Burden of Disease Due to Ambient Particulate Matter in Germany-Explaining the Differences in the Available Estimates.

Ambient particulate matter (PM2.5) pollution is an important threat to human health. The aim of this study is to estimate the environmental burden of disease (EBD) for the German population associated with PM2.5 exposure in Germany for the years 2010 until 2018. The EBD method was used to quantify relevant indicators, e.g., disability-adjusted life years (DALYs), and the life table approach was used to estimate the reduction in life expectancy caused by long-term PM2.5 exposure. The impact of varying assumptions and input data was assessed. From 2010 to 2018 in Germany, the annual population-weighted PM2.5 concentration declined from 13.7 to 10.8 µg/m3. The estimates of annual PM2.5-attributable DALYs for all disease outcomes showed a downward trend. In 2018, the highest EBD was estimated for ischemic heart disease (101.776; 95% uncertainty interval (UI) 62,713-145,644), followed by lung cancer (60,843; 95% UI 43,380-79,379). The estimates for Germany differ from those provided by other institutions. This is mainly related to considerable differences in the input data, the use of a specific German national life expectancy and the selected relative risks. A transparent description of input data, computational steps, and assumptions is essential to explain differing results of EBD studies to improve methodological credibility and trust in the results. Furthermore, the different calculated indicators should be explained and interpreted with caution.

Metal-Insulator Transition of Ultrathin Sputtered Metals on Phenolic Resin Thin Films: Growth Morphology and Relations to Surface Free Energy and Reactivity.

Nanostructured metal assemblies on thin and ultrathin polymeric films enable state of the art technologies and have further potential in diverse fields. Rational design of the structure-function relationship is of critical importance but aggravated by the scarcity of systematic studies. Here, we studied the influence of the interplay between metal and polymer surface free energy and reactivity on the evolution of electric conductivity and the resulting morphologies. In situ resistance measurements during sputter deposition of Ag, Au, Cu and Ni films on ultrathin reticulated polymer films collectively reveal metal-insulator transitions characteristic for Volmer-Weber growth. The different onsets of percolation correlate with interfacial energy and energy of adhesion weakly but as expected from ordinary wetting theory. A more pronounced trend of lower percolation thickness for more reactive metals falls in line with reported correlations. Ex situ grazing incidence small angle X-ray scattering experiments were performed at various thicknesses to gain an insight into cluster and film morphology evolution. A novel approach to interpret the scattering data is used where simulated pair distance distributions of arbitrary shapes and arrangements can be fitted to experiments. Detailed approximations of cluster structures could be inferred and are discussed in view of the established parameters describing film growth behavior.

Chimeric Cellobiose Dehydrogenases Reveal the Function of Cytochrome Domain Mobility for the Electron Transfer to Lytic Polysaccharide Monooxygenase.

The natural function of cellobiose dehydrogenase (CDH) to donate electrons from its catalytic flavodehydrogenase (DH) domain via its cytochrome (CYT) domain to lytic polysaccharide monooxygenase (LPMO) is an example of a highly efficient extracellular electron transfer chain. To investigate the function of the CYT domain movement in the two occurring electron transfer steps, two CDHs from the ascomycete Neurospora crassa (NcCDHIIA and NcCDHIIB) and five chimeric CDH enzymes created by domain swapping were studied in combination with the fungus' own LPMOs (NcLPMO9C and NcLPMO9F). Kinetic and electrochemical methods and hydrogen/deuterium exchange mass spectrometry were used to study the domain movement, interaction, and electron transfer kinetics. Molecular docking provided insights into the protein-protein interface, the orientation of domains, and binding energies. We find that the first, interdomain electron transfer step from the catalytic site in the DH domain to the CYT domain depends on steric and electrostatic interface complementarity and the length of the protein linker between both domains but not on the redox potential difference between the FAD and heme b cofactors. After CYT reduction, a conformational change of CDH from its closed state to an open state allows the second, interprotein electron transfer (IPET) step from CYT to LPMO to occur by direct interaction of the b-type heme and the type-2 copper center. Chimeric CDH enzymes favor the open state and achieve higher IPET rates by exposing the heme b cofactor to LPMO. The IPET, which is influenced by interface complementarity and the heme b redox potential, is very efficient with bimolecular rates between 2.9 × 105 and 1.1 × 106 M-1 s-1.

Tannin-Based Hybrid Materials and Their Applications: A Review.

Tannins are eco-friendly, bio-sourced, natural, and highly reactive polyphenols. In the past decades, the understanding of their versatile properties has grown substantially alongside a continuously broadening of the tannins' application scope. In particular, recently, tannins have been increasingly investigated for their interaction with other species in order to obtain tannin-based hybrid systems that feature advanced and/or novel properties. Furthermore, in virtue of the tannins' chemistry and their high reactivity, they either physicochemically or physically interact with a wide variety of different compounds, including metals and ceramics, as well as a number of organic species. Such hybrid or hybrid-like systems allow the preparation of various advanced nanomaterials, featuring improved performances compared to the current ones. Consequently, these diverse-shaped materials have potential use in wastewater treatment or catalysis, as well as in some novel fields such as UV-shielding, functional food packaging, and biomedicine. Since these kinds of tannin-based hybrids represent an emerging field, thus far no comprehensive overview concerning their potential as functional chemical building blocks is available. Hence, this review aims to provide a structured summary of the current state of research regarding tannin-based hybrids, detailed findings on the chemical mechanisms as well as their fields of application.

Responding to COVID-19 through Surveys of Public Servants.

Responding to COVID-19 presents unprecedented challenges for public sector practitioners. Addressing those challenges requires knowledge about the problems that public sector workers face. This Viewpoint essay argues that timely, up-to-date surveys of public sector workers are essential tools for identifying problems, resolving bottlenecks, and enabling public sector workers to operate effectively during and in response to the challenges posed by the pandemic. This essay presents the COVID-19 Survey of Public Servants, which is currently being rolled out in several countries by the Global Survey of Public Servants Consortium to assist governments in strategically compiling evidence to operate effectively during the COVID-19 pandemic.

S1PR4-dependent CCL2 production promotes macrophage recruitment in a murine psoriasis model.

The sphingolipid sphingosine-1-phosphate (S1P) fulfills distinct functions in immune cell biology via binding to five G protein-coupled receptors. The immune cell-specific sphingosine-1-phosphate receptor 4 (S1pr4) was connected to the generation of IL-17-producing T cells through regulation of cytokine production in innate immune cells. Therefore, we explored whether S1pr4 affected imiquimod-induced murine psoriasis via regulation of IL-17 production. We did not observe altered IL-17 production, although psoriasis severity was reduced in S1pr4-deficient mice. Instead, ablation of S1pr4 attenuated the production of CCL2, IL-6, and CXCL1 and subsequently reduced the number of infiltrating monocytes and granulocytes. A connection between S1pr4, CCL2, and Mϕ infiltration was also observed in Zymosan-A induced peritonitis. Boyden chamber migration assays functionally linked reduced CCL2 production in murine skin and attenuated monocyte migration when S1pr4 was lacking. Mechanistically, S1pr4 signaling synergized with TLR signaling in resident Mϕs to produce CCL2, likely via the NF-κB pathway. We propose that S1pr4 activation enhances TLR response of resident Mϕs to increase CCL2 production, which attracts further Mϕs. Thus, S1pr4 may be a target to reduce perpetuating inflammatory responses.

IL-38 Ameliorates Skin Inflammation and Limits IL-17 Production from γδ T Cells.

Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or γδ T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon γδ T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress γδ T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by γδ T cells. Our findings indicate a role for IL-38 in the regulation of γδ T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease.

Freestanding ultrathin films for separation of small molecules in an aqueous environment.

Alternative separation methods operating in an aqueous environment are of increasing importance for further progress of molecular separation in life sciences and other industrial sectors working towards a biobased economy. By spincoating, membranes with thicknesses under 100 nm and 20 cm2 surface area were prepared from an epoxy based resin. For the first time such ultrathin epoxy films were used for the selective separation of small molecules and metabolites within an aqueous environment. Initially, selectivity is demonstrated by the separation of two dyes of similar size (0.7 and 1.4 nm diameter). By variation of the precursor concentrations, both mechanical stability and selectivity for molecular transport are shown to be tunable. The observed transport properties of the different membranes correlated with their biaxial moduli and ultimate tensile strengths which were in the range of 0.3-3.5 GPa and 10-44 MPa, respectively. These observations agreed with the conclusion drawn from FTIR analysis that variations in the covalent crosslinking density determine the emergent properties. Finally, permeation rates for small molecules of industrial relevance were assessed to confirm a size based diffusion cutoff for compounds with hydrodynamic diameters below 2 nm.

Freely suspended perforated polymer nanomembranes for protein separations.

Selective removal of nanometer-sized compounds such as proteins from fluids is an often challenging task in many scientific and industrial areas. Addressing such tasks with highly efficient and selective membranes is desirable since commonly used chromatographic approaches are expensive and difficult to scale up. Nanomembranes, molecularly thin separation layers, have been predicted and shown to possess outstanding properties but in spite ultra-fast diffusion times and high-resolution separation, to date they generally lack either of two crucial characteristics: compatibility with biological fluids and low-cost production. Here we report the fast and easy fabrication of highly crosslinked polymer membranes based on a thermoset resin (poly[(o-cresyl glycidyl ether)-co-formaldehyde (PCGF) cured with branched polyethyleneimine (PEI)) with nanoscale perforations of 25 nm diameter. During spin casting, microphase separation of a polylactide-co-glycolide induces the formation of nanometer sized domains that serve as templates for perforations which penetrate the 80 nm thick membranes. Ultrathin perforated nanomembranes can be freely suspended on the cm scale, exhibit high mechanical strength, low surface energies and a sharp permeability cutoff at a hydrodynamic diameter of 10 nm suitable for protein separations.

High speed e-beam writing for large area photonic nanostructures - a choice of parameters.

Photonic nanostructures are used for many optical systems and applications. However, some high-end applications require the use of electron-beam lithography (EBL) to generate such nanostructures. An important technological bottleneck is the exposure time of the EBL systems, which can exceed 24 hours per 1 cm(2). Here, we have developed a method based on a target function to systematically increase the writing speed of EBL. As an example, we use as the target function the fidelity of the Fourier Transform spectra of nanostructures that are designed for thin film light trapping applications, and optimize the full parameter space of the lithography process. Finally, we are able to reduce the exposure time by a factor of 5.5 without loss of photonic performance. We show that the performances of the fastest written structures are identical to the original ones within experimental error. As the target function can be varied according to different purposes, the method is also applicable to guided mode resonant grating and many other areas. These findings contribute to the advancement of EBL and point towards making the technology more attractive for commercial applications.

Spatial Patterns of Heat-Related Cardiovascular Mortality in the Czech Republic.

The study examines spatial patterns of effects of high temperature extremes on cardiovascular mortality in the Czech Republic at a district level during 1994-2009. Daily baseline mortality for each district was determined using a single location-stratified generalized additive model. Mean relative deviations of mortality from the baseline were calculated on days exceeding the 90th percentile of mean daily temperature in summer, and they were correlated with selected demographic, socioeconomic, and physical-environmental variables for the districts. Groups of districts with similar characteristics were identified according to socioeconomic status and urbanization level in order to provide a more general picture than possible on the district level. We evaluated lagged patterns of excess mortality after hot spell occurrences in: (i) urban areas vs. predominantly rural areas; and (ii) regions with different overall socioeconomic level. Our findings suggest that climatic conditions, altitude, and urbanization generally affect the spatial distribution of districts with the highest excess cardiovascular mortality, while socioeconomic status did not show a significant effect in the analysis across the Czech Republic as a whole. Only within deprived populations, socioeconomic status played a relevant role as well. After taking into account lagged effects of temperature on excess mortality, we found that the effect of hot spells was significant in highly urbanized regions, while most excess deaths in rural districts may be attributed to harvesting effects.

A new flash-free orthodontic adhesive system: A first clinical and stereomicroscopic study.

OBJECTIVE: To analyze the clinical and laboratory properties of the recently introduced APC flash-free orthodontic adhesive. MATERIAL AND METHODS: After bonding of 80 brackets on human teeth (group A: APC flash-free adhesive n  =  40, group B: APC Plus adhesive n  =  40), the following measurements were recorded: time for bonding, stereomicroscopic evaluation of excess adhesive, color penetration (methylene blue, 0.5%/24 h), and Adhesive Remnant Index (ARI) score after debonding. RESULTS: The time needed for bonding differed significantly between the two groups (A: 19.5 s/tooth vs B: 33.8 s/tooth). The adhesive excess, which was metrically measured from the bracket edge, ranged from 166.27 µm to 81.66 µm (group A) and 988.53 µm to 690.81 µm (group B). After methylene coloration in group A, 52 of 80 measurements showed discoloration on the bracket-adhesive and/or adhesive-enamel interface, while for group B, 78 of 80 were coloration positive. The ARI scores did not differ, with an average ARI score of 2.0 for group A and 2.8 for group B. CONCLUSION: The flash-free adhesive significantly reduced the time needed for the bonding process. The excess resin expanded 0.16 to 0.08 mm over the bracket margin. The new technology seems to facilitate a smooth and sufficient marginal surface of the adhesive, which clinically might improve reduction of plaque accumulation.

Spatial resolution effect of light coupling structures.

The coupling of light between free space and thin film semiconductors is an essential requirement of modern optoelectronic technology. For monochromatic and single mode devices, high performance grating couplers have been developed that are well understood. For broadband and multimode devices, however, more complex structures, here referred to as "coupling surfaces", are required, which are often difficult to realise technologically. We identify general design rules based on the Fourier properties of the coupling surface and show how they can be used to determine the spatial resolution required for the coupler's fabrication. To our knowledge, this question has not been previously addressed, but it is important for the understanding of diffractive nanostructures and their technological realisation. We exemplify our insights with solar cells and UV photodetectors, where high-performance nanostructures that can be realised cost-effectively are essential.

Contact dermatitis: relevant differential diagnoses, simulators, and variants.

Similar to all eczematous disorders, irritant and allergic contact dermatitis are primarily defined by their morphology. In addition, the diagnosis of this specific reaction pattern on the skin (and mucous membranes) also requires prior exposure (direct or indirect) to an allergen or irritant. While it is quite easy to give a textbook description of the typical features of eczema, its clinical manifestations in daily practice are diverse and frequently uncharacteristic. Contact reactions may present as lichenoid, lymphomatoid, granulomatous, pigmented, purpuric, and erythema multiforme-like lesions, thus lacking the typical eczematous appearance and broadening the spectrum of differential diagnoses to be considered. Moreover, a considerable number of agents, acting by mechanisms other than contact, may trigger adverse reactions mimicking the eczematic morphology and distribution pattern of contact dermatitis. Increasingly used in oncology, this is especially true for drugs such as kinase inhibitors. Knowledge of these associations is crucial for the adequate diagnostic and therapeutic care of patients with supposed or actual contact dermatitis.

Total syntheses of murrayamine E, I, and K.

We describe efficient synthetic routes to murrayamine A (mukoenine C), O-methylmurrayamine A, mahanine, O-methylmahanine, and murrayamine D and the first total syntheses of murrayamine E, I, and K. Key steps are a palladium-catalyzed construction of the carbazole framework and an annulation of the pyran ring, which is either catalyzed by phenylboronic acid or promoted by a Lewis acid.

How to assess light trapping structures versus a Lambertian Scatterer for solar cells?

We propose a new figure of merit to assess the performance of light trapping nanostructures for solar cells, which we call the light trapping efficiency (LTE). The LTE has a target value of unity to represent the performance of an ideal Lambertian scatterer, although this is not an absolute limit but rather a benchmark value. Since the LTE aims to assess the nanostructure itself, it is, in principle, independent of the material, fabrication method or technology used. We use the LTE to compare numerous proposals in the literature and to identify the most promising light trapping strategies. We find that different types of photonic structures allow approaching the Lambertian limit, which shows that the light trapping problem can be approached from multiple directions. The LTE of theoretical structures significantly exceeds that of experimental structures, which highlights the need for theoretical descriptions to be more comprehensive and to take all relevant electro-optic effects into account.

Clinical proton MR spectroscopy in central nervous system disorders.

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units.

Loss of STAT3 in Lymphoma Relaxes NK Cell-Mediated Tumor Surveillance.

The transcription factors and proto-oncogenes STAT3 and STAT5 are highly activated in hematological malignancies and represent promising therapeutic targets. Whereas the importance of STAT5 as tumor promoter is beyond doubt, the role of STAT3 in hematological cancers is less well understood. Both, enforced as well as attenuated expression of STAT3 were reported in hematopoietic malignancies. Recent evidence implicates STAT3 as key player for tumor immune surveillance as it both mediates the production of and response to inflammatory cytokines. Here we investigated the effects of STAT3 deletion in a BCR/ABL-induced lymphoma model, which is tightly controlled by natural killer (NK) cells in vivo. Upon STAT3 deletion tumor growth is significantly enhanced when compared to STAT3-expressing controls. The increased tumor size upon loss of STAT3 was accompanied by reduced NK cell infiltration and decreased levels of the cytokine IFN-γ and the chemokine RANTES. Upon transplantation into NK cell-deficient mice differences in lymphoma size were abolished indicating that STAT3 expression in the tumor cells controls NK cell-dependent tumor surveillance. Our findings indicate that STAT3 inhibition in lymphoma patients will impair NK cell-mediated tumor surveillance, which needs to be taken into account when testing STAT3 inhibitors in preclinical or clinical trials.

Efficient keratinocyte differentiation strictly depends on JNK-induced soluble factors in fibroblasts.

Previous studies demonstrated that fibroblast-derived and JUN-dependent soluble factors have a crucial role on keratinocyte proliferation and differentiation during cutaneous wound healing. Furthermore, mice with a deficiency in Jun N-terminal kinases (JNKs) , JNK1 or JNK2, showed impaired skin development and delayed wound closure. To decipher the role of dermal JNK in keratinocyte behavior during these processes, we used a heterologous coculture model combining primary human keratinocytes and murine fibroblasts. Although cocultured JNK1/JNK2-deficient fibroblasts did not affect keratinocyte proliferation, temporal monitoring of the transcriptome of differentiating keratinocytes revealed that efficient keratinocyte differentiation not only requires the support by fibroblast-derived soluble factors, but is also critically dependent on JNK1 and JNK2 signaling in these cells. Moreover, we showed that the repertoire of fibroblast transcripts encoding secreted proteins is severely disarranged upon loss of JNK under the coculture conditions applied. Finally, our data demonstrate that efficient keratinocyte terminal differentiation requires constant presence of JNK-dependent and fibroblast-derived soluble factors. Taken together, our results imply that mesenchymal JNK has a pivotal role in the paracrine cross talk between dermal fibroblasts and epidermal keratinocytes during wound healing.