julilili42/papers huggingface dataset:
P01.31 Mammalian target of rapamycin complex 1 activation sensitizes human glioma cells to hypoxia-induced cell death
2017-04-01

Glioblastomas (GBs) are characterized by a fast uncontrolled growth leading to hypoxic areas and necrosis. Signalling from epidermal growth factor receptor (EGFR) via mammalian target of rapamycin complex 1 (mTORC1) is one of the most commonly altered signalling pathways in GBs. Therefore, EGFR and mTORC1 signalling are plausible targets for GB therapy and clinical trials with inhibitors are in progress. However, we have previously shown that EGFR and mTORC1 inhibition triggers metabolic changes leading to adverse effects under the conditions of the tumour microenvironment by protecting tumour cells from hypoxia-induced cell death. We hypothesized conversely that mTORC1 activation sensitizes glioma cells towards hypoxia-induced cell death. As a model for mTORC1 activation we used TSC2 gene suppression (TSC2sh). TSC2sh glioma cells showed increased sensitivity towards hypoxia-induced cell death that was accompanied by an earlier ATP depletion and an increase in reactive oxygen species. There was no difference in extracellular glucose consumption but an altered intracellular metabolic profile with an increase of intermediates of the pentose phosphate pathway (PPP). Mechanistically mTORC1 upregulates the first and rate limiting enzyme of the PPP, glucose 6-phosphate dehydrogenase (G6PD), in a post-transcriptional manner. Furthermore an increase in O2 consumption in TSC2sh cells was detected. This appears to be due to higher transcription rates of genes involved in mitochondrial respiratory function including PGC-1-α and -β. In a translational approach, the finding that mTORC1 activation causes an increase in O2 consumption and renders malignant glioma cells susceptible to hypoxia and nutrient deprivation could help identify GB patient cohorts more likely to benefit from hypoxia-inducing therapies such as the VEGF-A-targeting antibody bevacizumab.
Investigation of mixing enhancement in porous media under helical flow conditions: 3-D bench-scale experiments
2017-04-01

Lateral mass exchange at the fringe of solute plumes is a fundamental process leading to plume dilution and reactive mixing. Mass transfer between the plume and ambient water can be considerably enhanced by helical flow occurring in three-dimensional heterogeneous anisotropic porous media [1-3]. We performed steady-state conservative tracer experiments in a fully three-dimensional flow-through chamber to investigate the effects of helical flow on plume spiraling and deformation, as well as on its dilution [4]. Helical flow was created by packing the porous medium in angled stripes of materials with different grain sizes to create blocks with macroscopically anisotropic hydraulic conductivity. The hydraulic conductivity of the blocks was varied in different experiments. Solute concentrations and flow rates were measured at high spatial resolution for samples collected at 49 outlet ports. This allowed us to quantify spreading and dilution of the solute plumes at the outlet cross section. Moreover, we collected direct evidence of plume spiraling and visual proof of helical flow by freezing and slicing the porous medium at different cross sections and observing the dye-tracer distribution. Model-based interpretation of the results allowed substantiating the effect of the helical flow field on plume dilution and on mixing-controlled reactive transport. The simulation results were evaluated using metrics of reactive mixing such as the critical dilution index and the length of continuously injected steady-state plumes.
Sediment reallocations due to erosive rainfall events in the Three Gorges Reservoir Area, Central China
2017-04-01

Soil erosion by water outlines a major threat to the Three Gorges Reservoir Area in China. A detailed assessment of soil conservation measures requires a tool that spatially identifies sediment reallocations due to rainfall–runoff events in catchments. We applied EROSION 3D as a physically based soil erosion and deposition model in a small mountainous catchment. Generally, we aim to provide a methodological frame that facilitates the model parametrization in a data scarce environment and to identify sediment sources and deposits. We used digital soil mapping techniques to generate spatially distributed soil property information for parametrization. For model calibration and validation, we continuously monitored the catchment on rainfall, runoff and sediment yield for a period of 12 months. The model performed well for large events (sediment yield>1 Mg) with an averaged individual model error of 7.5%, while small events showed an average error of 36.2%. We focused on the large events to evaluate reallocation patterns. Erosion occurred in 11.1% of the study area with an average erosion rate of 49.9Mgha 1. Erosion mainly occurred on crop rotation areas with a spatial proportion of 69.2% for ‘corn-rapeseed’ and 69.1% for ‘potato-cabbage’. Deposition occurred on 11.0%. Forested areas (9.7%), infrastructure (41.0%), cropland (corn- rape seed: 13.6%, potato-cabbage: 11.3%) and grassland (18.4%) were affected by deposition. Because the vast majority of annual sediment yields (80.3%) were associated to a few large erosive events, the modelling approach provides a useful tool to spatially assess soil erosion control and conservation measures.
Individualized proteogenomics in analysis of resistance to BRAF inhibition in malignant melanoma
2017-04-01

Malignant melanoma is characterized by somatic BRAF and RAS mutations in the mitogen‐activated kinase pathway (MAPK), which strongly correlate with poor prognosis of the disease. The serine‐threonine kinase BRAF is mutated in ~70% of melanoma cases, resulting predominantly in V600E substitution and leading to constitutive activation of downstream MAP kinase signaling pathways. Targeted inhibition of the mutated BRAF with selective inhibitors like vemurafenib or dabrafenib results in the reduction of MAPK signaling and regression of the disease. However, most patients quickly develop resistance to drug treatment. Several mechanisms for the acquired resistance in melanoma have been detected in vivo and in vitro , but key (phospho)proteins involved in resistance as well as somatic mutations that can alter their modification status and can therefore influence development of resistance are still largely elusive. Here we use quantitative proteogenomics based on stable isotope labeling with amino acids in cell culture (SILAC) to investigate the proteome of five drug‐resistant and drug‐sensitive melanoma cell lines. Among 7,808 quantified proteins and 13,452 phosphorylation sites, we detect 53 proteins and 312 phosphorylation sites involved in major biological processes and cancer‐related signaling pathways that were significantly changing in resistant cells and therefore constitute potential therapeutic targets or markers of the resistance to BRAF inhibitors. To validate our data set, we focused on several interesting candidates and validated their levels by western blot across all investigated cell lines. We are currently knocking‐out respective genes using CRISPR/Cas9 and assaying genome‐edited melanoma cell lines for variability, cell migration, cell invasion and cell apoptosis. To study the influence of non‐synonymous somatic mutations on the signal transduction networks, we established a bioinformatics workflow for prediction of non‐synonymous single nucleotide variants (nsSNVs), as well as insertions or deletions (InDels) of nucleotides, and applied it to exome sequencing data from the vemurafenib‐sensitive and resistant melanoma cell line A375. This led to A375‐specific protein database containing 18,786 single amino acid variants (SAVs), of which 1,325 have not been reported previously. Over 8,800 SAVs affected modifiable amino acid residues Ser/Thr/Tyr and Lys, therefore potentially influencing signal transduction networks involved in resistance. To conclude, our (phospho)proteomics data provide important insights into molecular mechanisms underlying resistance to BRAF inhibition and the established proteogenomics workflow can be directly used for a personalized approach to cancer understanding and individualized treatment.
The renal benzamil‐insensitive K + excretion is independent of the BK channel
2017-04-01

Introduction Two different secretory K + channels are involved in the final homeostatic K + excretion that takes place in the aldosterone‐sensitive distal nephron. One is the ROMK channel that co‐localizes with ENaC in the apical membrane of principal cells (PC) in the connecting tubule and collecting duct. PCs have a high expression of basolateral Na + /K + ‐ATPase allowing for pump‐leak secretion of K + . K + secretion via ROMK depends on Na + reabsorption by ENaC to generate the necessary driving force. The BK (K Ca 1.1) channel is the other secretory pathway and is primarily found in the apical membrane of intercalated cells. The cellular mechanism of BK‐mediated K + secretion is not fully understood. It is associated with flow‐induced K + secretion (FIKS), since the kaliuretic response to increased flow is attenuated in KCNMA −/− (BK‐α knockout) mice as well as in IbTX treated tubules. Benzamil inhibits renal K + excretion, however, leaving a blocker‐insensitive component intact. After chronic high K + diet the benzamil‐insensitive renal K + excretion is upregulated. In this project we asked, if the benzamil‐insensitive K + excretion is mediated by the BK channel. Methods The benzamil‐sensitive and ‐insensitive kaliuresis was investigated in vivo in KCNMA +/+ and KCNMA −/− mice. This was performed on either control or high K + (5 %) diet. Mice were pretreated with vehicle or benzamil and then received a volume‐load via gavage containing either control (sucrose 2%) or high K + (2 %). Gavage increased diuresis and thus flow in the distal tubules. This is seen both with control gavage, where excess K + excretion is unnecessary, and with K + gavage that should naturally increase the need for K + excretion. Results We confirmed that benzamil attenuated, however, not completely abolished, urinary K + excretion in all experiments. Hence, the K + excretion could be divided into a benzamil‐sensitive and ‐insensitive fraction. The benzamil‐insensitive K + excretion was upregulated by K + loading, both acutely by K + gavage but especially by chronic K + ‐loading via high K + diet. Importantly, we found no difference in the benzamil‐insensitive K + excretion between KCNMA +/+ and KCNMA −/− mice in any of the investigated conditions. Conclusion Our data suggests (1) that K + secretion via both ROMK and BK is highly dependent on ENaC activity and (2) that ROMK‐mediated K + secretion compensates for the lack of BK‐mediated K + secretion in KCNMA −/− mice. Furthermore (3), the benzamil‐insensitive K + secretion appears independent of the BK channel and (4) is markedly regulated by both acute and chronic K + ‐loading.
Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia
2017-04-02

Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10-4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.
TreeBUGS: An R package for hierarchical multinomial-processing-tree modeling
2017-04-03

Multinomial processing tree (MPT) models are a class of measurement models that account for categorical data by assuming a finite number of underlying cognitive processes. Traditionally, data are aggregated across participants and analyzed under the assumption of independently and identically distributed observations. Hierarchical Bayesian extensions of MPT models explicitly account for participant heterogeneity by assuming that the individual parameters follow a continuous hierarchical distribution. We provide an accessible introduction to hierarchical MPT modeling and present the user-friendly and comprehensive R package TreeBUGS, which implements the two most important hierarchical MPT approaches for participant heterogeneity-the beta-MPT approach (Smith & Batchelder, Journal of Mathematical Psychology 54:167-183, 2010) and the latent-trait MPT approach (Klauer, Psychometrika 75:70-98, 2010). TreeBUGS reads standard MPT model files and obtains Markov-chain Monte Carlo samples that approximate the posterior distribution. The functionality and output are tailored to the specific needs of MPT modelers and provide tests for the homogeneity of items and participants, individual and group parameter estimates, fit statistics, and within- and between-subjects comparisons, as well as goodness-of-fit and summary plots. We also propose and implement novel statistical extensions to include continuous and discrete predictors (as either fixed or random effects) in the latent-trait MPT model.
Learner agency and non-native speaker identity in pedagogical lingua franca conversations: insights from intercultural telecollaboration in foreign language education
2017-04-03

This article discusses insights gained from a case study on telecollaboration for intercultural communication in foreign language school contexts. Focus was on non-native English and German lingua franca conversations between pairs of students (aged 14–16, B1 level) from schools in France, Germany, the Netherlands and Spain. Telecollaboration support included the BigBlueButton video communication platform and Moodle chat. The overall objective was to explore the pedagogical potential of pedagogical lingua franca exchanges via telecollaboration for authentic intercultural communication practice and foreign language competence development beyond the face-to-face classroom. Qualitative and quantitative analyses of oral and written lingua franca conversations and corresponding reflective feedback interviews provided evidence of (a) increased learner agency in connection with communicative participation, topic development, languaging for communicative success and rapport building, and (b) emerging emancipatory qualities of non-native speaker identity including a growing sense of speaker satisfaction and trust in one's own creativity and strategic resourcefulness. The crucial pedagogical key was an open, social constructivist language learning orientation combined with rich opportunities for authentic communication. Intercultural communicative competence development was significantly improved, and transcending the foreign language classroom to include elements of real life became a tangible experience for the students and teachers involved.
Facial shape differences between rats selected for tame and aggressive behaviors
2017-04-03

Domestication has been consistently accompanied by a suite of traits called the domestication syndrome. These include increased docility, changes in coat coloration, prolonged juvenile behaviors, modified function of adrenal glands and reduced craniofacial dimensions. Wilkins et al recently proposed that the mechanistic factor underlying traits that encompass the domestication syndrome was altered neural crest cell (NCC) development. NCC form the precursors to a large number of tissue types including pigment cells, adrenal glands, teeth and the bones of the face. The hypothesis that deficits in NCC development can account for the domestication syndrome was partly based on the outcomes of Dmitri Belyaev's domestication experiments initially conducted on silver foxes. After generations of selecting for tameness, the foxes displayed phenotypes observed in domesticated species. Belyaev also had a colony of rats selected over 64 generations for either tameness or defensive aggression towards humans. Here we focus on the facial morphology of Belyaev's tame, 'domesticated' rats to test whether: 1) tameness in rats causes craniofacial changes similar to those observed in the foxes; 2) facial shape, i.e. NCC-derived region, is distinct in the tame and aggressive rats. We used computed-tomography scans of rat skulls and landmark-based geometric morphometrics to quantify and analyze the facial skeleton. We found facial shape differences between the tame and aggressive rats that were independent of size and which mirrored changes seen in domesticated animals compared to their wild counterparts. However, there was no evidence of reduced sexual dimorphism in the face of the tame rats. This indicates that not all morphological changes in NCC-derived regions in the rats follow the pattern of shape change reported in domesticated animals or the silver foxes. Thus, certain phenotypic trends that are part of the domestication syndrome might not be consistently present in all experimental animal models.
Fragmentation and disk formation in high-mass star formation: The ALMA view of G351.77-0.54 at 0.06′′ resolution
2017-04-03

© ESO, 2017. Context. The fragmentation of high-mass gas clumps and the formation of the accompanying accretion disks lie at the heart of high-mass star formation research. Aims. We resolve the small-scale structure around the high-mass hot core G351.77-0.54 to investigate its disk and fragmentation properties. Methods. Using the Atacama Large Millimeter Array at 690 GHz with baselines exceeding 1.5 km, we study the dense gas, dust, and outflow emission at an unprecedented spatial resolution of 0.06'' (130 AU at 2.2 kpc). Results. Within the inner few 1000 AU, G351.77 is fragmenting into at least four cores (brightness temperatures between 58 and 201 K). The central structure around the main submm source #1 with a diameter of ~0.5'' does not show additional fragmentation. While the CO(6-5) line wing emission shows an outflow lobe in the northwestern direction emanating from source #1, the dense gas tracer CH 3 CN shows a velocity gradient perpendicular to the outflow that is indicative of rotational motions. Absorption profile measurements against the submm source #2 indicate infall rates on the order of 10 -4 to 10 -3 M . yr -1 , which can be considered as an upper limit of the mean accretion rates. The position-velocity diagrams are consistent with a central rotating disk-like structure embedded in an infalling envelope, but they may also be influenced by the outflow. Using the CH 3 CN(37 k -36 k ) k-ladder with excitation temperatures up to 1300 K, we derive a gas temperature map for source #1 exhibiting temperatures often in excess of 1000 K. Brightness temperatures of the submm continuum barely exceed 200 K. This discrepancy between gas temperatures and submm dust brightness temperatures (in the optically thick limit) indicates that the dust may trace the disk mid-plane, whereas the gas could trace a hotter gaseous disk surface layer. We conduct a pixel-by-pixel Toomre gravitational stability analysis of the central rotating structure. The derived high Q values throughout the structure confirm that this central region appears stable against gravitational instability. Conclusions. Resolving for the first time a high-mass hot core at 0.06'' resolution at submm wavelengths in the dense gas and dust emission allowed us to trace the fragmenting core and the gravitationally stable inner rotating disk-like structure. A temperature analysis reveals hot gas and comparably colder dust that may be attributed to different disk locations traced by dust emission and gas lines. The kinematics of the central structure #1 reveal contributions from a rotating disk, an infalling envelope, and potentially an outflow as well, whereas the spectral profile toward source #2 can be attributed to infall.
The human body odor compound androstadienone leads to anger-dependent effects in an emotional Stroop but not dot-probe task using human faces
2017-04-03

The androgen derivative androstadienone is a substance found in human sweat and thus is a putative human chemosignal. Androstadienone has been studied with respect to effects on mood states, attractiveness ratings, physiological and neural activation. With the current experiment, we aimed to explore in which way androstadienone affects attention to social cues (human faces). Moreover, we wanted to test whether effects depend on specific emotions, the participants' sex and individual sensitivity to smell androstadienone. To do so, we investigated 56 healthy individuals (thereof 29 females taking oral contraceptives) with two attention tasks on two consecutive days (once under androstadienone, once under placebo exposure in pseudorandomized order). With an emotional dot-probe task we measured visuo-spatial cueing while an emotional Stroop task allowed us to investigate interference control. Our results suggest that androstadienone acts in a sex, task and emotion-specific manner as a reduction in interference processes in the emotional Stroop task was only apparent for angry faces in men under androstadienone exposure. More specifically, men showed a smaller difference in reaction times for congruent compared to incongruent trials. At the same time also women were slightly affected by smelling androstadienone as they classified angry faces more often correctly under androstadienone. For the emotional dot-probe task no modulation by androstadienone was observed. Furthermore, in both attention paradigms individual sensitivity to androstadienone was neither correlated with reaction times nor error rates in men and women. To conclude, exposure to androstadienone seems to potentiate the relevance of angry faces in both men and women in connection with interference control, while processes of visuo-spatial cueing remain unaffected.