julilili42/papers huggingface dataset:
UDP-Glucuronosyltransferase (UGT) Polymorphisms Affect Atorvastatin Lactonization In Vitro and In Vivo
2009-09-30

The response to statins shows large interpatient variability. Atorvastatin delta-lactone is pharmacologically inactive but has been associated with toxicity. We investigated the role of UDP-glucuronosyltransferases (UGTs) in atorvastatin lactonization. In human liver microsomes, lactonization was correlated with UGT1A3 (r(s) = 0.61, P < 0.0001) but not with UGT1A1. Surprisingly, lactone formation was significantly higher in carriers of UGT1A1*28, an allele that is associated with lower UGT1A1 expression. We show that this inverse correlation is due to extensive linkage disequilibrium in the UGT1A locus and that several UGT1A3 haplotypes are associated with strong increases in UGT1A3 expression in vitro. Analyses of the pharmacokinetic parameters of atorvastatin and metabolites in genotyped volunteers confirmed that there is an increase in atorvastatin lactonization in carriers of UGT1A3*2 in vivo. The potential of UGT genotyping to identify patients who are at increased risk for failure of therapy and/or adverse effects of statins warrants further investigation.
Medical Antihyperglycaemic Treatment of Type 2 Diabetes Mellitus
2009-10-01

Foreword 522 1. Antihyperglycaemic treatment of type 2 diabetes mellitus 523 1.1 Oral antidiabetic drugs 523 1.1.1 Non-β-cytotropic oral antidiabetic drugs 523 1.1.1.1 Metformin 523 1.1.1.2 Alpha-glucosidase inhibitors (acarbose, miglitol) 526 1.1.1.3 PPAR-γ-ligands (rosiglitazone, pioglitazone) 528 1.1.1.4 Combination therapy with non-β-cytotropic oral antidiabetic drugs 531 1.1.2 β-cytotropic medications: potassium channel blockers 531 1.1.2.1 Sulphonylureas 531 1.1.2.2 Sulphonylurea analogues (repaglinide, nateglinide) 533 1.1.2.3 Combination therapy with non-β-cytotropic oral antidiabetic drugs 534 1.1.3 DPP-4 inhibitors 534 1.2. Injectable therapies 538 1.2.1 Incretin mimetics (exenatide) 538 1.2.2 Insulin therapy 539 1.2.2.1 Indication 539 1.2.2 2 Blood glucose self-monitoring 540 1.2.2.3 Application 540 1.2.2.4 Insulin administration 540 1.2.2.5 Conventional therapy 540 1.2.2.6 Intensified conventional insulin therapy 541 1.2.2.7 Combination treatment with insulin and oral antidiabetic drugs 541 1.2.2.8 Side-effects of insulin therapy 542 2. Flowchart of antihyperglycaemic treatment of type 2 diabetes 543 2.1 Legend to flowchart 544 3. References 545 4. Appendix 1: Statement by the DDG regarding the results of the ACCORD and ADVANCE trials 553
Strengths and Weaknesses of Diagnostic Tools for Tuberculous Uveitis
2009-10-01

Diagnostic criteria for tuberculous uveitis encompass exclusion of other known etiologies of uveitis, suggestive clinical history and signs, supportive systemic investigations, positive response to empiric antituberculosis treatment and evidence of Mycobacterium tuberculosis or its DNA in ocular fluids/tissues. Recent advances in diagnostic tools for tuberculous infection, including molecular biology techniques for detection of M. tuberculosis DNA and interferon-gamma release assays, have improved the specificity of the diagnosis and the ability to ascertain exposure to the infectious agent. However even with such advances, establishing the diagnosis of tuberculous uveitis remains a challenging issue because each of these available investigations has its strengths and limitations and tuberculous infection can present with clinical features of any type of extraocular or intraocular inflammation. This article critically analyzes the role of these tests in supporting the diagnosis of tuberculous uveitis and proposes a practical diagnostic approach, based on a judicious combination of these tests.
Suppression of Map Kinases Inhibits Microglial Activation and Attenuates Neuronal Cell Death Induced by α-Synuclein Protofibrils
2009-10-01

α-Synuclein (α-Syn) accounts, as a major component of Lewy bodies (LB), for the filamentous deposits in many cases of neurodegenerative diseases. Yet, little is known about the molecular mechanisms of neuronal loss in these diseases. The correlation between α-Syn oligomerization/aggregation and pathologies raises the key question of which molecular form of α-Syn (i.e. monomeric α-Syn, protofibrils or mature fibrils) represents the damage-inducing culprit in the scenario of synucleinopathies. We show that human α-Syn protofibrils (PFs) are potent activators of parallel proinflammatory signalling pathways (p38 and ERK1/2 MAP kinases and NF-κB) in microglial cells in vitro. Furthermore, stereotactic injection of α-Syn PFs into the substantia nigra of adult rats leads to a profound activation of microglia and adjacent neuronal cell loss, which can be attenuated by the MAP kinase inhibitor semapimod. We propose that the neurodegenerative process of α-synucleinopathies involves microglial activation through α-Syn released or extruded from cells with pathogenic α-Syn metabolism. Compounds that inhibit the MAPK/NF-κB pathways might be a promising pharmacological strategy for the treatment of the inflammatory component of synucleinopathies including PD.
Suppression of KATP channel activity protects murine pancreatic β cells against oxidative stress
2009-10-01

The enhanced oxidative stress associated with type 2 diabetes mellitus contributes to disease pathogenesis. We previously identified plasma membrane-associated ATP-sensitive K+ (KATP) channels of pancreatic beta cells as targets for oxidants. Here, we examined the effects of genetic and pharmacologic ablation of KATP channels on loss of mouse beta cell function and viability following oxidative stress. Using mice lacking the sulfonylurea receptor type 1 (Sur1) subunit of KATP channels, we found that, compared with insulin secretion by WT islets, insulin secretion by Sur1-/- islets was less susceptible to oxidative stress induced by the oxidant H2O2. This was likely, at least in part, a result of the reduced ability of H2O2 to hyperpolarize plasma membrane potential and reduce cytosolic free Ca2+ concentration ([Ca2+]c) in the Sur1-/- beta cells. Remarkably, Sur1-/- beta cells were less prone to apoptosis induced by H2O2 or an NO donor than WT beta cells, despite an enhanced basal rate of apoptosis. This protective effect was attributed to upregulation of the antioxidant enzymes SOD, glutathione peroxidase, and catalase. Upregulation of antioxidant enzymes and reduced sensitivity of Sur1-/- cells to H2O2-induced apoptosis were mimicked by treatment with the sulfonylureas tolbutamide and gliclazide. Enzyme upregulation and protection against oxidant-induced apoptosis were abrogated by agents lowering [Ca2+]c. Sur1-/- mice were less susceptible than WT mice to streptozotocin-induced beta cell destruction and subsequent hyperglycemia and death, which suggests that loss of KATP channel activity may protect against streptozotocin-induced diabetes in vivo.
Intra-Cystic Drug Concentration of Albendazole Sulphoxide in Patients with Echinococcus granulosus Cysts
2009-10-01

Albendazole therapy—alone or in combination with surgery—remains the standard of care for human echinococcosis depending on the stage of disease. However, only limited data are available on target site concentrations in liver cysts and data for non-liver cysts are lacking. We report on intra-cystic concentrations of the biologically active metabolite albendazole sulphoxide in non-liver cysts indicating a relative intra-cystic drug concentration of 48–156% compared with plasma levels. These data are evidence for a satisfactory penetration of albendazole sulphoxide into Echinococcus cysts localized in other organs than the liver and underline the usefulness of albendazole therapy for this indication.
Two New Plastomenine Softshell Turtles from the Paleocene of Montana and Wyoming
2009-10-01

The many fossil turtle remains collected by Princeton University throughout the 1950s and 1960s from Paleocene sediments in Montana and Wyoming include two new species of plastomenine softshell turtles (Trionychidae) that are referred to Hutchemys gen. nov., which corresponds to the previously used informal taxon "Plastomenine Type A." Hutchemys is unique among trionychids in having a broadly rounded entoplastron that is underlain by a large rectangular callosity and fully immobilized through lateral processes of the hyoplastra. Hutchemys rememdium sp. nov. is documented by specimens from the Torrejonian of Montana and the Tiffanian of Wyoming, whereas Hutchemys arctochelys sp. nov. is only known from a collection of shells from a single Clarkforkian locality in Montana. The holotype of a third taxon, Aspideretes nassau Hay 1908, is diagnostic for Hutchemys, but cannot be diagnosed to the species level and is thus considered a nomen dubium. A phylogenetic analysis places the new species in a clade that is sister to Plastomenus aff. thomasii along the phylogenetic stem of Cydanorbinae, thus tentatively confirming monophyly of Plastomeninae and a close relationship to cyclanorbines. However, given that many supposedly diagnostic postcranial characters of Plastomeninae are often found among trionychines as well, in particular characters pertaining to the extensively ossified plastron, we suggest that a wide and rounded entoplastron is a more useful character in diagnosing this clade. Representatives of Hutchemys seem to have preferred swampy habitats and their shell converges on that of testudinoid or pleurodiran pond turtles in the degree of ossification and the presence of an anterior plastral hinge.
Nucleophilic Aromatic Substitution with 2,3-Dihydro-1,3-diisopropyl- 4,5-dimethylimidazol-2-ylidene
2009-10-01

2,3-Dihydro-1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene (1) reacts with an excess of hexafluorobenzene in the presence of boron trifluoride diethyletherate to give 1,3-diisopropyl-4,5- dimethyl-2-(perfluorophenyl)imidazolium tetrafluoroborate (2). Solutions of 2 exhibit an equilibrium consisting also of hexafluorobenzene and 2,2ʹ-(perfluoro-1,4-phenylene)bis(1,3-diisopropyl- 4,5-dimethylimidazolium)bis(tetrafluoroborate) (3) which is obtained from 1 and hexafluorobenzene in the ratio 2 : 1 on a preparative scale. Similar to 2, 2-(4-cyano-2,3,5,6-tetrafluorophenyl)-1,3- diisopropyl-4,5-dimethylimidazolium tetrafluoroborate (4), 2-(2,4-dicyano-2,5,6-trifluorophenyl)- 1,3-diisopropyl-4,5-dimethylimidazolium tetrafluoroborate (5), and 2-(4,6-difluoro-1,3,5-triazin-2- yl)-1,3-diisopropyl-4,5-dimethylimidazolium tetrafluoroborate (6) are obtained from 1 and perfluorobenzonitrile, 1,3-dicyano-2,4,5,6-tetrafluorobenzene, and 2,4,6-trifluoro-1,3,5-triazin, respectively. The FAB mass spectra of compounds 2 - 6 and the results of the crystal structure analyses of compounds 2 - 4 are discussed.
Misleading functional magnetic resonance imaging mapping of the cortical hand representation in a 4-year-old boy with an arteriovenous malformation of the central region
2009-10-01

Functional MR imaging is dependent on the hemodynamic response function of the brain. Cerebrovascular anomalies may lead to hemodynamic artifacts, contorting the true localization of neural activation. This is illustrated in the case of a 4-year-old boy with an arteriovenous malformation (AVM) of the left central region undergoing extensive functional mapping prior to surgical removal. Intraoperative electrophysiological recording confirmed presurgical results of magnetoencephalography (MEG) and transcranial magnetic stimulation (TMS) examinations, detecting the sensorimotor hand representation within the brain tissue into which the AVM extended, whereas the activation demonstrated by functional MR (fMR) imaging was proven to be falsely localized by that modality, which showed it to be posterior to the affected central region. Thus, this case demonstrates that functional mapping can be performed even in very young patients and that combining fMR imaging with TMS and MEG is especially important in patients with vascular lesions, in whom fMR imaging can be misleading due to changes in blood flow.
Cytolytic toxins as triggers of plant immune response
2009-10-01

NEP1-like proteins (NLPs) are secreted proteins from fungi, oomycetes and bacteria, triggering immune responses and cell death in dicotyledonous plants. It has been unclear for a long time, whether NLPs are toxins or triggers of plant immunity. In a recent study we report that NLPs are toxins that exert cytolytic activity on dicotyledonous plants. Mutational analysis revealed a causal link between membrane damaging, cell death inducing and virulence promoting properties of NLPs. Interestingly, also induction of immune responses by NLPs required the same protein fold, providing evidence for damage-induced immunity in plants. Structural similarity to pore forming toxins from marine invertebrates allows the proposal of a model for the mode of NLP interaction with the host's membrane.
Purification and Characterization of Tyrosinases from Streptomyces albus
2009-10-01

The bacterium Streptomyces albus has so far never been investigated for tyrosinase activity. The studies presented in this communication show that this bacterium may be a future source for larger production of tyrosinase. The enzyme was purified starting with 5,600 ml of culture filtrate. The crude enzyme was first purified by centrifugation, followed by ammonium sulfate precipitation and ultrafiltration. Then, melanin was removed applying a Servacell DEAE 52 resin, using the batch technique. Thereafter, the crude enzyme was loaded on a SEC Sephacryl S-100 column and, after ultrafiltration, 1.17 mg of purified tyrosinase were obtained. The molecular mass of the purified enzyme was determined by MALDI mass spectrometry to be 30,096 Da which corresponds to the obtained results from SDS-PAGE. Using the diphenol L-DOPA and the monophenol L-tyrosine as substrates, the kinetic parameters for both substrates, K m = 7.8 mM and 0.5 mM and k cat /K m = 157 mM -1 s -1 and 23 mM -1 s -1 , respectively, were determined. Maximal activities of the purified enzyme were recorded at pH 7.0. Long-term experiments with Streptomyces albus tyrosinase revealed that storage of the lyophilized enzyme sample at temperatures below zero turned out to be the best. For tyrosinase in buffer containing 20% glycerol, no loss of activity was observed at 4°C and - 60°C
Visual steering of UAV in unknown environments
2009-10-01

In this paper, we propose a novel approach for the visual navigation of unmanned aerial vehicles (UAV). In contrast to most available methods, a single perspective camera is used to estimate the complete set of 3D motion parameters undergone by the UAV. We establish robust point correspondences between consecutive image frames captured by the flying vehicle. Based on the estimated motion parameters as well as the reconstructed relative scene depth, a visual steering algorithm has been realized so that the UAV is capable of avoiding obstacles during navigation. The advantage of our approach lies in the fact that decision for collision avoidance is made immediately, by using purely visual information extracted from the live video sequence. Furthermore, it eliminates the time-consuming steps of explicit obstacle recognition and global reconstruction of the environment. Experimental evaluation has been carried out based on computer simulation as well as using a commercially available flying drone. It has been shown that the UAV is capable of autonomous navigation in unknown environments with arbitrary configuration of obstacles.
Particle filter-based trajectory estimation with passive UHF RFID fingerprints in unknown environments
2009-10-01

In this paper we present a novel approach to estimating the trajectory of a robot by means of inexpensive passive RFID tags and odometry in unknown environments. We show how trajectory estimation, a prerequisite of mapping RFID transponder positions without a reference positioning system, can be achieved using a particle filter. The presented technique is based on a non-parametric model of spatial relationships between RFID measurements. It overcomes the noisy nature of RFID measurements and the absence of distance and bearing information. The accuracy of our method is investigated in a series of experiments with a mobile robot.
Automated segmentation of adipose tissue in magnetic resonance images of the whole body
2009-10-01

The amount and the bodily distribution of different adipose tissue (AT) compartments are important indicators for the risk of obesity-related diseases and play an important role in the investigation of their pathogenesis. Magnetic resonance imaging can be used to acquire images of the whole body, showing these compartments and their distribution. In this article, an automated segmentation algorithm is presented, being able to create tissue profiles of the whole body for tissue classes subcutaneous AT, visceral AT and total tissue. The images are segmented using a fuzzy c-means algorithm, which considers partial volume effects. A separation of the body into anatomic regions along the body axis is done to define regions with visceral AT present. In abdominal image slices, the AT compartments are divided into subcutaneous and visceral compartments using an active contour algorithm. The slice-wise areas of different tissues are plotted against the slice position to obtain their topography. The automatically obtained tissue profiles were compared to profiles created manually by an expert and show high correlation coefficients, indicating similar topography. Absolute error values were calculated for evaluation of the algorithm's absolute accuracy. These show low overall mean values for the classes of total tissue (4.48%) and visceral AT (3.26%). The deviation of total AT (sum of visceral and subcutaneous AT) was higher though (8.71%). Whole examination and analysis time is reduced to less than half an hour.
Spillovers from Multinationals to Heterogeneous Domestic Firms: Evidence from Hungary
2009-10-01

Firms cluster their economic activities to exploit technological and informational spillovers from other firms. Spillovers through the entry of multinational firms can be particularly beneficial to domestic firms because of their technological superiority. Yet, the importance of foreign firm's spillovers might depend on two key features of domestic firms: their productivity level and its export status. In line with theories and empirical evidence on the absorptive capacity of firms, we argue on the basis of an empirical analysis of Hungarian firms that larger and more productive firms are more able to reap spillovers from multinationals firms than smaller firms. The export status, in contrast, is of minor importance.
Production chain of isotopically modified ge-diodes for the 2β0ν-search with GERDA
2009-10-01

The procurement of Germanium-oxide (GeO2) depleted in 76Ge is presented. The quality control, the reduction and zone refinement as well as crystal pulling is described as new detection systems must be explored in order to reach the needs of modern rare event searches. The experiment GERDA aims at the detection of neutrinoless double beta (2-beta-0-neutrino) decay. The depleted Germanium project aims at the demonstration that working BEGe detectors can be produced based on a realistic material supply chain maximizing the Ge-metal to Ge-diode yield in an optimal usage of the expensive isotopically modified material.
Oscillations and instabilities of fast rotating neutron stars
2009-10-01

We present our results of our study of the oscillations and instabilities of rapidly rotating relativistic stars in the Cowling approximation. This is the first study of its kind and provides information on the effect of fast rotation on the oscillation spectra while it offers the possibility in studying the complete problem by including spacetime perturbations. Our study includes both axisymmetric and non-axisymmetric perturbations and provides limits for the onset of the secular bar mode rotational instability. We also present approximate formulae for the dependence of the oscillation spectrum from rotation. The results suggest that it is possible to extract the relativistic star's parameters from the observed gravitational wave spectrum.
Alfvén QPOs in Magnetars
2009-10-01

We investigate torsional Alfvén oscillations of relativistic stars with a global dipole magnetic field, via 2D numerical simulations. We find that a) there exist two families of quasi-periodic oscillations (QPOs) with harmonics at integer multiples of the fundamental frequency, b) the lower-frequency QPO is related to the region of closed field lines, near the equator, while the higher-frequency QPO is generated near the magnetic axis, c) the QPOs are long-lived, d) for the chosen form of dipolar magnetic field, the frequency ratio of the lower to upper fundamental QPOs is about 0.6, independent of the equilibrium model or of the strength of the magnetic field, and e) within a representative sample of EOSs and of various magnetar masses, the Alfvén QPO frequencies are given by accurate empirical relations that depend only on the compactness of the star and on the magnetic field strength. Compared to the observational frequencies, we also obtain an upper limit on the strength of magnetic field of SGR 1806-20 (if it is dominated by a dipolar component) between ~ 3 and 7×1015 Gauss.
Reputation Concerns and Herd Behavior of Audit Committees - A Corporate Governance Problem
2009-10-01

This paper offers an explanation for audit committee failures within a corporate governance context. We consider a setting in which the management of a firm sets up financial statements that are possibly biased. These statements are reviewed/audited by an external auditor and by an audit committee. Both agents report the result of their audit, the auditor acting first. The auditor and the audit committee use an imperfect auditing technology. As a result of their work they privately observe a signal regarding the quality of the financial statements. The probability for a correct signal in the sense that an unbiased report is labeled correct and a biased one incorrect, depends on the type of the agent. Good as well as bad agents exist in the economy. Importantly, two good agents observe identical informative signals while the signal observed by a bad agent is uninformative and uncorrelated to those of other good or bad agents.The audit committee as well as the auditor are anxious to build up reputation regarding their ability in the labor market. Given this predominate goal they report on the signal in order to maximize the market ́s assessment of their ability. At the end of the game the true character of the financial statements is revealed to the public with some positive probability. The market uses this information along with the agents ́ reports to update beliefs about the agents ́ types. We show that a herding equilibrium exists in which the auditor reports based on his signal but the audit committee "herds" and follows the auditor ́s judgement no matter what its own insights suggest. This results holds even if the audit committee members are held liable for detected failure. However, performance based bonus payments induce truthful reporting at least in some cases.