Model-based identification and testing of appropriate strategies to minimize N2O emissions from biofilm deammonification

Based on a one-year pilot plant operation of a two-step biofilm nitritation-anammox pilot plant, N2O mitigation strategies were identified by applying a newly developed biofilm modeling approach. Due to adapted plant operation, the N2O emission could be diminished by 75% (8.8% → 2.3% of NH4-Noxidized_AOB). The results (measurement and simulation) confirm the huge importance of denitrification as an N2O source or N2O sink, depending on the boundary conditions. A significant reduction of N2O emissions could only be achieved with a one-step deammonification system, which is related to low nitrite and HNO2 concentrations. Increased oxygen concentrations in the bulk phase are not related to decreased emissions. N2O formation by ammonium-oxidizing bacteria (AOB) just shifts deeper into the biofilm; zones with low oxygen concentrations are not avoidable in biofilm systems. Low oxygen concentrations in the bulk phase, however, result in a reduction of the total net N2O formation due to increased activity of heterotrophic bacteria directly at the source of N2O formation (outer biofilm layer). For the model-based identification of mitigation strategies, the standard modeling approaches for biofilms were expanded by including the factor-based N2O formation and emission approach. The new model 'Biofilm/N2OISAH' was successfully validated using data from pilot-scale measurement campaigns. Altogether, the investigation confirms that the employed digital model can strongly support the development of N2O mitigation strategies without the need for specialized measurement inside the biofilm

Model assisted identification of N2O mitigation strategies for full-scale reject water treatment plants

In a 3-year research project, a new approach to forecast biological N2O formation and emission at high-strength reject water treatment has been developed (ASM3/1_N2OISAH). It was calibrated by extensive batch-tests and finally evaluated by long-term measurement campaigns realized at three wastewater treatment plants (WWTPs) with different process configurations for nitrogen removal of reject water. To enable a model application with common full-scale data, the nitritation-connected supplementary processes that are responsible for N2O formation are not depicted in the model. Instead, within the new model approach the N2O formation is linked to the NH4-N oxidation rate by defining specific formation factors [N2O-Nform/NH4-Nox], depending on the concentrations of NO2 and O2 as well as the NH4 load. A comparison between the measured and the modeled N2O concentrations in the liquid and gas phase at the full-scale treatment plants prove the ability of the proposed modelling approach to represent the observed trends of N2O formation, emission and reduction using the standard parameter set of kinetics and formation factors. Thus, enabling a reliable estimation of the N2O emissions for different operational conditions. The measurements indicate that a formation of N2O by AOB cannot completely be avoided. However, a considerable reduction of the formed N2O was observed in an anoxic environment. Applying the model, operational settings and mitigation strategies can now be identified without extensive measurement campaigns. For further enhancement of the model, first results for kinetics of N2O reduction kinetics by denitrification processes were determined in laboratory-scale batch tests

Nasu-Hakola disease (PLOSL) : report of five cases and review of the literature

The combination of bilateral lytic lesions in the bones of the lower and upper extremities and presenile dementia is characteristic of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, also known as Nasu-Hakola disease. The clinical course of this rare and fatal disorder is characterized by pathologic fractures of these often painful lesions, rapid progression of dementia, and death in the fifth decade of life. The radiographic changes may be confused with cystic angiomatosis, focal metastasizing hemangioendothelioma, or Langerhans\u27; cell histiocytosis. We report five patients to illustrate the clinical presentation, radiographic images, psychiatric abnormalities, and new genetic findings. Three of the patients were siblings. A biopsy is not needed to confirm the diagnosis of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy because of the unique combination of radiographic and neurologic features

Modulation der Immunogenität von HPV-16 L1/E7 Chimären Virus-ähnlichen Partikeln

High-risk Papillomviren des Menschen (z.B. HPV16) stellen das ätiologische Agens von Gebärmutterhalskrebs (Zervixkarzinom) und dessen Vorstufen dar. Das Zervixkarzinom ist weltweit der dritt häufigsten Krebs bei Frauen. Trotz chirurgischer Entfernung des Tumors und einer anschließenden Kombination aus Strahlen- und Chemotherapie entwickeln 35% der Patientinnen Rezidive, für die heute keine effektive Therapie existiert. In der Pathogenese von HPV-assoziierten zervikalen Läsionen spielt die zelluläre Immunantwort eine große Rolle, was die Möglichkeit einer therapeutischen Vakzinierung bietet, welche die Progression von HPV-assoziierten Läsionen verhindern und eine Regression der Läsionen bedingen sollte. Einen potentiellen therapeutischen Impfstoff stellen HPV16 chimäre virus-like particles (CVLPs) dar, bestehend aus dem C-terminalen verkürzten Hauptkapsidprotein L1 und Teilen des E7 Proteins (HPV16L1CE7). E7 ist in Zervixkarzinomzellen konstitutiv exprimiert und wird deshalb als potentielles Tumorantigen angesehen. CVLPs erwiesen sich in präklinischen Studien als immunogen, doch eine noch nicht abgeschlossene klinische Studie zeigte, dass die Immunogenität von CVLPs beim Menschen noch verbessert werden muß. In dieser Arbeit sollte daher die Immunogenität von CVLPs im Maus-Modell moduliert werden, um so möglicherweise auch Verbesserungsansätze für die Anwendung beim Menschen zu schaffen. Dazu wurden Dendritische Zellen (DCs) aus dem Knochenmark der Mäuse (BMDCs) präpariert und mit CVLPs entweder als Immunkomplexe (CVLP-ICs) oder in Kombination mit unmethylierten Cytidin-Phosphat-Guanosin Oligodinukleotiden (CpG ODNs) beladen. Zudem wurden CVLP-beladene BMDCs durch Sorbitol hyperosmotischem Streß ausgesetzt, eine Methode, die in dieser Arbeit erstmalig beschrieben wird. Obwohl CVLP-ICs ähnlich wie CVLPs BMDCs zur Reifung induzieren konnten, stellten sie sich im Gegensatz zu CVLPs sowohl bei der cross Präsentation wie auch bei der Generierung von zytotoxischen T-Lymphozyten auch bei geringen Mengen als sehr immunogen heraus. Dieser Unterschied beruht nicht auf der Nutzung unterschiedlicher MHC Klasse I Präsentationswege, da beide Antigene in einen gemeinsamen, ungewöhnlichen Weg eingeschleust wurden, welcher transporter of antigen presentation (TAP)-unabhängig, jedoch Brefeldin A-sensitiv war. CpG ODNs konnten die Immunogenität der CVLPs verbessern, allerdings nur dann, wenn sie vier Stunden nach CVLP-Beladung auf BMDCs geladen wurden. Die Sorbitol-Behandlung führte bei CVLP-beladenen BMDCs ebenfalls zu einer Steigerung der Immunogenität. BMDCs erwiesen sich nicht nur als Bestandteil der Methoden zur Überprüfung der Immunogenität als sehr effizient, sondern auch als ‚nature’s adjuvans‘ und führten so ebenfalls zu einer Verbesserung der Immunogenität der CVLPs. Dabei wurden Mäuse mit BMDCs immunisiert, die ex vivo mit CVLPs, CVLP-ICs bzw. CVLPs in Kombination mit CpG ODNs beladen wurden bzw. mit CVLPs beladen und dann mit Sorbitol behandelt wurden. Die hier im Maus-Modell gezeigten Strategien zur Verbesserung der Immunogenität von CVLPs könnten möglicherweise auch beim Menschen Anwendung finden und so eine effektive therapeutische Vakzinierung gegen das Zervixkarzinom und seine Vorstufen darstellen

Discrete dynamic pricing and application of network revenue management for FlixBus

We consider a real discrete pricing problem in network revenue management for FlixBus. We improve the company's current pricing policy by an intermediate optimization step using booking limits from standard deterministic linear programs. We pay special attention to computational efficiency. FlixBus' strategic decision to allow for low-cost refunds might encourage large group bookings early in the booking process. In this context, we discuss counter-intuitive findings comparing booking limits with static bid price policies. We investigate the theoretical question whether the standard deterministic linear program for network revenue management does provide an upper bound on the optimal expected revenue if customer's willingness to pay varies over time

Alopecia Areata Susceptibility in Rodent Models

With our current view of alopecia areata as an autoimmune disease, it is probable that disease development in an individual is dependent on multiple genetic and environmental factors interacting in a complex system. Rodent models afford the opportunity to investigate alopecia areata development and to define the significance of the different factors involved. Recently, rodent model characterization has been conducted using flow cytometry, microarray analysis, and functional studies. From these a pattern of events in alopecia areata development has emerged. Although the preliminary activation events for the onset of alopecia areata remain unknown, the response of the immune system is characterized by antigen presentation and costimulation of lymphocytes in the lymph nodes and skin, a deficiency of CD4+/CD25+ regulatory cells, and an action of activated lymphocytes on hair follicles via Fas/FasL signaling and cytokines. Thus, onset of disease may require appropriate (or inappropriate) expression of stimulatory antigens within the hair follicle, the breakdown of the putative hair follicle immune privilege, the presentation of antigens to the immune system, a failure of immune system regulation, and the ability of the activated immune system to disrupt anagen-stage hair follicles. Once the sequence of events is initiated, it may become a self-perpetuating cycle, with epitope spreading leading to a wider range of targets in chronic alopecia areata. Rodent model studies have provided significant insight into alopecia areata, but much more remains to be explained about the mechanisms of disease development

Alopecia Areata: Treatment of Today and Tomorrow

It is the aim of this article to review and appraise available data on treatments for alopecia areata (AA) according to the demands of evidence based medicine. Studies evaluating the efficacy of a treatment for AA should include appropriate controls, use cosmetically acceptable hair regrowth as a parameter for treatment success, include patients with AA totalis, universalis or extensive patchy AA, and exclude patients suffering from AA for less than 3 months. Moreover, the treatment must be safe over a prolonged period of time. Among the various therapeutic approaches presently available for AA, only treatment with contact sensitizers such as diphenylcyclopropenone or squaric acid dibutylester has been shown to be effective in studies that fulfill these criteria.Improved future treatments may be immunosup-pressive or immunomodulatory targeting of the autoimmune pathogenesis of AA, or they may otherwise protect hair follicles from the injurious effects of inflammation. Such possible future therapeutic approaches include the incorporation of immunomodulatory agents into liposomes as an improved vehicle; inhibition of apoptosis mediated by the Fas-FasL system; inhibition of the lymphocyte homing receptor CD44v10; induction of tolerance

Overexpression of IL-1α in Skin Differentially Modulates the Immune Response to Scarification with Vaccinia Virus

Transepidermal inoculation of vaccinia virus (VV), or scarification, has been used effectively for the induction of specific and long-lasting immunity to smallpox and is superior to other routes of immunization. Scarification of individuals with atopic skin disease or immune deficiency, however, can lead to persistent viral replication and result in significant morbidity and mortality. These effects of scarification presumably reflect the unique immunological properties of skin and the immune cells resident in, or recruited to, the site of inoculation. To explore these phenomena, we utilized transgenic mice engineered to overexpress IL-1α, a critical mediator of cutaneous inflammation, in the epidermis. Following scarification with VV, both transgenic and wild-type mice develop local pox. At high doses of VV, IL-1α transgenic mice recruited immune cells to the inoculation site more rapidly and demonstrated enhanced T-cell and humoral immune responses. At limiting doses, however, IL-1α transgenic mice could effectively control virus replication without formation of pox lesions or activation of a memory response. This study suggests that IL-1 might be useful as an adjuvant to enhance antiviral immunity and promote safer vaccination strategies; however, understanding the balance of IL-1 effects on innate and adaptive immune functions will be critical to achieve optimal results

Treatment with an Anti-CD44v10-Specific Antibody Inhibits the Onset of Alopecia Areata in C3H/HeJ Mice

A murine CD44v10-neutralizing antibody has been reported to impair delayed-type hypersensitivity reactions. Because alopecia areata is characterized by a delayed-type hypersensitivity-like T cell mediated immune response, we addressed the question whether an anti-CD44v10-antibody influences the onset of alopecia areata. Therefore, we used the C3H/HeJ mouse model with the induction of alopecia areata in unaffected mice by the grafting of lesional alopecia areata mouse skin. Six grafted mice were injected (intraperitoneally) with anti-CD44v10, six grafted mice with anti-CD44standard, and six with phosphate-buffered saline only. After 11 wk phosphate-buffered saline injected animals on average had developed alopecia areata on 36.8% of their body. The onset of hair loss was slightly delayed and its extent reduced to 17.2% of their body in anti-CD44standard-treated mice. By contrast, five of six anti-CD44v10-treated mice did not show any hair loss and one mouse developed alopecia areata on only 1% of the body. Immunohistochemical examination revealed a marked reduction of perifollicular CD8+ lymphocytes and, to a lesser degree, CD4+ cells as well as a decreased expression of major histocompatibility complex class I on hair follicle epithelium in anti-CD44v10-treated mice as compared with phosphate-buffered saline or anti-CD44 standard-treated mice. Our data show that anti-CD44v10 is able to inhibit the onset of alopecia areata in C3H/HeJ mice. This might be accomplished by an anti-CD44v10-triggered impairment of immune cell homing (e.g., CD8+ T cells), resulting in a decrease of their number in target tissues

Sequential Combination Therapy Leading to Sustained Remission in a Patient with SAPHO Syndrome

The SAPHO syndrome represents a variety of clinically similar disorders with the key features of hyperostotic bone lesions in combination with chronic pustular skin disease. The respective pathophysiology of bone and joint manifestations in SAPHO syndrome is still a matter of discussion. For example it does not appear to represent reactive arthritis and HLA B27 antigen, with the latter being typically present in patients with spondyloarthopathies. Treatment of SAPHO syndrome is also not well established and consists of various antiinflammatory and antirheumatic drugs. Here, we report a female patient with active SAPHO syndrome suffering from sternal swelling of unknown origin that had been known for 10 years and a 4-year-history of severe lower back pain. Remarkable were also a typical pustulous palmar erythema associated with swelling and decreased motility of both MCP-I joints. Inflammation parameters were high with an ESR 68 mm/1st hour and a CRP of 19.6 mg/l. She was initially treated with rofecoxib and doxycycline, followed by sulfasalazine with only partial clinical response. Thereafter, both articular symptoms as well as cutaneous lesions responded well to a combination therapy with methotrexate and sulfasalazine. Thus, the case illustrates nicely that methotrexate in combination with another DMARD can be successfully applied to patients with long-term active SAPHO syndrome