julilili42/papers huggingface dataset:
Combined Blockade of ADP Receptors and PI3-Kinase p110β Fully Prevents Platelet and Leukocyte Activation during Hypothermic Extracorporeal Circulation
2012-06-06

Extracorporeal circulation (ECC) and hypothermia are used to maintain stable circulatory parameters and improve the ischemia tolerance of patients in cardiac surgery. However, ECC and hypothermia induce activation mechanisms in platelets and leukocytes, which are mediated by the platelet agonist ADP and the phosphoinositide-3-kinase (PI3K) p110β. Under clinical conditions these processes are associated with life-threatening complications including thromboembolism and inflammation. This study analyzes effects of ADP receptor P(2)Y(12) and P(2)Y(1) blockade and PI3K p110β inhibition on platelets and granulocytes during hypothermic ECC. Human blood was treated with the P(2)Y(12) antagonist 2-MeSAMP, the P(2)Y(1) antagonist MRS2179, the PI3K p110β inhibitor TGX-221, combinations thereof, or PBS and propylene glycol (controls). Under static in vitro conditions a concentration-dependent effect regarding the inhibition of ADP-induced platelet activation was found using 2-MeSAMP or TGX-221. Further inhibition of ADP-mediated effects was achieved with MRS2179. Next, blood was circulated in an ex vivo ECC model at 28°C for 30 minutes and various platelet and granulocyte markers were investigated using flow cytometry, ELISA and platelet count analysis. GPIIb/IIIa activation induced by hypothermic ECC was inhibited using TGX-221 alone or in combination with P(2)Y blockers (p<0.05), while no effect of hypothermic ECC or antiplatelet agents on GPIIb/IIIa and GPIbα expression and von Willebrand factor binding was observed. Sole P(2)Y and PI3K blockade or a combination thereof inhibited P-selectin expression on platelets and platelet-derived microparticles during hypothermic ECC (p<0.05). P(2)Y blockade alone or combined with TGX-221 prevented ECC-induced platelet-granulocyte aggregate formation (p<0.05). Platelet adhesion to the ECC surface, platelet loss and Mac-1 expression on granulocytes were inhibited by combined P(2)Y and PI3K blockade (p<0.05). Combined blockade of P(2)Y(12), P(2)Y(1) and PI3K p110β completely inhibits hypothermic ECC-induced activation processes. This novel finding warrants further studies and the development of suitable pharmacological agents to decrease ECC- and hypothermia-associated complications in clinical applications.
The Role of Arg13 in Protein Phosphatase M tPphA from Thermosynechococcus elongatus
2012-06-06

A highly conserved arginine residue is close to the catalytic center of PPM/PP2C-type protein phosphatases. Different crystal structures of PPM/PP2C homologues revealed that the guanidinium side chain of this arginine residue can adopt variable conformations and may bind ligands, suggesting an important role of this residue during catalysis. In this paper, we randomly mutated Arginine 13 of tPphA, a PPM/PP2C-type phosphatase from Thermosynechococcus elongatus , and obtained 18 different amino acid variants. The generated variants were tested towards p -nitrophenyl phosphate and various phosphopeptides. Towards p -nitrophenyl phosphate as substrate, twelve variants showed 3–7 times higher K m values than wild-type tPphA and four variants (R13D, R13F, R13L, and R13W) completely lost activity. Strikingly, these variants were still able to dephosphorylate phosphopeptides, although with strongly reduced activity. The specific inability of some Arg-13 variants to hydrolyze p -nitrophenyl phosphate highlights the importance of additional substrate interactions apart from the substrate phosphate for catalysis. The properties of the R13 variants indicate that this residue assists in substrate binding.
Ex vivo pharmacology of surgical samples of the uterosacral ligament. Part II: Effects of oxytocin and relaxin on arteries and vascular plexus
2012-06-06

Abstract Aims The uterosacral ligament (USL) contains prominent vessels, the function of which is unknown. Here we study the relationship between smooth muscle of the USL and the vascular bundles. Methods Native samples of arteries and vascular bundles were mounted in a perfusion chamber under the stereomicroscope. The effects of noradrenalin, carbachol, oxytocin, and relaxin were monitored by digital time‐lapse video and quantified by image processing. Results Arteries were adrenergic and the smooth muscle in the adventitia cholinergic. Relaxin‐2 shifted the dose response curve of noradrenalin to the right and widened the arterial lumen within 30 min. Oxytocin induced contraction of the adventitial smooth muscle leading to a slow opening of the artery. In a vascular bundle the differential pattern of both reactivities was demonstrated. Conclusions In the USL the smooth muscle extends into the adventitial layer of blood vessels and forms a functional unit with the vascular plexus, which is regulated by relaxin and oxytocin. Neurourol. Urodynam. 31:1300–1306, 2012. © 2012 Wiley Periodicals, Inc.
On Improving the Accuracy of Readability Classification using Insights from Second Language Acquisition
2012-06-07

The aim of the study was to evaluate the rate of obstetric complications and the burden of obstetric outcomes in antiphospholipid syndrome (APS), non-criteria APS and asymptomatic antiphospholipid antibodies (aPL) carriers. From 2013-2018, 163 pregnant subjects with aPL antibodies and 785 controls were enrolled. Penalized logistic regression was used to compare obstetric complications. Cases included 62 complete APS (38 %), 48 non-criteria APS (29.4 %) and 53 (32.5 %) asymptomatic aPL-carriers. Connective tissue diseases (CTDs) were diagnosed in 31.3 % of cases. The rate of high-risk aPL profile was higher (p < .01) in APS (67.7 %) compared to non-criteria (14.6 %) and aPL-carriers (9.4 %). Double/triple positivity was 33.9 % (p < .05 compared to non-criteria and aPL-carriers) in APS, 10.4 % in non-criteria and 9.4 % in aPL-carriers. The rate of adverse pregnancy outcomes were 5.6 % in controls, 41.9 % (adj.OR = 6.95 %CI = 2.7-13.5) in APS, 25 % (adj.OR = 4.4,95 %CI = 2-9.4) in non-criteria and 28.3 % (OR = 4.95 %CI = 1.8-8.8) in aPL-carriers. CTDs were independently associated with an increased risk of adverse obstetric outcomes (OR = 2.8,95 %CI = 1.36-5.89). The attributable fraction (AF) of adverse obstetric events was higher among low-risk antibodies compared to high-risk (AF = 0.27,95 %CI = 0.22-0.31 vs AF = 0.16,95 %CI = 0.16-0.2,p < .01) and among single positivity compared to double/triple positivity (AF = 0.32,95 %CI = 0.26-0.37 vs AF = 0.11,95 %CI = 0.09-0.13,p < .01) suggesting that low-risk subjects are responsible for a high burden of obstetric complications.
Claudin-4-targeted optical imaging detects pancreatic cancer and its precursor lesions
2012-06-07

C-CPE-Cy5.5 combined with novel optical imaging methods enables non-invasive visualisation of claudin-4 positive murine pancreatic tumours and their precursor lesions, representing a promising modality for early diagnostic imaging.
Retrocochlear function of the peripheral deafness gene Cacna1d
2012-06-07

Hearing impairment represents the most common sensory deficit in humans. Genetic mutations contribute significantly to this disorder. Mostly, only malfunction of the ear is considered. Here, we assessed the role of the peripheral deafness gene Cacna1d, encoding the L-type channel Ca(v)1.3, in downstream processing of acoustic information. To this end, we generated a mouse conditional Cacna1d-eGFP(flex) allele. Upon pairing with Egr2::Cre mice, Ca(v)1.3 was ablated in the auditory brainstem, leaving the inner ear intact. Structural assessment of the superior olivary complex (SOC), an essential auditory brainstem center, revealed a dramatic volume reduction (43-47%) of major nuclei in young adult Egr2::Cre;Cacna1d-eGFP(flex) mice. This volume decline was mainly caused by a reduced cell number (decline by 46-56%). Abnormal formation of the lateral superior olive was already present at P4, demonstrating an essential perinatal role of Ca(v)1.3 in the SOC. Measurements of auditory brainstem responses demonstrated a decreased amplitude in the auditory nerve between 50 and 75 dB stimulation in Egr2::Cre;Cacna1d-eGFP(flex) knockout mice and increased amplitudes in central auditory processing centers. Immunohistochemical studies linked the amplitude changes in the central auditory system to reduced expression of K(v)1.2. No changes were observed for K(v)1.1, KCC2, a determinant of inhibitory neurotransmission, and choline acetyltransferase, a marker of efferent olivocochlear neurons. Together, these analyses identify a crucial retrocochlear role of Ca(v)1.3 and demonstrate that mutations in deafness genes can affect sensory cells and neurons alike. As a corollary, hearing aids have to address central auditory processing deficits as well.
Design, Synthesis, and Biological Evaluation of Novel Disubstituted Dibenzosuberones as Highly Potent and Selective Inhibitors of p38 Mitogen Activated Protein Kinase
2012-06-07

Synthesis, biological testing, structure-activity relationships (SARs), and selectivity of novel disubstituted dibenzosuberone derivatives as p38 MAP kinase inhibitors are described. Hydrophilic moieties were introduced at the 7-, 8-, and 9-position of the 2-phenylamino-dibenzosuberones, improving physicochemical properties as well as potency. Extremely potent inhibitors were obtained, with half-maximal inhibitory concentration (IC(50)) values in the low nM range in a whole blood assay measuring the inhibition of cytokine release. The high potency of the target compounds together with the outstanding selectivity of this novel class of compounds toward p38 mitogen activated protein (MAP) kinase as compared to other kinases indicate them to be most applicable as tools in pharmacological research and eventually they may foster a new generation of anti-inflammatory drugs.
Magnetic fields in central stars of planetary nebulae?
2012-06-07

\\n Context. Most planetary nebulae have bipolar or other non-spherically symmetric shapes. Magnetic fields in the central star may be responsible for this lack of symmetry, but observational studies published to date have reported contradictory results. \\n Aims. We search for correlations between a magnetic field and departures from the spherical geometry of the envelopes of planetary nebulae.\\n Methods. We determine the magnetic fields from spectropolarimetric observations of ten central stars of planetary nebulae. The results of the analysis of the observations of four stars were previously presented and discussed in the literature, while the observations of six stars, plus additional measurements of a star previously observed, are presented here for the first time.\\n Results. All our determinations of magnetic field in the central planetary nebulae are consistent with null results. Our field measurements have a typical error bar of 150–300 G. Previous spurious field detections using data acquired with FORS1 (FOcal Reducer and low dispersion Spectrograph) of the Unit Telescope 1 (UT1) of the Very Large Telescope (VLT) were probably due to the use of different wavelength calibration solutions for frames obtained at different position angles of the retarder waveplate.\\n Conclusions. There is currently no observational evidence of magnetic fields with a strength of the order of hundreds Gauss or higher in the central stars of planetary nebulae.\\n
Informing determiner and preposition error correction with word clusters
2012-06-07

We extend our n-gram-based data-driven prediction approach from the Helping Our Own (HOO) 2011 Shared Task (Boyd and Meurers, 2011) to identify determiner and preposition errors in non-native English essays from the Cambridge Learner Corpus FCE Dataset (Yannakoudakis et al., 2011) as part of the HOO 2012 Shared Task. Our system focuses on three error categories: missing determiner, incorrect determiner, and incorrect preposition. Approximately two-thirds of the errors annotated in HOO 2012 training and test data fall into these three categories. To improve our approach, we developed a missing determiner detector and incorporated word clustering (Brown et al., 1992) into the n-gram prediction approach.
Phrase-Based Approach for Adaptive Tokenization
2012-06-07

Data are presented from one year of infections reported to PHE. The rate of MRSA bacteraemia episodes in England continues to fall. There was a higher rate of MSSA infections amongst renal dialysis patients. Findings from the first year of E. coli and C. difficile data collection are also reported. Future cycles will give us a further idea of the trend in incidences of these infections.
Similar autobiographical memory impairment in long-term secondary progressive multiple sclerosis and Alzheimer's disease
2012-06-08

Our neuropsychological findings suggest that episodic autobiographical memory is affected in long-term patients with SPMS, possibly due to neurodegenerative processes in functional relevant brain regions.
Non‐invasive identification of proteoglycans and chondrocyte differentiation state by Raman microspectroscopy
2012-06-08

Abstract Proteoglycans (PGs) are crucial extracellular matrix (ECM) components that are present in all tissues and organs. Pathological remodeling of these macromolecules can lead to severe diseases such as osteoarthritis or rheumatoid arthritis. To date, PG‐associated ECM alterations are routinely diagnosed by invasive analytical methods. Here, we employed Raman microspectroscopy, a laser‐based, marker‐free and non‐destructive technique that allows the generation of spectra with peaks originating from molecular vibrations within a sample, to identify specific Raman bands that can be assigned to PGs within human and porcine cartilage samples and chondrocytes. Based on the non‐invasively acquired Raman spectra, we further revealed that a prolonged in vitro culture leads to phenotypic alterations of chondrocytes, resulting in a decreased PG synthesis rate and loss of lipid contents. Our results are the first to demonstrate the applicability of Raman microspectroscopy as an analytical and potential diagnostic tool for non‐invasive cell and tissue state monitoring of cartilage in biomedical research. (© 2013 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)
GenomeRing: alignment visualization based on SuperGenome coordinates
2012-06-09

Abstract Motivation: The number of completely sequenced genomes is continuously rising, allowing for comparative analyses of genomic variation. Such analyses are often based on whole-genome alignments to elucidate structural differences arising from insertions, deletions or from rearrangement events. Computational tools that can visualize genome alignments in a meaningful manner are needed to help researchers gain new insights into the underlying data. Such visualizations typically are either realized in a linear fashion as in genome browsers or by using a circular approach, where relationships between genomic regions are indicated by arcs. Both methods allow for the integration of additional information such as experimental data or annotations. However, providing a visualization that still allows for a quick and comprehensive interpretation of all important genomic variations together with various supplemental data, which may be highly heterogeneous, remains a challenge. Results: Here, we present two complementary approaches to tackle this problem. First, we propose the SuperGenome concept for the computation of a common coordinate system for all genomes in a multiple alignment. This coordinate system allows for the consistent placement of genome annotations in the presence of insertions, deletions and rearrangements. Second, we present the GenomeRing visualization that, based on the SuperGenome, creates an interactive overview visualization of the multiple genome alignment in a circular layout. We demonstrate our methods by applying them to an alignment of Campylobacter jejuni strains for the discovery of genomic islands as well as to an alignment of Helicobacter pylori, which we visualize in combination with gene expression data. Availability: GenomeRing and example data is available at http://it.inf.uni-tuebingen.de/software/genomering/ Contact: kay.nieselt@uni-tuebingen.de
Proceedings of the 6th Annual Meeting of the Germany Society for Stem Cell Research
2012-06-10

In driving hES cell technology towards widespread applications considerable effort has been focused on the improvement of culture conditions and on enabling efficient differentiation.We have established two technologies which will better enable researchers to achieve these aims.
Formal language theory: refining the Chomsky hierarchy
2012-06-11

The first part of this article gives a brief overview of the four levels of the Chomsky hierarchy, with a special emphasis on context-free and regular languages. It then recapitulates the arguments why neither regular nor context-free grammar is sufficiently expressive to capture all phenomena in the natural language syntax. In the second part, two refinements of the Chomsky hierarchy are reviewed, which are both relevant to the extant research in cognitive science: the mildly context-sensitive languages (which are located between context-free and context-sensitive languages), and the sub-regular hierarchy (which distinguishes several levels of complexity within the class of regular languages).
Analysis of drug metabolism activities in a miniaturized liver cell bioreactor for use in pharmacological studies
2012-06-11

Abstract Based on a hollow fiber perfusion technology with internal oxygenation, a miniaturized bioreactor with a volume of 0.5 mL for in vitro studies was recently developed. Here, the suitability of this novel culture system for pharmacological studies was investigated, focusing on the model drug diclofenac. Primary human liver cells were cultivated in bioreactors and in conventional monolayer cultures in parallel over 10 days. From day 3 on, diclofenac was continuously applied at a therapeutic concentration (6.4 μM) for analysis of its metabolism. In addition, the activity and gene expression of the cytochrome P450 (CYP) isoforms CYP1A2, CYP2B6, CYP2C9, CYP2D6, and CYP3A4 were assessed. Diclofenac was metabolized in bioreactor cultures with an initial conversion rate of 230 ± 57 pmol/h/10 6 cells followed by a period of stable conversion of about 100 pmol/h/10 6 cells. All CYP activities tested were maintained until day 10 of bioreactor culture. The expression of corresponding mRNAs correlated well with the degree of preservation. Immunohistochemical characterization showed the formation of neo‐tissue with expression of CYP2C9 and CYP3A4 and the drug transporters breast cancer resistance protein (BCRP) and multidrug resistance protein 2 (MRP2) in the bioreactor. In contrast, monolayer cultures showed a rapid decline of diclofenac conversion and cells had largely lost activity and mRNA expression of the assessed CYP isoforms at the end of the culture period. In conclusion, diclofenac metabolism, CYP activities and gene expression levels were considerably more stable in bioreactor cultures, making the novel bioreactor a useful tool for pharmacological or toxicological investigations requiring a highly physiological in vitro representation of the liver. Biotechnol. Bioeng. 2012; 109: 3172–3181. © 2012 Wiley Periodicals, Inc.
Structural Analysis of Staphylococcus aureus Serine/Threonine Kinase PknB
2012-06-11

Effective treatment of infections caused by the bacterium Staphylococcus aureus remains a worldwide challenge, in part due to the constant emergence of new strains that are resistant to antibiotics. The serine/threonine kinase PknB is of particular relevance to the life cycle of S. aureus as it is involved in the regulation of purine biosynthesis, autolysis, and other central metabolic processes of the bacterium. We have determined the crystal structure of the kinase domain of PknB in complex with a non-hydrolyzable analog of the substrate ATP at 3.0 Å resolution. Although the purified PknB kinase is active in solution, it crystallized in an inactive, autoinhibited state. Comparison with other bacterial kinases provides insights into the determinants of catalysis, interactions of PknB with ligands, and the pathway of activation.
High Prevalence of Giardia duodenalis Assemblage B Infection and Association with Underweight in Rwandan Children
2012-06-12

The prevalence of G. duodenalis in high-endemicity areas may be greatly underestimated by light microscopy, particularly when only single stool samples are analysed. Children with submicroscopic infections show limited overt manifestation, but constitute unrecognized reservoirs of transmission. The predominance of assemblage B in Rwanda may be involved in the seemingly unimposing manifestation of G. duodenalis infection. However, the association with impaired child growth points to its actual relevance. Longitudinal studies considering abundant submicroscopic infections are needed to clarify the actual contribution of G. duodenalis to morbidity in areas of high endemicity.
Operator splitting for partial differential equations with Burgers nonlinearity
2012-06-12

We provide a new analytical approach to operator splitting for equations of the type where is a linear differential operator such that the equation is well-posed. Particular examples include the viscous Burgers equation, the Korteweg–de Vries (KdV) equation, the Benney–Lin equation, and the Kawahara equation. We show that the Strang splitting method converges with the expected rate if the initial data are sufficiently regular. In particular, for the KdV equation we obtain second-order convergence in for initial data in with arbitrary .
Critical role for cochlear hair cell BK channels for coding the temporal structure and dynamic range of auditory information for central auditory processing
2012-06-12

Large conductance, voltage‐ and Ca 2+ ‐activated K + (BK) channels in inner hair cells (IHCs) of the cochlea are essential for hearing. However, germ‐line deletion of BKα, the pore‐forming subunit KCNMA1 of the BK channel, surprisingly did not affect hearing thresholds in the first postnatal weeks, even though altered IHC membrane time constants, decreased IHC receptor potential alternating current/direct current ratio, and impaired spike timing of auditory fibers were reported in these mice. To investigate the role of IHC BK channels for central auditory processing, we generated a conditional mouse model with hair cell‐specific deletion of BKα from postnatal day 10 onward. This had an unexpected effect on temporal coding in the central auditory system: neuronal single and multiunit responses in the inferior colliculus showed higher excitability and greater precision of temporal coding that may be linked to the improved discrimination of temporally modulated sounds observed in behavioral training. The higher precision of temporal coding, however, was restricted to slower modulations of sound and reduced stimulus‐driven activity. This suggests a diminished dynamic range of stimulus coding that is expected to impair signal detection in noise. Thus, BK channels in IHCs are crucial for central coding of the temporal fine structure of sound and for detection of signals in a noisy environment.—Kurt, S., Sausbier, M., Rüttiger, L., Brandt, N., Moeller, C. K., Kindler, J., Sausbier, U., Zimmermann, U., van Straaten, H., Neuhuber, W., Engel, J., Knipper, M., Ruth, P., Schulze, H. Critical role for cochlear hair cell BK channels for coding the temporal structure and dynamic range of auditory information for central auditory processing. FASEB J. 26, 3834–3843 (2012). www.fasebj.org