Laser wakefield accelerators promise to revolutionize many areas of accelerator science. However, one of the greatest challenges to their widespread adoption is the difficulty in control and ...optimization of the accelerator outputs due to coupling between input parameters and the dynamic evolution of the accelerating structure. Here, we use machine learning techniques to automate a 100 MeV-scale accelerator, which optimized its outputs by simultaneously varying up to six parameters including the spectral and spatial phase of the laser and the plasma density and length. Most notably, the model built by the algorithm enabled optimization of the laser evolution that might otherwise have been missed in single-variable scans. Subtle tuning of the laser pulse shape caused an 80% increase in electron beam charge, despite the pulse length changing by just 1%.
Many global environmental agendas, including halting biodiversity loss, reversing land degradation, and limiting climate change, depend upon retaining forests with high ecological integrity, yet the ...scale and degree of forest modification remain poorly quantified and mapped. By integrating data on observed and inferred human pressures and an index of lost connectivity, we generate a globally consistent, continuous index of forest condition as determined by the degree of anthropogenic modification. Globally, only 17.4 million km
of forest (40.5%) has high landscape-level integrity (mostly found in Canada, Russia, the Amazon, Central Africa, and New Guinea) and only 27% of this area is found in nationally designated protected areas. Of the forest inside protected areas, only 56% has high landscape-level integrity. Ambitious policies that prioritize the retention of forest integrity, especially in the most intact areas, are now urgently needed alongside current efforts aimed at halting deforestation and restoring the integrity of forests globally.
Summary
Background
Inflammatory chemokines, such as macrophage‐derived chemokine (MDC/CCL22), are elevated in the serum and lesioned skin of patients with atopic dermatitis (AD), and are ligands for ...C‐C chemokine receptor 4, which is predominantly expressed on T helper 2 lymphocytes, basophils and natural killer cells. We have previously reported that quercetagetin has an inhibitory activity on inflammatory chemokines, which is induced by interferon (IFN)‐γ and tumour necrosis factor (TNF)‐α, occurring via inhibition of the signal transducer and activator of transcription 1 (STAT1) signal.
Objectives
To investigate the specific mechanisms of quercetagetin on the STAT1 signal.
Methods
We confirmed the inhibitory activity of quercetagetin on MDC and STAT1 in HaCaT keratinocytes. The interaction between STAT1 and IFN‐γR1 was investigated using immunoprecipitation. The small interfering RNA approach was used to investigate the role of suppressor of cytokine signalling 1 (SOCS1) and transforming growth factor (TGF)‐β1 induced by quercetagetin.
Results
Quercetagetin inhibited the expression of MDC at both the protein and mRNA levels in IFN‐γ‐ and TNF‐α‐stimulated HaCaT human keratinocytes. Moreover, quercetagetin inhibited the phosphorylation of STAT1 through upregulation of SOCS1. Increased expression of SOCS1 disrupted the binding of STAT1 to IFN‐γR1. Furthermore, quercetagetin augmented the expression of TGF‐β1, which is known to modulate the immune response and inflammation.
Conclusions
These results suggest that quercetagetin may be a potent inhibitor of the STAT1 signal, which could be a new molecular target for anti‐inflammatory treatment, and may thus have therapeutic applications as an immune modulator in inflammatory diseases such as AD.
What's already known about this topic?
Inflammatory chemokines are related to the presence of atopic dermatitis.
Quercetagetin inhibits inflammatory chemokines via regulation of the signal transducer and activator of transcription 1 (STAT1) signal.
What does this study add?
Quercetagetin increases the expression of suppressor of cytokine signalling 1, and it decreases the phosphorylation of STAT1 through the disruption of docking between STAT1 and interferon (IFN)‐γR1.
Quercetagetin also increases the expression of the anti‐inflammatory cytokine transforming growth factor‐β1.
Peatlands represent a vast store of global carbon. Observations of rapidly rising dissolved organic carbon concentrations in rivers draining peatlands have created concerns that those stores are ...beginning to destabilize. Three main factors have been put forward as potential causal mechanisms, but it appears that two alternativeswarming and increased river dischargecannot offer satisfactory explanations. Here we show that the third proposed mechanism, namely shifting trends in the proportion of annual rainfall arriving in summer, is similarly unable to account for the trend. Instead we infer that a previously unrecognized mechanismcarbon dioxide mediated stimulation of primary productivityis responsible. Under elevated carbon dioxide levels, the proportion of dissolved organic carbon derived from recently assimilated carbon dioxide was ten times higher than that of the control cases. Concentrations of dissolved organic carbon appear far more sensitive to environmental drivers that affect net primary productivity than those affecting decomposition alone.
Hydrated niobium oxides are used as strong solid acids with a wide variety of catalytic applications, yet the correlations between structure and acidity remain unclear. New insights into the ...structural features giving rise to Lewis and Brønsted acid sites are presently achieved. It appears that Lewis acid sites can arise from lower coordinate NbO5 and in some cases NbO4 sites, which are due to the formation of oxygen vacancies in thin and flexible NbO6 systems. Such structural flexibility of Nb–O systems is particularly pronounced in high surface area nanostructured materials, including few-layer to monolayer or mesoporous Nb2O5·nH2O synthesized in the presence of stabilizers. Bulk materials on the other hand only possess a few acid sites due to lower surface areas and structural rigidity: small numbers of Brønsted acid sites on HNb3O8 arise from a protonic structure due to the water content, whereas no acid sites are detected for anhydrous crystalline H-Nb2O5.
Micro alcohol gas sensor was fabricated based on micro-heater by using CMOS compatible MEMS process and ink jetting technique. The paste for ink jetting deposition was based on semiconducting In2O3 ...powder. In the structure of micro-heater, two semi-circled Pt heaters, where some etching holes including etching hole in the center of the micor-heater exist, are connected to the spreader for thermal uniformity and reduction of the Si etching time. Based on the above design, low power consumption alcohol gas sensor was fabricated, which showed substantial sensitivity down to 0.05ppm alcohol at low power consumption (24mW).
Unique peatland properties, such as their ability to preserve intact ancient human remains (bog bodies) and to store globally significant quantities of atmospheric CO
2, can be attributed to their ...low rates of enzymic decomposition. Peatland soils are normally devoid of molecular oxygen in all, but the uppermost layer, and thus enzymes such as phenol oxidase, which require molecular oxygen for their activity, are rarely active. Interestingly, even the activities of enzymes such as hydrolases that have no oxygen requirement, are also extremely limited in peatlands. Here, we show that those low hydrolase activities can be indirectly attributed to oxygen constraints on phenol oxidase. On addition of oxygen, phenol oxidase activity increased 7-fold,
P<0.05, a response that allowed phenolic depletion in the peatland soil. Phenolic materials are highly inhibitory to enzymes and their lower abundance allowed higher hydrolase activities (β-glucosidase 26%,
P<0.05, phosphatase 18%,
P<0.05, sulphatase 47%,
P<0.01, xylosidase 16%,
P<0.05 and chitinase 22%,
P<0.05). Thus, oxygen constraints upon phenol oxidase activity promote conditions that inhibit decomposition. This mechanism has important implications for preservation of archaeological organic materials, sequestration of atmospheric CO
2 and potentially in the preservation of food and treatment of water pollution.
BACKGROUND AND PURPOSE The transcriptional co‐activator with PDZ‐binding motif (TAZ) is characterized as a transcriptional modulator of mesenchymal stem cell differentiation into osteoblasts and ...adipocytes. Moreover, increased TAZ activity in the nucleus enhances osteoblast differentiation and suppresses adipocyte development by interacting with runt‐related transcription factor 2 (RUNX2) and PPARγ, respectively. Therefore, it would be of interest to identify low MW compounds that modulate nuclear TAZ activity.
EXPERIMENTAL APPROACH High‐throughput screening was performed using a library of low MW compounds in order to identify TAZ modulators that enhance nuclear TAZ localization. The effects and molecular mechanisms of a TAZ modulator have been characterized in osteoblast and adipocyte differentiation.
KEY RESULTS We identified 2‐butyl‐5‐methyl‐6‐(pyridine‐3‐yl)‐3‐2′‐(1H‐tetrazole‐5‐yl)‐biphenyl‐4‐ylmethyl‐3H‐imidazo4,5‐bpyridine (TM‐25659) as a TAZ modulator. TM‐25659 enhanced nuclear TAZ localization in a dose‐dependent manner and attenuated PPARγ‐mediated adipocyte differentiation by facilitating PPARγ suppression activity of TAZ. In addition, TAZ‐induced RUNX2 activity activation was further increased in osteoblasts, causing increased osteoblast differentiation. Accordingly, TM‐25659 suppressed bone loss in vivo and decreased weight gain in an obesity model. After oral administration, TM‐25659 had a favourable pharmacokinetic profile.
CONCLUSION AND IMPLICATIONS TM‐25659 stimulated nuclear TAZ localization and thus caused TAZ to suppress PPARγ‐dependent adipogenesis and enhance RUNX2‐induced osteoblast differentiation in vitro and in vivo. Our data suggest that TM‐25659 could be beneficial in the control of obesity and bone loss.
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