julilili42/papers huggingface dataset:
Molecular Characterization of Covalent Complexes between Tissue Transglutaminase and Gliadin Peptides
2004-04-01

Tissue transglutaminase (TG2) modifies proteins and peptides by transamidation or deamidation of specific glutamine residues. TG2 also has a central role in the pathogenesis of celiac disease. The enzyme is both the target of disease-specific autoantibodies and generates deamidated gliadin peptides recognized by intestinal T cells from patients. Incubation of TG2 with gliadin peptides also results in the formation of covalent TG2-peptide complexes. Here we report the characterization of complexes between TG2 and two immunodominant gliadin peptides. Two types of covalent complexes were found; the peptides are either linked via a thioester bond to the active site cysteine of TG2 or via isopeptide bonds to particular lysine residues of the enzyme. We quantified the number of gliadin peptides bound to TG2 under different conditions. After 30 min of incubation of TG2 at 1 microm with an equimolar ratio of peptides to TG2, approximately equal amounts of peptides were bound by thioester and isopeptide linkage. At higher peptide to TG2 ratios, more than one peptide was linked to TG2, and isopeptide bond formation dominated. The lysine residues in TG2 that act as acyl acceptors were identified by matrix assisted laser desorption ionization and nanoelectrospray mass spectrometry and tandem mass spectrometry analysis of proteolytic digests of the TG2-peptide complexes. At a high molar excess of gliadin peptides to TG2 altogether six lysine residues of TG2 were found to participate in isopeptide bond formation. The results are relevant to the understanding of how antibodies to TG2 are formed in celiac disease.
Impaired Regulation of Renal K+ Elimination in the sgk1-Knockout Mouse
2004-04-01

Serum- and glucocorticoid-regulated kinase 1 (Sgk1) contributes to Na+ reabsorption in the aldosterone-sensitive distal nephron. Sgk1-knockout (sgk1-/-) and littermate wild-type mice (sgk1+/+) were used to test the importance of Sgk1 in renal elimination of K+ . Intravenous application of K+ load under anesthesia increased plasma K+ concentration by 1.3 to 1.4 mM in both sgk1-/- (n = 6) and sgkl+/+ (n = 7) mice. However, the increase of absolute and fractional renal K+ excretion observed in sgk1+/+ was significantly blunted in sgk1-/- animals. Both groups of mice decreased or increased renal K+ excretion to a similar extent after a low (<0.03%) or high (5%) K+ diet for 6 d, respectively. In sgk1+/+, plasma K+ concentration was not significantly modified by either high or low K+ diet. In sgk1-/-, however, high K+ diet enhanced plasma K+ concentration by about 1.6 mM, despite an excessive increase of plasma aldosterone concentration reaching values about sixfold higher than in sgk1+/+. Electrophysiological and immunohistochemical studies under high K+ diet indicated that reduced epithelial Na+ channel ENaC and/or Na+/K+-ATPase activity in the aldosterone-sensitive distal nephron accounted for the impaired response in sgk1-/- and that an enhanced apical abundance of renal outer medullary K+ channel ROMK partly compensated for the defect. The acute and chronic regulation of renal K+ elimination involves Sgk1.
Infectivity of Prion Protein Bound to Stainless Steel Wires: A Model for Testing Decontamination Procedures for Transmissible Spongiform Encephalopathies
2004-04-01

Abstract Objectives: To establish an animal model to study transmissible spongiform encephalopathy using hamsters and steel wires contaminated with infectious brain materials as transfer vehicles, and, based on this model, to test decontamination procedures against the infectious prion proteins on the steel wires as a near real situation bioassay. Design: Infectious brain materials were given to healthy hamsters intracerebrally either as a suspension or as dried materials on the surface of steel wires. The animals were observed for 18 months. During this period, animals showing definitive clinical signs were euthanized. Decontamination studies were performed by reprocessing contaminated steel wires with different disinfection agents and procedures before implantation. Results: Pathological prion proteins were able to bind to the steel wires and caused disease after the contaminated wires were implanted in the brains of hamsters. When the contaminated wires were treated with different reprocessing procedures before implantation, infectivity was reduced, which was manifested directly by prolonged survival time of the test animals. These results show that this model can be used as a bioassay to validate reprocessing procedures for surgical instruments. Conclusions: At the time of submission of this article, only the group of hamsters incubated with wires reprocessed with an alkaline detergent, followed by sterilization with a modified cycle in a hydrogen peroxide gas plasma sterilizer (4 injections), showed no clinical signs of disease and remained alive. Two animals from the group receiving sodium hydroxide followed by autoclaving (at 134° C for 18 minutes) died. Furthermore, the tested enzymatic cleaning agent seemed to have no positive effect.
A Family of Acid-sensing Ion Channels from the Zebrafish
2004-04-01

Acid-sensing ion channels (ASICs) are excitatory receptors for extracellular H(+). Proposed functions include synaptic transmission, peripheral perception of pain, and mechanosensation. Despite the physiological importance of these functions, the precise role of ASICs has not yet been established. In order to increase our understanding of the physiological role and basic structure-function relationships of ASICs, we report here the cloning of six new ASICs from the zebrafish (zASICs). zASICs possess the basic functional properties of mammalian ASICs: activation by extracellular H(+), Na(+) selectivity, and block by micromolar concentrations of amiloride. The zasic genes are broadly expressed in the central nervous system, whereas expression in the peripheral nervous system is scarce. This pattern suggests a predominant role for zASICs in neuronal communication. Our results suggest a conserved function for receptors of extracellular H(+) in the central nervous system of vertebrates.
Upstream Stimulatory Factor (USF) Proteins Induce Human TGF-β1 Gene Activation via the Glucose-response Element–1013/–1002 in Mesangial Cells
2004-04-01

The hyperglycemia-enhanced flux through the hexosamine biosynthetic pathway (HBP) has been implicated in the up-regulated gene expression of transforming growth factor-beta1 (TGF-beta1) in mesangial cells, thus leading to mesangial matrix expansion and diabetic glomerulosclerosis. Since the -1013 to -1002 region of the TGF-beta1 promoter shows high homology to glucose-response elements (GlRE) formerly described in genes involved in glucose metabolism, we studied the function of the GlRE in the high glucose-induced TGF-beta1 gene activation in mesangial cells. We found that high glucose concentrations enhanced the nuclear amount of upstream stimulatory factors (USF) and their binding to this sequence. Fusion of the GlRE to the thymidine kinase promoter resulted in glucose responsiveness of this promoter construct. Overexpression of either USF-1 or USF-2 increased TGF-beta1 promoter activity 2-fold, which was prevented by mutation or deletion of the GlRE. The high glucose-induced activation of the GlRE is mediated by the HBP; increased flux through the HBP induced by high glucose concentrations, by glutamine, or by overexpression of the rate-limiting enzyme glutamine:fructose-6-phosphate aminotransferase (GFAT) particularly activated USF-2 expression. GFAT-overexpressing cells showed higher USF binding activity to the GlRE and enhanced promoter activation via the GlRE. Increasing O-GlcNAc modification of proteins by streptozotocin, thereby mimicking HBP activation, also resulted in increased mRNA and nuclear protein levels of USF-2, leading to enhanced DNA binding activity to the GlRE. USF proteins themselves were not found to be O-GlcNAc-modified. Thus, we have provided evidence for a new molecular mechanism linking high glucose-enhanced HBP activity with increased nuclear USF protein levels and DNA binding activity and with up-regulated TGF-beta1 promoter activity.
Acute Haemorrhagic Encephalomyelitis (AHEM): MRI Findings
2004-04-01

Acute disseminated encephalomyelitis (ADEM) comprises a group of demyelinating disorders of the CNS, of which a haemorrhagic variant indicates the most severe clinical course (AHEM). It is supposed to be caused by an overshooting immunological response following an infection or a vaccination. Restricted diffusion of protons could be demonstrated using DW-MRI in a case of rapidly progressive disease with additional haemorrhage. Hence, the addition of DWI adds to the diagnostic power of MRI in the setting of post-infectious demyelinating disorders of the CNS.
Randomized, Controlled Trial of Oral Creatine Supplementation (Not Effective) for Apnea of Prematurity
2004-04-01

Background. Hypoxic ventilatory depression in mice and muscle fatigue in adult humans are improved by creatine supplementation (CS). Because these issues may be operative in apnea of prematurity (AOP), we hypothesized that CS reduces episodes of hypoxemia and bradycardia in infants with AOP. Methods. Infants were eligible for this double-blind, controlled trial if gestational age was &amp;lt;32 weeks and AOP was severe enough to require treatment with caffeine. If they had ≥1 desaturation (pulse oximeter saturation [SpO2] ≤ 80%) or bradycardia (heart rate ≤ two thirds of baseline) per hour in an initial 6-hour recording, they were randomized to a 2-week course of oral CS (200 mg/kg per day) or placebo (P). Infants then underwent 2 additional 6-hour recordings of breathing movements, nasal airflow, heart rate, pulse oximeter saturation (SpO2) and pulse waveforms after 7 and 14 days of treatment. Urinary creatine excretion was measured also. Recordings were analyzed for the frequency of bradycardia and desaturation, the primary outcome parameter, as well as for apnea (≥10 seconds), baseline heart and respiratory rate, and SpO2. Results. Of 38 infants enrolled, 34 completed the study (17 in each group). Median (range) gestational age at birth was 27 (25–30) vs 27 (25–30) weeks, and at study 29 (26–36) vs 29 (27–33) weeks. Oral CS was well tolerated; no side effects were noted. Urinary creatine excretion was low in the P group (median: 27 mmol/mol of creatinine; range: 18–102) and increased in the CS group (6949 mmol/mol of creatinine; range: 1427–11807). CS, however, had no effect on the combined rate of bradycardia and desaturation (P: 2.7 per hour [range: 0.2–10.3]; CS: 4.1 per hour [range: 0.6–12.1]), nor was there any decrease in apnea rate (P: 1.7 per hour [range: 0–4.5]; CS: 2.2 per hour [range: 0.2–5.1]). Conclusion. Despite a significant increase in creatine excretion, suggesting good enteral absorption, CS did not, in the dose and for the duration given in this study, improve symptoms of AOP in these infants.
Stereological analysis of the reorganization of the dentate gyrus following entorhinal cortex lesion in mice
2004-04-01

Abstract Denervation of the dentate gyrus by entorhinal cortex lesion has been widely used to study the reorganization of neuronal circuits following central nervous system lesion. Expansion of the non‐denervated inner molecular layer (commissural/associational zone) of the dentate gyrus and increased acetylcholinesterase‐positive fibre density in the denervated outer molecular layer have commonly been regarded as markers for sprouting following entorhinal cortex lesion. However, because this lesion extensively denervates the outer molecular layer and causes tissue shrinkage, stereological analysis is required for an accurate evaluation of sprouting. To this end we have performed unilateral entorhinal cortex lesions in adult C57BL/6J mice and have assessed atrophy and sprouting in the dentate gyrus using modern unbiased stereological techniques. Results revealed the expected increases in commissural/associational zone width and density of acetylcholinesterase‐positive fibres on single brain sections. Yet, stereological analysis failed to demonstrate concomitant increases in layer volume or total acetylcholinesterase‐positive fibre length. Interestingly, calretinin‐positive fibres did grow beyond the border of the commissural/associational zone into the denervated layer and were regarded as sprouting axons. Thus, our data suggest that in C57BL/6J mice shrinkage of the hippocampus rather than growth of fibres underlies the two morphological phenomena most often cited as evidence of regenerative sprouting following entorhinal cortex lesion. Moreover, our data suggest that regenerative axonal sprouting in the mouse dentate gyrus following entorhinal cortex lesion may be best assessed at the single‐fibre level.
C825T Polymorphism of the G Protein β3 Subunit Is Associated with Obesity but Not with Insulin Sensitivity
2004-04-01

Abstract Objective : The common C825T polymorphism of the gene that encodes the G protein β 3 subunit has been shown to influence lipolysis in human adipocytes and to be associated with hypertension, body fat distribution, and obesity. In addition, it has been shown to be associated with insulin resistance in a small group of hypertensive subjects. We investigated whether this polymorphism contributed to the variability in obesity in our population from southern Germany and whether it was associated with insulin sensitivity of lipolysis and/or glucose disposal. Research Methods and Procedures : We determined percentage body fat, body fat distribution, glucose tolerance [oral glucose‐tolerance test (OGTT)], insulin sensitivity, and serum free fatty acids using data from OGTTs ( N = 774) and clamp (euglycemic hyperinsulinemic clamp, N = 216) in normal and impaired glucose tolerant subjects who were genotyped for this polymorphism. Results : Compared with noncarriers of the C825T mutation, subjects with the C825T variant (prevalence ∼32%) had higher percentage body fat ( p = 0.02) and higher BMI ( p = 0.03). No conclusive effect was seen on serum free fatty acids measured either during fasting or at the end of a 2‐hour OGTT. Insulin sensitivity determined during the OGTT and during the clamp, both adjusted for age, gender, and percentage body fat, was not different between the genotypes ( p = 0.33 and p = 0.48, respectively). Discussion : We have concluded that the C825T polymorphism in the G protein β 3 subunit played an important role in the determination of obesity in this German population. However, it probably had no direct effects on insulin sensitivity of lipolysis and glucose disposal.
On the deep minimum state in the Seyfert galaxy MCG−6-30-15
2004-04-01

(abridged) We present a detailed spectral analysis of the first observation of the Seyfert 1 galaxy MCG-6-30-15 by the European Photon Imaging Camera on board the XMM-Newton observatory, together with contemporaneous data from the Proportional Counter Array on the Rossi X-ray Timing Explorer. Confirming our previously published result, we find that the presence of extremely broadened reflection features from an ionized relativistic accretion disk is required even when one employs the latest X-ray reflection models and includes the effect of complex absorption. The extremely broadened reflection features are also present if the primary continuum is modeled with a thermal Comptonisation spectrum rather than a simple power-law continuum. With this fact established, we examine these data using a relativistic smearing function corresponding to a ``generalized thin accretion disk'' model. We find strong evidence for torquing of the central parts of the accretion disk (presumably through magnetic interactions with the plunging region of the disk and/or the rotating black hole itself). We also perform a study of spectral variability within our observation. We find that the disk reflection features maintain roughly a constant equivalent width with respect to the observed continuum, as predicted by simple reflection models. Taken together with other studies of MCG-6-30-15 that find disk features to possess constant intensity at higher flux states, we suggest that the flux of disk features undergoes a saturation once the source emerges from a Deep Minimum state.
Distances that Perfectly Mislead
2004-04-01

Given a collection of discrete characters (e.g., aligned DNA sites, gene adjacencies), a common measure of distance between taxa is the proportion of characters for which taxa have different character states. Tree reconstruction based on these (uncorrected) distances can be statistically inconsistent and can lead to trees different from those obtained using character-based methods such as maximum likelihood or maximum parsimony. However, in these cases the distance data often reveal their unreliability by some deviation from additivity, as indicated by conflicting support for more than one tree. We describe two results that show how uncorrected (and miscorrected) distance data can be simultaneously perfectly additive and misleading. First, multistate character data can be perfectly compatible and define one tree, and yet the uncorrected distances derived from these characters are perfectly treelike (and obey a molecular clock), only for a completely different tree. Second, under a Markov model of character evolution a similar phenomenon can occur; not only is there statistical inconsistency using uncorrected distances, but there is no evidence of this inconsistency because the distances look perfectly treelike (this does not occur in the classic two-parameter Felsenstein zone). We characterize precisely when uncorrected distances are additive on the true (and on a false) tree for four taxa. We also extend this result to a more general setting that applies to distances corrected according to an incorrect model.
Interaction of a novel dihydropyridine K+ channel opener, A‐312110, with recombinant sulphonylurea receptors and KATP channels: comparison with the cyanoguanidine P1075
2004-04-01

ATP‐sensitive K + channels ( K ATP channels) are composed of pore‐forming subunits (Kir6.x) and of regulatory subunits, the sulphonylurea receptors (SURx). Synthetic openers of K ATP channels form a chemically heterogeneous class of compounds that are of interest in several therapeutic areas. We have investigated the interaction of a novel dihydropyridine opener, A‐312110 ((9 R )‐9‐(4‐fluoro‐3‐iodophenyl)‐2,3,5,9‐tetrahydro‐4 H ‐pyrano[3,4‐b]thieno [2,3‐e]pyridin‐8(7 H )‐one‐1,1‐dioxide), with SURs and Kir6/SUR channels in comparison to the cyanoguanidine opener P1075. In the presence of 1 m M MgATP, A‐312110 bound to SUR2A (the SUR in cardiac and skeletal muscle) and to SUR2B (smooth muscle) with K i values of 14 and 18 n M ; the corresponding values for P1075 were 16 and 9 n M , respectively. Decreasing the MgATP concentration reduced the affinity of A312110 binding to SUR2A significantly more than that to SUR2B; for P1075, the converse was true. At SUR1 (pancreatic β ‐cell), both openers showed little binding up to 100 μ M . In the presence of MgATP, both openers inhibited [ 3 H]glibenclamide binding to the SUR2 subtypes in a biphasic manner. In the absence of MgATP, the high‐affinity component of the inhibition curves was absent. In inside‐out patches, the two openers activated the Kir6.2/SUR2A and Kir6.2/SUR2B channels with similar potency (∼50 n M ). Both were almost 2 × more efficacious in opening the Kir6.2/SUR2B than the Kir6.2/SUR2A channel. The results show that the novel dihydropyridine A‐312110 is a potent K ATP channel opener with binding and channel‐opening properties similar to those of P1075. British Journal of Pharmacology (2004) 141 , 1098–1105. doi: 10.1038/sj.bjp.0705718
A Model-Theoretic Description of Tree Adjoining Grammars1 1The research presented in this paper was supported by the Deutsche Forschungsgemeinschaft within the Sonderforschungsbereich 441, TP A2. The authors wish to thank Jens Michaelis and Stephan Kepser for helpful comments.
2004-04-01

In this paper we show that non-context-free phenomena can be captured using only limited logical means. In particular, we show how to encode a Tree Adjoining Grammar [16] into a weakly equivalent monadic context-free tree grammar (MCFTG). By viewing MCFTG-rules as terms in a free Lawvere theory, we can translate a given MCFTG into a regular tree grammar. The latter is characterizable by both a tree automaton and a corresponding formula in monadic second-order (MSO) logic. The trees of the resulting regular tree language are then unpacked into the intended "linguistic" trees through a model-theoretic interpretation in the form of an MSO transduction based upon tree-walking automata. This two-step approach gives a logical as well as an operational description of the tree sets involved.
Collective atomic recoil lasing
2004-04-01

Abstract A cloud of ultra-cold atoms is loaded into the attractive potential of a light wave that is generated by two counter-propagating modes of a high-finesse ring resonator. The two modes are coupled by the atoms due to coherent Rayleigh scattering and generate a potential which acts back on the motion of the atoms. This feedback leads to a new frequency component and can be described in terms of the long time proposed collective atomic recoil laser (CARL). This model is investigated experimentally and extended by introducing an optical friction force acting on the atoms. This allows for steady state operation of the CARL. Furthermore, it leads to a threshold behaviour of the CARL that translates into a novel type of phase transition: while passing the threshold the initially homogeneous atomic distribution is bunched in space and velocity. With this behaviour the system turns out to acquire some of the main features of the so-called Kuramoto model which provides a very general description of a network of limit cycle oscillators.
Molecular imaging: Bridging the gap between neuroradiology and neurohistology.
2004-04-01

Historically, in vivo imaging methods have largely relied on imaging gross anatomy. More recently it has become possible to depict biological processes at the cellular and molecular level. These new research methods use magnetic resonance imaging (MRI), positron emission tomography (PET), near-infrared optical imaging, scintigraphy, and autoradiography in vivo and in vitro. Of primary interest is the development of methods using MRI and PET with which the progress of gene therapy in glioblastoma (herpes simplex virus-thymidine kinase) and Parkinson's disease can be monitored and graphically displayed. The distribution of serotonin receptors in the human brain and the duration of serotonin-receptor antagonist binding can be assessed by PET. With PET, it is possible to localize neurofibrillary tangles (NFTs) and beta-amyloid senile plaques (APs) in the brains of living Alzheimer disease (AD) patients. MR tracking of transplanted oligodendrocyte progenitors is feasible for determining the extent of remyelinization in myelin-deficient rats. Stroke therapy in adult rats with subventricular zone cells can be monitored by MRI. Transgene expression (beta-galactosidase, tyrosinase, engineered transferrin receptor) can also be visualized using MRI. Macrophages can be marked with certain iron-containing contrast agents which, through accumulation at the margins of glioblastomas, ameliorate the visual demarcation in MRI. The use of near-infrared optical imaging techniques to visualize matrix-metalloproteinases and cathepsin B can improve the assessment of tumor aggressiveness and angiogenesis-inhibitory therapy. Apoptosis could be detected using near-infrared optical imaging representation of caspase 3 activity and annexin B. This review demonstrates the need for neurohistological research if further progress is to be made in the emerging but burgeoning field of molecular imaging.