| 1. |
- Birney, Ewan, et al.
(author)
-
Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
-
Journal article (peer-reviewed)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
|
|
| 2. |
- Adewumi, Oluseun, et al.
(author)
-
Characterization of human embryonic stem cell lines by the International Stem Cell Initiative
- 2007
-
In: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 25:7, s. 803-816
-
Journal article (peer-reviewed)abstract
- The International Stem Cell Initiative characterized 59 human embryonic stem cell lines from 17 laboratories worldwide. Despite diverse genotypes and different techniques used for derivation and maintenance, all lines exhibited similar expression patterns for several markers of human embryonic stem cells. They expressed the glycolipid antigens SSEA3 and SSEA4, the keratan sulfate antigens TRA-1-60, TRA-1-81, GCTM2 and GCT343, and the protein antigens CD9, Thy1 (also known as CD90), tissue- nonspecific alkaline phosphatase and class 1 HLA, as well as the strongly developmentally regulated genes NANOG, POU5F1 (formerly known as OCT4), TDGF1, DNMT3B, GABRB3 and GDF3. Nevertheless, the lines were not identical: differences in expression of several lineage markers were evident, and several imprinted genes showed generally similar allele-specific expression patterns, but some gene-dependent variation was observed. Also, some female lines expressed readily detectable levels of XIST whereas others did not. No significant contamination of the lines with mycoplasma, bacteria or cytopathic viruses was detected.
|
|
| 3. |
- Clark, Andrew G., et al.
(author)
-
Evolution of genes and genomes on the Drosophila phylogeny
- 2007
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
-
Journal article (peer-reviewed)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
|
|
| 4. |
- Ding, Li, et al.
(author)
-
Somatic mutations affect key pathways in lung adenocarcinoma
- 2008
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 455:7216, s. 1069-1075
-
Journal article (peer-reviewed)abstract
- Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
|
|
| 5. |
- Elsik, Christine G., et al.
(author)
-
The Genome Sequence of Taurine Cattle : A Window to Ruminant Biology and Evolution
- 2009
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 324:5926, s. 522-528
-
Journal article (peer-reviewed)abstract
- To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
|
|
| 6. |
- Heard-Costa, Nancy L, et al.
(author)
-
NRXN3 is a novel locus for waist circumference : a genome-wide association study from the CHARGE Consortium
- 2009
-
In: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 5:6, s. e1000539-
-
Journal article (peer-reviewed)abstract
- Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4×10−7)]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3×10−8 for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4×10−6, 0.024 z-score units (0.10 kg/m2) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07–1.19; p = 3.2×10−5 per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
|
|
| 7. |
- Blomberg, C, et al.
(author)
-
Pattern of Accessory Regions and Invasive Disease Potential in Streptococcus pneumoniae.
- 2009
-
In: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 199, s. 1032-1042
-
Journal article (peer-reviewed)abstract
- Background. The invasive disease potential (IDP) of Streptococcus pneumoniae differs between serotypes, but the reason for this is unknown. Methods. A total of 47 pneumococcal isolates from 13 serotypes with different IDPs in humans that belonged to 37 multilocus sequence types were compared by whole genome microarrays and mutant analyses. Results. Approximately 34% of the genes were variable, including 95 genes previously shown by signature-tagged mutagenesis (STM) to be required for invasive disease in mice. Many variable genes were localized to 41 accessory regions (ARs), of which 24 contained genes previously identified by STM as required for invasive disease. Only AR6 and AR34 were preferentially found in isolates of serotypes with high IDPs. Neither AR6, which carries a gene previously identified by STM as required for invasive disease and encodes a 6-phospho-beta glucosidase, nor the putative adhesin expressed by AR34 was required for mouse virulence in TIGR4. Conclusions. Pneumococci possess a repertoire of ARs that differ between clones and even between isolates of the same clone. The ARs required for invasive disease in humans may be redundant, as no unique pattern distinguished the most invasive clones from others. The ARs that contained genes previously identified by STM as required for virulence in mice were frequently absent from invasive human isolates. Only 1 AR (AR6) was present in almost all isolates from the serotypes with the highest IDP (1, 4, and 7F), whereas it was missing from many others.
|
|
| 8. |
|
|
| 9. |
- Albiger, Barbara, et al.
(author)
-
Role of the innate immune system in host defence against bacterial infections: focus on the Toll-like receptors.
- 2007
-
In: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 261:6, s. 511-528
-
Research review (peer-reviewed)abstract
- The innate immunity plays a critical role in host protection against pathogens and it relies amongst others on pattern recognition receptors such as the Toll-like receptors (TLRs) and the nucleotide-binding oligomerization domains proteins (NOD-like receptors, NLRs) to alert the immune system of the presence of invading bacteria. Since their recent discovery less than a decade ago, both TLRs and NLRs have been shown to be crucial in host protection against microbial infections but also in homeostasis of the colonizing microflora. They recognize specific microbial ligands and with the use of distinct adaptor molecules, they activate different signalling pathways that in turns trigger subsequent inflammatory and immune responses that allows a immediate response towards bacterial infections and the initiation of the long-lasting adaptive immunity. In this review, we will focus on the role of the TLRs against bacterial infections in humans in contrast to mice that have been used extensively in experimental models of infections and discuss their role in controlling normal flora or nonpathogenic bacteria. We also highlight how bacteria can evade recognition by TLRs.
|
|
| 10. |
- Barocchi, M A, et al.
(author)
-
A pneumococcal pilus influences virulence and host inflammatory responses
- 2006
-
In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 103:8, s. 2857-2862
-
Journal article (peer-reviewed)abstract
- Streptococcus pneumoniae (pneumococcus) is a major cause of morbidity and mortality world-wide. The initial event in invasive pneumococcal disease is the attachment of encapsulated pneumococci to epithelial cells in the upper respiratory tract. This work provides evidence that initial bacterial adhesion and subsequent ability to cause invasive disease is enhanced by pili, long organelles able to extend beyond the polysaccharide capsule, previously unknown to exist in pneumococci. These adhesive pili-like appendages are encoded by the pneumococcal rlrA islet, present in some, but not all, clinical isolates. Introduction of the rlrA islet into an encapsulated rlrA-negative isolate allowed pilus expression, enhanced adherence to lung epithelial cells, and provided a competitive advantage upon mixed intranasal challenge of mice. Furthermore, a pilus-expressing rlrA islet-positive clinical isolate was more virulent than a nonpiliated deletion mutant, and it out-competed the mutant in murine models of colonization, pneumonia, and bacteremia. Additionally, piliated pneumococci evoked a higher TNF response during systemic infection, compared with nonpiliated derivatives, suggesting that pneumococcal pili not only contribute to adherence and virulence but also stimulate the host inflammatory response.
|
|
| 11. |
- Clark, Peter, U., et al.
(author)
-
The Last Glacial Maximum
- 2009
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 325:5941, s. 710-714
-
Journal article (peer-reviewed)abstract
- We used 5704 14C, 10Be, and 3He ages that span the interval from 10,000 to 50,000 years ago (10 to 50 ka) to constrain the timing of the Last Glacial Maximum (LGM) in terms of global ice-sheet and mountain-glacier extent. Growth of the ice sheets to their maximum positions occurred between 33.0 and 26.5 ka in response to climate forcing from decreases in northern summer insolation, tropical Pacific sea surface temperatures, and atmospheric CO2. Nearly all ice sheets were at their LGM positions from 26.5 ka to 19 to 20 ka, corresponding to minima in these forcings. The onset of Northern Hemisphere deglaciation 19 to 20 ka was induced by an increase in northern summer insolation, providing the source for an abrupt rise in sea level. The onset of deglaciation of the West Antarctic Ice Sheet occurred between 14 and 15 ka, consistent with evidence that this was the primary source for an abrupt rise in sea level ~14.5 ka.
|
|
| 12. |
- Davids, Barbara J., et al.
(author)
-
Polymeric immunoglobulin receptor in intestinal immune defense against the lumen-dwelling protozoan parasite Giardia
- 2006
-
In: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 177:9, s. 6281-6290
-
Journal article (peer-reviewed)abstract
- The polymeric Ig receptor (pIgR) is conserved in mammals and has an avian homologue, suggesting evolutionarily important functions in vertebrates. It transports multimeric IgA and IgM across polarized epithelia and is highly expressed in the intestine, yet little direct evidence exists for its importance in defense against common enteric pathogens. In this study, we demonstrate that pIgR can play a critical role in intestinal defense against the lumen-dwelling protozoan parasite Giardia, a leading cause of diarrheal disease. The receptor was essential for the eradication of Giardia when high luminal IgA levels were required. Clearance of Giardia muris, in which IgA plays a dominant role, was severely compromised in pIgR-deficient mice despite significant fecal IgA output at 10% of normal levels. In contrast, eradication of the human strain Giardia lamblia GS/M, for which adaptive immunity is less IgA dependent in mice, was unaffected by pIgR deficiency, indicating that pIgR had no physiologic role when lower luminal IgA levels were sufficient for parasite elimination. Immune IgA was greatly increased in the serum of pIgR-deficient mice, conferred passive protection against Giardia, and recognized several conserved giardial Ags, including ornithine carbamoyltransferase, arginine deiminase, alpha-enolase, and alpha- and beta-giardins, that are also detected in human giardiasis. Corroborative observations were made in mice lacking the J chain, which is required for pIgR-dependent transepithelial IgA transport. These results, together with prior data on pIgR-mediated immune neutralization of luminal cholera toxin, suggest that pIgR is essential in intestinal defense against pathogenic microbes with high-level and persistent luminal presence.
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
- Kotsopoulos, J, et al.
(author)
-
Age at first birth and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.
- 2007
-
In: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 1573-7217 .- 0167-6806. ; 105:2, s. 221-228
-
Journal article (peer-reviewed)abstract
- An early age at first full-term birth is associated with a reduction in the subsequent development of breast cancer among women in the general population. A similar effect has not yet been reported among women who carry an inherited BRCA1 or BRCA2 mutation. We conducted a matched case–control study on 1816 pairs of women with a BRCA1 (n = 1405) or BRCA2 (n = 411) mutation in an attempt to elucidate the relationship between age at first full-term pregnancy and the risk of developing breast cancer. Information about the age at first childbirth and other pregnancy-related variables was derived from a questionnaire administered to women during the course of genetic counselling. There was no difference in the mean age at first full-term birth in the cases and controls (24.9 years vs. 24.8 years; P = 0.81, respectively). Compared to women whose first child was born at or before 18 years of age, a later age at first full-term birth did not influence the risk of developing breast cancer (OR = 1.00 per year; 95% CI 0.98–1.03; P-trend = 0.67). Stratification by mutation status did not affect the results. These findings suggest that an early first full-term birth does not confer protection against breast cancer in BRCA mutation carriers. Nonetheless, BRCA mutation carriers opting for a prophylactic oophorectomy as a breast and/or ovarian cancer risk-reducing strategy should complete childbearing prior to age 40 when this prevention modality is most effective.
|
|
| 17. |
- Lyon, Helen N., et al.
(author)
-
The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts
- 2007
-
In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 3:4
-
Journal article (peer-reviewed)abstract
- A SNP upstream of the INSIG2 gene, rs7566605, was recently found to be associated with obesity as measured by body mass index (BMI) by Herbert and colleagues. The association between increased BMI and homozygosity for the minor allele was first observed in data from a genome-wide association scan of 86,604 SNPs in 923 related individuals from the Framingham Heart Study offspring cohort. The association was reproduced in four additional cohorts, but was not seen in a fifth cohort. To further assess the general reproducibility of this association, we genotyped rs7566605 in nine large cohorts from eight populations across multiple ethnicities (total n = 16,969). We tested this variant for association with BMI in each sample under a recessive model using family-based, population-based, and case-control designs. We observed a significant (p < 0.05) association in five cohorts but saw no association in three other cohorts. There was variability in the strength of association evidence across examination cycles in longitudinal data from unrelated individuals in the Framingham Heart Study Offspring cohort. A combined analysis revealed significant independent validation of this association in both unrelated (p = 0.046) and family-based (p = 0.004) samples. The estimated risk conferred by this allele is small, and could easily be masked by small sample size, population stratification, or other confounders. These validation studies suggest that the original association is less likely to be spurious, but the failure to observe an association in every data set suggests that the effect of SNP rs7566605 on BMI may be heterogeneous across population samples.
|
|
| 18. |
- Sjoestroem, K., et al.
(author)
-
Clonal success of piliated penicillin nonsusceptible pneumococci
- 2007
-
In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 104:31, s. 12907-12912
-
Journal article (peer-reviewed)abstract
- Antibiotic resistance in pneumococci is due to the spread of strains belonging to a limited number of clones. The Spain(9v)-3 clone of sequence type (ST)156 is one of the most successful clones with reduced susceptibility to penicillin [pneumococci nonsusceptible to penicillin (PNSP)]. In Sweden during 2000-2003, a dramatic increase in the number of PNSP isolates was observed. Molecular characterization of these isolates showed that a single clone of sequence type ST156 increased from 40% to 80% of all serotype 14, thus causing the serotype expansion. Additionally, during the same time period, we examined the clonal composition of two serotypes 9V and 19F: all 9V and 20% of 19F isolates belonged to the clonal cluster of ST156, and overall approximate to 50% of all PNSP belonged to the ST156 clonal cluster. Moreover, microarray and PCR analysis showed that all ST156 isolates, irrespective of capsular type, carried the rlrA pilus islet. This islet was also found to be present in the penicillin-sensitive ST162 clone, which is believed to be the drug-susceptible ancestor of ST156. Competitive experiments between related ST156 serotype 19F strains confirmed that those containing the rlrA pilus islet were more successful in an animal model of carriage. We conclude that the pilus island is an important biological factor common to ST156 isolates and other successful PNSP clones. In Sweden, a country where the low antibiotic usage does not explain the spread of resistant strains, at least 70% of all PNSP isolates collected during year 2003 carried the pilus islet.
|
|
| 19. |
- Aguilar, Maria I., et al.
(author)
-
Treatment of warfarin-associated intracerebral hemorrhage: Literature review and expert opinion
- 2007
-
In: Mayo Clinic Proceedings. - 0025-6196. ; 82:1, s. 82-92
-
Research review (peer-reviewed)abstract
- Wider use of oral anticoagulants has led to an increasing frequency of warfarin-related intracerebral hemorrhage (ICH). The high early mortality of approximately 50% has remained stable in recent decades. In contrast to spontaneous ICH, the duration of bleeding is, 12 to 24 hours in many patients, offering a longer opportunity for Intervention. Treatment varies widely, and optimal therapy has yet to be defined. An OVID search was conducted from January 1996 to January 2006, combining the terms warfarin or anticoagulation with intracranial hemorrhage or intracerebral hemorrhage. Seven experts on clinical stroke, neurologic intensive care, and hematology were provided with the available information and were asked to independently address 3 clinical scenarios about acute reversal and resumption of anticoagulation in the setting of warfarin-associated ICH. No randomized trials assessing clinical outcomes were found on management of warfarin-associated ICH. All experts agreed that anticoagulation should be urgently reversed, but how to achieve it varied from use of prothrombin complex concentrates only (3 experts) to recombinant factor Vila only (2 experts) to recombinant factor Vila along with fresh frozen plasma (1 expert) and prothrombin complex concentrates or fresh frozen plasma (1 expert). All experts favored resumption of warfarin therapy within 3 to 10 days of ICH in stable patients in whom subsequent anticoagulation is mandatory. No general agreement occurred regarding subsequent anticoagulation of patients with atrial fibrillation who survived warfarin-associated ICH. For warfarin-associated ICH, discontinuing warfarin therapy with administration of vitamin K does not reverse the hemostatic defect for many hours and is inadequate. Reasonable management based on expert opinion includes a wide range of additional measures to reverse anticoagulation in the absence of solid evidence.
|
|
| 20. |
- Benzinou, Michael, et al.
(author)
-
Common nonsynonymous variants in PCSK1 confer risk of obesity.
- 2008
-
In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:8, s. 943-5
-
Journal article (peer-reviewed)abstract
- Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.
|
|
| 21. |
- Bernstein, Henry H., et al.
(author)
-
Comparison of the safety and immunogenicity of a refrigerator-stable versus a frozen formulation of ProQuad (measles, mumps, rubella, and varicella virus vaccine live)
- 2007
-
In: Pediatrics. - : American Academy of Pediatrics (AAP). - 1098-4275 .- 0031-4005. ; 119:6, s. 1299-1305
-
Journal article (peer-reviewed)abstract
- Objective. A refrigerator-stable formulation of ProQuad has been developed to expand the utility of ProQuad to areas in which maintenance of a frozen cold chain (- 15 degrees C or colder) during storage and transport may not be feasible. The objective of this study was to demonstrate that the immunogenicity and safety profiles of a refrigerator-stable formulation of ProQuad are similar to the recently licensed frozen formulation. Methods. In this double-blind, randomized, multicenter study, healthy 12- to 23-month- old children with negative vaccination and clinical histories for measles, mumps, rubella, varicella, and zoster were vaccinated with either the refrigerator-stable formulation of ProQuad (N = 1006) or the frozen formulation of ProQuad (N = 513). Patients were followed for 42 days after vaccination for adverse experiences. Immunogenicity was evaluated 6 weeks after vaccination. Results. The refrigerator-stable formulation of ProQuad was generally well tolerated. The incidence of adverse experiences was similar between groups. No vaccine-related serious adverse experiences were reported. For both groups, the response rate was >= 97.7% for measles, mumps, and rubella, and the percentage of patients with a varicella zoster virus antibody titer of >= 5 U/mL glycoprotein antigen-based enzyme-linked immunosorbent assay after vaccination was >= 88.8%. The geometric mean titers for all antigens were numerically slightly higher in patients who received the refrigerator-stable formulation. Conclusions. The refrigerator-stable formulation of ProQuad is generally well tolerated, highly immunogenic, and noninferior in terms of postvaccination antibody responses. This refrigerator-stable formulation may improve ease of vaccine administration, increase use of the vaccine throughout the world because of its improved storage conditions, and replace the frozen formulation of ProQuad or any dose of M-M-RII and Varivax in routine practice.
|
|
| 22. |
- Brena, Barbara, et al.
(author)
-
Functional and basis set dependence of K-edge shake-up spectra of molecules
- 2005
-
In: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 122:18, s. 184316-
-
Journal article (peer-reviewed)abstract
- A straightforward approach for computing the K -edge shake-up spectra of molecules based on equivalent core-hole linear response theory at both Hartree-Fock and density functional theory levels is proposed. Benchmark calculations have been performed to explore its sensitivity to different types of functionals and basis sets for the carbon 1s shake-up spectra of benzene and metal-free phthalocyanine (H2 Pc). A very good agreement with previous theoretical and experimental works for the benzene molecule has been obtained for all the functionals and basis sets tested. Electron correlation is found to be essential for a good description of the H2 Pc system, whose experimental C 1s shake-up spectrum is best reproduced by the hybrid density functional.
|
|
| 23. |
|
|
| 24. |
- Brown, Keith S, et al.
(author)
-
Chromosomal evolution in the South American Nymphalidae.
- 2007
-
In: Hereditas. - 1601-5223. ; 144:4, s. 137-48
-
Journal article (peer-reviewed)abstract
- We give the chromosome numbers of about 80 species or subspecies of Biblidinae as well as of numbers of neotropical Libytheinae (one species), Cyrestinae (4) Apaturinae (7), Nymphalinae (about 40), Limenitidinae (16) and Heliconiinae (11). Libytheana has about n=32, the Biblidinae, Apaturinae and Nymphalinae have in general n=31, the Limenitidinae have n=30, the few Argynnini n=31 and the few species of Acraeni studied have also mostly n=31. The results agree with earlier data from the Afrotropical species of these taxa. We supplement these data with our earlier observations on Heliconiini, Danainae and the Neotropical Satyroid taxa. The lepidopteran modal n=29-31 represents clearly the ancestral condition among the Nymphalidae, from which taxa with various chromosome numbers have differentiated. The overall results show that Neotropical taxa have a tendency to evolve karyotype instability, which is in stark contrast to the otherwise stable chromosome numbers that characterize both Lepidoptera and Trichoptera.
|
|
| 25. |
|
|
| 26. |
- Guo, Ya-Long, et al.
(author)
-
Recent speciation of Capsella rubella from Capsella grandiflora, associated with loss of self-incompatibility and an extreme bottleneck
- 2009
-
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:13, s. 5246-5251
-
Journal article (peer-reviewed)abstract
- Flowering plants often prevent selfing through mechanisms of self-incompatibility (S.I.). The loss of S.I. has occurred many times independently, because it provides short-term advantages in situations where pollinators or mates are rare. The genus Capsella, which is closely related to Arabidopsis, contains a pair of closely related diploid species, the self-incompatible Capsella grandiflora and the self-compatible Capsella rubella. To elucidate the transition to selfing and its relationship to speciation of C. rubella, we have made use of comparative sequence information. Our analyses indicate that C. rubella separated from C. grandiflora recently ( approximately 30,000-50,000 years ago) and that breakdown of S.I. occurred at approximately the same time. Contrasting the nucleotide diversity patterns of the 2 species, we found that C. rubella has only 1 or 2 alleles at most loci, suggesting that it originated through an extreme population bottleneck. Our data are consistent with diploid speciation by a single, selfing individual, most likely living in Greece. The new species subsequently colonized the Mediterranean by Northern and Southern routes, at a time that also saw the spread of agriculture. The presence of phenotypic diversity within modern C. rubella suggests that this species will be an interesting model to understand divergence and adaptation, starting from very limited standing genetic variation.
|
|
| 27. |
- Harzsch, Steffen, et al.
(author)
-
Development of pigment-dispersing hormone-immunoreactive neurons in the American lobster : homology to the insect circadian pacemaker system?
- 2009
-
In: Cell and tissue research. - : Springer Science and Business Media LLC. - 1432-0878 .- 0302-766X. ; 335:2, s. 417-29
-
Journal article (peer-reviewed)abstract
- We have examined the development of pigment-dispersing hormone (PDH)-immunoreactive neurons in embryos of the American lobster Homarus americanus Milne Edwards, 1837 (Decapoda, Reptantia, Homarida) by using an antiserum against beta-PDH. This peptide is detectable in the terminal medulla of the eyestalks and the protocerebrum where PDH immunoreactivity is present as early as 20% of embryonic development. During ontogenesis, an elaborate system of PDH-immunoreactive neurons and fibres develops in the eyestalks and the protocerebrum, whereas less labelling is present in the deuto- and tritocerebrum and the ventral nerve cord. The sinus gland is innervated by PDH neurites at hatching. This pattern of PDH immunoreactivity has been compared with that found in various insect species. Neurons immunoreactive to pigment-dispersing factor in the medulla have been shown to be a central component of the system that generates the circadian rhythm in insects. Our results indicate that, in view of the position of the neuronal somata and projection patterns of their neurites, the immunolabelled medulla neurons in insects have homologous counterparts in the crustacean eyestalk. Since locomotory and other activities in crustaceans follow distinct circadian rhythms comparable with those observed in insects, we suggest that PDH-immunoreactive medulla neurons in crustaceans are involved in the generation of these rhythms.
|
|
| 28. |
- Kainu, Kati, et al.
(author)
-
Association of psoriasis to PGLYRP and SPRR genes at PSORS4 locus on 1q shows heterogeneity between Finnish, Swedish and Irish families.
- 2009
-
In: Experimental dermatology. - : Wiley. - 1600-0625 .- 0906-6705. ; 18:2, s. 109-15
-
Journal article (peer-reviewed)abstract
- A susceptibility locus for psoriasis, PSORS4, has been mapped to chromosome 1q21 in the region of the epidermal differentiation complex. The region has been refined to a 115 kb interval around the loricrin (LOR) gene. However, no evidence of association between polymorphisms in the LOR gene and psoriasis has been found. Therefore, we have analysed association to three candidate gene clusters of the region, the S100, small proline-rich protein (SPRR) and PGLYRP (peptidoglycan recognition protein) genes, which all contain functionally interesting psoriasis candidate genes. In previous studies, the SPRR and S100 genes have shown altered expression in psoriasis. Also polymorphisms in the PGLYRP genes have shown to be associated with psoriasis. We genotyped altogether 29 single nucleotide polymorphisms (SNPs) in 255 Finnish psoriasis families and analysed association with psoriasis using transmission disequilibrium test. A five-SNP haplotype of PGLYRP SNPs associated significantly with psoriasis. There was also suggestive evidence of association to SPRR gene locus in Finnish families. To confirm the putative associations, selected SNPs were genotyped also in a family collection of Swedish and Irish patients. The families supported association to the two gene regions, but there was also evidence of allelic heterogeneity.
|
|
| 29. |
- Kloppenburg, Margreet, et al.
(author)
-
Research in hand osteoarthritis: time for reappraisal and demand for new strategies. An opinion paper
- 2007
-
In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 66:9, s. 1157-1161
-
Research review (peer-reviewed)abstract
- BACKGROUND: Osteoarthritis of the hands is a prevalent musculoskeletal disease with a considerable effect on patients' lives, but knowledge and research results in the field of hand osteoarthritis are limited. Therefore, the Disease Characteristics in Hand OA (DICHOA) initiative was founded in early 2005 with the aim of addressing key issues and facilitating research into hand osteoarthritis. OBJECTIVE: To review and discuss current knowledge on hand osteoarthritis with regard to aetiopathogenesis, diagnostic criteria, biomarkers and clinical outcome measures. METHODS: Recommendations were made based on a literature review. RESULTS: Outcomes of hand osteoarthritis should be explored, including patient perspective on the separate components of disease activity, damage and functioning. All imaging techniques should be cross-validated for hand osteoarthritis with clinical status, including disease activity, function and performance, biomarkers and long-term outcome. New imaging modalities are available and need scoring systems and validation. The role of biomarkers in hand osteoarthritis has to be defined. CONCLUSION: Future research in hand osteoarthritis is warranted.
|
|
| 30. |
- Martin, Francis, et al.
(author)
-
The genome of Laccaria bicolor provides insights into mycorrhizal symbiosis
- 2008
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 452:7183, s. 7-88
-
Journal article (peer-reviewed)abstract
- Mycorrhizal symbioses -- the union of roots and soil fungi -- are universal in terrestrial ecosystems and may have been fundamental to land colonization by plants1,2. Boreal, temperate, and montane forests all depend upon ectomycorrhizae1. Identification of the primary factors that regulate symbiotic development and metabolic activity will therefore open the door to understanding the role of 2 ectomycorrhizae in plant development and physiology, allowing the full ecological significance of this symbiosis to be explored. Here, we report the genome sequence of the ectomycorrhizal basidiomycete Laccaria bicolor (Fig. 1) and highlight gene sets involved in rhizosphere colonization and symbiosis. This 65-million-base genome assembly contains ~ 20,000 predicted protein-encoding genes and a very large number of transposons and repeated sequences. We detected unexpected genomic features most notably a battery of effector-type small secreted proteins (SSP) with unknown function, several of which are only expressed in symbiotic tissues. The most highly expressed SSP accumulates in the proliferating hyphae colonizing the host root. The ectomycorrhizae-specific proteins likely play a decisive role in the establishment of the symbiosis. The unexpected observation that the genome of L. bicolor lacks carbohydrate-active enzymes involved in degradation of plant cell walls, but maintains the ability to degrade non-plant cell walls, reveals the dual saprotrophic and biotrophic lifestyle of the mycorrhizal fungus which enables it to grow within both soil and living plant roots. The predicted gene inventory of the L. bicolor genome, therefore, points to previously unknown mechanisms of symbiosis operating in biotrophic mycorrhizal fungi. The availability of this genome provides an unparalleled opportunity to develop a deeper understanding of the processes by which symbionts interact with plants within their ecosystem in order to perform vital functions in the carbon and nitrogen cycles that are fundamental to sustainable plant productivity.
|
|
| 31. |
|
|
| 32. |
|
|
| 33. |
- McKay, James D., et al.
(author)
-
Vitamin D Receptor Polymorphisms and Breast Cancer Risk: Results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium
- 2009
-
In: Cancer Epidemiology Biomarkers & Prevention. - 1538-7755. ; 18:1, s. 297-305
-
Journal article (peer-reviewed)abstract
- Background: Vitamin D is hypothesized to lower the risk of breast cancer by inhibiting cell proliferation via the nuclear vitamin D receptor (VDR). Two common single nucleotide polymorphisms (SNP) in the VDR gene (VDR), rs154441.0 (BsmI), and rs2228570 (FokI), have been inconsistently associated with breast cancer risk. Increased risk has been reported for the FokIff genotype, which encodes a less transcriptionally active isoform of VDR, and reduced risk has been reported for the BsmI BB genotype, a SNP in strong linkage disequilibrium with a 3'-untranslated region, which may influence VDR mRNA stability. Methods: We pooled data from 6 prospective studies in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium to examine associations between these SNPs and breast cancer among >6,300 cases and 8,100 controls for each SNP using conditional logistic regression. Results: The odds ratio (OR) for the rs2228570 (FokI) ff versus FF genotype in the overall population was statistically significantly elevated [OR, 1-1.6; 95% confidence interval (95% CI), 1.04-1.28] but was weaker once data from the cohort with previously published positive findings were removed (OR, 1.1.0; 95% CI, 0.981.24). No association was noted between rs1544410 (Bsm I) BB and breast cancer risk overall (OR, 0.98; 95% CI, 0.89-1.09), but the BB genotype was associated with a significantly lower risk of advanced breast cancer (OR, 0.74; 95% CI, 0.60-0.92). Conclusions: Although the evidence for independent contributions of these variants to breast cancer susceptibility remains equivocal, future large studies should integrate genetic variation in VDR with biomarkers of vitamin D status. (Cancer Epidemiol Biomarkers Prev 2009;18(1):297-305)
|
|
| 34. |
- Miller, Webb, et al.
(author)
-
Sequencing the nuclear genome of the extinct woolly mammoth.
- 2008
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 456:7220, s. 387-390
-
Journal article (peer-reviewed)abstract
- In 1994, two independent groups extracted DNA from several Pleistocene epoch mammoths and noted differences among individual specimens. Subsequently, DNA sequences have been published for a number of extinct species. However, such ancient DNA is often fragmented and damaged, and studies to date have typically focused on short mitochondrial sequences, never yielding more than a fraction of a per cent of any nuclear genome. Here we describe 4.17 billion bases (Gb) of sequence from several mammoth specimens, 3.3 billion (80%) of which are from the woolly mammoth (Mammuthus primigenius) genome and thus comprise an extensive set of genome-wide sequence from an extinct species. Our data support earlier reports that elephantid genomes exceed 4 Gb. The estimated divergence rate between mammoth and African elephant is half of that between human and chimpanzee. The observed number of nucleotide differences between two particular mammoths was approximately one-eighth of that between one of them and the African elephant, corresponding to a separation between the mammoths of 1.5-2.0 Myr. The estimated probability that orthologous elephant and mammoth amino acids differ is 0.002, corresponding to about one residue per protein. Differences were discovered between mammoth and African elephant in amino-acid positions that are otherwise invariant over several billion years of combined mammalian evolution. This study shows that nuclear genome sequencing of extinct species can reveal population differences not evident from the fossil record, and perhaps even discover genetic factors that affect extinction.
|
|
| 35. |
- Morrison, Hilary G., et al.
(author)
-
Genomic minimalism in the early diverging intestinal parasite Giardia lamblia
- 2007
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 317:5846, s. 1921-1926
-
Journal article (peer-reviewed)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.
|
|
| 36. |
- Ringqvist, Emma, et al.
(author)
-
Release of metabolic enzymes by Giardia in response to interaction with intestinal epithelial cells
- 2008
-
In: Molecular and biochemical parasitology (Print). - : Elsevier BV. - 0166-6851 .- 1872-9428. ; 159:2, s. 85-91
-
Journal article (peer-reviewed)abstract
- Giardia lamblia, an important cause of diarrheal disease, resides in the small intestinal lumen in close apposition to epithelial cells. Since the disease mechanisms underlying giardiasis are poorly understood, elucidating the specific interactions of the parasite with the host epithelium is likely to provide clues to understanding the pathogenesis. Here we tested the hypothesis that contact of Giardia lamblia with intestinal epithelial cells might lead to release of specific proteins. Using established co-culture models, intestinal ligated loops and a proteomics approach, we identified three G. lamblia proteins (arginine deiminase, ornithine carbamoyl transferase and enolase), previously recognized as immunodominant antigens during acute giardiasis. Release was stimulated by cell-cell interactions, since only small amounts of arginine deiminase and enolase were detected in the medium after culturing of G. lamblia alone. The secreted G. lamblia proteins were localized to the cytoplasm and the inside of the plasma membrane of trophozoites. Furthermore, in vitro studies with recombinant arginine deiminase showed that the secreted Giardia proteins can disable host innate immune factors such as nitric oxide production. These results indicate that contact of Giardia with epithelial cells triggers metabolic enzyme release, which might facilitate effective colonization of the human small intestine.
|
|
| 37. |
- Scheele, Camilla, et al.
(author)
-
Altered regulation of the PINK1 locus: a link between Type 2 diabetes and neurodegeneration?
- 2007
-
In: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 21:13, s. 3653-3665
-
Journal article (peer-reviewed)abstract
- Mutations in PINK1 cause the mitochondrial-related neurodegenerative disease Parkinson’s. Here we investigate whether obesity, type 2 diabetes, or inactivity alters transcription from the PINK1 locus. We utilized a cDNA-array and quantitative real-time PCR for gene expression analysis of muscle from healthy volunteers following physical inactivity, and muscle and adipose tissue from nonobese or obese subjects with normal glucose tolerance or type 2 diabetes. Functional studies of PINK1 were performed utilizing RNA interference in cell culture models. Following inactivity, the PINK1 locus had an opposing regulation pattern (PINK1 was down-regulated while natural antisense PINK1 was up-regulated). In type 2 diabetes skeletal muscle, all transcripts from the PINK1 locus were suppressed and gene expression correlated with diabetes status. RNA interference of PINK1 in human neuronal cell lines impaired basal glucose uptake. In adipose tissue, mitochondrial gene expression correlated with PINK1 expression although remained unaltered following siRNA knockdown of Pink1 in primary cultures of brown preadipocytes. In conclusion, regulation of the PINK1 locus, previously linked to neurodegenerative disease, is altered in obesity, type 2 diabetes and inactivity, while the combination of RNAi experiments and clinical data suggests a role for PINK1 in cell energetics rather than in mitochondrial biogenesis.
|
|
| 38. |
|
|
| 39. |
- Veres, Daniel S., 1977-
(author)
-
Terrestrial response to Dansgaard-Oeschger cycles and Heinrich events : the lacustrine record of Les Echets, south-eastern France
- 2007
-
Doctoral thesis (other academic/artistic)abstract
- Marine Isotope Stage (MIS) 3 was an interval characterized by large and abrupt temperature changes on a millennial time scale, the so-called Dansgaard-Oeschger (DO) cycles and Heinrich events. Evidence for this high-frequency climate variability has been identified in many marine and ice core records. Reconstructions from continental Europe, however, are still too scarce to form a comprehensive environmental picture for this time interval. In this thesis, high-resolution multi-proxy sedimentological, geochemical and chronological analyses were conducted on two long sediment sequences from the site of Les Echets, France. The main objective of this study was to determine the extent and nature of the lacustrine response to the rapid climate variability of MIS 3 and 2. The results indicate that the lake underwent recurrent shifts in lake status that closely followed temperature variations associated with DO cycles and Heinrich events which occurred between ca 60-20,000 years BP. Organic matter elemental and isotopic results indicate that most of the organic matter is mainly autochthonous suggesting that increased lake organic primary productivity commenced during DO interstadials. DO stadials and Heinrich events on the other hand are clearly marked by a reduction in productivity, organic matter oxidation and an increase in catchment erosion indicators. The results discussed in this thesis provide new insights into the response of a terrestrial ecosystem to millennial-scale climate variability and highlight the potential of multi-proxy studies in lake sediment research. This research also demonstrates that the Les Echets site may represent a potential link between the more fragmented central and northern continental European sites and marine and terrestrial records from the Mediterranean region.
|
|
| 40. |
- Wegiel, Barbara, et al.
(author)
-
The role of VEGF and a functional link between VEGF and p27Kip1 in acute myeloid leukemia
- 2009
-
In: Leukemia. - : Nature Publishing Group. - 0887-6924 .- 1476-5551. ; 23:2, s. 251-61
-
Journal article (peer-reviewed)abstract
- Alterations in the expression and signalling pathways of vascular endothelial growth factor (VEGF) have been linked to the clinical features and pathogenesis of hematologic malignancies. In this study, we showed that VEGF protein expression was statistically significantly higher in the leukemic blasts than in the normal hematopoietic counterparts. A statistically significant correlation between expression of VEGF and p27(Kip1) was observed in bone marrows from 42 patients with acute myeloid leukemia (P<0.001). We further demonstrated that forced VEGF overexpression or autocrine VEGF stimulation of VEGFR-2 triggers proliferation and migration/invasion of U-937 leukemic cells, thereby inducing a more invasive tumor phenotype. U-937 cells overexpressing VEGF were resistant to all-trans-retinoic acid-(ATRA) or camptothecin-induced apoptosis. Finally, we showed that increased p27(Kip1) expression enhanced the ability of VEGF and VEGFR-2 to promote the migration of U-937 cells. Taken together, our results suggest that elevated level of VEGF may contribute to the adverse patient outcome by promoting cell growth, survival and migration of leukemic cells and by reducing the sensitivity of leukemic cells to therapeutic agents-induced apoptosis.
|
|
| 41. |
- Woulfe, Donna S., et al.
(author)
-
Serglycin proteoglycan deletion induces defects in platelet aggregation and thrombus formation in mice
- 2008
-
In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 111:7, s. 3458-3467
-
Journal article (peer-reviewed)abstract
- Serglycin (SG), the hematopoietic cell secretory granule proteoglycan, is crucial for storage of specific secretory proteins in mast cells, neutrophils, and cytotoxic T lymphocytes. We addressed the role of SG in platelets using SG-/- mice. Wild-type (WT) but not SG-/- platelets contained chondroitin sulfate proteoglycans. Electron microscopy revealed normal alpha-granule structure in SG-/- platelets. However, SG-/- platelets and megakaryocytes contained unusual scroll-like membranous inclusions, and SG-/- megakaryocytes showed extensive emperipolesis of neutrophils. SG-/- platelets had reduced ability to aggregate in response to low concentrations of collagen or PAR4 thrombin receptor agonist AYPGKF, and reduced fibrinogen binding after AYPGKF, but aggregated normally to ADP. 3H-serotonin and ATP secretion were greatly reduced in SG-/- platelets. The alpha-granule proteins platelet factor 4, beta-thromboglobulin, and platelet-derived growth factor were profoundly reduced in SG-/- platelets. Exposure of P-selectin and alphaIIb after thrombin treatment was similar in WT and SG-/- platelets. SG-/- mice exhibited reduced carotid artery thrombus formation after exposure to FeCl3. This study demonstrates that SG is crucial for platelet function and thrombus formation. We propose that SG-/- platelet function deficiencies are related to inadequate packaging and secretion of selected alpha-granule proteins and reduced secretion of dense granule contents critical for platelet activation.
|
|
