Search

Atopic dermatitis (AD) is a severe inflammatory skin disease. Langerhans cells and inflammatory dendritic epidermal cells (IDEC) are located in the epidermis of AD patients and contribute to the inflammatory processes. Both express robustly the high-affinity receptor for IgE, FcεRI, and thereby sense allergens. A beneficial role of vitamin D3 in AD is discussed to be important especially in patients with allergic sensitization. We hypothesized that vitamin D3 impacts FcεRI expression and addressed this in human ex vivo skin, in vitro Langerhans cells, and IDEC models generated from primary human precursor cells. We show in this article that biologically active vitamin D3 [1,25(OH)2-D3] significantly downregulated FcεRI at the protein and mRNA levels of the receptor’s α-chain, analyzed by flow cytometry and quantitative RT-PCR. We also describe the expression of a functional vitamin D receptor in IDEC. 1,25(OH)2-D3–mediated FcεRI reduction was direct and resulted in impaired activation of IDEC upon FcεRI engagement as monitored by CD83 expression. FcεRI regulation by 1,25(OH)2-D3 was independent of maturation and expression levels of microRNA-155 and PU.1 (as upstream regulatory axis of FcεRI) and transcription factors Elf-1 and YY1. However, 1,25(OH)2-D3 induced dissociation of PU.1 and YY1 from the FCER1A promotor, evaluated by chromatin immunoprecipitation. We show that vitamin D3 directly reduces FcεRI expression on dendritic cells by inhibiting transcription factor binding to its promotor and subsequently impairs IgE-mediated signaling. Thus, vitamin D3 as an individualized therapeutic supplement for those AD patients with allergic sensitization interferes with IgE-mediated inflammatory processes in AD patients.

Importance Atopic dermatitis (AD) is the most common chronic inflammatory skin disease and is driven by a complex pathophysiology underlying highly heterogeneous phenotypes. Current advances in precision medicine emphasize the need for stratification. Objective To perform deep phenotyping and identification of severity-associated factors in adolescent and adult patients with AD. Design, setting, and participants Cross-sectional data from the baseline visit of a prospective longitudinal study investigating the phenotype among inpatients and outpatients with AD from the Department of Dermatology and Allergy of the University Hospital Bonn enrolled between November 2016 and February 2020. Main outcomes and measures Patients were stratified by severity groups using the Eczema Area and Severity Index (EASI). The associations of 130 factors with AD severity were analyzed applying a machine learning-gradient boosting approach with cross-validation-based tuning as well as multinomial logistic regression. Results A total of 367 patients (157 male [42.8%]; mean [SD] age, 39 [17] years; 94% adults) were analyzed. Among the participants, 177 (48.2%) had mild disease (EASI ≤7), 120 (32.7%) had moderate disease (EASI >7 and ≤ 21), and 70 (19.1%) had severe disease (EASI >21). Atopic stigmata (cheilitis: odds ratio [OR], 8.10; 95% CI, 3.35-10.59; white dermographism: OR, 4.42; 95% CI, 1.68-11.64; Hertoghe sign: OR, 2.75; 95% CI, 1.27-5.93; nipple eczema: OR, 4.97; 95% CI, 1.56-15.78) was associated with increased probability of severe AD, while female sex was associated with reduced probability (OR, 0.30; 95% CI, 0.13-0.66). The probability of severe AD was associated with total serum immunoglobulin E levels greater than 1708 IU/mL and eosinophil values greater than 6.8%. Patients aged 12 to 21 years or older than 52 years had an elevated probability of severe AD; patients aged 22 to 51 years had an elevated probability of mild AD. Age at AD onset older than 12 years was associated with increased probability of severe AD up to a peak at 30 years; age at onset older than 33 years was associated with moderate to severe AD; and childhood onset was associated with mild AD (peak, 7 years). Lifestyle factors associated with severe AD were physical activity less than once per week and (former) smoking. Alopecia areata was associated with moderate (OR, 5.23; 95% CI, 1.53-17.88) and severe (OR, 4.67; 95% CI, 1.01-21.56) AD. Predictive performance of machine learning-gradient boosting vs multinomial logistic regression differed only slightly (mean multiclass area under the curve value: 0.71 [95% CI, 0.69-0.72] vs 0.68 [0.66-0.70], respectively). Conclusions and relevance The associations found in this cross-sectional study among patients with AD might contribute to a deeper disease understanding, closer monitoring of predisposed patients, and personalized prevention and therapy.

Objective Epidermal growth factor receptor inhibitors (EGFRI) are used as targeted cancer therapy. On average 70% of patients treated with EGFRIs suffer from skin toxicity. Studies showed a correlation between overall survival and the appearance of a skin rash, which is used as a biomarker for therapy efficacy. Micro RNAs (miRNA) as tumor or resistance biomarkers for cancer therapy are also highly investigated. In our study, we searched for associations of miRNA expression profiles in serum, with the severity of skin rash, in order to identify tentative therapy predictive biomarkers. Materials and methods Five candidate miRNAs were selected, based on an earlier in vitro next-generation-sequencing-experiment and after literature search. MiR-21, miR-31, miR-17, miR-106b and miR-520e were investigated in serum samples from patients (n = 254) treated with EGFRI. The quantitative expression of miRNA was tested for association with the occurrence/severity of the rash. Results In our cohort of patients treated with EGFR inhibiting monoclonal antibodies, miR-21 and miR-520e serum concentrations were negatively correlated with severity of skin rash (p-value 0.000582 and 1.53e-07 linear-trend-test) whereas for miR-31, a positive correlation was observed (p-value 9.01e-06 linear-trend-test). Conclusions This suggests that miR-21, miR-31 and miR-520e expression might be a treatment dependent marker for EGFRI induced skin rash.

Atopic dermatitis (AD) is a severe inflammatory skin disease. Langerhans cells and inflammatory dendritic epidermal cells (IDEC) are located in the epidermis of AD patients and contribute to the inflammatory processes. Both express robustly the high-affinity receptor for IgE, FcεRI, and thereby sense allergens. A beneficial role of vitamin D

Background The skin of atopic dermatitis (AD) patients presents a significant dysbalance of the microbiome with a high colonization by Staphylococcus aureus (S. aureus), which positively correlates with the severity of the disease. Objective Understanding the role of epidermal dendritic cells (DC) as link between the innate and the adaptive immune systems in AD. Methods Comparative phenotypic and functional analysis of TLR2 on Langerhans cells (LC) and inflammatory dendritic epidermal cells (IDEC) in organotypic models as well as freshly isolated cells from healthy and AD skin. Results In situ analysis of freshly isolated LC and IDEC from AD skin revealed decreased TLR2 expression compared to LC from healthy skin. In contrast to IDEC, LC from AD skin failed to display any evidence for in situ activation. Exposure to TLR2 ligand Pam3Cys resulted in maturation and increased migratory activity of LC from normal skin. LC and IDEC from AD were unresponsive to TLR2 ligand in that they failed to mature and displayed a high spontaneous migratory activity. Keratinocytes from both healthy and AD skin expressed similar levels of TLR2. The production of IL-6 and IL-10 was impaired by Pam3Cys in supernatants from AD skin. IL-18 was significantly higher in supernatants from AD skin and not influenced by TLR2 ligation, when compared to healthy skin. Conclusion Our results suggest that TLR2-mediated sensing of S. aureus-derived signals is strongly impaired in LC from AD skin. This phenomenon may partly contribute to the immune deviation in AD and the lack of S. aureus clearance.

Background Aryl hydrocarbon receptor (AhR), an important regulator of immune responses, is activated by UVB irradiation in the skin. Langerhans cells (LC) in the epidermis of patients with atopic dermatitis (AD) carry the high-affinity receptor for IgE, FceRI, and are crucially involved in the pathogenesis of AD by inducing inflammatory responses and regulating tolerogenic processes. Objectives We investigated AhR and AhR repressor (AhRR) expression and functional consequences of AhR activation in human ex vivo skin cells and in in vitro-generated LC. Methods Epidermal cells from healthy skin were analyzed for their expression of AhR and AhRR. LC generated from CD34+ hematopoietic stem cells (CD34LC) were treated with the UV photoproduct and AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ). Cell surface receptors, transcription factors, and the tolerogenic tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) were analyzed using flow cytometry and quantitative PCR. Results Epidermal LC and CD34LC express AhR and AhRR. AhR was also found in keratinocytes, which lack AhRR. AhR activation of LC by FICZ caused downregulation of FceRI in CD34LC without affecting their maturation. AhR-mediated regulation of FceRI did not involve any known transcription factors related to this receptor. Furthermore, we could show upregulation of IDO mediated by AhR engagement. Conclusions Our study shows that AhR activation by FICZ reduces FceRI and upregulates IDO expression in LC. This AhR-mediated anti-inflammatory feedback mechanism may dampen the allergen-induced inflammation in AD.

Background Janus kinase (JAK) inhibitors are a new class of therapeutic compounds for dermatological diseases. In atopic dermatitis (AD), data of clinical phase III trials show rapid improvement of pruritus and significant reduction of inflammation within the first weeks with a favorable safety profile. However, their mode of action in AD is not fully understood. Objectives In our study, we investigate the effect of different JAK inhibitors on cell differentiation, phenotype, and function of inflammatory dendritic epidermal cells (IDECs). Methods We analyzed the JAK expression in IDEC from ex vivo skin and in vitro generated IDECs using flow cytometry and PCR. Further, we studied in vitro the effect of different JAK inhibitors on IDEC cell differentiation, phenotype, and maturation. Results IDECs express JAK1 and JAK2 ex vivo and in vitro. We found that JAK1 and JAK2 were upregulated during the differentiation from monocytes to IDECs. Conversely, JAK2 inhibition by ruxolitinib (JAK1/2 inhibitor) or BMS-911543 (JAK2 inhibitor) abrogated the differentiation from monocytes into IDECs. Differentiated IDECs can redifferentiate into a more monocyte-like phenotype in the presence of ruxolitinib or BMS-911543. Furthermore, we showed that concomitant inhibition of JAK1/2 rather than blocking JAK1 or JAK2 alone, impaired maturation and the release of proinflammatory cytokines on lipopolysaccharide stimulation. Conclusions Our results suggest that inhibition of JAK1/2 impairs IDEC differentiation and function. We provide new insight into the mode of action of JAK inhibitors in AD and highlight the role of JAK1/2 inhibitors for the treatment of patients with AD.

Summary Background It is widely accepted that local anesthetics with epinephrine should not be used in areas served by terminal vessels. There is no evidence in studies for this in penile surgery, and given the anatomy of the penis, perfusion complications are highly unlikely. The goal of this study was to show that a penile block using a local anesthetic with epinephrine is safe. Patients and Methods In a follow-up study between 2005 and 2010, we analyzed 95 patients who got a penile ring block with subcutaneous infusion anesthesia (SIA). The SIA solution consisted of ropivacaine and lidocaine (0.11% and 0.21%) plus epinephrine. Results There were no anesthetic complications. Short-term negative postoperative occurrences (

Dendritic cells (DCs) have been recognized as key players bridging innate and adaptive immune systems. They control the balance of the adaptive immune response, and the functional behavior of DCs is mainly dictated by their microenvironment. Atopic dermatitis (AD) is a paradigmatic disease where the inflammatory microenvironment has a deep impact on DCs. The emergence of IgE-mediated sensitization is tightly related to the impact of locally released cytokines by either keratinocytes, T cells, or other cells involved in the inflammatory reaction. This review will focus on the recent and relevant findings in the field of immunobiology of DCs and their role in AD.

The family of SLPs (Src homology 2 domain-containing leukocyte adaptor proteins) are cytoplasmic signal effectors of lymphocyte antigen receptors. A main function of SLP is to orchestrate the assembly of Ca2+-mobilizing enzymes at the inner leaflet of the plasma membrane. For this purpose, SLP-76 in T cells utilizes the transmembrane adaptor LAT, but the mechanism of SLP-65 membrane anchoring in B cells remains an enigma. We now employed two genetic reconstitution systems to unravel structural requirements of SLP-65 for the initiation of Ca2+ mobilization and subsequent activation of gene transcription. First, mutational analysis of SLP-65 in DT40 B cells revealed that its C-terminal Src homology 2 domain controls efficient tyrosine phosphorylation by the kinase Syk, plasma membrane recruitment, as well as downstream signaling to NFAT activation. Second, we dissected these processes by expressing SLP-65 in SLP-76-deficient T cells and found that a kinase-independent adaptor function of Syk is required to link phosphorylated SLP-65 to Ca2+ mobilization. These approaches unmask a mechanistic complexity of SLP-65 activation and coupling to signaling cascades in that Syk is upstream as well as downstream of SLP-65. Moreover, membrane anchoring of the SLP-65-assembled Ca2+ initiation complex, which appears to be fundamentally different from that of closely related SLP-76, does not necessarily involve a B cell-specific component.

Analytical methods have been developed that allow for the determination of antiphlogistics, lipid regulators, the antiepileptic carbamazepine, cytostatic agents, the psychiatric drug diazepam and iodinated contrast media (ICM) as well as two major polycyclic musk fragrances HHCB (galaxolide) and AHTN (tonalide) in activated and digested sludge. The procedures consist of ultrasonic solvent extraction (USE) using methanol/acetone or pressurized liquid extraction (PLE) using 100% methanol. Clean-up was performed with C18ec material and silica gel followed by LC tandem MS (electrospray or atmospheric pressure chemical ionization) detection for pharmaceuticals and iodinated contrast media as well as GC/MS in the SIM mode for musk fragrances. Absolute recoveries from spiked activated sludge in general ranged from 88+/-4 to 119+/-20% for ICM and were 78+/-15 and 87+/-10% for the AHTN and HHCB, respectively. For the pharmaceuticals, absolute recoveries in activated sludge ranged between 43 and 78%. Subsequently, compensation of losses was carried out by using surrogate standards (acidic pharmaceuticals: fenoprop, neutral pharmaceuticals: dihydro-carbamazepine, musk fragrances: AHTN-D3). With one exception the recoveries were also adequate in digested sludge ranging from 43% to 120%.

The traditional view of how intracellular effector proteins are recruited to the B cell antigen receptor (BCR) complex at the plasma membrane is based on the occurrence of direct protein-protein interactions, as exemplified by the recruitment of the tyrosine kinase Syk (spleen tyrosine kinase) to phosphorylated motifs in BCR signaling subunits. By contrast, the subcellular targeting of the cytosolic adaptor protein SLP-65 (Src homology 2 domain-containing leukocyte adaptor protein of 65 kD), which serves as a proximal Syk substrate, is unclear. We showed that SLP-65 activation required its association at vesicular compartments in resting B cells. A module of similar to 50 amino acid residues located at the amino terminus of SLP-65 anchored SLP-65 to the vesicles. Nuclear magnetic resonance spectroscopy showed that the SLP-65 amino terminus was structurally disordered in solution, but could bind in a structured manner to noncharged lipid components of cellular membranes. Our finding that preformed vesicular signaling scaffolds are required for B cell activation indicates that vesicles may deliver preassembled signaling cargo to sites of BCR activation.

It is widely accepted that local anesthetics with epinephrine should not be used in areas served by terminal vessels. There is no evidence in studies for this in penile surgery, and given the anatomy of the penis, perfusion complications are highly unlikely. The goal of this study was to show that a penile block using a local anesthetic with epinephrine is safe.In a follow-up study between 2005 and 2010, we analyzed 95 patients who got a penile ring block with subcutaneous infusion anesthesia (SIA). The SIA solution consisted of ropivacaine and lidocaine (0.11% and 0.21%) plus epinephrine.There were no anesthetic complications. Short-term negative postoperative occurrences (72 hrs.) were swelling (42%), problems with suture material (22%), pain (19%), hematoma and paresthesia (each 13%), erectile dysfunction (12%), small-area skin necrosis after wound healing without requiring further surgery (13%), micturition disorders (7%), and wound infection (6%). Two patients on anticoagulation therapy had postoperative bleeding requiring revision surgery. 5% of the patients were given further analgesic sedation. 19% complained about postoperative pain. Persistent complaints (maximum 6 months) were disturbances of skin sensation (7%), swelling (4%), and redness and micturition disorders (3% each).Supplementing a local anesthetic with epinephrine in penis operations has many advantages, including high patient satisfaction, relatively painless infiltration, low complication rates, improved view of the operating field, and an extended effect of anesthetics with a prolonged reduction in pain. Because of the anatomy of the organ, there is no risk of necrosis related to using a subcutaneous penile ring block. Thus the view that epinephrine should not be used in penis procedures is obsolete.

Background Epidermal Langerhans cells (LC) expressing the high-affinity receptor for IgE (FceRI) play a key role in atopic dermatitis (AD). AD skin is highly colonized with Staphylococcus aureus (S.a.), which are sensed by Toll-like receptor 2 (TLR2). We hypothesized that TLR2 may impact on the expression of FceRI on LC. Objectives To study a putative impact of TLR2 signaling on FceRI, we analyzed FceRI and known transcription factors of the receptor after ligand binding to TLR2. Methods We generated LC from CD34+ progenitors in vitro (CD34LC) expressing FceRI and TLR2 as well as its partners TLR1 and TLR6. The expression of FceRI and known transcription factors of the receptor was analyzed on the protein and RNA level by flow cytometry, Western blotting, and real-time PCR. Results For CD34LC from 123 donors, we observed a high heterogeneity in FceRI surface expression correlating with mRNA level of its α-chain. Stimulation of TLR1/2 or TLR2/6 dramatically down-regulated FceRI on protein and mRNA level of both α- and γ-chain. Further analysis of putative transcription factors for FCER1A revealed the lack of GATA1 in CD34LC, weak expression of ELF1 and YY1, and high expression of PU.1. While ELF1 and YY1 appeared to be little affected by TLR2 engagement, PU.1 was significantly down-regulated. Conclusions Taken together, our findings show that in human, LC ligation of TLR2 by S.a.-derived products down-regulates FceRI and its transcription factor PU.1, thus suggesting that FceRI is controlled by PU.1 in these cells.

Specific antigen recognition by B cells is mediated via their antigen receptor (BCR), resulting in several intracellular signaling events. The recruitment of the Ca^2+ initiation complex, consisting of SLP-65, PLC-[gamma]2 and Btk, to the plasma membrane is a key element of BCR signal transduction. The exact mechanism of this SLP-65 mediated localization remains obscure. In 2005 the N-terminus of SLP-65 was described as an important component and a leucine-zipper function was postulated. However, I could show by targeted inactivation of this motif, that a leucine-zipper is not responsible for the correct subcellular organisation of the Ca^2+ initiation complex. The function depended rather on the basic characteristics of this region, which I name basic effector domain (BED). Furthermore, I could identify Calmodulin as a new BED-dependent binding partner of SLP-65. Ca^2+ concentration-dependent interaction studies, as well as Ca^2+ mobilization kinetics of cells expressing SLP-65 variants that do not bind Calmodulin, suggest a function downstream of the Ca^2+ mobilization. However, the importance of BED for the membrane localization of SLP-65 could be attributed to a different aspect. I showed a BED-mediated interaction of SLP-65 directly with lipid components of cell membranes in vitro, namely phosphatidylinositol-phosphates (PIP). I confirmed the functional relevance in vivo showing that the defined PIP binding motif of the adaptor protein TIRAP can fully substitute BED. This suggests that a direct interaction of BED with PIP is involved in membrane localization of SLP-65 and thus of the Ca^2+ initiation complex. I also contributed to the functional understanding of the SH2 domain as the second essential component for membrane recruitment of SLP-65. By co-expression of SLP-65 variants lacking BED or SH2 domain, I could show an in cis cooperation of these domains. To characterize this in more detail chimeric SLP-65 variants were generated, in which BED was replaced by various membrane recruitment domains. Additional inactivation of the SH2 domain within these proteins allowed analysis of an individual function of the SH2 domain. The results demonstrated that simple membrane localization is not sufficient to substitute for both membrane anchors of SLP-65. Instead, the protein must localize specifically to BCR-proximal signalling compartments within membrane microdomains. This is mediated by the SH2 domain. The results show that membrane recruitment of SLP-65 underlies a complex mechanism requiring the concerted function of at least two domains. The model I propose is, that BED contributes to SLP-65 membrane recruitment by direct PIP-binding and together with the SH2 domain stabilizes SLP-65 at the plasma membrane by a two-armed anchoring. The SH2 domain additionally mediates a specific localization of the protein, and therefore the Ca^2+ initiation complex, in defined signalling platforms, the lipid rafts., Die spezifische Antigenerkennung durch B-Zellen erfolgt über deren Antigenrezeptor (BCR) und resultiert in einer Reihe intrazellulärer Signale. Ein Schlüsselelement der BCR-Signalleitung ist die Rekrutierung des Ca^2+-Initiationskomplexes, bestehend aus SLP-65, PLC-[gamma]2 und Btk, an die Plasmamembran. Der genaue Mechanismus dieser SLP-65-vermittelten Lokalisation ist bislang unklar. Als wichtige Komponente wurde im Jahr 2005 die N-terminale Region von SLP-65 beschrieben und eine Leucin-Zipper-Funktion postuliert. Durch gezielte Inaktivierung des zugehörigen Motivs konnte ich jedoch zeigen, dass ein Leucin-Zipper nicht für die korrekte subzelluläre Organisation des Ca^2+-Initiationskomplexes verantwortlich ist. Stattdessen habe ich die Funktion auf die basischen Eigenschaften dieser Region zurückgeführt und sie als basische Effektordomäne (BED) bezeichnet. Des Weiteren konnte ich Calmodulin als neuen Bindungspartner der BED identifizieren. Ca^2+-konzentrationsabhängige Interaktionsstudien zusammen mit Ca^2+-Mobilisierungskinetiken in Zellen, welche unterschiedliche, nicht mehr mit Calmodulin interagierende SLP-65-Varianten exprimieren, lassen eine der Ca^2+-Mobilisierung nachgeschaltete Funktion vermuten. Die Bedeutung der BED für den Mechanismus der Membranlokalisation konnte ich einem anderen Aspekt zuordnen. So habe ich eine direkte, BED-vermittelte Interaktion von SLP-65 mit Lipidbestandteilen von Zellmembranen, nämlich Phosphatidylinositolphosphaten (PIP), in vitro nachgewiesen. Die funktionelle Relevanz konnte ich in vivo bestätigen, denn das bekannte PIP-Bindemotiv des Adapterproteins TIRAP konnte die BED funktionell ersetzen. Dies legt nahe, dass die BED durch direkte Interaktion mit PIP zur Membranlokalisation des Ca^2+-Initiationskomplexes beiträgt. Ferner konnte ich zum funktionellen Verständnis der SH2-Domäne von SLP-65 als zweite, essentielle Komponente für die Membranrekrutierung beitragen. Durch Koexpression von SLP-65-Varianten, denen BED oder SH2-Domäne fehlen, konnte ich eine in cis Kooperation beider Domänen zeigen. Um diese näher zu charakterisieren, wurden SLP-65-Chimären, bei denen BED durch verschiedene Membranrekrutierungsdomänen substituiert war, generiert. Kombiniert mit der Inaktivierung der SH2-Domäne innerhalb dieser Proteine, war die Analyse einer individuellen Funktion der SH2-Domäne möglich. Die Ergebnisse zeigten, dass eine einfache Membranlokalisation nicht ausreicht, um beide Membrananker zu ersetzen, sondern das Protein darüber hinaus in BCR-nahe Signalzentren in Membranmikrodomänen lokalisiert werden muss. Hierfür ist die SH2-Domäne verantwortlich. Die Studien zeigen, dass die Membranrekrutierung von SLP-65 einem komplexen Mechanismus unterliegt, der die konzertierte Funktion mindestens zweier Domänen benötigt. Mein Modell schlägt vor, dass BED durch eine direkte PIP-Bindung zur Membranrekrutierung von SLP-65 beiträgt und zusammen mit der SH2-Domäne in einer zweiarmigen Verankerung das Protein an der Plasmamembran stabilisiert. Die SH2-Domäne bestimmt darüber hinaus die konkrete Lokalisation des Proteins, und damit des Ca^2+-Initiationskomplexes, in definierten Signalplattformen, den lipid rafts.

In this study the fate of pharmaceuticals and personal care products which are irrigated on arable land with treated municipal wastewater was investigated. In Braunschweig, Germany, wastewater has been irrigated continuously for more than 45 years. In the winter time only the effluent of the sewage treatment plant (STP) of Braunschweig is used for irrigation, while during summer digested sludge is mixed with the effluent. In the present case study six wells and four lysimeters located in one of the irrigated agricultural fields were monitored with regard to the occurrence of 52 pharmaceuticals and two personal care products (PPCPs; e.g. betablockers, antibiotics, antiphlogistics, carbamazepine, musk fragrances, iodinated contrast media (ICM) and estrogens). No differences in PPCP pollution of the groundwater were found due to irrigation of STP effluents with and without addition of digested sludge, because many polar compounds do not sorb to sludge and lipophilic compounds are not mobile in the soil-aquifer. Most of the selected PPCPs were never detected in any of the lysimeter or groundwater samples, although they were present in the treated wastewater irrigated onto the fields. In the groundwater and lysimeter samples primarily the ICM diatrizoate and iopamidol, the antiepileptic carbamazepine and the antibiotic sulfamethoxazole were detected up to several mugl(-1), while the acidic pharmaceuticals, musk fragrances, estrogens and betablockers were likely sorbed or transformed while passing the top soil layer. Potential estrogenic effects are likely to disappear after irrigation, since the most potent steroid estrogens were not measurable.

A pilot plant for ozonation and UV-disinfection received effluent from a German municipal sewage treatment plant (STP) to test the removal of pharmaceuticals, iodinated X-ray contrast media (ICM) and musk fragrances from municipal wastewater. In the original STP effluent, 5 antibiotics (0.34-0.63 microgl(-1)), 5 betablockers (0.18-1.7 microgl(-1)), 4 antiphlogistics (0.10-1.3 microgl(-1)), 2 lipid regulator metabolites (0.12-0.13 microgl(-1)), the antiepileptic drug carbamazepine (2.1 microgl(-1)), 4 ICM (1.1-5.2 microgl(-1)), the natural estrogen estrone (0.015 microgl(-1)) and 2 musk fragrances (0.1-0.73 microgl(-1)) were detected by LC-electrospray tandem MS and/or GC/MS/MS. ICM, derived from radiological examinations, were present with the highest concentrations (diatrizoate: 5.7 microgl(-1), iopromide: 5.2 microgl(-1)). By applying 10-15 mgl(-1) ozone (contact time: 18 min), all the pharmaceuticals investigated as well as musk fragrances (HHCB, AHTN) and estrone were no longer detected. However, ICM (diatrizoate, iopamidol, iopromide and iomeprol) were still detected in appreciable concentrations. Even with a 15 mgl(-1) ozone dose, the ionic diatrizoate only exhibited removal efficiencies of not higher than 14%, while the non-ionic ICM were removed to a degree of higher than 80%. Advanced oxidation processes (O(3)/UV-low pressure mercury arc, O(3)/H(2)O(2)), which were non-optimized for wastewater treatment, did not lead significantly to a higher removal efficiency for the ICM than ozone alone.

International audience

Following the termination of the Messinian salinity crisis ~5.3 million years ago, massive sedimentation in the Eastern Mediterranean Sea formed the huge Nile Delta. Alongside delta propagation, a continental shelf was accreted along the Levant margin. For several decades it was assumed that these two sedimentary structures were closely connected. Levant shelf deposits are composed of Nile-derived sediments and present-day measurements show that sand is currently being transported alongshore from the Nile Delta to offshore Israel. This study reexamines the existing paradigm about sediment transport and shelf-delta connection. We show that longshore sand transport is just a small part of a much larger process termed here margin-parallel sediment transport (MPST). Sand is transported in a nearshore shallow-water belt where marine currents are highly energetic. At the same time, shale is transported at greater depths over the deeper shelf and the continental slope where marine currents are weaker. To model the accretion of the Levant shelf alongside the Nile Delta we use a 3D, diffusion-based, stratigraphic modeling tool (DionisosFlow) with a new module representing MPST. Our results show that margin-parallel transport of silt and clay in the deeper waters accounts for the bulk of deposition offshore Israel and is responsible for the development of the Levant shelf. Moreover, though MPST has begun coevally with delta formation, massive accretion of the Levant shelf was delayed by 2–3 My. Initially, a continental shelf formed offshore Sinai, then offshore Israel, and most recently along the Lebanon coast. Our model also demonstrates the significant lithological differences observed between sedimentation in front of the Nile River mouth and along adjacent continental margin. High energy down-slope sediment transport carries sand, silt, and clay, whereas margin-parallel currents are relatively weak and carry mainly silt and clay. One exception within the margin-parallel system is the highly energetic nearshore current that transports sand. Thus, we point out, MPST is an efficient separator between shale and sand. © 2020 Elsevier Ltd, This study was supported by the Israeli Ministry of Energy and by the Mediterranean Research Center of Israel (MERCI). The article is further based upon work of COST Action “Uncovering the Mediterranean salt giant” (MEDSALT) supported by the European Cooperation in Science and Technology

International audience; This article focuses on liquefaction of saturated granular soils, triggered by earthquakes. Liquefaction is definedhere as the transition from a rigid state, in which the granular soil layer supports structures placed on its surface, toa fluidlike state, in which structures placed initially on the surface sink to their isostatic depth within the granularlayer.We suggest a simple theoretical model for soil liquefaction and show that buoyancy caused by the presence ofwater inside a granular medium has a dramatic influence on the stability of an intruder resting at the surface of themedium.We confirm this hypothesis by comparison with laboratory experiments and discrete-element numericalsimulations. The external excitation representing ground motion during earthquakes is simulated via horizontalsinusoidal oscillations of controlled frequency and amplitude. In the experiments, we use particles only slightlydenser than water, which as predicted theoretically increases the effect of liquefaction and allows clear depth-of-sinkingmeasurements. In the simulations, a micromechanical model simulates grains using molecular dynamicswith friction between neighbors. The effect of the fluid is captured by taking into account buoyancy effects onthe grains when they are immersed. We show that the motion of an intruder inside a granular medium is mainlydependent on the peak acceleration of the ground motion and establish a phase diagram for the conditions underwhich liquefaction happens, depending on the soil bulk density, friction properties, presence of water, and peak acceleration of the imposed large-scale soil vibrations.We establish that in liquefaction conditions, most cases relaxtoward an equilibrium position following an exponential in time.We also show that the equilibrium position itself,for most liquefaction regimes, corresponds to the isostatic equilibrium of the intruder inside a medium of effectivedensity. The characteristic time to relaxation is shown to be essentially a function of the peak ground velocity.

Application of cavity ring down (CRD) spectrometry for measuring the optical properties of pure and mixed laboratory-generated aerosols is presented. The extinction coefficient (?ext), extinction cross section (?ext) and extinction efficiency (Qext) were measured for polystyrene spheres (PSS), ammonium sulphate ((NH4)2(SO4)), sodium chloride (NaCl), glutaric acid (GA), and Rhodamine-590 aerosols. The refractive indices of the different aerosols were retrieved by comparing the measured extinction efficiency of each aerosol type to the extinction predicted by Mie theory. Aerosols composed of sodium chloride and glutaric acid in different mixing ratios were used as model for mixed aerosols of two non-absorbing materials, and their extinction and complex refractive index were derived. Aerosols composed of Rhodamine-590 and ammonium sulphate in different mixing ratios were used as model for mixing of absorbing and non-absorbing species, and their optical properties were derived. The refractive indices of the mixed aerosols were also calculated by various optical mixing rules and a core plus shell Mie model. We found that for non-absorbing mixtures, the linear rule, Maxwell-Garnett rule, extended effective medium approximation (EEMA), and core plus shell model give comparable results, with the linear mixing rule giving a slightly better fit than the others. Overall, calculations for the mixed aerosols are not as good as for single component aerosols. For absorbing mixtures, the differences between the refractive indices calculated using the mixing rules and those retrieved by CRD are generally higher.

In this study, we measure the extinction efficiency at 532 nm of absorbing aerosol particles coated with a non-absorbing solid and liquid organic shell with coating thickness varying between 5 and 100 nm using cavity ring down aerosol spectrometry. For this purpose, we use nigrosin, an organic black dye, as a model absorbing core and two non–absorbing organic substances as shells, glutaric acid (GA) and Di-Ethyl-Hexyl-Sebacate (DEHS). The measured behavior of the coated particles is consistent with Mie calculations of core-shell particles. Errors between measured and calculated values for nigrosin coated with GA and DEHS are between 0.5% and 10.5% and between 0.5% and 9%, respectively. However, it is evident that the calculations are in better agreement with the measured results for thinner coatings. Possible reasons for these discrepancies are discussed.

The largest uncertainty in the radiative forcing of climate change over the industrial era is that due to aerosols, a substantial fraction of which is the uncertainty associated with scattering and absorption of shortwave (solar) radiation by anthropogenic aerosols in cloud-free conditions (IPCC, 2001). Quantifying and reducing the uncertainty in aerosol influences on climate is critical to understanding climate change over the industrial period and to improving predictions of future climate change for assumed emission scenarios. Measurements of aerosol properties during major field campaigns in several regions of the globe during the past decade are contributing to an enhanced understanding of atmospheric aerosols and their effects on light scattering and climate. The present study, which focuses on three regions downwind of major urban/population centers (North Indian Ocean (NIO) during INDOEX, the Northwest Pacific Ocean (NWP) during ACE-Asia, and the Northwest Atlantic Ocean (NWA) during ICARTT), incorporates understanding gained from field observations of aerosol distributions and properties into calculations of perturbations in radiative fluxes due to these aerosols. This study evaluates the current state of observations and of two chemical transport models (STEM and MOZART). Measurements of burdens, extinction optical depth (AOD), and direct radiative effect of aerosols (DRE – change in radiative flux due to total aerosols) are used as measurement-model check points to assess uncertainties. In-situ measured and remotely sensed aerosol properties for each region (mixing state, mass scattering efficiency, single scattering albedo, and angular scattering properties and their dependences on relative humidity) are used as input parameters to two radiative transfer models (GFDL and University of Michigan) to constrain estimates of aerosol radiative effects, with uncertainties in each step propagated through the analysis. Constraining the radiative transfer calculations by observational inputs increases the clear-sky, 24-h averaged AOD (34±8%), top of atmosphere (TOA) DRE (32±12%), and TOA direct climate forcing of aerosols (DCF – change in radiative flux due to anthropogenic aerosols) (37±7%) relative to values obtained with 'a priori' parameterizations of aerosol loadings and properties (GFDL RTM). The resulting constrained clear-sky TOA DCF is −3.3±0.47, −14±2.6, −6.4±2.1 Wm−2 for the NIO, NWP, and NWA, respectively. With the use of constrained quantities (extensive and intensive parameters) the calculated uncertainty in DCF was 25% less than the 'structural uncertainties' used in the IPCC-2001 global estimates of direct aerosol climate forcing. Such comparisons with observations and resultant reductions in uncertainties are essential for improving and developing confidence in climate model calculations incorporating aerosol forcing.