RepoMed (Medizinische Hochschule Hannover)
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Einfluss des deregulierten RB1-Imprinting im humanen hepatozellulären Karzinom auf die RB1-Proteinexpression und Korrelation mit klinischen und pathologischen Parametern
Get PDFA VirB4 ATPase of the mobile accessory genome orchestrates core genome-encoded features of physiology, metabolism, and virulence of Pseudomonas aeruginosa TBCF10839
Get PDFPseudomonas aeruginosa TBCF10839 is a highly virulent strain that can persist and replicate in human neutrophils. Screening of a signature-tagged mutagenesis (STM) TBCF10839 transposon library in phagocytosis tests identified a mutant that carried the transposon in the VirB4 homolog 5PG21 of an integrative and conjugative element (ICE)-associated type IV secretion system of the pKLC102 subtype. 5P21 TBCF10839 insertion mutants were deficient in metabolic versatility, secretion, quorum sensing, and virulence. The mutants were efficiently killed in phagocytosis tests in vitro and were avirulent in an acute murine airway infection model in vivo. The inactivation of 5PG21 silenced the rhl, las, and pqs operons and the gene expression for the synthesis of hydrogen cyanide, the antimetabolite l-2-amino-4-methoxy-trans-3-butenoic acid, and the H2- and H3-type VI secretion systems and their associated effectors. The mutants were impaired in the utilization of carbon sources and stored compounds that are not funneled into intermediary metabolism. This showcase demonstrates that a single gene of the mobile accessory genome can become an essential element to operate the core genome-encoded features of metabolism and virulence
Polysialic acid promotes remyelination in cerebellar slice cultures by Siglec-E-dependent modulation of microglia polarization
Get PDFMultiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Spontaneous restoration of myelin after demyelination occurs, but its efficiency declines during disease progression. Efficient myelin repair requires fine-tuning inflammatory responses by brain-resident microglia and infiltrating macrophages. Accordingly, promising therapeutic strategies aim at controlling inflammation to promote remyelination. Polysialic acid (polySia) is a polymeric glycan with variable chain lengths, presented as a posttranslational modification on select protein carriers. PolySia emerges as a negative regulator of inflammatory microglia and macrophage activation and has been detected on oligodendrocyte precursors and reactive astrocytes in multiple sclerosis lesions. As shown recently, polySia-modified proteins can also be released by activated microglia, and the intrinsically released protein-bound and exogenously applied free polySia were equally able to attenuate proinflammatory microglia activation via the inhibitory immune receptor Siglec-E. In this study, we explore polySia as a candidate substance for promoting myelin regeneration by immunomodulation. Lysophosphatidylcholine-induced demyelination of organotypic cerebellar slice cultures was used as an experimental model to analyze the impact of polySia with different degrees of polymerization (DP) on remyelination and inflammation. In lysophosphatidylcholine-treated cerebellar slice cultures, polySia-positive cells were abundant during demyelination but largely reduced during remyelination. Based on the determination of DP24 as the minimal polySia chain length required for the inhibition of inflammatory BV2 microglia activation, pools with short and long polySia chains (DP8-14 and DP24-30) were generated and applied to slice cultures during remyelination. Unlike DP8-14, treatment with DP24-30 significantly improved remyelination, increased arginase-1-positive microglia ratios, and reduced the production of nitric oxide in wildtype, but not in Siglec-E-deficient slice cultures. In vitro differentiation of oligodendrocytes was not affected by DP24-30. Collectively, these results suggest a beneficial effect of exogenously applied polySia DP24-30 on remyelination by Siglec-E-dependent microglia regulation
Natural killer cells- from innate cells to the discovery of adaptability
Get PDFNatural Killer (NK) cells have come a long way since their first description in the 1970's. The most recent reports of their adaptive-like behavior changed the way the immune system dichotomy is described. Adaptive NK cells present characteristics of both the innate and adaptive immune system. This NK cell subpopulation undergoes a clonal-like expansion in response to an antigen and secondary encounters with the same antigen result in an increased cytotoxic response. These characteristics can be of extreme importance in the clinical setting, especially as adoptive immunotherapies, since NK cells present several advantages compared other cell types. This review will focus on the discovery and the path to the current knowledge of the adaptive NK cell population
Moderat hypofraktionierte Strahlentherapie ohne Chemotherapie bei älteren oder gebrechlichen Patienten mit Kopf-Hals-Tumoren: eine retrospektive Studie zu Wirksamkeit und Toxizität
Get PDFCardiovascular health and potential cardiovascular risk factors in young athletes.
Get PDFIntroduction Cardiovascular disease remains the most common cause of death worldwide, and early manifestations are increasingly identified in childhood and adolescence. With physical inactivity being the most prevalent modifiable risk factor, the risk for cardiovascular disease is deemed low in people engaging in regular physical exercise. The aim of this study was to investigate early markers and drivers of cardiovascular disease in young athletes pursuing a career in competitive sports. Methods One hundred and five athletes (65 males, mean age 15.7 ± 3.7 years) were characterized by measurement of body impedance to estimate body fat, blood pressure (BP), carotid femoral pulse wave velocity (PWV) to evaluate arterial elasticity, ergometry to assess peak power output, echocardiography to calculate left ventricular mass, and blood tests. Results Systolic BP was elevated in 12.6% and thereby more than twice as high as expected for the normal population. Similarly, structural vascular and cardiac changes represented by elevated PWV and left ventricular mass were found in 9.5% and 10.3%. Higher PWV was independently associated with higher systolic BP (β = 0.0186, p < 0.0001), which in turn was closely correlated to hemoglobin levels (β = 0.1252, p = 0.0435). In this population, increased left ventricular mass was associated with lower resting heart rate (β = -0.5187, p = 0.0052), higher metabolic equivalent hours (β = 0.1303, p = 0.0002), sport disciplines with high dynamic component (β = 17.45, p = 0.0009), and also higher systolic BP (β = 0.4715, p = 0.0354). Conclusion Despite regular physical exercise and in the absence of obesity, we found an unexpected high rate of cardiovascular risk factors. The association of PWV, systolic BP, and hemoglobin suggested a possible link between training-induced raised hemoglobin levels and altered vascular properties. Our results point toward the need for thorough medical examinations in this seemingly healthy cohort of children and young adults. Long-term follow-up of individuals who started excessive physical exercise at a young age seems warranted to further explore the potential adverse effects on vascular health
MCK2-mediated MCMV infection of macrophages and virus dissemination to the salivary gland depends on MHC class I molecules.
Get PDFMurine cytomegalovirus (MCMV) infection of macrophages relies on MCMV-encoded chemokine 2 (MCK2), while infection of fibroblasts occurs independently of MCK2. Recently, MCMV infection of both cell types was found to be dependent on cell-expressed neuropilin 1. Using a CRISPR screen, we now identify that MCK2-dependent infection requires MHC class Ia/β-2-microglobulin (B2m) expression. Further analyses reveal that macrophages expressing MHC class Ia haplotypes H-2b and H-2d, but not H-2k, are susceptible to MCK2-dependent infection with MCMV. The importance of MHC class I expression for MCK2-dependent primary infection and viral dissemination is highlighted by experiments with B2m-deficient mice, which lack surface expression of MHC class I molecules. In those mice, intranasally administered MCK2-proficient MCMV mimics infection patterns of MCK2-deficient MCMV in wild-type mice: it does not infect alveolar macrophages and subsequently fails to disseminate into the salivary glands. Together, these data provide essential knowledge for understanding MCMV-induced pathogenesis, tissue targeting, and virus dissemination
Assoziation echokardiographischer Parameter mit reversem linksatrialen Remodeling nach Pulmonalvenenisolation
Get PDFRelationship Between the Response to Antibody Therapy and Symptoms of Depression and Anxiety Disorders in Patients with Severe Asthma
Get PDFPurpose Asthma is associated with a high prevalence of psychopathological disorders, especially depressive disorders or anxiety. In patients with uncontrolled severe asthma, monoclonal antibody (mAb)-therapy positively influenced control of mental disorders. Therefore, we evaluated the impact of antibody therapy on the burden of these mental diseases depending on responder status. Patients and methods Data were collected retrospectively in patients with uncontrolled severe asthma (n = 82) prior to mAb-therapy ("baseline") (omalizumab, dupilumab, benralizumab or mepolizumab). Symptoms of Major Depressive Disorder (MDD) or General Anxiety Disorder (GAD) were detected at baseline using the Hospital Anxiety and Depression Scale (HADS), as well as general sociodemographic data and lung function parameters. At 6-month (±3 month) follow-up, the burden of psychopathological symptoms under mAb-therapy was assessed using the Patient Health Questionnaire-2 (PHQ-2) and Generalized Anxiety Disorder Scale-2 (GAD-2). Response status was classified using the Biologics Asthma Response Score (BARS), assessing exacerbations, oral corticosteroid usage and asthma control test (ACT) score. Predictors for non-response to mAb-therapy were identified using linear regression analysis. Results Patients with severe asthma suffered from symptoms of MDD/GAD more often compared to the general population, with a higher prevalence among mAb therapy non-responders. mAb-responders exhibited a declining burden of MDD, better quality of life (QoL), less exacerbations, better lung function and better disease control compared to non-responders. A history of symptoms of depression was identified as a predictor for non-response to mAb-therapy. Conclusion Asthma symptoms and psychological problems are linked and more prevalent in our cohort of severe asthma patients than in the general population. Patients with signs of MDD/GAD before mAb-therapy show less mAb therapy response suggesting a negative impact of prior psychological problems on treatment response. In some patients, the score on MDD/GAD was caused by severe asthma - here symptoms decreased after effective treatment