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Neutrophil granulocytes possess a large arsenal of pro-inflammatory substances and mechanisms that empower them to drive local acute immune reactions to invading microorganisms or endogenous inflammatory triggers. The use of this armory needs to be tightly controlled to avoid chronic inflammation and collateral tissue damage. In gout, inflammation arises from precipitation of uric acid in the form of needle-shaped monosodium urate crystals. Inflammasome activation by these crystals in local immune cells results in a rapid and dramatic recruitment of neutrophils. This neutrophil influx is accompanied by the infamously intense clinical symptoms of inflammation during an acute gout attack. Neutrophilic inflammation however is equipped with a built-in safeguard; activated neutrophils form neutrophil extracellular traps (NETs). At the very high neutrophil densities that occur at the site of inflammation, NETs build aggregates that densely pack the monosodium urate (MSU) crystals and trap and degrade pro-inflammatory mediators by inherent proteases. Local removal of cytokines and chemokines by aggregated NETs explains how acute inflammation can stop in the consistent presence of the inflammatory trigger. Aggregated NETs resemble early stages of the typical large MSU deposits that constitute the pathognomonic structures of gout, tophi. Although tophi contribute to muscosceletal damage and mortality in patients with chronic gout, they can therefore be considered as a payoff that is necessary to silence the intense inflammatory response during acute gout. [ABSTRACT FROM AUTHOR]

Seven squamous cell carcinoma cell lines were disintegrated from biopsies of patients with head and neck cancer. Genotyping tests verified the authenticity and the human origin of all seven lines. The cell lines designated as University of Kiel, Head and Neck (UKHN) -1 to -3 and UKHN-6 to -9 were subjected to flow cytometry and indirect immunofluorescence to assess aberrant DNA content. To confirm the squamous epithelial origin of the cells, the cytokeratin profile was immunocytologically analysed. The cell lines showed individual differences in mitotic frequency. UKHN-1, -6, -7 and -9 grew as monolayers, whereas UKHN-2, -3, and -8 tend to multilayer stratification. Overexpression of LOXL4 and Pim-1 proteins as distinctive features of head and neck carcinomas were shown in all seven cell lines. Inoculating SCID mice with these cell lines resulted in tumour formation, hence corroborating the tumourigenicity of all seven cell lines. The cell lines were also tested for high-risk HPV types using different DNA-based assays and found to be negative. [ABSTRACT FROM AUTHOR]

The quality of the adaptive immune response depends on the differentiation of distinct CD4+ helper T cell subsets, and the magnitude of an immune response is controlled by CD4+Foxp3+ regulatory T cells (Treg cells). However, how a tissue- and cell type-specific suppressor program of Treg cells is mechanistically orchestrated has remained largely unexplored. Through the use of Treg cell-specific gene targeting, we found that the suppression of allergic immune responses in the lungs mediated by T helper type 2 (TH2) cells was dependent on the activity of the protein kinase CK2. Genetic ablation of the β-subunit of CK2 specifically in Treg cells resulted in the proliferation of a hitherto-unexplored ILT3+ Treg cell subpopulation that was unable to control the maturation of IRF4+PD-L2+ dendritic cells required for the development of TH2 responses in vivo. [ABSTRACT FROM AUTHOR]

Recently, we demonstrated a significant inverse correlation between HPV-infection and SLPI-expression suggesting that SLPI protects against HPV-infection of HNSCC. Here we analyzed in a single lab setting 307 formalin-fixed paraffin-embedded HNSCC cases (tonsillar n = 135; non-tonsillar: n = 172) from eight health care centers. Samples were analyzed for SLPI gene- and protein-expression. Annexin A2, its heterotetramer A2t, putatively facilitating HPV- and SLPI-cell entry, was measured to study the correlation between SLPI and annexin A2. Data were correlated with tobacco consumption and HPV-status. Overall, HPV-DNA prevalence was 23.5% (72/307); attributed to: 43.7% (59/135) tonsillar and 7.6% (13/172) non-tonsillar cases. Smoking resulted in 6.44-fold increased and HPV-infection in 3.46-fold decreased SLPI-gene expression in all HNSCC with similar significant results obtained in tonsillar and non-tonsillar SCC separately. Correlating annexin A2- and SLPI-gene expression showed a significant surplus of annexin A2 in HPV-positive tumors (4.21× more annexin A2) and 6.72× more annexin A2 than SLPI in nonsmokers in all HNSCCs and similar significant results for both tumor entities separately. The surplus of annexin A2 in non-smokers and HPV-positive patients supports our hypothesis that decreased SLPI levels facilitate HPV-infection i.e., increased SLPI-expression may protect against HPV-infection of tonsillar and non-tonsillar SCC. [ABSTRACT FROM AUTHOR]

Aims: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the phagocyte reactive oxygen species (ROS)-producing NOX2 enzyme complex and characterized by recurrent infections associated with hyperinflammatory and autoimmune manifestations. A translational, comparative analysis of CGD patients and the corresponding ROS-deficient Ncf1m1J mutated mouse model was performed to reveal the molecular pathways operating in NOX2 complex deficient inflammation. Results: A prominent type I interferon (IFN) response signature that was accompanied by elevated autoantibody levels was identified in both mice and humans lacking functional NOX2 complex. To further underline the systemic lupus erythematosus (SLE)-related autoimmune process, we show that naïve Ncf1m1J mutated mice, similar to SLE patients, suffer from inflammatory kidney disease with IgG and C3 deposits in the glomeruli. Expression analysis of germ-free Ncf1m1J mutated mice reproduced the type I IFN signature, enabling us to conclude that the upregulated signaling pathway is of endogenous origin. Innovation: Our findings link the previously unexplained connection between ROS deficiency and increased susceptibility to autoimmunity by the discovery that activation of IFN signaling is a major pathway downstream of a deficient NOX2 complex in both mice and humans. Conclusion: We conclude that the lack of phagocyte-derived oxidative burst is associated with spontaneous autoimmunity and linked with type I IFN signature in both mice and humans. Antioxid. Redox Signal. 21, 2231-2245. [ABSTRACT FROM AUTHOR]

Gout is characterized by an acute inflammatory reaction and the accumulation of neutrophils in response to monosodium urate (MSU) crystals. Inflammation resolves spontaneously within a few days, although MSU crystals can still be detected in the synovial fluid and affected tissues. Here we report that neutrophils recruited to sites of inflammation undergo oxidative burst and form neutrophil extracellular traps (NETs). Under high neutrophil densities, these NETs aggregate and degrade cytokines and chemokines via serine proteases. Tophi, the pathognomonic structures of chronic gout, share characteristics with aggregated NETs, and MSU crystals can induce NETosis and aggregation of NETs. In individuals with impaired NETosis, MSU crystals induce uncontrolled production of inflammatory mediators from neutrophils and persistent inflammation. Furthermore, in models of neutrophilic inflammation, NETosis-deficient mice develop exacerbated and chronic disease that can be reduced by adoptive transfer of aggregated NETs. These findings suggest that aggregated NETs promote the resolution of neutrophilic inflammation by degrading cytokines and chemokines and disrupting neutrophil recruitment and activation. [ABSTRACT FROM AUTHOR]

Mast cell-deficient KitW-sh "sash" mice are widely used to investigate mast cell functions. However, mutations of c-Kit also affect additional cells of hematopoietic and nonimmune origin. In this study, we demonstrate that KitW-sh causes aberrant extramedullary myelopoiesis characterized by the expansion of immature lineage-negative cells, common myeloid progenitors, and granulocyte/macrophage progenitors in the spleen. A consistent feature shared by these cell types is the reduced expression of c-Kit. Populations expressing intermediate and high levels of Ly6G, a component of the myeloid differentiation Ag Gr-1, are also highly expanded in the spleen of sash mice. These cells are able to suppress T cell responses in vitro and phenotypically and functionally resemble myeloid-derived suppressor cells (MDSC). MDSC typically accumulate in tumor-bearing hosts and are able to dampen immune responses. Consequently, transfer of MDSC from naive sash mice into line 1 alveolar cell carcinoma tumor-bearing wild-type littermates leads to enhanced tumor progression. However, although it can also be observed in sash mice, accelerated growth of transplanted line 1 alveolar cell carcinoma tumors is a mast cell-independent phenomenon. Thus, the KitW-sh mutation broadly affects key steps in myelopoiesis that may have an impact on mast cell research. [ABSTRACT FROM AUTHOR]

Objectives: Palytoxin (PTX), a marine toxin isolated from the Cnidaria (zooanthid) Palythoa caribaeorum is one of the most potent non-protein substances known. It is a very complex molecule that presents both lipophilic and hydrophilic areas. The effect of PTX was investigated in a series of experiments conducted in head and neck squamous cell carcinoma (HNSCC) cell lines and xenografts. Materials and methods: Cell viability, and gene expression of the sodium/potassium-transporting ATPase subumit alpha1 (ATP1AL1) and GAPDH were analyzed in HNSCC cells and normal epithelial cells after treatment with PTX using cytotoxicity-, clonogenic-, and enzyme inhibitor assays as well as RT-PCR and Northern Blotting. For xenograft experiments severe combined immunodeficient (SCID) mice were used to analyze tumor regression. The data were statistically analyzed using One-Way Annova (SPSS vs20). Results: Significant toxic effects were observed in tumor cells treated with PTX (LD50 of 1.5 to 3.5 ng/ml) in contrast to normal cells. In tumor cells PTX affected both the release of LDH and the expression of the sodium/ potassium-transporting ATPase subunit alpha1 gene suggesting loss of cellular integrity, primarily of the plasma membrane. Furthermore, strong repression of the c-Jun N-terminal kinase 3 (JNK3) mRNA expression was found in carcinoma cells which correlated with enhanced toxicity of PTX suggesting an essential role of the mitogen activated protein kinase (MAPK)/JNK signalling cascades pathway in the mechanisms of HNSCC cell resistance to PTX. In mice inoculated with carcinoma cells, injections of PTX into the xenografted tumors resulted within 24 days in extensive tumor destruction in 75% of the treated animals (LD50 of 68 ng/kg to 83 ng/kg) while no tumor regression occurred in control animals. Conclusions: These results clearly provide evidence that PTX possesses preferential toxicity for head and neck carcinoma cells and therefore it is worth further studying its impact which may extend our knowledge of the biology of head and neck cancer. [ABSTRACT FROM AUTHOR]

A number of composition dependent physicochemical propertiesweremeasured for the water–[C4mim][MeSO3]binary system at 85 °C. Specifically, we provide data for density,heat capacity, heats of dissolution, conductivity, viscosity, as wellas the self-diffusion coefficients of the cation, anion, and water.Ionic liquids based on the MeSO3anion constitute a suitablemedium for various chemistries. This study addresses the need to providephysicochemical data on [C4mim][MeSO3] and thewater–[C4mim][MeSO3] binary systems thatare currently unavailable. Additional analysis of the combined datais also presented to provide further insight into the molecular levelbehavior of the water–[C4mim][MeSO3]binary system. [ABSTRACT FROM AUTHOR]

Hydrocarbon oils such as pristane or hexadecane induce arthritis and lupus in rodents sharing clinical and pathological features with the human diseases rheumatoid arthritis and systemic lupus erythematosus, respectively. In pristane-induced lupus in the mouse induction of apoptosis and augmentation of type-I Interferon signalling by pristane have been suggested to contribute to pathology, whereas in pristane-induced arthritis (PIA) in the rat the pathological mechanisms are still elusive. Here we show that pristane induces cell death in rat and human cells. Increased numbers of apoptotic cells were found in draining lymph nodes of pristane-injected rats and increased percentages of apoptotic and necrotic cells were observed in peripheral blood. In addition, neutrophil extracellular trap formation was triggered by pristane and hexadecane in neutrophils. Because levels of interleukin (IL)-1β were elevated in sera of pristane-injected rats, with levels mirroring the course of PIA, we examined the effect of pristane at single cell level in vitro, using rat splenocytes and the human monocytic cell line THP-1. Pristane and other hydrocarbon oils induced IL-1β secretion in THP-1 cells as well as in rat splenocytes. The potassium channel inhibitor glibenclamide partly inhibited IL-1β induction, suggesting involvement of the inflammasome. Elevated levels of IL-1α were also found in supernatants of cells treated with pristane and hexadecane. In conclusion, autoimmunogenic hydrocarbon oils induce various forms of cell death in rat and human cells. The higher serum IL-1β levels in pristane-injected animals might be caused by both inflammasome-dependent and -independent mechanisms, such as passive release from dying-cells and probably extracellular maturation of pro-IL-1β. [ABSTRACT FROM AUTHOR]

Summary: Objectives: Infection with human papillomavirus (HPV) is linked to oropharyngeal cancer. This analysis investigated possible associations between HPV status, smoking history and survival outcome in patients with neck metastasis and carcinoma of unknown primary (CUP). Materials and methods: Registries at the Universities of Hamburg and Kiel were searched for patients with CUP diagnosed from 2002 to 2011 who had formalin-fixed and paraffin-embedded metastatic lymph node samples available. All patients underwent routine diagnostic procedures to establish the primary site and received radiotherapy (60Gy using conventional fractionation) with or without concurrent cisplatin-based chemotherapy depending on disease extent. Genotyping was performed using polymerase chain reaction; p16[INK4a] expression was assessed using immunohistochemistry. Results: Sixty-three patients were included; 23 (37%) had HPV DNA/p16+ samples and 40 (63%) were negative for either/both markers. A high proportion of patients had a history of tobacco smoking; significantly fewer patients with HPV+/p16+ samples were smokers than those who were negative for either/both markers (61% vs. 90%, respectively; p =0.0067). There were no statistically significant differences between overall or recurrence-free survival in HPV+/p16+ patients vs. those negative for either/both markers. Overall survival appeared to be superior in patients with <10 pack-years smoking history and HPV+/p16+ disease. Conclusions: This study, the largest to date investigating HPV status in head and neck CUP, identified HPV and p16 overexpression in over one-third of patients. Tobacco smoking history appeared to affect survival in HPV+/p16+ patients. Smoking status should be considered as a prognostic factor in patients with CUP, along with HPV DNA status. [ABSTRACT FROM AUTHOR]

It has been proposed that p16(INK4A) qualifies as a surrogate marker for viral oncogene activity in head and neck cancer (HNSCC). By analyzing 78 HNSCC we sought to validate the accuracy of p16(INK4A) as a reliable marker of active HPV infections in HNSCC. To this end we determined HPV DNA (HPVD) and E6*I mRNA (HPVR) expression status and correlated these results with p16(INK4A) staining. In tonsillar SCC 12/20 were HPVD+ and 12/12 of these showed active HPV infections whereas in non-tonsillar SCC 10/58 were HPVD+ and 5/10 showed active HPV infections. Thus, we prove about 8% of non-tonsillar SCC to be also correlated with HPV-associated carcinogenesis. Strikingly, 3/14 (21.4%) of tonsillar and non-tonsillar HPVD+/HPVR+ cases did not show p16(INK4A) overexpression and these cases would have been missed when applying initial p16(INK4A) staining only. However, in 13 cases negative for HPV, DNA p16(INK4A) was overexpressed. In conclusion, our data confirm tonsillar SCC to be predominantly but not only associated with active HPV infections. Furthermore, our data show that p16(INK4A) overexpression is not evident in a subgroup of HNSCC with active HPV infection. Definitive HPV data should therefore be utilized in diagnostics and treatment modalities of HPV positive and HPV negative HNSCC patients, resulting in a paradigm shift regarding these obviously different tumor entities. [ABSTRACT FROM AUTHOR]

Ticks developed a multitude of different immune evasion strategies to obtain a blood meal. Sialostatin L is an immunosuppressive cysteine protease inhibitor present in the saliva of the hard tick Ixodes scapularis. In this study, we demonstrate that sialostatin L strongly inhibits the production of IL-9 by Th9 cells. Because we could show recently that Th9-derived IL-9 is essentially involved in the induction of asthma symptoms, sialostatin L was used for the treatment of experimental asthma. Application of sialostatin L in a model of experimental asthma almost completely abrogated airway hyperresponsiveness and eosinophilia. Our data suggest that sialostatin L can prevent experimental asthma, most likely by inhibiting the IL-9 production of Th9 cells. Thus, alternative to IL-9 neutralization sialostatin L provides the basis for the development of innovative therapeutic strategies to treat asthma. [ABSTRACT FROM AUTHOR]

Linear π-conjugated oligomers have been widely investigated, but the behavior of the corresponding cyclic oligomers is poorly understood, despite the recent synthesis of π-conjugated macrocycles such as [n]cycloparaphenylenes and cyclo[n]thiophenes. Here we present an efficient template-directed synthesis of a π-conjugated butadiyne-linked cyclic porphyrin hexamer directly from the monomer. Small-angle X-ray scattering data show that this nanoring is shape-persistent in solution, even without its template, whereas the linear porphyrin hexamer is relatively flexible. The crystal structure of the nanoring-template complex shows that most of the strain is localized in the acetylenes; the porphyrin units are slightly curved, but the zinc coordination sphere is undistorted. The electrochemistry, absorption, and fluorescence spectra indicate that the HOMO-LUMO gap of the nanoring is less than that of the linear hexamer and less than that of the corresponding polymer. The nanoring exhibits six one-electron reductions and six one-electron oxidations, most of which are well resolved. Ultrafast fluorescence anisotropy measurements show that absorption of light generates an excited state that is delocalized over the whole p-system within a time of less than 0.5 ps. The fluorescence spectrum is amazingly structured and red-shifted. A similar, but less dramatic, red-shift has been reported in the fluorescence spectra of cycloparaphenylenes and was attributed to a high exciton binding energy; however the exciton binding energy of the porphyrin nanoring is similar to those of linear oligomers. Quantum-chemical excited state calculations show that the fluorescence spectrum of the nanoring can be fully explained in terms of vibronic Herzberg-Teller (HT) intensity borrowing. [ABSTRACT FROM AUTHOR]

Abstract: Studies report an increasing incidence of oropharyngeal cancers linked to infection by human papillomavirus (HPV). We reviewed trials assessing outcomes by HPV DNA status in patients with locally advanced oropharyngeal cancer. Seven of the eight studies identified showed significantly better survival in patients with HPV DNA-positive tumors vs. HPV DNA-negative tumors. The review also describes what needs to be defined regarding optimal treatments. Future trials should incorporate HPV DNA status as a risk determinant and explore treatments for high-risk patients needing therapy intensification, and low- and intermediate-risk patients needing treatment de-intensification to improve tolerability, without compromising survival. [Copyright &y& Elsevier]

Summary: Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper 2 (Th2) and Th17 cells. Herein, we report that IRF4 is also crucial for the development and function of an interleukin-9 (IL-9)-producing CD4+ T cell subset designated Th9. IRF4-deficient CD4+ T cells failed to develop into IL-9-producing Th9 cells, and IRF4-specific siRNA inhibited IL-9 production in wild-type CD4+ T cells. Chromatin-immunoprecipitation (ChIP) analyses revealed direct IRF4 binding to the Il9 promoter in Th9 cells. In a Th9-dependent asthma model, neutralization of IL-9 substantially ameliorated asthma symptoms. The relevance of these findings is emphasized by the fact that the induction of IL-9 production also occurs in human CD4+ T cells accompanied by the upregulation of IRF4. Our data clearly demonstrate the central function of IRF4 in the development of Th9 cells and underline the contribution of this T helper cell subset to the pathogenesis of asthma. [ABSTRACT FROM AUTHOR]

Natural or experimental infection of domestic cats and virus transmission from humans to captive predatory cats suggest that felids are highly susceptible to SARS-CoV-2 infection. However, it is unclear which cells and compartments of the respiratory tract are infected. To address this question, primary cell cultures derived from the nose, trachea, and lungs of cat and lion were inoculated with SARS-CoV-2. Strong viral replication was observed for nasal mucosa explants and tracheal air–liquid interface cultures, whereas replication in lung slices was less efficient. Infection was mainly restricted to epithelial cells and did not cause major pathological changes. Detection of high ACE2 levels in the nose and trachea but not lung further suggests that susceptibility of feline tissues to SARS-CoV-2 correlates with ACE2 expression. Collectively, this study demonstrates that SARS-CoV-2 can efficiently replicate in the feline upper respiratory tract ex vivo and thus highlights the risk of SARS-CoV-2 spillover from humans to felids. [ABSTRACT FROM AUTHOR]

Abstract: Selective up-regulation of the mRNA of LOXL4, a member of the LOX matrix amine oxidase family, significantly correlated with lymph node metastases and higher tumour stages in head and neck squamous cell carcinomas (HNSCC). To evaluate the diagnostic and prognostic value of the protein we produced an antibody specific for LOXL4 and assessed the expression in 317 human HNSCC specimens. The LOXL4 protein was detected in 92.7% of primary tumours, in 97.8% of lymph node metastases and in affected oral mucosa with high-grade dysplasia, but was absent in various non-neoplastic tissues of the head and neck. TNM categories and overall survival did not link to grades of immunoreactivity. Studies in cultured primary hypopharyngeal HTB-43 carcinoma cells detected perinuclear and cell surface expression of LOXL4, but no nuclear localisation. Therefore, its interactive SRCR-domains and catalytic activity combined with tumour cell specific expression and cell surface associated location indicate multiple functions in tumour cell adhesion and interactions with the extracellular matrix. Our data suggest that LOXL4 is useful both as tumour marker and target in the treatment of HNSCC. [Copyright &y& Elsevier]

Degenerative and inflammatory joint diseases lead to a destruction of the joint architecture. Whereas degenerative osteoarthritis results in the formation of new bone, rheumatoid arthritis leads to bone resorption. The molecular basis of these different patterns of joint disease is unknown. By inhibiting Dickkopf-1 (DKK-1), a regulatory molecule of the Wnt pathway, we were able to reverse the bone-destructive pattern of a mouse model of rheumatoid arthritis to the bone-forming pattern of osteoarthritis. In this way, no overall bone erosion resulted, although bony nodules, so-called osteophytes, did form. We identified tumor necrosis factor-α (TNF) as a key inducer of DKK-1 in the mouse inflammatory arthritis model and in human rheumatoid arthritis. These results suggest that the Wnt pathway is a key regulator of joint remodeling. [ABSTRACT FROM AUTHOR]

This study was conducted to compare attitudes of psychiatrists, other professionals, and laypeople towards compulsory admission and treatment of patients with schizophrenia in different European countries. Three case reports of patients with schizophrenia were presented to N=1,737 persons: 235 in England, 622 in Germany, 319 in Hungary, and 561 in Switzerland; 298 were psychiatrists, 687 other psychiatric or medical professionals, and 752 laypeople. The case reports presented typical clinical situations with refusal of consent to treatment (first episode and social withdrawal, recurrent episode and moderate danger to others and patient with multiple episodes and severe self-neglect). The participants were asked whether they would agree with compulsory admission and compulsory neuroleptic treatment. The rates of agreement varied between 50.8 and 92.1% across countries and between 41.1 and 93.6% across the different professional groups. In all countries, psychologists and social workers supported compulsory procedures significantly less than the psychiatrists who were in tune with laypeople and nurses. Country differences were highly significant showing more agreement with compulsion in Hungary and England and less in Germany and Switzerland (odds ratios up to 4.33). Own history of mental illness and having mentally ill relatives had no major impact on the decisions. Evidence suggests that compulsory procedures are based on traditions and personal attitudes to a considerable degree. Further research should provide empirical data and more definite criteria for indications of compulsive measures to achieve a common ethical framework for those critical decisions across Europe. [ABSTRACT FROM AUTHOR]

This study was conducted to compare attitudes of psychiatrists, other professionals, and laypeople towards compulsory admission and treatment of patients with schizophrenia in different European countries. Three case reports of patients with schizophrenia were presented to N=1,737 persons: 235 in England, 622 in Germany, 319 in Hungary, and 561 in Switzerland; 298 were psychiatrists, 687 other psychiatric or medical professionals, and 752 laypeople. The case reports presented typical clinical situations with refusal of consent to treatment (first episode and social withdrawal, recurrent episode and moderate danger to others and patient with multiple episodes and severe self-neglect). The participants were asked whether they would agree with compulsory admission and compulsory neuroleptic treatment. The rates of agreement varied between 50.8 and 92.1% across countries and between 41.1 and 93.6% across the different professional groups. In all countries, psychologists and social workers supported compulsory procedures significantly less than the psychiatrists who were in tune with laypeople and nurses. Country differences were highly significant showing more agreement with compulsion in Hungary and England and less in Germany and Switzerland (odds ratios up to 4.33). Own history of mental illness and having mentally ill relatives had no major impact on the decisions. Evidence suggests that compulsory procedures are based on traditions and personal attitudes to a considerable degree. Further research should provide empirical data and more definite criteria for indications of compulsive measures to achieve a common ethical framework for those critical decisions across Europe. [ABSTRACT FROM AUTHOR]

Examines the key features of SOILNDB, a decision support tool for the assessment of nitrogen leaching losses from arable land. Key issues of interest; Analysis of pertinent topics and relevant issues; Implications on environmental modeling and software.

The impact of smoking on survival in patients with squamous cell carcinoma of the head and neck is well established, despite some conflicting data in the literature. However, data on alterations of smoking habit following cancer diagnosis is sparse. In the present study, the effect of reduction of smoking compared with cessation on the course of disease was studied. Data from 643 patients with HNSCC from the tumor documentation registry of the Department of Otorhinolaryngology, Head and Neck Surgery of the Christian-Albrechts-University Kiel were collected and statistically analyzed, looking at pre- and post-treatment smoking habit and survival. Alteration of smoking at the first diagnosis of HNSCC led to a significantly beneficial effect on survival outcomes compared with continued smoking, without significant differences between reduction and cessation of smoking. Detailed analysis revealed that this effect was solely dependent on patients treated by surgery only. Lifelong non-smokers exhibited a significant survival advantage compared with active and former smokers, with no difference in survival between these last two groups. The positive influence of altered smoking habit following first time diagnosis on disease-specific survival paralleled the negative direct effect of active smoking on therapy, which is predominantly attributed to peritumoral tissue hypoxia leading to impaired efficacy of radiochemotherapy (RCT). In the present study cohort, the positive effect of smoking habit alterations were primarily observed in patients treated by surgery only instead of RCT, possibly due to fewer perioperative complications. These findings indicated that patients should be encouraged to at least minimize smoking following cancer diagnosis. Furthermore, for survival estimates and therapy planning, former smokers should be considered as active smokers. [ABSTRACT FROM AUTHOR]

Coronaviruses make use of a large envelope protein called spike (S) to engage host cell receptors and catalyze membrane fusion. Because of the vital role that these S proteins play, they represent a vulnerable target for the development of therapeutics. Here, we describe the isolation of single-domain antibodies (VHHs) from a llama immunized with prefusion-stabilized coronavirus spikes. These VHHs neutralize MERS-CoV or SARS-CoV-1 S pseudotyped viruses, respectively. Crystal structures of these VHHs bound to their respective viral targets reveal two distinct epitopes, but both VHHs interfere with receptor binding. We also show cross-reactivity between the SARS-CoV-1 S-directed VHH and SARS-CoV-2 S and demonstrate that this cross-reactive VHH neutralizes SARS-CoV-2 S pseudotyped viruses as a bivalent human IgG Fc-fusion. These data provide a molecular basis for the neutralization of pathogenic betacoronaviruses by VHHs and suggest that these molecules may serve as useful therapeutics during coronavirus outbreaks. • VHHs isolated from a llama immunized with prefusion-stabilized coronavirus spikes • Structural characterization of VHHs reveals conserved mechanism of neutralization • SARS-CoV-1 S-directed VHH cross-reacts with SARS-CoV-2 S • Bivalent VHH neutralizes SARS-CoV-2 pseudoviruses Using llamas immunized with prefusion-stabilized betacoronavirus spike proteins, Wrapp et al. identify neutralizing cross-reactive single-domain camelid antibodies, which may serve not only as useful reagents for researchers studying the viruses causing MERS, SARS, and COVID-19, but also potential therapeutic candidates. Crystal structures further reveal how these antibodies bind spike proteins to prevent virus entry into cells. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is characterized by autoimmune reactivity against components of the cell's nucleus arising after insufficient removal of dead cells. We used a lupus mouse model induced by the cytotoxic alkane oil pristane to elucidate the impact of ROS on SLE. Pristane-induced lupus was strongly exacerbated in NOX2-deficient (Ncf1**) compared to wild type mice, as seen from elevated levels of antinuclear autoantibodies (ANA), aggravated organ damage, and premature death. We observed a dramatically reduced ability to form neutrophil extracellular traps (NETs) in Ncf1** mice, accompanied by higher levels of inflammatory mediators. Similarly, NET-deficient peptidyl arginine deiminase 4-deficient mice and neutropenic Mcl-1 ΔMyelo mice exhibited higher levels of ANA, which indicates a regulatory function in lupus of NETs and neutrophils, respectively. Furthermore, Ncf1** mice and SLE patients displayed preferential uptake of dead cells into inflammatory monocytes and granulocytes. Treatment of mice with NOX2 activators induced NET formation and ameliorated lupus. Our results show that absence of ROS leads to lupus based on aberrant phagocytosis of dead cell remnants and impaired formation of NETs, which results in uncontrolled release of inflammatory mediators. [ABSTRACT FROM AUTHOR]

The production of reactive oxygen species (ROS) via the oxidative burst has been connected with promotion of inflammation and tissue damage, but in recent years has been implicated in regulation and resolution of inflammation. The aim of this project was to elucidate the impact of the oxidative burst on the development of lupus-like autoimmunity. Lupus was induced by with pristane oil. Ex vivo phagocytosis assays were deployed to assess the uptake of cell debris in ROS deficient mice. The formation of neutrophil extracellular traps (NETs) was analysed by immune fluorescence microscopy. ROS activators were injected into mice to investigate the possible beneficial clinical effects on lupus pathology. Determine the effects neutrophil serine proteases have on the degradation of inflammatory mediators The absence of ROS gives rise to dramatically exacerbated lupus. Aberrant phagocytosis in ROS-deficient animals leading to production of inflammatory mediators, accompanied by diminished pristane-induced but higher spontaneous formation of NETs could be responsible for this phenotype. Treatment with NOX2 agonists ameliorated the clinical course in mice, while application of a ROS scavenger worsened disease outcome. [ABSTRACT FROM AUTHOR]

Using spin-polarized scanning tunneling microscopy and density functional theory we demonstrate the occurrence of a novel type of noncollinear spin structure in Rh/Fe atomic bilayers on Ir(111). We find that higher-order exchange interactions depend sensitively on the stacking sequence. For fcc-Rh/Fe/Ir(111), frustrated exchange interactions are dominant and lead to the formation of a spin spiral ground state with a period of about 1.5 nm. For hcp-Rh/Fe/Ir(111), higher-order exchange interactions favor an up-up-down-down (↑↑↓↓) state. However, the Dzyaloshinskii-Moriya interaction at the Fe/Ir interface leads to a small angle of about 4° between adjacent magnetic moments resulting in a canted ↑↑↓↓ ground state. [ABSTRACT FROM AUTHOR]

The production of reactive oxygen species (ROS) via the oxidative burst has been connected with promotion of inflammation and tissue damage, but in recent years has been implicated in regulation of inflammation. We investigated the effects of ROS on the murine model of lupus and in patients (SLE). Aims The aim of this project was to elucidate the impact of the oxidative burst on the development of lupus-like autoimmunity. Lupus was induced by i.p. injection of pristane oil. Ex vivo phagocytosis assays were deployed to assess the uptake of cell debris in ROS deficient mice. The formation of neutrophil extracellular traps (NETs) was analysed by immune fluorescence microscopy. ROS activators were injected into mice to investigate the possible beneficial clinical effects on lupus pathology. Results The absence of ROS gives rise to dramatically exacerbated lupus. Aberrant phagocytosis in ROS-deficient animals leading to production of inflammatory mediators, accompanied by diminished pristane-induced but higher spontaneous formation of NETs could be responsible for this phenotype. Treatment with NOX2 agonists ameliorated the clinical course in mice, while application of a ROS scavenger worsened disease outcome. A fine-tuned balance of ROS-production is necessary to prevent autoimmunity and to avert the development of lupus in mice and men. [ABSTRACT FROM AUTHOR]

Hyperuricemia is strongly linked to cardiovascular complications including atherosclerosis and thrombosis. In individuals with hyperuricemia, needle-shaped monosodium urate crystals (nsMSU) frequently form within joints or urine, giving rise to gouty arthritis or renal calculi, respectively. These nsMSU are potent instigators of neutrophil extracellular trap (NET) formation. Little is known on the mechanism(s) that prevent nsMSU formation within hyperuricemic blood, which would potentially cause detrimental consequences for the host. Here, we report that complement proteins and fetuins facilitate the continuous clearance by blood-borne phagocytes and resident macrophages of small urate microaggregates (UMA; <1 μm in size) that initially form in hyperuricemic blood. If this clearance fails, UMA exhibit bipolar growth to form typical full-sized nsMSU with a size up to 100 μm. In contrast to UMA, nsMSU stimulated neutrophils to release NETs. Under conditions of flow, nsMSU and NETs formed densely packed DNase I-resistant tophus-like structures with a high obstructive potential, highlighting the importance of an adequate and rapid removal of UMA from the circulation. Under pathological conditions, intravascularly formed nsMSU may hold the key to the incompletely understood association between NET-driven cardiovascular disease and hyperuricemia. [ABSTRACT FROM AUTHOR]

The production of reactive oxygen species (ROS) via the oxidative burst has in the traditional view been connected with promotion of inflammation and tissue damage, but has in recent years also been implicated in regulation of inflammation and protection from autoimmunity. We have investigated the effects of ROS on the autoimmunity in a mouse model of lupus and in patients with systemic lupus erythematosus (SLE). Aims The aim of this project was to elucidate the impact of the oxidative burst on the development of lupus-like autoimmunity in wild type and Ncf1** mice which carry a point mutation in one of the subunits of the phagocyte NADPH oxidase 2 complex that abrogates ROS-production. Lupus was induced by intraperitoneal injection of 0.5 ml pristane oil and the clinical course was compared by analysis of serological markers and organ involvement. Ex vivo phagocytosis assays and flow cytometry were deployed to assess uptake of cell debris in ROS deficient mice. The formation of neutrophil extracellular traps (NETs) was analysed by immune fluorescence microscopy. Potential activators of ROS production were injected into mice to investigate the possible beneficial clinical effects on lupus pathology. Results Our results show that the absence of ROS in Ncf1** mice gives rise to dramatically exacerbated lupus. Aberrant phagocytosis in ROS-deficient animals leading to production of inflammatory mediators, accompanied by diminished pristane-induced but higher spontaneous formation of NETs could be responsible for this phenotype. Treatment of pristane-induced lupus with NOX2 agonists ameliorated the clinical course in BALB/c mice, while application of a ROS scavenger worsened disease outcome. Further, downstream nrf2 signalling was decreased in Ncf1** mice. Patients with SLE showed similar aberrant phagocytosis as in murine lupus, and were characterized by higher spontaneous formation of NETs. A fine-tuned balance of ROS-production is necessary to prevent autoimmunity and to avert the development of lupus in mice and men. [ABSTRACT FROM AUTHOR]

Ebolaviruses are highly pathogenic in humans and nonhuman primates and pose a severe threat to public health. The interferon-induced transmembrane (IFITM) proteins can restrict entry of ebolaviruses, influenza A viruses, and other enveloped viruses. However, the breadth and mechanism of the antiviral activity of IFITM proteins are incompletely understood. Here, we employed ebolavirus glycoprotein-pseudotyped vectors and ebolavirus-like particles to address this question. We show that IFITM proteins inhibit the cellular entry of diverse ebolaviruses and demonstrate that type I interferon induces IFITM protein expression in macrophages, major viral targets. Moreover, we show that IFITM proteins block entry of influenza A viruses and ebolaviruses by different mechanisms and provide evidence that antibodies and IFITM proteins can synergistically inhibit cellular entry of ebolaviruses. These results provide insights into the role of IFITM proteins in infection by ebolaviruses and suggest a mechanism by which antibodies, though poorly neutralizing in vitro, might contribute to viral control in vivo. [ABSTRACT FROM AUTHOR]

The article examines whether porphyrin oligomers will exhibit low attenuation factors when wired between metal electrodes at the single molecule level, by synthesizing a series of porphyrin oligomers with terminal thioacetates to promote gold attachment. Findings show that porphyrin oligomers exhibit ultralow attenuation factors with single molecule conductance.