julilili42/papers huggingface dataset:
Impact of Variation in the FTO Gene on Whole Body Fat Distribution, Ectopic Fat, and Weight Loss
2008-06-05

Polymorphisms in the fat mass‐ and obesity‐associated ( FTO ) gene have been identified to be associated with obesity and diabetes in large genome‐wide association studies. We hypothesized that variation in the FTO gene has an impact on whole body fat distribution and insulin sensitivity, and influences weight change during lifestyle intervention. To test this hypothesis, we genotyped 1,466 German subjects, with increased risk for type 2 diabetes, for single‐nucleotide polymorphism rs8050136 in the FTO gene and estimated glucose tolerance and insulin sensitivity from an oral glucose tolerance test (OGTT). Distribution of fat depots was quantified using whole body magnetic resonance (MR) imaging and spectroscopy in 298 subjects. Two‐hundred and four subjects participated in a lifestyle intervention program and were examined after a follow‐up of 9 months. In the cross‐sectional analysis, the A allele of rs8050136 in FTO was associated with a higher BMI, body fat, and lean body mass (all P &lt; 0.001). There was a significant effect of variation in the FTO gene on subcutaneous fat ( P ≤ 0.05) and a trend for liver fat content, nonvisceral adipose tissue, and visceral fat (all P ≤ 0.1). However, the single‐nucleotide polymorphism was not associated with insulin sensitivity or secretion independent of BMI (all P &gt; 0.05). During lifestyle intervention, there was also no influence of the FTO polymorphism on changes in body weight or fat distribution. In conclusion, despite an association with BMI and whole body fat distribution, variation in the FTO locus has no effect on the success of a lifestyle intervention program.
Design, Synthesis, and Biological Evaluation of Novel 3-Aryl-4-(1H-indole-3yl)-1,5-dihydro-2H-pyrrole-2-ones as Vascular Endothelial Growth Factor Receptor (VEGF-R) Inhibitors
2008-06-05

In this study we report on the design, synthesis, and biological evaluation of pyrrole-2-one 2 to be a highly potent VEGF-R2/3 inhibitor with IC 50 of 31/37 nM. The novel 3,4-diaryl-2 H-pyrrole-2-ones were designed on the basis of the modeled binding mode of the corresponding 1 H-pyrrole-2,5-dione (maleimide) VEGF-R2/3 inhibitor 1 indicating two H-bond ligand-protein interactions in the ATP pocket for the amide 2 but not for the isomer 3. Flexible synthetic routes to 3,4-diaryl-2 H-pyrrole-2-ones and structure-activity relationships for the compounds in a panel of 24 therapeutically relevant protein kinases (IC 50 values) are presented. Accordingly to the in vitro data, compounds 1 and 2 were found to possess highly potent antiangiogenic activities in the cellular HLMEC sprouting assay and also slightly induced apoptosis in HDMECs whereas 3 was determined to be significantly less active. Hence, the pyrrole-2-one moiety was dissected from the corresponding maleimide protein kinase inhibitor as a suitable key pharmacophore.
M2 Muscarinic Receptors Induce Airway Smooth Muscle Activation via a Dual, Gβγ-mediated Inhibition of Large Conductance Ca2+-activated K+ Channel Activity
2008-06-05

Airway smooth muscle is richly endowed with muscarinic receptors of the M(2) and M(3) subtype. Stimulation of these receptors inhibits large conductance calcium-activated K(+) (BK) channels, a negative feed back regulator, in a pertussis toxin-sensitive manner and thus facilitates contraction. The underlying mechanism, however, is unknown. We therefore studied the activity of bovine trachea BK channels in HEK293 cells expressing the M(2) or M(3) receptor (M(2)R or M(3)R). In M(2)R- but not M(3)R-expressing cells, maximal effective concentrations of carbamoylcholine (CCh) inhibited whole cell BK currents by 53%. This M(2)R-induced inhibition was abolished by pertussis toxin treatment or overexpression of the Gbetagamma scavenger transducin-alpha. In inside-out patches, direct application of 300 nm purified Gbetagamma decreased channel open probability by 55%. The physical interaction of Gbetagamma with BK channels was confirmed by co-immunoprecipitation. Interestingly, inhibition of phospholipase C as well as protein kinase C activities also reversed the CCh effect but to a smaller (approximately 20%) extent. Mouse tracheal cells responded similarly to CCh, purified Gbetagamma and phospholipase C/protein kinase C inhibition as M(2)R-expressing HEK293 cells. Our results demonstrate that airway M(2)Rs inhibit BK channels by a dual, Gbetagamma-mediated mechanism, a direct membrane-delimited interaction, and the activation of the phospholipase C/protein kinase C pathway.
Impact of the Meissner effect on magnetic microtraps for neutral atoms near superconducting thin films
2008-06-05

We theoretically evaluate changes in the magnetic potential arising from the magnetic field near superconducting thin films. An example of an atom chip based on a three-wire configuration has been simulated in the superconducting and the normal conducting state. Inhomogeneous current densities within the superconducting wires were calculated using an energy-minimization routine based on the London theory. The Meissner effect causes changes to both trap position and oscillation frequencies at short distances from the superconducting surface. Superconducting wires produce much shallower micro traps than normal conducting wires. The results presented in this paper demonstrate the importance of taking the Meissner effect into account when designing and carrying out experiments on magnetically trapped neutral atoms near superconducting surfaces.
Online Coupling of Gas Chromatography to Nuclear Magnetic Resonance Spectroscopy: Method for the Analysis of Volatile Stereoisomers
2008-06-06

The identification of volatile cis/trans-stereoisomers was accomplished by employing a hyphenated GC-NMR system. The chromatographic and spectroscopic conditions were optimized with respect to the (1)H NMR detection. A special processing technique was developed to handle the recorded NMR spectra in the gas phase with very low sample amounts. The processed stopped-flow (1)H NMR spectra of the investigated chromatographic peaks unequivocally revealed the structure of the corresponding compounds.
NagA-Dependent Uptake ofN-Acetyl-Glucosamine andN-Acetyl-Chitin Oligosaccharides across the Outer Membrane ofCaulobacter crescentus
2008-06-07

ABSTRACT Among the 67 predicted TonB-dependent outer membrane transporters of Caulobacter crescentus , NagA was found to be essential for growth on N -acetyl-β- d -glucosamine (GlcNAc) and larger chitin oligosaccharides. NagA (93 kDa) has a predicted typical domain structure of an outer membrane transport protein: a signal sequence, the TonB box EQVVIT, a hatch domain of 147 residues, and a β-barrel composed of 22 antiparallel β-strands linked by large surface loops and very short periplasmic turns. Mutations in tonB1 and exbBD , known to be required for maltose transport via MalA in C. crescentus , and in two additional predicted tonB genes (open reading frames cc2327 and cc3508) did not affect NagA-mediated GlcNAc uptake. nagA is located in a gene cluster that encodes a predicted PTS sugar transport system and two enzymes that convert GlcNAc-6-P to fructose-6-P. Since a nagA insertion mutant did not grow on and transport GlcNAc, diffusion of GlcNAc through unspecific porins in the outer membrane is excluded. Uptake of GlcNAc into tonB and exbBD mutants and reduction but not abolishment of GlcNAc transport by agents which dissipate the electrochemical potential of the cytoplasmic membrane (0.1 mM carbonyl cyanide 3-chlorophenylhydrazone and 1 mM 2,4-dinitrophenol) suggest diffusion of GlcNAc through a permanently open pore of NagA. Growth on (GlcNAc) 3 and (GlcNAc) 5 requires ExbB and ExbD, indicating energy-coupled transport by NagA. We propose that NagA forms a small pore through which GlcNAc specifically diffuses into the periplasm and functions as an energy-coupled transporter for the larger chitin oligosaccharides.
Methyl 4-[5-(4-fluorophenyl)-4-(pyridin-4-yl)-1H-imidazol-2-ylsulfanyl]butanoate
2008-06-07

The title compound, C(19)H(18)FN(3)O(2)S, was synthesized in the course of studies on 2-alkyl-sufanylimidazoles as p38 mitogen-activated protein kinase inhibitors. The synthesis was achieved by nucleophilic substitution of 4-(4-fluoro-phen-yl)-5-(pyridin-4-yl)-1,3-dihydro-imidazole-2-thione with methyl 4-bromo-butanoate. The five-membered heterocycle makes dihedral angles of 32.4 (2) and 18.3 (2)° with the fluoro-phenyl and pyridinyl rings, respectively, indicating a low degree of conjugation between these rings. Intra-molecular C-H⋯N and inter-molecular N-H⋯N hydrogen bonds as well as C-H⋯π inter-actions seem to be effective in stabilization of the crystal structure.
High-performance timing simulation of embedded software
2008-06-08

This paper presents an approach for cycle-accurate simulation of embedded software by integration in an abstract SystemC model. Compared to existing simulation-based approaches, we present a hybrid method that resolves performance issues by combining the advantages of simulation-based and analytical approaches. In a first step, cycle-accurate static execution time analysis is applied at each basic block of a cross-compiled binary program using static processor models. After that, the determined timing information is back-annotated into SystemC for fast simulation of all effects that can not be resolved statically. This allows the consideration of data dependencies during run-time and the incorporation of branch prediction and cache models by efficient source code instrumentation. The major benefit of our approach is that the generated code can be executed very efficiently on the simulation host with approximately 90% of the speed of the untimed software without any code instrumentation.
Occupational Noise, Smoking, and a High Body Mass Index are Risk Factors for Age-related Hearing Impairment and Moderate Alcohol Consumption is Protective: A European Population-based Multicenter Study
2008-06-09

A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average [PTA]) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high as well as in the low frequencies. The results suggest that a healthy lifestyle can protect against age-related hearing impairment.
Effect of Bevacizumab on Inflammation and Proliferation in Human Choroidal Neovascularization
2008-06-09

Unexpectedly, CNVM from patients treated by bevacizumab are characterized by significantly high inflammatory and proliferative activity and enhanced endostatin expression. These characteristics need to be considered when protocols for combination therapies are established.
Chiral corrections to the vector and axial couplings of quarks and baryons
2008-06-09

We calculate chiral corrections to the semileptonic vector and axial quark coupling constants using a manifestly Lorentz covariant chiral quark approach up to order O(p4) in the two- and tree-flavor picture. These couplings are then used in the evaluation of the corresponding couplings which govern the semileptonic transitions between octet baryon states. In the calculation of baryon matrix elements we use a general ansatz for the spatial form of the quark wave function, without referring to a specific realization of hadronization and confinement of quarks in baryons. Matching the physical amplitudes calculated within our approach to the model-independent predictions of baryon chiral perturbation theory (ChPT) allows one to deduce the connection between our parameters and those of baryon ChPT.
Intestinal Colonization of IL-2 Deficient Mice with Non-Colitogenic B. vulgatus Prevents DC Maturation and T-Cell Polarization
2008-06-10

From this data we conclude that the B. vulgatus triggered IL-6 secretion by LP DC in absence of proinflammatory cytokines such as IL-12 or TNF-alpha induces a semi-mature LP DC phenotype, which might prevent T-cell activation and thereby the induction of colitis in IL-2(-/-)-mice. The data provide new evidence that IL-6 might act as an immune regulatory cytokine in the mucosa by targeting intestinal DC.
Indoor Positioning via Three Different RF Technologies
2008-06-10

The continuous tracking of mobile systems via active or passive RFID is a desirable but difficult to achieve objective. In this paper, we present our experimental results of positioning techniques using passive UHF RFID, Bluetooth, and WLAN. We thereby employ three orthogonal measuring techniques: detection rates, signal strength, and round trip time. The orthogonality of the methods is designed to achieve robustness to noise and unforeseen changes in the surroundings. Moreover, due to their different read ranges, the technologies can complement each other at different scales of the environment.
Metastasizing epithelioid hemangioendothelioma of the nose in childhood
2008-06-10

Epithelioid hemangioendothelioma (EHE) arising in the skin is extremely rare, and the majority of documented cases have developed in soft tissues or parenchymatous organs. We report on a 9‐year‐old boy who presented with a painful erythematous plaque on the nose. Histopathological findings showed a dermal tumor composed of epithelioid cells with moderate cellular atypia and characteristic intracytoplasmic vacuoles. Immunohistochemical stainings confirmed the vascular nature of the tumor. On the basis of these findings, the diagnosis of an EHE was made. Then, two cervical lymph nodes were excised and adjuvant therapy with interferon alpha 2b was initiated. Eighteen months after diagnosis, there is no evidence of local tumor recurrence or metastases. To our knowledge, this is the first report of a metastasizing cutaneous EHE on the nose in childhood. As our case shows, this rare tumor entity has to be considered as a differential diagnosis in neoplasms of the skin, even in childhood.
Integrated Scenario for Machine-Aided Inventory Using Ambient Sensors
2008-06-10

We present a novel complete system for machine-aided inventory. Our system covers automatic product identification using RFID, localization based on ambient sensors, the enrichment of raw RFID data with product information from ERP (Enterprise Resource Planning) backend systems and real-time augmented reality (AR) visualization. We have integrated all of these components into a real-world demonstrator resembling a supermarket and successfully presented the system in the scope of an industry workshop.
TREM2 is upregulated in amyloid plaque‐associated microglia in aged APP23 transgenic mice
2008-06-12

Abstract Alzheimer's disease (AD) is characterized by extracellular deposits of amyloid‐β protein which attract dense clusters of microglial cells. Here, we analyzed amyloid plaque‐associated areas in aged APP23 transgenic mice, an animal model of AD, by combining laser microdissection with microarray analysis and quantitative RT‐PCR (qPCR). By comparing gene expression profiles, we found that 538 genes (1.3% of a total of 41,234 analyzed genes) were differentially expressed in plaque‐associated versus plaque‐free tissue of aged APP23 transgenic mice. One of these genes is the microglia‐associated triggering receptor expressed on myeloid cells (TREM2) which enhances phagocytosis, but abrogates cytokine production as well as TLR and Fc receptor‐mediated induction of TNF secretion. Western Blot analysis demonstrated an upregulation of TREM2 protein in APP23 transgenic compared with nontransgenic mice. Confocal imaging studies, furthermore, confirmed colocalization of TREM2 protein with microglia. Thus, when TREM2 is induced on microglia in plaque‐loaded brain areas the respective signaling may prevent inflammation‐induced bystander damage of neurons. At the same time, TREM2 signaling may also account for the failure to sufficiently eliminate extracellular amyloid with the help of a systemic immune response. © 2008 Wiley‐Liss, Inc.
Periplasmic chaperone FkpA is essential for imported colicin M toxicity
2008-06-12

Summary Chaperones facilitate correct folding of newly synthesized proteins. We show here that the periplasmic FkpA chaperone is required for killing Escherichia coli by colicin M entering cells from the outside. Highly active colicin M preparations were inactive against fkpA mutant cells; 10 4 ‐fold dilutions killed fkpA + cells. Three previously isolated spontaneous mutants tolerant to colicin M carried a stop codon or an IS 1 insertion in the peptidyl‐prolyl‐ cis‐trans ‐isomerase (PPIase) domain (C‐domain) of FkpA, which resulted in deletion of the domain. A randomly generated mutant carried a G148D mutation in the C‐domain. A temperature‐sensitive mutant tolerant to colicin M carried a Y25N mutation in the FkpA N‐domain. Mutants transformed with wild‐type fkpA were colicin M‐sensitive. Isolated FkpA‐His reduced colicin M‐His cleavage by proteinase K and renatured denatured colicin M‐His in vitro ; renaturation was prevented by the PPIase inhibitor FK506. In both assays, periplasmic SurA‐His had no effect. No other tested periplasmic chaperone could activate colicin M. Among the tested colicins, only colicin M required FkpA for activity. Colicin M bound to cells via FhuA was inactivated by trypsin; unbound colicin M retained activity. We propose that colicin M unfolds during import across the outer membrane, FkpA specifically assists in folding colicin M into an active toxin in the periplasm and PPIase is essential for colicin M activity. Colicin M is a suitable tool for the isolation of FkpA mutants used to elucidate the functions of the FkpA N‐ and C‐domains.
Distribution of Subcutaneous Fat Predicts Insulin Action in Obesity in Sex‐specific Manner
2008-06-12

The pattern of adipose tissue (AT) distribution is an important predictor of metabolic risk. The aim of this study was to analyze the association of peripheral (insulin‐mediated glucose disposal—M) and hepatic (suppression of endogenous glucose production—EGP) insulin action with abdominal (subcutaneous abdominal AT—SAAT, intraabdominal AT—IAAT) and thigh AT depots in obese individuals. Fifty‐seven Pima Indians with normal glucose tolerance underwent magnetic resonance imaging (MRI) and euglycemic‐hyperinsulinemic clamp. M was negatively related to intraperitoneal IAAT ( P = 0.02) and deep SAAT ( P = 0.03). Suppression of EGP was negatively related to total ( P &lt; 0.05) or deep SAAT ( P &lt; 0.05 and P = 0.01, respectively), and total or intraperitoneal IAAT ( P = 0.009 and P = 0.002, respectively). A significant interaction with sex was found in the association between superficial SAAT and M, so that in women, but not men, M negatively correlated with superficial SAAT ( P = 0.02). In stepwise regression analysis, both M ( r 2 = 0.09) and EGP suppression ( r 2 = 0.17) were associated only with intraperitoneal IAAT in the whole group. In the sex‐specific analysis (because of the significant interaction), lower M was associated with higher deep SAAT ( r 2 = 0.15) in combination with lower superficial SAAT ( r 2 = 0.09) in men, and with higher superficial SAAT ( r 2 = 0.29) in combination with lower thigh subcutaneous AT (r 2 = 0.16) in women. Although intraperitoneal IAAT and deep SAAT were major predictors of peripheral and hepatic insulin action in obese Pima Indians, the largest variance in M rate was explained in a sex‐specific manner by relative size of subcutaneous AT depots.
Human Parvovirus B19 NS1 Protein Modulates Inflammatory Signaling by Activation of STAT3/PIAS3 in Human Endothelial Cells
2008-06-13

ABSTRACT The pathogenic mechanism by which parvovirus B19 may induce inflammatory cardiomyopathy (iCMP) is complex but is known to involve inflammatory processes, possibly including activation of JAK/STAT signaling. The nonstructural B19 protein NS1 acts as a transactivator triggering signaling cascades that eventually lead to activation of interleukin 6 (IL-6). We examined the impact of NS1 on modulation of STAT signaling in human endothelial cells (HMEC-1). The NS1 sequences were identified from B19 DNA isolated from the myocardia of patients with fatal iCMP. B19 infection as well as NS1 overexpression in HMEC-1 cells produced a significant upregulation in the phosphorylation of both tyrosine 705 and serine 727 STAT3 ( P &lt; 0.05). The increased STAT3 phosphorylation was accompanied by dimerization, nuclear translocation, and DNA binding of pSTAT3. In contrast, NS1 expression did not result in increased STAT1 activation. Notably, the expression levels of the negative regulators of STAT activation, SOCS1 and SOCS3, were not altered by NS1. However, the level of PIAS3 was upregulated in NS1-expressing HMEC-1 cells. Analysis of the transcriptional activation of target genes revealed that NS1-induced STAT3 signaling was associated with upregulation of genes involved in immune response (e.g., the IFNAR1 and IL-2 genes) and downregulation of genes associated with viral defense (e.g., the OAS1 and TYK2 genes). Our results demonstrate that B19 NS1 modulates the STAT/PIAS pathway. The NS1-induced upregulation of STAT3/PIAS3 in the absence of STAT1 phosphorylation and the lack of SOCS1/SOCS3 activation may contribute to the mechanisms by which B19 evades the immune response and establishes persistent infection in human endothelial cells. Thus, NS1 may play a critical role in the mechanism of viral pathogenesis in B19-associated iCMP.