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University hospital research
(2019)
Vogler, Meike ; Shanmugalingam, Senthan ; Särchen, Vinzenz ; Reindl, Lisa Marie ; Grèze, Victoria ; Buchinger, Leon ; Kühn, Michael ; Ullrich, Evelyn
Due to their physiological role in removing damaged cells, natural killer (NK) cells represent ideal candidates for cellular immunotherapy in the treatment of cancer. Thereby, the cytotoxicity of NK cells is regulated by signals on both, the NK cells as well as the targeted tumor cells, and the interplay and balance of these signals determine the killing capacity of NK cells. One promising avenue in cancer treatment is therefore the combination of NK cell therapy with agents that either help to increase the killing capacity of NK cells or sensitize tumor cells to an NK cell-mediated attack. In this mini-review, we present different strategies that can be explored to unleash the potential of NK cell immunotherapy. In particular, we summarize how modulation of apoptosis signaling within tumor cells can be exploited to sensitize tumor cells to NK cell-mediated cytotoxicity.
Unmasking a temperature-dependent effect of the P. anserina i-AAA protease on aging and development
(2011)
Different molecular pathways involved in maintaining mitochondrial function are of fundamental importance to control cellular homeostasis. Mitochondrial i-AAA protease is part of such a surveillance system, and PaIAP is the putative ortholog in the fungal aging model Podospora anserina. Here, we investigate the role of PaIAP in aging and development. Deletion of the gene encoding PaIAP resulted in a specific phenotype. When incubated at 27°C, spore germination and fruiting body formation are not different from that of the corresponding wild-type strain. Unexpectedly, the lifespan of the deletion strain is strongly increased. In contrast, cultivation at an elevated temperature of 37°C leads to impairments in spore germination and fruiting body formation and to a reduced lifespan. The higher PaIAP abundance in wild-type strains of the fungus grown at elevated temperature and the phenotype of the deletion strain unmasks a temperature-related role of the protein. The protease appears to be part of a molecular system that has evolved to allow survival under changing temperatures, as they characteristically occur in nature.
Pletz, Mathias W. ; Jensen, Andreas Vestergaard ; Bahrs, Christina ; Davenport, Claudia ; Rupp, Jan ; Witzenrath, Martin ; Barten-Neiner, Grit ; Kolditz, Martin ; Dettmer, Sabine ; Chalmers, James D. ; Stolz, Daiana ; Suttorp, Norbert ; Aliberti, Stefano ; Kübler, Wolfgang Michael ; Rohde, Gernot Gerhard Ulrich
Introduction: Despite improvements in medical science and public health, mortality of community-acquired pneumonia (CAP) has barely changed throughout the last 15 years. The current SARS-CoV-2 pandemic has once again highlighted the central importance of acute respiratory infections to human health. The “network of excellence on Community Acquired Pneumonia” (CAPNETZ) hosts the most comprehensive CAP database worldwide including more than 12,000 patients. CAPNETZ connects physicians, microbiologists, virologists, epidemiologists, and computer scientists throughout Europe. Our aim was to summarize the current situation in CAP research and identify the most pressing unmet needs in CAP research.
Methods: To identify areas of future CAP research, CAPNETZ followed a multiple-step procedure. First, research members of CAPNETZ were individually asked to identify unmet needs. Second, the top 100 experts in the field of CAP research were asked for their insights about the unmet needs in CAP (Delphi approach). Third, internal and external experts discussed unmet needs in CAP at a scientific retreat.
Results: Eleven topics for future CAP research were identified: detection of causative pathogens, next generation sequencing for antimicrobial treatment guidance, imaging diagnostics, biomarkers, risk stratification, antiviral and antibiotic treatment, adjunctive therapy, vaccines and prevention, systemic and local immune response, comorbidities, and long-term cardio-vascular complications.
Conclusion: Pneumonia is a complex disease where the interplay between pathogens, immune system and comorbidities not only impose an immediate risk of mortality but also affect the patients’ risk of developing comorbidities as well as mortality for up to a decade after pneumonia has resolved. Our review of unmet needs in CAP research has shown that there are still major shortcomings in our knowledge of CAP.
Despite numerous clinical studies, which have investigated the therapeutic potential of repetitive transcranial magnetic stimulation (rTMS) in various brain diseases, our knowledge of the cellular and molecular mechanisms underlying rTMS-based therapies remains limited. Thus, a deeper understanding of rTMS-induced neural plasticity is required to optimize current treatment protocols. Studies in small animals or appropriate in vitro preparations (including models of brain diseases) provide highly useful experimental approaches in this context. State-of-the-art electrophysiological and live-cell imaging techniques that are well established in basic neuroscience can help answering some of the major questions in the field, such as (i) which neural structures are activated during TMS, (ii) how does rTMS induce Hebbian plasticity, and (iii) are other forms of plasticity (e.g., metaplasticity, structural plasticity) induced by rTMS? We argue that data gained from these studies will support the development of more effective and specific applications of rTMS in clinical practice.
Ingelfinger, Rebecca ; Henke, Marina ; Roser, Luise ; Ulshöfer, Thomas ; Calchera, Anjuli ; Singh, Garima ; Parnham, Michael J. ; Geisslinger, Gerd ; Fürst, Robert ; Schmitt, Imke ; Schiffmann, Susanne
Lichen-forming fungi are symbiotic organisms that synthesize unique natural products with potential for new drug leads. Here, we explored the pharmacological activity of six lichen extracts (Evernia prunastri, Pseudevernia furfuracea, Umbilicaria pustulata, Umbilicaria crustulosa, Flavoparmelia caperata, Platismatia glauca) in the context of cancer and inflammation using a comprehensive set of 11 functional and biochemical in vitro screening assays. We assayed intracellular Ca2+ levels and cell migration. For cancer, we measured tumor cell proliferation, cell cycle distribution and apoptosis, as well as the angiogenesis-associated proliferation of endothelial cells (ECs). Targeting inflammation, we assayed leukocyte adhesion onto ECs, EC adhesion molecule expression, as well as nitric oxide production and prostaglandin (PG)E2 synthesis in leukocytes. Remarkably, none of the lichen extracts showed any detrimental influence on the viability of ECs. We showed for the first time that extracts of F. caperata induce Ca2+ signaling. Furthermore, extracts from E. prunastri, P. furfuracea, F. caperata, and P. glauca reduced cell migration. Interestingly, F. caperata extracts strongly decreased tumor cell survival. The proliferation of ECs was significantly reduced by E. prunastri, P. furfuracea, and F. caperata extracts. The extracts did not inhibit the activity of inflammatory processes in ECs. However, the pro-inflammatory activation of leukocytes was inhibited by extracts from E. prunastri, P. furfuracea, F. caperata, and P. glauca. After revealing the potential biological activities of lichen extracts by an array of screening tests, a correlation analysis was performed to evaluate particular roles of abundant lichen secondary metabolites, such as atranorin, physodic acid, and protocetraric acid as well as usnic acid in various combinations. Overall, some of the lichen extracts tested in this study exhibit significant pharmacological activity in the context of inflammation and/or cancer, indicating that the group lichen-forming fungi includes promising members for further testing.
Ruggeri, Annalisa ; Volt, Fernanda ; Locatelli, Franco ; Michel, Gerard ; Diaz de Heredia, Cristina ; Abecasis, Manuel ; Zecca, Marco ; Vora, Ajay ; Yakouben, Karima ; O’Brien, Tracey A. ; Giardino, Stefano ; Cornish, Jacqueline ; Rocha, Vanderson ; Peters, Christina ; Bader, Peter ; Gluckman, Eliane ; Dalle, Jean Hugues
Infant acute leukemia still has a poor prognosis, and allogeneic hematopoietic stem cell transplantation is indicated in selected patients. Umbilical cord blood (UCB) is an attractive cell source for this population because of the low risk of chronic graft-versus-host disease (GVHD), the strong graft-versus-leukemia effect, and prompt donor availability. This retrospective, registry-based study reported UCB transplantation (UCBT) outcomes in 252 children with acute lymphoblastic leukemia (ALL; n = 157) or acute myelogenous leukemia (AML; n = 95) diagnosed before 1 year of age who received a single-unit UCBT after myeloablative conditioning between 1996 and 2012 in European Society for Blood and Marrow Transplantation centers. Median age at UCBT was 1.1 years, and median follow-up was 42 months. Most patients (57%) received a graft with 1 HLA disparity and were transplanted in first complete remission (CR; 55%). Cumulative incidence function (CIF) of day 100 acute GVHD (grades II to IV) was 40% ± 3% and of 4-year chronic GVHD was 13% ± 2%. CIF of 1-year transplant-related mortality was 23% ± 3% and of 4-year relapse was 27% ± 3%. Leukemia-free-survival (LFS) at 4 years was 50% ± 3%; it was 40% and 66% for those transplanted for ALL and AML, respectively (P = .001). LFS was better for patients transplanted in first CR, regardless of diagnosis. In multivariate model, diagnosis of ALL (P = .001), advanced disease status at UCBT (<.001), age at diagnosis younger than 3 months (P = .012), and date of transplant before 2004 were independently associated with worse LFS. UCBT is a suitable option for patients diagnosed with infant acute leukemia who achieve CR. In this cohort, patients with AML had better survival than those with ALL.
Aru, Juhan ; Aru, Jaan ; Priesemann, Viola ; Wibral, Michael ; Lana, Luiz ; Pipa, Gordon ; Singer, Wolf ; Vicente, Raul
Cross-frequency coupling (CFC) has been proposed to coordinate neural dynamics across spatial and temporal scales. Despite its potential relevance for understanding healthy and pathological brain function, the standard CFC analysis and physiological interpretation come with fundamental problems. For example, apparent CFC can appear because of spectral correlations due to common non-stationarities that may arise in the total absence of interactions between neural frequency components. To provide a road map towards an improved mechanistic understanding of CFC, we organize the available and potential novel statistical/modeling approaches according to their biophysical interpretability. While we do not provide solutions for all the problems described, we provide a list of practical recommendations to avoid common errors and to enhance the interpretability of CFC analysis.
Schwiedrzik, Caspar Martin ; Ruff, Christian C. ; Lazar, Andreea ; Leitner, Frauke C. ; Singer, Wolf ; Melloni, Lucia
Perception is an active inferential process in which prior knowledge is combined with sensory input, the result of which determines the contents of awareness. Accordingly, previous experience is known to help the brain “decide” what to perceive. However, a critical aspect that has not been addressed is that previous experience can exert 2 opposing effects on perception: An attractive effect, sensitizing the brain to perceive the same again (hysteresis), or a repulsive effect, making it more likely to perceive something else (adaptation). We used functional magnetic resonance imaging and modeling to elucidate how the brain entertains these 2 opposing processes, and what determines the direction of such experience-dependent perceptual effects. We found that although affecting our perception concurrently, hysteresis and adaptation map into distinct cortical networks: a widespread network of higher-order visual and fronto-parietal areas was involved in perceptual stabilization, while adaptation was confined to early visual areas. This areal and hierarchical segregation may explain how the brain maintains the balance between exploiting redundancies and staying sensitive to new information. We provide a Bayesian model that accounts for the coexistence of hysteresis and adaptation by separating their causes into 2 distinct terms: Hysteresis alters the prior, whereas adaptation changes the sensory evidence (the likelihood function).
Highlights
• High resolution profile of C. pipiens' sugar diet has been obtained using UHPLC-MS.
• Artificial feeding using ornamental plants provides similar sugar profiles as observed in field collected mosquitoes.
• Metabolomic profiling found secondary metabolites and pollutants of anthropogenic use.
Abstract: Culex pipiens (Linnaeus, 1758) mosquitoes search plant sources of sugars to cope with the energetic demand of various physiological processes. The crop as part of the digestive system is devoted to the storage of sugar-based meal obtained from various nectars sources. The profiling of sugars and metabolites in the Culex pipiens’ crop is scarce, and only few studies used Liquid Chromatography – Mass Spectrometry (LC-MS), which provides broad detection for biomonitoring environmental substances and even contaminants in the sugar diet of mosquitoes populations.
Therefore, sugar and metabolite profiling were performed on crops obtained from mosquitoes exposed to plant nectar under laboratory or natural conditions by Ultra High-Performance LC-MS (UHPLC-MS). This method allowed us a precise quantitative and qualitative identification of sugar diet and associated environmental compounds in the crop of the mosquito C. pipiens. Under laboratory condition, mosquitoes were allowed to feed on either glucose solution, commercially-available flowers or field collected flowers. In addition, we collected mosquitoes from the field to compare those crop metabolomes with metabolome patterns occurring after nectar feeding in the lab.
The sugar quantities and quality obtained from the crops of mosquitoes collected in the field were similar to those crops obtained from mosquitoes that fed on commercially-available flowers and from field collected flowers with a limit of detection of 10 μg/L for sucrose, glucose and sucrose. Next to sugar compounds, we identified 2 types of amino acids, 12 natural products, and 9 pesticides.
Next to the diversity of sugar compounds, we could confirm that secondary metabolites and environmental pollutants are typically up taken from floral nectar sources by C. pipiens. The in-depth knowledge on mosquito–plant interactions may inspire the development and further optimization of mosquito trap systems and arboviral surveillance systems.