulent Agrobacterium tumefaciens strain.

Agrobacterium tumefaciens Chry5, a wild-type strain originally isolated from chrysanthemum, is unusually tumorigenic, particularly on soybean. We have mapped the Chry5 Ti plasmid by genomic walking and restriction endonuclease analysis, and have located its virulence, T-DNA, plasmid incompatibility, and L,L-succinamopine utilization loci. Southern analysis has revealed that about 85% of the Chry5 Ti plasmid is highly homologous to another Ti plasmid, pTiBo542. Although all the functions that we have located on pTiChry5 are encoded by pTiBo542-homologous regions, the two Ti plasmids differ in their genetic organization. The overall patterns of restriction sites in the plasmids also differ, with the exception of an approximately 12 kb segment of the virulence region, where the BamHI sites appear to be conserved. Complementation analysis has shown that deletion of a DNA segment which flanks the oncogenic T-DNA results in severe attenuation of virulence. This region also contains a sequence that is repeated in the Chry5 genome outside the Ti plasmid, and that is widely distributed in the Rhizobiaceae.

Agrobacterium tumefaciens↗
PubMed1998

Ecto-phosphodiesterase/pyrophosphatase of lymphocytes and non-lymphoid cells: structure and function of the PC-1 family.

Many developmentally regulated membrane proteins of lymphocytes are ecto-enzymes, with their active sites on the external surface of the cell. These enzymes commonly have peptidase, phosphodiesterase or nucleotidase activity. Their biological roles are just beginning to be discovered. Although their expression is usually associated with particular stages of lymphoid differentiation, the same gene products are often expressed on the surface of certain non-lymphoid cell types outside the immune system, indicating that their functions cannot be unique to lymphocytes, nor can they be ubiquitous. The plasma cell membrane protein PC-1 (phosphodiesterase I; EC 3.1.4.1/nucleotide pyrophosphatase; EC 3.6.1.9), which was one of the first serological markers for lymphocyte subsets to be discovered, is a typical example. Within the immune system, PC-1 is confined to plasma cells, which represent about 0.1% of lymphocytes. However, PC-1 is also expressed on cells of the distal convoluted tubule of the kidney, chondrocytes, osteoblasts, epididymis and hepatocytes. Recent work has shown that PC-1 is a member of a multigene family of ecto-phosphodiesterases that currently has two other members, PD-1 alpha (autotaxin) and PD-1 beta (B10). Within this family, the extracellular domains are highly conserved, especially around the active site. In contrast, the transmembrane and cytoplasmic domains are highly divergent. Individual members of the eco-phosphodiesterase family have distinct patterns of distribution in different cell types, and even within the same cell. For example, PC-1 is present only on the basolateral surface of hepatocytes, while B10 (PD-1 beta) is confined to the apical surface. Analysis of conservation and differences in the sequence of their cytoplasmic tails may illuminate intracellular targetting signals. Ecto-phosphodiesterases may play a part in diverse activities in different tissues, including recycling of nucleotides. They may also regulate the concentration of pharmacologically active extracellular compounds such as adenosine or its derivatives and cell motility. Some members may modulate local concentrations of pyrophosphate, and hence influence calcification in bone and cartilage.

Amino Acid Sequence↗
PubMed1991

[Pancreatic conservation after autotransplantation in dogs. Value of histologic surface analysis].

A study of an artificial conservation fluid (hyperosmolar, pH = 8, rich in lactobionate and raffinose) was carried out by means of an experimental procedure involving segmental pancreatic autotransplants in dogs. The study covers 14 transplants, seven carried out without conservation and seven with 24-hour conservation at 4 degrees C. The caudal pancreas was removed after splenectomy and either transfused with 250 ml of 4 degrees C Euro-Collins before immediate transplant or with 250 ml of 4 degrees C conservation fluid for 24 hours before the transplant. The caudal pancreas was transplanted onto the right iliac vessels, while an arterio-venous fistula was created on the distal splenic vessels and the pancreatic duct was injected with modified tissucol. At the same time as the transplant, a cephalic pancreatectomy was performed. Laboratory tests included an intra venous glucose tolerance test monitored on days 0 and 28 and blood glucose and serum amylase measured every three days from days 1 to 28. The histological study of the pancreatic tissues 28 days after the transplants involved the light microscopic evaluation of the degree of fibrosis, inflammation of the pancreas, cystosteatonecrosis and peripancreatic inflammation. We used a computerized method to measure the surface area of the islets of Langerhans, as revealed by immunocytochemistry, and the surface area of fibrosis. The blood glucose and the serum amylase analyses from days 1 to 28, and the blood glucose variations during the intra venous glucose tolerance test, showed no differences between the two groups. Standard laboratory parameters were similar in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗
PubMed2026

Longitudinal whole-genome analysis of bluetongue virus identifies conserved serotype-specific genomes and distinct genomic constellations within a Colorado sheep flock (2021-2023).

Bluetongue virus (BTV) is a segmented double-stranded RNA virus of ruminants transmitted by Culicoides spp. biting midges. Although the genome consists of ten segments, classification into serotypes is primarily based on genome segment 2. However, reassortment among genomic segments is a major driver of BTV evolution and diversity. This study used longitudinal whole-genome sequencing to characterize BTV genomes collected from 2021 to 2023 within a single sheep flock in Colorado, where multiple serotypes co-circulate. Whole-genome sequences were generated from fourteen blood samples representing four serotypes: BTV-6, -11, -13, and -17. Longitudinal sampling identified multiple BTV serotypes within individual sheep across consecutive years. Tanglegram analysis comparing segment phylogenies to the segment 2 tree demonstrated incongruent topologies across all genomic segments, suggestive of reassortment or the circulation of distinct genomic constellations. Nucleotide-level comparisons revealed high sequence homology among same-serotype samples from the same year, while the greatest genetic divergence was observed among BTV-17 genomes collected in different years. Additionally, all BTV-13 genomes contained a previously undescribed nonsynonymous substitution in segment 10 predicted to extend the encoded protein by three amino acids. Together, these findings demonstrate that highly conserved BTV genomes and distinct genomic constellations can be detected at the flock level across multiple years. This longitudinal whole-genome approach reveals the genetic complexity of endemic BTV populations, including novel variants and genomic patterns consistent with reassortment that are lost with conventional serotyped-based approaches, highlighting the need to integrate whole-genome characterization into endemic BTV monitoring programs.

Animals↗
PubMed2005

cpbAg1 encodes an active carboxypeptidase B expressed in the midgut of Anopheles gambiae.

We previously used differential display to identify several Anopheles gambiae genes, whose expression in the mosquito midgut was regulated upon ingestion of Plasmodium falciparum. Here, we report the characterization of one of these genes, cpbAg1, which codes for the first zinc-carboxypeptidase B identified in An. gambiae and in any insect. Expression of cpbAg1 in baculovirus gave rise to an active enzyme, and determination of the N-terminal amino acids confirmed that CPBAg1 contains a signal peptide and a pro-peptide, typical features of digestive zinc carboxypeptidases. cpbAg1 mRNA was mainly produced in the mosquito midgut, where it accumulated in unfed females and was rapidly down-regulated upon blood feeding. Annotation of the An. gambiae genome predicts twenty-three sequences coding for zinc-carboxypeptidases of which only two (cpbAg1 and cpbAg2) are expressed at a significant level in the mosquito midgut.

Amino Acid Sequence↗
PubMed2002

Variability of critical epitopes within HIV-1 heptad repeat domains for selected entry inhibitors in HIV-infected populations worldwide [corrected].

BACKGROUND: Two of the fusion inhibitors T-20 and 5-helix polypeptide have been shown to be potent inhibitors of cell-to-cell fusion and are currently under investigation as therapy for HIV-1. OBJECTIVES: To examine variability of HIV-1 gp41 heptads repeat regions (HR1 and HR2), with special emphasis on the presence of T-20 resistance mutations and 5-helix variability at critical epitopes, in treatment-naive patients infected with diverse HIV-1 subtypes from different geographic regions. METHODS: A total of 150 specimens representing HIV-1 group M subtypes (A-G) from persons naive to HIV-1 viral entry inhibitor therapy were used to amplify and sequence a 506 bp segment of transmembrane protein. RESULTS: In general, both HR1 (a.a. 540-593) and HR2 (a.a. 628-673) domains were highly conserved. Sequence analysis of the T-20 resistant domain (a.a. 547-549, GIV) revealed that 99% of the specimens (149 of 150) carried a T-20 sensitive genotype. The critical epitopes involved in the 5-helix interaction include residues at positions 628W, 631W, 635I, 638Y, 642I, 645L, 649S, 652Q, 656N, and 659E. Analysis of the 150 specimens revealed that all had identical residues at six of these positions, whereas two positions had minor variations (635 and 649) and two (645 and 659) appeared to have subtype-specific substitutions. CONCLUSIONS: This data indicates that there is limited resistance to T-20 in these worldwide populations and that the critical epitopes for effective 5-helix binding are highly conserved across all subtypes. Taken together, these data suggest that T-20 and 5-helix should provide useful additives to current antiretroviral therapy for clinical management of HIV disease.

Amino Acid Sequence↗
PubMed2003

Strong conservation of the human NF2 locus based on sequence comparison in five species.

We analyzed 137 kb covering human neurofibromatosis 2 ( NF2) tumor suppressor locus and orthologous loci from baboon, mouse, rat, and pufferfish Takifugu rubripes. A predominant feature of human-rodent conservation is a very similar distribution of conserved islands, regarding length, position, and degree of identity. By use of a threshold of 75% identity over > or =100 bp of gap-free alignment, comparisons of human-mouse sequences resulted in 3.58% for extra-exonic conservation, which can be compared to 4.5% of exonic sequence content within the human locus. We identified a duplication of neurofibromin 2 in pufferfish, which resulted in two putative proteins with 74% and 76% identity to the human protein. One distinct island (called inter 1), conserved between all analyzed species, was located between promoters of the NIPSNAP1 and NF2 genes. Inter 1 might represent a novel regulatory element, important for the function of this locus. The high level of intronic conservation in the NF2 locus suggests that a number of unknown regulatory elements might exist within this gene. These elements could be affected by disease-causing mutations in NF2 patients and NF2-associated tumors. Alternatively, this conservation might be explained by presence of not yet characterized transcriptional unit(s) within this locus.

Amino Acid Sequence↗
PubMed1993

A smoking cessation pilot program.

National health-care costs are continuing to climb and employers in Hawaii and across the nation are forced to increase their share of the burden. To limit these costs, worksite health promotion programs are increasing in number and in scope. Smoking control programs in particular now rank as the most prevalent type of worksite program; as the disability, absenteeism, and early death on the part of smokers have been well-documented as contributing to the cost of health care. Our research describes a year-long, pilot smoking-cessation program implemented at Hawaiian Telephone Company. Our program used a combination of behavioral-modification, social support and incentives technique to assist people to stop smoking or to maintain their nonsmoking behavior. The 12 volunteer participants provided a multiethnic, long-term, heavy smoker employee sample. Survey results at 1 year demonstrated that 4 of them quit smoking (quit rate = 50%), 2 reduced their tobacco intake, 2 dropped out of the program and continued to smoke. The 4 who had entered the program for maintenance purposes remained smoke-free. Cost-benefit analysis yielded conservative estimates indicating that the program had paid for itself and saved an additional $350 a year per participant who remained a nonsmoker.

Adult↗
PubMed2005

TFBScluster: a resource for the characterization of transcriptional regulatory networks.

SUMMARY: One major challenge of the post-sequencing era of the human genome project will be the functional annotation of the non-coding portion of the genome, in particular gene regulatory sequences. We have developed a new web-based tool, TFBScluster, which performs genome-wide identification of transcription factor binding site clusters that are conserved in multiple mammalian genomes. Clusters representing candidate gene regulatory elements can be filtered further, based on the presence or absence of additional user-defined DNA sequence motifs or by constraining the orientation or order of binding sites. Comprehensive results files, returned by email, are designed to facilitate experimental validation of computationally identified candidate gene regulatory sequences. TFBScluster, therefore, has the potential to contribute to deciphering transcriptional networks that regulate a wide range of mammalian developmental processes.

Algorithms↗
PubMed2004

Genetic diversity and structure of urban populations of Pieris butterflies assessed using amplified fragment length polymorphism.

Conservation programs in urban ecosystems need to determine the genetic background in populations of urban dwellers. We examined the genetic diversity and structure of Pieris rapae and P. melete using AFLP markers, and compared them between species and between urban and rural environments. As a result: (i). in both species, there was no reduction in genetic diversity within urban populations by direct comparison of diversity measurements, although the analysis of molecular variance suggested significant reductions in the variance within seasonal subpopulations in urban populations; (ii). P. rapae retained greater genetic diversity within species and populations; (iii). populations of both species showed significant genetic differentiation, and P. melete was more strongly subdivided; (iv). in both species, geographically close populations did not cluster with one another in the upgma analysis; (v). there was no genetic isolation due to geographical distance in either species; (vi). the genetic composition of seasonal subpopulations differed in urban populations of both species, and the genetic distances among subpopulations were correlated with seasonal differences in P. rapae and with temporal differences in P. melete. These results indicate that the genetic diversity in urban populations of both species was reduced at times, but was maintained by dispersal from genetically differentiated populations. Differences in the ability and mode of dispersal in the two species may be reflected in the degree of population subdivision and patterns of seasonal change in the genetic composition.

Analysis of Variance↗
PubMed2004

Phylogeography of the Patelloida profunda group (Gastropoda: Lottidae): diversification in a dispersal-driven marine system.

In the last decade, greater than expected levels of genetic structure have been reported for many marine taxa with high dispersal capabilities. Although little-studied to date, it is predicted that taxa with poor dispersal abilities would exhibit even more genetic differentiation than high dispersal taxa. These systems may track biogeographical processes better than more dispersive taxa and, more critically, function as the 'lowest common denominators' in MPA design initiatives. We investigate phylogeographical patterns in the poorly dispersing, yet widely distributed Patelloida profunda group and related congeners across the Indo-west Pacific region. One hundred and twenty-five individuals were sequenced for COI mtDNA [593 base pairs (bp)] and 44 individuals were sequenced for 16S mtDNA (539 bp). Identified P. profunda group lineages are highly geographically structured, with 12 reciprocally monophyletic lineages reported from 13 localities. Divergences within Indian and Pacific basins range from d = 0.013 to 0.127 and between basins from d = 0.147 to 0.197. The latter split is ancient (> 15 Myr) and cannot be related to Plio-Pleistocene sea-level fluctuations, characteristic of previously reported divergences in the same region. Juxtaposed against this structure is genetic connectivity between two widely separated P. profunda populations that share a common haplotype (phiST = 0.001). This finding contrasts with previous work in the same geographical region and cautions strongly against single taxon indicators for designing conservation priorities or marine protected areas (MPAs). Historical and/or biological factors may play more significant roles than oceanography alone in determining the genetic structuring of taxa. In light of these findings, we discuss the difficulty in deriving biogeographical process or directionality from phylogenetic trees in dispersal-driven systems. Even with a well-resolved, highly supported topology, many equally parsimonious scenarios are possible.

Animals↗
PubMed2003

CREME: a framework for identifying cis-regulatory modules in human-mouse conserved segments.

MOTIVATION: The binding of transcription factors to specific regulatory sequence elements is a primary mechanism for controlling gene transcription. Recent findings suggest a modular organization of binding sites for transcription factors that cooperate in the regulation of genes. In this work we establish a framework for finding recurrent cis-regulatory modules in the promoters of a selected set of genes and scoring their statistical significance. RESULTS: Proceeding from a database of identified binding site motifs and their genomic locations we seek motifs whose frequency in the selected promoters is different than in a background promoter set. We present several statistical tests designed for this purpose. We provide a hashing algorithm for detecting combinations of these motifs that co-occur in clusters within the selected promoters. The significance of such co-occurrences is evaluated using novel statistical scores. Our methods are combined in CREME, a suite of software which includes a browser for viewing the pattern of occurrence of selected cis-regulatory modules. We applied our methodology to find modules within human-mouse conserved promoter segments, focusing on cell cycle regulated genes and stress response related genes. To validate the biological significance of the identified modules we tested whether the associated genes tended to be co-expressed or share similar function. In the cell cycle set five of the seven identified sets of genes were coherently expressed. On the stress response data four of the six detected sets fell predominantly into well-defined functional sub-categories.

Algorithms↗
PubMed2006

The molecular portraits of breast tumors are conserved across microarray platforms.

BACKGROUND: Validation of a novel gene expression signature in independent data sets is a critical step in the development of a clinically useful test for cancer patient risk-stratification. However, validation is often unconvincing because the size of the test set is typically small. To overcome this problem we used publicly available breast cancer gene expression data sets and a novel approach to data fusion, in order to validate a new breast tumor intrinsic list. RESULTS: A 105-tumor training set containing 26 sample pairs was used to derive a new breast tumor intrinsic gene list. This intrinsic list contained 1300 genes and a proliferation signature that was not present in previous breast intrinsic gene sets. We tested this list as a survival predictor on a data set of 311 tumors compiled from three independent microarray studies that were fused into a single data set using Distance Weighted Discrimination. When the new intrinsic gene set was used to hierarchically cluster this combined test set, tumors were grouped into LumA, LumB, Basal-like, HER2+/ER-, and Normal Breast-like tumor subtypes that we demonstrated in previous datasets. These subtypes were associated with significant differences in Relapse-Free and Overall Survival. Multivariate Cox analysis of the combined test set showed that the intrinsic subtype classifications added significant prognostic information that was independent of standard clinical predictors. From the combined test set, we developed an objective and unchanging classifier based upon five intrinsic subtype mean expression profiles (i.e. centroids), which is designed for single sample predictions (SSP). The SSP approach was applied to two additional independent data sets and consistently predicted survival in both systemically treated and untreated patient groups. CONCLUSION: This study validates the "breast tumor intrinsic" subtype classification as an objective means of tumor classification that should be translated into a clinical assay for further retrospective and prospective validation. In addition, our method of combining existing data sets can be used to robustly validate the potential clinical value of any new gene expression profile.

Breast Neoplasms↗
PubMed1989

Neoplastic involvement of nipple-areolar complex in invasive breast cancer.

The neoplastic involvement of the nipple-areolar complex was histologically studied in 1,291 available consecutive mastectomy specimens with primary invasive breast carcinoma. Tumor involvement of the nipple-areolar complex was found in 150 specimens (12 percent) and was not suspected on gross examination in 99 patients (8 percent). A significant finding of our study was the relatively high rate of tumor foci in the nipple-areolar complex (7 percent) in those patients with early invasive stage I or II breast carcinoma eligible for conservative therapy. Analysis of nipple-areolar complex involvement with consideration of different clinico-morphologic variables indicates that it was directly associated with tumor size. No significant correlation was found with axillary metastases, tumor histologic type, or with the presence of noninvasive cancer in the vicinity of the dominant tumor. Our estimate of the significant change of finding tumor in the nipple-areolar complex, especially in the patient group eligible for conservative therapy, underlines the need for postoperative radiation.

Adult↗
PubMed2003

Mutational analysis of the guanylyltransferase component of Mammalian mRNA capping enzyme.

RNA guanylyltransferase is an essential enzyme that catalyzes the second of three steps in the synthesis of the 5'-cap structure of eukaryotic mRNA. Here we conducted a mutational analysis of the guanylyltransferase domain of the mouse capping enzyme Mce1. We introduced 50 different mutations at 22 individual amino acids and assessed their effects on Mce1 function in vivo in yeast. We identified 16 amino acids as being essential for Mce1 activity (Arg299, Arg315, Asp343, Glu345, Tyr362, Asp363, Arg380, Asp438, Gly439, Lys458, Lys460, Asp468, Arg530, Asp532, Lys533, and Asn537) and clarified structure-activity relationships by testing the effects of conservative substitutions. The new mutational data for Mce1, together with prior mutational studies of Saccharomyces cerevisiae guanylyltransferase and the crystal structures of Chlorella virus and Candida albicans guanylyltransferases, provide a coherent picture of the functional groups that comprise and stabilize the active site. Our results extend and consolidate the hypothesis of a shared structural basis for catalysis by RNA capping enzymes, DNA ligases, and RNA ligases, which comprise a superfamily of covalent nucleotidyl transferases defined by a constellation of conserved motifs. Analysis of the effects of motif VI mutations on Mce1 guanylyltransferase activity in vitro highlights essential roles for Arg530, Asp532, Lys533, and Asn537 in GTP binding and nucleotidyl transfer.

Amino Acid Sequence↗
PubMed1984

DNA sequence analysis of the type-common glycoprotein-D genes of herpes simplex virus types 1 and 2.

The DNA sequences for the coding and flanking regions of the type-common glycoprotein-D (gD) genes of herpes simplex virus (HSV) types 1 and 2 have been determined. The resultant protein sequences are approximately 80% homologous. Both gD proteins are 393 amino acids long and both have maintained three identical potential glycosylation sites. Amino acid changes are found throughout the proteins, with the majority of changes located in the amino and carboxyl/termini. Most of the amino acid differences were found to be conservative. Hydropathy analysis, which determines hydrophobic and hydrophilic regions, reveals a remarkable structural similarity between the proteins. Examination of 5' flanking sequences demonstrates extensive DNA sequence homology adjacent to the start of gD gene transcription. In addition, another homologous noncoding region was found 3' to the gD gene. This second homologous sequence is 5' to a 1.6-kb transcription unit.

Amino Acid Sequence↗
PubMed1986

A clinical and histopathologic analysis of the results of conservation surgery and radiation therapy in stage I and II breast carcinoma.

One hundred eighty women with clinical Stage I or II operable breast carcinoma were treated by radiotherapy following local tumor excision at Yale-New Haven Hospital through 1980. With a median follow-up time of 6.9 years, the actuarial 5-year overall and disease-free survival rates were 82% and 78%, respectively. The 5-year actuarial breast-recurrence-free survival rate was 92%. Several clinical-histopathologic features and treatment parameters were assessed for their significance as predictors of local breast failure or distant relapse. Cox lifetable regression analysis showed that patients with clinical Stage II carcinomas had significantly worse overall and relapse-free survival rates, but clinical stage alone had no effect on the rate of breast recurrence. Furthermore, a decrease in overall and disease-free survival was evident when necrosis was present in the tumor or when patients had an infiltrating lobular carcinoma. Breast recurrence-free survival was also influenced adversely by the presence of these two tumor features, especially when either tumor necrosis or infiltrating lobular carcinoma was found in conjunction with clinical Stage II lesions. Other histologic features such as grade, vascular invasion, perineural invasion, or the presence of an intraductal component of carcinoma did not affect outcome, nor did the treatment techniques employed appear to have a differential effect.

Actuarial Analysis↗
PubMed2003

The first non-LTR retrotransposon characterised in the cephalochordate amphioxus, BfCR1, shows similarities to CR1-like elements.

BfCR1 is the first non-long terminal repeat retrotransposon to be characterised in the amphioxus genome. Sequence alignment of the predicted translation product reveals that BfCR1 belongs to the CR1-like retroposon class, a family widely distributed in vertebrate and invertebrate lineages. Structural analysis shows conservation of the specific motifs of the ORF2-CR1 elements: the N-terminal endonuclease, the reverse transcriptase and the C-terminal domains. The BfCR1 element possesses an atypical 3' terminus consisting of the tandem repeat (AAG)6. We gathered evidence supporting the mobility of this element and report an estimated 15 copies of BfCR1, mostly truncated, per haploid genome, a remarkably low number when compared to that of vertebrates. Phylogenetic analysis, including the amphioxus element, seems to indicate that (i) CR1-like retroposons cluster in a monophyletic group and (ii) the CR1-like family was already present in the chordate ancestor. Our data provide further support for the horizontal transmission of CR1-like elements during early vertebrate evolution.

Amino Acid Sequence↗