julilili42/papers huggingface dataset:
In Vitro Induction of Erythrocyte Phosphatidylserine Translocation by the Natural Naphthoquinone Shikonin
2014-05-13

Shikonin, the most important component of Lithospermum erythrorhizon, has previously been shown to exert antioxidant, anti-inflammatory, antithrombotic, antiviral, antimicrobial and anticancer effects. The anticancer effect has been attributed to the stimulation of suicidal cell death or apoptosis. Similar to the apoptosis of nucleated cells, erythrocytes may experience eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and by phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include the increase of cytosolic Ca2+-activity ([Ca2+]i) and ceramide formation. The present study explored whether Shikonin stimulates eryptosis. To this end, Fluo 3 fluorescence was measured to quantify [Ca2+]i, forward scatter to estimate cell volume, annexin V binding to identify phosphatidylserine-exposing erythrocytes, hemoglobin release to determine hemolysis and antibodies to quantify ceramide abundance. As a result, a 48 h exposure of human erythrocytes to Shikonin (1 μM) significantly increased [Ca2+]i, increased ceramide abundance, decreased forward scatter and increased annexin V binding. The effect of Shikonin (1 μM) on annexin V binding was significantly blunted, but not abolished by the removal of extracellular Ca2+. In conclusion, Shikonin stimulates suicidal erythrocyte death or eryptosis, an effect at least partially due to the stimulation of Ca2+ entry and ceramide formation.
Isoniazid Mediates the CYP2B6*6 Genotype-Dependent Interaction between Efavirenz and Antituberculosis Drug Therapy through Mechanism-Based Inactivation of CYP2A6
2014-05-13

ABSTRACT Efavirenz is commonly used to treat patients coinfected with human immunodeficiency virus and tuberculosis. Previous clinical studies have observed paradoxically elevated efavirenz plasma concentrations in patients with the CYP2B6*6/*6 genotype (but not the CYP2B6*1/*1 genotype) during coadministration with the commonly used four-drug antituberculosis therapy. This study sought to elucidate the mechanism underlying this genotype-dependent drug-drug interaction. In vitro studies were conducted to determine whether one or more of the antituberculosis drugs (rifampin, isoniazid, pyrazinamide, or ethambutol) potently inhibit efavirenz 8-hydroxylation by CYP2B6 or efavirenz 7-hydroxylation by CYP2A6, the main mechanisms of efavirenz clearance. Time- and concentration-dependent kinetics of inhibition by the antituberculosis drugs were determined using genotyped human liver microsomes (HLMs) and recombinant CYP2A6, CYP2B6.1, and CYP2B6.6 enzymes. Although none of the antituberculosis drugs evaluated at up to 10 times clinical plasma concentrations were found to inhibit efavirenz 8-hydroxylation by HLMs, both rifampin (apparent inhibition constant [ K i ] = 368 μM) and pyrazinamide ( K i = 637 μM) showed relatively weak inhibition of efavirenz 7-hydroxylation. Importantly, isoniazid demonstrated potent time-dependent inhibition of efavirenz 7-hydroxylation in both HLMs (inhibitor concentration required for half-maximal inactivation [ K I ] = 30 μM; maximal rate constant of inactivation [ k inact ] = 0.023 min −1 ) and recombinant CYP2A6 ( K I = 15 μM; k inact = 0.024 min −1 ) and also formed a metabolite intermediate complex consistent with mechanism-based inhibition. Selective inhibition of the CYP2B6.6 allozyme could not be demonstrated for any of the antituberculosis drugs using either recombinant enzymes or CYP2B6*6 genotype HLMs. In conclusion, the results of this study identify isoniazid as the most likely perpetrator of this clinically important drug-drug interaction through mechanism-based inactivation of CYP2A6.
XMM-Newtonobservation of the interacting galaxies NGC 1512 and NGC 1510
2014-05-13

The galaxy NGC1512 is interacting with the smaller galaxy NGC1510 and shows a\\npeculiar morphology, characterised by two extended arms immersed in an HI disc\\nwhose size is about four times larger than the optical diameter of NGC1512. For\\nthe first time we performed a deep X-ray observation of the galaxies NGC1512\\nand NGC1510 with XMM-Newton to gain information on the population of X-ray\\nsources and diffuse emission in a system of interacting galaxies. We identified\\nand classified the sources detected in the XMM-Newton field of view by means of\\nspectral analysis, hardness-ratios calculated with a Bayesian method, X-ray\\nvariability, and cross-correlations with catalogues in optical, infrared, and\\nradio wavelengths. We also made use of archival Swift (X-ray) and Australia\\nTelescope Compact Array (radio) data to better constrain the nature of the\\nsources detected with XMM-Newton. We detected 106 sources in the energy range\\nof 0.2-12 keV, out of which 15 are located within the D_25 regions of NGC1512\\nand NGC1510 and at least six sources coincide with the extended arms. We\\nidentified and classified six background objects and six foreground stars. We\\ndiscussed the nature of a source within the D_25 ellipse of NGC1512, whose\\nproperties indicate a quasi-stellar object or an intermediate ultra-luminous\\nX-ray source. Taking into account the contribution of low-mass X-ray binaries\\nand active galactic nuclei, the number of high-mass X-ray binaries detected\\nwithin the D_25 region of NGC1512 is consistent with the star formation rate\\nobtained in previous works based on radio, infrared optical, and UV\\nwavelengths. We detected diffuse X-ray emission from the interior region of\\nNGC1512 with a plasma temperature of kT=0.68(0.31-0.87) keV and a 0.3-10 keV\\nX-ray luminosity of 1.3E38 erg/s, after correcting for unresolved discrete\\nsources.\\n
UBE2E Ubiquitin-conjugating Enzymes and Ubiquitin Isopeptidase Y Regulate TDP-43 Protein Ubiquitination
2014-05-14

Trans-activation element DNA-binding protein of 43 kDa (TDP-43) characterizes insoluble protein aggregates in distinct subtypes of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. TDP-43 mediates many RNA processing steps within distinct protein complexes. Here we identify novel TDP-43 protein interactors found in a yeast two-hybrid screen using an adult human brain cDNA library. We confirmed the TDP-43 interaction of seven hits by co-immunoprecipitation and assessed their co-localization in HEK293E cells. As pathological TDP-43 is ubiquitinated, we focused on the ubiquitin-conjugating enzyme UBE2E3 and the ubiquitin isopeptidase Y (UBPY). When cells were treated with proteasome inhibitor, ubiquitinated and insoluble TDP-43 species accumulated. All three UBE2E family members could enhance the ubiquitination of TDP-43, whereas catalytically inactive UBE2E3(C145S) was much less efficient. Conversely, silencing of UBE2E3 reduced TDP-43 ubiquitination. We examined 15 of the 48 known disease-associated TDP-43 mutants and found that one was excessively ubiquitinated. This strong TDP-43(K263E) ubiquitination was further enhanced by proteasomal inhibition as well as UBE2E3 expression. Conversely, UBE2E3 silencing and expression of UBPY reduced TDP-43(K263E) ubiquitination. Moreover, wild-type but not active site mutant UBPY reduced ubiquitination of TDP-43 C-terminal fragments and of a nuclear import-impaired mutant. In Drosophila melanogaster, UBPY silencing enhanced neurodegenerative TDP-43 phenotypes and the accumulation of insoluble high molecular weight TDP-43 and ubiquitin species. Thus, UBE2E3 and UBPY participate in the regulation of TDP-43 ubiquitination, solubility, and neurodegeneration.
Airway Mucus Obstruction Triggers Macrophage Activation and Matrix Metalloproteinase 12–Dependent Emphysema
2014-05-14

Whereas cigarette smoking remains the main risk factor for emphysema, recent studies in β-epithelial Na(+) channel-transgenic (βENaC-Tg) mice demonstrated that airway surface dehydration, a key pathophysiological mechanism in cystic fibrosis (CF), caused emphysema in the absence of cigarette smoke exposure. However, the underlying mechanisms remain unknown. The aim of this study was to elucidate mechanisms of emphysema formation triggered by airway surface dehydration. We therefore used expression profiling, genetic and pharmacological inhibition, Foerster resonance energy transfer (FRET)-based activity assays, and genetic association studies to identify and validate emphysema candidate genes in βENaC-Tg mice and patients with CF. We identified matrix metalloproteinase 12 (Mmp12) as a highly up-regulated gene in lungs from βENaC-Tg mice, and demonstrate that elevated Mmp12 expression was associated with progressive emphysema formation, which was reduced by genetic deletion and pharmacological inhibition of MMP12 in vivo. By using FRET reporters, we show that MMP12 activity was elevated on the surface of airway macrophages in bronchoalveolar lavage from βENaC-Tg mice and patients with CF. Furthermore, we demonstrate that a functional polymorphism in MMP12 (rs2276109) was associated with severity of lung disease in CF. Our results suggest that MMP12 released by macrophages activated on dehydrated airway surfaces may play an important role in emphysema formation in the absence of cigarette smoke exposure, and may serve as a therapeutic target in CF and potentially other chronic lung diseases associated with airway mucus dehydration and obstruction.
How number-space relationships are assessed before formal schooling: A taxonomy proposal
2014-05-14

The last years of research on numerical development have provided evidence that spatial-numerical associations (SNA) can be formed independent of formal school training. However, most of these studies used various experimental paradigms that referred to slightly different aspects of number and space processing. This poses a question of whether all SNAs described in the developmental literature can be interpreted as a unitary construct, or whether they are rather examples of different, but related phenomena. Our review aims to provide a starting point for a systematic classification of SNA measures used from infancy to late preschool years, and their underlying representations. We propose to distinguish among four basic SNA categories: (i) cross-dimensional magnitude processing, (ii) associations between spatial and numerical intervals, (iii) associations between cardinalities and spatial directions, (iv) associations between ordinalities and spatial directions. Such systematization allows for identifying similarities and differences between processes and representations that underlie the described measures, and also for assessing the adequacy of using different SNA tasks at different developmental stages.
3‐D analysis of bacterial cell‐(iron)mineral aggregates formed during Fe(II) oxidation by the nitrate‐reducing Acidovorax sp. strain BoFeN1 using complementary microscopy tomography approaches
2014-05-14

Abstract The formation of cell‐(iron)mineral aggregates as a consequence of bacterial iron oxidation is an environmentally widespread process with a number of implications for processes such as sorption and coprecipitation of contaminants and nutrients. Whereas the overall appearance of such aggregates is easily accessible using 2‐D microscopy techniques, the 3‐D and internal structure remain obscure. In this study, we examined the 3‐D structure of cell‐(iron)mineral aggregates formed during Fe( II ) oxidation by the nitrate‐reducing Acidovorax sp . strain BoFeN1 using a combination of advanced 3‐D microscopy techniques. We obtained 3‐D structural and chemical information on different cellular encrustation patterns at high spatial resolution (4–200 nm, depending on the method): more specifically, (1) cells free of iron minerals, (2) periplasm filled with iron minerals, (3) spike‐ or platelet‐shaped iron mineral structures, (4) bulky structures on the cell surface, (5) extracellular iron mineral shell structures, (6) cells with iron mineral filled cytoplasm, and (7) agglomerations of extracellular globular structures. In addition to structural information, chemical nanotomography suggests a dominant role of extracellular polymeric substances ( EPS ) in controlling the formation of cell‐(iron)mineral aggregates. Furthermore, samples in their hydrated state showed cell‐(iron)mineral aggregates in pristine conditions free of preparation (i.e., drying/dehydration) artifacts. All these results were obtained using 3‐D microscopy techniques such as focused ion beam ( FIB )/scanning electron microscopy ( SEM ) tomography, transmission electron microscopy ( TEM ) tomography, scanning transmission (soft) X ‐ray microscopy ( STXM ) tomography, and confocal laser scanning microscopy ( CLSM ). It turned out that, due to the various different contrast mechanisms of the individual approaches, and due to the required sample preparation steps, only the combination of these techniques was able to provide a comprehensive understanding of structure and composition of the various Fe‐precipitates and their association with bacterial cells and EPS .
Safety, efficacy and weight effect of two 11β‐ HSD1 inhibitors in metformin‐treated patients with type 2 diabetes
2014-05-14

Aims We assessed safety and efficacy of two selective 11β‐HSD1 inhibitors (RO5093151/RO‐151 and RO5027383/RO‐838) in this randomized, controlled study in metformin‐treated patients with type 2 diabetes. Methods Patients either received placebo (N = 21), RO‐151 BID 5 mg (N = 24) or 200 mg (N = 20) or RO‐838 QD 50 mg (N = 21) or 200 mg (N = 24) for 28 days. Metabolic assessments comprising of nine‐point plasma glucose profiles, oral glucose tolerance tests and determination of metabolic biomarkers including insulin, C‐peptide, glucagon, HbA1c and lipids were done at baseline and end of treatment. Results Despite the short treatment duration, both RO‐151 and RO‐838 showed trends for improved HbA1c and consistent reductions in body weight (–0.86 to –1.67 kg) exceeding those observed with placebo (–0.28 kg, p = 0.019 for 200 mg RO‐151 vs. placebo). Insulin sensitivity parameters (e.g. HOMA‐IR and Matsuda‐Index) improved non‐significantly with 200 mg RO‐151. Lipid parameters did not consistently improve with either compound, but RO‐838 led to non‐significant increases in triglycerides and VLDL‐cholesterol versus placebo. Both compounds were well tolerated and showed inhibitory effects on 11β‐HSD1 activity based on urinary corticosteroid excretion. As reported for other 11β‐HSD1‐inhibitors increased concentrations of ACTH and adrenal androgen precursors were found with RO‐151, but not with RO‐838. Conclusions Slight metabolic improvements were seen, in particular with RO‐151 high dose, however, the observed changes often did not reach statistical significance and were not clearly dose dependent. Studies of longer duration are needed to further investigate potential benefits and risks of these compounds.
Sustainable Intensive Thermal Use of the Shallow Subsurface—A Critical View on the Status Quo
2014-05-14

Abstract Thermal use of the shallow subsurface for heat generation, cooling, and thermal energy storage is increasingly gaining importance in reconsideration of future energy supplies. Shallow geothermal energy use is often promoted as being of little or no costs during operation, while simultaneously being environmentally friendly. Hence, the number of installed systems has rapidly risen over the last few decades, especially among newly built houses. While the carbon dioxide reduction potential of this method remains undoubted, concerns about sustainability and potential negative effects on the soil and groundwater due to an intensified use have been raised—even as far back as 25 years ago. Nevertheless, consistent regulation and management schemes for the intensified thermal use of the shallow subsurface are still missing—mainly due to a lack of system understanding and process knowledge. In the meantime, large geothermal applications, for example, residential neighborhoods that are entirely dependent up on shallow geothermal energy use or low enthalpy aquifer heat storage, have been developed throughout Europe. Potential negative effects on the soil and groundwater due to an intensive thermal use of the shallow subsurface as well as the extent of potential system interaction still remain unknown.
Development and Successful Validation of Simple and Fast TLC Spot Tests for Determination of Kryptofix® 2.2.2 and Tetrabutylammonium in 18F-Labeled Radiopharmaceuticals
2014-05-14

Kryptofix® 2.2.2 (Kry) or tetrabutylammonium (TBA) are commonly used as phase transfer catalysts in 18F-radiopharmaceutical productions for positron emission tomography (PET). Due to their toxicity, quality control has to be performed before administration of the tracer to assure that limit concentration of residual reagent is not reached. Here, we describe the successful development and pharmaceutical validation (for specificity, accuracy and detection limit) of a simplified color spot test on TLC plates. We were able to prove its applicability as a general, time and resources saving, easy to handle and reliable method in daily routine analyzing 18F-tracer formulations for Kry (in [18F]FDG or [18F]FECh) or TBA contaminations (in [18F]FLT) with special regard to complex matrix compositions.
Consequences of climate and body size on the foraging performance of seed‐eating ants
2014-05-14

1. Changes in climatic factors could have major effects on the foraging performance of animals. To date, however, no study has attempted to examine the concurrent effect of different climatic factors on foraging performance of individual organisms. 2. In the present study, this issue was addressed by studying changes in foraging performance of seed‐eating ant colonies of the genus Messor in response to variation in precipitation and ambient temperature along a macroecological gradient. In addition, we examined the way three colony‐level attributes, foraging distance, forager number, and variance in worker‐size, could affect foraging performance in those ants. Foraging performance was measured as size matching, i.e. the correlation between forager size and load size. The study was carried out for 2 years in six sites along a south‐north productivity gradient in a semi‐arid region of the E astern‐ M editerranean. 3. Size matching increased with increased precipitation as well as with an increase in worker‐size variability, but slightly decreased with increasing temperatures, as predicted by foraging‐decision models. In contrast, foraging distance had no effect on size matching. Interestingly, size matching showed a unimodal relationship with forager number. 4. These results indicate that interplay between climate and body size affects foraging performance either directly via physiological constraints, or indirectly through their effect on food availability. Moreover, this is one of the first evidences to support the assumption that ant colonies can differ in their ability to optimally allocate their workforce in natural environments. This emphasises the importance of studying the way foraging strategies vary across environmental gradients at macroecological scales.
Evaluation of Toxicogenomics Approaches for Assessing the Risk of Nongenotoxic Carcinogenicity in Rat Liver
2014-05-14

The current gold-standard method for cancer safety assessment of drugs is a rodent two-year bioassay, which is associated with significant costs and requires testing a high number of animals over lifetime. Due to the absence of a comprehensive set of short-term assays predicting carcinogenicity, new approaches are currently being evaluated. One promising approach is toxicogenomics, which by virtue of genome-wide molecular profiling after compound treatment can lead to an increased mechanistic understanding, and potentially allow for the prediction of a carcinogenic potential via mathematical modeling. The latter typically involves the extraction of informative genes from omics datasets, which can be used to construct generalizable models allowing for the early classification of compounds with unknown carcinogenic potential. Here we formally describe and compare two novel methodologies for the reproducible extraction of characteristic mRNA signatures, which were employed to capture specific gene expression changes observed for nongenotoxic carcinogens. While the first method integrates multiple gene rankings, generated by diverse algorithms applied to data from different subsamplings of the training compounds, the second approach employs a statistical ratio for the identification of informative genes. Both methods were evaluated on a dataset obtained from the toxicogenomics database TG-GATEs to predict the outcome of a two-year bioassay based on profiles from 14-day treatments. Additionally, we applied our methods to datasets from previous studies and showed that the derived prediction models are on average more accurate than those built from the original signatures. The selected genes were mostly related to p53 signaling and to specific changes in anabolic processes or energy metabolism, which are typically observed in tumor cells. Among the genes most frequently incorporated into prediction models were Phlda3, Cdkn1a, Akr7a3, Ccng1 and Abcb4.
Brain mechanisms of acoustic communication in humans and nonhuman primates: An evolutionary perspective
2014-05-15

Abstract Any account of “what is special about the human brain” (Passingham 2008) must specify the neural basis of our unique ability to produce speech and delineate how these remarkable motor capabilities could have emerged in our hominin ancestors. Clinical data suggest that the basal ganglia provide a platform for the integration of primate-general mechanisms of acoustic communication with the faculty of articulate speech in humans. Furthermore, neurobiological and paleoanthropological data point at a two-stage model of the phylogenetic evolution of this crucial prerequisite of spoken language: (i) monosynaptic refinement of the projections of motor cortex to the brainstem nuclei that steer laryngeal muscles, presumably, as part of a “phylogenetic trend” associated with increasing brain size during hominin evolution; (ii) subsequent vocal-laryngeal elaboration of cortico-basal ganglia circuitries, driven by human-specific FOXP2 mutations.;&gt;This concept implies vocal continuity of spoken language evolution at the motor level, elucidating the deep entrenchment of articulate speech into a “nonverbal matrix” (Ingold 1994), which is not accounted for by gestural-origin theories. Moreover, it provides a solution to the question for the adaptive value of the “first word” (Bickerton 2009) since even the earliest and most simple verbal utterances must have increased the versatility of vocal displays afforded by the preceding elaboration of monosynaptic corticobulbar tracts, giving rise to enhanced social cooperation and prestige. At the ontogenetic level, the proposed model assumes age-dependent interactions between the basal ganglia and their cortical targets, similar to vocal learning in some songbirds. In this view, the emergence of articulate speech builds on the “renaissance” of an ancient organizational principle and, hence, may represent an example of “evolutionary tinkering” (Jacob 1977).