julilili42/papers huggingface dataset:
DrugTargetInspector: An assistance tool for patient treatment stratification
2015-10-26

Cancer is a large class of diseases that are characterized by a common set of features, known as the Hallmarks of cancer . One of these hallmarks is the acquisition of genome instability and mutations. This, combined with high proliferation rates and failure of repair mechanisms, leads to clonal evolution as well as a high genotypic and phenotypic diversity within the tumor. As a consequence, treatment and therapy of malignant tumors is still a grand challenge. Moreover, under selective pressure, e.g ., caused by chemotherapy, resistant subpopulations can emerge that then may lead to relapse. In order to minimize the risk of developing multidrug‐resistant tumor cell populations, optimal (combination) therapies have to be determined on the basis of an in‐depth characterization of the tumor's genetic and phenotypic makeup, a process that is an important aspect of stratified medicine and precision medicine. We present DrugTargetInspector (DTI), an interactive assistance tool for treatment stratification. DTI analyzes genomic, transcriptomic, and proteomic datasets and provides information on deregulated drug targets, enriched biological pathways, and deregulated subnetworks, as well as mutations and their potential effects on putative drug targets and genes of interest. To demonstrate DTI's broad scope of applicability, we present case studies on several cancer types and different types of input ‐omics data. DTI's integrative approach allows users to characterize the tumor under investigation based on various ‐omics datasets and to elucidate putative treatment options based on clinical decision guidelines, but also proposing additional points of intervention that might be neglected otherwise. DTI can be freely accessed at http://dti.bioinf.uni‐sb.de .
Targeting the Gatekeeper MET146 of C-Jun N-Terminal Kinase 3 Induces a Bivalent Halogen/Chalcogen Bond
2015-10-27

We target the gatekeeper MET146 of c-Jun N-terminal kinase 3 (JNK3) to exemplify the applicability of X···S halogen bonds in molecular design using computational, synthetic, structural and biophysical techniques. In a designed series of aminopyrimidine-based inhibitors, we unexpectedly encounter a plateau of affinity. Compared to their QM-calculated interaction energies, particularly bromine and iodine fail to reach the full potential according to the size of their σ-hole. Instead, mutation of the gatekeeper residue into leucine, alanine, or threonine reveals that the heavier halides can significantly influence selectivity in the human kinome. Thus, we demonstrate that, although the choice of halogen may not always increase affinity, it can still be relevant for inducing selectivity. Determining the crystal structure of the iodine derivative in complex with JNK3 (4X21) reveals an unusual bivalent halogen/chalcogen bond donated by the ligand and the back-pocket residue MET115. Incipient repulsion from the too short halogen bond increases the flexibility of Cε of MET146, whereas the rest of the residue fails to adapt being fixed by the chalcogen bond. This effect can be useful to induce selectivity, as the necessary combination of methionine residues only occurs in 9.3% of human kinases, while methionine is the predominant gatekeeper (39%).
Skin-Specific Unsaturated Fatty Acids Boost the Staphylococcus aureus Innate Immune Response
2015-10-27

ABSTRACT Antimicrobial fatty acids (AFAs) protect the human epidermis against invasion by pathogenic bacteria. In this study, we questioned whether human skin fatty acids (FAs) can be incorporated into the lipid moiety of lipoproteins and whether such incorporation would have an impact on innate immune stimulation in the model organism Staphylococcus aureus USA300 JE2. This organism synthesized only saturated FAs. However, when feeding USA300 with unsaturated FAs present on human skin (C 16:1 , C 18:1 , or C 18:2 ), those were taken up, elongated stepwise by two carbon units, and finally found in the bacterial (phospho)lipid fraction. They were also observed in the lipid moiety of lipoproteins. When USA300 JE2 was fed with the unsaturated FAs, the cells and cell lysates showed an increased innate immune activation with various immune cells and peripheral blood mononuclear cells (PBMCs). Immune activation was highest with linoleic acid (C 18:2 ). There are several pieces of evidence that the enhanced immune stimulating effect was due to the incorporation of unsaturated FAs in lipoproteins. First, the enhanced stimulation was dependent on Toll-like receptor 2 (TLR2). Second, an lgt mutant, unable to carry out lipidation of prolipoproteins, was unable to carry out immune stimulation when fed with unsaturated FAs. Third, the supplied FAs did not significantly affect growth, protein release, or expression of the model lipoprotein Lpl1. Although S. aureus is unable to synthesize unsaturated FAs, it incorporates long-chain unsaturated FAs into its lipoproteins, with the effect that the cells are better recognized by the innate immune system. This is an additional mechanism how our skin controls bacterial colonization and infection.
The influence of math anxiety on symbolic and non-symbolic magnitude processing
2015-10-27

Deficits in basic numerical abilities have been investigated repeatedly as potential risk factors of math anxiety. Previous research suggested that also a deficient approximate number system (ANS), which is discussed as being the foundation for later math abilities, underlies math anxiety. However, these studies examined this hypothesis by investigating ANS acuity using a symbolic number comparison task. Recent evidence questions the view that ANS acuity can be assessed using a symbolic number comparison task. To investigate whether there is an association between math anxiety and ANS acuity, we employed both a symbolic number comparison task and a non-symbolic dot comparison task, which is currently the standard task to assess ANS acuity. We replicated previous findings regarding the association between math anxiety and the symbolic distance effect for response times. High math anxious individuals showed a larger distance effect than less math anxious individuals. However, our results revealed no association between math anxiety and ANS acuity assessed using a non-symbolic dot comparison task. Thus, our results did not provide evidence for the hypothesis that a deficient ANS underlies math anxiety. Therefore, we propose that a deficient ANS does not constitute a risk factor for the development of math anxiety. Moreover, our results suggest that previous interpretations regarding the interaction of math anxiety and the symbolic distance effect have to be updated. We suggest that impaired number comparison processes in high math anxious individuals might account for the results rather than deficient ANS representations. Finally, impaired number comparison processes might constitute a risk factor for the development of math anxiety. Implications for current models regarding the origins of math anxiety are discussed.
Resiliency of Stable Isotope Fractionation (δ13C and δ37Cl) of Trichloroethene to Bacterial Growth Physiology and Expression of Key Enzymes
2015-10-27

Quantification of in situ (bio)degradation using compound-specific isotope analysis requires a known and constant isotope enrichment factor (ε). Because reported isotope enrichment factors for microbial dehalogenation of chlorinated ethenes vary considerably we studied the potential effects of metabolic adaptation to TCE respiration on isotope fractionation (δ(13)C and δ(37)Cl) using a model organism (Desulfitobacterium hafniesne Y51), which only has one reductive dehalogenase (PceA). Cells grown on TCE for the first time showed exponential growth until 10(9) cells/mL. During exponential growth, the cell-normalized amount of PceA enzyme increased steadily in the presence of TCE (up to 21 pceA transcripts per cell) but not with alternative substrates (<1 pceA transcript per cell). Cultures initially transferred or subcultivated on TCE showed very similar isotope fractionation, both for carbon (εcarbon: -8.6‰ ± 0.3‰ or -8.8‰ ± 0.2‰) and chlorine (εchlorine: -2.7‰ ± 0.3‰) with little variation (0.7‰) for the different experimental conditions. Thus, TCE isotope fractionation by D. hafniense strain Y51 was affected by neither growth phase, pceA transcription, or translation, nor by PceA content per cell, suggesting that transport limitations did not affect isotope fractionation. Previously reported variable ε values for other organohalide-respiring bacteria might thus be attributed to different expression levels of their multiple reductive dehalogenases.
Characterizing the Propagation of Uterine Electrophysiological Signals Recorded with a Multi-Sensor Abdominal Array in Term Pregnancies
2015-10-27

The objective of this study was to quantify the number of segments that have contractile activity and determine the propagation speed from uterine electrophysiological signals recorded over the abdomen. The uterine magnetomyographic (MMG) signals were recorded with a 151 channel SARA (SQUID Array for Reproductive Assessment) system from 36 pregnant women between 37 and 40 weeks of gestational age. The MMG signals were scored and segments were classified based on presence of uterine contractile burst activity. The sensor space was then split into four quadrants and in each quadrant signal strength at each sample was calculated using center-of-gravity (COG). To this end, the cross-correlation analysis of the COG was performed to calculate the delay between pairwise combinations of quadrants. The relationship in propagation across the quadrants was quantified and propagation speeds were calculated from the delays. MMG recordings were successfully processed from 25 subjects and the average values of propagation speeds ranged from 1.3-9.5 cm/s, which was within the physiological range. The propagation was observed between both vertical and horizontal quadrants confirming multidirectional propagation. After the multiple pairwise test (99% CI), significant differences in speeds can be observed between certain vertical or horizontal combinations and the crossed pair combinations. The number of segments containing contractile activity in any given quadrant pair with a detectable delay was significantly higher in the lower abdominal pairwise combination as compared to all others. The quadrant-based approach using MMG signals provided us with high spatial-temporal information of the uterine contractile activity and will help us in the future to optimize abdominal electromyographic (EMG) recordings that are practical in a clinical setting.
Triazine Annelated NHC Featuring Unprecedented Coordination Versatility
2015-10-27

The new N-heterocyclic carbene ligand 3 is presented, which features both a weak σ-donor and a pronounced π-acceptor character. This electronic feature is realized by a side-on annelation of a bis(imidazo)triazine fragment. The coordination chemistry shows the ability of the species to act as a monodentate as well as a chelating and a bridging ligand. The last coordination mode is realized in the solid state of the complex [Rh(cod)(3)]BF4, in which three fragments are assembled around a BF4– fragment via anion−π interactions with the triazine moieties.
Richard Goodwin’s recruitment of non-linearity into a monolithic scientific community: an homage
2015-10-27

The historical hypothesis is proposed that Richard Goodwin’s seminal decision to base economic theory on the non-linear mathematics of chaos theory had to do with his visit to Tubingen in the mid-1980s. In the decade after, another non-linear dynamical phenomenon related to chaos, the Milnor attractor of differential topology, was recruited into mathematical economics. The development swerve is outlined in a bit more detail.
Attention Modulates TMS-Locked Alpha Oscillations in the Visual Cortex
2015-10-28

Cortical oscillations, such as 8–12 Hz alpha-band activity, are thought to subserve gating of information processing in the human brain. While most of the supporting evidence is correlational, causal evidence comes from attempts to externally drive (“entrain”) these oscillations by transcranial magnetic stimulation (TMS). Indeed, the frequency profile of TMS-evoked potentials (TEPs) closely resembles that of oscillations spontaneously emerging in the same brain region. However, it is unclear whether TMS-locked and spontaneous oscillations are produced by the same neuronal mechanisms. If so, they should react in a similar manner to top-down modulation by endogenous attention. To test this prediction, we assessed the alpha-like EEG response to TMS of the visual cortex during periods of high and low visual attention while participants attended to either the visual or auditory modality in a cross-modal attention task. We observed a TMS-locked local oscillatory alpha response lasting several cycles after TMS (but not after sham stimulation). Importantly, TMS-locked alpha power was suppressed during deployment of visual relative to auditory attention, mirroring spontaneous alpha amplitudes. In addition, the early N40 TEP component, located at the stimulation site, was amplified by visual attention. The extent of attentional modulation for both TMS-locked alpha power and N40 amplitude did depend, with opposite sign, on the individual ability to modulate spontaneous alpha power at the stimulation site. We therefore argue that TMS-locked and spontaneous oscillations are of common neurophysiological origin, whereas the N40 TEP component may serve as an index of current cortical excitability at the time of stimulation. SIGNIFICANCE STATEMENT Rhythmic transcranial magnetic stimulation (TMS) is a promising tool to experimentally “entrain” cortical activity. If TMS-locked oscillatory responses actually recruit the same neuronal mechanisms as spontaneous cortical oscillations, they qualify as a valid tool to study the causal role of neuronal oscillations in cognition but also to enable new treatments targeting aberrant oscillatory activity in, for example, neurological conditions. Here, we provide first-time evidence that TMS-locked and spontaneous oscillations are indeed tightly related and are likely to rely on the same neuronal generators. In addition, we demonstrate that an early local component of the TMS-evoked potential (the N40) may serve as a new objective and noninvasive probe of visual cortex excitability, which so far was only accessible via subjective phosphene reports.
Do We Need to Distance Ourselves from the Distance Concept? Why Home and Host Country Context Might Matter More Than (Cultural) Distance
2015-10-28

Abstract We scrutinize the explanatory power of one of the key concepts in International Business: the concept of (cultural) distance. Here we focus on its effect on entry mode choice, one of the most researched fields in international business strategy. Our findings might, however, be equally be relevant for the field of International Business as a whole. Our analysis is based on a review of 92 prior studies on entry mode choice, as well as an empirical investigation in over 800 subsidiaries of MNCs, covering nine host and fifteen home countries across the world. We conclude that the explanatory power of distance is highly limited once home and host country context are accounted for, and that any significant effects of cultural distance on entry mode choice might simply be caused by inadequate sampling. Entry mode studies in particular, and International Business research in general, would do well to reconsider its fascination with distance measures, and instead, focus first and foremost on differences in home and host country context. We argue that serious engagement with deep contextualization is necessary in International Business research to pose new and relevant questions and develop new and innovative theories that explain empirical phenomena.
Crohn's disease-derived monocytes fail to induce Paneth cell defensins
2015-10-28

Significance Paneth cell defensins (human α-defensins 5 and 6) are central players in the regulation of the human microbiome in the small intestine, but their regulation remains unclear. Here, we show that healthy monocytes can induce the expression of these defensins via Wnt ligands, especially in patients with Crohn’s disease (CD), who normally display reduced levels of human α-defensin 5 (HD5) and HD6, resulting in impaired host defense and, consequently, mucosal inflammation. However, monocytes from these patients are lacking this defensin-inducing capability, which seems to be based on compromised expression of Wnt ligands. This translational human study demonstrates defective cross-talk between monocytes and Paneth cells in CD with implications for gastrointestinal infections and bone marrow transplantation.
Robustness of sensory-evoked excitation is increased by inhibitory inputs to distal apical tuft dendrites
2015-10-28

Significance Even the simplest sensory stimulus activates millions of synapses across the cortex. How neurons integrate these highly specialized, but noisy synaptic input patterns to generate robust electrophysiological responses—that ultimately translate into behavior—remains elusive. Here, we provide first insight into a mechanism that may underlie the general phenomenon, observed across sensory modalities and species, that stimulation decreases variability in neuronal activity. Specifically, we show that during sensory stimulation, highly specialized inhibitory neurons provide synaptic input to distal dendrites of excitatory neurons, which reduces variability but not the mean amplitude of the response. Distal dendritic shunting may thus represent a general principle of cortex organization to ensure that noisy synaptic input patterns translate into robust sensory-evoked neuronal activity.
Biosynthetic Origin of the Antibiotic Pseudopyronines A and B in Pseudomonas putida BW11M1
2015-10-28

Abstract Within the framework of our effort to discover new antibiotics from pseudomonads, pseudopyronines A and B were isolated from the plant‐derived Pseudomonas putida BW11M1. Pseudopyronines are 3,6‐dialkyl‐4‐hydroxy‐2‐pyrones and displayed high in vitro activities against several human pathogens, and in our hands also towards the plant pathogen Pseudomonas savastanoi . Here, the biosynthesis of pseudopyronine B was studied by a combination of feeding experiments with isotopically labeled precursors, genomic sequence analysis, and gene deletion experiments. The studies resulted in the deduction of all acetate units and revealed that the biosynthesis of these α‐pyrones occurs with a single PpyS‐homologous ketosynthase. It fuses, with some substrate flexibility, a 3‐oxo‐fatty acid and a further unbranched saturated fatty acid, both of medium chain‐length and provided by primary metabolism.
XMM-Newtonstudy of the Draco dwarf spheroidal galaxy
2015-10-28

Aims. We present the results of the analysis of five XMM-Newton observations of the Draco dwarf spheroidal galaxy (dSph). The aim of the work is the study of the X-ray population in the field of the Draco dSph.
A KEPLERIAN-LIKE DISK AROUND THE FORMING O-TYPE STAR AFGL 4176
2015-10-29

We present Atacama Large Millimeter/submillimeter Array (ALMA) line and\\ncontinuum observations at 1.2mm with ~0.3" resolution that uncover a\\nKeplerian-like disk around the forming O-type star AFGL 4176. The continuum\\nemission from the disk at 1.21 mm (source mm1) has a deconvolved size of\\n870+/-110 AU x 330+/-300 AU and arises from a structure ~8 M_sun in mass,\\ncalculated assuming a dust temperature of 190 K. The first-moment maps,\\npixel-to-pixel line modeling, assuming local thermodynamic equilibrium (LTE),\\nand position-velocity diagrams of the CH3CN J=13-12 K-line emission all show a\\nvelocity gradient along the major axis of the source, coupled with an increase\\nin velocity at small radii, consistent with Keplerian-like rotation. The LTE\\nline modeling shows that where CH3CN J=13-12 is excited, the temperatures in\\nthe disk range from ~70 to at least 300 K and that the H2 column density peaks\\nat 2.8x10^24 cm^-2. In addition, we present Atacama Pathfinder Experiment\\n(APEX) 12CO observations which show a large-scale outflow from AFGL 4176\\nperpendicular to the major axis of mm1, supporting the disk interpretation.\\nFinally, we present a radiative transfer model of a Keplerian disk surrounding\\nan O7 star, with a disk mass and radius of 12 M_sun and 2000 AU, that\\nreproduces the line and continuum data, further supporting our conclusion that\\nour observations have uncovered a Keplerian disk around an O-type star.\\n
Low-grade Glioma Surgery in Intraoperative Magnetic Resonance Imaging
2015-10-29

EoR, extent of resectionFLAIR, fluid-attenuated inversion recoveryGTR, gross total resectionIDH1, isocitrate dehydrogenase 1iMRI, intraoperative magnetic resonance imagingLGG, low-grade gliomaMGMT, methylguanine-deoxyribonucleic acid methyltransferasenPND, new permanent neurological deficitOS, overall survivalPFS, progression-free survivalSTR, subtotal resectionWHO, World Health Organization.
Long-term survival correlates with immunological responses in renal cell carcinoma patients treated with mRNA-based immunotherapy
2015-10-29

Renal cell carcinoma (RCC) is an immunogenic tumor for which immunotherapeutic approaches could be associated with clinically relevant responses. It was recently shown, that induction of T-cell responses against multiple tumor-associated antigen (TAA) epitopes results in prolonged overall survival in RCC patients. In 2003-2005, we performed a phase I/II trial testing an mRNA-based vaccine formulation consisting of a mixture of in vitro transcribed RNA coding for six different TAAs (MUC1, CEA, Her2/neu, telomerase, survivin, MAGE-A1) in 30 metastatic RCC (mRCC) patients. In the first 14 patients, vaccinations were applied i.d. on days 0, 14, 28, and 42. In the consecutive 16 patients, an intensified protocol consisting of i.d. injections (daily on days 0-3, 7-10, 28, and 42) was used. After the respective induction periods, patients in both cohorts were vaccinated monthly until tumor progression. At survival update performed in July 2015, one of the 30 patients was still alive. One patient was lost to follow-up. Median survival of 24.5 mo (all patients) and 89 mo (favorable risk patients) exceeded predicted survival according to Memorial Sloan Kettering Cancer Center (MSKCC) risk score. Impressively, long-term survivors displayed immunological responses to the applied antigens while vice versa no patient without detectable immune response had survived more than 33 mo. The current survival update shows a clear correlation between survival and immunological responses to TAAs encoded by the naked mRNA vaccine. This is one of the first vaccination studies and the only RNA trial that reports on safety and efficacy after a follow-up of more than 10 y.
Artesunate-amodiaquine versus artemether-lumefantrine for the treatment of acute uncomplicated malaria in Congolese children under 10 years old living in a suburban area: a randomized study
2015-10-29

This first randomized study in Brazzaville confirmed the excellent efficacy of these co-formulated anti-malarial drugs in children. Sickle cell genotype did not influence the treatment efficacy of artemisinin-based combination therapy.
In Vivo Evaluation of 11C-DASB for Quantitative SERT Imaging in Rats and Mice
2015-10-29

Our data showed that in rats, (11)C-DASB can be used to quantify SERT density with good reproducibility. BPND agreed with the distribution of SERT in the rat brain. It remains difficult to estimate quantitative parameters accurately from mouse measurements because of the high injected tracer mass and underestimation of the binding parameters due to high displaceable binding in the reference region.