•Immunogenicity of infliximab and adalimumab is a problem causing loss of response.•Monitoring of anti-drug antibodies is recommended in clinical guidelines.•Quantitative point-of-care tests for ...anti-drug antibodies determination are being developed.•We performed the first comparison between a quantitative rapid method and ELISA kits.•Different clinical decisions could be chosen depending on the method used.
Adalimumab (ADL), infliximab (IFX) and their biosimilars are widely used biological drugs. Some patients, however, generate neutralizing antibodies that hamper the effectiveness of these drugs. Evidence shows therapeutic drug monitoring of serum levels ADL/IFX and anti-drug antibodies (ADA) is useful to improve treatment effectiveness. We evaluated a new rapid quantitative method, Quantum Blue (QB), for determining serum anti-ADL and anti-IFX antibodies (Research Use Only labelling) by comparing it with two established ELISA kits, Promonitor (PM) and Lisa-Tracker (LT).
Eighty samples (40 for each drug type) were analysed. Percentage of agreement and kappa statistic were used to compare positive/negative ADA results. Clinical implications for drug treatment in the patients with discordant results were evaluated. The Chi-square test was used to analyze differences for ADA detection in patients with disease flare and without concomitant immunosuppressant treatment.
Agreement exceeded 80 % among anti-ADL methods. Although LT ELISA showed a lower capacity in detecting anti-ADL antibodies, discrepancies were found for levels close to the cut-off concentration, thus having minimal impact on clinical decisions. Conversely, QB anti-IFX displayed low agreement with PM and LT ELISA kits (67.5 % and 50 %, respectively), and was unable to detect high levels of antibodies, therefore having major clinical implications. Agreement between PM and LT ELISA anti-IFX kits was 82.5 % with all discordant results being undetected for PM and slightly positive for LT.
QB anti-ADL shows similar performance to ELISA kits while QB anti-IFX needs further improvements to achieve reliable antibody detection.
We previously reported the in vitro spontaneous transformation of human mesenchymal stem cells (MSC) generating a population with tumorigenic potential, that we termed transformed mesenchymal cells ...(TMC).
Here we have characterized the molecular changes associated with TMC generation. Using microarrays techniques we identified a set of altered pathways and a greater number of downregulated than upregulated genes during MSC transformation, in part due to the expression of many untranslated RNAs in MSC. Microarray results were validated by qRT-PCR and protein detection.
In our model, the transformation process takes place through two sequential steps; first MSC bypass senescence by upregulating c-myc and repressing p16 levels. The cells then bypass cell crisis with acquisition of telomerase activity, Ink4a/Arf locus deletion and Rb hyperphosphorylation. Other transformation-associated changes include modulation of mitochondrial metabolism, DNA damage-repair proteins and cell cycle regulators. In this work we have characterized the molecular mechanisms implicated in TMC generation and we propose a two-stage model by which a human MSC becomes a tumor cell.
Vitamin D is an environmental factor related to multiple sclerosis that plays a significant role in immune regulation. TGF-β is a superfamily of cytokines with an important dual effect on the immune ...system. TGF-β inhibits the Th1 response while facilitating the preservation of regulatory T cells (FOXP3+) in an immunoregulatory capacity. However, when IL-6 is present, it stimulates the Th17 response. Our aim was to analyze the regulatory effect of vitamin D on the in vivo TGF-β signaling pathway in patients with relapsing-remitting multiple sclerosis (RRMS). A total of 21 patients with vitamin D levels < 30 ng/mL were recruited and supplemented with oral vitamin D. All patients were receiving disease-modifying therapy, with the majority being on natalizumab. Expression of SMAD7, ERK1, ZMIZ1, BMP2, BMPRII, BMP4, and BMP5 was measured in CD4+ lymphocytes isolated from peripheral blood at baseline and one and six months after supplementation. SMAD7 was overexpressed at six months with respect to baseline and month one. ERK1 was overexpressed at six months with respect to month one of treatment. No significant differences in expression were observed for the remaining genes. No direct correlation was found with serum vitamin D levels. BMPRII expression changed differentially in non–natalizumab- versus natalizumab-treated patients. Changes were observed in the expression of ERK1, BMP2, and BMP5 based on disease activity measured using the Rio-Score, BMP2 in patients who had relapses, and BMP5 in those whose EDSS worsened. Our results suggest indirect regulation of vitamin D in TGF-β pathway genes in patients with RRMS.
For the past few decades, there has been great interest in determining if even the most massive stars in our galaxy (namely the spectral O-type stars) are formed in a similar manner as the low- and ...intermediate-mass stars, that is, through the presence of accreting disks and powerful outflows. Here, using sensitive observations of the Atacama Large Millimeter/Submillimeter Array, we report a resolved Keplerian disk (with 15 synthesized beams across its major axis) surrounding the deeply embedded O-type protostar IRAS 16547−4247. The disk shows some asymmetries that could arise because the disk is unstable and fragmenting or because of different excitation conditions within the disk. The enclosed mass estimated from the disk Keplerian radial velocities is 25 3 M . The molecular disk is at the base of an ionized thermal radio jet and is approximately perpendicular to the jet axis orientation. We additionally find the existence of a binary system of compact dusty objects at the center of the accreting disk, which indicates the possible formation of an O-type star and a companion of lower mass. This is not surprising due to the high binary fraction reported in massive stars. Subtracting the contribution of the dusty disk plus the envelope and the companion, we estimated a mass of 20 M for the central star.
We report the gold-catalyzed reaction of vinyldiazo compounds and alkenylsilanes to produce skipped dienes, which are common structural motifs in an array of bioactive compounds. This carbon–carbon ...bond-forming transformation proceeds with complete regio- and stereoselectivity with the silyl group serving as a regio- and stereocontrolling element. Likewise, the use of alkynylsilanes as reaction partners yielded skipped enynes resulting from a C(sp)–C(sp3) coupling. Mechanistic experiments and DFT studies have provided support for a stepwise mechanism.
Abstract
We present archival Atacama Large Millimeter/submillimeter Array band 6 observations of the
13
CO (
J
= 2–1) and
12
CO (
J
= 2–1) molecular line emission of the protostellar system ...associated with HH 30. The
13
CO molecular line shows the accretion disk while the molecular outflow is traced by the emission of the
12
CO molecular line. We estimated a dynamical mass for the central object of 0.45 ± 0.14
M
⊙
, and a mass for the molecular outflow of (1.83 ± 0.19) × 10
−4
M
⊙
. The molecular outflow presents an internal cavity as well as multiple outflowing shell structures. We distinguish three different shells with constant expansion (∼4–6 km s
−1
) and possible rotation signatures (≤0.5 km s
−1
). We find that the shells can be explained by magnetocentrifugal disk winds with launching radii
R
launch
≲ 4 au and a small magnetic lever arm
λ
∼ 1.6–1.9. The multiple shell structure may be the result of episodic ejections of the material from the accretion disk associated with three different epochs with dynamical ages of 497 ± 15 yr, 310 ± 9 yr, and 262 ± 11 yr for the first, second, and third shells, respectively. The outermost shell was ejected 187 ± 17 yr before the middle shell, while the middle shell was launched 48 ± 14 yr before the innermost shell. Our estimations of the linear and angular momentum rates of the outflow as well as the accretion luminosity are consistent with the values expected if the outflow of HH 30 is produced by a wide-angle disk wind.
This paper (Part II) presents a study of the zero-sequence permissible temperature rise ( T perm ) on metallic structural components in wye-wye-connected transformers without a (stabilizing) tertiary ...winding. The paper shows the direct heating-time relationship associated to a neutral current in terms of CCF o . A thermal protection criterion is proposed to control the time scale of the time-neutral current characteristic. The strategy is successfully applied to (and experimentally verified with) ONAN, three-phase, three-legged, core type, wye-wye-connected transformers based on factory acceptance tests (FATs) data. It is uncovered that the maximum permissible heating on the transformer structural metallic components due to the zero-sequence flux is determined by inverse-time CCF o . This is provided by a family of characteristic curves. The companion paper (Part I) presents where and when eddy losses and circulating current losses are induced in the transformer structural metallic components due to the zero-sequence current. The ultimate goal of these two papers is to provide engineering practical knowledge to design effective protection procedures for two-winding transformers with wye-connected primary and secondary and one neutral grounded.
We present new Atacama Large Millimeter/submillimeter Array (ALMA) Band 6 observations including the CO(2−1) line and 1.3 mm continuum emission from the surroundings of the young stellar object DO ...Tauri. The ALMA CO molecular data show three different series of rings at different radial velocities. These rings have radii around 220 and 800 au. We make individual fits to the rings and note that their centers are aligned with DO Tauri and its optical high-velocity jet. In addition, we notice that the velocity of these structures increases with the separation from the young star. We discuss the data under the hypothesis that the rings represent velocity cuts through three outflowing shells that are possibly driven by a wide-angle wind, dragging the environment material along a direction close to the line of sight (i = 19°). We estimate the dynamical ages, the mass, the momentum, and the energy of each individual outflow shell and those of the whole outflow. The results are in agreement with those found in outflows from Class II sources. We make a rough estimate for the size of the jet/wind launching region, which needs to be of 15 au. We report the physical characteristics of DO Tauri's disk continuum emission (almost face-on and with a projected major axis in the north-south direction) and its velocity gradient orientation (north-south), indicative of disk rotation for a 1-2 M central star. Finally, we show a Hubble Space Telescope S ii image of the optical jet and report a measurement of its orientation in the plane of the sky.
In this article (Part I), a study of the zero-sequence stray losses in wye-wye-connected transformers without a (stabilizing) tertiary winding is presented. The paper shows where and when eddy losses ...and circulating current losses appear in the transformer structural metallic components. The overheating hazard potential due to the presence of zero-sequence flux is categorized (as severe, serious, and moderate) by the permitted neutral current. The method is successfully applied to (and experimentally verified with) three-phase, three-legged, core type, wye-wye-connected transformers based on factory acceptance tests (FATs) data. It is uncovered that the severity of the overheating is determined by the phase angle difference between the zero-sequence current and the positive-sequence current. This is formulated by the proposed complex current capacity factor (<inline-formula><tex-math notation="LaTeX">{\bm{CC}}{{{\bm{F}}}_{{\bm{o}}}</tex-math></inline-formula>). In the companion paper (Part II), the maximum permitted heating on the transformer structural metallic components due to the zero-sequence current vs. time duration is presented. The idea is to gauge the temperature of the hot spots in structural metallic components by monitoring (magnitude and angle) the neutral current. The ultimate goal of these two papers is to provide engineering practical knowledge to properly design protection procedures for two-winding transformers with wye-connected primary and secondary and one neutral grounded without stabilizing winding.
We present sensitive and high angular-resolution (∼0 2-0 3) (sub)millimeter (230 and 345 GHz) continuum and CO(2−1)/CO(3−2) line archive observations of the disk star system in UX Tauri carried out ...with the Atacama Large Millimeter/Submillimeter Array. These observations reveal the gas and dusty disk surrounding the young star UX Tauri A with a large signal-to-noise ratio (>400 in the continuum and >50 in the line), and for the first time we detect the molecular gas emission associated with the disk of UX Tauri C (with a size for the disk of <56 au). No (sub)millimeter continuum emission is detected at the 5 level (0.2 mJy at 0.85 mm) associated with UX Tauri C. For the component UX Tauri C, we estimate a dust disk mass of ≤0.05 M⊕. Additionally, we report a strong tidal disk interaction between both disks, UX Tauri A/C, separated 360 au in projected distance. The CO line observations reveal marked spiral arms in the disk of UX Tauri A and an extended redshifted stream of gas associated with the UX Tauri C disk. No spiral arms are observed in the dust continuum emission of UX Tauri A. Assuming a Keplerian rotation we estimate the enclosed masses (disk+star) from their radial velocities in 1.4 0.6 M for UX Tauri A, and 70 30/sin i Jupiter masses for UX Tauri C (the latter coincides with the mass upper limit value for a brown dwarf). The observational evidence presented here lead us to propose that UX Tauri C has a close approach of a possible wide, evolving, and eccentric orbit around the disk of UX Tauri A, causing the formation of spiral arms and a stream of molecular gas falling toward UX Tauri C.
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