julilili42/papers huggingface dataset:
Enzymatically Modified Low‐Density Lipoprotein Is Present in All Stages of Aortic Valve Sclerosis: Implications for Pathogenesis of the Disease
2015-10-17

Background We have demonstrated previously that enzymatically degraded low‐density lipoprotein ( eLDL ) is an essential causative component for the initiation of atherosclerosis. Here, we investigated the different stages of human aortic valve sclerosis for the presence of eLDL and effectors of the innate immune system, as well as the interaction of eLDL with isolated valvular interstitial cells/myofibroblasts to discover possible pathways leading to aortic valve sclerosis. Methods and Results Human aortic valvular tissue was obtained from 68 patients undergoing valve replacement surgery. Patients were classified into 3 groups (mild, moderate, or severe aortic valve sclerosis), and clinical data for statistical analysis were gathered from all patients. Immunohistochemical staining demonstrated extensive extracellular deposits of eLDL throughout all grades of aortic valve sclerosis. Complementary analysis of lipid composition revealed higher concentrations of the decisive components of eLDL (ie, unesterified cholesterol and linoleic acid) compared with internal control tissues. Further, the complement component C3d and terminal complement complexes colocalized with eLDL compatible with the proposal that subendothelially deposited eLDL is enzymatically transformed into a complement activator at early stages of valvular cusp lesion development. Gene expression profiles of proteases and complement components corroborated by immunohistochemistry demonstrated an upregulation of the protease cathepsin D (a possible candidate for LDL degradation to eLDL ) and the complement inhibitor CD 55. Surprisingly, substantial C‐reactive protein expression was not observed before grade 2 aortic valve sclerosis as investigated with microarray analysis, reverse transcription–polymerase chain reaction analysis, and immunohistochemistry. Finally, we demonstrated cellular uptake of eLDL by valvular interstitial cells/myofibroblasts. Conclusions The present study is a startup of a hypothesis on the pathogenesis of aortic valve sclerosis declaring extracellular lipoprotein modification, subsequent complement activation, and cellular uptake by valvular interstitial cells/myofibroblasts as integral players.
Contemporary management of acute kidney trauma
2015-10-17

Renal injury occurs in 1%–5% of all traumas, causing disability or even death. The American Association for the Surgery of Trauma (AAST) renal injury scale should be used when injuries are reported. Although there is a consensus regarding handling of lower-grade injuries conservatively, the same cannot be said for the higher-grades, for which different specialists handle either conservatively or surgically. A search of the MEDLINE database was undertaken by using the following filters: English language articles, full-text availability, last five years, humans. Pediatric studies were excluded. For most renal injuries in hemodynamically stable, patients can be safely handled conservatively. An organized assessment and treatment system can reduce the need for nephrectomy in most other cases, as has occurred in the last two decades. The AAST injury scale should be updated in light of the advancements in imaging techniques, in order to fine tune grading and treatment.
Differential neutrophil activation in viral infections: Enhanced TLR‐7/8‐mediated CXCL8 release in asthma
2015-10-18

Abstract Background and objective Respiratory viral infections are a major cause of asthma exacerbations. Neutrophils accumulate in the airways and the mechanisms that link neutrophilic inflammation, viral infections and exacerbations are unclear. This study aims to investigate anti‐viral responses in neutrophils from patients with and without asthma and to investigate if neutrophils can be directly activated by respiratory viruses. Methods Neutrophils from peripheral blood from asthmatic and non‐asthmatic individuals were isolated and stimulated with lipopolysaccharide ( LPS ) (1 μg/mL), f‐met‐leu‐phe (f MLP ) (100 nM), imiquimod (3 μg/mL), R 848 (1.5 μg/mL), poly I : C (10 μg/mL), RV 16 (multiplicity of infection ( MOI )1), respiratory syncytial virus ( RSV ) ( MOI 1) or influenza virus ( MOI 1). Cell‐free supernatants were collected after 1 h of neutrophil elastase ( NE ) and matrix metalloproteinase ( MMP )‐9 release, or after 24 h for CXCL 8 release. Results LPS , f MLP , imiquimod and R 848 stimulated the release of CXCL 8, NE and MMP ‐9 whereas poly I : C selectively induced CXCL 8 release only. R 848‐induced CXCL 8 release was enhanced in neutrophils from asthmatics compared with non‐asthmatic cells ( P &lt; 0.01). RSV triggered the release of CXCL 8 and NE from neutrophils, whereas RV 16 or influenza had no effect. Conclusion Neutrophils release CXCL 8, NE and MMP ‐9 in response to viral surrogates with R 848‐induced CXCL 8 release being specifically enhanced in asthmatic neutrophils. Toll‐like receptor ( TLR 7/8) dysregulation may play a role in neutrophilic inflammation in viral‐induced exacerbations.
Posaconazole plasma concentration in pediatric patients receiving antifungal prophylaxis after allogeneic hematopoietic stem cell transplantation
2015-10-18

Posaconazole has been proven to be effective for antifungal prophylaxis in adults after hematopoietic stem cell transplantation (HSCT). Due to low gastrointestinal resorption of posaconazole suspension, bioavailability is impaired. Fatty food improves the uptake of posaconazole, but insufficient data on the pharmacokinetics of posaconazole in pediatric patients are available so far. The single-center analysis investigated 161 posaconazole serum concentrations in 27 pediatric patients after HSCT receiving 12 mg·kg BW(-1)·d(-1) posaconazole suspension depending on age, gender, and intestinal graft-versus-host (iGvHD) disease, and the influence of posaconazole on cyclosporine A plasma concentrations. To improve the uptake of posaconazole, one patient cohort received higher fat nutrition with the drug administration. A comparison of the regular nutrition and higher-fat nutrition groups revealed the following values: 31 (27.4%) versus 8 (16.7%) < 500 ng/ml; 12 (10.6%) versus 7 (14.6%) 500-700 ng/ml; 8 (7.1%) versus 6 (12.5%) 700-1000 ng/ml; 51 (45.1%) versus 21 (43.8%) 1000-2000 ng/ml; and 11 (9.7%) versus 6 (12.5%) > 2000 ng/ml. The mean posaconazole concentrations in patients with regular nutrition was 1123 ± 811 ng/ml and with higher-fat nutrition was 1191 ± 673 ng/ml. Posaconazole levels in patients with iGvHD were significantly lower (P = 0.0003) than in patients without GvHD. The majority of samples showed a sufficient posaconazole concentration above 700 ng/ml. Posaconazole levels were slightly higher in patients with higher-fat nutrition and significantly lower in patients with iGvHD. Cyclosporine A levels were not significantly higher during posaconazole administration.
DNA-binding proteins from marine bacteria expand the known sequence diversity of TALE-like repeats
2015-10-19

Transcription Activator-Like Effectors (TALEs) of Xanthomonas bacteria are programmable DNA binding proteins with unprecedented target specificity. Comparative studies into TALE repeat structure and function are hindered by the limited sequence variation among TALE repeats. More sequence-diverse TALE-like proteins are known from Ralstonia solanacearum (RipTALs) and Burkholderia rhizoxinica (Bats), but RipTAL and Bat repeats are conserved with those of TALEs around the DNA-binding residue. We study two novel marine-organism TALE-like proteins (MOrTL1 and MOrTL2), the first to date of non-terrestrial origin. We have assessed their DNA-binding properties and modelled repeat structures. We found that repeats from these proteins mediate sequence specific DNA binding conforming to the TALE code, despite low sequence similarity to TALE repeats, and with novel residues around the BSR. However, MOrTL1 repeats show greater sequence discriminating power than MOrTL2 repeats. Sequence alignments show that there are only three residues conserved between repeats of all TALE-like proteins including the two new additions. This conserved motif could prove useful as an identifier for future TALE-likes. Additionally, comparing MOrTL repeats with those of other TALE-likes suggests a common evolutionary origin for the TALEs, RipTALs and Bats.
Enhanced suicidal erythrocyte death in acute cardiac failure
2015-10-19

Abstract Background A common complication of acute cardiac failure ( AHF ) is anaemia, which negatively influences the clinical outcome. Causes of anaemia include enhanced eryptosis, a suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation. Signalling triggering eryptosis include oxidative stress, increase of cytosolic Ca 2+ ‐activity ([Ca 2+ ] i ) and ceramide. The present study explored whether AHF is associated with accelerated eryptosis. Materials and Methods Erythrocytes were drawn from healthy volunteers ( n = 10) and patients hospitalized for AHF ( n = 22). Phosphatidylserine exposure was estimated from annexin‐V‐binding, cell volume from forward scatter, [Ca 2+ ] i from Fluo3‐fluorescence, ceramide abundance utilizing specific antibodies and reactive oxygen species ( ROS ) abundance from 2′,7′‐dichlorodihydrofluorescein diacetate ( DCFDA ) fluorescence, as determined by flow cytometry. Results In AHF ‐patients, haemoglobin concentration (11·5 ± 0·5 g/dL), and haematocrit (35·6 ± 1·2%) were significantly lower than haemoglobin concentration (14·1 ± 0·4 g/dL), and haematocrit (40·1 ± 1·0%) in healthy volunteers, even though reticulocyte number was significantly higher in AHF patients (2·3 ± 0·3%) than in healthy volunteers (1·1 ± 0·2%). The percentage of erythrocytes exposing phosphatidylserine was significantly higher in AHF patients (1·8 ± 0·1%) than in healthy volunteers (1·2 ± 0·2%). The forward scatter was significantly lower and the ROS abundance significantly larger in AHF patients than in healthy volunteers. In erythrocytes drawn from healthy volunteers, phosphatidylserine and ROS abundance was increased to significantly higher values following a 24 h treatment with plasma from AHF patients than with plasma from healthy volunteers. Conclusion AHF leads to anaemia despite increased reticulocyte number and at least partially due to enhanced eryptosis. Underlying mechanisms include oxidative stress imposed by a plasma borne component.
Ten years of INTEGRAL observations of the hard X-ray emission from SGR 1900+14
2015-10-19

We exploited the high sensitivity of the INTEGRAL IBIS/ISGRI instrument to\\nstudy the persistent hard X-ray emission of the soft gamma-ray repeater SGR\\n1900+14, based on ~11.6 Ms of archival data. The 22-150 keV INTEGRAL spectrum\\ncan be well fit by a power law with photon index 1.9 +/- 0.3 and flux F_x =\\n(1.11 +/- 0.17)E-11 erg/cm^2/s (20-100 keV). A comparison with the 20-100 keV\\nflux measured in 1997 with BeppoSAX, and possibly associated with SGR 1900+14,\\nshows a luminosity decrease by a factor of ~5. The slope of the power law above\\n20 keV is consistent within the uncertainties with that of SGR 1806-20, the\\nother persistent soft gamma-ray repeater for which a hard X-ray emission\\nextending up to 150 keV has been reported.\\n
High salt reduces the activation of IL-4– and IL-13–stimulated macrophages
2015-10-20

A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt. In stark contrast to Th17 cells and M1 macrophages, high salt blunted the alternative activation of BM-derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages. Salt-induced reduction of M(IL-4+IL-13) activation was not associated with increased polarization toward a proinflammatory M1 phenotype. In vitro, high salt decreased the ability of M(IL-4+IL-13) macrophages to suppress effector T cell proliferation. Moreover, mice fed a high salt diet exhibited reduced M2 activation following chitin injection and delayed wound healing compared with control animals. We further identified a high salt-induced reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR signaling, which indicates a mechanism by which NaCl inhibits full M2 macrophage activation. Collectively, this study provides evidence that high salt reduces noninflammatory innate immune cell activation and may thus lead to an overall imbalance in immune homeostasis.
Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment
2015-10-20

Key Points Ten of 36 patients (28%) achieved an OS ≥30 months in a blinatumomab study in relapsed/refractory acute lymphoblastic leukemia. Long-term survival may be associated with T-cell expansion, B-cell depletion, and a minimal residual disease response.
A subject-independent pattern-based Brain-Computer Interface
2015-10-20

While earlier Brain-Computer Interface (BCI) studies have mostly focused on modulating specific brain regions or signals, new developments in pattern classification of brain states are enabling real-time decoding and modulation of an entire functional network. The present study proposes a new method for real-time pattern classification and neurofeedback of brain states from electroencephalographic (EEG) signals. It involves the creation of a fused classification model based on the method of Common Spatial Patterns (CSPs) from data of several healthy individuals. The subject-independent model is then used to classify EEG data in real-time and provide feedback to new individuals. In a series of offline experiments involving training and testing of the classifier with individual data from 27 healthy subjects, a mean classification accuracy of 75.30% was achieved, demonstrating that the classification system at hand can reliably decode two types of imagery used in our experiments, i.e., happy emotional imagery and motor imagery. In a subsequent experiment it is shown that the classifier can be used to provide neurofeedback to new subjects, and that these subjects learn to "match" their brain pattern to that of the fused classification model in a few days of neurofeedback training. This finding can have important implications for future studies on neurofeedback and its clinical applications on neuropsychiatric disorders.
Molecular and functional interactions between AKT and SOX2 in breast carcinoma
2015-10-20

The transcription factor SOX2 is a key regulator of pluripotency in embryonic stem cells and plays important roles in early organogenesis. Recently, SOX2 expression was documented in various cancers and suggested as a cancer stem cell (CSC) marker. Here we identify the Ser/Thr-kinase AKT as an upstream regulator of SOX2 protein turnover in breast carcinoma (BC). SOX2 and pAKT are co-expressed and co-regulated in breast CSCs and depletion of either reduces clonogenicity. Ectopic SOX2 expression restores clonogenicity and in vivo tumorigenicity of AKT-inhibited cells, suggesting that SOX2 acts as a functional downstream AKT target. Mechanistically, we show that AKT physically interacts with the SOX2 protein to modulate its subcellular distribution. AKT kinase inhibition results in enhanced cytoplasmic retention of SOX2, presumably via impaired nuclear import, and in successive cytoplasmic proteasomal degradation of the protein. In line, blockade of either nuclear transport or proteasomal degradation rescues SOX2 expression in AKT-inhibited BC cells. Finally, AKT inhibitors efficiently suppress the growth of SOX2-expressing putative cancer stem cells, whereas conventional chemotherapeutics select for this population. Together, our results suggest the AKT/SOX2 molecular axis as a regulator of BC clonogenicity and AKT inhibitors as promising drugs for the treatment of SOX2-positive BC.
Robustness of quantitative hypoxia PET image analysis for predicting local tumor control
2015-10-20

Using a common pre-defined TBRmax threshold in multicenter trials requires careful standardization and harmonization of all steps from patient preparation to image analysis. Our results indicate that TBRmax should deviate less than 10% from reference conditions (absolute value in this dataset ± 0.2). This conclusion likely applies to all low contrast nitroimidazole hypoxia PET tracers.
Quinine‐Based Zwitterionic Chiral Stationary Phase as a Complementary Tool for Peptide Analysis: Mobile Phase Effects on Enantio‐ and Stereoselectivity of Underivatized Oligopeptides
2015-10-20

Abstract Peptide stereoisomer analysis is of importance for quality control of therapeutic peptides, the analysis of stereochemical integrity of bioactive peptides in food, and the elucidation of the stereochemistry of peptides from a natural chiral pool which often contains one or more D‐amino acid residues. In this work, a series of model peptide stereoisomers (enantiomers and diastereomers) were analyzed on a zwitterionic ion‐exchanger chiral stationary phase (Chiralpak ZWIX(+) 5 μm), in order to investigate the retention and separation performance for such compounds on this chiral stationary phase and elucidate its utility for this purpose. The goal of the study focused on 1) investigations of the effects of the sample matrix used to dissolve the peptide samples; 2) optimization of the mobile phase (enabling deriving information on factors of relevance for retention and separation); and 3) derivation of structure–selectivity relationships. It turned out that small di‐ and tripeptides can be well resolved under optimized conditions, typically with resolutions larger than 1.5. The optimized mobile phase often consisted of methanol–tetrahydrofuran–water (49:49:2; v/v/v) with 25 mM formic acid and 12.5 mM diethylamine. This work proposes some guidance on which mobile phases can be most efficiently used for peptide stereoisomer separations on Chiralpak ZWIX. Chirality 28:5–16, 2016 . © 2015 Wiley Periodicals, Inc.
The imprint of carbon combustion on a superburst from the accreting neutron star 4U 1636−536
2015-10-20

Superbursts are hours-long X-ray flares attributed to the thermonuclear\\nrunaway burning of carbon-rich material in the envelope of accreting neutron\\nstars. By studying the details of the X-ray light curve, properties of carbon\\ncombustion can be determined. In particular, we show that the shape of the rise\\nof the light curve is set by the the slope of the temperature profile left\\nbehind by the carbon flame. We analyse RXTE/PCA observations of 4U 1636-536 and\\nseparate the direct neutron star emission from evolving photoionized reflection\\nand persistent spectral components. This procedure results in the highest\\nquality light curve ever produced for the superburst rise and peak, and\\ninteresting behaviour is found in the tail. The rising light curve between 100\\nand 1000 seconds is inconsistent with the idea that the fuel burned locally and\\ninstantaneously everywhere, as assumed in some previous models. By fitting\\nimproved cooling models, we measure for the first time the radial temperature\\nprofile of the superbursting layer. We find . Furthermore,\\n20% of the fuel may be left unburned. This gives a new constraint on models of\\ncarbon burning and propagation in superbursts.\\n
Cross‐country Services Versus Manufacturing Activity of Multinational Firms in Response to Services Versus Goods Policy
2015-10-20

Abstract This paper assesses the consequences of trade costs on goods and services for the distribution of foreign direct investment ( FDI ) across goods and services as well as across countries. The paper employs data on the universe of G erman FDI abroad which are collected at the firm level and aggregated for the purpose of this paper to two sectors – goods and services – and 79 countries, using data for the year 2005. Key findings are that services trade costs as reflected in the services trade restrictiveness index and bilateral investment treaty membership are the most important policy drivers of the activity of G erman‐owned multinational firms in both goods and services. An increase in services trade restrictions raises goods activity at the expense of services activity. This effect is more pronounced the more important host countries in terms of the G erman FDI are.
Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine
2015-10-21

These results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles. (Funded by the National Institutes of Health and others.).
Olesoxime suppresses calpain activation and mutant huntingtin fragmentation in the BACHD rat
2015-10-21

Huntington's disease is a fatal human neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene, which translates into a mutant huntingtin protein. A key event in the molecular pathogenesis of Huntington's disease is the proteolytic cleavage of mutant huntingtin, leading to the accumulation of toxic protein fragments. Mutant huntingtin cleavage has been linked to the overactivation of proteases due to mitochondrial dysfunction and calcium derangements. Here, we investigated the therapeutic potential of olesoxime, a mitochondria-targeting, neuroprotective compound, in the BACHD rat model of Huntington's disease. BACHD rats were treated with olesoxime via the food for 12 months. In vivo analysis covered motor impairments, cognitive deficits, mood disturbances and brain atrophy. Ex vivo analyses addressed olesoxime's effect on mutant huntingtin aggregation and cleavage, as well as brain mitochondria function. Olesoxime improved cognitive and psychiatric phenotypes, and ameliorated cortical thinning in the BACHD rat. The treatment reduced cerebral mutant huntingtin aggregates and nuclear accumulation. Further analysis revealed a cortex-specific overactivation of calpain in untreated BACHD rats. Treated BACHD rats instead showed significantly reduced levels of mutant huntingtin fragments due to the suppression of calpain-mediated cleavage. In addition, olesoxime reduced the amount of mutant huntingtin fragments associated with mitochondria, restored a respiration deficit, and enhanced the expression of fusion and outer-membrane transport proteins. In conclusion, we discovered the calpain proteolytic system, a key player in Huntington's disease and other neurodegenerative disorders, as a target of olesoxime. Our findings suggest that olesoxime exerts its beneficial effects by improving mitochondrial function, which results in reduced calpain activation. The observed alleviation of behavioural and neuropathological phenotypes encourages further investigations on the use of olesoxime as a therapeutic for Huntington's disease.