Miracle-dz/UniFAR-FTUs huggingface dataset:
The metabolic drug-drug interaction profile of dabrafenib: In vitro investigations and quantitative extrapolation of the P450-mediated DDI risk

Nonstandard abbreviations: CL i = intrinsic clearance; CliCYP = intrinsic clearance for recombinant CYP enzyme; CYP = cytochrome P450; DDI = drug drug interaction; human liver K achieve ABSTRACT Dabrafenib is a potent ATP-competitive inhibitor for the V600 mutant BRAF kinase currently approved in the United States for the treatment of metastatic melanoma. Studies were conducted in HLMs, recombinant human CYP enzymes and human hepatocytes to investigate dabrafenib’s and its major circulating metabolites’ potential to perpetrate pharmacokinetic DDI’s as well as have its own pharmacokinetics affected (victim) by co-administered drugs. Dabrafenib metabolism was mediated by CYP2C8 (56-67%) and CYP3A4 (24%) and demonstrated inhibition of CYP2C8, 2C9, 2C19, 3A4 (atorvastatin) and (nifedipine), with calculated IC 50 values of 8.2, 7.2, 22.4, 16 and 32 μ M. It also demonstrated MDI of CYP3A4 with a k inact of 0.040 min -1 and a K I for CYP3A4 of 38 μ M. Hydroxy-dabrafenib inhibited CYP1A2, 2C9 and 3A4 (midazolam) with calculated IC 50 values of 83, 29 and 44 μ M, and carboxy-dabrafenib did not inhibit any of the CYP enzymes tested. Desmethyl-dabrafenib inhibited CYP2B6, 2C8, 2C9, 2C19 and 3A4 (midazolam, atorvastatin and nifedipine) with calculated IC 50 values of 78, 47, 6.3, 36, 17, 20 and 28 μ M. At 30 μ M dabrafenib, showed increases in CYP2B6 and CYP3A4 mRNA expression indicative of induction. The potential clinical relevance of these findings was explored by using mechanistic static mathematical models to estimate the magnitude of change (AUC change) as a result of CYP-mediated DDI interactions. This risk assessment approach indicated that dabrafenib is unlikely to perpetrate any in vivo DDIs by inhibition mechanisms, but is a likely inducer of CYP3A4 and a victim of CYP3A4 LC/MS analysis for the quantification of dabrafenib and its metabolites from in vitro samples: Dabrafenib, hydroxy-dabrafenib and desmethyl-dabrafeninb were extracted by liquid-liquid extraction using ethyl acetate. Carboxy-dabrafenib was extracted by protein precipitation using 80/20 ethanol/water. All extracts were analyzed by UHPLC MS/MS using a TurboIonspray™ interface with positive ion multiple reaction monitoring. Change in peak area ratio of each analyte relative to its respective isotopically labelled internal standard ([ 2 H 9 ] dabrafenib, [ 2 H 6 13 C 2 ] hydroxy-dabrafenib, [ 2 H 6 13 C 2 ] desmethyl- dabrafenib) and, [ 2 H 6 13 C 2 ] carboxy-dabrafenib, was utilized to monitor depletion kinetics.
Late crustal growth on Mars: Evidence from lithospheric extension

We apply the pure shear model of lithospheric extension to rifting on Mars and investigate the range of initial ambient conditions that allow for narrow rifting. The results are applied to the Coracis Fossae, constraining the crustal thickness at the time the rift formed. We thus find that the crustal thickness at 3.5–3.9 Gyr is unlikely to have exceeded ∼50 km. This is significantly lower than the estimates for the present day crustal thickness in that region (∼70 km) and interpreted as an indication for continued crustal production at that time.
Biogenic sulfur emissions from the Subantarctic and Antarctic Oceans

Measurements of the atmospheric distributions of dimethylsulfide (DMS), sulfur dioxide (SO2), methanesulfonate (MSA), non-seasalt sulfate (nss-SO42−), and methylmercaptan (MeSH) were made over the Drake Passage and the coastal and inshore waters west of the Antarctic Peninsula during the 1986 austral fall season. DMS concentrations were also measured in the surface ocean, and vertical profiles were obtained at several locations in the inshore water areas. Surface seawater concentrations of DMS were on the order of 2 nmol L−1, similar to values observed in temperate latitudes. The vertical profiles showed maximum values at depths between 5–40 m. DMS concentrations in the atmosphere were near 4 nmol m−3 (96 parts per trillion by volume, (pptv)), close to the global average for remote oceanic regions. The sea-to-air flux of DMS ranged between 1–5 μmol m−2 d−1, with the highest values found in the open ocean areas. The total sea-to-air flux of DMS from the Southern Ocean is estimated to be 0.2 Tmol yr −1. MeSH was detected occasionally at concentrations up to 0.15 nmol m−3 (3.6 pptv). The average aerosol MSA concentration (0.27 nmol m−3) was surprisingly high relative to the level of nss-SO42− (0.31 nmol m−3). Both compounds were found predominantly in fine particles. The nss-SO42− values were extremely low, comparable to winter values reported for the South Pole. SO2 concentrations were also very low (0.45 nmol m−3 (11 pptv)), consistent with the low levels of nss-SO42−. The residence time of DMS in the Antarctic marine atmosphere is estimated to be about 2–3 days during clear weather and about 6–7 days during overcast conditions. Photooxidation of DMS in the Southern Ocean atmosphere may lead to a higher yield of MSA and a lower yield of SO2 compared to other world ocean areas.
A clinico-epidemiological study of pediatric dermatoses in tertiary care centre, Ujjain

Introduction: Skin diseases in pediatric age are common health problem with wide variation in the presentation in various regions. Pediatric dermatoses differs from adult dermatoses in clinical presentation, treatment and prognosis. This variation among dermatoses is due to region of study, environmental factors, type of population studied, hygiene, nutritional status. Objectives: To determine the clinical pattern of dermatological disorders and their prevalence in pediatric population. Material and Methods: The present study was hospital based cross-sectional observational study, conducted in department of dermatology, venereology and leprosy, R. D. Gardi Medical College Ujjain over a period of one year. A total of 160 cases with age 0-15 yrs, who presented in our OPD/IPD were included in this study. A detailed general, cutaneous and systemic examination followed by investigations were carried out and recorded in proforma for analysis and interpretation of data. Results: Out of all the subjects recruited, 53.1% were males and 46.9% were females with M:F ratio1.13:1. The maximum no. of patients were in the age group of 7-9 years (26.9%). Etiological analysis revealed that infections and infestations were the most common dermatoses (48.8%) followed by dermatitis and eczemas (15.5%), papulosquamous disorder (8.8%), pigmentary disorders (6.9%), keratinization disorders (4.4%), urticaria (3.1%), nevoid disorders (3.1%), miliaria (1.9%), vascular malformations (1.9%) and others (3.8%). Conclusion: Dermatoses in children is wide spread problem responsible for significant morbidity in them. Infections and infestations were most prevalent dermatoses possibly due to poverty, overcrowding, under nutrition, poor hygiene and lack of health education.
Changes in Moisture Flux over the Tibetan Plateau during 1979–2011 and Possible Mechanisms

AbstractChanges in moisture as represented by P − E (precipitation − evapotranspiration) and the possible causes over the Tibetan Plateau (TP) during 1979–2011 are examined based on the Global Land Data Assimilation Systems (GLDAS) ensemble mean runoff and reanalyses. It is found that the TP is getting wetter as a whole but with large spatial variations. The climatologically humid southeastern TP is getting drier while the vast arid and semiarid northwestern TP is getting wetter. The Clausius–Clapeyron relation cannot be used to explain the changes in P − E over the TP.Through decomposing the changes in P − E into three major components—dynamic, thermodynamic, and transient eddy components—it is noted that the dynamic component plays a key role in the changes of P − E over the TP. The thermodynamic component contributes positively over the southern and central TP whereas the transient eddy component tends to reinforce (offset) the dynamic component over the southern and parts of the northern TP (central T.
Evaluation of second‐order texture parameters for sea ice classification from radar images

With the advent of airborne and spaceborne synthetic aperture radar (SAR) systems, sea ice classification from SAR images has become an important research subject. Since gray tone alone has proven to be of limited capability in differentiating ice types, texture has naturally become an attractive avenue to explore. Accordingly, performance of texture quantification parameters as related to their ability to discriminate ice types has to be examined. SAR image appearance depends on radar parameters involved in the image construction procedures from the doppler history record. Therefore the feasibility of using universal texture/ice type relationships that hold for all combinations of radar parameters also has to be investigated. To that end, imagery data from three different SAR systems were used in this study. Five conventional texture parameters, derived from the gray level co-occurrence matrix (GLCM), were examined. Two of them were modified to ensure their invariant character under linear gray tone transformations. Results indicated that all parameters were highly correlated. The parameters did not, in general, vary with the computational variables used in generating co-occurrence matrices. Ice types can be identified uniquely by the mean value of any texture parameter. The relatively high variability of texture parameters, however, confuses ice discrimination, particularly of smoother ice types. Ice classification was conducted using a per-pixel maximum likelihood supervised scheme. When texture was combined with gray tone, the overall average classification accuracy was improved. Texture was successful in improving the classification accuracy of multiyear ice but was less promising in discriminating first-season ice types. The best two GLCM texture parameters, according to the computed overall average classification accuracies, were the inverse difference moment and the entropy. A brief description of GLCM texture parameters as related to ice's physical characteristics is presented.
Compact Reconnaissance Imaging Spectrometer observations of water vapor and carbon monoxide

[1] The Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) onboard the Mars Reconnaissance Orbiter (MRO) spacecraft began taking observations in September 2006 and has now collected more than a full Martian year of data. Retrievals performed using the near-infrared spectra obtained by CRISM are used to characterize the seasonal and spatial variation of the column abundance of water vapor and the column-averaged mixing ratio of carbon monoxide. CRISM retrievals show nominal behavior in water vapor during northern hemisphere spring and summer with maximum abundance reaching 50 precipitable micrometers. Water vapor abundance during the southern hemisphere spring and summer appears significantly reduced compared to observations by other instruments taken during previous years. The CRISM retrievals show the seasonally and globally averaged carbon monoxide mixing ratio to be 700 ppm, but with strong seasonal variations at high latitudes. The summertime near-polar carbon monoxide mixing ratio falls to 200 ppm in the south and 400 ppm in the north as carbon dioxide sublimates from the seasonal polar ice caps and dilutes noncondensable species including carbon monoxide. At low latitudes, the carbon monoxide mixing ratio varies in response to the mean seasonal cycle of surface pressure.
Variation of lunar sodium during passage of the Moon through the Earth's magnetotail

We measured sodium emission above the lunar equator over a range of lunar altitudes from 100 to 4000 km. The measurements were repeated approximately every 24 hours from June 7 to 16, 1998, covering the period during which the Moon passed through the Earth's magnetotail. Sodium temperatures derived from the altitude dependence of emission intensity ranged from 1200 to 2900 K. This result supports the view that photodesorption is a primary source of sodium in the exosphere since the most probable temperature of sodium form this source is in this range. Passage of the Moon through the Earth's magnetotail (where solar wind is essentially absent) affected the sodium density, such that it was higher before the Moon entered the Earth's magnetotail than after the Moon left it. This suggests that the solar wind plays a role in production of lunar sodium. We propose that its function is to mobilize sodium and bring it to the surface, where photodesorption can eject it into the exosphere. A two-step process such as this could help to explain the latitude dependence of sodium density, which varies as the second or higher power of cosine latitude.
Accurate Calculation of Barnase and SNase Folding Energetics using short MD simulations and an Atomistic Model of the Unfolded Ensemble. Evaluation of Force Fields and Water Models.

As proteins perform most cellular functions, quantitative understanding of protein energetics is required to gain control of biological phenomena. Accurate models of native proteins can be obtained experimentally but the lack of equally fine models of unfolded ensembles impedes the calculation of protein folding energetics from first principles. Here we show that an atomistic unfolded ensemble model, consisting on a few dozen conformations built from a protein sequence, can be used in conjunction with an X-ray structure of its native state to calculate accurately by difference the changes in enthalpy and in heat capacity of the polypeptide upon folding. The calculation is done using Molecular Dynamics simulations and popular force fields and water models and, for the two model proteins studied (barnase and SNase), the results agree within error or are very close to their experimentally determined properties. The enthalpy sampling of the unfolded ensemble is done through short 2-ns simulations that do not significantly modify the representative distribution of Rg of the starting conformations. The impressive accuracy obtained opens the possibility to investigate quantitatively systems or phenomena not amenable to experiment, and paves the way for addressing the calculation of protein conformational stability (i.e. the change in Gibbs energy upon folding), a central goal of Structural Biology. So far, these calculated enthalpy and heat capacity changes, combined with the experimentally determined melting temperatures of the corresponding protein, allow to reproduce the stability curves of both barnase and SNase.
Fundamental Toxicological Sciences

In this study, we evaluated the toxicity of 16 veterinary drugs approved in Japan (antimicrobial substances, antiparasitic agents, and disinfectants) using a fish acute toxicity test, Daphnia swimming inhibition test, algae growth inhibition test, and earthworm acute toxicity test. Test organisms included Oryzias latipes, Daphnia magna, Pseudokirchneriella subcapitata, and Eisenia fetida. The tests were performed in accordance with the Organisation for Economic Co-operation and Development guidelines for testing chemicals. In the Globally Harmonized System of Classification and Labelling of Chemicals, when the EC/LC50 value of a substance is < 1 mg/mL, then the substance is classified as Category 1, or highly toxic to aquatic organisms. The results of the present study indicate that the toxicity of tylosin phosphate, lincomycin, oxytetracycline chloride, and chlortetracycline to algae; that of ivermectin to crustaceans and fish; and that of didecyldimethylammonium chloride to all organisms examined should be classified as Category 1. In terrestrial organism, weak toxicity was observed with ivermectin, fenbendazole, and didecyldimethylammonium chloride. These data are considered to be valuable data for actually knowing the toxicity of veterinary drugs, in particular, since there is hardly any data following the guidelines using Eisenia fetida. Our results also suggest that the environmental risk of the tested veterinary drugs might be low at present researched environmental levels in river. In addition, our data indicate that the possibility of many veterinary drugs adversely affecting the environment is low if they are properly used.
Tactile Sensibility of Single-Tooth Implants and Natural Teeth Under Local Anesthesia of the Natural Antagonistic Teethcid_252

Introduction and Aim: The term osseoperception describes the capability of developing a subtle tactile sensibility over dental implants. The present clinical study aims at clarifying the question of how far tactile sensibility is to be attributed to the periodontium of the natural opposing tooth of the implant. Material and Method: Thirty-two subjects with single-tooth implants with natural opposing teeth were included in this clinical, single-blind, split-mouth study. The natural antagonistic tooth of the implant and the corresponding natural contralateral tooth were anesthetized with a locally infiltrated articaine anesthetic. In a computer-assisted and randomized way, copper foils of varying thickness (0–100 mm) were placed interocclusally between the single-tooth implant and the natural opposing tooth, and between the contralateral pair of natural opposing teeth in order to investigate the active tactile sensibility according to the psychophysical method of constant stimuli and evaluate it statistically by the Weibull distribution. Results: The average tactile sensibility of the implants with anesthetized antagonists at the 50% value calculated by means of the Weibull distribution was 20 1 11 mm with a support area (90%–10% value) of 77 1 89 mm. For the pair of natural teeth, the tactile sensibility at the 50% value was 16 1 9 mm with a support area of 48.4 1 93 mm. This resulted in an average intraindividual difference of 3.5 1 7 mm at the 50% value and 29 1 93 mm in the support area. The statistical calculations demonstrated an equivalent tactile sensibility (50% value) of the single-tooth implant and the contralateral natural control tooth with the natural antagonists being anesthetized in each case (double t-test, equivalence limit 1 8 mm, P < 0.01, power >80%). Conclusion: Apparently, the active tactile sensibility of single-tooth implants with natural opposing teeth is not only to be attributed to the periodontium of the opposing tooth but also to a perception over the implant itself. This could support the hypothesis according to which the implant may have a tactile sensibility of its own.
The isotopic composition of atmospheric oxygen

Atmospheric O2 is almost 24‰ more enriched in 18O than seawater, and this enrichment is known as the Dole effect. For a long time it has been accepted that there is no oxygen isotope fractionation in photosynthesis, and thus the Dole effect should be the result of preferential terrestrial and marine respiratory consumption of 16O over 18O, and also several permil enrichment of leaf water from which terrestrial photosynthesis produces 18O enriched O2. This concept has led to the understanding that the record of past Dole effect variations was strongly affected by changes in the ratio of photosynthetic production between land and sea. However, recent studies in our lab have led to two major new observations: (1) O2 produced by certain marine phytoplankton, representing important groups of primary producers, is significantly enriched (up to 6‰) in 18O with respect to the substrate seawater and (2) effective oxygen isotope fractionation in soil respiration is considerably smaller than the intrinsic respiratory fractionation. Here we take these two observations into account and show that the magnitudes of the terrestrial and marine components of the Dole effect are close, and both are close to the measured Dole effect. As a result, the magnitude of the global Dole effect should not be sensitive to past changes in the ratio of land‐to‐sea photosynthetic rates. Instead of the land‐sea control, variations in low‐latitude hydrology, and possibly changes of fractionations in the marine biosphere, are more important in regulating the magnitude of the Dole effect and its past variations.
6 (cid:1) -Guanidinonaltrindole (6 (cid:1) -GNTI) Is a G Protein-biased (cid:1) -Opioid Receptor Agonist That Inhibits Arrestin Recruitment

Background: Arrestin recruitment to the (cid:1) -opioid receptor (KOR) has been linked to several adverse effects of analgesics, such as dysphoria and tolerance. Results: We identified 6 (cid:1) -guanidinonaltrindole (6 (cid:1) -GNTI) as a potent KOR agonist for G protein activation that fails to recruit arrestin. Conclusion: 6 (cid:1) -GNTI is an extreme G protein-biased KOR ligand. Significance: analgesics with fewer arrestin-mediated adverse effects.
Movement imitation depends on an abstract trajectory representation in dorsal premotor cortex

body-independent) trajectory-path representation for planning and executing complex actions such as copying gestures, which can be dissociated behaviorally and neurally from the ability to accurately report the shape of the observed action. Furthermore, we provide strong evidence that damage to dorsal premotor cortex disrupts this ability to represent trajectory shapes, giving rise to deficits in the ability to imitate meaningless actions.
Climatological Extremes of Simulated Annual Mean Rainfall

Abstract The Commonwealth Scientific and Industrial Research Organisation (CSIRO) Mark 2 global coupled climatic model has been used to generate a 10 000-yr simulation of “present” climate. The resultant dataset has been used to investigate a number of aspects of extremes associated with annual mean rainfall. Multimillennial time series of normalized rainfall amounts for selected points are used to highlight secular variability, spatial variations, and the differences between pluvial and drought conditions. Global distributions are also presented for selected rainfall characteristics, including the frequency of occurrence of specified rainfall anomalies with annual durations, the frequency of occurrence of 5-yr sequences of specified rainfall anomalies, and the maximum and minimum normalized rainfall amounts attained in the simulation. Such features cannot be obtained from observations because of their limited duration. A case study is also made of a megadrought over the southwestern United States, togeth.
LARGE BRACHYTHORACID ARTHRODIRES (PLACODERM FISHES) FROM THE EARLY DEVONIAN OF WEE JASPER, NEW SOUTH WALES, AUSTRALIA, WITH A DISCUSSION OF BASAL BRACHYTHORACID CHARACTERS

Abstract Two new brachythoracids are described from the Emsian limestones of the Lake Burrinjuck area, both based on skull remains. They are the largest and most advanced arthrodires so far known from the fauna, and amongst the largest fishes recorded anywhere from the Early Devonian. Dhanguura johnstoni gen. et sp. nov. is based on a single incomplete skull with an estimated length of at least 40 cm, which possesses the derived character of a strongly T-shaped rostral plate, not recorded in any other arthrodire from the fauna. Cathlesichthys weejasperensis gen. et sp. nov. was of similar size, and shows a derived dunkleosteid type of development of the posterior skull margin. In both forms the paranuchal plates have narrow anterior margins, suggesting affinities with the family Homostiidae. Some new material of the genus Taemasosteus is illustrated for comparison. Skull characters used in phylogenetic analyses of brachythoracid arthrodires are reviewed; in Dhanguura johnstoni the similar overlap of the nuchal plate onto centrals, central plates onto preorbitals, and preorbital plates onto the rostral plate may reflect a single developmental pattern. The preorbital plates completely separated by the pineal and rostral plates are interpreted as a homoplasy with coccosteomorphs, and instead of a preorbital embayment of the centrals, as seen in that group, this bone has a posterolateral process, as in Arenipiscis. Cathlesichthys is derived in the massive transverse nuchal ridge, one of three defining characters of the Eubrachythoraci, but shows no evidence of an anterior nuchal thickening.