| 1. |
- Imanishi, T., et al.
(författare)
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Integrative annotation of 21,037 human genes validated by full-length cDNA clones
- 2004
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Ingår i: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 2:6, s. 856-875
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Tidskriftsartikel (refereegranskat)abstract
- The human genome sequence defines our inherent biological potential; the realization of the biology encoded therein requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level. Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following: integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms, non-protein-coding RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein three-dimensional structure, mapping of known single nucleotide polymorphisms (SNPs), identification of polymorphic microsatellite repeats within human genes, and comparative results with mouse full-length cDNAs. The H-InvDB analysis has shown that up to 4% of the human genome sequence (National Center for Biotechnology Information build 34 assembly) may contain misassembled or missing regions. We found that 6.5% of the human gene candidates (1,377 loci) did not have a good protein-coding open reading frame, of which 296 loci are strong candidates for non-protein-coding RNA genes. In addition, among 72,027 uniquely mapped SNPs and insertions/deletions localized within human genes, 13,215 nonsynonymous SNPs, 315 nonsense SNPs, and 452 indels occurred in coding regions. Together with 25 polymorphic microsatellite repeats present in coding regions, they may alter protein structure, causing phenotypic effects or resulting in disease. The H-InvDB platform represents a substantial contribution to resources needed for the exploration of human biology and pathology.
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| 2. |
- Kritikou, Joanna S, et al.
(författare)
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Constitutive activation of WASp leads to abnormal cytotoxic cells with increased granzyme B and degranulation response to target cells.
- 2021
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Ingår i: JCI insight. - : American Society for Clinical Investigation. - 2379-3708. ; 6:6
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Tidskriftsartikel (refereegranskat)abstract
- X-linked neutropenia (XLN) is caused by gain-of-function mutations in the actin regulator Wiskott-Aldrich Syndrome protein (WASp). XLN patients have reduced numbers of cytotoxic cells in peripheral blood; however, their capacity to kill tumor cells remains to be determined. Here, we examined NK and T cells from 2 patients with XLN harboring the activating WASpL270P mutation. XLN patient NK and T cells had increased granzyme B content and elevated degranulation and IFN-γ production when compared with healthy control cells. Murine WASpL272P NK and T cells formed stable synapses with YAC-1 tumor cells and anti-CD3/CD28-coated beads, respectively. WASpL272P mouse T cells had normal degranulation and cytokine response whereas WASpL272P NK cells showed an enhanced response. Imaging experiments revealed that while WASpL272P CD8+ T cells had increased accumulation of actin upon TCR activation, WASpL272P NK cells had normal actin accumulation at lytic synapses triggered through NKp46 signaling but had impaired response to lymphocyte function associated antigen-1 engagement. When compared with WT mice, WASpL272P mice showed reduced growth of B16 melanoma and increased capacity to reject MHC class I-deficient cells. Together, our data suggest that cytotoxic cells with constitutively active WASp have an increased capacity to respond to and kill tumor cells.
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| 3. |
- Chafik, L., et al.
(författare)
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Global linkages originating from decadal oceanic variability in the subpolar North Atlantic
- 2016
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Ingår i: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 43:20, s. 10909-10919
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Tidskriftsartikel (refereegranskat)abstract
- The anomalous decadal warming of the subpolar North Atlantic Ocean (SPNA), and the northward spreading of this warm water, has been linked to rapid Arctic sea ice loss and more frequent cold European winters. Recently, variations in this heat transport have also been reported to covary with global warming slowdown/acceleration periods via a Pacific climate response. We here examine the role of SPNA temperature variability in this Atlantic-Pacific climate connectivity. We find that the evolution of ocean heat content anomalies from the subtropics to the subpolar region, likely due to ocean circulation changes, coincides with a basin-wide Atlantic warming/cooling. This induces an Atlantic-Pacific sea surface temperature seesaw, which in turn, strengthens/weakens the Walker circulation and amplifies the Pacific decadal variability that triggers pronounced global-scale atmospheric circulation anomalies. We conclude that the decadal oceanic variability in the SPNA is an essential component of the tropical interactions between the Atlantic and Pacific Oceans.
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| 9. |
- Hammarberg, T, et al.
(författare)
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Calcium binding to 5-lipoxygenase
- 2002
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Ingår i: Advances in experimental medicine and biology. - Boston, MA : Springer US. - 0065-2598. ; 507, s. 117-121
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Tidskriftsartikel (refereegranskat)
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| 10. |
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| 11. |
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| 12. |
- Liang, Y., et al.
(författare)
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Desmosomal COP9 regulates proteome degradation in arrhythmogenic right ventricular dysplasia/cardiomyopathy
- 2021
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Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 131:11
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulated protein degradative pathways are increasingly recognized as mediators of human disease. This mechanism may have particular relevance to desmosomal proteins that play critical structural roles in both tissue architecture and cell-cell communication, as destabilization/breakdown of the desmosomal proteome is a hallmark of genetic-based desmosomal-targeted diseases, such as the cardiac disease arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, no information exists on whether there are resident proteins that regulate desmosomal proteome homeostasis. Here, we uncovered a cardiac constitutive photomorphogenesis 9 (COP9) desmosomal resident protein complex, composed of subunit 6 of the COP9 signalosome (CSN6), that enzymatically restricted neddylation and targeted desmosomal proteome degradation. CSN6 binding, localization, levels, and function were affected in hearts of classic mouse and human models of ARVD/C affected by desmosomal loss and mutations, respectively. Loss of desmosomal proteome degradation control due to junctional reduction/loss of CSN6 and human desmosomal mutations destabilizing junctional CSN6 were also sufficient to trigger ARVD/C in mice. We identified a desmosomal resident regulatory complex that restricted desmosomal proteome degradation and disease.
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| 13. |
- Morrison, Hilary G., et al.
(författare)
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Genomic minimalism in the early diverging intestinal parasite Giardia lamblia
- 2007
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 317:5846, s. 1921-1926
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Tidskriftsartikel (refereegranskat)abstract
- The genome of the eukaryotic protist Giardia lamblia, an important human intestinal parasite, is compact in structure and content, contains few introns or mitochondrial relics, and has simplified machinery for DNA replication, transcription, RNA processing, and most metabolic pathways. Protein kinases comprise the single largest protein class and reflect Giardia's requirement for a complex signal transduction network for coordinating differentiation. Lateral gene transfer from bacterial and archaeal donors has shaped Giardia's genome, and previously unknown gene families, for example, cysteine-rich structural proteins, have been discovered. Unexpectedly, the genome shows little evidence of heterozygosity, supporting recent speculations that this organism is sexual. This genome sequence will not only be valuable for investigating the evolution of eukaryotes, but will also be applied to the search for new therapeutics for this parasite.
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| 14. |
- Rozenblum, E, et al.
(författare)
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A genomic map of a 6-Mb region at 13q21-q22 implicated in cancer development: identification and characterization of candidate genes
- 2002
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 1432-1203 .- 0340-6717. ; 110:2, s. 111-121
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Tidskriftsartikel (refereegranskat)abstract
- Chromosomal region 13q21-q22 harbors a putative breast cancer susceptibility gene and has been implicated as a common site for somatic deletions in a variety of malignant tumors. We have built a complete physical clone contig for a region between D13S1308 and AFM220YE9 based on 18 yeast artificial chromosome and 81 bacterial artificial chromosome (BAC) clones linked together by 22 genetic markers and 61 other sequence tagged sites. Combining data from 47 sequenced BACs (as of June 2001), we have assembled in silico an integrated 5.7-Mb genomic map with 90% sequence coverage. This area contains eight known genes, two hypothetical proteins, 24 additional Unigene clusters, and approximately 100 predicted genes and exons. We have determined the cDNA and genomic sequence, and tissue expression profiles for the KIAA1008 protein (homologous to the yeast mitotic control protein dis3+), KLF12 (AP-2 repressor), progesterone induced blocking factor 1, zinc finger transcription factor KLF5, and LIM domain only-7, and for the hypothetical proteins FLJ22624 and FLJ21869. Mutation screening of the five known genes in 19 breast cancer families has revealed numerous polymorphisms, but no deleterious mutations. These data provide a basis and resources for further analyses of this chromosomal region in the development of cancer.
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| 17. |
- Thodeti, Charles Kumar, et al.
(författare)
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Leukotriene D4-induced calcium signaling in human intestinal epithelial cells
- 2002
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Ingår i: Eicosanoids and other bioactive Lipids in Cancer, Inflammation, and Radiation Injury, 5. - Boston, MA : Springer US. - 0065-2598. - 9781461501930 - 9780306472831 ; 507, s. 91-187
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Bokkapitel (refereegranskat)abstract
- LTD4 induces a calcium signal that consists of a mobilization from internal stores regulated by PTX-insensitive G protein, Rho, and, an influx across the plasma membrane regulated by PTX-sensitive Gi protein in human intestinal epithelial cells. The LTD4 induced mobilization of Ca2+ is mediated by a PH domain dependent association between PLC-gamma 1 and G beta gamma subunits. This interaction requires Src kinase activity as well as the association of this kinase with PLC-gamma 1, suggesting a G beta gamma mediated recruitment of proteins to the plasma membrane and formation of a signaling complex which is essential for the downstream Ca2+ signal. We found a cAMP-dependent protein kinase activity upstream of tyrosine kinase(s) and downstream of Gi protein, that is essential for LTD4-induced Ca2+ influx. This model of the LTD4-induced Ca2+ signaling pathways in intestinal epithelial cells is outlined schematically in Fig. 1.
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| 18. |
- Twigger, S, et al.
(författare)
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Rat Genome Database : A comparative genomics platform for rat mouse and human.
- 2001
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Ingår i: Journal of Molecular Medicine. - : Springer. - 0946-2716 .- 1432-1440. ; , s. B30-
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Konferensbidrag (refereegranskat)abstract
- The Rat Genome Database (RGD) is a NIH funded project who’s stated mission is “to collect, consolidate, and integrate data generated from ongoing rat genetic and genomic research efforts and make these data widely available to the scientific community.” In a collaboration between the Medical College of Wisconsin, the Jackson Lab, the National Center for Biotechnology and Information and the Genetics Lundberg Laboratory, Gothenburg, Sweden, RGD has been created to meet these stated aims. The primary focus of RGD is to aid Rat researchers in their work studying the rat as a model organism for human disease. To support these studies we have integrated a large amount of rat genetic and genomic resources in RGD and these are constantly being expanded through ongoing literature curation. One of the major features of RGD version 1.1, released in January of this year, is incorporation of QTL data to facilitate physiological genomics studies relating disease with the genome. In addition, a dynamic sequence-based homology tool is in final testing which will enable Rat, Mouse and Human researchers to view mapped genes and sequences and their locations in the other two organisms. We hope to release this tool in the second quarter of 2001. This will facilitate the application of results in one species to experiments in another species. In collaboration with the Mouse Genome Database and NCBI, close links are being created between RGD and MGD, LocusLink and UniGene to increase access to each set of data. To support its other general functions RGD has a variety of tools available for the rat researcher, plus ones that are equally useful to researchers working in other organisms and a sampling of these tools will be presented. Thus RGD is not only a valuable resource for those working with the rat but also for researchers in other model organisms wishing to harness the existing genetic and physiological data available in the rat to complement their own work.
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| 19. |
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| 21. |
- Öhd, John F, et al.
(författare)
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Do leukotrienes increase cell viability in human intestinal epithelial cells?
- 2002
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Ingår i: Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury, 5. - Boston, MA : Springer US. - 0065-2598. - 9781461501930 - 9780306472831 ; 507, s. 8-193
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Bokkapitel (refereegranskat)abstract
- In this preliminary report we present data showing that leukotrienes increase the baseline cell viability in human intestinal epithelial cells and that LTB4 partially reverses the morphological hallmarks of non-necrotic cell death induced by the COX-2 specific inhibitor NS-398. The proposed signaling mechanisms regulating these events are summarized in fig. 3. Please view the work on LT signal transduction in these cells by Thodeti et al. in this volume.
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