Showing papers by "Uppsala University published in 2001"

GROMACS 3.0: a package for molecular simulation and trajectory analysis

Abstract: GROMACS 3.0 is the latest release of a versatile and very well optimized package for molecular simulation. Much effort has been devoted to achieving extremely high performance on both workstations and parallel computers. The design includes an extraction of virial and periodic boundary conditions from the loops over pairwise interactions, and special software routines to enable rapid calculation of x–1/2. Inner loops are generated automatically in C or Fortran at compile time, with optimizations adapted to each architecture. Assembly loops using SSE and 3DNow! Multimedia instructions are provided for x86 processors, resulting in exceptional performance on inexpensive PC workstations. The interface is simple and easy to use (no scripting language), based on standard command line arguments with self-explanatory functionality and integrated documentation. All binary files are independent of hardware endian and can be read by versions of GROMACS compiled using different floating-point precision. A large collection of flexible tools for trajectory analysis is included, with output in the form of finished Xmgr/Grace graphs. A basic trajectory viewer is included, and several external visualization tools can read the GROMACS trajectory format. Starting with version 3.0, GROMACS is available under the GNU General Public License from http://www.gromacs.org.

Bayesian inference of phylogeny and its impact on evolutionary biology

Abstract: As a discipline, phylogenetics is becoming transformed by a flood of molecular data. These data allow broad questions to be asked about the history of life, but also present difficult statistical and computational problems. Bayesian inference of phylogeny brings a new perspective to a number of outstanding issues in evolutionary biology, including the analysis of large phylogenetic trees and complex evolutionary models and the detection of the footprint of natural selection in DNA sequences.

Loss of Huntingtin-Mediated BDNF Gene Transcription in Huntington's Disease

Abstract: Huntingtin is a 350-kilodalton protein of unknown function that is mutated in Huntington's disease (HD), a neurodegenerative disorder. The mutant protein is presumed to acquire a toxic gain of function that is detrimental to striatal neurons in the brain. However, loss of a beneficial activity of wild-type huntingtin may also cause the death of striatal neurons. Here we demonstrate that wild-type huntingtin up-regulates transcription of brain-derived neurotrophic factor (BDNF), a pro-survival factor produced by cortical neurons that is necessary for survival of striatal neurons in the brain. We show that this beneficial activity of huntingtin is lost when the protein becomes mutated, resulting in decreased production of cortical BDNF. This leads to insufficient neurotrophic support for striatal neurons, which then die. Restoring wild-type huntingtin activity and increasing BDNF production may be therapeutic approaches for treating HD.

Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study.

Abstract: Aims/hypothesis. The amount and quality of fat in the diet could be of importance for development of insulin resistance and related metabolic disorders. Our aim was to determine whether a change in dietary fat quality alone could alter insulin action in humans. Methods. The KANWU study included 162 healthy subjects chosen at random to receive a controlled, isoenergetic diet for 3 months containing either a high proportion of saturated (SAFA diet) or monounsaturated (MUFA diet) fatty acids. Within each group there was a second assignment at random to supplements with fish oil (3.6 g n-3 fatty acids/d) or placebo. Results. Insulin sensitivity was significantly impaired on the saturated fatty acid diet (-10 %, p = 0.03) but did not change on the monounsaturated fatty acid diet ( + 2 %, NS) (p = 0.05 for difference between diets). Insulin secretion was not affected. The addition of n-3 fatty acids influenced neither insulin sensitivity nor insulin secretion. The favourable effects of substituting a monounsaturated fatty acid diet for a saturated fatty acid diet on insulin sensitivity were only seen at a total fat intake below median (37E %). Here, insulin sensitivity was 12.5 % lower and 8.8 % higher on the saturated fatty acid diet and monounsaturated fatty acid diet respectively (p = 0.03). Low density lipoprotein cholesterol (LDL) increased on the saturated fatty acid diet ( + 4.1 %, p 37E %). [Diabetologia (2001) 44: 312–319]

Accessing genetic variation: genotyping single nucleotide polymorphisms

Abstract: Understanding the relationship between genetic variation and biological function on a genomic scale is expected to provide fundamental new insights into the biology, evolution and pathophysiology of humans and other species. The hope that single nucleotide polymorphisms (SNPs) will allow genes that underlie complex disease to be identified, together with progress in identifying large sets of SNPs, are the driving forces behind intense efforts to establish the technology for large-scale analysis of SNPs. New genotyping methods that are high throughput, accurate and cheap are urgently needed for gaining full access to the abundant genetic variation of organisms.

Gene Mutations in the Succinate Dehydrogenase Subunit SDHB Cause Susceptibility to Familial Pheochromocytoma and to Familial Paraganglioma

Abstract: The pheochromocytomas are an important cause of secondary hypertension. Although pheochromocytoma susceptibility may be associated with germline mutations in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RET, the genetic basis for most cases of nonsyndromic familial pheochromocytoma is unknown. Recently, pheochromocytoma susceptibility has been associated with germline SDHD mutations. Germline SDHD mutations were originally described in hereditary paraganglioma, a dominantly inherited disorder characterized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane. Although mutations in SDHC and in SDHD may cause hereditary paraganglioma, germline SDHA mutations are associated with juvenile encephalopathy, and the phenotypic consequences of SDHB mutations have not been defined. To investigate the genetic causes of pheochromocytoma, we analyzed SDHB and SDHC, in familial and in sporadic cases. Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma. These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.

The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo

Abstract: Divergent results from in vitro studies on the thickness and appearance of the gastrointestinal mucus layer have previously been reported. With an in vivo model, we studied mucus gel thickness over time from stomach to colon. The gastrointestinal tissues of Inactin-anesthetized rats were mounted luminal side up for intravital microscopy. Mucus thickness was measured with a micropipette before and after mucus removal by suction. The mucus layer was translucent and continuous; it was thickest in the colon (∼830 μm) and thinnest in the jejunum (∼123 μm). On mucus removal, a continuous, firmly adherent mucus layer remained attached to the epithelial surface in the corpus (∼80 μm), antrum (∼154 μm), and colon (∼116 μm). In the small intestine, this layer was very thin (∼20 μm) or absent. After mucus removal, there was a continuous increase in mucus thickness with the highest rate in the colon and the lowest rate in the stomach. In conclusion, the adherent gastrointestinal mucus gel in vivo is continuous and can be divided into two layers: a loosely adherent layer removable by suction and a layer firmly attached to the mucosa.

Purpose-Built Anisotropic Metal Oxide Material: 3D Highly Oriented Microrod Array of ZnO

Abstract: We are reporting here on the inexpensive fabrication of large three-dimensional and highly oriented porous microrod array of n-type ZnO semiconductor with a unique designed architecture consisting of well-defined, length-tailored, monodisperse, perpendicularly oriented single-crystalline hexagonal rods, grown directly onto polycrystalline, single-crystalline, or amorphous substrates, from an aqueous solution of zinc salt at low temperature.

Generalized linear precoder and decoder design for MIMO channels using the weighted MMSE criterion

Abstract: We address the problem of designing jointly optimum linear precoder and decoder for a MIMO channel possibly with delay-spread, using a weighted minimum mean-squared error (MMSE) criterion subject to a transmit power constraint. We show that the optimum linear precoder and decoder diagonalize the MIMO channel into eigen subchannels, for any set of error weights. Furthermore, we derive the optimum linear precoder and decoder as functions of the error weights and consider specialized designs based on specific choices of error weights. We show how to obtain: (1) the maximum information rate design; (2) QoS-based design (we show how to achieve any set of relative SNRs across the subchannels); and (3) the (unweighted) MMSE and equal-error design for fixed rate systems.

Comparison of genetic differentiation at marker loci and quantitative traits

Abstract: The comparison of the degree of differentiation in neutral marker loci and genes coding quantitative traits with standardized and equivalent measures of genetic differentiation (FST and QST, respectively) can provide insights into two important but seldom explored questions in evolutionary genetics: (i) what is the relative importance of random genetic drift and directional natural selection as causes of population differentiation in quantitative traits, and (ii) does the degree of divergence in neutral marker loci predict the degree of divergence in genes coding quantitative traits? Examination of data from 18 independent studies of plants and animals using both standard statistical and meta-analytical methods revealed a number of interesting points. First, the degree of differentiation in quantitative traits (QST) typically exceeds that observed in neutral marker genes (FST), suggesting a prominent role for natural selection in accounting for patterns of quantitative trait differentiation among contemporary populations. Second, the FST – QST difference is more pronounced for allozyme markers and morphological traits, than for other kinds of molecular markers and life-history traits. Third, very few studies reveal situations were QST < FST, suggesting that selection pressures, and hence optimal phenotypes, in different populations of the same species are unlikely to be often similar. Fourth, there is a strong correlation between QST and FST indices across the different studies for allozyme (r=0.81), microsatellite (r=0.87) and combined (r=0.75) marker data, suggesting that the degree of genetic differentiation in neutral marker loci is closely predictive of the degree of differentiation in loci coding quantitative traits. However, these interpretations are subject to a number of assumptions about the data and methods used to derive the estimates of population differentiation in the two sets of traits.

Three-dimensional array of highly oriented crystalline ZnO microtubes

Abstract: The ability to generate homogeneous particulate thin films of highly oriented and highly porous microparticles of a post transition metal oxide onto polycrystalline and single-crystalline substrates, at low cost, by a template-free, aqueous low-temperature coating process is demonstrated by the fabrication of a large three-dimensional array of perpendicularly oriented hexagonal microtubes of crystalline zincite ZnO from an aqueous solution of zinc nitrate and methenamine.

Attitudes towards organic foods among Swedish consumers.

Abstract: The present study reports demographic differences with respect to Swedish consumers’ attitudes towards organic foods (milk, meat, potatoes, bread), purchase frequency, purchase criteria, perceived availability, and beliefs about organic foods A random nation‐wide sample of 2,000 respondents, aged 18‐65 years, were mailed a questionnaire and 1,154 (58 per cent) responded The majority of consumers, and particularly women and young respondents (18‐25 years) reported positive attitudes, but purchase frequency was low A total of 13 per cent stated that they regularly bought organic milk Corresponding figures for organic meat, potatoes, and bread were 13, 16, and 8 per cent respectively The most important purchase criterion was good taste, and the least important was “organically produced” Approximately half of the respondents were satisfied with the availability of the organic foods The organic foods were perceived to be more expensive and healthier than conventionally produced alternatives A major obstacle to the purchase of organic foods was reported to be premium prices The results suggest that the consumption will not increase as long as important purchase criteria and perceived beliefs about organic foods do not match

Reverse Monte Carlo modelling

Abstract: Reverse Monte Carlo (RMC) modelling is a general method of structural modelling based on experimental data. RMC modelling can be applied to many different sorts of data, simultaneously if wished. Powder and single-crystal neutron diffraction (including isotopic substitution), x-ray diffraction (including anomalous scattering) and electron diffraction, extended x-ray absorption fine structure and nuclear magnetic resonance (magic angle spinning and second moment) have already been used to provide data. RMC modelling can also be applied to many different types of system - liquids, glasses, polymers, crystals and magnetic materials. This article outlines the RMC method and discusses some of the common misconceptions about it. It is stressed that RMC models are neither unique nor `correct'. However, they are often useful for aiding our understanding either of the structure itself, or of the relationships between local structure and other physical properties. Examples are given and the possibilities for further development of the RMC method are discussed.

VEGF receptor signal transduction.

Abstract: The family of vascular endothelial growth factors (VEGFs) currently includes VEGF-A, -B, -C, -D, -E, and placenta growth factor (PlGF). Several of these factors, notably VEGF-A, exist as different isoforms, which appear to have unique biological functions. The VEGF family proteins bind in a distinct pattern to three structurally related receptor tyrosine kinases, denoted VEGF receptor-1, -2, and -3. Neuropilins, heparan-sulfated proteoglycans, cadherins, and integrin alphavbeta3 serve as coreceptors for certain but not all VEGF proteins. Moreover, the angiogenic response to VEGF varies between different organs and is dependent on the genetic background of the animal. Inactivation of the genes for VEGF-A and VEGF receptor-2 leads to embryonal death due to the lack of endothelial cells. Inactivation of the gene encoding VEGF receptor-1 leads to an increased number of endothelial cells, which obstruct the vessel lumen. Inactivation of VEGF receptor-3 leads to abnormally organized vessels and cardiac failure. Although VEGF receptor-3 normally is expressed only on lymphatic endothelial cells, it is up-regulated on vascular as well as nonvascular tumors and appears to be involved in the regulation of angiogenesis. A large body of data, such as those on gene inactivation, indicate that VEGF receptor-1 exerts a negative regulatory effect on VEGF receptor-2, at least during embryogenesis. Recent data imply a positive regulatory role for VEGF receptor-1 in pathological angiogenesis. The VEGF proteins are in general poor mitogens, but binding of VEGF-A to VEGF receptor-2 leads to survival, migration, and differentiation of endothelial cells and mediation of vascular permeability. This review outlines the current knowledge about the signal transduction properties of VEGF receptors, with focus on VEGF receptor-2.

Patterns of animal dispersal, vicariance and diversification in the Holarctic

Abstract: We analysed patterns of animal dispersal, vicariance and diversification in the Holarctic based on complete phylogenies of 57 extant non-marine taxa, together comprising 770 species, documenting biogeographic events from the Late Mesozoic to the present. Four major areas, each corresponding to a historically persistent landmass, were used in the analyses: eastern Nearctic (EN), western Nearctic (WN), eastern Palaeoarctic (EP) and western Palaeoarctic (WP). Parsimony-based tree fitting showed that there is no significantly supported general area cladogram for the dataset. Yet, distributions are strongly phylogenetically conserved, as revealed by dispersalvicariance analysis (DIVA). DIVA-based permutation tests were used to pinpoint phylogenetically determined biogeographic patterns. Consistent with expectations, continental dispersals (WP↔EP and WN↔EN) are significantly more common than palaeocontinental dispersals (WN↔EP and EN↔WP), which in turn are more common than disjunct dispersals (EN↔EP and WN↔WP). There is significant dispersal asymmetry both within the Nearctic (WN→EN more common than EN→WN) and the Palaeoarctic (EP→WP more common than WP→EP). CrossBeringian faunal connections have traditionally been emphasized but are not more important than cross-Atlantic connections in our data set. To analyse changes over time, we sorted biogeographic events into four major time periods using fossil, biogeographic and molecular evidence combined with a ‘branching clock’. These analyses show that trans-Atlantic distributions (EN–WP) were common in the Early–Mid Tertiary (70–20 Myr), whereas transBeringian distributions (WN–EP) were rare in that period. Most EN–EP disjunctions date back to the Early Tertiary (70–45 Myr), suggesting that they resulted from division of cross-Atlantic rather than cross-Beringian distributions. Diversification in WN and WP increased in the Quaternary (< 3 Myr), whereas in EP and EN it decreased from a maximum in the Early–Mid Tertiary.  2001 The Linnean Society of London

Brominated flame retardants: a novel class of developmental neurotoxicants in our environment?

Abstract: Brominated flame retardants are a novel group of global environmental contaminants. Within this group the polybrominated diphenyl ethers (PBDE) constitute one class of many that are found in electr...

Chitosan as a nonviral gene delivery system. Structure-property relationships and characteristics compared with polyethylenimine in vitro and after lung administration in vivo.

Abstract: Chitosan is a natural cationic linear polymer that has recently emerged as an alternative nonviral gene delivery system. We have established the relationships between the structure and the properties of chitosan-pDNA polyplexes in vitro. Further, we have compared polyplexes of ultrapure chitosan (UPC) of preferred molecular structure with those of optimised polyethylenimine (PEI) polyplexes in vitro and after intratracheal administration to mice in vivo. Chitosans in which over two out of three monomer units carried a primary amino group formed stable colloidal polyplexes with pDNA. Optimized UPC and PEI polyplexes protected the pDNA from serum degradation to approximately the same degree, and they gave a comparable maximal transgene expression in 293 cells. In contrast to PEI, UPC was non toxic at escalating doses. After intratracheal administration, both polyplexes distributed to the mid-airways, where transgene expression was observed in virtually every epithelial cell, using a sensitive pLacZ reporter containing a translational enhancer element. However, the kinetics of gene expression differed - PEI polyplexes induced a more rapid onset of gene expression than UPC. This was attributed to a more rapid endosomal escape of the PEI polyplexes. Although this resulted in a more efficient gene expression with PEI polyplexes, UPC had an efficiency comparable to that of commonly used cationic lipids. In conclusion, this study provides insights into the use of chitosan as a gene delivery system. It emphasises that chitosan is a nontoxic alternative to other cationic polymers and it forms a platform for further studies of chitosan-based gene delivery systems.

Restorative experience and self-regulation in favorite places

Abstract: The authors report further evidence bearing on the relations among restorative experiences, self-regulation, and place attachment. University students (n = 101) described their favorite places and experiences in them, and 98 other students described unpleasant places. Natural settings were overrepresented among favorite places and underrepresented among the unpleasant places. In open-ended accounts, frequent mention of being relaxed, being away from everyday life, forgetting worries, and reflecting on personal matters indicated a link between favorite places and restorative experience. Restoration was particularly typical of natural favorite places. Structured evaluations of being away, fascination, coherence, and compatibility indicated they were experienced to a high degree in the favorite places, although fascination to a lesser degree than compatibility. The favorite and unpleasant places differed substantially in all four restorative qualities but especially in being away and compatibility. Self-refe...

Beyond randomized controlled trials: organized mammographic screening substantially reduces breast carcinoma mortality.

Abstract: BACKGROUND, The efficacy of mammographic screening in the reduction of breast carcinoma mortality has been demonstrated in randomized controlled trials. However, the evaluation of organized screeni ...

Space-time block codes: a maximum SNR approach

Abstract: In Tarokh et al. (1999) space-time block codes were introduced to obtain coded diversity for a multiple-antenna communication system, in this work, we cast space-time codes in an optimal signal-to-noise ratio (SNR) framework and show that they achieve the maximum SNR and, in fact, they correspond to a generalized maximal ratio combiner. The maximum SNR framework also helps in calculating the distribution of the SNR and in deriving explicit expressions for bit error rates. We bring out the connection between the theory of amicable orthogonal designs and space-time codes. Based on this, we give a much simpler proof to one of the main theorems on space-time codes for complex symbols. We present a rate 1/2 code for complex symbols which has a smaller delay than the code already known. We also present another rate 3/4 code which is simpler than the one already known, in the sense it does not involve additions or multiplications. We also point out the connection between generalized real designs and generalized orthogonal designs.

Towards artificial photosynthesis: ruthenium–manganese chemistry for energy production

Abstract: The synthesis and characterisation of supramolecular model systems mimicking the light reactions on the donor side of Photosystem II (PSII) in green plants have been reviewed In these systems, manganese complexes and tyrosine are electron donors, modelling the manganese cluster and tyrosineZ in PSII The donors have been covalently linked to a photosensitizer, a ruthenium(II) tris-bipyridyl complex, that plays the role of the P680 chlorophylls in PSII It has been demonstrated that, in the presence of an external electron acceptor in solution, the model systems can undergo an intermolecular electron transfer from the photoexcited state of RuII to an acceptor, followed by an intramolecular electron transfer from the coordinated Mn complexes or the tyrosine unit to the photogenerated RuIII This leads to regeneration of the RuII and oxidation of the Mn complexes or generation of a tyrosine radical The process closely mimics the primary reaction steps on the donor side of PSII

Anisotropic Lattice Distortions in Random Alloys from First-Principles Theory

Abstract: Within the framework of the exact muffin-tin orbitals (EMTO) theory we have developed a new method to calculate the total energy for random substitutional alloys. The problem of disorder is treated within the coherent potential approximation (CPA), and the total energy is obtained using the full charge density (FCD) technique. The FCD-EMTO-CPA method is suitable for determination of energy changes due to anisotropic lattice distortions in random alloys. In particular, we calculate the elastic constants of the Cu-rich face centered cubic Cu-Zn alloys ( alpha-brass) and optimize the c/a ratio for the hexagonal Zn-rich alloys for both the epsilon and eta phases.

Renal Function and Intensive Lowering of Blood Pressure in Hypertensive Participants of the Hypertension Optimal Treatment (HOT) Study

Abstract: This article reports further analyses of the Hypertension Optimal Treatment (HOT) Study data with the aim to describe (1) the value of baseline serum creatinine and its clearance (estimated by Cockroft and Gault formula) as predictors of cardiovascular events, (2) the effects of intensive lowering of BP on cardiovascular events and renal function in patients with reduced renal function, and (3) the effects on cardiovascular events of adding acetylsalicylic acid to antihypertensive therapy in patients with reduced renal function. The results show that (1) baseline elevation in serum creatinine and a reduction in estimated creatinine clearance are powerful predictors of cardiovascular events and death. (2) Reduced renal function at baseline did not preclude the desired control of BP. In contrast to patients with normal renal function, the incidence of major cardiovascular events did not differ in the three groups of patients with mild renal insufficiency randomized to different diastolic BP targets. No significant changes in serum creatinine were seen at the end of the 3.8-yr treatment period in the great majority of patients. However, there was a small group of patients (0.58% of the total study population) whose renal function deteriorated (increase > or =30% over baseline and final serum creatinine concentration > or =2 mg/dl) despite satisfactory reduction of diastolic BP. (3) The results of this reanalysis of the HOT Study suggest though do not prove that the association of acetylsalicylic acid with intensive antihypertensive therapy offers additional benefit in hypertensive patients with reduced renal function.

Chemical Composition and Morphology of the Elevated Temperature SEI on Graphite

Abstract: The relationship between the elevated temperature performance of Li/graphite half-cells and the composition and morphology of the solid electrolyte interphase (SEI) formed on the graphite surface has been investigated for two electrolyte systems: I M LiPF 6 in ethylene carbonate/dimethyl carbonate EC/DMC (2:1) and 1 M LiBF 4 in EC/DMC (2:1). Precycled cells were stored at different temperatures up to 80°C, and the graphite electrodes were analyzed chemically (by X-ray photoelectron spectroscopy) and electrochemically under continued cycling. Loss of charge (for both salts) and of intercalation capacity (for LiBF 4 ) occurred after elevated temperature storage. The charge loss could be coupled to disappearance of the R-OCO 2 Li phase from the surface, with subsequent exposure of the graphite surface. The amount of LiF increased with increased storage temperature, but the LiF morphology differed between the two electrolyte systems. A model for the morphological changes of the SEI layer on storage at elevated temperature is proposed.