Showing papers by "Uppsala University published in 1998"
TL;DR: Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension was assessed.
5,664 citations
TL;DR: The complete genome sequence of the obligate intracellular parasite Rickettsia prowazekii, the causative agent of epidemic typhus, is described, which contains 834 protein-coding genes and is more closely related to mitochondria than is any other microbe studied so far.
Abstract: We describe here the complete genome sequence (1,111,523 base pairs) of the obligate intracellular parasite Rickettsia prowazekii, the causative agent of epidemic typhus. This genome contains 834 p ...
1,599 citations
TL;DR: It is proposed to be a non-self recognition system because conversion of prophenoloxidase to active enzyme can be brought about by minuscule amounts of molecules such as lipopolysaccharide, peptidoglycan and beta-1, 3-glucans from micro-organisms.
1,313 citations
TL;DR: Xpose is presented, a model building aid for population PK/PD analysis using NONMEM, which simplifies the task of producing documentation, data set checkout plots, goodness of fit plots and graphical model comparison.
972 citations
TL;DR: It is reported that murine embryonic stem cells nullizygous for the major DNA methyl transferase (Dnmt1) gene exhibited significantly elevated mutation rates at both the endogenous hypoxanthine phosphoribosyltransferase (Hprt) gene and an integrated viral thymidine kinase (tk) transgene, implying an important role for mammalian DNA methylation in maintaining genome stability.
Abstract: Genome-wide demethylation has been suggested to be a step in carcinogenesis. Evidence for this notion comes from the frequently observed global DNA hypomethylation in tumour cells, and from a recent study suggesting that defects in DNA methylation might contribute to the genomic instability of some colorectal tumour cell lines. DNA hypomethylation has also been associated with abnormal chromosomal structures, as observed in cells from patients with ICF (Immunodeficiency, Centromeric instability and Facial abnormalities) syndrome and in cells treated with the demethylating agent 5-azadeoxycytidine. Here we report that murine embryonic stem cells nullizygous for the major DNA methyltransferase (Dnmt1) gene exhibited significantly elevated mutation rates at both the endogenous hypoxanthine phosphoribosyltransferase (Hprt) gene and an integrated viral thymidine kinase (tk) transgene. Gene deletions were the predominant mutations at both loci. The major cause of the observed tk deletions was either mitotic recombination or chromosomal loss accompanied by duplication of the remaining chromosome. Our results imply an important role for mammalian DNA methylation in maintaining genome stability.
927 citations
TL;DR: Data provide evidence that SPGP is the human bile salt export pump (BSEP), and the product of the orthologous rat gene has been shown to be an effective bile acid transporter in vitro.
Abstract: The progressive familial intrahepatic cholestases (PFIC) are a group of inherited disorders with severe cholestatic liver disease from early infancy. A subgroup characterized by normal serum cholesterol and gamma-glutamyltranspeptidase (gammaGT) levels is genetically heterogeneous with loci on chromosomes 2q (PFIC2) and 18q. The phenotype of the PFIC2-linked group is consistent with defective bile acid transport at the hepatocyte canalicular membrane. The PFIC2 gene has now been identified by mutations in a positional candidate, BSEP, which encodes a liver-specific ATP-binding cassette (ABC) transporter, sister of p-glycoprotein (SPGP). The product of the orthologous rat gene has been shown to be an effective bile acid transporter in vitro. These data provide evidence that SPGP is the human bile salt export pump (BSEP).
908 citations
TL;DR: Alcohol consumption is associated with a linear increase in breast cancer incidence in women over the range of consumption reported by most women, and reducing alcohol consumption is a potential means to reduce breast cancer risk.
Abstract: Objective. - To assess the risk of invasive breast cancer associated with total and beverage-specific alcohol consumption and to evaluate whether dietary and nondietary factors modify the association. Data Sources. - We included in these analyses 6 prospective studies that had at least 200 incident breast cancer cases, assessed long-term intake of food and nutrients, and used a validated diet assessment instrument. The studies were conducted in Canada, the Netherlands, Sweden, and the United States. Alcohol intake was estimated by food frequency questionnaires in each study. The studies included a total of 322 647 women evaluated for up to 11 years, including 4335 participants with a diagnosis of incident invasive breast cancer. Data Extraction. - Pooled analysis of primary data using analyses consistent with each study's original design and the random-effects model for the overall pooled analyses. Data Synthesis. - For alcohol intakes less than 60 g/d (reported by >99% of participants), risk increased linearly with increasing intake; the pooled multivariate relative risk for an increment of 10 g/d of alcohol (about 0.75-1 drink) was 1.09 (95% confidence interval [CI], 1.04-1.13; P for heterogeneity among studies, .71). The multivariate- adjusted relative risk for total alcohol intakes of 30 to less than 60 g/d (about 2-5 drinks) vs nondrinkers was 1.41 (95% CI, 1.18-1.69). Limited data suggested that alcohol intakes of at least 60 g/d were not associated with further increased risk. The specific type of alcoholic beverage did not strongly influence risk estimates. The association between alcohol intake and breast cancer was not modified by other factors. Conclusions. - Alcohol consumption is associated with a linear increase in breast cancer incidence in women over the range of consumption reported by most women. Among women who consume alcohol regularly, reducing alcohol consumption is a potential means to reduce breast cancer risk.
892 citations
University of Oregon1, New York University2, University of California, San Francisco3, Howard Hughes Medical Institute4, National University of Singapore5, École Normale Supérieure6, University of Bath7, Harvard University8, Brigham and Women's Hospital9, Uppsala University10, Washington University in St. Louis11
TL;DR: This zebrafish gene map will facilitate molecular identification of mutated zebra-fish genes, which can suggest functions for human genes known only by sequence, and is likely that two polyploidization events occurred prior to the divergence of fish and mammal lineages.
Abstract: In chordate phylogeny, changes in the nervous system, jaws, and appendages transformed meek filter feeders into fearsome predators. Gene duplication is thought to promote such innovation. Vertebrate ancestors probably had single copies of genes now found in multiple copies in vertebrates and gene maps suggest that this occurred by polyploidization. It has been suggested that one genome duplication event occurred before, and one after the divergence of ray-finned and lobe-finned fishes. Holland et al., however, have argued that because various vertebrates have several HOX clusters, two rounds of duplication occurred before the origin of jawed fishes. Such gene-number data, however, do not distinguish between tandem duplications and polyploidization events, nor whether independent duplications occurred in different lineages. To investigate these matters, we mapped 144 zebrafish genes and compared the resulting map with mammalian maps. Comparison revealed large conserved chromosome segments. Because duplicated chromosome segments in zebrafish often correspond with specific chromosome segments in mammals, it is likely that two polyploidization events occurred prior to the divergence of fish and mammal lineages. This zebrafish gene map will facilitate molecular identification of mutated zebrafish genes, which can suggest functions for human genes known only by sequence.
783 citations
TL;DR: These mechanisms, which implicate CaM kinase IV and CREB in the control of BDNF expression, are likely to be centrally involved in activity-dependent plasticity during development.
695 citations
TL;DR: The evidence for regulated expression of specific domains in HS chains and its relation to selective protein binding is outlined and the current information on HS biosynthesis is considered, with the aim of understanding the mechanisms in control of generating specific saccharide sequences.
692 citations
TL;DR: This work found the Phi29 DNA polymerase to be superior to the Klenow fragment in displacing the target DNA strand, and it maintained the polymerization reaction for at least 12 h, yielding an extension product that represents several thousand-fold the length of the padlock probe.
Abstract: Circularizing oligonucleotide probes (padlock probes) have the potential to detect sets of gene sequences with high specificity and excellent selectivity for sequence variants, but sensitivity of detection has been limiting. By using a rolling circle replication (RCR) mechanism, circularized but not unreacted probes can yield a powerful signal amplification. We demonstrate here that in order for the reaction to proceed efficiently, the probes must be released from the topological link that forms with target molecules upon hybridization and ligation. If the target strand has a nearby free 3' end, then the probe-target hybrids can be displaced by the polymerase used for replication. The displaced probe can then slip off the targetstrand and a rolling circle amplification is initiated. Alternatively, the target sequence itself can prime an RCR after its non-base paired 3' end has been removed by exonucleolytic activity. We found the Phi29 DNA polymerase to be superior to the Klenow fragment in displacing the target DNA strand, and it maintained the polymerization reaction for at least 12 h, yielding an extension product that represents several thousand-fold the length of the padlock probe.
TL;DR: VEGF-C may regulate physiological angiogenesis and participate in the development and progression of angiogenic diseases in addition to lymphangiogenesis, and is sufficiently potent to stimulate neovascularization from limbal vessels in the mouse cornea.
Abstract: Vascular endothelial growth factor C (VEGF-C) recently has been described to be a relatively specific growth factor for the lymphatic vascular system. Here we report that ectopic application of recombinant VEGF-C also has potent angiogenic effects in vivo. VEGF-C is sufficiently potent to stimulate neovascularization from limbal vessels in the mouse cornea. Similar to VEGF, the angiogenic response of corneas induced by VEGF-C is intensive, with a high density of new capillaries. However, the outgrowth of microvessels stimulated by VEGF-C was significantly longer than that induced by VEGF. In the developing embryo, VEGF-C was able to induce branch sprouts from the established blood vessels. VEGF-C also induced an elongated, spindle-like cell shape change and actin reorganization in both VEGF receptor (VEGFR)-2 and VEGFR-3-overexpressing endothelial cells, but not in VEGFR-1-expressing cells. Further, both VEGFR-2 and VEGFR-3 could mediate proliferative and chemotactic responses in endothelial cells on VEGF-C stimulation. Thus, VEGF-C may regulate physiological angiogenesis and participate in the development and progression of angiogenic diseases in addition to lymphangiogenesis.
TL;DR: This work investigated the vertical distribution of seeds in the soil, using data from nine studies in five European countries and discovered significant correlations between seed shape and distributio ...
Abstract: 1. We investigated the vertical distribution of seeds in the soil, using data from nine studies in five European countries. We discovered significant correlations between seed shape and distributio ...
TL;DR: Small, asexual populations are expected to accumulate deleterious substitutions and deletions in an irreversible manner, which in the long-term will lead to mutational meltdown and genome decay.
TL;DR: There is a good correlation between the measured human effective permeability values and the extent of absorption of drugs in humans determined by pharmacokinetic studies, and it is shown that it is possible to determine the Peff for carrier-mediated transported compounds and to classify them according to the proposed biopharmaceutical classification system (BCS).
TL;DR: Applications of structural databases in the protein crystallographic structure determination process are reviewed, using mostly examples from work carried out by the authors.
Abstract: Applications of structural databases in the protein crystallographic structure determination process are reviewed, using mostly examples from work carried out by the authors. Four application areas are discussed: model building, model refinement, model validation and model analysis.
TL;DR: Three high-resolution crystal structures of different catalytically deficient mutants of CBHI in complex with cellotetraose, cellopentaose and cellohexaose have been refined and support the hypothesis that hydrolysis by CBHI proceeds from the reducing towards the non-reducing end of a cellulose chain, and they provide a structural explanation for the observed distribution of initial Hydrolysis products.
TL;DR: A recent method for estimating ligand binding affinities is extended and incorporation of systematic deviations from electrostatic linear response, derived from free energy perturbation studies, into the absolute binding free energy expression significantly enhances the accuracy of the approach.
Abstract: A recent method for estimating ligand binding affinities is extended. This method employs averages of interaction potential energy terms from molecular dynamics simulations or other thermal conformational sampling techniques. Incorporation of systematic deviations from electrostatic linear response, derived from free energy perturbation studies, into the absolute binding free energy expression significantly enhances the accuracy of the approach. This type of method may be useful for computational prediction of ligand binding strengths, e.g., in drug design applications.
TL;DR: Effects of experimental manipulation of reproductive effort on subsequent specific immune function and parasite resistance in the collared flycatcher, Ficedula albicollis provide support for the hypothesis that immune suppression caused by reproductive effort may be an important mechanism mediating the life–history cost of reproduction.
Abstract: If a trade-off exists between reproductive effort and immune function, life-history decisions may have important implications for parasite resistance. Here, we report effects of experimental manipulation of reproductive effort on subsequent specific immune function and parasite resistance in the collared flycatcher, Ficedula albicollis. Our results show that increased reproductive effort of females immunized with Newcastle disease virus (NDV) vaccine negatively affected the ability to respond with NDV-specific antibodies. We further show that increased reproductive effort increased the intensity of Haemoproteus infections and that such infections are associated with higher mortality. Our results thus provide support for the hypothesis that immune suppression caused by reproductive effort may be an important mechanism mediating the life-history cost of reproduction.
TL;DR: The effective permeability (Peff) in the human jejunum (in vivo) of 22 structurally diverse compounds was correlated with both experimentally determined lipophilicity values and calculated molecular descriptors, and models that correlate passive intestinal permeability to physicochemical descriptors were derived.
Abstract: The effective permeability (Peff) in the human jejunum (in vivo) of 22 structurally diverse compounds was correlated with both experimentally determined lipophilicity values and calculated molecular descriptors. The permeability data were previously obtained by using a regional in vivo perfusion system in the proximal jejunum in humans as part of constructing a biopharmaceutical classification system for oral immediate-release products. pKa, log P, and, where relevant, log Pion values were determined using the pH-metric technique. On the basis of these experiments, log D values were calculated at pH 5.5, 6.5, and 7.4. Multivariate data analysis was used to derive models that correlate passive intestinal permeability to physicochemical descriptors. The best model obtained, based on 13 passively transcellularly absorbed compounds, used the variables HBD (number of hydrogen bond donors), PSA (polar surface area), and either log D5.5 or log D6.5 (octanol/water distribution coefficient at pH 5.5 and 6.5, respe...
TL;DR: McCormick et al. as mentioned in this paper reported the purification of a protein from bovine serum that harbored the D-glucuronyl (GlcA) and N-acetyl-Dglucosaminyl(GlcNAc) transferase activities required for biosynthesis of the glycosaminoglycan, heparan sulfate.
TL;DR: This study explored how rapidly emotion specific facial muscle reactions were elicited when subjects were exposed to pictures of angry and happy facial expressions, and found that distinctive facial electromyographic reactions were detectable after only 300-400 ms of exposure.
Abstract: This study explored how rapidly emotion specific facial muscle reactions were elicited when subjects were exposed to pictures of angry and happy facial expressions. In three separate experiments, it was found that distinctive facial electromyographic reactions, i.e., greater Zygomaticus major muscle activity in response to happy than to angry stimuli and greater Corrugator supercilii muscle activity in response to angry stimuli, were detectable after only 300-400 ms of exposure. These findings demonstrate that facial reactions are quickly elicited, indicating that expressive emotional reactions can be very rapidly manifested and are perhaps controlled by fast operating facial affect programs.
TL;DR: Eleven, mostly hemato-serological, health state indices are described and their suitability for sensing the condition of breeding Great Tits (Parus major L.) in terms of measurement precision, constancy in time, diurnal variation, and sex- and site-related differences, is examined.
Abstract: 1. A cornerstone concept of ecological immunology is that immune function, interacting with various aspects of individual health state, plays a central role in the life-history trade-offs between conflicting demands of survival and reproduction. In order to develop this research, more knowledge about the applicability and usefulness of different health state assays is needed.
2. Eleven, mostly hemato-serological, health state indices are described and their suitability for sensing the condition of breeding Great Tits (Parus major L.) in terms of measurement precision, constancy in time, diurnal variation, and sex- and site-related differences, is examined.
3. Measurement errors for the plasma albumin content, residual body mass, heterophile/lymphocyte ratio and total plasma protein content were relatively small compared with the total variation, suggesting these indices to be most adequate for ecological research. Measurement precision was lowest for the heterophile count and ‘buffy coat’ layer height (relative amount of leucocytes in total blood volume). Buffy coat layer height correlated weakly (r=0·21) with total leucocyte count estimated from blood smears and therefore appeared inappropriate for estimation of the leucocyte number.
4. Body mass (residual in respect to size) and intensity of Haemoproteus blood parasite infection were the least variable state indices during the nestling period (for both, the correlation between the values measured on the 8th and 15th days of the nestling period=0·71). Haematocrit, heterophile count and albumin/globulin ratio showed no individual constancy across the nestling period, while other traits revealed moderate but statistically significant correlations between 8th- and 15th-day values.
5. Leucocyte (both lymphocyte and heterophile) counts were higher among females captured at night compared with those captured during the day.
6. Females had higher intensities of Haemoproteus infection, higher heterophile counts and higher heterophile/lymphocyte ratios than males. Contrary to published information, females had higher haematocrits than males.
7. Haematocrit values in both sexes, as well as total plasma protein and albumin concentrations in males, differed significantly between Great Tits breeding in urban habitat and rural woodlands, respectively.
TL;DR: The decline in life expectancy in Russia in the 1990s cannot be attributed simply to impoverishment, instead, the impact of social and economic transition, exacerbated by a lack of social cohesion, seems to have played a major part.
Abstract: Objective: To identify which aspects of socioeconomic change were associated with the steep decline in life expectancy in Russia between 1990 and 1994. Design: Regression analysis of regional data, with percentage fall in male life expectancy as dependent
TL;DR: It is shown that, although REST/NRSF/XBR expression decreases during neuronal development, it proceeds in the adult nervous system and counteracts with positive regulators to modulate target gene expression quantitatively in different cell types, including neurons.
Abstract: The identification of a common cis-acting silencer element, a neuron-restrictive silencer element (NRSE), in multiple neuron-specific genes, together with the finding that zinc finger transcription factor REST/NRSF/XBR could confer NRSE-mediated silencing in non-neuronal cells, suggested that REST/NRSF/XBR is a master negative regulator of neurogenesis. Here we show that, although REST/NRSF/XBR expression decreases during neuronal development, it proceeds in the adult nervous system. In situhybridization analysis revealed neuronal expression of rat REST/NRSF/XBR mRNA in adult brain, with the highest levels in the neurons of hippocampus, pons/medulla, and midbrain. The glutamate analog kainic acid increased REST/NRSF/XBR mRNA levels in various hippocampal and cortical neurons in vivo, suggesting that REST/NRSF/XBR has a role in neuronal activity-implied processes. Several alternatively spliced REST/NRSF/XBR mRNAs encoding proteins with nine, five, or four zinc finger motifs are transcribed from REST/NRSF/XBR gene. Two of these transcripts are generated by neuron-specific splicing of a 28-bp-long exon. Rat REST/NRSF/XBR protein isoforms differ in their DNA binding specificities; however, all mediate repression in transient expression assays. Our data suggest that REST/NRSF/XBR is a negative regulator rather than a transcriptional silencer of neuronal gene expression and counteracts with positive regulators to modulate target gene expression quantitatively in different cell types, including neurons.
TL;DR: A general framework for covariance matching techniques is presented and it is shown that they are well suited to solve several problems arising in array signal processing.
TL;DR: The results suggested the absence of PERV infection in 10 diabetic patients who had received porcine fetal islets between 1990 and 1993, and establishes a minimum standard for post-transplant surveillance of patients given Porcine xenografts.
TL;DR: It is generally believed that success in male-male competition genuinely reflects high quality and that female preference for dominant males should therefore be widespread, but recent studies suggest that male dominance is not always attractive and that it does not necessarily predict superior parental quality, better genes or other forms of benefit to females.
Abstract: It is generally believed that success in male-male competition genuinely reflects high quality and that female preference for dominant males should therefore be widespread. However, recent studies ...
TL;DR: In this paper, a dye-sensitized nanoporous TiO2 solar cells are studied under influences of light intensity, redox couple concn., temp., different cations and water in the nonaq. soln.
TL;DR: 4-Hydroxynonenal and other reactive electrophiles produced by oxidative metabolism have been linked to aging, atherosclerosis, cataract formation, Parkinson's disease and Alzheimer's disease, as well as other degenerative human conditions, suggesting that human GST A4-4 fulfills an important protective role and that variations in its expression may have significant pathophysiological consequences.
Abstract: A sequence encoding a novel glutathione transferase, GST A4-4, has been identified in a human fetal brain cDNA library. The protein has been produced in Escherichia coli after optimization of the codon usage for high-level heterologous expression. The dimeric protein has a subunit molecular mass of 25704 Da based on the deduced amino acid composition. Human GST A4-4 is a member of the Alpha class but shows only 53% amino acid sequence identity with the major liver enzyme GST A1-1. High catalytic efficiency with 4-hydroxyalkenals and other cytotoxic and mutagenic products of radical reactions and lipid peroxidation is a significant feature of GST A4-4. The kcat/Km values for 4-hydroxynonenal and 4-hydroxydecenal are > 3 x 10(6) M-1. s-1, several orders of magnitude higher than the values for conventional GST substrates. 4-Hydroxynonenal and other reactive electrophiles produced by oxidative metabolism have been linked to aging, atherosclerosis, cataract formation, Parkinson's disease and Alzheimer's disease, as well as other degenerative human conditions, suggesting that human GST A4-4 fulfills an important protective role and that variations in its expression may have significant pathophysiological consequences.