Diversity in neutrophil biology : from simple foot soldiers to versatile commanders of immunity in infectious diseases

Pathogen clearance in infectious diseases strongly depends on a fine-tuned interplay between innate and adaptive immunity. Undoubtedly, neutrophils as first line defense against invading pathogens play a major role to recognize, phagocytose and kill the invaders. However, the diverse role of neutrophils under inflammatory conditions in infectious diseases has been largely ignored so far. In my PhD thesis, I addressed the implications of the versatile neutrophil functions in immunity encountering pathogenic microorganisms that cause infectious diseases. In particular, experimental approaches with human neutrophils from healthy individuals and from patients suffering from various infectious diseases and immunological disorders, respectively, were combined with a mouse model of Salmonella infection with the help of techniques such as flow cytometry, reverse transcription- polymerase chain reaction (RT-PCR) and proteomics to reveal the so far underestimated diversity in neutrophil function. We showed that “simple foot soldier” neutrophils are important for host defense against bacterial and fungal pathogens. With the help of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and myeloperoxidase (MPO), neutrophils are able to produce large amounts of reactive oxygen species (ROS) that are important for pathogen destruction. We could show that neutrophils from patients receiving allogeneic hematopoietic stem cell transplantations (HSCT) have significantly impaired ROS production against Candida (C.) albicans and Aspergillus (A.) fumigatus. However, ROS can also cause detrimental damage in host tissues. We showed that MPO, one of the key enzymes in ROS production, has a protective role in the host by scavenging diffusible hydrogen peroxide (H2O2) at the Salmonella surface and converting it into highly reactive hypochlorite (HOCl) within a short reach. This sophisticated mechanism of MPO- to confine potential harmful molecules to the pathogen microenvironment- leads to both effective pathogen destruction and minimal collateral host tissue damage. Neutrophils as “versatile commanders” are unambiguously involved in the pathogenesis of sepsis, the dysregulated host response to infection. We could observe that neutrophils and monocytes accumulate neutral lipids during Salmonella infection and change their lipid metabolic program in sepsis comparable to atherosclerosis. Moreover, we identified a subset of antigen-presenting cell (APC)-like neutrophils with major histocompatibility complex (MHC) class II molecule expression, which could be induced under inflammatory conditions. The inflammatory environment triggers highly specific signaling pathways in neutrophils that orchestrate intracellular protein phosphorylation cascades, finally leading to the formation of the MHC class II enhanceosome.   We could show that the MHC class II enhanceosome is responsible for the subsequent MHC class II expression on neutrophils and that targeting Janus kinase (JAK) 1/2 could be a promising therapeutic approach in sepsis to reach homeostasis. Overall, these data show that the immunological function of neutrophils in sepsis is highly versatile and goes far beyond simple pathogen destruction. Together, these data show that infectious disease control implies a specialized, but versatile immune system with diverse neutrophil functionality

Evaluation of a high-resolution regional climate simulation over Greenland

A simulation of the 1991 summer has been performed over south Greenland with a coupled atmosphere–snow regional climate model (RCM) forced by the ECMWF re-analysis. The simulation is evaluated with in-situ coastal and ice-sheet atmospheric and glaciological observations. Modelled air temperature, specific humidity, wind speed and radiative fluxes are in good agreement with the available observations, although uncertainties in the radiative transfer scheme need further investigation to improve the model’s performance. In the sub-surface snow-ice model, surface albedo is calculated from the simulated snow grain shape and size, snow depth, meltwater accumulation, cloudiness and ice albedo. The use of snow metamorphism processes allows a realistic modelling of the temporal variations in the surface albedo during both melting periods and accumulation events. Concerning the surface albedo, the main finding is that an accurate albedo simulation during the melting season strongly depends on a proper initialization of the surface conditions which mainly result from winter accumulation processes. Furthermore, in a sensitivity experiment with a constant 0.8 albedo over the whole ice sheet, the average amount of melt decreased by more than 60%, which highlights the importance of a correctly simulated surface albedo. The use of this coupled atmosphere–snow RCM offers new perspectives in the study of the Greenland surface mass balance due to the represented feedback between the surface climate and the surface albedo, which is the most sensitive parameter in energy-balance-based ablation calculations.Peer reviewe

Immune Reconstitution After Allogeneic Hematopoietic Stem Cell Transplantation and Association With Occurrence and Outcome of Invasive Aspergillosis

Background. Invasive aspergillosis (IA) remains a leading cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). To date, no reliable immunological biomarkers for management and outcome of IA exist. Here, we investigated reconstitution of antifungal immunity in patients during the first 12 months after HSCT and correlated it with IA. Methods. Fifty-one patients were included, 9 with probable/proven IA. We determined quantitative and qualitative reconstitution of polymorphonuclear (PMN), CD4, CD8, and natural killer (NK) cells against Aspergillus fumigatus over 5 time points and compared the values to healthy donors. Results. Absolute CD4 and CD8 cell counts, antigen-specific T-cell responses, and killing capacity of PMN against A. fumigatus were significantly decreased in all patients over 12 months. In patients with probable/proven IA, reactive oxygen species (ROS) production tended to be lower compared to patients without IA, and absolute NK-cell counts remained below 200 cells/µL. Patients with well-controlled IA showed significantly higher ROS production and NK-cell counts compared to patients with poor outcome. Conclusions. This study highlights the importance of functional PMN, T-cell, and NK-cell immunity for the outcome of IA. Larger multicenter studies should address the potential use of NK-cell counts for the management of antifungal therap

Myeloperoxidase targets oxidative host attacks to Salmonella and prevents collateral tissue damage

Host control of infections crucially depends on the capability to kill pathogens with reactive oxygen species (ROS). However, these toxic molecules can also readily damage host components and cause severe immunopathology. Here, we show that neutrophils use their most abundant granule protein, myeloperoxidase, to target ROS specifically to pathogens while minimizing collateral tissue damage. A computational model predicted that myeloperoxidase efficiently scavenges diffusible H2O2 at the surface of phagosomal Salmonella and converts it into highly reactive HOCl (bleach), which rapidly damages biomolecules within a radius of less than 0.1 μm. Myeloperoxidase-deficient neutrophils were predicted to accumulate large quantities of H2O2 that still effectively kill Salmonella, but most H2O2 would leak from the phagosome. Salmonella stimulation of neutrophils from normal and myeloperoxidase-deficient human donors experimentally confirmed an inverse relationship between myeloperoxidase activity and extracellular H2O2 release. Myeloperoxidase-deficient mice infected with Salmonella had elevated hydrogen peroxide tissue levels and exacerbated oxidative damage of host lipids and DNA, despite almost normal Salmonella control. These data show that myeloperoxidase has a major function in mitigating collateral tissue damage during antimicrobial oxidative bursts, by converting diffusible long-lived H2O2 into highly reactive, microbicidal and locally confined HOCl at pathogen surfaces

Unveiling signaling pathways inducing MHC class II expression in neutrophils

IntroductionGram-negative bacillary bacteremia poses a significant threat, ranking among the most severe infectious diseases capable of triggering life-threatening sepsis. Despite the unambiguous involvement of neutrophils in this potentially fatal disease, there are limited data about the molecular signaling mechanisms, phenotype, and function of human neutrophils during the early phase of gram-negative bacillary bacteremia.MethodsBy using an unbiased proteomics and flow cytometry approach, we identified an antigen-presenting cell (APC)-like phenotype in human peripheral blood neutrophils (PMN) with MHC class II molecule expression in the early phase of bacteremia. Using an in-vitro model of GM-CSF-mediated induction of APC-like phenotype in PMN, we investigated downstream signaling pathways leading to MHC class II expression.ResultsGM-CSF stimulation of neutrophils leads to the activation of three major signaling pathways, the JAK-STAT, the mitogen-activated protein kinase (MAPK), and the phosphoinositide 3-kinase (PI3K)-Akt-mTOR pathways, while MHC class II induction is mediated by a MAPK-p38-MSK1-CREB1 signaling cascade and the MHC class II transactivator CIITA in a strictly JAK1/2 kinase-dependent manner.DiscussionThis study provides new insights into the signaling pathways that induce MHC class II expression in neutrophils, highlighting the potential for therapeutic targeting of JAK1/2 signaling in the treatment of gram-negative bacteremia and sepsis. Understanding these mechanisms may open up novel approaches for managing inflammatory responses during sepsis

Bewertung unter Unsicherheit : Herausforderungen bei der Bestimmung des Fair Values von Start-up-Unternehmen

In vielen Bewertungssituationen stossen traditionelle Methoden hinsichtlich ihrer Eignung zur Erfassung der spezifischen Gegebenheiten an Grenzen. Dies ist insbesondere bei hoher ökonomischer und technischer Unsicherheit der Fall. Im folgenden Beitrag wird daher am typischen Beispiel von Jungunternehmen diskutiert, welche Ansätze zu einer Verbesserung der Bewertungsqualität führen können

Venture Capital

Abstract The venture capital industry has seen tremendous growth over the past two decades. However, research provides mixed results for investment outcomes and reveals several methodological challenges and constraints arising from the lack of a comprehensive historical dataset. Strong evidence suggests that a small number of funds perform extremely well, while the majority of venture capital funds underperform public stock markets. Furthermore, academic research points out several distinct determinants of investment outcomes. Various studies, for instance, indicate that performance drivers such as the experience and skills of both the general partners and the limited partners have a strong affect on performance. Additionally, evidence of performance persistence exists as well as of a strong impact of macroeconomic conditions. The venture capital industry exhibits a cyclical pattern or cyclicality characterized by repeated periods of dramatic growth followed by slumps. Yet, whether booms are caused by fundamental factors or whether they constitute an overreaction to perceived investment opportunities is unclear.</jats:p

Venture Capital

Many entrepreneurial businesses require substantial capital in the startup phase. The period needed until a firm can bring its products to the market and generate revenues can take years, particularly in high-tech sectors involving scientific research and a complex development process. Often the founders do not have sufficient resources to finance the startup phase on their own. Thus, they need external financing, which, by nature, is mostly equity capital. Because startup firms face uncertain future prospects and lack a strong track record, they are unlikely to receive debt financing. Thus, venture capitalists are investors specialized in funding young businesses. They help close the gap when conventional financing is inapplicable. This chapter provides an overview of the venture capital market, the financial economies of venture capital, and the special features of venture investing