Bruton's tyrosine kinase (BTK) was initially discovered as a critical mediator of B cell receptor signaling in the development and functioning of adaptive immunity. Growing evidence also suggests ...multiple roles for BTK in mononuclear cells of the innate immune system, especially in dendritic cells and macrophages. For example, BTK has been shown to function in Toll-like receptor-mediated recognition of infectious agents, cellular maturation and recruitment processes, and Fc receptor signaling. Most recently, BTK was additionally identified as a direct regulator of a key innate inflammatory machinery, the NLRP3 inflammasome. BTK has thus attracted interest not only for gaining a more thorough basic understanding of the human innate immune system but also as a target to therapeutically modulate innate immunity. We here review the latest developments on the role of BTK in mononuclear innate immune cells in mouse versus man, with specific emphasis on the sensing of infectious agents and the induction of inflammation. Therapeutic implications for modulating innate immunity and critical open questions are also discussed.
Numerous volatile organic compounds (VOCs) exist in Earth's atmosphere, most of which originate from biogenic emissions. Despite VOCs' critical role in tropospheric chemistry, studies for evaluating ...their atmosphere-ecosystem exchange (emission and deposition) have been limited to a few dominant compounds owing to a lack of appropriate measurement techniques. Using a high—mass resolution proton transfer reaction—time of flight—mass spectrometer and an absolute value eddy-covariance method, we directly measured 186 organic ions with net deposition, and 494 that have bidirectional flux. This observation of active atmosphere-ecosystem exchange of the vast majority of detected VOCs poses a challenge to current emission, air quality, and global climate models, which do not account for this extremely large range of compounds. This observation also provides new insight for understanding the atmospheric VOC budget.
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Psoriasis is an inflammatory skin disease with strong neutrophil (PMN) infiltration and high levels of the antimicrobial peptide, LL37. LL37 in complex with DNA and RNA is thought to initiate disease ...exacerbation via plasmacytoid dendritic cells. However, the source of nucleic acids supposed to start this initial inflammatory event remains unknown. We show here that primary murine and human PMNs mount a fulminant and self-propagating neutrophil extracellular trap (NET) and cytokine response, but independently of the canonical NET component, DNA. Unexpectedly, RNA, which is abundant in NETs and psoriatic but not healthy skin, in complex with LL37 triggered TLR8/TLR13-mediated cytokine and NET release by PMNs in vitro and in vivo. Transfer of NETs to naive human PMNs prompts additional NET release, promoting further inflammation. Our study thus uncovers a self-propagating vicious cycle contributing to chronic inflammation in psoriasis, and NET-associated RNA (naRNA) as a physiologically relevant NET component.
The annual potential of solar energy far exceeds the world's total energy consumption. However, the vision of photovoltaics (PVs) providing a substantial fraction of global electricity generation and ...total energy demand is far from being realized. What technical, infrastructure, economic, and policy barriers need to be overcome for PVs to grow to the multiple terawatt (TW) scale? We assess realistic future scenarios and make suggestions for a global agenda to move toward PVs at a multi-TW scale.
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Abstract
Antibody engineering is often performed to improve therapeutic properties by directed evolution, usually by high-throughput screening of phage or yeast display libraries. Engineering ...antibodies in mammalian cells offer advantages associated with expression in their final therapeutic format (full-length glycosylated IgG); however, the inability to express large and diverse libraries severely limits their potential throughput. To address this limitation, we have developed homology-directed mutagenesis (HDM), a novel method which extends the concept of CRISPR/Cas9-mediated homology-directed repair (HDR). HDM leverages oligonucleotides with degenerate codons to generate site-directed mutagenesis libraries in mammalian cells. By improving HDR to a robust efficiency of 15-35% and combining mammalian display screening with next-generation sequencing, we validated this approach can be used for key applications in antibody engineering at high-throughput: rational library construction, novel variant discovery, affinity maturation and deep mutational scanning (DMS). We anticipate that HDM will be a valuable tool for engineering and optimizing antibodies in mammalian cells, and eventually enable directed evolution of other complex proteins and cellular therapeutics.
Background and purpose
In contrast to anterior circulation stroke (ACS), there is no evidence from randomized trials that mechanical thrombectomy (MT) with modern stent retrievers or ...thromboaspiration is safe and effective in posterior circulation stroke (PCS).
Methods
The present analysis was based on the prospective multicentre Registry on Revascularization in Ischemic Stroke Patients (REVASK) in Germany. Demographic data, periprocedural times and complications, recanalization rates, and functional outcome at discharge and after 3 months were compared between 139 consecutive patients with PCS (84.9% basilar artery, 16.5% vertebral artery and 4.3% posterior cerebral artery occlusion) and 961 patients with ACS treated with MT.
Results
Compared to ACS, PCS patients were significantly younger (65 vs. 69 years, P = 0.021) and had a lower median National Institutes of Health Stroke Scale (NIHSS) score at baseline (12 vs. 15, P = 0.024). Patients with PCS had a significantly longer time delay between symptom onset and both start and end of the MT procedure. Successful recanalization and thrombectomy passes did not significantly differ between the two groups. No symptomatic intracranial haemorrhage occurred in PCS compared to 3% in ACS (P = 0.010). The median NIHSS score at discharge was 3 in PCS and 4 in ACS. Favourable functional outcome at 3 months (modified Rankin Scale 0–2 38.0% vs. 42.6%, P = 0.392) and mortality (33.7% vs. 30.8%, P = 0.539) did not differ significantly between PCS and ACS.
Conclusions
The study suggests that MT in PCS shows a lower risk of symptomatic intracranial haemorrhage and similar effectiveness compared to ACS. PCS patients also seem to benefit from MT started beyond 6 h after symptom onset.
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Water-soluble redox-active metals are potentially toxic due to its ability to catalytically generate reactive oxygen species (ROS) in vivo, leading to oxidative stress. As part of the Southeastern ...Center for Air Pollution and Epidemiology (SCAPE), we developed a method to quantify water-soluble elements, including redox-active metals, from a large number of filter samples (N=530) in support of the center's health studies. PM2.5 samples were collected during 2012–2013 at various sites (three urban, two rural, a near-road site, and a road-side site) in the southeastern United States, using high-volume samplers. Water-soluble elements (S, K, Ca, Ti, Mn, Fe, Cu, Zn, As, Se, Br, Sr, Ba, and Pb) were determined by extracting filters in deionized water and re-aerosolized for analyses by X-ray fluorescence (XRF) using an online aerosol element analyzer (Xact, Cooper Environmental). Concentrations ranged from detection limits (nominally 0.1 to 30 ngm-3) to 1.2 µgm-3, with S as the most abundant element, followed by Ca, K, Fe, Cu, Zn, and Ba. Positive matrix factorization (PMF) identified four factors that were associated with specific sources based on relative loadings of various tracers. These include brake/tire wear (with tracers Ba and Cu), biomass burning (K), secondary formation (S, Se, and WSOC), and mineral dust (Ca). Of the four potentially toxic and relatively abundant metals (redox-active Cu, Mn, Fe, and redox-inactive Zn), 51 % of Cu, 32 % of Fe, 17 % of Mn, and 45 % of Zn were associated with the brake/tire factor. Mn was mostly associated with the mineral dust factor (45 %). Zn was found in a mixture of factors, with 26 % associated with mineral dust, 14 % biomass burning, and 13 % secondary formation. Roughly 50 % of Fe and 40 % of Cu were apportioned to the secondary formation factor, likely through increases in the soluble fraction of these elements by sulfur-driven aerosol water and acidity. Linkages between sulfate and water-soluble Fe and Cu may account for some of the past observed associations between sulfate/sulfur oxide and health outcomes. For Cu, Mn, Fe, and Zn, only Fe was correlated with PM2.5 mass (r=0.73–0.80). Overall, mobile source emissions generated through mechanical processes (re-entrained road dust, tire and break wear) and processing by secondary sulfate were major contributors to water-soluble metals known to be capable of generating ROS.
We report measurements of ambient amines and ammonia with a fast response chemical ionization mass spectrometer (CIMS) in a southeastern US forest and a moderately polluted midwestern site during the ...summer. At the forest site, mostly C3-amines (from pptv to tens of pptv) and ammonia (up to 2 ppbv) were detected, and they both showed temperature dependencies. Aerosol-phase amines measured thermal-desorption chemical ionization mass spectrometer (TDCIMS) showed a higher mass fraction in the evening with cooler temperatures and lower in the afternoon with warmer temperatures, a trend opposite to the gas-phase amines. Concentrations of aerosol-phase primary amines measured with Fourier transform infrared spectroscopy (FTIR) from micron and submicron particles were 2 orders of magnitude higher than the gas-phase amines. These results indicate that gas to particle conversion is one of the major processes that control the ambient amine concentrations at this forest site. Temperature dependencies of C3-amines and ammonia also imply reversible processes of evaporation of these nitrogen-containing compounds from soil surfaces in daytime and deposition to soil surfaces at nighttime. During the transported biomass burning plume events, various amines (C1-C6) appeared at the pptv level, indicating that biomass burning is a substantial source of amines in the southeastern US. At the moderately polluted Kent site, there were higher concentrations of C1- to C6-amines (pptv to tens of pptv) and ammonia (up to 6 ppbv). C1- to C3-amines and ammonia were well correlated with the ambient temperature. C4- to C6-amines showed frequent spikes during the nighttime, suggesting that they were emitted from local sources. These abundant amines and ammonia may in part explain the frequent new particle formation events reported from Kent. Higher amine concentrations measured at the polluted site than at the rural forested site highlight the importance of constraining anthropogenic emission sources of amines.
Persistent organic pollutants (POPs) including PCDD/Fs, PCBs and organochlorine pesticides (OCPs) are among the most important and hazardous pollutants of soil. Food producing animals such as ...chicken, beef, sheep and goats can take up soil while grazing or living outdoors (free-range) and this can result in contamination.
In recent decades, large quantities of brominated flame retardants such as polybrominated diphenyl ethers (PBDEs), short-chain chlorinated paraffins (SCCPs) and per- and polyfluorinated alkylated substances (PFAS) have been produced and released into the environment and this has resulted in widespread contamination of soils and other environmental matrices. These POPs also bioaccumulate and can contaminate food of animal origin resulting in indirect exposure of humans.
Recent assessments of chicken and beef have shown that surprisingly low concentrations of PCBs and PCDD/Fs in soil can result in exceedances of regulatory limits in food. Soil contamination limits have been established in a number of countries for PCDD/Fs but it has been shown that the contamination levels which result in regulatory limits in food (the maximum levels in the European Union) being exceeded, are below all the existing soil regulatory limits. ‘Safe’ soil levels are exceeded in many areas around emission sources of PCDD/Fs and PCBs. On the other hand, PCDD/F and dioxin-like PCB levels in soil in rural areas, without a contamination source, are normally safe for food producing animals housed outdoors resulting in healthy food (e.g. meat, eggs, milk).
For the majority of POPs (e.g. PBDEs, PFOS, PFOA, SCCP) no regulatory limits in soils exist.
There is, therefore, an urgent need to develop appropriate and protective soil standards minimising human exposure from food producing animals housed outdoors. Furthermore, there is an urgent need to eliminate POPs pollution sources for soils and to control, secure and remediate contaminated sites and reservoirs, in order to reduce exposure and guarantee food safety.
Display omitted
•PCDD/F below regulatory limits in soil can exceed regulatory limits in chicken/egg.•‘Safe’ soil levels for PCDD/Fs and PCBs are often exceeded around emission sources.•No regulatory limits in soils exist for the majority of new listed POPs.•Protective POPs soil standards for food producing animals are needed.•There is an urgent need to control POPs pollution sources for soils and food safety.
POPs contaminated sites are relevant pollutants in soils with human exposure risk. Science based soil standards for POPs are needed to protect human exposure from food producing animals.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
30.
Quantum computing with defects Weber, J.R; Koehl, W.F; Varley, J.B ...
Proceedings of the National Academy of Sciences - PNAS,
05/2010, Volume:
107, Issue:
19
Journal Article
Peer reviewed
Open access
Identifying and designing physical systems for use as qubits, the basic units of quantum information, are critical steps in the development of a quantum computer. Among the possibilities in the solid ...state, a defect in diamond known as the nitrogen-vacancy (NV⁻¹) center stands out for its robustness--its quantum state can be initialized, manipulated, and measured with high fidelity at room temperature. Here we describe how to systematically identify other deep center defects with similar quantum-mechanical properties. We present a list of physical criteria that these centers and their hosts should meet and explain how these requirements can be used in conjunction with electronic structure theory to intelligently sort through candidate defect systems. To illustrate these points in detail, we compare electronic structure calculations of the NV⁻¹ center in diamond with those of several deep centers in 4H silicon carbide (SiC). We then discuss the proposed criteria for similar defects in other tetrahedrally coordinated semiconductors.
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