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Asthma is a chronic respiratory disease of global importance. Mouse models of allergic asthma have been instrumental in advancing research and novel therapeutic strategies for patients. The application of relevant allergens and physiological routes of exposure in such models has led to valuable insights into the complexities of asthma onset and development as well as key disease mechanisms. Furthermore, environmental microbial exposures and infections have been shown to play a fundamental part in asthma pathogenesis and alter disease outcome. In this review, we delve into physiological mouse models of allergic asthma and explore literature reports on most significant interplays between microbial infections and asthma development with relevance to human disease.

Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ nociceptor-MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions.

Water quality indices (WQI) are a useful tool to assess river water pollution. We defined pollution shares (indicating the relative importance of pollutants) from a WQI and studied their dynamics. Using open data from 2012 to 2020 for 105 monitoring stations along river Ganga in India, we fitted systems of generalized Lotka-Volterra (LV) differential equations to these shares. We used autonomous LV-systems (the interaction coefficients were constant) and LV-systems with variable (linear) interaction coefficients. 28 of the 105 stations had sufficient data for these models, whereby for 10 stations the autonomous system fitted well to all timeseries of the eight considered pollutants, and for 9 stations the model with linear interaction coefficients. For them we defined three candidates for “importance-growth indicators”: (a) the interaction coefficients of the autonomous LV-system, (b) the leading coefficient of the interaction coefficient of the system with linear coefficients, and (c) the roots of these linear coefficients. We explored the variability of the indicators and applied them to identify stations with a similar temporal evolution of the pollutants. Further, we suggested applications to wastewater management, as at several stations the indicators (a) and (b) forecasted an increasing relative importance of nitrates/nitrites, which currently pose no problems but finally may require an upgrading of existing wastewater treatment.

Three workshops with representatives of stakeholders from academia, business, civil society and government in India were organized in Chennai, Kolkata, and Mumbai with the aim to identify and elaborate on key barriers to resource recovery in wastewater treatment (WWT). A structured questionnaire was designed to capture the views of participating stakeholders. Using a new Mathematica function, namely, Around, the responses of the representatives of each stakeholder were aggregated to an approximate number representing that stakeholder’s view. Overall, the stakeholder consensus on WWT technologies was rather conservative, with a focus on the functioning of WWT. Concerning the drivers and barriers for resource recovery and policies to support the implementation of recycling technologies in WWT, stakeholders expected government action to drive recycling. A social network analysis identified potential conflicts between the stakeholder groups.

As ACE2 is the critical SARS-CoV-2 receptor, we hypothesized that aerosol administration of clinical grade soluble human recombinant ACE2 (APN01) will neutralize SARS-CoV-2 in the airways, limit spread of infection in the lung, and mitigate lung damage caused by deregulated signaling in the renin-angiotensin (RAS) and Kinin pathways. Here, after demonstrating in vitro neutralization of SARS-CoV-2 by APN01, and after obtaining preliminary evidence of its tolerability and preventive efficacy in a mouse model, we pursued development of an aerosol formulation. As a prerequisite to a clinical trial, we evaluated both virus binding activity and enzymatic activity for cleavage of Ang II following aerosolization. We report successful aerosolization for APN01, retaining viral binding as well as catalytic RAS activity. Dose range-finding and IND-enabling repeat-dose aerosol toxicology testing were conducted in dogs. Twice daily aerosol administration for two weeks at the maximum feasible concentration revealed no notable toxicities. Based on these results, a Phase I clinical trial in healthy volunteers has now been initiated (NCT05065645), with subsequent Phase II testing planned for individuals with SARS-CoV-2 infection.

Despite tremendous progress in the understanding of COVID-19, mechanistic insight into immunological, disease-driving factors remains limited. We generated maVie16, a mouse-adapted SARS-CoV-2, by serial passaging of a human isolate. In silico modeling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. maVie16 induced profound pathology in BALB/c and C57BL/6 mice, and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia, and specific adaptive immunity. Inhibition of the proinflammatory cytokines IFNγ and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo.

Lipocalin 2 (LCN2) is a secreted glycoprotein with roles in multiple biological processes. It contributes to host defense by interference with bacterial iron uptake and exerts immunomodulatory functions in various diseases. Here, we aimed to characterize the function of LCN2 in lung macrophages and dendritic cells (DCs) using Lcn2-/- mice. Transcriptome analysis revealed strong LCN2-related effects in CD103+ DCs during homeostasis, with differential regulation of antigen processing and presentation and antiviral immunity pathways. We next validated the relevance of LCN2 in a mouse model of influenza infection, wherein LCN2 protected from excessive weight loss and improved survival. LCN2-deficiency was associated with enlarged mediastinal lymph nodes and increased lung T cell numbers, indicating a dysregulated immune response to influenza infection. Depletion of CD8+ T cells equalized weight loss between WT and Lcn2-/- mice, proving that LCN2 protects from excessive disease morbidity by dampening CD8+ T cell responses. In vivo T cell chimerism and in vitro T cell proliferation assays indicated that improved antigen processing by CD103+ DCs, rather than T cell intrinsic effects of LCN2, contribute to the exacerbated T cell response. Considering the antibacterial potential of LCN2 and that commensal microbes can modulate antiviral immune responses, we speculated that LCN2 might cause the observed influenza phenotype via the microbiome. Comparing the lung and gut microbiome of WT and Lcn2-/- mice by 16S rRNA gene sequencing, we observed profound effects of LCN2 on gut microbial composition. Interestingly, antibiotic treatment or co-housing of WT and Lcn2-/- mice prior to influenza infection equalized lung CD8+ T cell counts, suggesting that the LCN2-related effects are mediated by the microbiome. In summary, our results highlight a novel regulatory function of LCN2 in the modulation of antiviral immunity.

As the assessment of the economic, environmental, institutional, and social sustainability of wastewater treatment systems may have several conceivable goals and intended recipients, there are numerous different approaches. This paper surveys certain aspects of sustainability assessment that may be of interest to the planners of wastewater treatment systems. Here, the key criteria assess the system’s costs and financing, including its affordability for the users, the environmental impact, the benefits for health and hygiene, the cultural acceptance of the system and its recycled products, the technical functioning, and the administrative, political, and legal framework for its construction and operation. A multi-criteria approach may then be used to analyze possible trade-offs and identify the most suitable system for a certain location.

BackgroundIgE antibodies play a paramount role in the pathogenesis of various intestinal disorders. To gain insights in IgE-mediated pathophysiology of the gut, we investigated the expression of the high affinity IgE receptor Fc epsilonRI in human intestinal epithelium.Methodology/principal findingsFc epsilonRI alpha-chain, as detected by immunohistochemistry, was positive in epithelial cells for eight of eleven (8/11) specimens from colon cancer patients and 5/11 patients with inflammation of the enteric mucosa. The Fc epsilonRIalpha positive epithelial cells co-expressed Fc epsilonRIgamma, whereas with one exception, none of the samples was positive for the beta-chain in the epithelial layer. The functionality of Fc epsilonRI was confirmed in situ by human IgE binding. In experiments with human intestinal tumor cell lines, subconfluent Caco-2/TC7 and HCT-8 cells were found to express the alpha- and gamma-chains of Fc epsilonRI and to bind IgE, whereas confluent cells were negative for gamma-chains.Conclusions/significanceOur data provide the first evidence that the components of a functional Fc epsilonRI are in vitro expressed by the human intestinal epithelial cells depending on differentiation and, more importantly, in situ in epithelia of patients with colon cancer or gastrointestinal inflammations. Thus, a contribution of Fc epsilonRI either to immunosurveillance or pathophysiology of the intestinal epithelium is suggested.

BackgroundIgE antibodies play a paramount role in the pathogenesis of various intestinal disorders. To gain insights in IgE-mediated pathophysiology of the gut, we investigated the expression of the high affinity IgE receptor Fc epsilonRI in human intestinal epithelium.Methodology/principal findingsFc epsilonRI alpha-chain, as detected by immunohistochemistry, was positive in epithelial cells for eight of eleven (8/11) specimens from colon cancer patients and 5/11 patients with inflammation of the enteric mucosa. The Fc epsilonRIalpha positive epithelial cells co-expressed Fc epsilonRIgamma, whereas with one exception, none of the samples was positive for the beta-chain in the epithelial layer. The functionality of Fc epsilonRI was confirmed in situ by human IgE binding. In experiments with human intestinal tumor cell lines, subconfluent Caco-2/TC7 and HCT-8 cells were found to express the alpha- and gamma-chains of Fc epsilonRI and to bind IgE, whereas confluent cells were negative for gamma-chains.Conclusions/significanceOur data provide the first evidence that the components of a functional Fc epsilonRI are in vitro expressed by the human intestinal epithelial cells depending on differentiation and, more importantly, in situ in epithelia of patients with colon cancer or gastrointestinal inflammations. Thus, a contribution of Fc epsilonRI either to immunosurveillance or pathophysiology of the intestinal epithelium is suggested.

From birth onward, the lungs are exposed to the external environment and therefore harbor a complex immunological milieu to protect this organ from damage and infection. We investigated the homeostatic role of the epithelium-derived alarmin interleukin-33 (IL-33) in newborn mice and discovered the immediate upregulation of IL-33 from the first day of life, closely followed by a wave of IL-13-producing type 2 innate lymphoid cells (ILC2s), which coincided with the appearance of alveolar macrophages (AMs) and their early polarization to an IL-13-dependent anti-inflammatory M2 phenotype. ILC2s contributed to lung quiescence in homeostasis by polarizing tissue resident AMs and induced an M2 phenotype in transplanted macrophage progenitors. ILC2s continued to maintain the M2 AM phenotype during adult life at the cost of a delayed response to Streptococcus pneumoniae infection in mice. These data highlight the homeostatic role of ILC2s in setting the activation threshold in the lung and underline their implications in anti-bacterial defenses.

TNFSF14 (LIGHT) contributes to airway inflammation and remodelling. Here the authors show that TNFSF14 acting on its receptor TNFRSF14 on mast cells enhances their IgE-dependent activation and that interference with this pathway attenuates features of asthma pathology in mice.

Physicians think of mast cells and IgE primarily in the context of allergic disorders, including fatal anaphylaxis. This ‘bad side’ of mast cells and IgE is so well accepted that it can be difficult to think of them in other contexts, particularly those in which they may have beneficial functions. However, there is evidence that mast cells and IgE, as well as basophils (circulating granulocytes whose functions partially overlap with those of mast cells), can contribute to host defense as components of adaptive type 2 immune responses to helminths, ticks and certain other parasites. Accordingly, allergies often are conceptualized as “misdirected” type 2 immune responses, in which IgE antibodies are produced against any of a diverse group of apparently harmless antigens, as well as against components of animal venoms. Indeed, certain unfortunate patients who have become sensitized to venoms develop severe IgE-associated allergic reactions, including fatal anaphylaxis, upon subsequent venom exposure. In this review, we will describe evidence that mast cells can enhance innate resistance to reptile or arthropod venoms during a first exposure to such venoms. We also will discuss findings indicating that, in mice which survive an initial encounter with venom, acquired type 2 immune responses, IgE antibodies, the high affinity IgE receptor (FcɛRI), and mast cells can contribute to acquired resistance to the lethal effects of both honeybee venom and Russell's viper venom. These findings support the hypothesis that mast cells and IgE can help protect the host against venoms and perhaps other noxious substances.

Recent concerns about alleged insufficient water provision to the poor in Detroit, USA, has put the Human Right to Water (HRW) into the international discussion. The paper asks: “To what extent did international human rights treaties make HRW judiciable?” and “How did government policies implement it?” In a cross-country comparison of performance indicators, merely accepting HRW has not been helpful in promoting affordable access to potable water or sanitation facilities close to the home, amongst the reasons being deficiencies in water-governance. Case-law confirmed that with respect to affordable access HRW obliges governments to a “progressive realization” only, also in countries accepting HRW (India, South Africa). The paper focuses on the resulting positive state obligation to establish funding programs for better water and sanitation services and analyzes funding policies by a mathematical model of policy goals. It identifies two viable goals namely the successful support for the poor, as in developing countries, and the most economic use of public funds, as in industrialized countries. Other goals conceivable for the model have been tried in the past and failed.

When flowing through Hyderabad, the capital of Telangana, India, the Musi River picks up (partially) treated and untreated sewage from the city. Downstream of the city, farmers use this water for the irrigation of rice and vegetables. Treatment of the river water before it is used for irrigation would address the resulting risks for health and the environment. To keep the costs and operational efforts low for the farmers, the use of constructed wetlands is viewed as a suitable option. Towards this end, the paper investigates the interests and perceptions of government stakeholders and famers on the treatment of wastewater for irrigation and further explores the consumer willingness to pay a higher price for cleaner produced vegetables. Full cost recovery from farmers and consumers cannot be expected, if mass scale treatment of irrigation water is implemented. Instead, both consumers and farmers would expect that the government supports treatment of irrigation water. Most stakeholders associated with the government weigh health and environment so high, that these criteria outweigh cost concerns. They also support the banning of irrigation with polluted water. However, fining farmers for using untreated river water would penalize them for pollution caused by others. Therefore public funding of irrigation water treatment is recommended.

The objective of this study is to bring out the policy changes with respect to managed aquifer recharge (focusing on infiltration ponds), which in the view of relevant stakeholders may ease the problem of groundwater depletion in the context of Chennai City; Tamil Nadu; India. Groundwater is needed for the drinking water security of Chennai and overexploitation has resulted in depletion and seawater intrusion. Current policies at the municipal; state and national level all support recharge of groundwater and rainwater harvesting to counter groundwater depletion. However, despite such favorable policies, the legal framework and the administrative praxis do not support systematic approaches towards managed aquifer recharge in the periphery of Chennai. The present study confirms this, considering the mandates of governmental key-actors and a survey of the preferences and motives of stakeholder representatives. There are about 25 stakeholder groups with interests in groundwater issues, but they lack a common vision. For example, conflicting interest of stakeholders may hinder implementation of certain types of managed aquifer recharge methods. To overcome this problem, most stakeholders support the idea to establish an authority in the state for licensing groundwater extraction and overseeing managed aquifer recharge.

Gouty arthritis is caused by the deposition of monosodium urate (MSU) crystals in joints. Despite many treatment options for gout, there is a substantial need for alternative treatments for patients unresponsive to current therapies. Tyrosine kinase inhibitors have demonstrated therapeutic benefit in experimental models of antibody-dependent arthritis and in rheumatoid arthritis in humans, but to date, the potential effects of such inhibitors on gouty arthritis has not been evaluated. Here we demonstrate that treatment with the tyrosine kinase inhibitor imatinib mesylate (imatinib) can suppress inflammation induced by injection of MSU crystals into subcutaneous air pouches or into the ankle joint of wild type mice. Moreover, imatinib treatment also largely abolished the lower levels of inflammation which developed in IL-1R1-/- or KitW-sh/W-sh mice, indicating that this drug can inhibit IL-1-independent pathways, as well as mast cell-independent pathways, contributing to pathology in this model. Imatinib treatment not only prevented ankle swelling and synovial inflammation when administered before MSU crystals but also diminished these features when administrated after the injection of MSU crystals, a therapeutic protocol more closely mimicking the clinical situation in which treatment occurs after the development of an acute gout flare. Finally, we also assessed the efficiency of local intra-articular injections of imatinib-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles in this model of acute gout. Treatment with low doses of this long-acting imatinib:PLGA formulation was able to reduce ankle swelling in a therapeutic protocol. Altogether, these results raise the possibility that tyrosine kinase inhibitors might have utility in the treatment of acute gout in humans.

Based on experiences about the planning of decentralized wastewater treatment systems for slums of two rural towns in India, the paper asks to what extent affordability for the future users may impede the realization of other sustainability goals. The planning aimed at ensuring economic, social, and environmental sustainability. To this end the planning process promoted the participation of stakeholders and it was supplemented by an in-depth analysis (using novel methods) of the socio-economic situation of the future users. In particular, an approach towards estimating willingness to pay from small samples was developed. Taking all this information into account, planning identified a well-established technology that it is inexpensive, robust, and easy to maintain. The experiences of this planning process may generalize to other developing countries seeking socially acceptable low cost solutions with reasonable pollution reduction for resolving the sanitation crisis.

Often centralized water supply, sanitation and solid waste services struggle to keep up with the rapid expansion of urban areas. The peri-urban areas are at the forefront of this expansion and it is here where decentralized technologies are increasingly being implemented. The introduction of decentralized technologies allows for the development of new opportunities that enable the recovery and reuse of resources in the form of water, nutrients and energy. This resource-oriented management of water, nutrients and energy requires a sustainable system aimed at low resource use and high recovery and reuse rates. Instead of investigating each sector separately, as has been traditionally done, this article proposes and discusses a concept that seeks to combine the in- and outflows of the different sectors, reusing water and other liberated resources where possible. This paper shows and demonstrates examples of different types of sustainable technologies that can be implemented in the peri-urban areas of Mexico City [rainwater harvesting, EcoSan and biofiltros (small constructed wetlands), and (vermi-)composting]. An innovative participatory planning method, combining scenario development with a participatory planning workshop with key stakeholders, was applied and resulted in three concept scenarios. Specific technologies were then selected for each concept scenario that the technical feasibility and applicability was assessed. Following this, the resulting resource flows (nutrients, water and energy) were determined and analyzed. The results show that decentralized technologies not only have the potential to deliver adequate water supply, sanitation and solid waste services in peri-urban areas and lessen environmental pollution, but also can recover significant amounts of resources thereby saving costs and providing valuable inputs in, for instance, the agricultural sector. Social acceptance of the technologies and institutional cooperation, however, is key for successful implementation.

Often centralized water supply, sanitation and solid waste services struggle to keep up with the rapid expansion of urban areas. The peri-urban areas are at the forefront of this expansion and it is here where decentralized technologies are increasingly being implemented. The introduction of decentralized technologies allows for the development of new opportunities that enable the recovery and reuse of resources in the form of water, nutrients and energy. This resource-oriented management of water, nutrients and energy requires a sustainable system aimed at low resource use and high recovery and reuse rates. Instead of investigating each sector separately, as has been traditionally done, this article proposes and discusses a concept that seeks to combine the in- and outflows of the different sectors, reusing water and other liberated resources where possible. This paper shows and demonstrates examples of different types of sustainable technologies that can be implemented in the peri-urban areas of Mexico City [rainwater harvesting, EcoSan and biofiltros (small constructed wetlands), and (vermi-)composting]. An innovative participatory planning method, combining scenario development with a participatory planning workshop with key stakeholders, was applied and resulted in three concept scenarios. Specific technologies were then selected for each concept scenario that the technical feasibility and applicability was assessed. Following this, the resulting resource flows (nutrients, water and energy) were determined and analyzed. The results show that decentralized technologies not only have the potential to deliver adequate water supply, sanitation and solid waste services in peri-urban areas and lessen environmental pollution, but also can recover significant amounts of resources thereby saving costs and providing valuable inputs in, for instance, the agricultural sector. Social acceptance of the technologies and institutional cooperation, however, is key for successful implementation.

Nitration of proteins on tyrosine residues, which can occur due to polluted air under "summer smog" conditions, has been shown to increase the allergic potential of allergens. Since nitration of tyrosine residues is also observed during inflammatory responses, this modification could directly influence protein immunogenicity and might therefore contribute to food allergy induction. In the current study we have analyzed the impact of protein nitration on sensitization via the oral route.BALB/c mice were immunized intragastrically by feeding untreated ovalbumin (OVA), sham-nitrated ovalbumin (snOVA) or nitrated ovalbumin (nOVA) with or without concomitant acid-suppression. To analyze the impact of the sensitization route, the allergens were also injected intraperitoneally. Animals being fed OVA or snOVA under acid-suppressive medication developed significantly elevated levels of IgE, and increased titers of specific IgG1 and IgG2a antibodies. Interestingly, oral immunizations of nOVA under anti-acid treatment did not result in IgG and IgE formation. In contrast, intraperitoneal immunization induced high levels of OVA specific IgE, which were significantly increased in the group that received nOVA by injection. Furthermore, nOVA triggered significantly enhanced mediator release from RBL cells passively sensitized with sera from allergic mice. Gastric digestion experiments demonstrated protein nitration to interfere with protein stability as nOVA was easily degraded, whereas OVA and snOVA remained stable up to 120 min. Additionally, HPLC-chip-MS/MS analysis showed that one tyrosine residue (Y(107)) being very efficiently nitrated is part of an ovalbumin epitope recognized exclusively after oral sensitization.These data indicated that despite the enhanced triggering capacity in existing allergy, nitration of OVA may be associated with a reduced de novo sensitizing capability via the oral route due to enhanced protein digestibility and/or changes in antibody epitopes.

IgE antibodies play a paramount role in the pathogenesis of various intestinal disorders. To gain insights in IgE-mediated pathophysiology of the gut, we investigated the expression of the high affinity IgE receptor Fc epsilonRI in human intestinal epithelium.Fc epsilonRI alpha-chain, as detected by immunohistochemistry, was positive in epithelial cells for eight of eleven (8/11) specimens from colon cancer patients and 5/11 patients with inflammation of the enteric mucosa. The Fc epsilonRIalpha positive epithelial cells co-expressed Fc epsilonRIgamma, whereas with one exception, none of the samples was positive for the beta-chain in the epithelial layer. The functionality of Fc epsilonRI was confirmed in situ by human IgE binding. In experiments with human intestinal tumor cell lines, subconfluent Caco-2/TC7 and HCT-8 cells were found to express the alpha- and gamma-chains of Fc epsilonRI and to bind IgE, whereas confluent cells were negative for gamma-chains.Our data provide the first evidence that the components of a functional Fc epsilonRI are in vitro expressed by the human intestinal epithelial cells depending on differentiation and, more importantly, in situ in epithelia of patients with colon cancer or gastrointestinal inflammations. Thus, a contribution of Fc epsilonRI either to immunosurveillance or pathophysiology of the intestinal epithelium is suggested.

The paper presents a special class of embedding problems whoes solutions are important for the explicit solution of nonlinear partial differential equations. It is shown that these embedding problems are solvable and explicit solutions are given. Not only are the solutions new but also the mathematical framework of their construction which is defined by a nonstandard function theory built over nonstandard algebraical structures, denoted as “GAPs”. These GAPs must not be neither associative nor division algebras, but the corresponding function theories built over them preserve the most important symmetries from the classical complex function theory in a generalized form: a generalization of the Cauchy-Riemannian differential equations exists as well as a generalization of the classical Cauchy Integral Theorem.

There is one mistake in this article [1]. On page 753, line 12, the phrase “(application load of 80 tons/ha)” should be “(application load of 80 kg/ha)”.