julilili42/papers huggingface dataset:
Genetic variation in human drug-related genes
2017-06-07

Abstract Variability in drug efficacy and adverse effects are observed in clinical practice. While the extent of genetic variability in classical pharmacokinetic genes is rather well understood, the role of genetic variation in drug targets is typically less studied. Based on 60,706 human exomes from the ExAC dataset, we performed an in-depth computational analysis of the prevalence of functional-variants in in 806 drug-related genes, including 628 known drug targets. We find that most genetic variants in these genes are very rare (f &lt; 0.1%) and thus likely not observed in clinical trials. Overall, however, four in five patients are likely to carry a functional-variant in a target for commonly prescribed drugs and many of these might alter drug efficacy. We further computed the likelihood of 1,236 FDA approved drugs to be affected by functional-variants in their targets and show that the patient-risk varies for many drugs with respect to geographic ancestry. A focused analysis of oncological drug targets indicates that the probability of a patient carrying germline variants in oncological drug targets is with 44% high enough to suggest that not only somatic alterations, but also germline variants carried over into the tumor genome should be included in therapeutic decision-making.
Weekly Time Course of Neuro-Muscular Adaptation to Intensive Strength Training
2017-06-07

Detailed description of the time course of muscular adaptation is rarely found in literature. Thus, models of muscular adaptation are difficult to validate since no detailed data of adaptation are available. In this article, as an initial step toward a detailed description and analysis of muscular adaptation, we provide a case report of 8 weeks of intense strength training with two active, male participants. Muscular adaptations were analyzed on a morphological level with MRI scans of the right quadriceps muscle and the calculation of muscle volume, on a voluntary strength level by isometric voluntary contractions with doublet stimulation (interpolated twitch technique) and on a non-voluntary level by resting twitch torques. Further, training volume and isokinetic power were closely monitored during the training phase. Data were analyzed weekly for 1 week prior to training, pre-training, 8 weeks of training and 2 weeks of detraining (no strength training). Results show a very individual adaptation to the intense strength training protocol. While training volume and isokinetic power increased linearly during the training phase, resting twitch parameters decreased for both participants after the first week of training and stayed below baseline until de-training. Voluntary activation level showed an increase in the first 4 weeks of training, while maximum voluntary contraction showed only little increase compared to baseline. Muscle volume increased for both subjects. Especially training status seemed to influence the acute reaction to intense strength training. Fatigue had a major influence on performance and could only be overcome by one participant. The results give a first detailed insight into muscular adaptation to intense strength training on various levels, providing a basis of data for a validation of muscle fatigue and adaptation models.
(Electro)chemical Oxidation of 6,13‐Bis[tri(isopropyl)silylethynyl]pentacene to its Radical Cation and Dication
2017-06-07

Abstract 6,13‐Bis[tri(isopropyl)silylethynyl]pentacene is a prototypical molecule for organic semiconductor and photovoltaic materials, which makes its electrochemical (redox) properties highly interesting. However, previous cyclic voltammetric studies have provided only limited information. Kinetic and persistence information and identification of the oxidation product(s) and their further reaction or oxidation have not been reported. Thus, an extended electrochemical and spectroscopic investigation of this compound was conducted in CH 2 Cl 2 and THF electrolytes at Pt electrodes. The electrochemically and chemically generated radical cation of the title compound was characterized by using ESR and UV/Vis/NIR spectroscopy and quantum‐chemical modeling. In CH 2 Cl 2 , further oxidation to a dication with chemical reversibility at fast timescales but follow‐up reactivity at slow timescales was observed. Pertinent parameters of the electron transfers (formal potentials E 0 , electron transfer rate constants k s , electron stoichiometry n ) were determined. The diffusion coefficients, D , in the two electrolytes were estimated from electrochemical and pulse gradient spin echo (PGSE) NMR spectroscopy data. Simulations of cyclic voltammograms supported the proposed oxidation mechanism and allowed the estimation of further reaction parameters.
More Effective Consolidation of Episodic Long‐Term Memory in Children Than Adults—Unrelated to Sleep
2017-06-08

Abilities to encode and remember events in their spatiotemporal context (episodic memory) rely on brain regions that mature late during childhood and are supported by sleep. We compared the temporal dynamics of episodic memory formation and the role of sleep in this process between 62 children (8–12 years) and 57 adults (18–37 years). Subjects recalled “what–where–when” memories after a short 1‐hr retention interval or after a long 10.5‐hr interval containing either nocturnal sleep or daytime wakefulness. Although children showed diminished recall of episodes after 1 hr, possibly resulting from inferior encoding, unlike adults, they showed no further decrease in recall after 10.5 hr. In both age groups, episodic memory benefitted from sleep. However, children's more effective offline retention was unrelated to sleep.
Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices
2017-06-08

Abstract The benzodiazepine midazolam is widely used in critical care medicine. Midazolam has a clinically active metabolite, 1-hydroxymidazolam. The contribution of 1-hydroxymidazolam to the effects of midazolam is controversial. The aim of the current study was to compare the actions of midazolam and 1-hydroxymidazolam on network activity of cortical neurons. Midazolam depressed neuronal activity at a low concentration of 5 nM. When midazolam concentration was increased, it depressed neuronal discharge rates in a biphasic manner. In comparison, 1-hydroxymidazolam did not depress the cortical network activity at low nanomolar concentrations. Higher concentrations of 1-hydroxymidazolam consistently inhibited neuronal activity. Moreover, midazolam shortened cortical up states at low, but not at high concentrations, while the opposite effect was observed with 1-hydroxymidazolam. The network depressant action of midazolam at low concentrations was absent in slices from GABA A receptor α 1 (H101R)mutant mice. The α 1 (H101R)mutation renders α 1 -subunit containing GABA A receptors insensitive towards benzodiazepines. This GABA A receptor subtype is thought to mediate sedation. As midazolam is more potent than its metabolite 1-hydroxymidazolam, the major clinical effects are thus likely caused by midazolam itself. However, 1-hydroxymidazolam could add to the effects of midazolam, especially after the application of high doses of midazolam, and in case of impaired drug metabolism.
Laser-induced fluorescence detection platform for point-of-care testing
2017-06-08

Point-of-care testing (POCT) devices for continuous low-cost monitoring of critical patient parameters require miniaturized and integrated setups for performing quick high-sensitivity analyses, away from central clinical laboratories. This work presents a novel and promising laser-induced fluorescence platform for measurements in direct optical test formats that leads towards such powerful POCT devices based on fluorescence-labeled immunoassays. Ultimate sensitivity of thin film photodetectors, integrated with microfluidics, and a comprehensive optimization of all system components aim at low-level signal detection in the targeted biosensor application. The setup acquires fluorescence signals from the volume of a microfluidic channel. An innovative sandwiching process forms a flow channel in the microfluidic chips by embedding laser-cut double-sided adhesive tapes. The custom fit of amorphous silicon based photodiode arrays to the geometry of the flow channel enables miniaturization, fully adequate for POCT devices. A free-beam laser excitation with line focus provides excellent alignment stability, allows for easy and reliable swapping of the disposable microfluidic chips, and therewith greatly improves the ease of use of the resulting integrated device. As a proof-of-concept of this novel in-volume measurement approach, the limit of detection for the dye DY636-COOH in pure water as a model fluorophore is examined and found to be 26 nmol .
Chronotype correlates with developmental index, intelligence and academic achievement: A study based on nationwide indicators
2017-06-08

Chronotype or morningness-eveningness (M/E) is an individual trait with a biological basis. In this study, I analysed the relationship between M/E and nationwide available data, such as economic variables, school achievement, intelligence and conscientiousness, which is a personality trait. These variables have been chosen because, first, they are linked on the individual level with circadian preference, and, second these associations have been found based on meta-analyses, which gives these findings a high plausibility. In addition, economic status has also been proposed to be related to M/E. Higher developed countries showed a lower morningness, based on both, the ranking of countries as well as on the HDI value. Similarly, GNI was related to morningness, while higher intelligence and performance in PISA were related to eveningness. Conscientiousness was related to morningness, although the results failed the significance level marginally. When using IQ as a control variable in partial correlations, the relationship between GNI and morningness disappeared, as did the correlation between eveningness and PISA results.
Self‐gated 4D‐MRI of the liver: Initial clinical results of continuous multiphase imaging of hepatic enhancement
2017-06-08

Purpose To evaluate the feasibility of a self‐gated free‐breathing volume‐interpolated breath‐hold examination (VIBE) sequence using compressed sensing (CS) for contrast‐enhanced multiphase liver MRI. Materials and Methods We identified 23 patients who underwent multiphase gadobutrol‐enhanced liver magnetic resonance imaging (MRI) using 1) a prototype free‐breathing VIBE sequence with respiratory self‐gating and CS (VIBE CS ), and 2) a standard breath‐hold VIBE (VIBE STD ) on the same 1.5T scanner at two timepoints. VIBE CS was continuously acquired for 128 seconds and a time‐series of 16 timepoints was jointly reconstructed from the dataset. The unenhanced, arterial, portal‐venous, and venous timepoints with the best image quality were selected and compared to the corresponding VIBE STD series serving as reference. Image quality was assessed qualitatively (image quality, sharpness, lesion conspicuity, vessel contrast, noise, motion/other artifacts; two readers independently; 5‐point Likert scale; 5 = excellent) and quantitatively (vessel contrast [VC], coefficient‐of‐variation [CV]) Statistics were performed using Wilcoxon‐sign‐rank (ordinal) and paired t ‐test (continuous variables). Results Image quality and lesion conspicuity revealed no significant differences between the sequences ( P ≥ 0.3). VIBE STD showed a tendency to higher motion artifacts ( P ≥ 0.07). Image sharpness significantly increased in VIBE CS as compared to VIBE STD ( P ≤ 0.03). Arterial phase vessel contrast appeared significantly lower in VIBE CS than in VIBE STD ( P = 0.04). VIBE CS showed reconstruction artifacts not present in VIBE STD ( P = 0.001). Image noise was significantly lower in VIBE CS than in VIBE STD ( P ≤ 0.004). Arterial phase VC was significantly lower in VIBE CS than in VIBE STD ( P = 0.01). CV revealed no differences between sequences ( P = 0.7). Conclusion VIBE CS is feasible for continuous free‐breathing contrast‐enhanced multiphase liver MRI, providing similar image quality and lesion conspicuity as VIBE STD . Level of Evidence: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:459–467.
Pyruvate Kinase and Fcγ Receptor Gene Copy Numbers Associated With Malaria Phenotypes
2017-06-08

Genetic factors are associated with susceptibility to many infectious diseases and may be determinants of clinical progression. Gene copy number variation (CNV) has been shown to be associated with phenotypes of numerous diseases, including malaria. We quantified gene copy numbers of the pyruvate kinase, liver, and red blood cell (PKLR) gene as well as of the Fcγ receptor 2A and Fcγ receptor 2C (FCGR2A, FCGR2C) and Fcγ receptor 3 (FCGR3) genes using real-time quantitative polymerase chain reaction (RT-qPCR) assays in Gabonese children with severe (n = 184) or and mild (n = 189) malaria and in healthy Gabonese and white individuals (n = 76 each). The means of PKLR, FCGR2A, FCGR2C, and FCGR3 copy numbers were significantly higher among children with severe malaria compared to those with mild malaria (P < .002), indicating that a surplus of copies of those genes is significantly associated with malaria severity. Copy numbers of the FCGR2A and FCGR2C genes were significantly lower (P = .005) in Gabonese individuals compared with white individuals. In conclusion, CNV of the PKLR, FCGR2A, FCGR2C, and FCGR3 genes is associated with malaria severity, and our results provide evidence for a role of CNV in host responses to malaria.
Rapid Complexation of Aptamers by Their Specific Antidotes
2017-06-08

Nucleic acid ligands, aptamers, harbor the unique characteristics of small molecules and antibodies. The specificity and high affinity of aptamers enable their binding to different targets, such as small molecules, proteins, or cells. Chemical modifications of aptamers allow increased bioavailability. A further great benefit of aptamers is the antidote (AD)-mediated controllability of their effect. In this study, the AD-mediated complexation and neutralization of the thrombin binding aptamer NU172 and Toll-like receptor 9 (TLR9) binding R10-60 aptamer were determined. Thereby, the required time for the generation of aptamer/AD-complexes was analyzed at 37 °C in human serum using gel electrophoresis. Afterwards, the blocking of aptamers’ effects was analyzed by determining the activated clotting time (ACT) in the case of the NU172 aptamer, or the expression of immune activation related genes IFN-1β, IL-6, CXCL-10, and IL-1β in the case of the R10-60 aptamer. Gel electrophoresis analyses demonstrated the rapid complexation of the NU172 and R10-60 aptamers by complementary AD binding after just 2 min of incubation in human serum. A rapid neutralization of anticoagulant activity of NU172 was also demonstrated in fresh human whole blood 5 min after addition of AD. Furthermore, the TLR9-mediated activation of PMDC05 cells was interrupted after the addition of the R10-60 AD. Using these two different aptamers, the rapid antagonizability of the aptamers was demonstrated in different environments; whole blood containing numerous proteins, cells, and different small molecules, serum, or cell culture media. Thus, nucleic acid ADs are promising molecules, which offer several possibilities for different in vivo applications, such as antagonizing aptamer-based drugs, immobilization, or delivery of oligonucleotides to defined locations.
Factors associated with delayed defibrillation in cardiopulmonary resuscitation: A prospective simulation study
2017-06-08

Our study shows that novice resuscitators rarely achieve guideline-recommended defibrillation times. The most relative delays were observed when participants had to choose what to do next or which algorithm to follow, and thus i.e. performed extensive airway management before a life-saving defibrillation. Our data provides a first insight in the process of defibrillation delay and can be used to generate new hypotheses on how to provide a timely defibrillation.
European Trade, Colonialism, and Human Capital Accumulation in Senegal, Gambia and Western Mali, 1770-1900
2017-06-08

The data contain estimates of numeracy across regions of Western Sudan (Senegal, Gambia and Western Mali) between 1770 and 1900, as well as correlates linked to factor endowments, European trade and early colonialism.
Defining and Predicting Patterns of Early Response in a Web-Based Intervention for Depression
2017-06-09

These findings suggest that in Web-based interventions outcome and adherence can be predicted by patterns of early change, which can inform treatment decisions and potentially help optimize the allocation of scarce clinical resources.
Embryotoxicity Caused by DON-Induced Oxidative Stress Mediated by Nrf2/HO-1 Pathway
2017-06-09

Deoxynivalenol (DON) belongs to the type B group of trichothecenes family, which is composed of sesquiterpenoid metabolites produced by Fusarium and other fungi in grain. DON may cause various toxicities, such as cytotoxicity, immunotoxicity, genotoxicity as well as teratogenicity and carcinogenicity. In the present study, we focus on a hypothesis that DON alters the expressions of Nrf2/HO-1 pathway by inducing embryotoxicity in C57BL/6 mouse (5.0, 2.5, 1.0, and 0 mg/kg/day) and BeWo cell lines (0 and 50 nM; 3 h, 12 h and 24 h). Our results indicate that DON treatment in mice during pregnancy leads to ROS accumulation in the placenta, which results in embryotoxicity. At the same time Nrf2/HO-1 pathway is up-regulated by ROS to protect placenta cells from oxidative damage. In DON-treated BeWo cells, the level of ROS has time–effect and dose–effect relationships with HO-1 expression. Moderate increase in HO-1 protects the cell from oxidative damage, while excessive increase in HO-1 aggravates the oxidative damage, which is called in some studies the “threshold effect”. Therefore, oxidative stress may be the critical molecular mechanism for DON-induced embryotoxicity. Besides, Nrf2/HO-1 pathway accompanied by the “threshold effect” also plays an important role against DON-induced oxidative damage in this process.
Enumeration of complex and real surfaces via tropical geometry
2017-06-09

Abstract We prove a correspondence theorem for singular tropical surfaces in R 3 , which recovers singular algebraic surfaces in an appropriate toric three-fold that tropicalize to a given singular tropical surface. Furthermore, we develop a three-dimensional version of Mikhalkin’s lattice path algorithm that enumerates singular tropical surfaces passing through an appropriate configuration of points in R 3 . As application we show that there are pencils of real surfaces of degree d in P 3 containing at least (3/2) d 3 + O ( d 2 ) singular surfaces, which is asymptotically comparable to the number 4( d − 1) 3 of all complex singular surfaces in the pencil. Our result relies on the classification of singular tropical surfaces [12].
Linking Genes to Microbial Biogeochemical Cycling: Lessons from Arsenic
2017-06-11

The biotransformation of arsenic is highly relevant to the arsenic biogeochemical cycle. Identification of the molecular details of microbial pathways of arsenic biotransformation coupled with analyses of microbial communities by meta-omics can provide insights into detailed aspects of the complexities of this biocycle. Arsenic transformations couple to other biogeochemical cycles, and to the fate of both nutrients and other toxic environmental contaminants. Microbial redox metabolism of iron, carbon, sulfur, and nitrogen affects the redox and bioavailability of arsenic species. In this critical review we illustrate the biogeochemical processes and genes involved in arsenic biotransformations. We discuss how current and future metagenomic-, metatranscriptomic-, metaproteomic-, and metabolomic-based methods will help to decipher individual microbial arsenic transformation processes, and their connections to other biogeochemical cycle. These insights will allow future use of microbial metabolic capabilities for new biotechnological solutions to environmental problems. To understand the complex nature of inorganic and organic arsenic species and the fate of environmental arsenic will require integrating systematic approaches with biogeochemical modeling. Finally, from the lessons learned from these studies of arsenic biogeochemistry, we will be able to predict how the environment changes arsenic, and, in response, how arsenic biotransformations change the environment.
Trisubstituted Pyridinylimidazoles as Potent Inhibitors of the Clinically Resistant L858R/T790M/C797S EGFR Mutant: Targeting of Both Hydrophobic Regions and the Phosphate Binding Site
2017-06-12

Inhibition of the epidermal growth factor receptor represents one of the most promising strategies in the treatment of lung cancer. Acquired resistance compromises the clinical efficacy of EGFR inhibitors during long-term treatment. The recently discovered EGFR-C797S mutation causes resistance against third-generation EGFR inhibitors. Here we present a rational approach based on extending the inhibition profile of a p38 MAP kinase inhibitor toward mutant EGFR inhibition. We used a privileged scaffold with proven cellular potency as well as in vivo efficacy and low toxicity. Guided by molecular modeling, we synthesized and studied the structure-activity relationship of 40 compounds against clinically relevant EGFR mutants. We successfully improved the cellular EGFR inhibition down to the low nanomolar range with covalently binding inhibitors against a gefitinib resistant T790M mutant cell line. We identified additional noncovalent interactions, which allowed us to develop metabolically stable inhibitors with high activities against the osimertinib resistant L858R/T790M/C797S mutant.
Relapse-Free Survival as a Surrogate for Overall Survival in the Evaluation of Stage II–III Melanoma Adjuvant Therapy
2017-06-12

In high-risk stage II-III melanoma, RFS appeared to be a valid surrogate end point for OS for adjuvant randomized studies assessing interferon or a checkpoint inhibitor. In future similar adjuvant studies, a hazard ratio for RFS of 0.77 or less would predict a treatment impact on OS.
Time‐resolved photoluminescence spectroscopy of charge transfer states in blends of pentacene and perfluoropentacene
2017-06-12

Charge transfer states in blends of organic semiconductors have significant importance for the functioning of organic optoelectronic devices, but are also interesting from the perspective of fundamental research as many of their properties as well as their influence on the photophysics of the material are not yet completely understood. We report on a time‐resolved photoluminescence study of the photophysics of the charge transfer state in the prototypical donor–acceptor system pentacene mixed with its perfluorinated counterpart. We find indications for the existence of two distinct charge‐transfer states, one of them formed in the bulk of the mixed phase, the other one formed at the interface to phase‐separated pentacene domains. We discuss the implications of the difference in temperature dependence of the emission intensity and the lifetime observed for these charge transfer states.
Modular Synthesis of Triazole‐Based Chiral Iodoarenes for Enantioselective Spirocyclizations
2017-06-13

Abstract A new triazole‐based C 1 ‐symmetrical chiral iodoarene was synthesized in a highly modular route. Based on enzymatic kinetic resolution of an easily accessible propargylic alcohol both enantiomers were accessible in enantiopure form. By Huisgen‐type azide‐alkyne cycloaddtion a series of differently substituted iodoarenes was synthesized in high overall yields. Finally this novel iodoarene was successfully applied in the oxidative Kita cyclization of naphthol derivatives. Good yields and high ee values were obtained in the asymmetric spirocyclization via in situ generation of the hypervalent iodine species using m CPBA as the terminal oxidant. magnified image