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Europe is a key normative power. Its legitimacy as a force for ensuring the reign of rule of law in international relations is unparalleled. It also packs an economic punch. In data protection and the fight against cybercrime, European norms have been successfully globalized. The time is right to take the next step: Europe must now become the international normative leader for developing a new deal on internet governance. To ensure this, European powers should commit to rules that work in security, economic development and human rights on the internet and implement them in a reinvigorated IGF.
Atherosclerosis and its sequelae, such as myocardial infarction and stroke, are the leading cause of death worldwide. Vascular endothelial cells (EC) play a critical role in vascular homeostasis and disease. Atherosclerosis as well as its independent risk factors including diabetes, obesity, and aging, are hallmarked by endothelial activation and dysfunction. Metabolic pathways have emerged as key regulators of many EC functions, including angiogenesis, inflammation, and barrier function, processes which are deregulated during atherogenesis. In this review, we highlight the role of glucose, fatty acid, and amino acid metabolism in EC functions during physiological and pathological states, specifically atherosclerosis, diabetes, obesity and aging.
The present study evaluated the tissue response toward a resorbable collagen membrane derived from bovine achilles tendon (test group) in comparison to physiological wound healing (control group). After subcutaneous implantation in Wistar rats over 30 days, histochemical and immunohistochemical methods elucidated the cellular inflammatory response, vascularization pattern, membrane protein and cell absorbance capacity. After 30 days, the test-group induced two different inflammatory patterns. On the membrane surface, multinucleated giant cells (MNGCs) were formed after the accumulation of CD-68-positive cells (macrophages), whereas only mononuclear cells (MNCs) were found within the membrane central region. Peri-implant vascularization was significantly enhanced after the formation of MNGCs. No vessels were found within the central region of the membrane. Physiological wound healing revealed no MNGCs at any time point. These dynamic changes in the cellular reaction and vascularization within the test-group are related typical indications of a foreign body reaction. Due to the membrane-specific porosity, mononuclear cells migrated into the central region, and the membrane maintained its integrity over 30 days by showing no breakdown or disintegration. The ex vivo investigation analyzed the interaction between the membrane and a blood concentrate system, liquid platelet-rich fibrin (liquid PRF), derived from human peripheral blood and consisting of platelets, leukocytes and fibrin. PRF penetrated the membrane after just 15 min. The data question the role of biomaterial-induced MNGCs as a pathological reaction and whether this is acceptable to trigger vascularization or should be considered as an adverse reaction. Therefore, further pre-clinical and clinical studies are needed to identify the types of MNGCs that are induced by clinically approved biomaterials.
Many cellular processes are regulated via pH, and maintaining the pH of different organelles is crucial for cell survival. A pH-sensitive GFP variant, the so-called pHluorin, has proven to be a valuable tool to study the pH of the cytosol, mitochondria and other organelles in vivo. We found that the fluorescence intensity of Endoplasmic Reticulum (ER)-targeted pHluorin in the yeast Saccharomyces cerevisiae was very low and barely showed pH sensitivity, probably due to misfolding in the oxidative environment of the ER. We therefore developed a superfolder variant of pHluorin which enabled us to monitor pH changes in the ER and the cytosol of S. cerevisiae in vivo. The superfolder pHluorin variant is likely to be functional in cells of different organisms as well as in additional compartments that originate from the secretory pathway like the Golgi apparatus and pre-vacuolar compartments, and therefore has a broad range of possible future applications.
Background: Treatment complexity rises in line with the number of drugs, single doses, and administration methods, thereby threatening patient adherence. Patients with multimorbidity often need flexible, individualised treatment regimens, but alterations during the course of treatment may further increase complexity. The objective of our study was to explore medication changes in older patients with multimorbidity and polypharmacy in general practice.
Methods: We retrospectively analysed data from the cluster-randomised PRIMUM trial (PRIoritisation of MUltimedication in Multimorbidity) conducted in 72 general practices. We developed an algorithm for active pharmaceutical ingredients (API), strength, dosage, and administration method to assess changes in physician-reported medication data during two intervals (baseline to six-months: ∆1; six- to nine-months: ∆2), analysed them descriptively at prescription and patient levels, and checked for intervention effects.
Results: Of 502 patients (median age 72 years, 52% female), 464 completed the study. Changes occurred in 98.6% of patients (changes were 19% more likely in the intervention group): API changes during ∆1 and ∆2 occurred in 414 (82.5%) and 338 (67.3%) of patients, dosage alterations in 372 (74.1%) and 296 (59.2%), and changes in API strength in 158 (31.5%) and 138 (27.5%) respectively. Administration method changed in 79 (16%) of patients in both ∆1 and ∆2. Simvastatin, metformin and aspirin were most frequently subject to alterations.
Conclusion: Medication regimens in older patients with multimorbidity and polypharmacy changed frequently. These are mostly due to discontinuations and dosage alterations, followed by additions and restarts. These findings cast doubt on the effectiveness of cross-sectional assessments of medication and support longitudinal assessments where possible.
Trial registration: 1. Prospective registration: Trial registration number: NCT01171339; Name of registry: ClinicalTrials.gov; Date of registration: July 27, 2010; Date of enrolment of the first participant to the trial: August 12, 2010.
2. Peer reviewed trial registration: Trial registration number: ISRCTN99526053; Name of registry: Controlled Trials; Date of registration: August 31, 2010; Date of enrolment of the first participant to the trial: August 12, 2010.
In the publication of this article, there are reference errors in four positions the respective references are missing since reference Fischer was omitted. In addition for reference Egli et al. the in text citation only appeared at the end of the paragraph, but not following important statements. This has now been included in this correction. ...
Objective: Classifications of posture deviations are only possible compared with standard values. However, standard values have been published for healthy male adults but not for female adults.
Design: Observational study.
Setting: Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe-University Frankfurt/Main.
Participants: 106 healthy female volunteers (21–30 years old; 25.1±2.7 years) were included. Their body weight ranged from 46 to 106 kg (60.3±7.9 kg), the heights from 1.53 to 1.82 m (1.69±0.06 m) and the body mass index from 16.9 kg/m² to 37.6 kg/m² (21.1±2.6 kg/m²).
Outcome measures: A three-dimensional back scan was performed to measure the upper back posture in habitual standing. The tolerance ranges and CI were calculated. Group differences were tested by the Wilcoxon Mann-Whitney U test.
Results: In normal posture, the spinal column was marginally twisted to the left, and the vertebrae were marginally rotated to the right. The kyphosis angle is larger than the lumbar angle. Consequently, a more kyphotic posture is observed in the sagittal plane. The habitual posture is slightly scoliotic with a rotational component (scapular depression right, right scapula marginally more dorsally, high state of pelvic right, iliac right further rotated anteriorly).
Conclusions: Healthy young women have an almost ideally balanced posture with minimal ventral body inclination and a marginal scoliotic deviation. Compared with young males, women show only marginal differences in the upper body posture. These values allow a comparison to other studies, both for control and patient data, and may serve as guideline in both clinical practice and scientific studies.
Self-organized robots may develop attracting states within the sensorimotor loop, that is within the phase space of neural activity, body and environmental variables. Fixpoints, limit cycles and chaotic attractors correspond in this setting to a non-moving robot, to directed, and to irregular locomotion respectively. Short higher-order control commands may hence be used to kick the system from one self-organized attractor robustly into the basin of attraction of a different attractor, a concept termed here as kick control. The individual sensorimotor states serve in this context as highly compliant motor primitives. We study different implementations of kick control for the case of simulated and real-world wheeled robots, for which the dynamics of the distinct wheels is generated independently by local feedback loops. The feedback loops are mediated by rate-encoding neurons disposing exclusively of propriosensoric inputs in terms of projections of the actual rotational angle of the wheel. The changes of the neural activity are then transmitted into a rotational motion by a simulated transmission rod akin to the transmission rods used for steam locomotives. We find that the self-organized attractor landscape may be morphed both by higher-level control signals, in the spirit of kick control, and by interacting with the environment. Bumping against a wall destroys the limit cycle corresponding to forward motion, with the consequence that the dynamical variables are then attracted in phase space by the limit cycle corresponding to backward moving. The robot, which does not dispose of any distance or contact sensors, hence reverses direction autonomously.
Objective: To evaluate the efficacy and tolerability of brivaracetam (BRV) in a severely drug refractory cohort of patients with epileptic encephalopathies (EE).
Method: A multicenter, retrospective cohort study recruiting all patients treated with EE who began treatment with BRV in an enrolling epilepsy center between 2016 and 2017.
Results: Forty-four patients (27 male [61%], mean age 29 years, range 6 to 62) were treated with BRV. The retention rate was 65% at 3 months, 52% at 6 months and 41% at 12 months. A mean retention time of 5 months resulted in a cumulative exposure to BRV of 310 months. Three patients were seizure free during the baseline. At 3 months, 20 (45%, 20/44 as per intention-to-treat analysis considering all patients that started BRV including three who were seizure free during baseline) were either seizure free (n = 4; 9%, three of them already seizure-free at baseline) or reported at least 25% (n = 4; 9%) or 50% (n = 12; 27%) reduction in seizures. An increase in seizure frequency was reported in two (5%) patients, while there was no change in the seizure frequency of the other patients. A 50% long-term responder rate was apparent in 19 patients (43%), with two (5%) free from seizures for more than six months and in nine patients (20%, with one [2 %] free from seizures) for more than 12 months. Treatment-emergent adverse events were predominantly of psychobehavioural nature and were observed in 16%.
Significance: In this retrospective analysis the rate of patients with a 50% seizure reduction under BRV proofed to be similar to those seen in regulatory trials for focal epilepsies. BRV appears to be safe and relatively well tolerated in EE and might be considered in patients with psychobehavioral adverse events while on levetiracetam.
Cultural psychology assumes that the ecocultural conditions of a particular setting shape children’s pathways, resulting in multiple adaptive solutions to universal developmental tasks. While the adaptivity of attachment and children’s psychosocial development during the early years has been thoroughly investigated, attachment research during middle childhood continues to reflect Western ideals of family. Adhering to ideas of monotropy, most studies only focus on parental attachment figures. However, this restricted empirical perspective does not only result in a Eurocentric bias, it also neglects theoretical reflections on the growing complexity of attachment during middle childhood, thus only considering a limited selection of all individuals contributing to the children’s feeling of security, even in Western settings. To investigate the variability and adaptivity of attachment during middle childhood, this study assessed children’s attachment figures in two extreme settings of development, introducing an exhaustive network perspective on attachment during this developmental stage. Children of the Cameroonian Nseh (N = 11) and German children from Bad Nauheim (N = 11) identified and differentiated all individuals contributing to their attachment need in an exploratory and transdisciplinary approach. The socio-structural composition of children’s attachment networks follows the context-specific systems of care and concepts of interconnectedness and the ecological features of each setting, resulting in marked differences between both contexts. The functional composition, however, reflects children’s preoccupation with similar developmental challenges across settings. Same-aged peers contribute to the children’s feeling of safety in both settings, thereby deviating from previous reflections on their subordinate relevance during middle childhood. Overall, these results support the adaptiveness of children’s attachment patterns while also demonstrating universal trends across contexts. They highlight the collective nature of attachment during middle childhood that exceeds the impact of individual dyads. Thus, broad and context-sensitive research strategies become a necessary addition to attachment research in order to generate an exhaustive understanding for children’s development across cultural contexts.
Our ability to select relevant information from the environment is limited by the resolution of attention – i.e., the minimum size of the region that can be selected. Neural mechanisms that underlie this limit and its development are not yet understood. Functional magnetic resonance imaging (fMRI) was performed during an object tracking task in 7- and 11-year-old children, and in young adults. Object tracking activated canonical fronto-parietal attention systems and motion-sensitive area MT in children as young as 7 years. Object tracking performance improved with age, together with stronger recruitment of parietal attention areas and a shift from low-level to higher-level visual areas. Increasing the required resolution of spatial attention – which was implemented by varying the distance between target and distractors in the object tracking task – led to activation increases in fronto-insular cortex, medial frontal cortex including anterior cingulate cortex (ACC) and supplementary motor area, superior colliculi, and thalamus. This core circuitry for attentional precision was recruited by all age groups, but ACC showed an age-related activation reduction. Our results suggest that age-related improvements in selective visual attention and in the resolution of attention are characterized by an increased use of more functionally specialized brain regions during the course of development.
The social construction of technological stasis : the stagnating data structure in OpenStreetMap
(2018)
The article aims for examining the ‘technological stasis’ of the data structure in OpenStreetMap – the successful global collaborative geodata project devoted to ‘create and distribute free geographic data for the world’. Digital structures are strongly influenced by continuing stagnation. This technological stasis – the lack of change in technology – influences data in various ways, as demonstrated by the intensive discussion of the issue by computer scientists and software engineers. However, existing research describing stagnating software is often technic centred and fuzzy, while critical research is barely considering issues of technological stasis in the digital context at all. Therefore, this paper aims for enriching this body of knowledge in order to shed light on aging data structures. I reframe technological stasis with a social-constructivist perspective – using the approach of Social Construction of Technology – especially with the concept of technological frames. Based on the case example of OpenStreetMap, my findings suggest that the data structure – and its stasis – is the outcome of competing understandings and perspectives, shaped by power asymmetries. Although the data structure did not significantly change for more than 10 years, I demonstrate that this is not because of a lack of motivation, nor technological difficulties of carrying out such changes. The technological stasis is rather rooted in the dominant position of few project members who are able to change the software design; it is their perception of the project that defines how data should be stored and what features are dispensable.
Auf Knopfdruck geht es sekundenschnell in die Tiefe. Als sich die Aufzugstür drei Stockwerke unter der Erde öffnet, tauchen im Licht von Neonröhren unendlich lang erscheinende Regale auf. Viele sind vollgestellt mit Büchern. Andere warten darauf, dass sich ihre Reihen noch füllen. Etwa 2,7 Millionen Bände lagern in unterirdischen Magazinen der Universitätsbibliothek (UB) Johann Christian Senckenberg am Campus Bockenheim. Der Name UB umfasst zum einen die Zentralbibliothek (ZB) am Campus Bockenheim, zum anderen die fünf Bereichsbibliotheken Naturwissenschaften, Recht und Wirtschaft, Sozialwissenschaften und Psychologie, Geisteswissenschaften sowie Medizin.
Parkinson’s disease (PD) is characterized by distinct motor and non-motor symptoms. Sleep disorders are the most frequent and challenging non-motor symptoms in PD patients, and there is growing evidence that they are a consequence of disruptions within the circadian system. PD is characterized by a progressive degeneration of the dorsal vagal nucleus and midbrain dopaminergic neurons together with an imbalance of many other neurotransmitters. Mutations in α-synuclein (SNCA), a protein modulating SNARE complex-dependent neurotransmission, trigger dominantly inherited PD variants and sporadic cases of PD. The A53T SNCA missense mutation is associated with an autosomal dominant early-onset familial PD. To test whether this missense mutation affects the circadian system, we analyzed the spontaneous locomotor behavior of non-transgenic wildtype mice and transgenic mice overexpressing mutant human A53T α-synuclein (A53T). The mice were subjected to entrained- and free-running conditions as well as to experimental jet lag. Furthermore, the vesicular glutamate transporter 2 (VGLUT2) in the suprachiasmatic nucleus (SCN) was analyzed by immunohistochemistry. Free-running circadian rhythm and, thus, circadian rhythm generation, were not affected in A53T mice. A53T mice entrained to the light–dark cycle, however, with an advanced phase angle of 2.65 ± 0.5 h before lights off. Moreover, re-entrainment after experimental jet lag was impaired in A53T mice. Finally, VGLUT2 immunoreaction was reduced in the SCN of A53T mice. These data suggest an impaired light entrainment of the circadian system in A53T mice.
Bei Autismus-Spektrum-Störungen (ASS) handelt es sich um genetisch komplexe Störungen mit hoher Erblichkeit. Als zugrundeliegender Pathomechanismus von ASS werden unter anderem Veränderungen der neuronalen Entwicklung diskutiert. Der Phänotyp von ASS ist definiert durch Einschränkungen in der sozialen Interaktion und Kommunikation sowie repetitives und stereotypes Verhalten. Genkopiepolymorphismen (englisch „copy number variations“/CNVs), also Deletionen oder Duplikationen einer chromosomalen Region, wurden wiederholt in Probanden mit ASS identifiziert. Hierbei ist in ASS die Region 16p11.2 mit am häufigsten von CNVs betroffen. Einige Gene aus diesem chromosomalen Abschnitt wurden bereits funktionell charakterisiert. Dennoch können die Befunde der bisherigen Einzelgenstudien nicht alle Aspekte erklären, die durch 16p11.2 CNVs hervorgerufen werden. Ziel dieser Studie war es daher, ein weiteres neuronal assoziiertes Kandidatengen dieser Region zu identifizieren und im Anschluss funktionell im Kontext der neuronalen Differenzierung zu charakterisieren.
Das SH-SY5Y Neuroblastom-Zellmodell wurde auf Transkriptom- und morphologischer Ebene auf seine Eignung als Modell für neuronale Differenzierung untersucht und bestätigt. Eine Analyse der Expressionen aller Gene der 16p11.2-Region zeigte, dass das Gen Quinolinat-Phosphoribosyltransferase (QPRT) eine vergleichsweise hohe Expression mit der stärksten und robustesten Regulierung über die Zeit aufwies. Eine de novo Deletion der 16p11.2-Region wurde in einem Patienten im Vergleich zu seinen Eltern validiert. In Patienten-spezifischen lymphoblastoiden Zelllinien derselben Familie konnten wir eine Gendosis-abhängige Expression von QPRT auf RNA-Ebene bestätigen. In SH-SY5Y-Zellen korrelierte die Expression von QPRT signifikant mit der Entwicklung von Neuriten während der Differenzierung. Um QPRT funktionell zu charakterisieren, benutzten wir drei verschiedene Methoden zur Reduktion der QPRT-Gendosis: (i) knock down (KD) durch siRNA, (ii) chemische Inhibition durch Phthalsäure und (iii) knock out (KO) über CRISPR/Cas9-Geneditierung. Eine Reduktion von QPRT durch siRNA führte zu einer schwachen Veränderung der neuronalen Morphologie differenzierter SH-SY5Y-Zellen. Die chemische Inhibition sowie der genetische KO von QPRT waren letal für differenzierende aber nicht für proliferierende Zellen. Eine Metabolitenanalyse zeigte keine Veränderungen des QPRT-assoziierten Tryptophanstoffwechsels. Gene, welche auf Transkriptomebene im Vergleich zwischen KO- und Kontrollzellen differenziell reguliert vorlagen, waren häufig an Prozessen der neuronalen Entwicklung sowie an der Bildung, Stabilität und Funktion synaptischer Strukturen beteiligt. Die Liste differenziell regulierter Gene enthielt außerdem überdurchschnittlich viele ASS-Risikogene und ko-regulierte Gengruppen waren assoziiert mit der Entwicklung des dorsolateralen präfrontalen Cortex, des Hippocampus sowie der Amygdala.
In dieser Studie zeigten wir einen kausalen Zusammenhang zwischen QPRT und der neuronalen Differenzierung in vitro sowie einen Einfluss von QPRT auf die Regulation von ASS-assoziierten Genen und Gen-Netzwerken. Funktionell standen diese Gene im Kontext mit synaptischen Vorgängen, welche durch Veränderungen zu einem Exzitations-Inhibitions-Ungleichgewicht und letztendlich zum Zelltod von Neuronen führen können. Unsere Ergebnisse heben in Summe die wichtige Rolle von QPRT in der Krankheitsentstehung von ASS, insbesondere in Trägern einer 16p11.2 Deletion, hervor.
Chronic kidney disease and diabetes mellitus are associated with extensive media calcification, which leads to increased cardiovascular morbidity and mortality. Here, we investigated the role of autophagy in the pathogenesis of uremic vascular media calcification. DBA/2 mice were fed with high-phosphate diet (HPD) in order to cause vascular calcification. DBA/2 mice on standard chow diet were used as control. In parallel, autophagy and its response to rapamycin, 3-methyladenine (3-MA), and bafilomycin were studied in an in vitro model using mouse vascular smooth muscle cells (MOVAS). DBA/2 mice on HPD developed severe vascular media calcification, which is mirrored in vitro by culturing MOVAS under calcifying conditions. Both, in vitro and in vivo, autophagy significantly increased in MOVAS under calcifying conditions and in aortas of HPD mice, respectively. Histologically, autophagy was located to the aortic Tunica media, but also vascular endothelial cells, and was found to continuously increase during HPD treatment. 3-MA as well as bafilomycin blocked autophagy in MOVAS and increased calcification. Vice versa, rapamycin treatment further increased autophagy and resulted in a significant decrease of vascular calcification in vitro and in vivo. Rapamycin reduced Runx2 transcription levels in aortas and MOVAS to control levels, whereas it increased α-smooth muscle actin and Sm22α transcription in MOVAS to control levels. Furthermore, rapamycin-treated HPD mice survived significantly longer compared to HPD controls. These findings indicate that autophagy is an endogenous response of vascular smooth muscle cells (VSMC) to protect from calcification in uremia. Induction of autophagy by rapamycin protects cells and mice from uremic media calcification possibly by inhibiting osteogenic transdifferentiation of VSMC.
Rapid immune reconstitution (IR) following stem cell transplantation (SCT) is essential for a favorable outcome. The optimization of graft composition should not only enable a sufficient IR but also improve graft vs. leukemia/tumor effects, overcome infectious complications and, finally, improve patient survival. Especially in haploidentical SCT, the optimization of graft composition is controversial. Therefore, we analyzed the influence of graft manipulation on IR in 40 patients with acute leukemia in remission. We examined the cell recovery post haploidentical SCT in patients receiving a CD34+-selected or CD3/CD19-depleted graft, considering the applied conditioning regimen. We used joint model analysis for overall survival (OS) and analyzed the dynamics of age-adjusted leukocytes; lymphocytes; monocytes; CD3+, CD3+CD4+, and CD3+CD8+ T cells; natural killer (NK) cells; and B cells over the course of time after SCT. Lymphocytes, NK cells, and B cells expanded more rapidly after SCT with CD34+-selected grafts (P = 0.036, P = 0.002, and P < 0.001, respectively). Contrarily, CD3+CD4+ helper T cells recovered delayer in the CD34 selected group (P = 0.026). Furthermore, reduced intensity conditioning facilitated faster immune recovery of lymphocytes and T cells and their subsets (P < 0.001). However, the immune recovery for NK cells and B cells was comparable for patients who received reduced-intensity or full preparative regimens. Dynamics of all cell types had a significant influence on OS, which did not differ between patients receiving CD34+-selected and those receiving CD3/CD19-depleted grafts. In conclusion, cell reconstitution dynamics showed complex diversity with regard to the graft manufacturing procedure and conditioning regimen.
Background: Scientifically evaluated cognitive intervention programs are essential to meet the demands of our increasingly aging society. Currently, one of the “hottest” topics in the field is the improvement of working memory function and its potential impact on overall cognition. The present study evaluated the efficacy of WOME (WOrking MEmory), a theory-based working memory training program, in a double-blind, placebo-controlled, and randomized controlled trial (www.drks.de, DRKS00013162).
Methods: N = 60 healthy older adults were allocated to (1) the WOME intervention, (2) an active low-level intervention, or (3) a passive control group. Overall, the intervention groups practiced twelve sessions of 45 min within 4 weeks of their respective training. Transfer effects were measured via an extensive battery of neuropsychological tests and questionnaires both pre-/post-training and at a 3-month follow-up.
Results: WOME led to a significant improvement in working memory function, demonstrated on a non-trained near transfer task and on two different composite scores with moderate to large effect sizes. In addition, we found some indication of relevant impact on everyday life. The effects were short-term rather than stable, being substantially diminished at follow-up with only little evidence suggesting long-term maintenance. No transfer effects on other cognitive functions were observed.
Conclusion: WOME is an appropriate and efficient intervention specifically targeting the working memory system in healthy older adults.
Trial Registration: German Clinical Trials Register (DRKS), Identifier: DRKS00013162.
Nucleation and growth of aerosol particles from atmospheric vapors constitutes a major source of global cloud condensation nuclei (CCN). The fraction of newly formed particles that reaches CCN sizes is highly sensitive to particle growth rates, especially for particle sizes <10 nm, where coagulation losses to larger aerosol particles are greatest. Recent results show that some oxidation products from biogenic volatile organic compounds are major contributors to particle formation and initial growth. However, whether oxidized organics contribute to particle growth over the broad span of tropospheric temperatures remains an open question, and quantitative mass balance for organic growth has yet to be demonstrated at any temperature. Here, in experiments performed under atmospheric conditions in the Cosmics Leaving Outdoor Droplets (CLOUD) chamber at the European Organization for Nuclear Research (CERN), we show that rapid growth of organic particles occurs over the range from −25 ∘C to 25 ∘C. The lower extent of autoxidation at reduced temperatures is compensated by the decreased volatility of all oxidized molecules. This is confirmed by particle-phase composition measurements, showing enhanced uptake of relatively less oxygenated products at cold temperatures. We can reproduce the measured growth rates using an aerosol growth model based entirely on the experimentally measured gas-phase spectra of oxidized organic molecules obtained from two complementary mass spectrometers. We show that the growth rates are sensitive to particle curvature, explaining widespread atmospheric observations that particle growth rates increase in the single-digit-nanometer size range. Our results demonstrate that organic vapors can contribute to particle growth over a wide range of tropospheric temperatures from molecular cluster sizes onward.
Pretubulysin (PT), a biosynthetic precursor of the myxobacterial compound tubulysin D, was recently identified as a novel microtubule-targeting agent (MTA) causing microtubule destabilization. MTAs are the most frequently used chemotherapeutic drugs. They are well studied regarding their direct cytotoxic effects against various tumors as well as for their anti-angiogenic and vascular-disrupting action addressing endothelial cells of the tumor vasculature. However, the impact of MTAs on endothelial cells of the non-tumor vasculature has been largely neglected, although tumor cell interactions with the healthy endothelium play a crucial role in the process of cancer metastasis. Besides their use as potent anti-cancer drugs, some MTAs such as colchicine are traditionally used or recommended for the therapy of inflammatory diseases. Here, too, the role of endothelial cells has been largely neglected, although the endothelium is crucially involved in regulating the process of inflammation.
In the present study, the impact of PT on tumor-endothelial cell interactions was therefore analyzed in vitro to gain insights into the mechanism underlying its anti-metastatic effect that was recently confirmed in vivo. In the second part of this work, the influence of PT and other MTAs, namely the microtubule-destabilizing compounds vincristine (VIN) and colchicine (COL) and the microtubule-stabilizing drug paclitaxel (PAC), on leukocyte-endothelial cell interactions was investigated in vitro and in vivo (only PT). It is important to mention that in all in vitro experiments solely endothelial cells and not tumor cells or leukocytes were treated with the MTAs to strictly focus on the role of the endothelium in the action of these compounds.
The impact of PT on tumor-endothelial cell interactions was analyzed in vitro by cell adhesion and transendothelial migration assays as well as immunocytochemistry using the breast cancer cell line MDA-MB-231 and primary human umbilical vein endothelial cells (HUVECs). The treatment of HUVECs with PT increased the adhesion of MDA cells onto the endothelial monolayer, whereas their transendothelial migration was reduced by the compound. Thereafter, the influence of PT on the endothelial cell adhesion molecules (CAMs) E-selectin, N-cadherin, ICAM-1, VCAM-1 and galectin-3 and on the CXCL12/CXCR4 chemokine system was examined, since they might be involved in the PT-triggered tumor cell adhesion. Interestingly, although PT induced the upregulation of ICAM-1, VCAM-1, N-cadherin and CXCL12, cell adhesion assays using neutralizing antibodies or the CXCL12 inhibitor AMD3100 revealed that all these molecules were dispensable for the PT-evoked tumor cell adhesion. As PT induces the formation of interendothelial gaps and MDA cells might adhere onto components of the underlying extracellular matrix (ECM), the precise location of MDA cells attached to the PT-treated endothelial monolayer was investigated. Instead of a direct interaction between tumor and endothelial cells, this work showed that MDA cells preferred to adhere to the ECM component collagen that was exposed within PT-triggered endothelial gaps. Both the PT-evoked increase in tumor cell adhesion onto and the decrease in trans-endothelial migration were completely abolished when β1-integrins were blocked on MDA cells. Similar results were obtained when endothelial cells were treated with VIN and COL but not PAC, indicating that the observed effects of PT depend on its microtubule-destabilizing activity.
The impact of PT, VIN, COL and PAC on leukocyte-endothelial cell interactions was analyzed in vivo (only PT) by intravital microscopy of the mouse cremaster muscle and in vitro by cell adhesion assays using the monocyte-like cell line THP-1 and TNFα-activated human dermal microvascular endothelial cells (HMEC-1). While PT did not affect the rolling of leukocytes on the endothelium, their firm adhesion onto and transmigration through the activated endothelium was reduced by PT in vivo. In accordance, the treatment of HMEC-1 with PT, VIN and COL decreased the TNFα-induced adhesion of THP-1 cells onto the endothelial monolayer, whereas PAC had no influence on this process. Thereafter, the influence of PT, VIN, COL and PAC on endothelial ICAM-1 and VCAM-1 was examined, since these molecules are substantially involved in the firm adhesion of leukocytes onto the endothelium. The cell surface protein expression of ICAM-1 and VCAM-1 was reduced by PT, VIN and COL in activated endothelial cells, whereas PAC did only slightly affect the TNFα-induced upregulation of VCAM-1. As the pro-inflammatory transcription factor NFκB plays a crucial role in the TNFα-induced expression of these CAMs, the impact of the MTAs on the NFκB promotor activity was investigated. While PT, VIN and COL decreased the activation of NFκB in activated endothelial cells, PAC did not affect this process. However, in contrast to the strong effects regarding the cell surface protein expression of ICAM-1 and VCAM-1, the effects of PT, VIN and COL on the NFκB activity was rather low. Thus, the used MTAs might also affect other relevant signaling pathways and/or the intracellular transport of CAMs might be influenced by the impact of the MTAs on the microtubule network.
Taken together, the current study provides – at least in part – an explanation for the anti-metastatic potential of PT and gives first insights into the use of PT and VIN as anti-inflammatory drugs. Moreover, this work highlights the endothelium as an attractive target for the development of new anti-cancer and anti-inflammatory drugs.
An aerosol foam formulation of a once-daily, fixed-dose combination of a synthetic vitamin D3 analog/synthetic corticosteroid (calcipotriol [Cal] 50 µg/g and betamethasone dipropionate [BD] 0.5 mg/g) has recently been introduced for the topical treatment of plaque psoriasis in adults. Data from several sources – randomized controlled trials, case reports (as highlighted in this review), and real-world evidence (RWE) – underscore the considerable and rapid clinical response, effectiveness, and favorable safety and tolerability of Cal/BD aerosol foam in mild-to-moderate psoriatic patients previously treated with class 3 or 4 topical corticosteroids, in patients unsatisfied with ongoing phototherapy in combination with topical therapy and in patients with moderate-to-severe psoriasis. In addition, our case series, considered together with other RWE, highlights that Cal/BD aerosol foam is more effective and with greater levels of patient preference and acceptability than comparator preparations. Thus, Cal/BD aerosol foam offers several treatment advantages, including relief of itch, and is an appropriate first-line topical therapy for consideration in patients with psoriasis of any severity.
Damaged mitochondria are selectively eliminated by mitophagy. Parkin and PINK1, gene products mutated in familial Parkinson’s disease, play essential roles in mitophagy through ubiquitination of mitochondria. Cargo ubiquitination by E3 ubiquitin ligase Parkin is important to trigger selective autophagy. Although autophagy receptors recruit LC3-labeled autophagic membranes onto damaged mitochondria, how other essential autophagy units such as ATG9A-integrated vesicles are recruited remains unclear. Here, using mammalian cultured cells, we demonstrate that RABGEF1, the upstream factor of the endosomal Rab GTPase cascade, is recruited to damaged mitochondria via ubiquitin binding downstream of Parkin. RABGEF1 directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria, whose associations are further regulated by mitochondrial Rab-GAPs. Furthermore, depletion of RAB7A inhibited ATG9A vesicle assembly and subsequent encapsulation of the mitochondria by autophagic membranes. These results strongly suggest that endosomal Rab cycles on damaged mitochondria are a crucial regulator of mitophagy through assembling ATG9A vesicles.
Photolabile protecting groups (PPGs, cages, photocages) are molecules which can block the activity of a functional group and be removed by irradiation of light of an appropriate wavelength. One of the goals of this work was to design new photolabile protecting groups, based on a literature known one. The far-UV absorbing diethylamino benzyl (DEAMb) photocage, developed by Wang et al., was selected as structural basis for this work. In order to trigger the uncaging reaction with longer wavelengths (≥365 nm), thus allowing also biological applications, its structure was optimized. This was done by elongating the π-orbital conjugation using biphenyl derivatives instead of a single aromatic moiety. The photocage was loaded with glutamic acid as the leaving group.
The highest bathochromic shift was shown by compounds, which had the smallest sterical hindrance imposed on the second aromatic ring. The absorption spectrum was more redshifted if the second aromatic ring contained an electron withdrawing group. However, the stronger the substituents electron withdrawing strength was, the lower the uncaging quantum yield was. It was rationalized, that this is due to a decreased excited state electron density at the benzylic carbon of the DEAMb core which is necessary to trigger bond dissociation. This has been confirmed using TDDFT (time-dependent density functional theory) computations done by Jan von Cosel, Konstantin Falahati and Carsten Hamerla (from the group of Irene Burghardt). The best uncaging quantum yield was 42% for m-phenyl substituted DEAMb, while if a strong electron withdrawing group was present (nitro group), there was no photoactivity at all.
In order to achieve a better π-orbital conjugation of the non-coplanar biphenyl derivatives, a C-C bond was introduced between the benzylic carbon and the second aromatic ring. The resulting planar compounds belong to the fluorene class. The computational data predicted the photochemical meta effect to some extent to be preserved in these molecules. A set of fluorene derivatives was synthesized and photochemically characterized. The molar absorption coefficients of all prepared fluorene derivatives were higher than for any of the biphenyl derivatives. Quantum yields of the acetate release ranged between 3-42%, thus being as good as the best glutamic acid releasing biphenyl compounds. The highest uncaging cross section of the acetate release from the prepared fluorene derivatives was above 5000 M^-1 cm^-1. This value proves the high potential of the new fluorene based photocages developed in this work. Furthermore, release of hydroxide ion from fluorenol could be shown along with generation of, presumably, fluorenyl cation. These intriguing results paves a way for further exploration of fluorene based photocages for the release of bad leaving groups.
The second part of this work describes the custom synthesis of 13C labeled compounds for the VIPER (VIbrationally Promoted Electronic Resonance) project. In the VIPER pulse sequence, a molecule is vibrationally excited by a narrow band IR-pump pulse. The following Vis-pump pulse will promote the vibrationally pre-excited molecules to an electronically excited state. This Vis-pump pulse is offresonant for the not vibrationally pre-selected species and only resonant with the molecules, which are already pre-excited by the IR-pump pulse. Since the IR absorption bands usually are well resolved, a selective excitation of one molecule in an ensemble of similar ones is possible in the IR frequency range. Isotopologues and isotopomers are an extreme case of molecules which are near identical and differ only by isotopic composition or position. As a result in solution and at room temperature they have an identical UV-Vis absorption spectrum but different IR spectrum. This allows vibrational excitation of only one isotopologue (or isotopomer).
Isotopic labels were introduced in known photocages: 7-diethylamino coumarin (DEACM) and para-hydroxy phenacyl (pHP). The position for isotopic label incorporation in these molecules was guided by computations done by Jan von Cosel and Carsten Neumann. To allow control of the photoreactions in an ultrafast timescale, an IR active leaving group was used. The uncaging behavior of the prepared molecules in steady state was tested using chromatography (HPLC) and spectroscopy (1H NMR, FTIR and UV-Vis). The VIPER experiments were performed by Daniela Kern-Michler, Carsten Neumann, Nicole Mielke and Luuk van Wilderen (from the group of Jens Bredenbeck). A selective uncaging of only the vibrationally pre-excited molecules could be achieved.
Background: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group.
Methods: The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation.
Results: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years.
Conclusions: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.
Background: The city of Wrocław in Poland represents one of Central Europeans oldest capitals of science with numerous Nobel laureates. Due to a long history of political suppressions with Nazi Germany and Communism from 1933 until 1989, its scientific community was suppressed for more than half a century.
Methods: The present study assessed scientific activities in the field of social and neighbouring sciences using density equalizing mapping. On the basis of the NewQIS (New Quality and Quantity Indices in Science) platform and the Social Sciences Citation Index (SSCI) of the Web of Science database, a total of 1787 articles originating from Wrocław were identified between 1966 and 2017.
Results: In total, 549 research collaborations of Wrocław with 96 different countries were present (30.7%). Among the 107 research areas the highest activity was found for the field of Business and Economics with n = 272 articles (average citation rate (AVR) of 12.54), followed by Psychology (n = 252 articles, AVR = 9.06), Psychiatry (n = 205 articles, AVR = 4.74) and Public, Environmental and Occupational Health (n = 145 articles, AVR = 7.96). The highest AVR was found for Operations Research (25.36 with n = 87 articles). Density equalizing mapping procedures revealed a global pattern of social sciences research collaborations with scientists from Germany, the UK and the US as the primary cooperating partner of Wrocław. The different countries had major differences in the area of research collaborations.
Conclusions: This is the first study that depicts the global network of Wrocław scientific activities in the field of social sciences. The exorbitant increase in research activity from 2006 onwards can lead to the assumption that Wrocław social sciences encounter a fruitful future.
Martin Luthers theologische Idee der Unterscheidung von Gnade/Evangelium und Gesetz/Vernunft, Glauben/Unglauben und Werk, schränkte die Zweiwertigkeitslogik des Aristoteles auf die Gestaltung der Existenz ein und erwies ihre Ungültigkeit für die Erfassung des Grundes der Existenz. Während Luther die dialektische Struktur der Beziehung von Gestaltung und Grund der Existenz in der Form der o.g. Vorstellung zum Ausdruck brachte, hat G.W.F. Hegel sie auf den Begriff gebracht und damit Luthers Theologie in die Philosophie transformiert.
Determining the cell fate and the distribution of mesenchymal stromal/stem cells (MSCs) after transplantation are essential parts of characterizing the mechanisms of action and biosafety profile of stem cell therapy. Many recent studies have shown that MSCs migrate into injured tissues, but are only detectable at extremely low frequencies. We investigated the cell fate of MSCs after transplantation in an acute kidney injury (AKI) mouse model using in vivo bioluminescence imaging (BLI) and subsequent verification of cell migration using quantitative real-time polymerase chain reaction (qRT-PCR). The AKI was induced by a single injection of cisplatin (8 or 12 mg/kg). One day later, adipose-derived mesenchymal stromal/stem cells isolated from luciferase transgenic mice (Luc+-mASCs, 5 × 105) were intravenously transplanted. Migration kinetics of the cells was monitored using BLI on day 1, 3, and 6, and finally via quantitative real-time PCR at the endpoint on day 6. Using BLI, infused Luc+-mASCs could only be detected in the lungs, but not in the kidneys. In contrast, PCR endpoint analysis revealed that Luc-specific mRNA could be detected in injured renal tissue; compared to the control group, the induction was 2.2-fold higher for the 8 mg/kg cisplatin group (p < 0.05), respectively 6.1-fold for the 12 mg/kg cisplatin group (p < 0.001). In conclusion, our study demonstrated that Luc-based real-time PCR rather than BLI is likely to be a better tool for cell tracking after transplantation in models such as cisplatin-induced AKI.
This paper argues that the introduction of the Banking Recovery and Resolution Directive (BRRD) improved market discipline in the European bank market for unsecured debt. The different impact of the BRRD on bank bonds provides a quasi-natural experiment that allows to study the effect of the BRRD within banks using a difference-in-difference approach. Identification is based on the fact that (otherwise identical) bonds of a given bank maturing before 2016 are explicitly protected from BRRD bail-in. The empirical results are consistent with the hypothesis that debt holders actively monitor banks and that the BRRD diminished bail-out expectations. Bank bonds subject to BRRD bail-in carry a 10 basis points bail-in premium in terms of the yield spread. While there is some evidence that the bail-in premium is more pronounced for non-GSIB banks and banks domiciled in peripheral European countries, weak capitalization is the main driver.
Subduction zone magmas are more oxidised on eruption than those at mid-ocean ridges. This is attributed either to oxidising components, derived from subducted lithosphere (slab) and added to the mantle wedge, or to oxidation processes occurring during magma ascent via differentiation. Here we provide direct evidence for contributions of oxidising slab agents to melts trapped in the sub-arc mantle. Measurements of sulfur (S) valence state in sub-arc mantle peridotites identify sulfate, both as crystalline anhydrite (CaSO4) and dissolved SO42− in spinel-hosted glass (formerly melt) inclusions. Copper-rich sulfide precipitates in the inclusions and increased Fe3+/∑Fe in spinel record a S6+–Fe2+ redox coupling during melt percolation through the sub-arc mantle. Sulfate-rich glass inclusions exhibit high U/Th, Pb/Ce, Sr/Nd and δ34S (+ 7 to + 11‰), indicating the involvement of dehydration products of serpentinised slab rocks in their parental melt sources. These observations provide a link between liberated slab components and oxidised arc magmas.
GD2-directed immunotherapies improve survival of high-risk neuroblastoma (NB) patients (pts). Treatment with chimeric anti-GD2 antibodies (Ab), such as ch14.18, can induce development of human anti-chimeric Ab (HACA). Here, we report HACA effects on ch14.18/CHO pharmacokinetics, pharmacodynamics and pain intensity in pts treated by long-term infusion (LTI) of ch14.18/CHO combined with IL-2. 124 pts received up to 5 cycles of ch14.18/CHO 10 days (d) infusion (10 mg/m2/d; d8–18) combined with s.c. IL-2 (6 × 106 IU/m2/d; d1–5, d8–12). HACA, treatment toxicity, ch14.18/CHO levels, Ab-dependent cellular- (ADCC) and complement-dependent cytotoxicity (CDC) were assessed using respective validated assays. HACA-negative pts showed a steadily decreased pain in cycle 1 (74% pts without morphine by d5 of LTI) with further decrease in subsequent cycles. Ch14.18/CHO peak concentrations of 11.26 ± 0.50 µg/mL found in cycle 1 were further elevated in subsequent cycles and resulted in robust GD2-specific CDC and ADCC. Development of HACA (21% of pts) resulted in strong reduction of ch14.18/CHO levels, abrogated CDC and ADCC. Surprisingly, no difference in pain toxicity between HACA-positive and -negative pts was found. In conclusion, ch14.18/CHO LTI combined with IL-2 results in strong activation of Ab effector functions. Importantly, HACA response abrogated CDC but did not affect pain intensity indicating CDC-independent pain induction.
Introduction: Hip fracture surgery is associated with high in-hospital and 30-day mortality rates and serious adverse patient outcomes. Evidence from randomised controlled trials regarding effectiveness of spinal versus general anaesthesia on patient-centred outcomes after hip fracture surgery is sparse.
Methods and analysis: The iHOPE study is a pragmatic national, multicentre, randomised controlled, open-label clinical trial with a two-arm parallel group design. In total, 1032 patients with hip fracture (>65 years) will be randomised in an intended 1:1 allocation ratio to receive spinal anaesthesia (n=516) or general anaesthesia (n=516). Outcome assessment will occur in a blinded manner after hospital discharge and inhospital. The primary endpoint will be assessed by telephone interview and comprises the time to the first occurring event of the binary composite outcome of all-cause mortality or new-onset serious cardiac and pulmonary complications within 30 postoperative days. In-hospital secondary endpoints, assessed via in-person interviews and medical record review, include mortality, perioperative adverse events, delirium, satisfaction, walking independently, length of hospital stay and discharge destination. Telephone interviews will be performed for long-term endpoints (all-cause mortality, independence in walking, chronic pain, ability to return home cognitive function and overall health and disability) at postoperative day 30±3, 180±45 and 365±60.
Ethics and dissemination: iHOPE has been approved by the leading Ethics Committee of the Medical Faculty of the RWTH Aachen University on 14 March 2018 (EK 022/18). Approval from all other involved local Ethical Committees was subsequently requested and obtained. Study started in April 2018 with a total recruitment period of 24 months. iHOPE will be disseminated via presentations at national and international scientific meetings or conferences and publication in peer-reviewed international scientific journals.
Trial registration number: DRKS00013644; Pre-results
Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects’ fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectrometry-based complexome profiling. This confirmed a marked reduction in incorporated NDUFA6 and a concomitant reduction in other Q-module subunits, including NDUFAB1, NDUFA7, and NDUFA12. Lentiviral transduction of subjects’ fibroblasts showed normalization of complex I. These data also support supercomplex formation, whereby the ∼830 kDa complex I intermediate (consisting of the P- and Q-modules) is in complex with assembled complex III and IV holoenzymes despite lacking the N-module. Interestingly, RNA-sequencing data provided evidence that the consensus RefSeq accession number does not correspond to the predominant transcript in clinically relevant tissues, prompting revision of the NDUFA6 RefSeq transcript and highlighting not only the importance of thorough variant interpretation but also the assessment of appropriate transcripts for analysis.
Aims: The ILUVIEN Registry Safety Study is an ongoing, multicentre, open-label, observational study collecting real-world data on the safety and effectiveness of the 0.2 µg/day fluocinolone acetonide (FAc) implant in patients treated according to the European label requirements.
Methods: Patients included in this analysis were treated for the licensed indication of chronic diabetic macular oedema (cDMO; that is, DMO that persists or recurs despite treatment). Data presented in the current analysis were collected from patient records up to 6 March 2017. Visual acuity (VA) data, including mean change in VA over time and at last observation, intraocular pressure (IOP) over the course of the study, IOP events, use of IOP-lowering therapy and cup:disc ratio were analysed. Information on additional DMO treatments post-FAc implant was also captured.
Results: Five hundred and sixty-three patients (593 eyes) were enrolled on the study. Mean IOP for the overall population remained within the normal range throughout follow-up and 76.7% of patients did not require IOP-lowering therapy following treatment with the FAc implant. Sixty-nine per cent of eyes did not require additional DMO treatments. Mean VA in the overall population increased from 51.9 letters at baseline to 55.6 letters at month 12, with a significant increase of 2.9 letters at last observation. Patients with short-term cDMO experienced greater VA gains than those with long-term cDMO.
Conclusions: The results of this analysis are comparable with those of other studies, including the Fluocinolone Acetate for Macular Edema study. The study reinforces the good safety and effectiveness profile of FAc, and demonstrates the benefit of early FAc treatment.
This dissertation aimed to shed light on changes of the epigenetic landscape in heart and skeletal muscle tissue of the turquoise Killifish N. furzeri, a novel, short-lived animal model for aging research. The following results could be obtained:
1. A global trend towards closed chromatin conformation could be observed; histone markers for H3K27me3, H3K9me3 and H4K20me3 accumulated in skeletal muscle tissue from old N. furzeri. Markers for open chromatin conformation such as H3K4me3, H3K9ac and H4K16ac decreased in old skeletal muscle tissue. In old hearts from N. furzeri an accumulation of H3K27me3 could be detected while H3K9ac was found to increase with age as well. mRNA expression levels of methylating enzymes were higher in skeletal muscle tissue from old N. furzeri when compared to expression levels in skeletal muscle tissue from young N. furzeri.
2. The shift of epigenetic pattern was accompanied by a change of gene expression. Via mRNA sequencing in collaboration with the MPI, Bad Nauheim it could be shown that genes associated with cell cycle and DNA repair were lower expressed in skeletal muscle tissue from old N. furzeri than in tissue from young N. furzeri. Genes, associated with inflammatory signaling and glycolysis, displayed increased mRNA levels in skeletal muscle tissue from old N. furzeri. These results could be confirmed by Western blot and qRT-PCR analyses.
3. Markers for DNA damage and senescence increased in skeletal muscle tissue from old N. furzeri.
4. Cells derived from young and old N. furzeri skeletal muscle could be isolated and cultured for many passages. These cells were a mix of different cell types with properties and features of the native tissue. They could be used for treatment with drugs and/small compounds modulating the epigenetic landscape via specific interference with methylating enzymes.
5. DNA methylation and hydroxy-methylation were found to go in different directions in skeletal muscle and heart tissue from N. furzeri: while increasing in skeletal muscle tissue, a both DNA modifications declined in heart tissue with age.
6. In the heart of N. furzeri microRNA expression changes with age were assed with sequencing in collaboration with the FLI, Jena. It could be demonstrated that miRNA expression is age-dependent. Particular focus was on miR-29 and its target genes: miR-29 was highly upregulated in heart and skeletal muscle tissue, while target genes such as collagens and dnmts were reduced with age in the heart of N. furzeri.
7. Cardiac function remained stable with age and no accumulation of collagens could be found when comparing hearts of young and old N. furzeri despite the increase of markers for oxidative stress.
8. Cell culture experiments with human cardiac fibroblasts revealed that miR-29 is upregulated with increasing age of the donor. In addition to that, it could be shown that miR-29 is positively regulated by oxidative stress.
9. A zebrafish mutant with modified expression of miR-29 that was created in collaboration with the SNS, Pisa, presented a severe hypoxic phenotype and an altered mRNA expression profile compared to wild type control zebrafish. Cardiac dysfunction and hypertrophy were observed as well as an increase in DNA methylation and collagens.
Taken together, it could be shown that the aging process in skeletal muscle and heart tissue from N. furzeri leads to a series of changes on epigenetic levels. It remains to be elucidated whether these changes are result or cause for further changes of mRNA expression, protein levels and pathophysiology, yet the N. furzeri represents a promising research model for further aging studies.
Lizards of Paraguay: an integrative approach to solve taxonomic problems in central South America
(2018)
Paraguay is located in the center of South America with drier and warmer climatic conditions in the western part of the country, and more temperate and humid in the eastern region. Biogeographically, Paraguay is a key spot in South America, where several ecoregions converge. In my study, I sampled most of the ecoregions of Paraguay. The main objective of my work is to solve taxonomic problems, identified through genetic barcoding analyses, in the central region of South America. To achieve this objective, I used selected taxa of the Paraguayan Squamata as models taking into consideration the crucial geographic position of the country, plus the scarce available genetic data of Paraguayan reptiles.
The collecting activities were performed in the framework of a barcoding inventory project of the Paraguayan herpetofauna and carried out mostly in rural areas searching for animals in different types of habitats using active search as the sampling technique.
For genetics, the extraction of DNA was performed with DNeasy® Blood & Tissue Kit of Qiagen® for sets of few samples, and the fiber glass plate protocol for sets of 96 samples. I assessed the quality of sequences after amplification in agarose gel electrophoresis. The first marker sequenced was 16S mtDNA, used for barcoding analysis. A DNA barcode is a genetic identifier for a species. Once a taxonomic problem was detected, I generate more gene sequences to target the issue.
All the analyses to test phylogenetic hypotheses (based on single genes or concatenated datasets) were performed under Maximum Likelihood and Bayesian approaches. To root the phylogenetic trees, I chose the available taxon (or taxa) most closely related to the respective studied group as outgroups. For the general tree of Paraguayan Squamata, based on barcodes of 16S, I chose Sphenodon punctatus.
I generated a total of 142 sequences of 64 species of Squamata from Paraguay (Appendix I). The final alignment of 615 bp comprised 249 samples. The best substitution model for the Barcoding dataset based on the gene 16S was GTR+G, according to the BIC.
To complement molecular evidence generated with the ML grouping of 16S barcodes, I took a morphological approach based on voucher specimens collected during fieldwork (usually the same specimens that I used for genetic analysis), supplemented by the revision of museum collections.
Summarizing my results, samples of Colobosaura exhibit large genetic distances, and accordingly I revalidated Colobosaura kraepelini (Appendix II). Tropidurus of the spinulosus group show two clades and among them there is little genetic and morphological variation, I synonymized T. tarara and T. teyumirim with T. lagunablanca, and T. guarani with T. spinulosus (Appendix III). I detected the presence of candidate species of Homonota, and I restricted the name H. horrida for Argentina, and described two new species of Homonota (Appendices IV and V), and a new species of Phyllopezus also in the Family Phyllodactylidae (Appendix VI).
In this work I present the most comprehensive analysis of genetic samples of Squamata from Paraguay. The results obtained here will be useful to help to clarify further taxonomic issues regarding the squamate fauna from the central region of South America. Moreover, the data generated for this study will have a positive impact in a larger geographic context, beyond Paraguayan borders.
Regarding the conservation of the Paraguayan reptiles, and considering the taxonomic changes accomplished here, it is important to note that many species lack legal protection. In Paraguay, the major problem for conservation is habitat loss due to extensive crop farming. Thus, currently, the protected areas are the best strategy for conservation of biodiversity in the country. However, many such areas face legal problems (e.g., lack of official measurements, management plans, forest guards, infrastructure, etc.) so that the maintenance of their biodiversity over time is not guaranteed.
In conclusion, in this study I present contributions on the taxonomy of mostly lizards from Paraguay. Due to lack of samples, I was not able to deal with a deep taxonomic revision of the country's snakes. Based on my results, I can argue that analyses of Xenodontini and Pseudoboini are currently a pressing research issue. This barcoding project may continue since some colleagues in Paraguay are interested in collaboration. Given that the sequenced specimens are yet a small portion of the actual diversity of Paraguay, it will be of utmost importance to continue and expand these studies that will further improve our taxonomic knowledge. Furthermore, it is desirable to have Paraguayan scientists not only involved, but to see them taking the lead of high quality taxonomic research.
Lange Zeit galt das Exil, das durch die gewaltvolle Politik der Nationalsozialisten bedingt wurde, mit dem Ende des Zweiten Weltkrieges 1945 als beendet. Die implizite Begründung, die in der Exilliteraturforschung bis in die Anfänge des 21. Jahrhunderts dominierte, greift allerdings zu kurz: Mit dem Wegfall der Fluchtursachen werde das erzwungene Exil, das mit einer Rückkehr beendet werden könnte, zu einer freiwilligen Migration. Bei diesem Erklärungsmuster wurde die eigentliche Frage nach der Rückkehr der Exilanten lange vernachlässigt. Ist die Rückkehr in ein Land, das einen zuvor gewaltvoll vertrieben hat, überhaupt ohne weiteres möglich? Und vor allem: Lässt sich mittels einer geografischen Rückkehr das Exil beenden?
Das Standardmodell der Elementarteilchenphysik beschreibt nach aktuellem Kenntnisstand die Entstehung, den Aufbau und das Verhalten der Materie in unserem Universum am erfolgreichsten. Dennoch gibt es einige Phänomene, die sich nicht in dessen Rahmen beschreiben lassen, wie z. B. die Existenz von dunkler Materie und Energie, nicht-verschwindende Neutrinomassen oder die Baryonenasymmetrie. Speziell im Hinblick auf die starke Wechselwirkung, welche im Standardmodell durch die Quantenchromodynamik (QCD) beschrieben wird, gibt es noch immer viele offene Fragen.
Eine Umgebung, in der man die QCD experimentell ergründen kann, bieten vor allem Schwerionenkollisionen, die insbesondere am Large Hadron Collider (LHC) oder am Relativistic Heavy Ion Collider (RHIC) durchgeführt werden.
In dieser Arbeit soll ein Beitrag von theoretischer Seite aus hinsichtlich eines besseren Verständnisses dieser Schwerionenkollisionen und der zugrundeliegenden QCD erbracht werden. Der Fokus liegt dabei auf dem Isotropisierungsprozess unmittelbar nach der Kollision der beiden Kerne.
Neben etlichen effektiven Theorien, die sehr gute Ergebnisse in den entsprechenden Grenzbereichen liefern, ist die Beschreibung der QCD im Rahmen der Gittereichtheorie (Gitter-QCD) die am meisten etablierte. Diese beinhaltet in den meisten Fällen einen Übergang zur euklidischen Raumzeit, da somit ein Auswerten der hochdimensionalen Pfadintegrale mithilfe von Monte-Carlo-Simulation basierend auf dem sogenannten Importance Sampling ermöglicht wird. Aufgrund der Komplexwertigkeit der euklidischen Zeitkomponente ist man jedoch an das Studieren von statischen Observablen gebunden. Da wir aber gerade an einer Zeitentwicklung des Systems interessiert sind, sehen wir von dem Übergang zur euklidischen Raumzeit ab, was den Namen “real-time” im Titel der Arbeit erklärt.
Wir folgen dem sogenannten Hamilton-Ansatz und leiten damit Feldgleichungen in Form von partiellen Differentialgleichungen her, die wir dann mit den Methoden der Gitter-QCD numerisch lösen. Dabei bedienen wir uns der effektive Theorie des Farb-Glas-Kondensats (CGC, aus dem Englischen: “Color Glass Condensate”), um geeignete Anfangsbedingungen zu erhalten. Genauer gesagt basieren unsere Gitter-Anfangsbedingungen auf dem McLerran-Venugopalan-Modell (MV-Modell), das eine klassische Approximation in niedrigster Ordnung darstellt und nur Beiträge rein gluonischer Felder berücksichtigt.
Die klassische Näherung sowie das Vernachlässigen der fermionischen Felder wird insbesondere mit den hohen Besetzungszahlen der Feldmoden begründet. Einerseits dominieren Infrarot-Effekte, welche klassischer Natur sind, und andererseits ist dadurch der Einfluss der Fermionen, die dem Pauli-Prinzip gehorchen, unterdrückt. Gerade bei letzterer Aussage fehlt es jedoch an numerischen Belegen. Wir erweitern daher die klassische MV-Beschreibung durch stochastische Gitter-Fermionen, um diesem Punkt nachzugehen. Da sich Fermionen nicht klassisch beschreiben lassen, spricht man hierbei oft von einem semi-klassischen Ansatz.
Eines der Hauptziele dieser Arbeit liegt darin, den Isotropisierungsprozess, der bislang noch viele Fragen aufwirft, aber unter anderem Voraussetzung für das Anwenden von hydrodynamischen Modellen ist, zu studieren. Wir legen dabei einen besonderen Fokus auf die systematische Untersuchung der verschiedenen Parameter, die durch die CGC-Anfangsbedingungen in unsere Beschreibung einfließen, und deren Auswirkungen auf etwa die Gesamtenergiedichte des Systems oder die zugehörigen Isotropisierungszeiten. Währenddessen überprüfen wir zudem den Einfluss von unphysikalischen Gitter-Artefakten und präsentieren eine eichinvariante Methode zur Analyse der Güte unserer klassischen Näherung. Die Zeitentwicklung des Systems betrachten wir dabei sowohl in einer statischen Box als auch in einem expandierenden Medium, wobei Letzteres durch sogenannte comoving Koordinaten beschrieben wird. Zudem liefern wir einen Vergleich von der realistischen SU(3)-Eichgruppe und der rechentechnisch ökonomischeren SU(2)-Eichgruppe.
Mit unseren numerischen Ergebnissen zeigen wir, dass das System hochempfindlich auf die verschiedenen Modellparameter reagiert, was das Treffen quantitativer Aussagen in dieser Formulierung deutlich erschwert, insbesondere da einige dieser Parameter rein technischer Natur sind und somit keine zugehörigen physikalisch motivierten Größen, die den Definitionsbereich einschränken könnten, vorhanden sind. Es ist jedoch möglich, die Anzahl der freien Parameter zu reduzieren, indem man ihren Einfluss auf die Gesamtenergie des Systems analysiert und sich diesen zunutze macht. Dadurch gelingt es uns mithilfe von Konturdiagrammen einige Abhängigkeiten zu definieren und somit die Unbestimmtheit des Systems einzuschränken. Des Weiteren finden wir dynamisch generierte Filamentierungen in der Ortsdarstellung der Energiedichte, die ein starkes Indiz für die Präsenz von sogenannten chromo-Weibel-Instabilitäten sind. Unsere Studie des fermionischen Einflusses auf den Isotropisierungsprozess des CGC-Systems weist auf, dass dieser bei kleiner Kopplung vernachlässigbar ist. Bei hinreichend großen Werten für die Kopplungskonstante sehen wir allerdings einen starken Effekt hinsichtlich der Isotropisierungszeiten, was ein bemerkenswertes Resultat ist.
EBV Infektionen nach allogener hämatopoetischer Stammzelltransplantation sind neben dem Rezidiv eine häufige Komplikation und verbleiben ein häufiger Grund der Morbidität. Langanhaltende Immunsuppression oder die verspätete T-Zell Recovery können EBV Infektionen nach Transplantation begünstigen, welche unter diesen Umständen zu lebensbedrohlichen lymphoproliferativen Erkrankungen (PTLD) führen können. Für die optimale Behandlung der PTLD gibt es keinen Konsens. Adoptive Immuntherapien mit sowohl anti-Tumor Kapazität als auch wiederhergestellter virus-spezifischer zellulärer Immunität könnten, vor allem im Bezug einer PTLD, eine optimale Behandlungs-Option darstellen.
Zytokin-induzierte Killer (CIK)-Zellen repräsentieren einen neuen immuntherapeutischen Ansatz, da sie trotz hoher Mengen an T-Zellen nur ein geringes alloreaktives Potential besitzen und selbst im haploidenten Setting nur ein geringes Risiko zur Induktion einer GvHD besitzen. Der Graft versus Leukämie/Tumor-Effekt nach allogener SZT wird durch die Zellen verstärkt. Durch das dual spezifische zytotoxische Potential der CIK-Zellen über den nicht-MHC restringierten NKG2D Killing-Mechanismus und den MHC restringierten Mechanismus über den T-Zell Rezeptor können sowohl virusinfizierte als auch transformierte Zellen bekämpft werden. In der Literatur gibt es bisher nur eine Arbeit (aus unserer Arbeitsgruppe), in der CIK-Zellen mit spezifischen viralen Antigenen für eine antileukämische und potentielle anti-virale Aktivität stimuliert werden.
Im Rahmen dieser Arbeit wurde sowohl in prä-klinischen als auch in einem klinischen Ansatz die Durchführbarkeit, Anwendbarkeit, Effektivität und Sicherheit von EBV-spezifischen CIK-Zellen untersucht. Dazu wurde in einem ersten Schritt untersucht, ob sich durch die Modifizierung des konventionellen Herstellungsprotokolls EBV-spezifische CIK-Zellen generieren lassen.
Im präklinischen in vitro Setting wurde eine Modifizierung im CIK Herstellungsprotokoll vorgenommen um EBV-spezifische CIK-Zellen zu generieren, die sowohl ein anti-leukämisches als auch ein spezifisches anti-virales (EBV) Potential besitzen. Die Generierung erfolgte aus peripheren, mononukleären Zellen EBV-seropositiver Spender. Zusätzlich zu den CIK-Stimulanzien wurden die Zellen zweimal mit dem EBV Consensus Peptid Pool stimuliert, der Peptidsequenzen von verschiedenen latenten und lytischen EBV-Proteinen enthält. Durch die Modifikation konnte eine Ko-Expansion an EBV-spezifischen Zellen innerhalb des CD3+CD8+ Kompartiments der CIK-Zellen von bis zu 8% erreicht werden. In Zytotoxizitätsanalysen wurde das effektorische Potential der generierten Zellen überprüft. Gegenüber EBV peptidbeladenen Zielzellen zeigten die zusätzlich mit EBV-Peptid stimulierten CIK-Zellen in allen E:T Ratios (40:1, 20:1 und 5:1) eine signifikant höhere lytische Aktivität im Vergleich zur Aktivität konventioneller CIK-Zellen. Durch Blocking des NKG2D Rezeptors wurde die TCR-vermittelte lytische Aktivität in Bezug auf ein virales Ziel weiter gezeigt. Das anti-leukämische Killing Potential über den nicht-MHC restringierten NKG2D Rezeptor blieb zeitgleich erhalten, was sich in spezifischen Lysen gegenüber K562 und THP-1 Zellen von bis zu knapp 60% wiederspiegelt. Die durchflusszytometrische immunphänotypische Charakterisierung der EBV-stimulierten CIK-Zellen mittels 10-Farb Panel ergab keine signifikanten Unterschiede in Bezug auf Phänotyp und Rezeptor-Repertoire im Vergleich zu den konventionellen CIK-Zellen. Die Zytokin- und Chemokin Analysen der EBV-spezifischen CIK-Zellen spiegelten ein CD8+ TH1 Profil wieder und reflektierten den zytotoxischen Charakter der Zellen. Mit dem modifizierten Protokoll war es möglich für eine Patientin GMP-konforme CIK-Zellen mit EBV-Spezifität zu generieren, die 9,6 x 103 EBV-spezifische T-Zellen/kg Körpergewicht enthielten. Die Infusion der EBV-spezifischen CIK-Zellen resultierte in einer rapiden Beseitigung der Plasma EBV DNA und langanhaltendem Verschwinden des großen (27 cm3) PTLD-malignen Lymphoms. Während des anschließenden Immun-Monitorings der Patientin konnten CD4+ und CD8+ EBV-spezifische CIK-Zellen mittels der Dextramer Technologie in vivo im Blut der Patientin über einen Zeitraum von 32 Tagen nachgewiesen werden. Weitere FACS Analysen ergaben, dass sich im CD8+ Kompartiment der Patientin neben den CD8bright T-Zellen eine wachsende Population an CD8dim Zellen nachweisen ließ. Diese bestand zu einem bemerkenswerten Prozentsatz von bis zu 95% aus TEMRA Zellen, die auf virusspezifische T-Zellen hinweisen. Die Infusion der Zellen induzierte weder ein CRS noch andere Toxizitäten. Zytokin-Analysen aus dem Serum der Patientin reflektierten ein zytotoxisches und anti-virales Potential der infundierten Zellen. In vitro zeigten die unter GMP generierten Zellen im E:T Verhältnis von 40:1 und 20:1 ein 2-fach höheres zytotoxisches Potential gegenüber peptidbeladenen T2 Zellen im Vergleich gegenüber WT T2 Zellen. Der anti-leukämische Effekt gegen K562 Zellen blieb auch hier erhalten. 2 Jahre nach Behandlung ist die Patientin immer noch in Remission.
Die in dieser Arbeit erzielten prä-klinischen und klinischen Ergebnisse zeigen, dass virusspezifische CIK-Zellen eine neue, potentielle Immuntherapie darstellen, da die Zellen eine wirksame anti-leukämische Immunität mit antiviraler Immunrekonstitution vereinen. EBV-spezifische CIK-Zellen erwiesen sich als ein vielversprechender Ansatz für die Prävention von malignen Erkrankungen sowie in der Behandlung von EBV-Komplikationen nach allogener SZT.
Unter Web-based Trainings (WBTs) versteht man multimediale, interaktive und thematisch abgeschlossene Lerneinheiten in einem Browser. Seit der Entstehung des Internets in den 1990er Jahren sind diese ein wichtiger und etablierter Baustein bei der Konzeption und Entwicklung von eLearning-Szenarien. Diese Lerneinheiten werden üblicherweise von Lehrenden mit entsprechenden Autorensystemen erstellt. In selteneren Fällen handelt es sich bei deren Umsetzungen um individuell programmierte Einzellösungen. Betrachtet man WBTs aus der Sicht der Lernenden, dann lässt sich feststellen, dass zunehmend auch nicht explizit als Lerneinheiten erstellte Inhalte genutzt werden, die jedoch genau den Bedürfnissen des jeweiligen Lernenden entsprechen (im Rahmen des informellen und selbstgesteuerten Lernens). Zum einen liegt das an der zunehmenden Verfügbarkeit und Vielfalt von „alternativen Lerninhalten“ im Internet generell (freie Lizenzen und innovative Autorentools). Zum anderen aber auch an der Möglichkeit, diese Inhalte von überall aus und zu jeder Zeit einfach finden zu können (mobiles Internet, Suchmaschinen und Sprachassistenten) bzw. eingeordnet und empfohlen zu bekommen (Empfehlungssysteme und soziale Medien).
Aus dieser Veränderung heraus ergibt sich im Rahmen dieser Dissertation die zentrale Fragestellung, ob das Konzept eines dedizierten WBT-Autorensystems den neuen Anforderungen von frei verfügbaren, interaktiven Lerninhalten (Khan Academy, YouTube und Wikipedia) und einer Vielzahl ständig wachsender und kostenfreier Autorentools für beliebige Web-Inhalte (H5P, PowToon oder Pageflow) überhaupt noch gerecht wird und wo in diesem Fall genau die Alleinstellungsmerkmale eines WBTs liegen?
Zur Beantwortung dieser Frage beschäftigt sich die Arbeit grundlegend mit dem Begriff „Web-based Training“, den über die Zeit geänderten Rahmenbedingungen und den daraus resultierenden Implikationen für die Entwicklung von WBT-Autorensystemen. Mittels des gewählten Design-based Research (DBR)-Ansatzes konnte durch kontinuierliche Zyklen von Gestaltung, Durchführung, Analyse und Re-Design am Beispiel mehrerer eLearning-Projekte der Begriff WBT neudefininiert bzw. reinterpretiert werden, so dass sich der Fokus der Definition auf das konzentriert, was WBTs im Vergleich zu anderen Inhalten und Funktionen im Internet im Kern unterscheidet: dem Lehr-/Lernaspekt (nachfolgend Web-based Training 2.0 (WBT 2.0)).
Basierend auf dieser Neudefinition konnten vier Kernfunktionalitäten ausgearbeitet werden, die die zuvor genannten Herausforderungen adressieren und in Form eines Design Frameworks detailliert beschreiben. Untersucht und entwickelt wurden die unterschiedlichen Aspekte und Funktionen der WBTs 2.0 anhand der iterativen „Meso-Zyklen“ des DBR-Ansatzes, wobei jedes der darin durchgeführten Projekte auch eigene Ergebnisse mit sich bringt, welche jeweils unter didaktischen und vor allem aber technischen Gesichtspunkten erörtert wurden. Die dadurch gewonnenen Erkenntnisse flossen jeweils in den Entwicklungsprozess der LernBar ein („Makro-Zyklus“), ein im Rahmen dieser Arbeit und von studiumdigitale, der zentralen eLearning-Einrichtung der Goethe-Universität, entwickeltes WBT-Autorensystem. Dabei wurden die Entwicklungen kontinuierlich unter Einbezug von Nutzerfeedbacks (jährliche Anwendertreffen, Schulungen, Befragungen, Support) überprüft und weiterentwickelt.
Abschließend endet der letzte Entwicklungszyklus des DBR-Ansatzes mit der Konzeption und Umsetzung von drei WBT 2.0-Systemkomponenten, wodurch sich flexibel beliebige Web-Inhalte mit entsprechenden WBT 2.0-Funktionalitäten erweitern lassen, um auch im Kontext von offenen Lehr-/Lernprozessen durchgeführte Aktivitäten transparent, nachvollziehbar und somit überprüfbar zu machen (Constructive Alignment).
Somit bietet diese Forschungsarbeit einen interdisziplinären, nutzerzentrierten und in der Praxis erprobten Ansatz für die Umsetzung und den Einsatz von WBTs im Kontext offener Lehr-/Lernprozesse. Dabei verschiebt sich der bisherige Fokus von der reinen Medienproduktion hin zu einem ganzheitlichen Ansatz, bei dem der Lehr-/Lernaspekt im Vordergrund steht (Lernbedarf erkennen, decken und überprüfen). Entscheidend ist dabei, dass zum Decken eines Lernbedarfs sämtliche zur Verfügung stehenden Ressourcen des Internets genutzt werden können, wobei WBTs 2.0 dazu lediglich den didaktischen Prozess definieren und diesen für die Lehrenden und Lernende transparent und zugänglich machen.
WBTs 2.0 profitieren dadurch zukünftig von der zunehmenden Vielfalt und Verfügbarkeit von Inhalten und Funktionen im Internet und ermöglichen es, den Entwicklern von WBT 2.0-Autorensystemen sich auf das Wesentliche zu konzentrieren: den Lehr-/Lernprozess.
Landwirtschaft ist der Hauptmotor der westafrikanischen Wirtschaft und Kleinbauern liefern fast 70 % des Nahrungsmittelbedarfs. Traditionell wird hauptsächlich Regenfeldbau betrieben, der durch geringen Agrarinput und die Nutzung von einfachen Werkzeugen wie Hacke und Buschmesser gekennzeichnet ist. Die Ernteerträge sind gering und die Bodenfruchtbarkeit sinkt schnell nach einigen Anbaujahren. Infolgedessen werden Wald- und Weidefläche gerodet und die Landdegradation wird beschleunigt. Dies hat direkte Auswirkungen auf die landwirtschaftliche Produktivität und die Ernährungssicherheit der Kleinbauern.
Die vorliegende Arbeit hat sich das Ziel gesetzt, sozio-ökonomische und geo-ökologische Faktoren, die den Landnutzungswandel in zwei Agrarökosystemen der Atakora Gebirgskette steuern, aufzudecken. Schließlich sollen ortsangepasste Maßnahmen vorgeschlagen werden, um die Agrarökosysteme wiederherzustellen und ihre Dienstleistungen für Kleinbauern zu erhalten.
Haushaltsbefragungen und Gruppendiskussionen wurden während Geländeaufenthalten in den Jahren 2014 und 2015 in den Dörfern der beiden Ethnien durchgeführt. Die Landnutzung und ihr Wandel werden über knapp 30 Jahre anhand von Bildern des Satellitensystems LANDSAT aus den Jahren 1987, 2001 und 2015 ausgewertet. Eine überwachte Klassifikation nach dem „Maximum Likelihood“-Klassifkationsalgorithmus und Veränderungs-analysen wurden durchgeführt. Zum Erfassen der Variabilität der Agrarparameter der Böden wurden Bodenprofile nach dem Catena-Prinzip gegraben. Bodenproben wurden aus jedem Horizont genommen. Anschließend wurden einige physische Parameter und die Nährstoffgehalte vom Fachpersonal des bodenkundlichen Labors des Instituts für Physische Geographie (Geowissenschaften) bestimmt.
Innerhalb der knapp letzten dreißig Jahre (1987-2015) ist die natürliche Vegetation bei den beiden Ethnien zugunsten der Landwirtschaft und der bebauten bzw. vegetationsfreien Flächen zurückgegangen. Über die analysierten Zeiträume liegen mehr Flächen bei den Ditamari (47,24%) unter einer negativen Dynamik als bei den Éwé (36,41%). Die Untersuchung der Steuerungsfaktoren des Landnutzungswandels bringt heraus, dass der höhere Anteil an positiv veränderten Flächen bei den Éwé ist nicht durch bessere Landnutzungsstrategien begründet. Vielmehr stellt das Relief der begrenzende Faktor für die Ausdehnung der Ackerflächen und damit die bessere Erhaltung der natürlichen Vegetation bei den Éwé dar.
Die erste Annahme, dass Veränderungen in der Landnutzung die Landdegradation zur Folge haben, wird in den beiden Untersuchungsgebieten bestätigt. Die abnehmende Dichte der Vegetationsdecke begünstigt Prozesse der Flächen-, Rillen- und Rinnenspülung. Zudem werden die ökologischen Bodenfunktionen vermindert. Erscheinungen der Landdegradation bei den Ditamari sind die Ausdehnung von oberflächlich verkrusteten Arealen und die Verbreitung des Unkrautes Striga hermontica. Bei den Éwés tritt eine starke Profilverkürzung der Böden ein und das anstehende Gestein wird an mehreren Stellen freigelegt.
Die zweite Hypothese wird in Hinsicht auf die räumliche und ethnische Differenzierung der Folgen der Landdegradation bestätigt. Allerdings sind nicht, wie vermutet, die Ditamari verletzbarer als die Éwés. Die beiden Ethnien betreiben eine intensive Subsistenzwirtschaft und die Éwé entwickeln weniger Anpassungsstrategien als die Ditamari. Im Hinblick auf die globale Erwärmung könnte die Landdegradation in den beiden Gebieten fortschreiten und die Folgen auf der Landschaft und den Kleinbauern verschärfen. Die Éwé wären, anders als vermutet, verletzbarer als die Ditamari. Eine Fortschreitung der Landdegradation könnte bei den Kleinbauern Éwés langfristig den Zusammenbruch des Agrarökosystemen hervorrufen. Sie könnten langfristig die Grundlage ihrer Existenzsicherung verlieren.
Die Studie zeigt auf, dass traditionell, zurückgezogen lebende Völker wie die Ditamari das Agrarökosystem nachhaltiger bewirtschaften und angesichts der Landdegradation anpassungsfähiger sind als tief umgewandelte Gesellschaften wie die Éwés. Sie bringt heraus, dass Kleinbauern Westafrikas keinesfalls als eine Einheit betrachtet werden sollten. Jede Ethnie ist durch Merkmale gekennzeichnet, die ihre Gestaltung der Landschaft beeinflussen. Diese Vielfältigkeit und Besonderheiten der kleinbäuerlichen Gesellschaften müssen in der Entwicklungszusammenarbeit stärker berücksichtigt werden.
Oral anticoagulant-associated intracerebral hemorrhage (OAC-ICH) accounts for nearly 20% of all ICH. The number of patients with an indication for oral anticoagulant therapy (OAT) increases with increasing age. OAT became less complicate with the introduction of non-vitamin K oral anticoagulants (NOAC) OAT because of easier handling, favorable risk-benefit profile, reduced rates of ICH compared to vitamin K antagonists and no need for routine coagulation testing. Consequently, despite a better safety profile of NOAC the number of patients with OAC-ICH will increase. The mortality and complication rates of OAC-ICH are high and therefore they are the most feared complication of OAT. Immediate normalization of coagulation is the main goal and therefore knowledge of pharmacodynamics and coagulation status is essential. Laboratory measurements of anticoagulant activity in NOAC patients is challenging as specific tests are not widely available. More accessible tests such as the prothrombin time and activated partial thromboplastin time have important limitations. In dabigatran-associated ICH 5 g Idarucizumab should be administered. In rivaroxaban and apixaban-associated ICHs administration of andexanet alpha should be considered. Prothrombin complex concentrate may be considered if andexanet alpha is not available or in case of an ICH associated with edoxaban.
The authors review the current status of percutaneous left atrial appendage (LAA) occlusion therapy in patients with atrial fibrillation with the goal to prevent ischemic stroke and systemic embolism and to reduce oral anticoagulation associated bleeding. While we cover the historical and also surgical background, and all tested devices, the main focus rests on the single currently U.S. Food and Drug Administration (FDA) approved LAA occluder, the WATCHMAN device, and its approval process. The authors also give a critical appraisal beyond the review of mere facts, trying to put the current data into perspective.
Background: Obesity is a global problem leading to reduced life expectancy, cardiovascular diseases, diabetes and many types of cancer. Even people willing to accept treatment only achieve a mean weight loss of about 5 kg using commercial weight loss programs. Surgical interventions, e.g. sleeve gastrectomy or gastric bypass are effective but accompanied by risk of serious complications and side effects. Less invasive endoscopic procedures mainly comprise the intragastric balloon (IB) and the duodenal-jejunal bypass liner (DJBL). To date, a randomized comparison between these devices has not been undertaken or shown to be superior to a sham procedure.
Methods: We designed a multi-center, randomized, patient and assessor-blinded, controlled trial comparing weight loss in endoscopically implanted IB vs. DJBL vs. a sham procedure. A total of 150 patients with a BMI > 35 kg/m2 or > 30 with obesity-related comorbidities and indication for proton pump inhibitors are randomized to receive either IB, DJBL or a sham gastroscopy (2:2:1 ratio). All participants undergo regular dietary consultation. The IB will be removed after 6 months, whereas the DJBL will be explanted after 12 months. All patients will receive gastroscopies at implantation and explantation of the devices or sedation without gastroscopy to maintain blinding. Main exclusion criteria are malignant diseases, peptic ulcer or previous bariatric intervention. Weight loss 12 months after explantation of the devices, changes in comorbidities, quality of life, complication rates and safety will be evaluated.
Discussion: This trial could help to identify the most effective and safest endoscopic device, thus determining the new standard procedure for endoscopic bariatric treatment.
Trial registration: 16th January 2017. DRKS00011036. Funded by the German Research Foundation (DFG).
Different response of Ptch mutant and Ptch wildtype Rhabdomyosarcoma toward SMO and PI3K inhibitors
(2018)
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. RMS frequently show Hedgehog (HH) pathway activity, which is predominantly seen in the embryonal subtype (ERMS). They also show activation of Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling. Here we compared the therapeutic effectiveness and the impact on HH target gene expression of Smoothened (SMO) antagonists with those of the PI3K inhibitor pictilisib in ERMS with and without mutations in the HH receptor Patched1 (PTCH). Our data demonstrate that growth of ERMS showing canonical Hh signaling activity due to Ptch germline mutations is efficiently reduced by SMO antagonists. This goes along with strong downregulation of the Hh target Gli1. Likewise Ptch mutant tumors are highly responsive toward the PI3K inhibitor pictilisib, which involves modulation of AKT and caspase activity. Pictilisib also modulates Hh target gene expression, which, however, is rather not correlated with its antitumoral effects. In contrast, sporadic ERMS, which usually express HH target genes without having PTCH mutation, apparently lack canonical HH signaling activity. Thus, stimulation by Sonic HE (SHH) or SAG (Smoothened agonist) or inhibition by SMO antagonists do not modulate HH target gene expression. In addition, SMO antagonists do not provoke efficient anticancer effects and rather exert off-target effects. In contrast, pictilisib and other PI3K/AKT/mTOR inhibitors potently inhibit cellular growth. They also efficiently inhibit HH target gene expression. However, of whether this is correlated with their antitumoral effects it is not clear. Together, these data suggest that PI3K inhibitors are a good and reliable therapeutic option for all ERMS, whereas SMO inhibitors might only be beneficial for ERMS driven by PTCH mutations.
Hämophilie A ist eine X-chromosomal rezessiv vererbte Krankheit, die aufgrund von Mutationen innerhalb des Gens von Gerinnungsfaktor VIII (FVIII) zum funktionellen Defekt oder zum Fehlen des körpereigenen FVIII führt. FVIII zirkuliert als Heterodimer und besteht aus einer schweren Kette mit der Domänenstruktur A1-A2-B und einer leichten Kette mit der Domänenstruktur A3-C1-C2. Bei Patienten unter Prophylaxe wird durch regelmäßige Substitution mit rekombinanten oder aus Plasma gewonnenen FVIII-Präparaten die Hämostase wiederhergestellt. Allerdings entwickeln hierbei etwa 30% der Patienten mit einer schweren Hämophilie eine FVIII-spezifische Immunantwort in Form von neutralisierenden Antikörpern (Inhibitoren). Die sogenannte Immuntoleranz-Therapie (engl. immune tolerance induction therapy, ITI) ist bisher die einzige etablierte Therapie, die zu einer dauerhaften Eradikation der FVIII-Inhibitoren und Induktion von Toleranz gegenüber FVIII führen kann. Die Therapie beruht auf einer meist täglichen Gabe hoher FVIII-Dosen, welche sich, je nach Behandlungsdauer, über Wochen bis hin zu Jahren erstrecken kann. Bei etwa 30% der Patienten ist diese Therapie nicht erfolgreich. Für solche Patienten besteht die Gefahr lebensbedrohlicher, unkontrollierbarer Blutungen und erheblicher Gelenkschäden.
Die spezifische Ansteuerung des Membran-gebundenen Immunglobulin G (mIg) des B-Zellrezeptors (BZR) mithilfe von Immuntoxinen ist eine mögliche Option zur selektiven Eliminierung FVIII-spezifischer B-Zellen und somit zur Eradikation von FVIII-Inhibitoren. Solche Immuntoxine bestehen aus einer zellbindenden und einer zytotoxischen Domäne, welche nach Internalisierung zur Apoptose der Zielzelle führen soll. Da FVIII aufgrund der Größe als zellbindende Domäne ungeeignet ist, beschäftigt sich die vorliegende Arbeit mit der Entwicklung und Evaluierung alternativer Immuntoxine zur selektiven Eliminierung FVIII-spezifischer B-Zellen. Die FVIII-spezifische Immunantwort ist zwar polyklonal, jedoch vor allem gegen A2- und die C2-Domäne gerichtet. Aus diesem Grund wurden die humane A2- und C2-Domäne (hA2, hC2) als zellbindende Domäne verwendet und jeweils genetisch an eine verkürzte Version des Exotoxin A (ETA) aus Pseudomonas aeruginosa fusioniert, bei welcher die natürliche zellbindende Domäne entfernt wurde. Die rekombinanten Proteine wurden bakteriell produziert und im Anschluss an die Aufreinigung biochemisch charakterisiert. Während das bakterielle Expressionssystem für hA2-ETA nicht geeignet war, konnte hC2-ETA neben weiteren Kontrollproteinen mit korrekter Konformation der hC2-Domäne hergestellt und aufgereinigt werden.
Die Fähigkeit zur selektiven Eliminierung hC2-spezifischer B-Zellen wurde im weiteren Verlauf sowohl in vitro mithilfe einer hC2-spezifischen Hybridomazelllinie als auch ex vivo und in vivo mithilfe von Splenozyten aus FVIII-immunisierten FVIII-knockout Mäusen untersucht.
Durch Inkubation der hC2-spezifischen Hybridomazelllinie mit hC2-ETA konnten ca. 38 % der Zellen eliminiert werden. Weitere Untersuchungen der Zelllinie ergaben, dass diese keinen vollständigen funktionalen B-Zellrezeptor auf der Oberfläche exprimierte, welcher für die Bindung und die korrekte Internalisierung des Immuntoxins notwendig ist. Aufgrund dessen eignet sich diese Zelllinie nicht als Modell für eine genauere Analyse der in vitro Eliminierungseffizienz von hC2-ETA.
Weitere Analysen mithilfe von Splenozyten aus FVIII-immunisierten FVIII-knockout Mäusen haben jedoch gezeigt, dass durch ex vivo Inkubation der Splenozyten mit hC2-ETA, alle hC2-spezifischen B-Zellen vollständig, selektiv und konzentrations-abhängig eliminiert werden konnten. Auch die mehrfache Applikation von hC2-ETA in FVIII-immunisierten FVIII-knockout Mäusen führte bei der Hälfte der Tiere zur vollständigen Eliminierung aller hC2-spezifischen B-Zellen. Eine Reduktion des hC2-spezifischen Antikörpersignals konnte nach Gabe von hC2-ETA in allen behandelten Tieren beobachtet werden. Die unvollständige Eliminierung in der Hälfte der Tiere ist vermutlich auf die Präsenz hC2-spezifischer Antikörper zurückzuführen, die einen Teil des applizierten Immuntoxins neutralisiert haben, sodass nicht alle hC2-spezifischen Gedächtnis-B-Zellen erreicht und eliminiert werden konnten. Um die Eliminierungseffizienz von hC2-ETA weiter zu erhöhen, müsste das Behandlungsprotokoll geändert werden. Sowohl eine Verlängerung des Behandlungszeitraums als auch eine kombinierte Therapie aus FVIII und hC2-ETA sollte zu einer erhöhten Bioverfügbarkeit des Toxins und dadurch zu einer gesteigerten Eliminierungseffizienz führen.
Die Ausweitung des hier vorgestellten Ansatzes auf weitere FVIII-Domänen ist generell möglich, jedoch muss hierzu ein alternatives Expressionssystem aufgrund des eukaryotischen Ursprungs von FVIII in Betracht gezogen werden. Die hier vorgestellten Ergebnisse zeigen dennoch, dass FVIII-Domänen-Immuntoxine ein wirkungsvolles Mittel sind, um FVIII-spezifische B-Zellen selektiv zu eliminieren. Die Anpassung der Gabe von FVIII-Domänen-Immuntoxinen an die individuelle Immunantwort des Patienten könnte das Auftreten von Nebenwirkungen minimieren. Außerdem könnte eine kombinierte Therapie aus ITI und FVIII-Domänen-Immuntoxinen die Zeit bis zur Induktion von Toleranz verkürzen und die Chancen für den generellen Therapieerfolg erhöhen.
The opportunistic pathogen Acinetobacter baumannii is able to grow on carnitine. The genes encoding the pathway for carnitine degradation to the intermediate malic acid are known but the transporter mediating carnitine uptake remained to be identified. The open reading frame HMPREF0010_01347 (aci01347) of Acinetobacter baumannii is annotated as a gene encoding a potential transporter of the betaine/choline/carnitine transporter (BCCT) family. To study the physiological function of Aci01347, the gene was deleted from A. baumannii ATCC 19606. The mutant was no longer able to grow on carnitine as sole carbon and energy source demonstrating the importance of this transporter for carnitine metabolism. Aci01347 was produced in Escherichia coli MKH13, a strain devoid of any compatible solute transporter, and the recombinant E. coli MKH13 strain was found to take up carnitine in an energy‐dependent fashion. Aci01347 also transported choline, a compound known to be accumulated under osmotic stress. Choline transport was osmolarity‐independent which is consistent with the absence of an extended C‐terminus found in osmo‐activated BCCT. We propose that the Aci01347 is the carnitine transporter mediating the first step in the growth of A. baumannii on carnitine.
Danger signals in trauma
(2018)
This review summarizes a short list of currently discussed trauma-induced danger-associated molecular patterns (DAMP). Due to the bivalent character and often pleiotropic effects of a DAMP, it is difficult to describe its “friend or foe” role in post-traumatic inflammation and regeneration, both systemically as well locally in tissues. DAMP can be used as biomarkers to indicate or monitor disease or injury severity, but also may serve as clinically applicable parameters for better indication and timing of surgery. Due to the inflammatory processes at the local tissue level or the systemic level, the precise role of DAMP is not always clear to define. While in vitro and experimental studies allow for the detection of these biomarkers at the different levels of an organism—cellular, tissue, circulation—this is not always easily transferable to the human setting. Increased knowledge exploring the dual role of DAMP after trauma, and concentrating on their nuclear functions, transcriptional targets, release mechanisms, cellular sources, multiple functions, their interactions and potential therapeutic targeting is warranted.
Oncogenic rearrangements leading to targetable gene fusions are well-established cancer driver events in lung adenocarcinoma. Accurate and reliable detection of these gene fusions is crucial to select the appropriate targeted therapy for each patient. We compared the targeted next-generation-sequencing Oncomine Focus Assay (OFA; Thermo Fisher Scientific) with conventional ALK FISH and anti-Alk immunohistochemistry in a cohort of 52 lung adenocarcinomas (10 ALK rearranged, 18 non-ALK rearranged, and 24 untested cases). We found a sensitivity and specificity of 100% for detection of ALK rearrangements using the OFA panel. In addition, targeted next generation sequencing allowed us to analyze a set of 23 driver genes in a single assay. Besides EML4-ALK (11/52 cases), we detected EZR-ROS1 (1/52 cases), KIF5B-RET (1/52 cases) and MET-MET (4/52 cases) fusions. All EML4-ALK, EZR-ROS1 and KIF5B-RET fusions were confirmed by multiplexed targeted next generation sequencing assay (Oncomine Solid Tumor Fusion Transcript Kit, Thermo Fisher Scientific). All cases with EML4-ALK rearrangement were confirmed by Alk immunohistochemistry and all but one by ALK FISH. In our experience, targeted next-generation sequencing is a reliable and timesaving tool for multiplexed detection of targetable rearrangements. Therefore, targeted next-generation sequencing represents an efficient alternative to time-consuming single target assays currently used in molecular pathology.
Die aktuelle Gesetzeslage fordert mit der im Rahmen der Gesundheitsreform 2007 eingeführten Versicherungspflicht und dem 2013 in Kraft getretenen Gesetz zur Beseitigung sozialer Überforderung bei Beitragsschulden in der Krankenversicherung eine Vollversicherung aller in Deutschland lebenden Personen. Die Erfahrungen aus medizinischen Versorgungseinrichtungen zeigen, dass dieses Ziel nicht erreicht wurde. Nach wie vor wird eine bedeutende Anzahl von Patienten ohne Krankenversicherung in Krankenhäusern, Arztpraxen und medizinischen Hilfseinrichtungen versorgt. In der vorliegenden Studie wird in einer praxisnahen Herangehensweise am Beispiel der Stadt Frankfurt am Main untersucht, wo die Ursachen dafür zu finden sind, wenn die Einbindung in das Regelsystem der Krankenversicherung nicht gelingt und wie sich dies auf die medizinische Versorgung der Betroffenen auswirkt.
Basierend auf einem qualitativen Studienkonzept wird das empirische Material mit Leitfadeninterviews erhoben und mit der qualitativen Inhaltsanalyse nach Gläser und Laudel ausgewertet. Die Auswahl der Interviewpartner erfolgt mittels Sampling über die Zusammenarbeit mit zwei medizinischen Hilfseinrichtungen als zentrale Kontakte im Forschungsfeld. Die 25 Patienteninterviews stellen eine exemplarische Auswahl an dort behandelten nichtversicherten Patienten dar. Die 21 Experteninterviews mit Gesprächspartnern aus den Arbeitsbereichen Hilfseinrichtungen, Krankenhäuser und Behörden bilden die unterschiedlichen Akteure und Sichtweisen im Handlungsfeld der Nichtversicherung ab. Mithilfe der qualitativen Inhaltsanalyse werden die erfassten Fälle rekonstruiert und auf ihre Kausalmechanismen hin analysiert.
Als Ergebnis der Untersuchung werden 13 Grundsituationen typischer Fälle von Nichtversicherung dargestellt und mit den strukturellen Rahmenbedingungen in Zusammenhang gebracht. Daraus werden die Entstehungsmechanismen von Nichtversicherung ersichtlich. Diese zeigen, dass das Fehlen der Krankenversicherung das Resultat einer multifaktoriellen Entwicklung ist. So wirken sich einerseits die individuellen Verhaltensweisen der Betroffenen sowie ihre jeweiligen Lebensum-stände, wie die berufliche Situation, die Wohnsituation, Herkunft, Aufenthaltsstatus und die gesundheitliche Situation, auf die Versicherungssituation aus. Andererseits kommt strukturellen Hürden eine wesentliche Bedeutung bei der Entstehung von Nichtversicherung zu. So lässt die Gesetzgebung in der Versicherungspflicht, dem Sozialleistungsbezug und im Aufenthaltsrecht Lücken, die zwar nicht notgedrungen zum Verlust der Krankenversicherung führen, aber in Wechselwirkung mit bestimmten Lebensumständen und Verhaltensweisen der einzelnen Personen die Eingliederung in das reguläre Versicherungssystem verhindern oder erschweren.
Im zweiten Teil der Studienergebnisse wird die Versorgungssituation für Patienten ohne Krankenversicherung beurteilt. Darin wird deutlich, dass Nichtversicherte im Vergleich zu regulär versicherten Personen schlechter medizinisch versorgt sind. Dies ist einem erschwerten Zugang zum Regelsystem der medizinischen Versorgung sowie den eingeschränkten Behandlungsmöglichkeiten im Hilfsnetz geschuldet. Trotz der gut ausgebauten Hilfestrukturen in Frankfurt am Main muss demnach die Versorgungs-situation für Nichtversicherte als unzureichend beurteilt werden.
Neben den Patienten sind auch die anderen Akteure von den Folgen des Nichtversichertseins betroffen. Dabei zeigen sich zwei gegensätzliche Perspektiven auf das Problemfeld. Auf der einen Seite stehen die hilfeleistenden Einrichtungen, die den Patienten eine medizinische Versorgung zukommen lassen, auf der anderen Seite die Kostenträger, die als Institutionen des Regelsystems diese medizinische Behandlung finanzieren. Die versorgenden Einrichtungen geraten in einen Konflikt zwischen ihrem Behandlungsauftrag, der sich aus der gesetzlich verankerten Behandlungspflicht und der ethischen Verantwortung den Patienten gegenüber ergibt, und dem wirtschaftli-chen Druck, der die Behandlungsmöglichkeiten bei unzureichender Finanzierung begrenzt. Die Kostenträger können ihre Zuständigkeit als Leistungsträger im Einzelfall prüfen und diese gegebenenfalls ablehnen. Da Nichtversicherte als unattraktive Kunden gelten, geht die Ablehnung meist mit einer Kostenersparnis einher und bedeutet somit für die Kostenträger keinen Nachteil. Die daraus entstehenden Versorgungsvakanzen werden wiederum vom Hilfsnetz aufgefangen.
Vor dem Hintergrund dieser Ergebnisse muss das Auftreten von Nichtversicherung als Problem gesehen werden, aus dem Handlungsbedarf hervorgeht, auch wenn die Gruppe der Nichtversicherten insgesamt nur einen kleinen Anteil an der Gesamtbevölkerung ausmacht. Die Zielsetzung dieser Studie ist es, eine fundierte Grundlage zu geben, auf der Lösungsansätze für die beschriebenen Konflikte erarbeitet werden können.
Objective. Traumatic injury or severe surgery leads to a profound immune response with a diminished functionality of monocytes and subsequently their IL-1β release. IL-1β plays an important role in host immunity and protection against infections. Its biological activation via IL-1β-precursor processing requires the transcription of inflammasome components and their activation. Deregulated activity of NOD-like receptor inflammasomes (NLR) like NLRP3 that leads to the maturation of IL-1β has been described in various diseases. While the role of other inflammasomes has been studied in monocytes, nothing is known about NLRP3 inflammasome after a traumatic injury. Here, the role of the NLRP3 inflammasome in impaired monocyte functionality after a traumatic injury was analyzed.
Measurements and Main Results. Ex vivo-in vitro stimulation of isolated CD14+ monocytes with lipopolysaccharide (LPS) showed a significantly higher IL-1β secretion in healthy volunteers (HV) compared to trauma patients (TP) after admission. Reduced IL-1β secretion was paralleled by significantly lowered gene expression of NLRP3 in monocytes from TP compared to those of HV. Transfection of monocytes with NLRP3-encoding plasmid recovered the functionality of monocytes from TP regarding the IL-1β secretion.
Conclusions. This study demonstrates that CD14+ monocytes from TP are significantly diminished in their function and that the presence of NLRP3 components is necessary in recovering the ability of monocytes to produce active IL-1β. This recovery of the NLRP3 inflammasome in monocytes may imply a new target for treatment and therapy of immune suppression after severe injury.
In the period 18th – 31st May 2017, 33 localities were examined for Odonata in the Central Zagros area of Iran: 16 in Markazi Province, 14 in Lorestan Province and 3 in Esfahan Province; in 27 of those localities Odonata were found, 25 species in total. For Markazi Province, only one species, Calopteryx splendens, was previously reported (and also found by us), so of 17 species found there 16 are formally new provincial records (Epallage fatime, Lestes barbarus, Coenagrion ornatum, C. persicum, Enallagma cyathigerum, Ischnura elegans, I. intermedia, I. pumilio, Platycnemis kervillei, Anax imperator, Anaciaeschna isoceles, Caliaeschna microstigma, Libellula depressa, Onychogomphus lefebvrii, Orthetrum brunneum, Sympetrum fonscolombii). Of 17 species
found in Lorestan, 5 are new for this province (L. barbarus, Aeshna mixta, Orthetrum taeniolatum, Sympetrum arenicolor, S. striolatum). Only two species were seen in Esfahan Province, in which little time was spent. Notes on variation and taxonomy are provided for Sympecma paedisca, C. ornatum (considered to be a senior synonym of C. vanbrinkae because of variation in the presumed main diagnostic character), E. cyathigerum, I. elegans, Gomphus schneideri (including discussion of G. amseli), as well as notes on habitats of most species and the general characteristics of the area.
Biological invasions are frequently studied topics in ecological research. Unfortunately, within invasion ecology parasite-associated aspects such as parasite impacts on new environments and on local host populations are less well-studied. Round gobies migrating from the Ponto-Caspian region into the Rhine River system are heavily infested with the Ponto-Caspian acanthocephalan parasite Pomphorhynchus laevis. As shown by experimental infestations the acanthocephalans occur as pre-adults in host-encapsulated cysts within the internal organs of the migrating gobies, but remain infective for their definitive host chub. Recently, we described the occurrence of larvae of another parasite, the invasive eel swim bladder nematode Anguillicola crassus, in these Pomphorhynchus cysts. In the present study, we could prove the infectivity of the nematode larvae for European eels for the first time. After experimental inoculation of Pomphorhynchus cysts occasionally infested with A. crassus larvae, the nematodes grow to maturity and reproduce whereas all P. laevis were unviable. We therefore postulate that the nematode larvae behave like immunological hitchhikers that follow a “Trojan horse strategy” in order to avoid the paratenic host’s immune response. Accordingly, the interaction between both invasive parasites gives first evidence that the invasional meltdown hypothesis may also apply to parasites.
New technologies and therapies designed to facilitate development of personalized treatments are rapidly emerging in the field of biomedicine. Strikingly, the goal of personalized medicine refined the concept of therapy by developing cell-based therapies, the so-called “living drugs”. Breakthrough advancements were achieved in this regard in the fields of gene therapy, cell therapy, tissue-engineered products and advanced therapeutic techniques. The Advanced Therapies in Healthcare symposium, organized by the Clinical Research Center Department of Sidra Medicine, in Doha, Qatar (October 2017), brought together world-renowned experts from the fields of oncology, hematology, immunology, inflammation, autoimmune disorders, and stem cells to offer a comprehensive picture of the status of worldwide advanced therapies in both pre-clinical and clinical development, providing insights to the research phase, clinical data and regulatory aspects of these therapies. Highlights of the meeting are provided in this meeting report.
New field sampling was carried out in June 2011 in northern Moldova, the most unstudied area in the Republic of Moldova. A total of 19 Odonata species was recorded during a field trip, with Libellula fulva and Gomphus flavipes new for Moldova. The presence of species of European concern is discussed. Photos of all visited habitats are included. The fauna of Moldova mostly consists of species which are able to survive in biotopes with high anthropogenic pressure.
We describe three new species of damselflies from streams draining into Lake Kutubu in Southern Highlands Province, Papua New Guinea. They are Drepanosticta johncanni sp. nov. (Platystictidae), Pseudagrion parafarinicolle sp. nov. (Coenagrionidae) and Wahnesia kutubuensis sp. nov. (Argiolestidae). Diagnostic characters of the males and, where available of the females, are illustrated and the probable affinities of the new species are discussed.
Background: Histological evidence suggests that autism spectrum disorder (ASD) is accompanied by a reduced integrity of the grey-white matter boundary. This has also recently been confirmed by a structural neuroimaging study in vivo reporting significantly reduced grey-white matter tissue contrast (GWC) in adult individuals (18–42 years of age) with ASD relative to typically developing (TD) controls. However, it remains unknown whether the neuroanatomical differences in ASD at the grey-white matter boundary are stable across development or are age-dependent.
Methods: Here, we examined differences in the neurodevelopmental trajectories of GWC in a cross-sectional sample of 77 male ASD individuals and 76 typically developing (TD) controls across childhood and early adulthood (from 7 to 25 years).
Results: Using nested model comparisons, we first established that the developmental trajectory of GWC is complex in many regions across the cortex and includes linear and non-linear effects of age. Second, while ASD individuals have significantly reduced GWC overall, these differences are age-dependent and are most prominent during childhood (< 15 years).
Conclusions: Taken together, our findings suggest that differences in GWC in ASD are unlikely to reflect atypical grey matter cytoarchitecture alone, but may also represent other aspects of the cortical architecture such as age-dependent variability in myelin integrity.
A catalogue of all types of subfamilies Protoneurinae and Disparoneurinae currently housed in the entomological collection of the Museum für Naturkunde − Leibniz Institute for Evolution and Biodiversity Science in Berlin (Germany) is presented. It includes current status of the familygroup, genusgroup and speciesgroup names, transcriptions of data labels and references to the original descriptions.
Background: The focus of this study is to identify particular microRNA (miRNA) signatures in exosomes derived from plasma of 435 human epidermal growth factor receptor 2 (HER2)-positive and triple-negative (TN) subtypes of breast cancer (BC).
Methods: First, miRNA expression profiles were determined in exosomes derived from the plasma of 15 TNBC patients before neoadjuvant therapy using a quantitative TaqMan real-time PCR-based microRNA array card containing 384 different miRNAs. Forty-five miRNAs associated with different clinical parameters were then selected and mounted on microRNA array cards that served for the quantification of exosomal miRNAs in 435 BC patients before therapy and 20 healthy women. Confocal microscopy, Western blot, and ELISA were used for exosome characterization.
Results: Quantification of 45 exosomal miRNAs showed that compared with healthy women, 10 miRNAs in the entire cohort of BC patients, 13 in the subgroup of 211 HER2-positive BC, and 17 in the subgroup of 224 TNBC were significantly deregulated. Plasma levels of 18 exosomal miRNAs differed between HER2-positive and TNBC subtypes, and 9 miRNAs of them also differed from healthy women. Exosomal miRNAs were significantly associated with the clinicopathological and risk factors. In uni- and multivariate models, miR-155 (p = 0.002, p = 0.003, respectively) and miR-301 (p = 0.002, p = 0.001, respectively) best predicted pathological complete response (pCR).
Conclusion: Our findings show a network of deregulated exosomal miRNAs with specific expression patterns in exosomes of HER2-positive and TNBC patients that are also associated with clinicopathological parameters and pCR within each BC subtype.
Records of Odonata from the Lanjak Entimau Wildlife Sanctuary (LEWS) in Sarawak, Malaysian Borneo are presented. Previous records of Odonata from LEWS are critically examined. One hundred and ten species have been recorded within the sanctuary, including three that have yet to be found outside (Drepanosticta adenani, Telosticta iban and "Elattoneura" mauros); records of four more species are regarded as in need of confirmation, those of another six are incorrect. In addition to the three species only known from LEWS, other notable records include: Drepanosticta sbong, Dysphaea lugens, Euphaea sp. cf basalis, Pericnemis kiautarum, Burmagomphus insularis, Gomphidia caesarea, Merogomphus species, Phaenandrogomphus safei, Macromia callisto and Idionyx montana. A fresh illustration of the anal appendages of Drepanosticta sbong in lateral view is provided to make up for inaccuracies in the original illustration. The taxonomy of Phaenandrogomphus safeii is briefly discussed. Zygonyx errans Lieftinck, 1953 is considered a subspecies of Z. ida not Z. iris Additional records from areas adjacent to LEWS are given in an appendix.
Sympetrum fonscolombii is for the first time reported for Tuva (Tyva Republic, Russia), as found in the UbsuNur Depression. New data are provided on Odonata of the Turan or TuranUyuk Depression of Tuva, including the first record of Somatochlora exuberata in Tuva beyond the Todzha Depression and Coenagrion armatum, C. ecornutum, Aeshna juncea, A. grandis, Somatochlora graeseri and Libellula quadrimaculata for the first time reported for the Turan Depression. New distributional data and comments on Ophiogomphus spinicornis Selys, 1878 are added. Somatochlora alpestris found at Lake Oyskoe is for the first time reported for the southern Krasnoyarskiy Kray.
We examined alterations in E/I-balance in schizophrenia (ScZ) through measurements of resting-state gamma-band activity in participants meeting clinical high-risk (CHR) criteria (n = 88), 21 first episode (FEP) patients and 34 chronic ScZ-patients. Furthermore, MRS-data were obtained in CHR-participants and matched controls. Magnetoencephalographic (MEG) resting-state activity was examined at source level and MEG-data were correlated with neuropsychological scores and clinical symptoms. CHR-participants were characterized by increased 64–90 Hz power. In contrast, FEP- and ScZ-patients showed aberrant spectral power at both low- and high gamma-band frequencies. MRS-data showed a shift in E/I-balance toward increased excitation in CHR-participants, which correlated with increased occipital gamma-band power. Finally, neuropsychological deficits and clinical symptoms in FEP and ScZ-patients were correlated with reduced gamma band-activity, while elevated psychotic symptoms in the CHR group showed the opposite relationship. The current study suggests that resting-state gamma-band power and altered Glx/GABA ratio indicate changes in E/I-balance parameters across illness stages in ScZ.
Background: This study assessed the impact of medical students’ emotion recognition ability and extraversion on their empathic communication, as perceived by simulated patients in a training context.
Methods: This study used a crossed-effect data structure and examined 245 students in their fourth year of medical school. The students’ personality traits were assessed based on a self-assessment questionnaire of the short form of the Big Five Inventory; their emotion recognition ability was measured using a performance test (Diagnostic Analysis of Nonverbal Accuracy-2, Adult Facial Expressions). Simulated patients evaluated the medical students’ empathic communication.
Results: Students with a combination of high emotion recognition ability and extraversion received more positive ratings from simulated patients than their fellow students with a combination of emotion recognition ability and low extraversion. The main effects of emotion recognition or extraversion were not sufficient to yield similar effects. There were no other effects related to the remaining Big Five variables.
Conclusions: The results support the hypothesis that to build rapport with patients, medical staff need to combine emotional capabilities with a dispositional interest in interpersonal encounters.
An odonatological survey, based on sighting and photographic documenting, was conducted in Palawan and in Cuyo Island. Ten species were found in Cuyo Island raising the number of known species from five to eleven. There are six additions to the Cuyo Island fauna: Agriocnemis f. femina, Ischnura senegalensis, Pseudagrion microcephalum, Brachydiplax c. chalybea, Neurothemis fluctuans and Neurothemis t. terminata. The occurrence of Coeliccia boettcheri, known from Cuyo, but not recorded during this survey, is discussed in some detail. Forty species were recorded in Palawan. Four new additions to the Palawan fauna were recorded: Lestes p. praemorsus, Pseudagrion microcephalum, Xiphiagrion cyanomelas, and Anax guttatus. Neurobasis daviesi, a rare calopterygid damselfly endemic in Palawan, was encountered at the northern side of Cleopatra Needle during the survey.
Most studies in the life sciences and other disciplines involve generating and analyzing numerical data of some type as the foundation for scientific findings. Working with numerical data involves multiple challenges. These include reproducible data acquisition, appropriate data storage, computationally correct data analysis, appropriate reporting and presentation of the results, and suitable data interpretation.
Finding and correcting mistakes when analyzing and interpreting data can be frustrating and time-consuming. Presenting or publishing incorrect results is embarrassing but not uncommon. Particular sources of errors are inappropriate use of statistical methods and incorrect interpretation of data by software. To detect mistakes as early as possible, one should frequently check intermediate and final results for plausibility. Clearly documenting how quantities and results were obtained facilitates correcting mistakes. Properly understanding data is indispensable for reaching well-founded conclusions from experimental results. Units are needed to make sense of numbers, and uncertainty should be estimated to know how meaningful results are. Descriptive statistics and significance testing are useful tools for interpreting numerical results if applied correctly. However, blindly trusting in computed numbers can also be misleading, so it is worth thinking about how data should be summarized quantitatively to properly answer the question at hand. Finally, a suitable form of presentation is needed so that the data can properly support the interpretation and findings. By additionally sharing the relevant data, others can access, understand, and ultimately make use of the results.
These quick tips are intended to provide guidelines for correctly interpreting, efficiently analyzing, and presenting numerical data in a useful way.
Perception of irony has been observed to be impaired in adults with autism spectrum disorder. In typically developed adults, the mismatch of verbal and nonverbal emotional cues can be perceived as an expression of irony even in the absence of any further contextual information. In this study, we evaluate to what extent high functioning autists perceive this incongruence as expressing irony. Our results show that incongruent verbal and nonverbal signals create an impression of irony significantly less often in participants with high-functioning autism than in typically developed control subjects. The extent of overall autistic symptomatology as measured with the autism-spectrum questionnaire (AQ), however, does not correlate with the reduced tendency to attribute incongruent stimuli as expressing irony. Therefore, the attenuation in irony attribution might rather be related to specific subdomains of autistic traits, such as a reduced tendency to interpret communicative signals in terms of complex intentional mental states. The observed differences in irony attribution support the assumption that a less pronounced tendency to engage in higher order mentalization processes might underlie the impairment of pragmatic language understanding in high functioning autism.
Ambrosia artemisiifolia (common ragweed) is an invasive species native to North America and was accidentally introduced to Europe in the 19th century. Widespread in disturbed habitats, it is a major weed in spring-sown crops and it causes serious allergic rhinitis and asthma due to its allergenic pollen. The aim of this research was to analyse the effects of both competitive vegetation and herbivory by Ophraella communa to control A. artemisiifolia in an agricultural area of north-western Italy. Hayseed mixtures, both over-seeded over the resident plant community or after ploughing, when seeded before the winter season, were able to suppress the establishment of A. artemisiifolia as well as to reduce its growth in terms of plant height and inflorescence size. Defoliation of A. artemisiifolia by O. communa at the end of the growing season was conspicuous but most of the plants still produced flowers and seeds. However, significant O. communa attack was recorded for reproductive structures. As for non-target species, O. communa was mainly recorded on Asteraceae, with low density and low degree of damage. Reduction of inflorescence size due to competitive vegetation and damage to male flowers by O. communa may diminish the amount of available pollen. The results of this study may be useful for the implementation of management measures to control A. artemisiifolia in agricultural areas using mixtures of native species.
Biosecurity measures are commonly used to prevent the introduction of non-native species to natural environments globally, yet the efficacy of practices is rarely tested under operational conditions. A voluntary biosecurity measure was trialled in the Norwegian high Arctic following concern that non-native species might be transferred to the region on the footwear of travellers. Passengers aboard an expedition cruise ship disinfected their footwear with the broad spectrum disinfectant Virkon S prior to and in-between landing at sites around the remote Svalbard archipelago. The authors evaluated the efficacy of simply stepping through a disinfectant foot bath, which is the most common practice of footwear disinfection aboard expedition cruise ships in the Arctic. This was compared to a more time consuming and little-used method involving drying disinfected footwear, as proposed by other studies. The two practices were evaluated by measuring microbial growth on paired footwear samples before and after disinfection under both conditions. Step-through disinfection did not substantially reduce microbial growth on the footwear. Allowing disinfected footwear to dry, however, reduced the microbial burden significantly to lower levels. Thus, the currently adopted procedures used aboard ships are ineffective at removing microbial burden and are only effective when footwear is given more time to dry than currently granted under operational conditions. These findings underscore results from empirical research performed elsewhere and suggest the need to better relay this information to practitioners. It is suggested that footwear should minimally be wiped dry after step-through disinfection as a reasonable compromise between biosecurity and practicability.
Im Folgenden werden für das östliche Ruhrgebiet bemerkenswerte Funde aufgeführt. Das Gebiet umfasst die Städte Gelsenkirchen, Essen, Herne, Bochum, Dortmund, Hagen und Hamm sowie die Kreise Recklinghausen, Unna und den Ennepe-Ruhr-Kreis. Zur besseren Auswertung sind hinter den Fundorten die MTB-Angaben (Topographische Karte 1:25.000) und ggf. eine Bewertung des Fundes für den hiesigen Raum und der floristische Status hinzugefügt. Funde aus dem östlichen Ruhrgebiet, die von nordrhein-westfälischer Bedeutung sind, sind im Beitrag BOCHUMER BOTANISCHER VEREIN (2018) aufgeführt. Die Zuordnung der Arten zu Pflanzenfamilien richtet sich nach PAROLLY & ROHWER (2016).
The fluvial systems in the north-east of the Iberian Peninsula are highly disturbed habitats, with widespread occurrence of alien species. Previous studies have shown that alien species have a major impact on native freshwater fauna, but it is not known what effect they have on semi-aquatic reptiles. Here the author investigated the factors that influence the occurrence of three species of semi-aquatic reptiles, one turtle (Mauremys leprosa) and two snakes (Natrix astreptophora and Natrix maura), at 261 sites in seven rivers/streams in Girona (north-eastern Spain). The studied semi-aquatic reptiles are habitat generalists which can occupy sections of rivers with altered regimes. The relationships of reptile presence to abiotic niche parameters and the presence of alien species were evaluated, as well as the patterns of pairwise co-occurrence between the reptiles. The presence of alien species did impact one out of three reptiles in this community. The association between both species of natricines was weakly negative, suggesting that interspecific competition does not structure their co-occurrences. The removal of alien species is the most appropriate strategy to preserve the complete diversity of native semi-aquatic reptiles.
The relevance of using various scoring schemes revealed by an impact assessment of feral mammals
(2018)
Impact scoring schemes are useful for identifying to what extent alien species cause damage. Quantifying the similarity and differences between impact scoring schemes can help determine how to optimally use these tools for policy decisions. Using feral mammals (including rats and mice) as a case study, environmental and socio-economic impacts were assessed using three schemes, namely the Generic Impact Scoring System (GISS), Environmental Impact Classification for Alien Taxa (EICAT) and Socio-Economic Impact Classification for Alien Taxa (SEICAT). The results show that socio-economic impacts scores differ between the respective schemes (GISS and SEICAT) possibly because they assess different aspects of social life and economy. This suggests that both scoring schemes should ideally be applied in concert to get a complete picture of socio-economic impacts. In contrast, environmental impact scores are correlated between GISS and EICAT assessments and this similarity is consistent over most mechanisms except for predation and ecosystems, suggesting that one scoring scheme is sufficient to capture all the environmental impacts. Furthermore, we present evidence for the island susceptibility hypothesis as impacts of feral mammals were found to be higher on islands compared to mainlands.
Robust predictions of alien species richness are useful to assess global biodiversity change. Nevertheless, the capacity to predict spatial patterns of alien species richness remains largely unassessed. Using 22 data sets of alien species richness from diverse taxonomic groups and covering various parts of the world, we evaluated whether different statistical models were able to provide useful predictions of absolute and relative alien species richness, as a function of explanatory variables representing geographical, environmental and socio-economic factors. Five state-of-the-art count data modelling techniques were used and compared: Poisson and negative binomial generalised linear models (GLMs), multivariate adaptive regression splines (MARS), random forests (RF) and boosted regression trees (BRT). We found that predictions of absolute alien species richness had a low to moderate accuracy in the region where the models were developed and a consistently poor accuracy in new regions. Predictions of relative richness performed in a superior manner in both geographical settings, but still were not good. Flexible tree ensembles-type techniques (RF and BRT) were shown to be significantly better in modelling alien species richness than parametric linear models (such as GLM), despite the latter being more commonly applied for this purpose. Importantly, the poor spatial transferability of models also warrants caution in assuming the generality of the relationships they identify, e.g. by applying projections under future scenario conditions. Ultimately, our results strongly suggest that predictability of spatial variation in richness of alien species richness is limited. The somewhat more robust ability to rank regions according to the number of aliens they have (i.e. relative richness), suggests that models of aliens species richness may be useful for prioritising and comparing regions, but not for predicting exact species numbers.
Various mechanisms can facilitate the success of plant invasions simultaneously, but may be difficult to disentangle. In the present study, plants of the range-expanding species Bunias orientalis from native, invasive and naturalised, not yet invasive populations were compared in a field common garden over two years. Plants were grown under two nitrate-regimes and multiple traits regarding growth, defence, antagonist loads and reproduction were measured. A rank-based clustering approach was used to assign correlated traits to distinct suites. These suites were analysed for "syndromes" that are expressed as a function of population origin and/or fertilisation treatment and might represent different invasion mechanisms. Indeed, distinct suites of traits were differentially affected by these factors. The results suggest that several preadaptation properties, such as certain growth characteristics and intraspecific chemical variation, as well as post-introduction adaptations to antagonists and resource availability in novel habitats, are candidate mechanisms that facilitate the success of invasive B. orientalis in parallel. It was concluded that rank-based clustering is a robust and expedient approach to integrate multiple traits for elucidating invasion syndromes within individual species. Studying a multitude of traits at different life-history and establishment stages of plants grown under distinct resource treatments reveals species-specific trade-offs and resource sinks and simplifies the interpretation of trait functions for the potential invasive success of plants.
Die Echte Katzenminze, auch Katzenkraut, Katzenmelisse oder Steinmelisse genannt, ist eine alte Heilpflanze, die bereits von den Römern in Mitteleuropa kultiviert wurde. Ihre Ver-wilderungen gehörten zur typischen Flora der Dörfer, der Umgebung von Klöstern und Gehöften. Die Art tritt aber auch im Siedlungsbereich größerer Städte auf. Sie war in der nordrhein-westfälischen Flora zumindest im letzten Jahrhundert nie häufig und ist heute nur noch sehr selten zu finden (z. B. BECKHAUS 1893, HÖPPNER & PREUSS 1926, RUNGE 1990, HAEUPLER & al. 2003, GORISSEN 2015). Derzeit steht sie landesweit als stark gefährdet auf der Roten Liste (RL 2, RAABE & al. 2011), in einigen Großlandschaften wird sie sogar als "vom Aussterben bedroht" (RL 1) oder "ausgestorben" (RL 0) eingestuft. Dabei muss man aber wissen, dass aktuelle Vorkommen der Echten Katzenminze oft als neophytisch klassifi-ziert und deswegen nicht in der Roten Liste berücksichtigt werden. Hierbei drängt sich die Frage auf, inwiefern sich solche neophytischen Vorkommen überhaupt von anderen Vorkommen unterscheiden.
In an era of global change, the process of biotic homogenisation by which regional biotas become more similar through time has attracted considerable attention from ecologists. Here, a retrospective look at the literature is taken and the question asked how comprehensive is the understanding of this global phenomenon? The goal is to identify potential areas for additional and future enquiries to advance this research frontier and best ensure the long-term preservation of biological diversity across the world. Six propositions are presented here to; (1) broaden our geographic and taxonomic understanding, (2) diversify the spatial and temporal scales of inquiry, (3) reconcile past and embrace new approaches to quantification, (4) improve our knowledge of the underlying drivers, (5) reveal the conservation implications and (6) forecast future homogenisation. It is argued that significant progress in the understanding of the causes, consequences and conservation implication of biotic homogenisation will come by integrating concepts and approaches from ecology, evolution and conservation across a hierarchy of spatial and temporal scales.
Previously, we have synthesized a diverse range of 2,5-furandicarboxylic acid (FDCA)-based semiaromatic polyamides via enzymatic polymerization. This novel class of polymers are biobased alternatives to polyphthalamides, which are petrol-based semiaromatic polyamides. From a commercial perspective, they have interesting properties as high-performance materials and engineering thermoplastics. It is even more appealing to explore novel FDCA-based polyamides with added functionality, for the development of sustainable functional materials. Here, a set of FDCA-based heteroatom polyamides have been successfully produced via Novozyme 435 (N435)-catalyzed polymerization of biobased dimethyl 2,5-furandicarboxylate with (potentially)heteroatom diamines, namely, 4,9-dioxa-1,12-dodecanediamine (DODA), diethylenetriamine, and 3,3-ethylenediiminopropylamine. We performed the enzymatic polymerization in solution and bulk. The latter approach is more sustainable and results in higher molecular weight products. Among the tested heteroatom diamines, N435 shows the highest catalytic activity toward DODA. Furthermore, we find that all obtained FDCA-based heteroatom polyamides are amorphous materials with a relatively high thermal stability. These heteroatom polyamides display a glass-transition temperature ranging from 41 to 107 °C.
Fibroblasts were isolated from skin biopsies from two patients with bipolar I disorder. One patient was a 26 year old female carrying a risk haplotype in the DGKH (diacylglycerol kinase eta) gene and the other was a non-carrier 27 year old male. Patient fibroblasts were reprogrammed into human induced pluripotent stem cells (hiPSCs) by using a Sendai virus vector. DGKH-risk haplotype and non-risk haplotype hiPSCs showed expression of pluripotency markers and were able to differentiate into cells of the three germ layers. These cell models are useful to investigate the role of risk gene variants in bipolar disorder.
Radiographic outcomes following lateral alveolar ridge augmentation using autogenous tooth roots
(2018)
Background: To assess and compare the radiographic outcomes following lateral alveolar ridge augmentation using autogenous tooth roots (TR) and autogenous bone (AB) blocks.
Methods: In a total of 30 patients, lateral ridge augmentation was conducted in parallel groups using either (1) healthy autogenous tooth roots (e.g., retained wisdom or impacted teeth) (n = 15) or (2) cortical autogenous bone blocks harvested from the retromolar area. Cone-beam computed tomographic (CBCT) scans taken at 26 weeks of submerged healing were analyzed for the basal graft integration (i.e., contact between the graft and the host bone in %) (BI26) and the cross-sectional grafted area (mm2) (SA26).
Results: Both groups revealed a comparable clinical width of the alveolar ridge at baseline (CWb). Mean BI26 and SA26 values amounted to 69.26 ± 26.01% (median 72.44) and 22.07 ± 12.98 mm2 (median 18.83) in the TR group and 79.67 ± 15.66% (median 78.85) and 12.42 ± 10.11 mm2 (median 11.36) in the AB group, respectively. Between-group differences in mean SA26 values were statistically significant (p = 0.031). Linear regression analysis failed to reveal any significant correlations between BI26 and CWb/SA26 values in either group.
Conclusions: TR grafts may be associated with improved SA26 values following lateral alveolar ridge augmentation.
Trial registration: DRKS00009586. Registered 10 February 2016.
Site-specific recombinases (SSR) are utilized as important genome engineering tools to precisely modify the genome of mice and other model organisms. Reporter mice that mark cells that at any given time had expressed the enzyme are frequently used for lineage tracing and to characterize newly generated mice expressing a recombinase from a chosen promoter. With increasing sophistication of genome alteration strategies, the demand for novel SSR systems that efficiently and specifically recombine their targets is rising and several SSR-systems are now used in combination to address complex biological questions in vivo. Generation of reporter mice for each one of these recombinases is cumbersome and increases the number of mouse lines that need to be maintained in animal facilities. Here we present a multi-reporter mouse line for loci-of-recombination (X) (MuX) that streamlines the characterization of mice expressing prominent recombinases. MuX mice constitutively express nuclear green fluorescent protein after recombination by either Cre, Flp, Dre or Vika recombinase, rationalizing the number of animal lines that need to be maintained. We also pioneer the use of the Vika/vox system in mice, illustrating its high efficacy and specificity, thereby facilitating future designs of sophisticated recombinase-based in vivo genome engineering strategies.
Detecting associations between genomic changes and phenotypic differences is fundamental to understanding how phenotypes evolved. By systematically screening for parallel amino acid substitutions, we detected known as well as novel cases (Strc, Tecta, and Cabp2) of parallelism between echolocating bats and toothed whales in proteins that could contribute to high-frequency hearing adaptations. Our screen also showed that echolocating mammals exhibit an unusually high number of parallel substitutions in fast-twitch muscle fiber proteins. Both echolocating bats and toothed whales produce an extremely rapid call rate when homing in on their prey, which was shown in bats to be powered by specialized superfast muscles. We show that these genes with parallel substitutions (Casq1, Atp2a1, Myh2, and Myl1) are expressed in the superfast sound-producing muscle of bats. Furthermore, we found that the calcium storage protein calsequestrin 1 of the little brown bat and the bottlenose dolphin functionally converged in its ability to form calcium-sequestering polymers at lower calcium concentrations, which may contribute to rapid calcium transients required for superfast muscle physiology. The proteins that our genomic screen detected could be involved in the convergent evolution of vocalization in echolocating mammals by potentially contributing to both rapid Ca2+ transients and increased shortening velocities in superfast muscles.
Background: In Germany, patients suffering from life-limiting conditions are eligible for specialized outpatient palliative care (SOPC). Evaluation of the quality of this service lacks currently integration of patient-relevant outcomes. There is also no scientific consensus how to prove quality of care in the special context of SOPC adequately. Existing quality reports are primarily based on descriptive structural data which do not allow for estimation of process quality or result quality. The ELSAH study ("Evaluation of Specialized Outpatient Palliative Care in the German state of Hesse") aims to choose - or, if necessary, to adopt - to evaluate and to implement a suit of measures to assess, evaluate and monitor the quality of specialized, home-based palliative care.
Methods: All 22 SOPC teams providing their services in the state of Hesse, Germany, participate in the ELSAH study. The study is divided in two phases: a preparation phase and a main study phase. Based on the findings of the preparation phase we have chosen a preliminary set of instruments including the Integrated Palliative Outcome Scale, Views on Care, Zarit Burden Interview, Phase of Illness, Goal Attainment Scaling, Eastern Cooperative Oncology Group Performance Status, Consumer Quality Indices Palliative Care and Sense of Security in Care. During the main study phase, we will use a mixed-methods approach to evaluate the instruments’ psychometric properties (reliability, validity, feasibility and practicability), to identify barriers, facilitators and limitations of their routine use and to explore how their use affects the care within the SOPC setting.
Discussion: At the end of this study, an outcome- and patient-centered, validated measurement approach should be provided, adapted for standardized evaluations in SOPC across patient groups, palliative care services and regions nationwide. The standardized application of instruments should allow for making valid statements and comparisons of health care quality in SOPC based on process- and outcome-evaluation rather than relying on structural data only. Moreover, the instruments might directly influence the care of patients in palliative situations.
Trial registration: German Clinical Trials Register (DRKS-ID: DRKS00012421).
Background: Many gene variants modulate the individual perception of pain and possibly also its persistence. The limited selection of single functional variants is increasingly being replaced by analyses of the full coding and regulatory sequences of pain-relevant genes accessible by means of next generation sequencing (NGS).
Methods: An NGS panel was created for a set of 77 human genes selected following different lines of evidence supporting their role in persisting pain. To address the role of these candidate genes, we established a sequencing assay based on a custom AmpliSeqTM panel to assess the exomic sequences in 72 subjects of Caucasian ethnicity. To identify the systems biology of the genes, the biological functions associated with these genes were assessed by means of a computational over-representation analysis.
Results: Sequencing generated a median of 2.85 ⋅ 106 reads per run with a mean depth close to 200 reads, mean read length of 205 called bases and an average chip loading of 71%. A total of 3,185 genetic variants were called. A computational functional genomics analysis indicated that the proposed NGS gene panel covers biological processes identified previously as characterizing the functional genomics of persisting pain.
Conclusion: Results of the NGS assay suggested that the produced nucleotide sequences are comparable to those earned with the classical Sanger sequencing technique. The assay is applicable for small to large-scale experimental setups to target the accessing of information about any nucleotide within the addressed genes in a study cohort.
Das Kleine Schneeglöckchen (Galanthus nivalis) zählt zu den klassischen Frühjahrsgeophyten, wobei die Bezeichnung Wintergeophyt an dieser Stelle viel treffender wäre, denn die Art gehört neben dem Winterling (Eranthis hyemalis) bei uns zu den allerersten blühenden Pflanzen im Jahr. Ihre Blüten erscheinen massenhaft zwischen Januar und März, in milden Jahren blühen einzelne Pflanzen auch schon im Dezember. Somit kommt dem Schneeglöckchen nicht nur unter Botanikern eine symbolische Bedeutung zu: Sein Erscheinen versinnbildlicht das allmähliche Erwachen der Natur nach der Winterruhe und den Neubeginn des Pflanzenjahres.
Maintenance of the bacterial homeostasis initially emanates from interactions between proteins and the bacterial nucleoid. Investigating their spatial correlation requires high spatial resolution, especially in tiny, highly confined and crowded bacterial cells. Here, we present super-resolution microscopy using a palette of fluorescent labels that bind transiently to either the membrane or the nucleoid of fixed E. coli cells. The presented labels are easily applicable, versatile and allow long-term single-molecule super-resolution imaging independent of photobleaching. The different spectral properties allow for multiplexed imaging in combination with other localisation-based super-resolution imaging techniques. As examples for applications, we demonstrate correlated super-resolution imaging of the bacterial nucleoid with the position of genetic loci, of nascent DNA in correlation to the entire nucleoid, and of the nucleoid of metabolically arrested cells. We furthermore show that DNA- and membrane-targeting labels can be combined with photoactivatable fluorescent proteins and visualise the nano-scale distribution of RNA polymerase relative to the nucleoid in drug-treated E. coli cells.
Hier werden bemerkenswerte floristische Funde aus Nordrhein-Westfalen aus dem Jahr 2017 und einige Nachträge aus 2015 und 2016 zusammengestellt, die aus Sicht der Schriftleitung von landesweiter Bedeutung sind. Die Funde werden im Laufe des Jahres zunächst chronologisch auf die Homepage des Bochumer Botanischen Vereins gestellt und am Ende des Jahres zu einem Artikel zusammengefasst. Bei der Auswahl der Arten für diese Liste ist nicht an Bestätigung bereits lange bekannter Vorkommen gedacht, die an Ort und Stelle durchgehend vorkommen, sondern z. B. an Neufunde seltener Arten, Wieder-funde seltener Arten, die zwischendurch verschwunden schienen (wie z. B. Ackerunkräuter) oder auch an bekannte Vorkommen, die erloschen sind oder kurz vor dem Erlöschen stehen. Außerdem nehmen Beobachtungen von neophytischen Arten einen großen Raum ein, die entweder auf dem Wege der Einbürgerung sind, deren Einbürgerung noch nicht allgemein bekannt bzw. anerkannt ist oder deren Vorkommen bisher erst selten für Nordrhein-Westfalen veröffentlicht wurden. Ein wichtiges Kriterium für aufgeführte Arten ist die Seltenheit im Bundesland oder in der betreffenden Großlandschaft bzw. Region. Die Zuordnung der Arten zu Pflanzenfamilien richtet sich nach PAROLLY & ROHWER 2016.
Background: Ataxia telangiectasia (A-T) is a devastating multi-system disorder characterized by progressive cerebellar ataxia, growth retardation, immunodeficiency, chronic pulmonary disease and chromosomal instability. Cutaneous granulomas are a known phenomenon in A-T but extra-dermal manifestation of granulomas at bone and synovia has not been reported so far. The clinical presentation, immunological findings, the long-term course and treatment options of eight patients with severe granulomas will be reported.
Methods: From our cohort of 44 classical A-T patients, eight patients aged 2–11 years (18.2%) presented with granulomas. Immunological features of patients with and without granulomas were compared. Five patients suffered from cutaneous manifestation, in two patients we detected a bone and in one a joint involvement. Patients with significant extra-dermal involvement as well as one patient with massive skin manifestation were treated with TNF inhibitors. The patient with granulomas at his finger joint and elbow was treated with hematopoietic stem cell transplantation (HSCT).
Results: Interestingly, seven of eight patients with granulomas were total IgA deficient, but there were no differences in IgG and IgM levels. All lymphocytes subsets were equally distributed except patients with granuloma had significantly lower naïve CD8 cells. In patients without treatment, four of eight showed a slow but significant enlargement of the granuloma. Treatment success with TNF inhibitors was variable. In one patient, treatment with TNF inhibitors led to a total remission for 3 years up to now. In two patients, treatment with TNF inhibitors led to a partial regression of granulomas. Treatment interruptions caused deterioration again.
Conclusions: Granulomas in A-T progress slowly over years and can lead to significant morbidity.Treatment with TNF inhibitors was safe and in part successful in our patients. Interestingly HSCT leads to complete remission, and indicates that aberrant immune function is responsible for granulomas in A-T patients.
At a glance commentary:
Scientific knowledge on the subject: Little is known about the clinical presentation, course and treatment of granulomas in ataxia telangiectasia (A-T). In addition, this is the first report of extra-dermal manifestation of granulomas at bone and synovia in patients with A-T.
What This Study Adds to the Field: Granulomas in A-T progress slowly over years and can lead to significant morbidity. Treatment with TNF inhibitors was safe and in part successful in our patients.
Vorgestellt werden zwei eingebürgerte Vorkommen des Rundblättrigen Labkrauts (Galium rotundifolium) in Fichtenforsten in Attendorn und Lennestadt (Kreis Olpe/Sauerland). Die Herkunft dieser im Süden Deutschlands heimischen Art ist ungewiss. Als Quelle kommt am ehesten forstliches Pflanzgut in Frage.
Neuerdings werden in der ursprünglich nordamerikanischen Epilobium ciliatum-Gruppe drei Arten unterschieden. Intensive Studien im Aachener Raum haben gezeigt, dass weitere Sippen existieren. Im vorliegenden ersten Teil werden die Sippen, die morphologisch E. glandulosum entsprechen oder nahe stehen, besprochen. Neben E. glandulosum wird eine bisher nicht beachtete Sippe als E. pallidiglandulosum neu beschrieben. Sie unterscheidet sich von E. glandulosum unter anderem durch kleinere, zartrosa bis weißlich gefärbte Blüten, bleich- oder schwach blaugrün gefärbte Blätter und abweichend geformte Samen. Hybriden von E. glandulosum mit anderen Sippen der E. ciliatum-Gruppe werden vorgestellt.
Background and purpose: The astroglial protein GFAP is a blood biomarker indicative of intracerebral hemorrhage in patients with acute stroke. Due to its brain specificity and the necessity of brain damage for its detectability in blood, we hypothesized that GFAP could be an interesting marker in cases with primary cerebral cause of death, e.g., traumatic brain injury.
Methods: All corpses scheduled for an autopsy in the Frankfurt Department of Forensic medicine within a 15-month period were included in the study. Cases with a known history of brain disease in the 3 months before death were excluded. During autopsy, blood was collected and GFAP serum levels were determined using a commercially available ELISA. The autopsy protocols were reviewed for the presence of a primary cerebral or a primary non-cerebral cause of death. Agony time was also determined.
Results: A total of 129 autopsy cases were included. GFAP concentrations did not differ between cerebral (median 0.96 μg/l, IQR 5.03) and non-cerebral causes of death (1.21 μg/l, 3.58). GFAP levels were found to be unaffected by hemolysis or post-mortem interval. GFAP levels were found to be increased in cases with prolonged agony times (median 1.76 μg/l [IQR 4.70]) compared to short (0.58 μg/l [0.58]; p<0.001) and ultra-short agony times (0.21 μg/l [0.12]; p = 0.002).
Conclusion: Post-mortem GFAP serum concentrations correlate with agony time and might therefore be useful for the evaluation of the severity of brain damage in prolonged death. Elevated GFAP serum levels do not indicate a primary cerebral cause of death.