Biomedical subjects

D Richter

Publications and source records attributed to D Richter.

At least 37 records · Page 2Linked to original sources

PubMed2003

Direct observation of the transition from free to constrained single-segment motion in entangled polymer melts.

We report a direct determination of the time dependent mean-squared segment displacement of a polymer chain in the melt covering the transition from free to constraint Rouse relaxation along the virtual tube of the reptation model. This has been achieved by a neutron spin-echo (NSE) measurement of the segmental self-correlation function as conveyed by the spin-incoherent scattering from two fully protonated polymer melts, polyethylene and polyethylene propylene. Within the scenario of de Gennes reptation model a transition of the time dependence of segmental mean-squared displacements from proportional, variant t(1/2) to proportional, variant t(1/4) is expected and clearly corroborated by the incoherent NSE results.

Journal Article↗

PubMed2003

Blockade of HMG-CoA reductase activity causes changes in microtubule-stabilizing protein tau via suppression of geranylgeranylpyrophosphate formation: implications for Alzheimer's disease.

Histopathologically, Alzheimer's disease is characterized by plaques and tangles that develop progressively over time. Experimental data described a statin-induced decrease in beta-amyloid production, a major constituent of the plaques. Others reported data on statin-mediated changes in neuronal survival and cytoskeleton, including the microtubule-associated protein tau, a major constituent of the tangles. However, these latter reports remain contradictory. To clarify and extend our knowledge on the effect of statin on the cytoskeleton, we challenged rat primary neuron cultures by lovastatin and determined the metabolite that is critical for structural integrity and survival of neurons. During the blockade of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the neuritic network was affected and eventually was completely destroyed. This process was not part of the execution phase of apoptosis and was marked by alterations in the microfilament and microtubule system. The distribution and phosphorylation of protein tau changed. Immunoblot analysis and indirect immunofluorescence revealed a transient increase in tau phosphorylation, which ceased during the execution of apoptosis. All of these effects could be linked to the lack of the geranylgeranylpyrophosphate intermediate. Inhibition of the geranylgeranylation of Rho family GTPases (geranylgeranyl-transferase I) evoked similar changes in neurons. These data and our findings that statin treatment reduced the membrane-bound fraction of RhoA-GTPase in neurons suggest that reduced levels of functional small G proteins are responsible for the observed effects. Our data demonstrate that lovastatin concentrations able to suppress not only cholesterol but also geranylgeranylpyrophosphate formation may evoke phosphorylation of tau reminiscent of preclinical early stages of Alzheimer's disease and, when prolonged, apoptosis.

Alzheimer Disease↗

PubMed2002

Non-Gaussian nature of the alpha relaxation of glass-forming polyisoprene.

We report quasielastic neutron scattering experiments exploring the alpha relaxation in polyisoprene over an unprecedented range in momentum transfer. Corroborating and validating earlier molecular dynamics simulations, the measurements reveal a crossover from a Gaussian regime of sublinear diffusion to a strongly non-Gaussian regime at short distances. We show that a consistent interpretation in terms of a distribution of finite jumps underlying the alpha process is possible. This model leads to a time-dependent non-Gaussian parameter exhibiting all features revealed so far from various simulations.

Journal Article↗

PubMed2002

Lipoprotein lipase gene variants relate to presence and degree of microalbuminuria in Type II diabetes.

AIMS/HYPOTHESIS: Lipids and lipoproteins, particularly triglyceride rich lipoproteins, could influence the development and progression of microalbuminuria in diabetes. Lipoprotein lipase gene variants have been found to correlate with lipid/lipoprotein concentrations, especially hypertriglyceridaemia. We assessed the influence of this gene on microalbuminuria in Type II (insulin-dependent) diabetes mellitus. METHODS: Microalbuminuria was determined quantitatively in 386 sequential Type II diabetic patients by measurement of the albumin-to-creatinine ratio (ACR). DNA was analysed for two common intronic LPL single nucleotide polymorphisms (Pvu II, intron 6, and Hind III, intron 8), and three common exonic mutations (Asp(9)-Asn, exon 2, Asn(291)-Ser, exon 6, and Ser(447)-Ter, exon 9). RESULTS: Individuals with P (2) P (2) (Pvu II) and H (2) H (2) (Hind III) genotypes had significantly greater ACRs ( P(2)P(2) vs P(1)P(1)+ P(1)P(2), 5.0+/-0.5 vs 3.4+/-0.3, p=0.0004 and H(2)H(2) vs H(1)H(1)+ H(1)H(2), 4.3+/-0.4 vs 3.4+/-0.3, p=0.04). Logistic regression analysis demonstrated that only the P(2)P(2) genotype ( p=0.0004), systolic BP ( p=0.008) and creatinine ( p=0.031) were independently associated with the presence of microalbuminuria/proteinuria. P(2) homozygotes were 170% more likely to have microalbuminuria or proteinuria, O.R. 2.7 (1.6-4.5, p=0.0001), 150% more likely to have microalbuminuria, O.R. 2.5 (1.5-4.3, p=0.001), and 330% more likely to have proteinuria, O.R. 4.3 (1.6-11.4, p=0.004). There were no associations of microalbuminuria with any of the exonic polymorphisms. CONCLUSION/INTERPRETATION: Genetic variants of lipoprotein lipase correlate with presence and severity of microalbuminuria in Type II diabetes, independent of effect on serum lipids. This association is only apparent in genetic variants demonstrating greatest heterozygosity.

Aged↗

PubMed2002

Intermediate length scale dynamics of polyisobutylene.

We report on a neutron spin echo investigation of the intermediate scale dynamics of polyisobutylene studying both the self-motion and the collective motion. The momentum transfer (Q) dependences of the self-correlation times are found to follow a Q(-2/beta) law in agreement with the picture of Gaussian dynamics. In the full Q range of observation, their temperature dependence is weaker than the rheological shift factor. The same is true for the stress relaxation time as seen in sound wave absorption. The collective times show both temperature dependences; at the structure factor peak, they follow the temperature dependence of the viscosity, but below the peak, one finds the stress relaxation behavior.

Journal Article↗

PubMed2002

Molecular observation of contour-length fluctuations limiting topological confinement in polymer melts.

In order to study the mechanisms limiting the topological chain confinement in polymer melts, we have performed neutron-spin-echo investigations of the single-chain dynamic-structure factor from polyethylene melts over a large range of chain lengths. While at high molecular weight the reptation model is corroborated, a systematic loosening of the confinement with decreasing chain length is found. The dynamic-structure factors are quantitatively described by the effect of contour-length fluctuations on the confining tube, establishing this mechanism on a molecular level in space and time.

Journal Article↗

PubMed2002

[Mobility of unstable fractures of the odontoid during helmet removal. A biomechanical study].

In severe motorcyclist accidents unstable injuries of the cervical spine can usually not be excluded before an X-ray has been taken in the hospital. Despite this the helmet has to be taken off at the place of the accident in order to provide adequate treatment and airway management of the injured driver. There are no data in the current literature showing what happens to unstable lesions of the cervical spine during helmet removal. An experimental unstable lesion of the cervical spine was created by an osteotomy of the odontoid in 10 fresh frozen cadavers with intact soft tissues. All motions occurring in the segments C1-2 and C2-3 during helmet removal were recorded by fluoroscopy. The average motion in the unstable segment C1-2 was 23.7 degrees during a full range of extension-flexion movement of the cervical spine without any signs of dislocation of the segment. After application of the helmet there was one case of dislocation of C1-2 in neutral supine position already, and two further cases of dislocations during helmet removal. The average motion of C1-2 recorded during helmet removal was 19.0 degrees (2-25 degrees ), median 18.0 degrees. In order to avoid fracture dislocations and motion in the unstable upper cervical spine the helmet should better be cut in pieces at the place of the accident. There is a need for discussions with helmet producers to develop a new generation of helmets that can be removed easily without manipulating the head.

Accidents, Traffic↗

PubMed2002

Development of a tunable mid-IR difference frequency laser source for highly sensitive airborne trace gas detection.

The development of a compact tunable mid-IR laser system at 3.5 micrometers for quantitative airborne spectroscopic trace gas absorption measurements is reported. The mid-IR laser system is based on difference frequency generation (DFG) in periodically poled LiNbO3 and utilizes optical fiber amplified near-IR diode and fiber lasers as pump sources operating at 1083 nm and 1562 nm, respectively. This paper describes the optical sensor architecture, performance characteristics of individual pump lasers and DFG, as well as its application to wavelength modulation spectroscopy employing an astigmatic Herriott multi-pass gas absorption cell. This compact system permits detection of formaldehyde with a minimal detectable concentration (1 sigma replicate precision) of 74 parts-per-trillion by volume (pptv) for 1 min of averaging time and was achieved using calibrated gas standards, zero air background and rapid dual-beam subtraction. This corresponds to a pathlength-normalized replicate fractional absorption sensitivity of 2.5 x 10-(10 )cm-1.

Air Pollutants↗

PubMed2002

13CO2/12CO2 isotopic ratio measurements using a difference frequency-based sensor operating at 4.35 micrometers.

A portable modular gas sensor for measuring the 13C/12C isotopic ratio in CO2 with a precision of 0.8%(+/-1 sigma) was developed for volcanic gas emission studies. This sensor employed a difference frequency generation (DFG)-based spectroscopic source operating at 4.35 micrometers (approximately 2300 cm-1) in combination with a dual-chamber gas absorption cell. Direct absorption spectroscopy using this specially designed cell permitted rapid comparisons of isotopic ratios of a gas sample and a reference standard for appropriately selected CO2 absorption lines. Special attention was given to minimizing undesirable precision degrading effects, in particular temperature and pressure fluctuations.

Atmosphere↗

PubMed2002

Interaction of G-protein-coupled receptors with synaptic scaffolding proteins.

The calcium-independent receptors for latrotoxin (CIRL1-CIRL3) constitute a family of seven-transmembrane receptors with an unsually large N-terminal extracellular domain which comprises several motifs usually found in cell adhesion molecules. By yeast two-hybrid screening, we have identified the intracellular C-termini of CIRL1 and CIRL2 as interaction partners of the PDZ domain of the proline-rich synapse-associated protein (ProSAP)/somatostatin receptor-interacting protein (SSTRIP) family of postsynaptic proteins (SSTRIP, ProSAP1 and ProSAP2, also known as shank1-shank3 respectively). Overlay assays indicate that the ProSAP1/shank2 PDZ domain in particular interacts strongly with the C-terminus of CIRL1 and CIRL2. Co-immunoprecipitation of ProSAP1 and CIRL1 (but not CIRL2) from rat brain extracts indicates that this interaction also occurs in vivo in rat brain. The known postsynaptic localization of ProSAP1, as well as our observation that CIRL1 (but not CIRL2) is enriched in postsynaptic density preparations from the rat brain, suggests that CIRL1 is localized pre- as well as post-synaptically in the central nervous system.

Amino Acid Sequence↗

PubMed2002

Microarray analysis of differentially expressed genes in placental tissue of pre-eclampsia: up-regulation of obesity-related genes.

Susceptibility genes present in both mother and fetus most likely contribute to the risk of pre-eclampsia. Placental biopsies were therefore investigated by high-density DNA microarray analysis to determine genes differentially regulated within chorionic villous tissue in pre-eclampsia and normal pregnancy. The pooled RNAs of pre-eclamptic and normotensive subjects were hybridized to the HuGeneFL array representing sequences from approximately 5600 full-length human cDNAs. The differentially expressed genes that were detected could be categorized into nine groups: adhesion molecules, obesity-related genes, transcription factors/signalling molecules, immunological factors, neuromediators, oncogenic factors, protease inhibitors, hormones and growth factor-binding proteins. Among those, the obesity-related genes included putative candidate genes associated with the pathogenesis of pre-eclampsia. One of the most up-regulated transcripts was the obese gene (43.6-fold change), and this was reflected by elevated leptin protein levels. In the case of feto-maternal contribution of polymorphic genes to pre-eclampsia, expression analysis of placental tissue has lead to numerous target genes waiting for large scale genetic linkage analyses.

Female↗

PubMed2001

Cloning and functional pharmacology of two corticotropin-releasing factor receptors from a teleost fish.

Although it is well established that fish possess corticotropin-releasing factor (CRF) and a CRF-like peptide, urotensin I, comparatively little is known about the pharmacology of their cognate receptors. Here we report the isolation and functional expression of two complementary DNAs (cDNAs), from the chum salmon Oncorhynchus keta, which encode orthologues of the mammalian and amphibian CRF type 1 (CRF(1)) and type 2 (CRF(2)) receptors. Radioligand competition binding experiments have revealed that the salmon CRF(1) and CRF(2) receptors bind urotensin I with approximately 8-fold higher affinity than rat/human CRF. These two peptides together with two related CRF-like peptides, namely, sauvagine and urocortin, were also tested in cAMP assays; for cells expressing the salmon CRF(1) receptor, EC(50) values for the stimulation of cAMP production were between 4.5+/-1.8 and 15.3+/-3.1 nM. For the salmon CRF(2) receptor, the corresponding values were: rat/human CRF, 9.4+/-0.4 nM; urotensin I, 21.2+/-2.1 nM; sauvagine, 0.7+/-0.1 nM; and urocortin, 2.2+/-0.7 nM. We have also functionally coupled the O. keta CRF(1) receptor, in Xenopus laevis oocytes, to the endogenous Ca(2+)-activated chloride conductance by co-expression with the G-protein alpha subunit, G(alpha16). The EC(50) value for channel activation by rat/human CRF (11.2+/-2.6 nM) agrees well with that obtained in cAMP assays (15.3+/-3.1 nM). We conclude that although sauvagine is 13- and 30-fold more potent than rat/human CRF and urotensin I, respectively, in activating the salmon CRF(2) receptor, neither receptor appears able to discriminate between the native ligands CRF and urotensin I.

Amino Acid Sequence↗

PubMed2001

Comparative morphology and paleobiology of Middle Pleistocene human remains from the Bau de l'Aubesier, Vaucluse, France.

The discovery of later Middle Pleistocene human remains from the Bau de l'Aubesier, France reinforces an evolutionary model of the gradual accumulation of Neandertal-derived facial and dental features during the Middle Pleistocene of the northwestern Old World. The pronounced maxillary incisor beveling of Aubesier 4 helps to extend the antiquity of nondietary use of the anterior dentition. The interproximal "toothpick" groove on the Aubesier 10 molar increases the sample for these lesions. The pathological loss of the mandibular dentition of Aubesier 11 indicates advanced antemortem masticatory impairment, at a level previously undocumented before the Late Pleistocene. These remains support a view of later Middle Pleistocene humans able to support debilitated individuals despite the considerable use of their bodies to accomplish routine activities.

Animals↗

PubMed2001

Synaptic scaffolding proteins in rat brain. Ankyrin repeats of the multidomain Shank protein family interact with the cytoskeletal protein alpha-fodrin.

The postsynaptic density is the ultrastructural entity containing the neurotransmitter reception apparatus of excitatory synapses in the brain. A recently identified family of multidomain proteins termed Src homology 3 domain and ankyrin repeat-containing (Shank), also known as proline-rich synapse-associated protein/somatostatin receptor-interacting protein, plays a central role in organizing the subsynaptic scaffold by interacting with several synaptic proteins including the glutamate receptors. We used the N-terminal ankyrin repeats of Shank1 and -3 to search for interacting proteins by yeast two-hybrid screening and by affinity chromatography. By cDNA sequencing and mass spectrometry the cytoskeletal protein alpha-fodrin was identified as an interacting molecule. The interaction was verified by pull-down assays and by coimmunoprecipitation experiments from transfected cells and brain extracts. Mapping of the interacting domains of alpha-fodrin revealed that the highly conserved spectrin repeat 21 is sufficient to bind to the ankyrin repeats. Both interacting partners are coexpressed widely in the rat brain and are colocalized in synapses of hippocampal cultures. Our data indicate that the Shank1 and -3 family members provide multiple independent connections between synaptic glutamate receptor complexes and the cytoskeleton.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Even minimal symptoms of depression increase mortality risk after acute myocardial infarction.

Mild to moderate levels of depressive symptoms as characterized by Beck Depression Inventory (BDI) scores of > or =10 are associated with decreased survival after acute myocardial infarction (AMI). We investigated whether lower levels of depressive symptoms are also associated with increased mortality risk after AMI. We prospectively studied 285 patients with AMI who survived to discharge for evidence, at the time of hospitalization, of a DSM-IIIR mood disorder (using a structured clinical interview) and for symptoms of depression (using the BDI). The overall mortality rate at 4 months was 6.7%. Multiple logistic regression (chi-square 35.79, p < or =0.001) revealed that the independent predictors of mortality were: age > or =65 years, left ventricular ejection fraction <35%, diabetes mellitus, and any depression (DSM-IIIR mood disorder or BDI > or =10) present at the time of AMI. Among patients > or =65 years old with left ventricular ejection fraction <35%, the 4-month mortality was 12%. However, in this same group, those with any depression at the time of AMI had a 4-month mortality of 50% (relative risk 4.1, p = 0.01). Among patients aged > or =65 years, the mortality according to BDI scale grouping 0 to 3, 4 to 9, and 10+ was 2.6%, 17.1%, and 23.3%, respectively (p <0.002). Highest mortality rates were observed in patients with most severe depressive symptoms. However, compared with those without depression, higher mortality was also observed at very low levels of depressive symptoms (BDI 4 to 9) not generally considered clinically significant and below the level usually considered predictive of increased post-AMI mortality.

Aged↗

PubMed2001

Phase separation in star-polymer-colloid mixtures.

We examine the demixing transition in star-polymer-colloid mixtures for star arm numbers f=2,6,16,32 and different star-polymer-colloid size ratios 0.18< or =q< or =0.50. Theoretically, we solve the thermodynamically self-consistent Rogers-Young integral equations for binary mixtures using three effective pair potentials obtained from direct molecular computer simulations. The numerical results show a spinodal instability. The demixing binodals are approximately calculated and found to be consistent with experimental observations.

Journal Article↗

PubMed2001

Vasopressin mRNA localization in nerve cells: characterization of cis-acting elements and trans-acting factors.

mRNA localization is a complex pathway. Besides mRNA sorting per se, this process includes aspects of regulated translation. It requires protein factors that interact with defined sequences (or sequence motifs) of the transcript, and the protein/RNA complexes are finally guided along the cytoskeleton to their ultimate destinations. The mRNA encoding the vasopressin (VP) precursor protein is localized to the nerve cell processes in vivo and in primary cultured nerve cells. Sorting of VP transcripts to dendrites is mediated by the last 395 nucleotides of the mRNA, the dendritic localizer sequence, and it depends on intact microtubules. In vitro interaction studies with cytosolic extracts demonstrated specific binding of a protein, enriched in nerve cell tissues, to the radiolabeled dendritic localizer sequence probe. Biochemical purification revealed that this protein is the multifunctional poly(A)-binding protein (PABP). It is well known for its ability to bind with high affinity to poly(A) tails of mRNAs, prerequisite for mRNA stabilization and stimulation of translational initiation, respectively. With lower affinities, PABP can also associate with non-poly(A) sequences. The physiological consequences of these PABP/RNA interactions are far from clear but may include functions such as translational silencing. Presumably, the translational state of mRNAs subject to dendritic sorting is influenced by external stimuli. PABP thus could be a component required to regulate local synthesis of the VP precursor and possibly of other proteins.

Amino Acid Sequence↗

PubMed2001

Molecular kinesis in cellular function and plasticity.

Intracellular transport and localization of cellular components are essential for the functional organization and plasticity of eukaryotic cells. Although the elucidation of protein transport mechanisms has made impressive progress in recent years, intracellular transport of RNA remains less well understood. The National Academy of Sciences Colloquium on Molecular Kinesis in Cellular Function and Plasticity therefore was devised as an interdisciplinary platform for participants to discuss intracellular molecular transport from a variety of different perspectives. Topics covered at the meeting included RNA metabolism and transport, mechanisms of protein synthesis and localization, the formation of complex interactive protein ensembles, and the relevance of such mechanisms for activity-dependent regulation and synaptic plasticity in neurons. It was the overall objective of the colloquium to generate momentum and cohesion for the emerging research field of molecular kinesis.

Animals↗