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- neurite outgrowth (2)
- neurodevelopmental disorders (2)
- neuroendocrine tumor (NET) (2)
- neurofilaments (2)
- neuron (2)
- neuronal ceroid lipofuscinosis (2)
- neuronal dendrites (2)
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- neurotransmission (2)
- neurotransmitter release (2)
- neutral sphingomyelinase-2 (2)
- neutralino (2)
- neutrino astronomy (2)
- neutrino emission (2)
- neutrino telescope (2)
- neutrinos (2)
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- next generation sequencing (NGS) (2)
- nicht-kartesische Bildgebung (2)
- nicht-kovalente Wechselwirkungen (2)
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- nilotinib (2)
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- nociception (2)
- nomenclature (2)
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- normal distribution (2)
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- nucleotide sequence (2)
- nude-mice (2)
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- numerical hydrodynamics (2)
- nurse bee (2)
- nurses (2)
- o-methoxy-sila-hexocyclium (2)
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- object-based image analysis (2)
- observer (2)
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- occupational medicine/industrial medicine (2)
- oculomotor control (2)
- oestrogen receptor signalling (2)
- office-workers (2)
- oil palm (2)
- older adults (2)
- olfaktorisches Lernen (2)
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- onset (2)
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- organische Solarzellen (2)
- origin (2)
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- orthopedics (2)
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- osteonecrosis of the jaw (2)
- osteopontin (2)
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- outer membrane protein (2)
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- outer-membrane proteins (2)
- outpatients (2)
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- oxidative addition (2)
- oxygen reduction reaction (2)
- oxygen uptake (2)
- oxytocin (2)
- p-Halbleiter (2)
- p34 (2)
- p38 MAP kinase (2)
- p44 (2)
- p90 ribosomal S6 kinase (2)
- pCa (2)
- pICln (2)
- paediatric patients (2)
- paediatrics (2)
- pain regulation (2)
- pain sensation (2)
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- parallel imaging (2)
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- patient-specific (2)
- pattern (2)
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- penicillin hypersensitivity (2)
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- photoinduzierter Elektronentransfer (2)
- photolysis (2)
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- photon-counting (2)
- photoreceptor (2)
- photoreceptors (2)
- photoswitchable organic fluorophores (2)
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- planning (2)
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- plant cuticle (2)
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- power training (2)
- pp Collisions (2)
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- rice (2)
- ring expansion (2)
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- root (2)
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- see (2)
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- sentinel-2 (2)
- septic (2)
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- shedding (2)
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- sizing (2)
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- speech (2)
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- spermatocytes (2)
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- succession (2)
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- supervisors (2)
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- supramolekulare Chemie (2)
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- synapsis (2)
- synaptische Proteine (2)
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- syndrome (2)
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- tolerability (2)
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- tracking (2)
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- transcranial magnetic stimulation (2)
- transcription factor MIZ-1 (2)
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- type VII secretion system (2)
- tyramine (2)
- tyrosine (2)
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- ultrafast spectroscopy (2)
- ultrafiltration (2)
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- umbilical hernia (2)
- unconventional superconductivity (2)
- unexpressed needs (2)
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- universal prevention (2)
- universality (2)
- unmanned aerial vehicles (2)
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The present work deals with the preparation of hydrogels in different size scales for various applications. Thus, macroscopic bulk hydrogels were prepared from differently modified pig gastric mucin (PGM), microgels were made from PGM in combination with hyaluronic acid (HA), as well as from gelatin in combination with poly(ethylene glycol) (PEG), and nanogels were fabricated from poly(glycidol) (PG). According to their size, each hydrogels have different applications. First, it was investigated whether previously existing studies involving the preparation of covalently crosslinked hydrogels via free radical polymerization from bovine submaxillary gland mucin (BSM) could also be carried out with the much cheaper alternative PGM. After this was successfully demonstrated and the hydrogels were systematically investigated for their mechanical properties and biocompatibility, a second hydrogel system was established. Here, PGM was functionalized with allyl glycidyl ether (AGE) and crosslinked in combination with thiolated HA via thiol-ene reaction. These hydrogels were also systematically evaluated and compared with the hydrogels prepared via free radical polymerization. It was confirmed that the more random free radical polymerization leads to more disordered networks than the thiol-ene reaction. In both systems, biocompatibility was demonstrated with both L929 CCL1 murine fibroblasts and human mesenchymal stem cells (hMSCs). Using this knowledge as background and the request to make mucin printable, microgels were prepared via the emulsion technique using the previously established thiol-ene hydrogel precursor solution. Here, applying the recently used photoinitiator 2-hydroxy-4-(2-hydroxyethoxy)-2- methylpropiophenone (Irgacure 2959), which is more soluble in oil than in water, was challenging and did not result in well-crosslinked microgels. Therefore, a third hydrogel system was established, which was based on thiol-ene crosslinked AGE functionalized pig gastric mucin (PGM-AGE)-thiolated hyaluronic acid (HASH) hydrogels and with lithium phenyl-2,4,6- trimethylbenzoylphosphinate (LAP) being used as photoinitiator. Hereby, stably crosslinked microgels could be prepared via the emulsion technique. After the jamming process, which means the extraction of the microgel solution by vacuum, the resulting so-called granular ink could be successfully printed via extrusion-based printing. The widely known challenge of printing living cells was also successfully managed. Cells were encapsulated in the microgels during microgel synthesis. Here, the stirring velocity had to be adjusted to avoid harming the cells during the manufacturing process. The cell-loaded microgels were successfully printed in the same way as the empty microgels in multiple layers resulting in dimensionally stable constructs. Live/dead experiments verified that many viable cells were printable after 24 hours. In the next part of this thesis, microgels were prepared from AGE-functionalized gelatin and thiol-functionalized PEG by the same procedure. Again, cells were incorporated and printed by extrusion-based printing. After the addition of hydroxypropyl-methylcellulose, the right conditions for viable cells and stable constructs were found. The printed constructs were further secondarily crosslinked by immersion in initiator solution after the printing process followed by re-irradiating with light. Hereafter, a strongly increased stability of the constructs could be observed. Microgels for use as cell sensor particles were produced as part of this thesis. Here, microfluidic was applied to prepare microgels with a monodisperse size distribution. After adjusting the oil phase, as well as optimizing the manufacturing parameters to the mucin hydrogel system, the microfluidic setup established by Ilona Paulus in this research group could be used. By setting very fast flow rates, microgels in the size range of cells could be obtained. Furthermore, various parameters affecting the stiffness of the particles were varied. This laid the foundation for follow-up studies within the framework of the SFB TRR225 to be able to produce cellmimicking particles. Further follow-up experiments could include the investigation of hydrogels being based only on mucin, like a crosslinking of thiolated mucin and mucin modified with an allyl function such as the PGM-AGE. Furthermore, the granular mucin ink could serve as a supporting material for other microgels or less stable inks during the printing process and thus expand the field of applicable materials for three dimensional (3D) printing.
Cardio- and cerebrovascular diseases (CVDs), such as myocardial infarction and ischemic stroke, are the leading cause of death worldwide, caused by overshooting platelet activation and subsequent thrombus formation. However, at sites of vascular injury this tightly-regulated, multi¬step process is critical to limit blood loss and to prevent bleeding. Anti-platelet agents, such as aspirin or clopidogrel, have been proven to be beneficial in prevention of CVDs, but are associated with an elevated bleeding risk and therefore are often contraindicative.
In recent years, the (hem)ITAM-bearing receptors GPVI and CLEC-2 have been identified as critical regulators of platelet activation and thrombus formation, rendering them promising targets for novel anti-platelet drugs. Yet, they are also involved in a plethora of (patho)physiological processes. Consequently, interference with the (hem)ITAM signaling cascade may lead to severe side-effects. In this context, GPV has previously been identified as a mediator of thrombotic and hemostatic function, while its mode of action remains elusive. Therefore, this thesis focused on the function of GPV in thrombotic and hemostatic processes.
Extensive characterization of GPV-deficient mice as well as generation and analysis of anti-GPV antibodies and mice with a mutation rendering GPV uncleavable by thrombin (Gp5Kin/Kin) revealed an unexpected role of GPV as a central modulator of platelet activation and thrombus formation. Gp5-/- as well as Gp5Kin/Kin mice restored the thrombotic and hemostatic defect in the absence of both (hem)ITAM receptors. The in-house generated monoclonal anti-GPV antibodies 89F12 and 5G2 were found to reproduce the knockout phenotype and extended the thrombus-modulatory role of GPV beyond (hem)ITAM receptors, pointing to a critical role of thrombin-cleaved soluble GPV (sGPV). Surprisingly, recombinant sGPV had a strong antithrombotic effect in in vivo throm¬bosis models as well as in in vitro flow adhesion assays using human or murine blood, without affecting hemostasis. These data establish GPV as a key player in platelet physiology. Although data gained from studies using genetically modified mice cannot always directly be transferred to humans, the findings presented in this thesis may serve as basis for the generation of novel treatment options for bleeding complications (anti-GPV antibodies) and thrombotic diseases (sGPV) with a good safety profile. The newly generated humanized GPV mouse provides a valuable tool to study human GPV in vivo.
A second part of this thesis focused on the analysis of protein kinase C (PKC) ι/λ. PKC family of serine/threonine kinases is involved in several physiological processes regulating platelet activation. However, little is known about atypical PKC isoforms and particularly PKCι/λ has never been studied before in platelets. Therefore, platelet- and megakaryocyte-specific PKCι/λ knockout mice were used to assess its role in platelet function in vitro and in vivo. Surprisingly, PKCι/λ was found to be dispensable for platelet function in thrombosis and hemostasis.
Background
A significant number of oncological patients are heavily burdened by psychosocial stress. Doctors recommending or referring their patients to psycho-oncologists in the course of routine consultations can positively influence psycho-oncological care. The aim of this study was to analyze the frequency and predictors of such recommendations and to examine the use of these services by patients.
Methods
4,020 cancer patients (mean age 58 years; 51% women) were evaluated in a multicenter, cross-sectional study in Germany. Data was gathered about doctors’ referral practices, patients’ utilization of psycho-oncological care services, and disease-related symptoms. The PHQ-9 depression scale and the GAD-7 anxiety scale were used to measure psychological burden. Descriptive data analysis was conducted on the basis of subgroup comparisons and multivariable analysis was done using binary logistical regression.
Results
21.9% of the respondents reported having been given a recommendation or referral for psycho-oncological care by a doctor within the course of their cancer diagnosis and treatment. This comprises 29.5% of the patients identified by screening as being psychologically burdened. Nearly half of the patients who received a recommendation or referral (49.8%) acted on it. Predictors for seeking out psycho-oncological care included: patient desire (OR = 2.0), previous experience with psycho-oncological care (OR = 1.59), and female gender (OR = 1.57). Multivariable analysis indicated that patients’ level of psychological burden (depression, anxiety) had no effect on whether doctors gave them a recommendation or referral.
Conclusions
Along with examining the degree to which patients are burdened (e.g. using screening instruments), determining whether or not patients would like to receive psycho-oncological care is an important aspect of improving referral practices and, by extension, will allow important progress in the field of psycho-oncological care to be made.
Hematopoietic stem cell transplantation (HSCT) has been an effective method for treating a wide range of malignant or non-malignant disorders. In case of an autologous HSCT, patients receive their own stem cells after myeloablation before extraction. Allogeneic HSCT uses stem cells derived from a donor. Despite being associated with a high risk of early and long-term complications, it is often the last curative option. 229 pediatric patients, who between 1 January 2005 and 31 December 2015 received an HSCT at the University Children’s Hospital Wuerzburg, were studied. Correlations between two groups were calculated with the Chi square test or with a 2x2-contingency table. To calculate metric variables, the Mann-Whitney-U-test was used. Survival curves were calculated according to Kaplan and Meier. Significance was assumed for results with a p-value <0.05 (CI (Confident Interval) 95%). We retrospectively analyzed 229 pediatric patients (105 females, 124 males) for early and late complications of allogeneic and autologous hematopoietic stem cell transplantation. Median age at HSCT was seven years. Underlying diseases were leukemia (n = 73), lymphoma (n = 22), solid tumor (n = 65), CNS (central nervous system)- tumor (n = 41), and “other diseases” (n = 28). Survival times, overall survival, and event-free survival were calculated. Of all patients, 80.8% experienced complications of some degree, including mild and transient complications. Allo-HSCT (allogeneic HSCT) carried a significantly higher risk of complications than auto-HSCT (autologous HSCT) (n = 118 vs. n = 67; p = < .001) and the remission rate after allo-HSCT was also higher (58.7% vs. 44,7%; p = .032). Especially infection rates and pulmonary complications are different between auto- and allo-HSCT. Leukemia patients had the highest risk of early and late complications (95,0%; p < .001). Complications within HSCT are major risk factors following morbidity and mortality. In order to detect complications and risk factors early, strict recordings are needed to reduce the rate of complication by recognition and prevention of triggering factors. In the future, these factors should receive greater attention in the planning of HSCT post-transplantation care in order to improve the results of the transplantation and establish protocols to prevent their occurrence.
Objective
Recent preliminary studies indicated a seasonal association of BMI at admission to inpatient treatment for anorexia nervosa (AN), indicating lower BMI in the cold season for restrictive AN. An impaired thermoregulation was proposed as the causal factor, based on findings in animal models of AN. However, findings regarding seasonality of BMI and physical activity levels in the general population indicate lower BMI and higher physical activity in summer than in winter. Therefore, we aimed to thoroughly replicate the findings regarding seasonality of BMI at admission in patients with AN in this study.
Method
AN subtype, age- and gender-standardized BMI scores (BMI-SDS) at admission, mean daily sunshine duration and ambient temperature at the residency of 304 adolescent inpatients with AN of the multi-center German AN registry were analyzed.
Results
A main effect of DSM-5 AN subtype was found (F(2,298) = 6.630, p = .002), indicating differences in BMI-SDS at admission between restrictive, binge/purge and subclinical AN. No main effect of season on BMI-SDS at admission was found (F(1,298) = 4.723, p = .025), but an interaction effect of DSM-5 subtype and season was obtained (F(2,298) = 6.625, p = .001). Post-hoc group analyses revealed a lower BMI-SDS in the warm season for restrictive AN with a non-significant small effect size (t(203.16) = 2.140, p = .033; Hedges′g = 0.28). Small correlations of mean ambient temperature (r = −.16) and daily sunshine duration (r = −.22) with BMI-SDS in restrictive AN were found. However, the data were widely scattered.
Conclusions
Our findings are contrary to previous studies and question the thermoregulatory hypothesis, indicating that seasonality in AN is more complex and might be subject to other biological or psychological factors, for example physical activity or body dissatisfaction. Our results indicate only a small clinical relevance of seasonal associations of BMI-SDS merely at admission. Longitudinal studies investigating within-subject seasonal changes might be more promising to assess seasonality in AN and of higher clinical relevance.
It was previously shown that the estrogen-receptor negative breast cancer cell line MBA-MD-231 expresses high levels of A2B adenosine receptors as the sole adenosine receptor subtype. These receptors couple to both, stimulation of adenylyl cyclase and a Ca2+ signal. In order to establish a potential role of A2B adenosine receptors in tumor growth and development MAPK signaling was investigated in these breast cancer cells. Although it is known that A2B adenosine receptors may stimulate MAPK it was found that in MBA-MD-231 cells ERK1/2 phosphorylation is reduced upon agonist-stimulation of A2B adenosine receptors. This reduction is also triggered by forskolin, but abolished by the PKA inhibitor H89, suggesting an important role for the cAMP-PKA pathway. Likewise, a role for intracellular Ca2+ was established as the Ca2+ chelator 1,2-bis-(o-aminophenoxy)-ethane-N,N,N’,N’-tetraacetic acid, tetraacetoxymethyl ester (BAPTA-AM) abolished the reduction of ERK1/2 phosphorylation triggered by A2B stimulation. It was shown that various pathways downstream from A2B adenosine receptors resulted in a stimulation of MAPK phosphatase-1 (MKP-1) which dephosphorylates phospho ERK1/2, and thus plays a critical role in the regulation of the phosphorylation state of ERK1/2. The reduction of ERK1/2 phosphorylation mediated by A2B adenosine receptors might provide an interesting approach for adjuvant treatment leading to reduced growth of certain tumors expressing the A2B subtype.
We assessed the prevalence, awareness, treatment and control of hypertension in patients with moderate chronic kidney disease (CKD) under nephrological care in Germany. In the German Chronic Kidney Disease (GCKD) study, 5217 patients under nephrology specialist care were enrolled from 2010 to 2012 in a prospective observational cohort study. Inclusion criteria were an estimated glomerular filtration rate (eGFR) of 30–60 mL/min/1.73 m2 or overt proteinuria in the presence of an eGFR>60 mL/min/1.73 m2. Office blood pressure was measured by trained study personnel in a standardized way and hypertension awareness and medication were assessed during standardized interviews. Blood pressure was considered as controlled if systolic < 140 and diastolic < 90 mmHg. In 5183 patients in whom measurements were available, mean blood pressure was 139.5 ± 20.4 / 79.3 ± 11.8 mmHg; 4985 (96.2%) of the patients were hypertensive. Awareness and treatment rates were > 90%. However, only 2456 (49.3%) of the hypertensive patients had controlled blood pressure. About half (51.0%) of the patients with uncontrolled blood pressure met criteria for resistant hypertension. Factors associated with better odds for controlled blood pressure in multivariate analyses included younger age, female sex, higher income, low or absent proteinuria, and use of certain classes of antihypertensive medication. We conclude that blood pressure control of CKD patients remains challenging even in the setting of nephrology specialist care, despite high rates of awareness and medication use.
Exploratory behavior of re-orienting foragers differs from other flight patterns of honeybees
(2018)
Honeybees, Apis mellifera, perform re-orientation flights to learn about the new surroundings of the hive when their hive is transported to a new location. Since the pattern of re-orientation flights has not yet been studied, we asked whether this form of exploratory behavior differs from the well described exploratory orientation flights performed by young honeybees before they start foraging. We also investigated whether the exploratory components of re-orientation flights differ from foraging flights and if so how. We recorded re-orientation flights using harmonic radar technology and compared the patterns and flight parameters of these flights with the first exploratory orientation flights of young honeybees and foraging flights of experienced foragers. Just as exploratory orientation flights of young honeybees, re-orientation flights can be classified into short- and long-range flights, and most short-range re-orientation flights were performed under unfavorable weather conditions. This indicates that bees adapt the flight pattern of their re-orientation and orientation flights to changing weather conditions in a similar way. Unlike exploratory orientation flights, more than one sector of the landscape was explored during a long-range re-orientation flight, and significantly longer flight durations and flight distances were observed. Thus, re-orienting bees explored a larger terrain than bees performing their first exploratory orientation flight. By displacing some bees after their first re-orientation flight, we could demonstrate that a single re-orientation flight seems to be sufficient to learn the new location of the hive. The flight patterns of re-orientation flights differed clearly from those of foraging flights. Thus, re-orientation flights represent a special exploratory behavior that is triggered by a change in the location of the hive.
Effect of progesterone on Smad signaling and TGF-β/Smad-regulated genes in lung epithelial cells
(2018)
The effect of endogenous progesterone and/or exogenous pre- or postnatal progesterone application on lung function of preterm infants is poorly defined. While prenatal progesterone substitution may prevent preterm birth, in vitro and in vivo data suggest a benefit of postnatal progesterone replacement on the incidence and severity of bronchopulmonary dysplasia (BPD). However, the molecular mechanisms responsible for progesterone’s effects are undefined. Numerous factors are involved in lung development, airway inflammation, and airway remodeling: the transforming growth factor beta (TGF-β)/mothers against decapentaplegic homolog (Smad) signaling pathway and TGF-β-regulated genes, such as connective tissue growth factor (CTGF), transgelin (TAGLN), and plasminogen activator inhibitor-1 (PAI-1). These processes contribute to the development of BPD. The aim of the present study was to clarify whether progesterone could affect TGF-β1-activated Smad signaling and CTGF/transgelin/PAI-1 expression in lung epithelial cells. The pharmacological effect of progesterone on Smad signaling was investigated using a TGF-β1-inducible luciferase reporter and western blotting analysis of phosphorylated Smad2/3 in A549 lung epithelial cells. The regulation of CTGF, transgelin, and PAI-1 expression by progesterone was studied using a promoter-based luciferase reporter, quantitative real-time PCR, and western blotting in the same cell line. While progesterone alone had no direct effect on Smad signaling in lung epithelial cells, it dose-dependently inhibited TGF-β1-induced Smad3 phosphorylation, as shown by luciferase assays and western blotting analysis. Progesterone also antagonized the TGF-β1/Smad-induced upregulation of CTGF, transgelin, and PAI-1 at the promoter, mRNA, and/or protein levels. The present study highlights possible new molecular mechanisms involving progesterone, including inhibition of TGF-β1-activated Smad signaling and TGF-β1-regulated genes involved in BPD pathogenesis, which are likely to attenuate the development of BPD by inhibiting TGF-β1-mediated airway remodeling. Understanding these mechanisms might help to explain the effects of pre- or postnatal application of progesterone on lung diseases of preterm infants.
The role of the subthalamic nucleus in human locomotion is unclear although relevant, given the troublesome management of gait disturbances with subthalamic deep brain stimulation in patients with Parkinson’s disease. We investigated the subthalamic activity and inter-hemispheric connectivity during walking in eight freely-moving subjects with Parkinson’s disease and bilateral deep brain stimulation. In particular, we compared the subthalamic power spectral densities and coherence, amplitude cross-correlation and phase locking value between resting state, upright standing, and steady forward walking. We observed a phase locking value drop in the β-frequency band (≈13-35Hz) during walking with respect to resting and standing. This modulation was not accompanied by specific changes in subthalamic power spectral densities, which was not related to gait phases or to striatal dopamine loss measured with [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane and single-photon computed tomography. We speculate that the subthalamic inter-hemispheric desynchronization in the β-frequency band reflects the information processing of each body side separately, which may support linear walking. This study also suggests that in some cases (i.e. gait) the brain signal, which could allow feedback-controlled stimulation, might derive from network activity.