Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. ...Therefore, tofacitinib effects on synovial pathobiology were investigated.
A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699).
Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo.
Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response.
NCT00976599.
Sequence-based typing (SBT) of
is a valuable tool in epidemiological studies and outbreak investigations of Legionnaires' disease. In the
SBT scheme,
is one of seven genes that determine the sequence ...type (ST). The
genome typically contains two copies of
and
When they are non-identical it can be challenging to determine the
allele, and subsequently the ST, from Illumina short-reads. In our collection of 233
genomes, there were 62 STs, 18 of which carried non-identical
copies. Using short-reads, the
allele was misassembled or untypeable in several STs. Genomes belonging to ST154 and ST574, which carried
allele 7 and
allele 15, were assigned an incorrect
allele and/or
gene copy number when short-read assembled. For other isolates, mainly those carrying non-identical
copies, short-read assemblers occasionally failed to resolve the structure of the
region, also resulting in untypeability from the short-read data. In this study, we wanted to understand the challenges we observed with calling the
2 allele from short-reads, assess if other short-read methods were able to resolve the
-region, and investigate the possibility of using long-reads to obtain the
alleles, and thereby perform
SBT from long-reads only. We found that the choice of short-read assembler had a major impact on resolving the
-region and thus SBT from short-reads, but no method consistently solved the
allele. By using Oxford Nanopore Technology (ONT) sequencing together with Trycycler and Medaka for long-read assembly and polishing we were able to resolve the
copies and correctly identify the
allele, in accordance with Sanger sequencing/EQA results for all tested isolates (n=35). The remaining six genes of the SBT profile could also be determined from the ONT-only reads. The STs called from ONT-only assemblies were also consistent with hybrid-assemblies of Illumina and ONT reads. We therefore propose ONT sequencing as an alternative method to perform
SBT to overcome the
challenge observed with short-reads. To facilitate this, we have developed ONTmompS (https://github.com/marithetland/ONTmompS), an
approach to determine
ST from long-read or hybrid assemblies.
The CDEX-1 experiment conducted a search of low-mass (< 10GeV/c super(2)) weakly interacting massive particles dark matter at the China Jinping Underground Laboratory using a p-type point-contact ...germanium detector with a fiducial mass of 915 g at a physics analysis threshold of 475 eVee. We report the hardware setup, detector characterization, data acquisition, and analysis procedures of this experiment. No excess of unidentified events is observed after the subtraction of the known background. Using 335.6 kg-days of data, exclusion constraints on the weakly interacting massive particle-nucleon spin-independent and spin-dependent couplings are derived.
Electronic and crystal structure studies are presented to describe the role of intersite and onsite interactions for antiferromagnetic ordering in CeAg2Ge2. The crystal structure showed a prominent ...magnetovolume effect with anomalous negative thermal expansion at low temperature as a consequence of itinerant electron magnetism. The direct hybridization gap with a V-shaped band observed in the angle resolved photoemission data at room temperature, indicates that spin polarized quasiparticle states exist in the gapped region. Valence band broadening and enhanced localization effects at low temperature indicate strong hybridization of the valence orbitals of Ce atoms with the near neighbor Ge atoms. We find that the intersite interaction between the Ce atoms at high temperature stabilizes the onsite interaction at low temperature that leads to the spin density wave type antiferromagnetism in CeAg2Ge2.
We report new limits on a spin-independent weakly interacting massive particle (WIMP)-nucleon interaction cross section using 39.5 kg days of data taken with a p-type point-contact germanium detector ...of 840 g fiducial mass at the Kuo-Sheng Reactor Neutrino Laboratory. Crucial to this study is the understanding of the selection procedures and, in particular, the bulk-surface events differentiation at the sub-keV range. The signal-retaining and background-rejecting efficiencies were measured with calibration gamma sources and a novel n-type point-contact germanium detector. Part of the parameter space in the cross section versus WIMP-mass implied by various experiments is probed and excluded.
The p-type point-contact germanium detectors are novel techniques offering kg-scale radiation sensors with sub-keV sensitivities. They have been used for light dark matter WIMPs searches and may have ...potential applications in neutrino physics. There are, however, anomalous surface behaviour which needs to be characterized and understood. We describe the methods and results of a research program whose goals are to identify the bulk and surface events via software pulse shape analysis techniques, and to devise calibration schemes to evaluate the selection efficiency factors. Efficiencies-corrected background spectra from the low-background facility at Kuo-Sheng Neutrino Laboratory are derived.
Electronic and crystal structure studies are presented to describe the role of intersite and onsite interactions for antiferromagnetic ordering in CeAg
Ge
. The crystal structure showed a prominent ...magnetovolume effect with anomalous negative thermal expansion at low temperature as a consequence of itinerant electron magnetism. The direct hybridization gap with a V-shaped band observed in the angle resolved photoemission data at room temperature, indicates that spin polarized quasiparticle states exist in the gapped region. Valence band broadening and enhanced localization effects at low temperature indicate strong hybridization of the valence orbitals of Ce atoms with the near neighbor Ge atoms. We find that the intersite interaction between the Ce atoms at high temperature stabilizes the onsite interaction at low temperature that leads to the spin density wave type antiferromagnetism in CeAg
Ge
.
While destruction associated with floods during the monsoon season and cyclones receives wide attention, the extreme weather in the form of hail, lightning and high winds have also caused widespread ...devastation over India on a small spatial scale in recent years, especially during the period of March to June. India Meteorological Department (IMD) organized a special forecast improvement campaign during the period March to June of 2017–2019 when the weather forecasts at all offices of IMD were targeted towards an accurate forecast of the extreme form of thunderstorms and their associated impact in short range to nowcasting timescale and their dissemination. The purpose of this study is to quantify the improvement in operational thunderstorm forecast accuracy, in short range (24 h Severe Weather Guidance at subdivisional level) and nowcast scale (nowcasts for individual stations valid for 3 h and issued every three hours) during March to June of 2017 to 2019 and compare the same with the accuracy of previous years. As a result of these efforts, there has been a significant jump in forecast accuracy in the 24-h thunderstorm forecast as well as 3-h nowcast guidance for thunderstorms across the country. Probability of Detection (POD) scores for India as a whole for the 24-h thunderstorm forecast has doubled, while the false alarms (FAR) have remained at the same level as before the start of the forecast campaign. The results indicate that since a thunderstorm is a disastrous weather event, the forecasters generally tend towards spatial over-forecasting. However, this is not uniform across the months. There is systematic lower accuracy in the season transition months of March (winter to summer) and June (dry summer to wet summer). While POD decreases in both March and June, FAR decrease throughout the season. The significant evolution of atmospheric parameters (moisture in particular) as the season changes, favours the maturation of thunderstorms to cumulonimbus stage as the season progresses, and the problem of over forecasting in March becomes a problem of under forecasting of thunderstorms in June. Another reason for false alarms is the unconscious linkage of the thunderstorm with the pattern of rainfall occurrence. However, since all rain-giving clouds over India do not necessarily mature to the cumulonimbus stage, and vice versa, the two are not always related. This is particularly true for the more arid regions of the country, especially in March, where false alarms are higher. The poor density of reporting observatories compared to the mesoscale nature of the events may also increase false alarms, especially over the small maritime islands and the arid regions of the mainland. The accuracy of the All India 3 hourly station level nowcast also improved systematically since 2017. Despite these constraints, the improvements at all scales were possible due to (a) augmentation of observation network by the rapid expansion of Doppler radars network throughout the Indian mainland as well as the installation of a ground-based lightning detection network, (b) numerical modeling products introduced in 2019 to provide short-range forecasts for all aspects of convection; both of which are incorporated into the forecast framework through Standard Operating Procedures (SOP) to standardize the forecast procedure throughout the Indian region. A more objective forecast strategy, using data generated from a denser network of DWRs and crowdsourcing methods as well as more accurate mesoscale models will go a long way to further improve the thunderstorm forecasts.
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