MODOMICS is a database of RNA modifications that provides comprehensive information concerning the chemical structures of modified ribonucleosides, their biosynthetic pathways, RNA-modifying enzymes ...and location of modified residues in RNA sequences. In the current database version, accessible at http://modomics.genesilico.pl, we included new features: a census of human and yeast snoRNAs involved in RNA-guided RNA modification, a new section covering the 5'-end capping process, and a catalogue of 'building blocks' for chemical synthesis of a large variety of modified nucleosides. The MODOMICS collections of RNA modifications, RNA-modifying enzymes and modified RNAs have been also updated. A number of newly identified modified ribonucleosides and more than one hundred functionally and structurally characterized proteins from various organisms have been added. In the RNA sequences section, snRNAs and snoRNAs with experimentally mapped modified nucleosides have been added and the current collection of rRNA and tRNA sequences has been substantially enlarged. To facilitate literature searches, each record in MODOMICS has been cross-referenced to other databases and to selected key publications. New options for database searching and querying have been implemented, including a BLAST search of protein sequences and a PARALIGN search of the collected nucleic acid sequences.
The eleventh generation of the International Geomagnetic Reference Field (IGRF) was adopted in December 2009 by the International Association of Geomagnetism and Aeronomy Working Group V-MOD. It ...updates the previous IGRF generation with a definitive main field model for epoch 2005.0, a main field model for epoch 2010.0, and a linear predictive secular variation model for 2010.0–2015.0. In this note the equations defining the IGRF model are provided along with the spherical harmonic coefficients for the eleventh generation. Maps of the magnetic declination, inclination and total intensity for epoch 2010.0 and their predicted rates of change for 2010.0–2015.0 are presented. The recent evolution of the South Atlantic Anomaly and magnetic pole positions are also examined.
The Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy (PRIME) demonstrated that panitumumab–FOLFOX4 significantly improved ...progression-free survival (PFS) versus FOLFOX4 as first-line treatment of wild-type (WT) KRAS metastatic colorectal cancer (mCRC), the primary end point of the study.
Patients were randomized 1:1 to panitumumab 6.0 mg/kg every 2 weeks + FOLFOX4 (arm 1) or FOLFOX4 (arm 2). This prespecified final descriptive analysis of efficacy and safety was planned for 30 months after the last patient was enrolled.
A total of 1183 patients were randomized. Median PFS for WT KRAS mCRC was 10.0 months 95% confidence interval (CI) 9.3–11.4 months for arm 1 and 8.6 months (95% CI 7.5–9.5 months) for arm 2; hazard ratio (HR) = 0.80; 95% CI 0.67–0.95; P = 0.01. Median overall survival (OS) for WT KRAS mCRC was 23.9 months (95% CI 20.3–27.7 months) for arm 1 and 19.7 months (95% CI 17.6–22.7 months) for arm 2; HR = 0.88; 95% CI 0.73–1.06; P = 0.17 (68% OS events). An exploratory analysis of updated survival (>80% OS events) was carried out which demonstrated improvement in OS; HR = 0.83; 95% CI 0.70–0.98; P = 0.03 for WT KRAS mCRC. The adverse event profile was consistent with the primary analysis.
In WT KRAS mCRC, PFS was improved, objective response was higher, and there was a trend toward improved OS with panitumumab–FOLFOX4, with significant improvement in OS observed in an updated analysis of survival in patients with WT KRAS mCRC treated with panitumumab + FOLFOX4 versus FOLFOX4 alone (P = 0.03). These data support a positive benefit-risk profile for panitumumab–FOLFOX4 for patients with previously untreated WT KRAS mCRC. KRAS testing is critical to select appropriate patients for treatment with panitumumab.
Abstract Background The TRPV1 receptor is a key molecule in pain generation. Previous development of oral TRPV1‐antagonists was halted due to systemic heat insensitivity and body temperature ...alterations. The present Phase 1b study investigated the efficacy, safety and plasma exposure of a topically administered TRPV1‐antagonist (ACD440 Gel) in healthy subjects. Methods The study comprised two parts. In part 1, 24 healthy subjects were included in this randomized double‐blind, placebo‐controlled, crossover trial. ACD440 Gel or Placebo was applied once daily and wiped off after 1 h, for 5 consecutive days. Assessments were done in normal skin, skin optimized for penetration (by stripping and occlusive gel application) and UVB‐irradiated skin. Pain induced by thermo‐nociceptive CO 2 laser impulses generated laser‐evoked potentials (LEPs), with readouts of peak‐to‐peak (PtP) amplitude in vertex‐EEG and pain assessments by VAS (0–100). Endpoints include effects at 1 hour post‐dose, AUC(Days 1–5) and AUC (0–24, Day 4) . In UVB‐irradiated skin, also pain on pinprick and skin redness were assessed. Part 2 explored the plasma pharmacokinetics of ACD440. Results ACD440 Gel reduced LEP PtP amplitude and VAS pain, p < 0.001, in all skin conditions, versus placebo. In UVB‐irradiated skin, pinprick pain was also reduced, p = 0.047. Effects were significant after 1 h, maintaining for at least 9 h. There were no adverse events or drug‐induced erythema. Plasma exposures of ACD440 were too low to establish an elimination half‐life of ACD400. Conclusions Topical ACD440 Gel demonstrated a significant analgesic effect on LEP, VAS score and pinprick pain, with low systemic exposures, supporting further clinical development. Significance This study demonstrates that the topical administration of a TRPV1‐antagonist, ACD440 Gel, has potential as a new treatment for painful conditions affecting the skin, such as chronic peripheral neuropathic pain, without any local or systemic side effects.
We present a continuous benchmarking approach for the assessment of RNA secondary structure prediction methods implemented in the CompaRNA web server. As of 3 October 2012, the performance of 28 ...single-sequence and 13 comparative methods has been evaluated on RNA sequences/structures released weekly by the Protein Data Bank. We also provide a static benchmark generated on RNA 2D structures derived from the RNAstrand database. Benchmarks on both data sets offer insight into the relative performance of RNA secondary structure prediction methods on RNAs of different size and with respect to different types of structure. According to our tests, on the average, the most accurate predictions obtained by a comparative approach are generated by CentroidAlifold, MXScarna, RNAalifold and TurboFold. On the average, the most accurate predictions obtained by single-sequence analyses are generated by CentroidFold, ContextFold and IPknot. The best comparative methods typically outperform the best single-sequence methods if an alignment of homologous RNA sequences is available. This article presents the results of our benchmarks as of 3 October 2012, whereas the rankings presented online are continuously updated. We will gladly include new prediction methods and new measures of accuracy in the new editions of CompaRNA benchmarks.
Magnetic observations on board the CHAMP satellite are used for the first comprehensive study of magnetic signatures of the postsunset equatorial spread F (ESF) events. This is derived from a ...continuous database covering the years 2001–2004. On the basis of an extended survey, the global distribution of magnetic signatures is derived. We find a distinct seasonal/longitudinal variation of the occurrence rate of magnetic signatures that is consistent with that obtained from previous satellite observations of plasma depletions. The latitudinal distribution of the ESF magnetic signatures from CHAMP is symmetrical about the dip equator. It can be approximated by two Gaussian curves peaking at ±9.5° magnetic latitude, both exhibiting an 1σ‐width of 4.5°. We further find a close relation between the occurrence frequency and the solar EUV flux. The global average of the occurrence rate is linearly proportional to solar activity attaining ∼0.1% times the F10.7 value. The response of the ESF magnetic signatures to geomagnetic activity is also investigated. However, only a weak relation between the signature occurrence rate and the Kp index is found. Using high‐resolution magnetic field measurements of the ESF structures, we are able to identify very small spatial scales of spread F of only few tens of meters. The vector magnetic field observations provide experimental evidence of the electromagnetic characteristics of ESF, valuable for testing model predictions. Finally, we discuss the effect of the ESF phenomenon on magnetic field modeling efforts based on satellite data.
We present the GFZ candidate field models for the
13
th
Generation International Geomagnetic Reference Field (IGRF-13). These candidates were derived from the Mag.num.IGRF13 geomagnetic core field ...model, which is constrained by Swarm satellite and ground observatory data from November 2013 to August 2019. Data were selected from magnetically quiet periods, and the model parameters have been obtained using an iteratively reweighted inversion scheme approximating a robust modified Huber norm as a measure of misfit. The root mean square misfit of the Mag.num.IGRF13 model to Swarm and observatory data is in the order of 3–5 nT for mid and low latitudes, with a maximum of 44 nT for the satellite east component data at high latitudes. The time-varying core field is described by order 6 splines and spherical harmonic coefficients up to degree and order 20. We note that the temporal variation of the core field component of the Mag.num.IGRF13 model is strongly damped and shows a smooth secular variation that suits well for the IGRF, where secular variation is represented as constant over 5-year intervals. Further, the external field is parameterised by a slowly varying part and a more rapidly varying part controlled by magnetic activity and interplanetary magnetic field proxies. Additionally, the Euler angles of the magnetic field sensor orientation are co-estimated. A widely discussed feature of the geomagnetic field is the South Atlantic Anomaly, a zone of weak and decreasing field strength stretching from southern Africa over to South America. The IGRF and Mag.num.IGRF13 indicate that the anomaly has developed a second, less pronounced eastern minimum at Earth’s surface since 2007. We observe that while the strong western minimum continues to drift westwards, the less pronounced eastern minimum currently drifts eastward at Earth’s surface. This does not seem to be linked to any eastward motion at the core–mantle boundary, but rather to intensity changes of westward drifting flux patches contributing to the observed surface field. Also, we report a sudden change in the secular variation measured at two South Atlantic observatories around 2015.0, which occurred shortly after the well-known jerk of 2014.0.
The climatological model of the equatorial electrojet, EEJM‐1, derived from Ørsted, CHAMP and SAC‐C satellite measurements provides the opportunity to investigate the longitudinal variation of the ...current strength in detail. Special emphasis is put in this study on the effect of nonmigrating tides. We have found that the influence of the diurnal eastward‐propagating mode with wavenumber‐3, DE3, is particularly strong. In polar orbiting satellite observations the DE3 tidal signal appears as a four‐peaked longitudinal structure. We have put special emphasis in our analysis to isolate the DE3 contribution from other sources contributing to the wavenumber‐4 structure in satellite data. The amplitude of the DE3 signature in the EEJ not only peaks during equinox seasons, but is also strong around the June solstice. When looking at the modulation of the EEJ intensity the DE3 accounts for about 25% during the months of April through September. It is thus the dominant cause for longitudinal variations. During December solstice months the influence of DE3 is negligible. A secondary three‐peaked longitudinal pattern emerges during solstice seasons when the DE3 influence is removed. From the data available it is, however, not clear whether this pattern is related to any tidal drivers.
In December 2019, the 13th revision of the International Geomagnetic Reference Field (IGRF) was released by the International Association of Geomagnetism and Aeronomy (IAGA) Division V Working Group ...V-MOD. This revision comprises two new spherical harmonic main field models for epochs 2015.0 (DGRF-2015) and 2020.0 (IGRF-2020) and a model of the predicted secular variation for the interval 2020.0 to 2025.0 (SV-2020-2025). The models were produced from candidates submitted by fifteen international teams. These teams were led by the British Geological Survey (UK), China Earthquake Administration (China), Universidad Complutense de Madrid (Spain), University of Colorado Boulder (USA), Technical University of Denmark (Denmark), GFZ German Research Centre for Geosciences (Germany), Institut de physique du globe de Paris (France), Institut des Sciences de la Terre (France), Pushkov Institute of Terrestrial Magnetism, Ionosphere and Radio Wave Propagation (Russia), Kyoto University (Japan), University of Leeds (UK), Max Planck Institute for Solar System Research (Germany), NASA Goddard Space Flight Center (USA), University of Potsdam (Germany), and Université de Strasbourg (France). The candidate models were evaluated individually and compared to all other candidates as well to the mean, median and a robust Huber-weighted model of all candidates. These analyses were used to identify, for example, the variation between the Gauss coefficients or the geographical regions where the candidate models strongly differed. The majority of candidates were sufficiently close that the differences can be explained primarily by individual modeling methodologies and data selection strategies. None of the candidates were so different as to warrant their exclusion from the final IGRF-13. The IAGA V-MOD task force thus voted for two approaches: the median of the Gauss coefficients of the candidates for the DGRF-2015 and IGRF-2020 models and the robust Huber-weighted model for the predictive SV-2020-2025. In this paper, we document the evaluation of the candidate models and provide details of the approach used to derive the final IGRF-13 products. We also perform a retrospective analysis of the IGRF-12 SV candidates over their performance period (2015–2020). Our findings suggest that forecasting secular variation can benefit from combining physics-based core modeling with satellite observations.
The Gravity Recovery and Climate Experiment Follow-On (GRACE-FO) mission carries magnetometers that are dedicated to enhance the satellite’s navigation. After appropriate calibration and ...characterisation of artificial magnetic disturbances, these observations are valuable assets to characterise the natural variability of Earth’s magnetic field. We describe the data pre-processing, the calibration, and characterisation strategy against a high-precision magnetic field model applied to the GRACE-FO magnetic data. During times of geomagnetic quiet conditions, the mean residual to the magnetic model is around 1 nT with standard deviations below 10 nT. The mean difference to data of ESA’s Swarm mission, which is dedicated to monitor the Earth’s magnetic field, is mainly within ± 10 nT during conjunctions. The performance of GRACE-FO magnetic data is further discussed on selected scientific examples. During a magnetic storm event in August 2018, GRACE-FO reveals the local time dependence of the magnetospheric ring current signature, which is in good agreement with results from a network of ground magnetic observations. Also, derived field-aligned currents (FACs) are applied to monitor auroral FACs that compare well in amplitude and statistical behaviour for local time, hemisphere, and solar wind conditions to approved earlier findings from other missions including Swarm. On a case event, it is demonstrated that the dual-satellite constellation of GRACE-FO is most suitable to derive the persistence of auroral FACs with scale lengths of 180 km or longer. Due to a relatively larger noise level compared to dedicated magnetic missions, GRACE-FO is especially suitable for high-amplitude event studies. However, GRACE-FO is also sensitive to ionospheric signatures even below the noise level within statistical approaches. The combination with data of dedicated magnetic field missions and other missions carrying non-dedicated magnetometers greatly enhances related scientific perspectives.
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