It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep ...molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86
pDC frequencies than normal donors (P<0.0024), whereas TFR patients had consistently low CD86
pDC (n=12). This suggested that low CD86
pDC might be predictive of TFR. Indeed, in a prospective analysis of 122 patients discontinuing their TKI within the EURO-SKI trial, the one-year relapse-free survival (RFS) was 30.1% (95% CI 15.6-47.9) for patients with >95 CD86
pDC per 10
lymphocytes, but 70.0% (95% CI 59.3-78.3) for patients with <95 CD86
pDC (hazard ratio (HR) 3.4, 95%
CI: 1.9-6.0; P<0.0001). Moreover, only patients with <95 CD86
pDC derived a significant benefit from longer (>8 years) TKI exposure before discontinuation (HR 0.3, 95% CI 0.1-0.8; P=0.0263). High CD86
pDC counts significantly correlated with leukemia-specific CD8
T
cell exhaustion (Spearman correlation: 0.74, 95%-CI: 0.21-0.92; P=0.0098). Our data demonstrate that CML patients with high CD86
pDC counts have a higher risk of relapse after TKI discontinuation.
Cellular functions of arrestins are determined in part by the pattern of phosphorylation on the G protein-coupled receptors (GPCRs) to which arrestins bind. Despite high-resolution structural data of ...arrestins bound to phosphorylated receptor C-termini, the functional role of each phosphorylation site remains obscure. Here, we employ a library of synthetic phosphopeptide analogues of the GPCR rhodopsin C-terminus and determine the ability of these peptides to bind and activate arrestins using a variety of biochemical and biophysical methods. We further characterize how these peptides modulate the conformation of arrestin-1 by nuclear magnetic resonance (NMR). Our results indicate different functional classes of phosphorylation sites: 'key sites' required for arrestin binding and activation, an 'inhibitory site' that abrogates arrestin binding, and 'modulator sites' that influence the global conformation of arrestin. These functional motifs allow a better understanding of how different GPCR phosphorylation patterns might control how arrestin functions in the cell.
The Global Coupled 3 (GC3) configuration of the Met Office Unified Model is presented. Among other applications, GC3 is the basis of the United Kingdom's submission to the Coupled Model ...Intercomparison Project 6 (CMIP6). This paper documents the model components that make up the configuration (although the scientific descriptions of these components are in companion papers) and details the coupling between them. The performance of GC3 is assessed in terms of mean biases and variability in long climate simulations using present‐day forcing. The suitability of the configuration for predictability on shorter time scales (weather and seasonal forecasting) is also briefly discussed. The performance of GC3 is compared against GC2, the previous Met Office coupled model configuration, and against an older configuration (HadGEM2‐AO) which was the submission to CMIP5. In many respects, the performance of GC3 is comparable with GC2, however, there is a notable improvement in the Southern Ocean warm sea surface temperature bias which has been reduced by 75%, and there are improvements in cloud amount and some aspects of tropical variability. Relative to HadGEM2‐AO, many aspects of the present‐day climate are improved in GC3 including tropospheric and stratospheric temperature structure, most aspects of tropical and extratropical variability and top‐of‐atmosphere and surface fluxes. A number of outstanding errors are identified including a residual asymmetric sea surface temperature bias (cool northern hemisphere, warm Southern Ocean), an overly strong global hydrological cycle and insufficient European blocking.
Key Points
Description of the Global Coupled 3 (GC3) configuration of the Met Office Unified Model
A cross‐time‐scale evaluation of the GC3 configuration is presented
Overall, GC3 is an improvement on previous configurations
Aims
To evaluate the antibiofilm potential of water‐soluble Moringa oleifera seed lectin (WSMoL) on Serratia marcescens and Bacillus sp.
Methods and Results
WSMoL inhibited biofilm formation by S. ...marcescens at concentrations lower than 2·6 μg ml−1 and impaired bacterial growth at higher concentrations, avoiding biofilm formation. For Bacillus sp., the lectin inhibited bacterial growth at all concentrations. The antibiofilm action of WSMoL is associated with damage to bacterial cells. WSMoL did not disrupt preformed S. marcescens biofilms but was able to damage cells inside them. On the other hand, the lectin reduced the number of cells in Bacillus sp. biofilm treated with it. WSMoL was able to control biofilm formation when immobilized on glass surface (116 μg cm−2), damaging S. marcescens cells and avoiding adherence of Bacillus sp. cells on glass. The Bacillus sp. isolate is member of Bacillus subtilis species complex and closely related to species of the conspecific ‘amyloliquefaciens’ group.
Conclusion
WSMoL prevented biofilm development by S. marcescens and Bacillus sp. and the antibiofilm effect is also observed when the lectin is immobilized on glass.
Significance and Impact of the StudyTaking together, our results provide support to the potential use of WSMoL for controlling biofilm formation by bacteria.
Abstract
Chemical vapor deposition-based growth techniques allow flexible design of complementary metal-oxide semiconductor (CMOS) compatible materials. Here, we report the deuterated silicon-rich ...nitride films grown using plasma-enhanced chemical vapor deposition. The linear and nonlinear properties of the films are characterized, and we experimentally confirm that the silicon-rich nitride films grown with SiD
4
eliminates Si–H and N–H related absorption. The performance of identical waveguides for films grown with SiH
4
and SiD
4
are compared demonstrating a 2 dB/cm improvement in line with that observed in literature. Waveguides fabricated on the SRN:D film are further shown to possess a nonlinear parameter of 95 W
−1
m
−1
, with the film exhibiting a linear and nonlinear refractive index of 2.46 and 9.8
$$\times$$
×
10
–18
m
2
W
−1
respectively.
Ultra-silicon-rich nitride with refractive indices ~ 3 possesses high nonlinear refractive index-100× higher than stoichiometric silicon nitride and presents absence of two-photon absorption, making ...it attractive to be used in nonlinear integrated optics at telecommunications wavelengths. Despite its excellent nonlinear properties, ultra-silicon-rich nitride photonics devices reported so far still have fairly low quality factors of Formula: see text, which could be mainly attributed by the material absorption bonds. Here, we report low temperature plasma-deposited dichlorosilane-based ultra-silicon-rich nitride (Si
N) with lower material absorption bonds, and ~ 2.5× higher quality factors compared to ultra-silicon-rich nitride conventionally prepared with silane-based chemistry. This material is found to be highly rich in silicon with refractive indices of ~ 3.12 at telecommunications wavelengths and atomic concentration ratio Si:N of ~ 8:1. The material morphology, surface roughness and binding energies are also investigated. Optically, the material absorption bonds are quantified and show an overall reduction. Ring resonators fabricated exhibit improved intrinsic quality factors Formula: see text, ~ 2.5× higher compared to conventional silane-based ultra-silicon-rich nitride films. This enhanced quality factor from plasma-deposited dichlorosilane-based ultra-silicon-rich nitride signifies better photonics device performance using these films. A pathway has been opened up for further improved device performance of ultra-silicon-rich nitride photonics devices at material level tailored by choice of different chemistries.
Savannas are globally important ecosystems of great significance to human economies. In these biomes, which are characterized by the co-dominance of trees and grasses, woody cover is a chief ...determinant of ecosystem properties. The availability of resources (water, nutrients) and disturbance regimes (fire, herbivory) are thought to be important in regulating woody cover, but perceptions differ on which of these are the primary drivers of savanna structure. Here we show, using data from 854 sites across Africa, that maximum woody cover in savannas receiving a mean annual precipitation (MAP) of less than approximately 650 mm is constrained by, and increases linearly with, MAP. These arid and semi-arid savannas may be considered 'stable' systems in which water constrains woody cover and permits grasses to coexist, while fire, herbivory and soil properties interact to reduce woody cover below the MAP-controlled upper bound. Above a MAP of approximately 650 mm, savannas are 'unstable' systems in which MAP is sufficient for woody canopy closure, and disturbances (fire, herbivory) are required for the coexistence of trees and grass. These results provide insights into the nature of African savannas and suggest that future changes in precipitation may considerably affect their distribution and dynamics.
Silicon nitride (SiN) has surged into prominence as a material for photonic-integrated circuits (PICs) in the past decade, well regarded for its broadband transparency, compatibility with ...complementary metal oxide semiconductor (CMOS) fabrication processes and high optical bandgap that avoids two-photon absorption. However, current fabrication methods result in users having to choose between low thermal budgets and low losses, which are suboptimal given that both are necessary to facilitate a wide range of applications. Recently, works have emerged featuring PICs fabricated using deuterated silicon nitride (SiNx:D) – SiNx films grown using deuterated precursors instead of conventional hydrogenated ones. This decreases material absorption near the telecommunications bands at 1.55 µm previously present due to parasitic silicon–hydrogen and nitrogen–hydrogen bonds, attaining low-loss PICs realised using a low temperature, back-end-of-line CMOS-compatible fabrication plasma-enhanced chemical vapour deposition process. These devices have shown promise for both linear and nonlinear applications and the platform has the potential to be instrumental in realising highly efficient chips with co-packaged electronics and photonics devices. This paper reviews recent developments on the SiNx:D platform and provides a glance at future advancements for this highly promising material.
High‐dose corticosteroids have been associated with increased risk of serious infection in patients with metastatic melanoma treated with immune checkpoint inhibitors targeting cytotoxic T‐lymphocyte ...antigen 4. This potential association needs to be examined further among patients with other cancer types and for other immune checkpoint inhibitors. We examined whether receipt of high‐dose corticosteroids was associated with increased rates of hospitalization for infection among 981 Danish renal, urothelial, and lung cancer patients followed from first administration of programmed death receptor 1 (PD‐1)/programmed death ligand 1 (PD‐L1) immune checkpoint inhibitors. Our cohort analysis was based on the information from national medical registries. During follow‐up, 522 patients (53.2%) initiated treatment with high‐dose corticosteroids and 317 patients (32.3%) experienced at least one hospitalization for infection. In analyses adjusted for age, sex, and previous use of chemotherapy/targeted therapy, initiation of high‐dose systemic corticosteroids was associated with increased rate of hospitalization for infections (hazard ratio (HR) = 2.96, 95% confidence interval (CI) = 2.41–3.65) even in patients not receiving any chemotherapy/targeted therapy (HR = 3.66, 95% CI = 2.25–5.96). Our findings showed that high‐dose corticosteroid initiation is associated with hospitalization for infection in patients treated with PD‐1/PD‐L1 immune checkpoint inhibitors. Clinicians and patients should be aware of this risk of infection when initiating treatment with high‐dose corticosteroids.
High‐dose corticosteroids have been associated with increased risk of serious infection in metastatic melanoma patients treated with immune checkpoint inhibitors (ICIs) targeting cytotoxic T‐lymphocyte antigen 4. The present study adds that use of high‐dose corticosteroids is also associated with increased rate of hospitalization for infection among lung, kidney, and urothelial cancer patients treated with ICIs targeting programmed death receptor 1 or programmed death ligand 1 even in patients who did not receive chemotherapy/targeted therapy.
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