Showing papers by "Uppsala University published in 2006"

Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia

Abstract: BACKGROUND: The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyrosine kinase. Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa ...

Direct observation of individual endogenous protein complexes in situ by proximity ligation

Abstract: Cellular processes can only be understood as the dynamic interplay of molecules. There is a need for techniques to monitor interactions of endogenous proteins directly in individual cells and tissues to reveal the cellular and molecular architecture and its responses to perturbations. Here we report our adaptation of the recently developed proximity ligation method to examine the subcellular localization of protein-protein interactions at single-molecule resolution. Proximity probes-oligonucleotides attached to antibodies against the two target proteins-guided the formation of circular DNA strands when bound in close proximity. The DNA circles in turn served as templates for localized rolling-circle amplification (RCA), allowing individual interacting pairs of protein molecules to be visualized and counted in human cell lines and clinical specimens. We used this method to show specific regulation of protein-protein interactions between endogenous Myc and Max oncogenic transcription factors in response to interferon-gamma (IFN-gamma) signaling and low-molecular-weight inhibitors.

The epigenetic progenitor origin of human cancer

Abstract: Cancer is widely perceived as a heterogeneous group of disorders with markedly different biological properties, which are caused by a series of clonally selected genetic changes in key tumour-suppressor genes and oncogenes. However, recent data suggest that cancer has a fundamentally common basis that is grounded in a polyclonal epigenetic disruption of stem/progenitor cells, mediated by 'tumour-progenitor genes'. Furthermore, tumour cell heterogeneity is due in part to epigenetic variation in progenitor cells, and epigenetic plasticity together with genetic lesions drives tumour progression. This crucial early role for epigenetic alterations in cancer is in addition to epigenetic alterations that can substitute for genetic variation later in tumour progression. Therefore, non-neoplastic but epigenetically disrupted stem/progenitor cells might be a crucial target for cancer risk assessment and chemoprevention.

The genome of the sea urchin Strongylocentrotus purpuratus.

Abstract: We report the sequence and analysis of the 814-megabase genome of the sea urchin Strongylocentrotus purpuratus, a model for developmental and systems biology. The sequencing strategy combined whole-genome shotgun and bacterial artificial chromosome (BAC) sequences. This use of BAC clones, aided by a pooling strategy, overcame difficulties associated with high heterozygosity of the genome. The genome encodes about 23,300 genes, including many previously thought to be vertebrate innovations or known only outside the deuterostomes. This echinoderm genome provides an evolutionary outgroup for the chordates and yields insights into the evolution of deuterostomes.

Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra-and interchromosomal interactions

Abstract: Accumulating evidence converges on the possibility that chromosomes interact with each other to regulate transcription in trans. To systematically explore the epigenetic dimension of such interactions, we devised a strategy termed circular chromosome conformation capture (4C). This approach involves a circularization step that enables high-throughput screening of physical interactions between chromosomes without a preconceived idea of the interacting partners. Here we identify 114 unique sequences from all autosomes, several of which interact primarily with the maternally inherited H19 imprinting control region. Imprinted domains were strongly overrepresented in the library of 4C sequences, further highlighting the epigenetic nature of these interactions. Moreover, we found that the direct interaction between differentially methylated regions was linked to epigenetic regulation of transcription in trans. Finally, the patterns of interactions specific to the maternal H19 imprinting control region underwent reprogramming during in vitro maturation of embryonic stem cells. These observations shed new light on development, cancer epigenetics and the evolution of imprinting.

Mechanistic aspects of transition metal-catalyzed hydrogen transfer reactions.

Abstract: In this tutorial review recent mechanistic studies on transition metal-catalyzed hydrogen transfer reactions are discussed. A common feature of these reactions is that they involve metal hydrides, which may be monohydrides or dihydrides. An important question is whether the substrate coordinates to the metal (inner-sphere hydrogen transfer) or if there is a direct concerted transfer of hydrogen from the metal to substrate (outer-sphere hydrogen transfer). Both experimental and theoretical studies are reviewed.

Femtosecond diffractive imaging with a soft-X-ray free-electron laser

Abstract: Theory predicts that with an ultrashort and extremely bright coherent X-ray pulse, a single diffraction pattern may be recorded from a large macromolecule, a virus, or a cell before the sample explodes and turns into a plasma. Here we report the first experimental demonstration of this principle using the FLASH soft X-ray free-electron laser. An intense 25 fs, 4 x 10{sup 13} W/cm{sup 2} pulse, containing 10{sup 12} photons at 32 nm wavelength, produced a coherent diffraction pattern from a nano-structured non-periodic object, before destroying it at 60,000 K. A novel X-ray camera assured single photon detection sensitivity by filtering out parasitic scattering and plasma radiation. The reconstructed image, obtained directly from the coherent pattern by phase retrieval through oversampling, shows no measurable damage, and extends to diffraction-limited resolution. A three-dimensional data set may be assembled from such images when copies of a reproducible sample are exposed to the beam one by one.

On Probing Signal Design for MIMO Radar

Abstract: A multiple-input multiple-output (MIMO) radar system, unlike a standard phased-array radar, can choose freely the probing signals transmitted via its antennas to maximize the power around the locations of the targets of interest, or more generally to approximate a given transmit beampattern, and also to minimize the cross-correlation of the signals reflected back to the radar by the targets of interest. In this paper, we show how the above desirable features can be achieved by designing the covariance matrix of the probing signal vector transmitted by the radar. Moreover, in a numerical study, we show that the proper choice of the probing signals can significantly improve the performance of adaptive MIMO radar techniques. Additionally, we demonstrate the advantages of several MIMO transmit beampattern designs, including a beampattern matching design and a minimum sidelobe beampattern design, over their phased-array counterparts.

Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis

Abstract: OBJECTIVE:Chronic inflammatory conditions such as rheumatoid arthritis (RA) have been associated with malignant lymphomas. This study was undertaken to investigate which patients are at highest ris ...

ER stress and neurodegenerative diseases.

Abstract: Endoplasmic reticulum (ER) stress is caused by disturbances in the structure and function of the ER with the accumulation of misfolded proteins and alterations in the calcium homeostasis. The ER response is characterized by changes in specific proteins, causing translational attenuation, induction of ER chaperones and degradation of misfolded proteins. In case of prolonged or aggravated ER stress, cellular signals leading to cell death are activated. ER stress has been suggested to be involved in some human neuronal diseases, such as Parkinson's disease, Alzheimer's and prion disease, as well as other disorders. The exact contributions to and casual effects of ER stress in the various disease processes, however, are not known. Here we will discuss the possible role of ER stress in neurodegenerative diseases, and highlight current knowledge in this field that may reveal novel insight into disease mechanisms and help to design better therapies for these disorders.

Optical properties of deep glacial ice at the South Pole

Abstract: We have remotely mapped optical scattering and absorption in glacial ice at the South Pole for wavelengths between 313 and 560 nm and depths between 1100 and 2350 m. We used pulsed and continuous light sources embedded with the AMANDA neutrino telescope, an array of more than six hundred photomultiplier tubes buried deep in the ice. At depths greater than 1300 m, both the scattering coefficient and absorptivity follow vertical variations in concentration of dust impurities, which are seen in ice cores from other Antarctic sites and which track climatological changes. The scattering coefficient varies by a factor of seven, and absorptivity (for wavelengths less than ∼450 nm) varies by a factor of three in the depth range between 1300 and 2300 m, where four dust peaks due to stadials in the late Pleistocene have been identified. In our absorption data, we also identify a broad peak due to the Last Glacial Maximum around 1300 m. In the scattering data, this peak is partially masked by scattering on residual air bubbles, whose contribution dominates the scattering coefficient in shallower ice but vanishes at ∼1350 m where all bubbles have converted to nonscattering air hydrates. The wavelength dependence of scattering by dust is described by a power law with exponent -0.90 ± 0.03, independent of depth. The wavelength dependence of absorptivity in the studied wavelength range is described by the sum of two components: a power law due to absorption by dust, with exponent -1.08 ± 0.01 and a normalization proportional to dust concentration that varies with depth; and a rising exponential due to intrinsic ice absorption which dominates at wavelengths greater than ∼500 nm. Copyright 2006 by the American Geophysical Union.

A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus.

Abstract: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by activation of the type I interferon (IFN) pathway. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE in four independent case-control cohorts (P = 4.4 x 10(-16)) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5' donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.

Building global knowledge pipelines: The role of temporary clusters

Abstract: Business people and professionals come together regularly at trade fairs, exhibitions, conventions, congresses, and conferences. Here, their latest and most advanced findings, inventions and products are on display to be evaluated by customers and suppliers, as well as by peers and competitors. Participation in events like these helps firms to identify the current market frontier, take stock of relative competitive positions and form future plans. Such events exhibit many of the characteristics ascribed to permanent spatial clusters, albeit in a temporary and intensified form. These short-lived hotspots of intense knowledge exchange, network building and idea generation can thus be seen as temporary clusters. This paper compares temporary clusters with permanent clusters and other types of inter-firm interactions. If regular participation in temporary clusters can satisfy a firm's need to learn through interaction with suppliers, customers, peers and rivals, why is the phenomenon of permanent spa...

Two-year follow-up of amyloid deposition in patients with Alzheimer's disease.

Abstract: Beta amyloid is one of the major histopathological hallmarks of Alzheimer's disease. We recently reported in vivo imaging of amyloid in 16 Alzheimer patients, using the PET ligand N-methyl[11C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole (PIB). In the present study we rescanned these 16 Alzheimer patients after 2.0 +/- 0.5 years and have described the interval change in amyloid deposition and regional cerebral metabolic rate for glucose (rCMRGlc) at follow-up. Sixteen patients with Alzheimer's disease were re-examined by means of PET, using PIB and 2-[18F]fluoro-2-deoxy-d-glucose (FDG) after 2.0 +/- 0.5 years. The patients were all on cholinesterase inhibitor treatment and five also on treatment with the N-methyl-d-aspartate (NMDA) antagonist memantine. In order to estimate the accuracy of the PET PIB measurements, four additional Alzheimer patients underwent repeated examinations with PIB within 20 days (test-retest). Relative PIB retention in cortical regions differed by 3-7% in the test-retest study. No significant difference in PIB retention was observed between baseline and follow-up while a significant (P 3 (21.4 +/- 3.5 to 15.6 +/- 3.9, P < 0.01) (AD-progressive) while the rest of the patients were cognitively more stable (MMSE score = 25.6 +/- 3.1 to 25.9 +/- 3.7) (AD-stable) compared with baseline. A positive correlation (P = 0.001) was observed in the parietal cortex between Rey Auditory Verbal Learning (RAVL) test score and rCMRGlc at follow-up while a negative correlation (P = 0.018) was observed between RAVL test and PIB retention in the parietal at follow-up. Relatively stable PIB retention after 2 years of follow-up in patients with mild Alzheimer's disease suggests that amyloid deposition in the brain reaches a plateau by the early clinical stages of Alzheimer's disease and therefore may precede a decline in rCMRGlc and cognition. It appears that anti-amyloid therapies will need to induce a significant decrease in amyloid load in order for PIB PET images to detect a drug effect in Alzheimer patients. FDG imaging may be able to detect a stabilization of cerebral metabolism caused by therapy administered to patients with a clinical diagnosis of Alzheimer's disease.

Health-related quality of life in parents of school-age children with Asperger Syndrome or High-Functioning Autism.

Abstract: The estimated prevalence rate of Pervasive Developmental Disorders (PDD) in children is 6 per 1.000. Parenting children who are intellectually impaired and have PDDs is known to be linked to the impaired well-being of the parents themselves. However, there is still little available data on health-related quality of life (HRQL) in parents of children with Asperger Syndrome (AS) and High-Functioning Autism (HFA), or other PDD diagnoses in children of normal intelligence. The present study aimed to evaluate aspects of HRQL in parents of school-age children with AS/HFA and the correlates with child behaviour characteristics. The sample consisted of 31 mothers and 30 fathers of 32 children with AS/HFA and 30 mothers and 29 fathers of 32 age and gender matched children with typical development. Parental HRQL was surveyed by the use of the 12 Item Short Form Health Survey (SF-12) which measures physical and mental well-being. The child behaviour characteristics were assessed using the structured questionnaires: The High-Functioning Autism Spectrum Screening Questionnaire (ASSQ) and The Strengths and Difficulties Questionnaire (SDQ). The mothers of children with AS/HFA had lower SF-12 scores than the controls, indicating poorer physical health. The mothers of children with AS/HFA also had lower physical SF-12 scores compared to the fathers. In the AS/HFA group, maternal health was related to behaviour problems such as hyperactivity and conduct problems in the child. Mothers but not fathers of children with AS/HFA reported impaired HRQL, and there was a relationship between maternal well-being and child behaviour characteristics.

Theoretical investigation of magnetoelectric behavior in Bi Fe O 3

Abstract: The magnetoelectric behavior of $\mathrm{Bi}\mathrm{Fe}{\mathrm{O}}_{3}$ has been explored on the basis of accurate density functional calculations. We are able to predict structural, electronic, magnetic, and ferroelectric properties of $\mathrm{Bi}\mathrm{Fe}{\mathrm{O}}_{3}$ correctly without including any strong correlation effect in the calculation. Unlike earlier calculations, the equilibrium structural parameters are found to be in very good agreement with the experimental findings. In particular, the present calculation correctly reproduced experimentally observed elongation of cubic perovskitelike lattice along the [111] direction. At high pressure we predicted a pressure-induced structural transition from rhombohedral $(R3c)$ to an orthorhombic $(Pnma)$ structure. The total-energy calculations at expanded lattice show two lower energy ferroelectric phases (with monoclinic $Cm$ and tetragonal $P4mm$ structures), closer in energy to the ground-state phase. Spin-polarized band-structure calculations show that $\mathrm{Bi}\mathrm{Fe}{\mathrm{O}}_{3}$ will be an insulator in $A$- and $G$-type antiferromagnetic phases and a metal in $C$-type antiferromagnetic, ferromagnetic configurations, and in the nonmagnetic state. Chemical bonding in $\mathrm{Bi}\mathrm{Fe}{\mathrm{O}}_{3}$ has been analyzed using partial density of states, charge density, charge transfer, electron localization function, Born-effective-charge tensor, and crystal orbital Hamiltonian population analyses. Our electron localization function analysis shows that stereochemically active lone-pair electrons are present at the Bi sites which are responsible for displacements of the Bi atoms from the centrosymmetric to the noncentrosymmetric structure and hence the ferroelectricity. A large ferroelectric polarization of $88.7\phantom{\rule{0.3em}{0ex}}\ensuremath{\mu}\mathrm{C}∕{\mathrm{cm}}^{2}$ is predicted in accordance with recent experimental findings, but differing by an order of magnitude from earlier experimental values. The strong spontaneous polarization is related to the large values of the Born-effective charges at the Bi sites along with their large displacement along the [111] direction of the cubic perovskite-type reference structure. Our polarization analysis shows that partial contributions to polarization from the Fe and O atoms almost cancel each other and the net polarization present in $\mathrm{Bi}\mathrm{Fe}{\mathrm{O}}_{3}$ mainly $(g98%)$ originates from Bi atoms. We found that the large scatter in experimentally reported polarization values in $\mathrm{Bi}\mathrm{Fe}{\mathrm{O}}_{3}$ is associated with the large anisotropy in the spontaneous polarization.

The effects of attitudes and personality traits on mode choice

Abstract: We hypothesise that differences in people's attitudes and personality traits lead them to attribute varying importance to environmental considerations, safety, comfort, convenience and flexibility. ...

CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2

Abstract: It is thought that the H19 imprinting control region (ICR) directs the silencing of the maternally inherited Igf2 allele through a CTCF-dependent chromatin insulator. The ICR has been shown to interact physically with a silencer region in Igf2, differentially methylated region (DMR)1, but the role of CTCF in this chromatin loop and whether it restricts the physical access of distal enhancers to Igf2 is not known. We performed systematic chromosome conformation capture analyses in the Igf2/H19 region over >160 kb, identifying sequences that interact physically with the distal enhancers and the ICR. We found that, on the paternal chromosome, enhancers interact with the Igf2 promoters but that, on the maternal allele, this is prevented by CTCF binding within the H19 ICR. CTCF binding in the maternal ICR regulates its interaction with matrix attachment region (MAR)3 and DMR1 at Igf2, thus forming a tight loop around the maternal Igf2 locus, which may contribute to its silencing. Mutation of CTCF binding sites in the H19 ICR leads to loss of CTCF binding and de novo methylation of a CTCF target site within Igf2 DMR1, showing that CTCF can coordinate regional epigenetic marks. This systematic chromosome conformation capture analysis of an imprinting cluster reveals that CTCF has a critical role in the epigenetic regulation of higher-order chromatin structure and gene silencing over considerable distances in the genome.

The imprint of the geographical, evolutionary and ecological context on species–area relationships

Abstract: Species–area relationships (SAR) are fundamental in the understanding of biodiversity patterns and of critical importance for predicting species extinction risk worldwide. Despite the enormous attention given to SAR in the form of many individual analyses, little attempt has been made to synthesize these studies. We conducted a quantitative meta-analysis of 794 SAR, comprising a wide span of organisms, habitats and locations. We identified factors reflecting both pattern-based and dynamic approaches to SAR and tested whether these factors leave significant imprints on the slope and strength of SAR. Our analysis revealed that SAR are significantly affected by variables characterizing the sampling scheme, the spatial scale, and the types of organisms or habitats involved. We found that steeper SAR are generated at lower latitudes and by larger organisms. SAR varied significantly between nested and independent sampling schemes and between major ecosystem types, but not generally between the terrestrial and the aquatic realm. Both the fit and the slope of the SAR were scale-dependent. We conclude that factors dynamically regulating species richness at different spatial scales strongly affect the shape of SAR. We highlight important consequences of this systematic variation in SAR for ecological theory, conservation management and extinction risk predictions.

Infants predict other people's action goals.

Abstract: Do infants come to understand other people's actions through a mirror neuron system that maps an observed action onto motor representations of that action? We demonstrate that a specialized system for action perception guides proactive goal-directed eye movements in 12-month-old but not in 6-month-old infants, providing direct support for this view. The activation of this system requires observing an interaction between the hand of the agent and an object.

Search for neutral MSSM Higgs bosons at LEP

Abstract: The four LEP collaborations, ALEPH, DELPHI, L3 and OPAL, have searched for the neutral Higgs bosons which are predicted by the Minimal Supersymmetric standard model (MSSM). The data of the four collaborations are statistically combined and examined for their consistency with the background hypothesis and with a possible Higgs boson signal. The combined LEP data show no significant excess of events which would indicate the production of Higgs bosons. The search results are used to set upper bounds on the cross-sections of various Higgs-like event topologies. The results are interpreted within the MSSM in a number of “benchmark” models, including CP-conserving and CP-violating scenarios. These interpretations lead in all cases to large exclusions in the MSSM parameter space. Absolute limits are set on the parameter cosβ and, in some scenarios, on the masses of neutral Higgs bosons.

Interactions between heparan sulfate and proteins: the concept of specificity

Abstract: Proteoglycan (PG) coreceptors carry heparan sulfate (HS) chains that mediate interactions with growth factors, morphogens, and receptors. Thus, PGs modulate fundamental processes such as cell survival, division, adhesion, migration, and differentiation. This review summarizes recent biochemical and genetic information that sheds new light on the nature of HS–protein binding. Unexpectedly, many interactions appear to depend more on the overall organization of HS domains than on their fine structure.