Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinical Drug–Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib

The efficacy and safety of alectinib, a central nervous system–active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK‐positive (ALK+) non–small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time‐dependent inhibition and small induction of CYP3A in vitro. We present results from 3 fixed‐sequence studies evaluating drug–drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is coadministered with CYP3A inhibitors or inducers or for coadministered CYP3A substrates.
The effect of sub-zero temperature on the formation and composition of secondary organic aerosol from ozonolysis of alpha-pinene.

This study presents a newly constructed temperature controlled cold-room smog chamber at Aarhus University, Denmark. The chamber is herein utilized to study the effect of sub-zero temperature on the formation and chemical composition of secondary organic aerosol (SOA) from ozone initiated oxidation of α-pinene. The chemical composition of α-pinene SOA formed from dark ozonolysis of α-pinene at 293 K and 258 K was investigated using High-Resolution Time-of-Flight Aerosol Mass Spectrometry (HR-ToF-AMS) and Ultra-High Performance Liquid Chromatography/Electrospray Ionization Quadrupole Time-of-Flight Mass Spectrometry (UHPLC/ESI-qToF-MS). For comparison, an OH-initiated oxidation experiment was performed at 293 K. In ozonolysis experiments it was found that oxygen-to-carbon (O : C) ratios were higher in the particles formed at 293 K compared to 258 K. A total of 16 different organic acids and 30 dimers esters were quantified in the collected particles composing up to 34% of the total α-pinene SOA mass with increased mass fraction of carboxylic acids in particles from α-pinene ozonolysis at 258 K compared to 293 K. In contrast, dimer esters showed suppressed formation at the sub-zero reaction temperature, thus contributing 3% to SOA mass at 258 K while contributing 9% at 293 K. SOA formed in the OH-initiated oxidation of α-pinene at 293 K resulted in low concentrations of dimer esters supporting Criegee intermediates as a possible pathway to dimer ester formation. Vapour pressure estimates of the identified carboxylic acids and dimer esters are presented and show how otherwise semi-volatile carboxylic acids at sufficiently low temperatures may classify as low or even extremely low volatile organic compounds (ELVOC), thus may add to an enhanced particle formation observed at the sub-zero temperature through gas-to-particle conversion. The change in chemical composition of the SOA particles with temperature is ascribed to a combination of effects: the decreased vapour pressures and hence increased condensation of carboxylic acids from the gas phase to the particle phase along with suppressed formation of the high molecular weight dimer esters and different gas and particle phase chemistry results in particles of different chemical composition as a consequence of low reaction temperatures.
Stability of DC Distribution Systems: An Algebraic Derivation

Instability caused by low inertia and constant power loads is a major challenge of DC distribution grids. Previous research uses oversimplified models or does not provide general rules for stability. Therefore, a comprehensive approach to analyze the stability of DC distribution systems is desired. This paper presents a method to algebraically analyze the stability of any DC distribution system through the eigenvalues of its state-space matrices. Furthermore, using this method, requirements are found for the stability of three example systems. Additionally, a sensitivity analysis is performed, which considers the effect of several system parameters on the stability and disputes some overgeneralized conclusions of previous research. Moreover, various simulations are performed to illustrate the dynamic behavior of a stable and an unstable DC distribution system.
Documentation of Significant Losses in Cornus florida L. Populations throughout the Appalachian Ecoregion

Over the last three decades the fungus Discula destructiva Redlin has severely impacted Cornus florida L. (flowering dogwood—hereafter “dogwood”) populations throughout its range. This study estimates historical and current dogwood populations (number of trees) across the Appalachian ecoregion. Objectives were to (1) quantify current dogwood populations in the Appalachian ecoregion, (2) quantify change over time in dogwood populations, and (3) identify trends in dogwood population shifts. Data from the USDA Forest Service Forest Inventory and Analysis (FIA) database were compiled from 41 FIA units in 13 states for county-level estimates of the total number of all live dogwood trees on timberland within the Appalachian ecoregion. Analysis of covariance, comparing historical and current county-level dogwood population estimates with average change in forest density as the covariate, was used to identify significant changes within FIA units. Losses ranging from 25 to 100 percent of the sample population (𝑃l.05) were observed in 33 of the 41 (80 percent) sampled FIA units. These results indicate that an important component of the eastern deciduous forest has experienced serious losses throughout the Appalachians and support localized empirical results and landscape-scale anecdotal evidence.
Anti-Wolbachia drug discovery and development: safe macrofilaricides for onchocerciasis and lymphatic filariasis

SUMMARY Anti-Wolbachia therapy delivers safe macrofilaricidal activity with superior therapeutic outcomes compared to all standard anti-filarial treatments, with the added benefit of substantial improvements in clinical pathology. These outcomes can be achieved, in principle, with existing registered drugs, e.g. doxycycline, that are affordable, available to endemic communities and have well known, albeit population-limiting, safety profiles. The key barriers to using doxycycline as an mass drug administration (MDA) strategy for widespread community-based control are the logistics of a relatively lengthy course of treatment (4–6 weeks) and contraindications in children under eight years and pregnancy. Therefore, the primary goal of the anti-Wolbachia (A·WOL) consortium is to find drugs and regimens that reduce the period of treatment from weeks to days (7 days or less), and to find drugs which would be safe in excluded target populations (pregnancy and children). A secondary goal is to refine regimens of existing antibiotics suitable for a more restricted use, prior to the availability of a regimen that is compatible with MDA usage. For example, for use in the event of the emergence of drug-resistance, in individuals with high loiasis co-infection and at risk of severe adverse events (SAE) to ivermectin, or in post-MDA ‘endgame scenarios’, where test and treat strategies become more cost effective and deliverable.
Partial power DC-DC converter for photovoltaic microinverters

In order to increase the conversion efficiency in photovoltaic (PV) systems, different configurations and topologies were developed. Depending on the application, the converters used for grid connection are built using one or two conversion stages. The advantages of the converters with a DC-stage are mainly the distributed maximum power point tracking algorithm per PV string or PV module and, when required for grid connection, the possibility of voltage elevation. However, the conversion efficiency is lower than configurations with a single-stage as the central inverter. Therefore, the proposed work presents a Partial Power DC-DC converter (PPC) which process part of the entire system power, and the remaining power is directly supplied to the output side. A topology is proposed and the details of its operation are explained based on the operating principle. Simulations are performed in order to evaluate the converter performance.
Consumer perceptions of strain differences in Cannabis aroma

The smell of marijuana (Cannabis sativa L.) is of interest to users, growers, plant breeders, law enforcement and, increasingly, to state-licensed retail businesses. The numerous varieties and strains of Cannabis produce strikingly different scents but to date there have been few, if any, attempts to quantify these olfactory profiles directly. Using standard sensory evaluation techniques with untrained consumers we have validated a preliminary olfactory lexicon for dried cannabis flower, and characterized the aroma profile of eleven strains sold in the legal recreational market in Colorado. We show that consumers perceive differences among strains, that the strains form distinct clusters based on odor similarity, and that strain aroma profiles are linked to perceptions of potency, price, and smoking interest.
Comparison of Composition and Diversity of Bacterial Microbiome in Human Upper and Lower Respiratory Tract

inTroducTion Microbiome residing in the airways and parenchymal tissues, as a biological barrier of respiratory tract, plays an important role in maintaining the normal functions of individual’s respiratory system and preventing the invasion and colonization of exogenous pathogens. [1] Changes of microbial community may result in the occurrence and progression of infectious pneumonia and acute exacerbation of chronic diseases, through disordering commensal microorganisms and increasing invasive ability of pathogens. [2] Traditional methods for detecting bacteria normally rely on culture technique, which have a number of critical problems, including time‐consuming and relatively low positive rate of detection. In the last 10 years, 16S rRNA gene sequencing technique has been thought to be more comprehensive and reliable than those of culture‐dependent methods for monitoring bacterial microbiome in skin, organs, and tracts quantitatively and qualitatively. [3] In this case, choosing credible samples are critical to evaluate the community composition of microbiome in the host tracts, including respiratory tract. In the present study, we aimed to compare the composition and diversity of bacterial community structure in different samples collected from the individuals’ airways using 16S rRNA gene sequencing technique.
Measuring Heightened Attention to Alcohol in a Naturalistic Setting: A Validation Study

Attentional bias to alcohol-related stimuli is believed to be an important contributor to the development and maintenance of drug abuse. There is a considerable body of research examining attentional bias, much of which has typically utilized image-display tasks as a means to assess the phenomenon. Little, however, is known about the nature of this bias in an individual’s natural environment. The current study sought to implement a novel approach to assessing attentional bias in vivo. Participants wore portable eye-tracking glasses that recorded video from their point of view and measured fixation time to objects they observed. They entered a room that was designed to represent a recreational setting in which both alcohol- and nonalcoholic-neutral beverages were placed along with other stimuli. In two different testing sessions, participants were free to visually explore the room. Participants showed similar fixation times to alcohol and neutral beverages during Session 1. Attentional bias to alcoholic beverages was observed in Session 2 because fixation time decreased to neutral but not to alcoholic beverages. The magnitude of attentional bias was positively associated with drinking habits, with heavier drinkers demonstrating a higher degree of bias to alcohol. These findings provide an ecological model of how attentional bias can develop as the net result of attention being sustained to alcoholic stimuli while diminishing to other stimuli over time.
How concave are river channels?

Abstract. For over a century, geomorphologists have attempted to unravel information about landscape evolution, and processes that drive it, using river profiles. Many studies have combined new topographic datasets with theoretical models of channel incision to infer erosion rates, identify rock types with different resistance to erosion, and detect potential regions of tectonic activity. The most common metric used to analyse river profile geometry is channel steepness, or ks. However, the calculation of channel steepness requires the normalisation of channel gradient by drainage area. This normalisation requires a power law exponent that is referred to as the channel concavity index. Despite the concavity index being crucial in determining channel steepness, it is challenging to constrain. In this contribution, we compare both slope–area methods for calculating the concavity index and methods based on integrating drainage area along the length of the channel, using so-called “chi” (χ) analysis. We present a new χ-based method which directly compares χ values of tributary nodes to those on the main stem; this method allows us to constrain the concavity index in transient landscapes without assuming a linear relationship between χ and elevation. Patterns of the concavity index have been linked to the ratio of the area and slope exponents of the stream power incision model (m∕n); we therefore construct simple numerical models obeying detachment-limited stream power and test the different methods against simulations with imposed m and n. We find that χ-based methods are better than slope–area methods at reproducing imposed m∕n ratios when our numerical landscapes are subject to either transient uplift or spatially varying uplift and fluvial erodibility. We also test our methods on several real landscapes, including sites with both lithological and structural heterogeneity, to provide examples of the methods' performance and limitations. These methods are made available in a new software package so that other workers can explore how the concavity index varies across diverse landscapes, with the aim to improve our understanding of the physics behind bedrock channel incision.
Fundamental movement skills in adolescents: Secular trends from 2003 to 2010 and associations with physical activity and BMI

The aim of this study was to examine the secular trends in fundamental movement skills (FMS) among 15‐ to 16‐year‐old adolescents at 2 assessment points scheduled in 2003 and 2010 and to investigate the associations between FMS, physical activity (PA), and body mass index (BMI). In 2003, self‐reported PA, weight and height, and objective FMS scores were collected from 2390 students, and in 2010, similar data were generated from a second sample of 1346 students. FMS were assessed during both assessment phases using 3 identical objective FMS tests that were figure 8 dribbling, jumping laterally, and coordination track tests. This study indicated that the sum index of FMS did not change among the boys and the girls between 2 data collection points. However, findings demonstrated a secular decline in coordination test scores in both gender groups between 2 measurement points but an improvement in girls’ object control skills between 2003 and 2010. The results also showed that FMS had a significant main effect on BMI in both gender groups, whereas the main effect of PA on BMI was not significant for either gender group. Results also demonstrated that there was no significant interaction effect between FMS and PA on BMI in either of the girls’ or the boys’ groups.
On the Interpretation of the Fermi-GBM Transient Observed in Coincidence with LIGO Gravitational-wave Event GW150914

The weak transient detected by the Fermi Gamma-ray Burst Monitor (GBM) 0.4 s after GW150914 has generated much speculation regarding its possible association with the black hole binary merger. Investigation of the GBM data by Connaughton et al. revealed a source location consistent with GW150914 and a spectrum consistent with a weak, short gamma-ray burst. Greiner et al. present an alternative technique for fitting background-limited data in the low-count regime, and call into question the spectral analysis and the significance of the detection of GW150914-GBM presented in Connaughton et al. The spectral analysis of Connaughton et al. is not subject to the limitations of the low-count regime noted by Greiner et al. We find Greiner et al. used an inconsistent source position and did not follow the steps taken in Connaughton et al. to mitigate the statistical shortcomings of their software when analyzing this weak event. We use the approach of Greiner et al. to verify that our original spectral analysis is not biased. The detection significance of GW150914-GBM is established empirically, with a false-alarm rate (FAR) of Hz. A post-trials false-alarm probability (FAP) of ( ) of this transient being associated with GW150914 is based on the proximity in time to the gravitational-wave event of a transient with that FAR. The FAR and the FAP are unaffected by the spectral analysis that is the focus of Greiner et al.
Physiological and Metagenomic Characterizations of the Synergistic Relationships between Ammonia- and Nitrite-Oxidizing Bacteria in Freshwater Nitrification

Nitrification plays a crucial role in global nitrogen cycling and treatment processes. However, the relationships between the nitrifier guilds of ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB) are still poorly understood, especially in freshwater habitats. This study examined the physiological interactions between the AOB and NOB present in a freshwater aquarium biofilter by culturing them, either together or separately, in a synthetic medium. Metagenomic and 16S rRNA gene sequencing revealed the presence and the draft genomes of Nitrosomonas-like AOB as well as Nitrobacter-like NOB in the cultures, including the first draft genome of Nitrobacter vulgaris. The nitrifiers exhibited different growth rates with different ammonium (NH4+) or nitrite concentrations (50–1,500 μM) and the growth rates were elevated under a high bicarbonate (HCO3-) concentration. The half-saturation constant (Ks for NH4+), the maximum growth rate (μmax), and the lag duration indicated a strong dependence on the synergistic relationships between the two guilds. Overall, the ecophysiological and metagenomic results in this study provided insights into the phylogeny of the key nitrifying players in a freshwater biofilter and showed that interactions between the two nitrifying guilds in a microbial community enhanced nitrification.
Wild-type ALK and activating ALK-R1275Q and ALK-F1174L mutations upregulate Myc and initiate tumor formation in murine neural crest progenitor cells

The anaplastic lymphoma kinase (ALK) gene is overexpressed, mutated or amplified in most neuroblastoma (NB), a pediatric neural crest-derived embryonal tumor. The two most frequent mutations, ALK-F1174L and ALK-R1275Q, contribute to NB tumorigenesis in mouse models, and cooperate with MYCN in the oncogenic process. However, the precise role of activating ALK mutations or ALK-wt overexpression in NB tumor initiation needs further clarification. Human ALK-wt, ALK-F1174L, or ALK-R1275Q were stably expressed in murine neural crest progenitor cells (NCPC), MONC-1 or JoMa1, immortalized with v-Myc or Tamoxifen-inducible Myc-ERT, respectively. While orthotopic implantations of MONC-1 parental cells in nude mice generated various tumor types, such as NB, osteo/chondrosarcoma, and undifferentiated tumors, due to v-Myc oncogenic activity, MONC-1-ALK-F1174L cells only produced undifferentiated tumors. Furthermore, our data represent the first demonstration of ALK-wt transforming capacity, as ALK-wt expression in JoMa1 cells, likewise ALK-F1174L, or ALK-R1275Q, in absence of exogenous Myc-ERT activity, was sufficient to induce the formation of aggressive and undifferentiated neural crest cell-derived tumors, but not to drive NB development. Interestingly, JoMa1-ALK tumors and their derived cell lines upregulated Myc endogenous expression, resulting from ALK activation, and both ALK and Myc activities were necessary to confer tumorigenic properties on tumor-derived JoMa1 cells in vitro.
Being on the Field When the Game Is Still Under Way. The Financial Press and Stock Markets in Times of Crisis

This paper looks at the relationship between negative news and stock markets in times of global crisis, such as the 2008/2009 period. We analysed one year of front page banner headlines of three financial newspapers, the Wall Street Journal, Financial Times, and Il Sole24ore to examine the influence of bad news both on stock market volatility and dynamic correlation. Our results show that the press and markets influenced each other in generating market volatility and in particular, that the Wall Street Journal had a crucial effect both on the volatility and correlation between the US and foreign markets. We also found significant differences between newspapers in their interpretation of the crisis, with the Financial Times being significantly pessimistic even in phases of low market volatility. Our results confirm the reflexive nature of stock markets. When the situation is uncertain and unpredictable, market behaviour may even reflect qualitative, big picture, and subjective information such as streamers in a newspaper, whose economic and informative value is questionable.
Effects of Aging Structures and Humidity on Fatigue Properties of Age-Hardened Al Alloy

In order to investigate the effects of aging structures and humidity on fatigue properties of an extruded bar of age-hardened Al alloy 7075, rotating bending fatigue tests were carried out on T62, T73 and RRA (retrogression and reaging) treated plain specimens in two relative humidity of 25% and 85%. Fatigue strength in low humidity was higher in the order of the RRA, T62 and T73 treated specimens corresponding to the order of static strength. On the other hand, fatigue strength decreased in high humidity in all of the alloys and the decrease was the highest in the RRA treated specimen, which means that the RRA treated alloy is very sensitive to humidity environment. In case of the T73 treated alloy, cracks propagated in shear mode in high humidity and under high stress levels due to the marked texture of the alloy, though tensile mode crack growth is more common in the alloy. Similar crack growth behavior was found in the T62 treated alloy, too. In case of the RRA treated alloy, however, the tendency for a crack to grow in the shear mode was very weak even in high humidity and under high stress levels in spite that the alloy had the same marked texture. The effects of microstructure and humidity on the initiation and propagation of small cracks were marked in all of the alloys.