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Biomedical subjects

M A Eriksson

Publications and source records attributed to M A Eriksson.

17 recordsLinked to original sources
PubMed2006

Effect of ozone oxidation on single-walled carbon nanotubes.

Exposing single-walled carbon nanotubes to room-temperature UV-generated ozone leads to an irreversible increase in their electrical resistance. We demonstrate that the increased resistance is due to ozone oxidation on the sidewalls of the nanotubes rather than at the end caps. Raman and X-ray photoelectron spectroscopies show an increase in the defect density due to the oxidation of the nanotubes. Using ultraviolet photoelectron spectroscopy, we show that these defects represent the removal of pi-conjugated electron states near the Fermi level, leading to the observed increase in electrical resistance. Oxidation of carbon nanotubes is an important first step in many chemical functionalization processes. Because the oxidation rate can be controlled with short exposures, UV-generated ozone offers the potential for use as a low-thermal-budget processing tool.

Carbon↗
PubMed2004

Spin readout and initialization in a semiconductor quantum dot.

Electron spin qubits in semiconductors are attractive from the viewpoint of long coherence times. However, single spin measurement is challenging. Several promising schemes incorporate ancillary tunnel couplings that may provide unwanted channels for decoherence. Here, we propose a novel spin-charge transduction scheme, converting spin information to orbital information within a single quantum dot by microwave excitation. The same quantum dot can be used for rapid initialization, gating, and readout. We present detailed modeling of such a device in silicon to confirm its feasibility.

Journal Article↗
PubMed2002

Material anisotropy revealed by phase contrast in intermittent contact atomic force microscopy.

Phase contrast in intermittent-contact atomic force microscopy (AFM) reveals in-plane structural and mechanical properties of polymer monolayers. This is surprising, because measurements of nanoscale in-plane properties typically require contact mode microscopies. Our measurements are possible because the tip oscillates not just perpendicular but also parallel to the sample surface along the long axis of the cantilever. This lateral tip displacement is virtually universal in AFM, implying that any oscillating-tip AFM technique is sensitive to in-plane material properties.

Journal Article↗
PubMed2001

Celiac disease and mineralisation disturbances of permanent teeth.

In a study from Finland in 1986 it was shown that celiac disease was often associated with tooth enamel defects of permanent teeth. This study also showed a strong association between the time of gluten challenge in the diagnostic procedure and enamel defects. In the current study, dental examinations were carried out for a group of 40 children and adolescents suffering from celiac disease diagnosed according to the criteria of The European Society of Paediatric Gastroenterology and Nutrition (ESPGAN) at the Department of Paediatrics, Hospital of Uddevalla, Sweden. A control group made of 40 healthy children of the same age, sex and living area was examined in the same way. The results failed to show disturbances of the same type, degree of severity or frequency as was reported in Finland and no statistically significant differences concerning enamel defects were found between the patients with celiac disease and the controls.

Adolescent↗
PubMed1999

Prediction of the binding free energies of new TIBO-like HIV-1 reverse transcriptase inhibitors using a combination of PROFEC, PB/SA, CMC/MD, and free energy calculations.

We have ranked 13 different TIBO derivatives with respect to their relative free energies of binding using two approximate computational methods: adaptive chemical Monte Carlo/molecular dynamics (CMC/MD) and Poisson-Boltzmann/solvent accessibility (PB/SA) calculations. Eight of these derivatives have experimentally determined binding affinities. The remaining new derivatives were constructed based on contour maps around R86183 (8Cl-TIBO), generated with the program PROFEC (pictorial representation of free energy changes). The rank order among the derivatives with known binding affinity was in good agreement with experimental results for both methods, with average errors in the binding free energies of 1. 0 kcal/mol for CMC/MD and 1.3 kcal/mol for the PB/SA method. With both methods, we found that one of the new derivatives was predicted to bind 1-2 kcal/mol better than R86183, which is the hitherto most tightly binding derivative. This result was subsequently supported by the most rigorous free energy computational methods: free energy perturbation (FEP) and thermodynamic integration (TI). The strategy we have used here should be generally useful in structure-based drug optimization. An initial ligand is derivatized based on PROFEC suggestions, and the derivatives are ranked with CMC/MD and PB/SA to identify promising compounds. Since these two methods rely on different sets of approximations, they serve as a good complement to each other. Predictions of the improved affinity can be reinforced with FEP or TI and the best compounds synthesized and tested. Such a computational strategy would allow many different derivatives to be tested in a reasonable time, focusing synthetic efforts on the most promising modifications.

Algorithms↗
PubMed1999

Structural and dynamic differences of the estrogen receptor DNA-binding domain, binding as a dimer and as a monomer to DNA: molecular dynamics simulation studies.

Molecular dynamics (MD) simulations of the estrogen receptor DNA-binding domain (ERDBD) as a dimer in complex with its DNA response element (ERE) show a significant difference in both structure and dynamics, compared to a MD simulation of monomeric ERDBD bound to its half-site response element (EREH). The C-terminal zinc binding domain (ZnII), including a region (helix II) which is in a helical conformation in ERE-(ERDBD)2, is considerably more flexible in EREH-ERDBD than in the dimeric complex. In EREH-ERDBD, all helical hydrogen bonds in helix II are broken and the entire ZnII region is detached from a hydrogen bonding network that in ERE-(ERDBD)2 connects to other parts of the protein as well as to the DNA. The regions that become flexible in EREH-ERDBD are identical to the regions where the NMR solution structure of free ERDBD is poorly ordered. This strongly suggests that dimerisation of ERDBD is required for ordering of the ZnII region and that monomeric binding to DNA is not sufficient for the ordering. This contrasts to the glucocorticoid receptor DNA-binding domain (GRDBD) which has essentially the same mobility (uniform and limited), regardless of whether it is free as a monomer in solution, bound as a monomer to its half-site response element or in a dimeric complex with the full response element. The hydrogen bonding network that connects ZnII with other parts of the protein and to DNA is almost identical in ERDBD and GRDBD. However, in GRDBD there is also a serine (in the N-terminal zinc coordinating region) with a central role in this network, connecting to the ZnII region. This serine is replaced by a glycine in ERDBD and we suggest that this substitution is sufficient for destabilisation of the network, thus leading to a more flexible ZnII region, which becomes ordered first upon forming a complex with another ERDBD and DNA.

Amino Acid Sequence↗
PubMed1998

Structural and dynamic effects of point mutations in the recognition helix of the glucocorticoid receptor DNA-binding domain.

We have studied the wild type and two variants of the glucocorticoid receptor DNA-binding domain (GRDBD): in one variant the three residues (the 'P-box' in GRDBD) that are essential for the discrimination between GREH and EREH are mutated to those in the estrogen receptor DBD (GRDBDega) and the other variant is a point mutation of one P-box residue, Ser459Gly (GRDBDggv). Molecular dynamics simulations (0.5-0.7 ns) have been performed on the GRDBDs, free in solution as well as in complex with the half-site response elements of the glucocorticoid (GREH) and estrogen (EREH) receptors. The residues which are central when forming the protein dimer interface in GRE-(GRDBD)2 (the 'D-box') were found to have different conformations in the different GRDBD-DNA complexes. This is consistent with experimental results showing that the cooperativity of dimeric GRDBD binding to DNA strongly depends on both the response element and the P-box residues. In our simulations the structures of GREH-GRDBDgsv (i.e. wild-type) and GREH-GRDBDggv were more similar to each other than to the respective GRDBDs bound to EREH. This is due to a thymine methyl group which is present in the major groove of the GREH and prevents the first zinc coordinating subdomain in GRDBD to approach GREH, but which is absent in EREH. Thus, EREH-GRDBD is able to respond more to the Ser459Gly mutation than GREH-GRDBD.

Amino Acid Sequence↗
PubMed1995

Structure, thermodynamics and cooperativity of the glucocorticoid receptor DNA-binding domain in complex with different response elements. Molecular dynamics simulation and free energy perturbation studies.

Molecular dynamics simulations and free energy perturbation calculations have been performed on the glucocorticoid receptor DNA-binding domain (GRDBD) in complex with three different half-site response elements (RE). These are the glucocorticoid receptor RE (GREH), the estrogen receptor RE (EREH) and an "intermediate" RE (GRE2H), where the base-pair 6A.T in GREH has been replaced by 6G.C. The molecular dynamics/free energy perturbation calculations reveal the same order of stability of the three complexes, i.e. GREH-GRDBD > GRE2H-GRDBD > EREH-GRDBD, as found experimentally, with reasonable quantitative agreement of the relative stabilities with the experiments. The more favourable entropy in associating GRDBD to GREH than to GRE2H could be explained by the additional non-polar surface that is removed from the solvent in the former complex formation. Part of this additional surface originates from the 6T methyl group in GREH. Sequence-dependent hydration patterns of the DNA major groove, which is interrupted by the GRDBD binding, could also contribute to the relatively more favourable entropy in forming GREH-GRDBD than GRE2H-GRDBD. The tenfold reduced cooperativity in the dimeric GRDBD binding to a partially palindromic ERE (palERE) compared to palGRE/GRE2 could be attributed to conformational changes in the residues of the "D-box" (Cys476 to Cys482) observed in the molecular dynamics simulations of EREH-GRDBD, but not in the other two complexes. Moreover, the conformations of the base-pairs at positions 5 and 6 are distorted (compared to free B-DNA) in GREH and GRE2H, due to the binding of GRDBD. Since the corresponding conformational distortions were not found in EREH-GRDBD, it is plausible that the distortions mediate cooperative binding through a propagation of the distortions to the other half site, thus facilitating binding of the second GRDBD.

Amino Acid Sequence↗
PubMed1995

On the pH dependence of amide proton exchange rates in proteins.

We have analyzed the pH dependencies of published amide proton exchange rates (kex) in three proteins: bovine pancreatic trypsin inhibitor (BPTI), bull seminal plasma proteinase inhibitor IIA (BUSI IIA), and calbindin D9K. The base-catalyzed exchange rate constants (kOH) of solvent exposed amides in BPTI are lower for residues with low peptide carbonyl exposure, showing that the environment around the carbonyl oxygen influences kOH. We also examined the possible importance of an exchange mechanism that involves formations of imidic acid intermediates along chains of hydrogen-bonded peptides in the three proteins. By invoking this "relayed imidic acid exchange mechanism," which should be essentially acid-catalyzed, we can explain the surprisingly high pHmin (the pH value at which kex reaches a minimum) found for the non-hydrogen-bonded amide protons in the beta-sheet in BPTI. The successive increase of pHmin along a chain of hydrogen-bonded peptides from the free amide to the free carbonyl, observed in BPTI, can be explained as an increasing contribution of the proposed mechanism in this direction of the chain. For BUSI IIA (pH 4-5) and calbindin D9K (pH 6-7) the majority of amide protons with negative pH dependence of kex are located in chains of hydrogen-bonded peptides; this situation is shown to be consistent with the proposed mechanism.

Amides↗
PubMed1995

Molecular dynamics simulations of the glucocorticoid receptor DNA-binding domain in complex with DNA and free in solution.

Molecular dynamics simulations have been performed on the glucocorticoid receptor DNA binding domain (GR DBD) in aqueous solution as a dimer in complex with DNA and as a free monomer. In the simulated complex, we find a slightly increased bending of the DNA helix axis compared with the crystal structure in the spacer region of DNA between the two half-sites that are recognized by GR DBD. The bend is mainly caused by an increased number of interactions between DNA and the N-terminal extended region of the sequence specifically bound monomer. The recognition helices of GR DBD are pulled further into the DNA major groove leading to a weakening of the intrahelical hydrogen bonds in the middle of the helices. Many ordered water molecules with long residence times are found at the intermolecular interfaces of the complex. The hydrogen-bonding networks (including water bridges) on either side of the DNA major groove involve residues that are highly conserved within the family of nuclear receptors. Very similar hydrogen-bonding networks are found in the estrogen receptor (ER) DBD in complex with DNA, which suggests that this is a common feature for proper positioning of the recognition helix in ER DBD and GR DBD.

Amino Acid Sequence↗
PubMed1993

A comparison of 15N NMR relaxation measurements with a molecular dynamics simulation: backbone dynamics of the glucocorticoid receptor DNA-binding domain.

The rapid motions of the backbone of the DNA-binding domain of the glucocorticoid receptor (GR DBD) have been investigated using proton-detected heteronuclear NMR experiments on 15N-labeled protein at pH 6.0 and with a 200 psec molecular dynamics simulation of hydrated GR DBD. The experimental data were interpreted in terms of a generalized order parameter (S2) and an effective correlation time (tau e) for the internal motion of each amide bond. A back calculation, using the same model, yielded the [1H]-14N nuclear Overhauser effects (NOEs) and the 15N spin-lattice relaxation times (T1) from the simulated data. The rapid motions of the backbone turned out to be rather limited and uniform throughout the protein, with a somewhat reduced mobility in the two major alpha-helical regions and a slightly enhanced flexibility for some residues in the first zinc coordinating region. The agreement between the experimental and simulated S2-values was as good as quantitative for most of the residues, except for some residues that were subject to a more large-scale, and in the simulation thus poorly sampled, motion. Examples of such motions that were found in the simulation include jumps of the amide bond of Ile-487 between the charged oxygens of the side chain of Asp-485 and less distinct large scale motions for some of the residues in the extended regions, that were shown to give rise to noisy and/or fast decaying internal reorientational correlation functions. For these residues large differences in the simulated and experimental tau e-values were found, indicating that motions on different time scales were dominating in the experimental and simulated values. The lower (< 0.7) experimental NOEs for these residues could not be reproduced in the simulation and were shown to be a consequence of the lower tau e-values estimated in the simulation. By combining information from the simulation and the experiment a more complete picture of the motions for these residues can be obtained as is illustrated with an estimation of the jump angle and jump frequency for the amide bond of Ile-487.

Amino Acid Sequence↗
PubMed1992

A molecular dynamics study of conformational changes and hydration of left-handed d(CGCGCGCGCGCG)2 in a nonsalt solution.

Twelve dinucleotides (one complete turn) of left-handed, flexible, double-helix poly(dG-dC) Z-DNA have been simulated in aqueous solution with K+ counterions for 70 ps. Most of the d(GpC) phosphates have rotated in accordance with a ZI----ZII transition. The ZII conformation was probably partly stabilized by counterions, which coordinate one of the anionic oxygens and the guanine-N7 of the next (5'----3' direction) base. The presence of base-coordinating ions close to the helical axis rotated and pulled about half of the d(CpG) phosphates further into the groove. These ions also gave rise to rather large deviations from the crystal structure (ZI) with their tendency of pulling the bases closer toward the helical axis. A flipping of the orientation about the glycosyl bond from the +sc to the -sc region was observed for one guanosine, also leading to deviations from the crystal structure. Many bridges containing one or two water molecules were found, with a dominance for the latter. They essentially formed a network of intra- and interstrand bridges between anionic and esterified phosphate oxygens. A "spine" of water molecules could be distinguished as a dark zig-zag pattern in the water density map. The lifetime of a bridge containing one water was about twice as long as that of a two-water bridge and it lasted 5-15 times longer than a hydrogen bond in water. The lifetimes were also calculated for a selection of bridge types, in order of decreasing stability: O1P/O2P ... W ... O'4 much greater than O1P/O2P ... W ... guanine-N2 greater than O1P/O2P ... W ... O1P/O2P. The reorientational motion of water molecules in the first hydration shell around selected groups was slowed down considerably compared to bulk water and the decreasing order of correlation times was guanine-N2 greater than O'4 greater than O'3/O'5 greater than O1P/O2P.

Base Sequence↗
PubMed1980

Naturally occurring alterations of cortical layers surrounding the fissura prima of rat cerebellum.

We have regularly observed alterations in the three-layered arrangement of cerebellar cortex surrounding fissura prima in normal adult and neonatal rats. In 90 of 110 rat brains analyzed, the cortical layers surrounding fissura prima were found to be altered from the four-layered (neonatal) or three-layered (adult) arrangement found in the majority of the remainder of cerebellar cortex. This common alteration extended long distances (as much as 320 microns) on either side of the midline, causing fissura prima to become more and more shallow from its lateral to medial extent. In sagittal sections at the lateral edge of the alteration in neonatal cerebellum, the external granular layer and pial cells disappeared, leaving an expanse of molecular layer lying between internal granular layer cells of lobules V and VI. Proceeding medially toward the midsagittal region, the cells of the internal granular layer of lobules V and VI were situated closer together and often merged. In such sections Purkinje cells did not usually remain in a monolayer, but were displaced, and clusters of these cells were sometimes found within the white matter. Various complex configurations of internal granular layer, molecular layer, and Purkinje cell groups surrounding fissura prima were commonplace in regions of cerebellum as far lateral as 320 microns on either side of the midsagittal plane. The greatest dorsoventral extent of such alterations measured was 400 microns. The presence of these previously unreported deviations is unrelated to experimental stress, as they occur spontaneously, possibly due to a vestigeal disorganization left in midline zones after early cell migration phases.

Animals↗
PubMedDate not supplied

Malformation of Purkinje cell dendrites induced by graft-versus-host disease.

Impairment of cerebral Purkinje cell growth was assessed in Golgi-Cox stained tissue in 14 day old (Fischer X DA)F1 hybrid rats subjected to graft versus host disease (GVHD). GVHD was induced by grafting parental strain lymph node cells (PSLNC) into the anterior facial vein on the day of birth. We have previously described GVHD induced changes in nucleotide and protein content [12] and RNA function [14] as well as alterations in cell numbers and areas of the external granular and molecular layers in diseased animals [13]. In this report some effects of GVHD on the gross morphology of Purkinje cells in 14 day old animals are enumerated. Most Purkinje cells (62%) from GVHD animals had a height to width ratio greater than 1, whereas most from control animals (71%) had ratios of less than 1. The majority of Purkinje cells (67%) from diseased animals had elongated main dendrites which were devoid of branches and often (13%) these elongated main dendrites were S-shaped. In addition, comparison of Purkinje cells from GVHD and control animals revealed a greater tendency (15%) toward retention of extrasomal process in GVHD animals. These findings suggest that GVHD affects nondividing, differentiating cell populations as well as those which are proliferating and migrating. Our evidence that, as a result of GVHD, the protein synthesizing capacity of the cerebellum is altered [14] and that Purkinje cells are more closely spaced at day 11 suggests that both intrinsic and extrinsic factors are involved in producing the changes in dendritic shape reported here.

Animals↗
PubMedDate not supplied

In-plane contributions to phase contrast in intermittent contact atomic force microscopy.

Contrast in the phase response of intermittent-contact atomic force microscopy (IC-AFM) reveals in-plane structural and mechanical properties of polymer monolayers. This result is unexpected, as IC-AFM has previously only been considered as a probe of out-of-plane properties. Until now, AFM measurements of nanoscale in-plane properties have employed contact mode techniques. In-plane property measurements are possible with intermittent contact AFM because there is a small but significant component of tip motion parallel to the sample surface. This in-plane component of tip displacement is virtually universal in AFM, implying that oscillating-tip techniques generally are sensitive to in-plane material properties. We present a simple Hertzian model of intermittent-contact AFM that includes such an in-plane displacement.

Journal Article↗
PubMedDate not supplied

Novel mutations in the APC gene and clinical features in Swedish patients with polyposis coli.

The adenomatous polyposis coli (APC) gene was investigated in Swedish patients with familial adenomatous polyposis (FAP). A combination of analyses including single stranded conformation polymorphism (SSCP), heteroduplex (HD), protein truncation test (PTT) and direct sequencing was used to enable optimal mutation detection. Three novel mutations in the gene were identified, i.e. nt2644C- > T (giving an Arg876Stop mutation), nt4025del173 (leading to premature truncation of the protein at codon 1337) and nt3526insG (giving truncation at codon 1178). In addition, one previously described mutation, i.e. the 5-bp-deletion nt3942del5(AAAGA) in codon 1309 (giving a premature termination of the protein at codon 1314) was detected. All four mutations were located in the 5'-half of exon 15. The two latter mutations were associated with the CHRPE (congenital hypertrophy of retina pigment epithelium) phenotype (CHRPE was not examined in the other two cases). The patients with mutations in codon 1309 and 1336 had a more severe FAP phenotype.

Adenomatous Polyposis Coli↗