Summary
Background
Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids.
...Objectives
To evaluate the efficacy and safety of baricitinib in patients with moderate‐to‐severe AD who had an inadequate response to topical therapies.
Methods
In two independent, multicentre, double‐blind, phase III monotherapy trials, BREEZE‐AD1 and BREEZE‐AD2, adults with moderate‐to‐severe AD were randomized 2 : 1 : 1 : 1 to once‐daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks.
Results
At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE‐AD1 N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%, and BREEZE‐AD2 N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night‐time awakenings, skin pain and quality‐of‐life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage.
Conclusions
Baricitinib improved clinical signs and symptoms in patients with moderate‐to‐severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns.
What is already known about this topic?
Atopic dermatitis (AD) is a chronic heterogeneous inflammatory skin disease with few approved therapies for patients with moderate‐to‐severe disease.
What does this study add?
These two phase III trials show that baricitinib, an oral inhibitor of Janus kinase 1 and 2, significantly improved clinical signs and symptoms of AD compared with placebo within the first 16 weeks of treatment.
Baricitinib may represent a first‐in‐class oral treatment option for adult patients with moderate‐to‐severe AD.
Linked Comment: Drucker. Br J Dermatol 2020; 183:199–200.
Plain language summary available online
A novel experimental setup dedicated to the study of liquid and amorphous materials, on the white beam station of the PSICHÉ beamline at SOLEIL, is described. The Beer–Lambert absorption method has ...been developed using a broad‐spectrum (white) incident beam for in situ density measurements at extreme conditions of pressure and temperature. This technique has been combined with other existing X‐ray techniques (radiographic imaging, tomography and combined angle energy dispersive X‐ray diffraction). Such a multi‐technical approach offers new possibilities for the characterization of liquid and amorphous materials at high pressure and high temperature. The strength of this approach is illustrated by density measurements of liquid gallium at pressures up to 4 GPa, combining the three independent X‐ray techniques (the Beer–Lambert absorption method, tomography and X‐ray diffraction).
The feasibility of density measurements at extreme conditions of pressure and temperature is demonstrated using the X‐ray absorption method. This technique has been integrated with other existing techniques available at the white beam station of PSICHÉ.
In situ microtomography at high pressure and temperature has developed rapidly in the last decade, driven by the development of new high‐pressure apparatus. It is now routinely possible to ...characterize material under high pressure with acquisition times for tomograms of the order of tens of minutes. Here, advantage was taken of the possibility to combine the use of a pink beam projected through a standard Paris–Edinburgh press in order to demonstrate the possibility to perform high‐speed synchrotron X‐ray tomography at high pressure and temperature allowing complete high‐resolution tomograms to be acquired in about 10 s. This gives direct visualization to rapidly evolving or unstable systems, such as flowing liquids or reacting components, and avoids assumptions in the interpretation of quenched samples. Using algebraic reconstruction techniques allows the missing angle artefacts that result from the columns of the press to be minimized.
An experimental setup has been developed in order to perform ultrafast X‐ray tomography at high pressure and temperature. Pink beam projected through a standard Paris–Edinburgh press and an algebraic reconstruction technique were used in order to acquire a tomograph in about 10 s.
Although deep learning has revolutionized protein structure prediction, almost all experimentally characterized de novo protein designs have been generated using physically based approaches such as ...Rosetta. Here, we describe a deep learning-based protein sequence design method, ProteinMPNN, that has outstanding performance in both in silico and experimental tests. On native protein backbones, ProteinMPNN has a sequence recovery of 52.4% compared with 32.9% for Rosetta. The amino acid sequence at different positions can be coupled between single or multiple chains, enabling application to a wide range of current protein design challenges. We demonstrate the broad utility and high accuracy of ProteinMPNN using x-ray crystallography, cryo-electron microscopy, and functional studies by rescuing previously failed designs, which were made using Rosetta or AlphaFold, of protein monomers, cyclic homo-oligomers, tetrahedral nanoparticles, and target-binding proteins.
On 6 March 2015, Dawn arrived at Ceres to find a dark, desiccated surface punctuated by small, bright areas. Parts of Ceres' surface are heavily cratered, but the largest expected craters are absent. ...Ceres appears gravitationally relaxed at only the longest wavelengths, implying a mechanically strong lithosphere with a weaker deep interior. Ceres' dry exterior displays hydroxylated silicates, including ammoniated clays of endogenous origin. The possibility of abundant volatiles at depth is supported by geomorphologie features such as flat crater floors with pits, lobate flows of materials, and a singular mountain that appears to be an extrusive cryovolcanic dome. On one occasion, Ceres temporarily interacted with the solar wind, producing a bow shock accelerating electrons to energies of tens of kilovolts.
Regulation of circulating free fatty acid (FFA) levels and delivery is crucial to maintain tissue homeostasis. Exosomes are nanomembranous vesicles that are released from diverse cell types and ...mediate intercellular communication by delivering bioactive molecules. Here, we sought to investigate the uptake of FFAs by circulating exosomes, the delivery of FFA-loaded exosomes to cardiac cells and the possible role of the FFA transporter CD36 in these processes. Circulating exosomes were purified from the serum of healthy donors after an overnight fast (F) or 20 minutes after a high caloric breakfast (postprandial, PP). Western blotting, Immunogold Electron Microscopy and FACS analysis of circulating exosomes showed that CD36 was expressed under both states, but was higher in postprandial-derived exosomes. Flow cytometry analysis showed that circulating exosomes were able to take-up FFA directly from serum. Importantly, preincubation of exosomes with a blocking CD36 antibody significantly impeded uptake of the FFA analogue BODIPY, pointing to the role of CD36 in FFA exosomal uptake. Finally, we found that circulating exosomes could delivery FFA analogue BODIPY into cardiac cells ex vivo and in vivo in a mice model. Overall, our results suggest a novel mechanism in which circulating exosomes can delivery FFAs from the bloodstream to cardiac tissue. Further studies will be necessary to understand this mechanism and, in particular, its potential involvement in metabolic pathologies such as obesity, diabetes and atherosclerosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
We have performed ground-based transmission spectroscopy of the hot Jupiter orbiting the cool dwarf WASP-80 using the ACAM instrument on the William Herschel Telescope (WHT) as part of the ...Low-Resolution Ground-Based Exoplanet Atmosphere Survey using Transmission Spectroscopy programme. This is the third paper of a ground-based transmission spectroscopy survey of hot Jupiters using low-resolution grism spectrographs. We observed two transits of the planet and have constructed transmission spectra spanning a wavelength range of 4640–8840 Å. Our transmission spectrum is inconsistent with a previously claimed detection of potassium in WASP-80b's atmosphere, and is instead most consistent with a haze. We also do not see evidence for sodium absorption at a resolution of 100 Å.
We employ reactive molecular-beam epitaxy to synthesize the metastable perovskite SrIrO3 and utilize in situ angle-resolved photoemission to reveal its electronic structure as an exotic narrow-band ...semimetal. We discover remarkably narrow bands which originate from a confluence of strong spin-orbit interactions, dimensionality, and both in- and out-of-plane IrO6 octahedral rotations. The partial occupation of numerous bands with strongly mixed orbital characters signals the breakdown of the single-band Mott picture that characterizes its insulating two-dimensional counterpart, Sr2IrO4, illustrating the power of structure-property relations for manipulating the subtle balance between spin-orbit interactions and electron-electron interactions.
A desirable but as yet unachieved property of a human immunodeficiency virus type 1 (HIV-1) vaccine candidate is the ability to induce broadly neutralizing antibodies (bNAbs). One approach to the ...problem is to create trimeric mimics of the native envelope glycoprotein (Env) spike that expose as many bNAb epitopes as possible, while occluding those for non-neutralizing antibodies (non-NAbs). Here, we describe the design and properties of soluble, cleaved SOSIP.664 gp140 trimers based on the subtype A transmitted/founder strain, BG505. These trimers are highly stable, more so even than the corresponding gp120 monomer, as judged by differential scanning calorimetry. They are also homogenous and closely resemble native virus spikes when visualized by negative stain electron microscopy (EM). We used several techniques, including ELISA and surface plasmon resonance (SPR), to determine the relationship between the ability of monoclonal antibodies (MAbs) to bind the soluble trimers and neutralize the corresponding virus. In general, the concordance was excellent, in that virtually all bNAbs against multiple neutralizing epitopes on HIV-1 Env were highly reactive with the BG505 SOSIP.664 gp140 trimers, including quaternary epitopes (CH01, PG9, PG16 and PGT145). Conversely, non-NAbs to the CD4-binding site, CD4-induced epitopes or gp41ECTO did not react with the trimers, even when their epitopes were present on simpler forms of Env (e.g. gp120 monomers or dissociated gp41 subunits). Three non-neutralizing MAbs to V3 epitopes did, however, react strongly with the trimers but only by ELISA, and not at all by SPR and to only a limited extent by EM. These new soluble trimers are useful for structural studies and are being assessed for their performance as immunogens.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We formally introduce 14 new high-level stratigraphic names to augment existing names and to hierarchically organise all of New Zealand's onland and offshore Cambrian-Holocene rocks and ...unconsolidated deposits. The two highest-level units are Austral Superprovince (new) and Zealandia Megasequence (new). These encompass all stratigraphic units of the country's Cambrian-Early Cretaceous basement rocks and Late Cretaceous-Holocene cover rocks and sediments, respectively. Most high-level constituents of the Austral Superprovince are in current and common usage: Eastern and Western Provinces consist of 12 tectonostratigraphic terranes, 10 igneous suites, 5 batholiths and Haast Schist. Ferrar, Tarpaulin and Jaquiery suites (new) have been added to existing plutonic suites to describe all known compositional variation in the Tuhua Intrusives. Zealandia Megasequence consists of five predominantly sedimentary, partly unconformity-bounded units and one igneous unit. Momotu and Haerenga supergroups (new) comprise lowermost rift to passive margin (terrestrial to marine transgressive) rock units. Waka Supergroup (new) includes rocks related to maximum marine flooding linked to passive margin culmination in the east and onset of new tectonic subsidence in the west. Māui and Pākihi supergroups (new) comprise marine to terrestrial regressive rock and sediment units deposited during Neogene plate convergence. Rūaumoko Volcanic Region (new) is introduced to include all igneous rocks of the Zealandia Megasequence and contains the geochemically differentiated Whakaari, Horomaka and Te Raupua supersuites (new). Our new scheme, Litho2014, provides a complete, high-level stratigraphic classification for the continental crust of the New Zealand region.
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