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Are nearby places (e.g., cities) described by related words? In this article, we transfer this research question in the field of lexical encoding of geographic information onto the level of intertextuality. To this end, we explore Volunteered Geographic Information (VGI) to model texts addressing places at the level of cities or regions with the help of so-called topic networks. This is done to examine how language encodes and networks geographic information on the aboutness level of texts. Our hypothesis is that the networked thematizations of places are similar, regardless of their distances and the underlying communities of authors. To investigate this, we introduce Multiplex Topic Networks (MTN), which we automatically derive from Linguistic Multilayer Networks (LMN) as a novel model, especially of thematic networking in text corpora. Our study shows a Zipfian organization of the thematic universe in which geographical places (especially cities) are located in online communication. We interpret this finding in the context of cognitive maps, a notion which we extend by so-called thematic maps. According to our interpretation of this finding, the organization of thematic maps as part of cognitive maps results from a tendency of authors to generate shareable content that ensures the continued existence of the underlying media. We test our hypothesis by example of special wikis and extracts of Wikipedia. In this way, we come to the conclusion that geographical places, whether close to each other or not, are located in neighboring semantic places that span similar subnetworks in the topic universe.
We test the hypothesis that the extent to which one obtains information on a given topic through Wikipedia depends on the language in which it is consulted. Controlling the size factor, we investigate this hypothesis for a number of 25 subject areas. Since Wikipedia is a central part of the web-based information landscape, this indicates a language-related, linguistic bias. The article therefore deals with the question of whether Wikipedia exhibits this kind of linguistic relativity or not. From the perspective of educational science, the article develops a computational model of the information landscape from which multiple texts are drawn as typical input of web-based reading. For this purpose, it develops a hybrid model of intra- and intertextual similarity of different parts of the information landscape and tests this model on the example of 35 languages and corresponding Wikipedias. In the way it measures the similarities of hypertexts, the article goes beyond existing approaches by examining their structural and semantic aspects intra- and intertextually. In this way it builds a bridge between reading research, educational science, Wikipedia research and computational linguistics.
Consensus on definition and severity grading of lymphatic complications after kidney transplantation
(2020)
Background: The incidence of lymphatic complications after kidney transplantation varies considerably in the literature. This is partly because a universally accepted definition has not been established. This study aimed to propose an acceptable definition and severity grading system for lymphatic complications based on their management strategy.
Methods: Relevant literature published in MEDLINE and Web of Science was searched systematically. A consensus for definition and a severity grading was then sought between 20 high-volume transplant centres.
Results: Lymphorrhoea/lymphocele was defined in 32 of 87 included studies. Sixty-three articles explained how lymphatic complications were managed, but none graded their severity. The proposed definition of lymphorrhoea was leakage of more than 50 ml fluid (not urine, blood or pus) per day from the drain, or the drain site after removal of the drain, for more than 1 week after kidney transplantation. The proposed definition of lymphocele was a fluid collection of any size near to the transplanted kidney, after urinoma, haematoma and abscess have been excluded. Grade A lymphatic complications have a minor and/or non-invasive impact on the clinical management of the patient; grade B complications require non-surgical intervention; and grade C complications require invasive surgical intervention.
Conclusion: A clear definition and severity grading for lymphatic complications after kidney transplantation was agreed. The proposed definitions should allow better comparisons between studies.
Mon intention première était de comprendre la façon dont la République romaine avait sombré. Mais lorsque j’ai examiné dans ce but les explications les plus sérieuses qui avaient déjà été avancées, sa faillite m’a toutefois paru moins étonnante que sa très longue existence. Au point que, progressivement, une deuxième question a pris le pas sur la première, celle de savoir comment cette chose commune [Gemeinwesen], cette res publica amissa avait pu fonctionner si longtemps. Je me suis donc concentré sur sa structure. ...
Cerumen was found to be a promising alternative specimen for the detection of drugs. In a pilot study, drugs of abuse were identified at a higher detection rate and a longer detection window in cerumen than in urine. In this study, cerumen from subjects was analyzed after they ingested the designer stimulant 4-fluoroamphetamine (4-FA) in a controlled manner. Methods: Twelve subjects ingested placebo and 100 mg of 4-FA. Five of them were also given 150 mg of 4-FA in 150 mL Royal Club bitter lemon drink at least after 7 days. Cerumen was sampled using cotton swabs at baseline, 1 h after the ingestion of the drug and at the end of the study day (12 h). After extraction with ethyl acetate followed by solid-phase extraction, the extracts were analyzed using liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). Results and discussion: In the cerumen of all 12 subjects, 4-FA was detected 12 h after its ingestion; in most subjects, cerumen was detected after 1 h of ingestion, ranging from 0.06 to 13.90 (median 1.52) ng per swab. The detection of 4-FA in cerumen sampled 7 days or more after the first dose suggested a long detection window of cerumen. Conclusions: Cerumen can be successfully used to detect a single drug ingestion even immediately after the ingestion when a sufficient amount of cerumen is used.
Hepatocyte nuclear factor 4α (HNF4α) is a ligand-sensing transcription factor and presents as a potential drug target in metabolic diseases and cancer. In humans, mutations in the HNF4α gene cause maturity-onset diabetes of the young (MODY), and the elevated activity of this protein has been associated with gastrointestinal cancers. Despite the high therapeutic potential, available ligands and structure–activity relationship knowledge for this nuclear receptor are scarce. Here, we disclose a chemically diverse collection of orthogonally validated fragment-like activators as well as inverse agonists, which modulate HNF4α activity in a low micromolar range. These compounds demonstrate the druggability of HNF4α and thus provide a starting point for medicinal chemistry as well as an early tool for chemogenomics.
RNA-protein complexes (RNPs) are essential components in a variety of cellular processes, and oftentimes exhibit complex structures and show mechanisms that are highly dynamic in conformation and structure. However, biochemical and structural biology approaches are mostly not able to fully elucidate the structurally and especially conformationally dynamic and heterogeneous nature of these RNPs, to which end single molecule Förster resonance energy transfer (smFRET) spectroscopy can be harnessed to fill this gap. Here we summarize the advantages of strategic smFRET studies to investigate RNP dynamics, complemented by structural and biochemical data. Focusing on recent smFRET studies of three essential biological systems, we demonstrate that investigation of RNPs on a single molecule level can answer important functional questions that remained elusive with structural or biochemical approaches alone: The complex structural rearrangements throughout the splicing cycle, unwinding dynamics of the G-quadruplex (G4) helicase RHAU, and aspects in telomere maintenance regulation and synthesis.
Astrozyten erfüllen verschiedene Funktionen im Zentralnervensystem, welche sich in die Bereiche Entwicklung, Durchblutung, Metabolismus, Strukturerhalt und Gliotransmission unterteilen lassen. Astrozyten sind an der synaptischen Informationsverarbeitung beteiligt und wirken an zahlreichen höheren Hirnfunktionen mit. Durch Regulation der synaptischen Transmission und Plastizität sind Astrozyten am Lernverhalten und Erinnerungsvermögen, sowie an der Verhaltensmodulation und Verarbeitung emotionaler Reize involviert. Im Zuge dieser zahlreichen Funktionen können Astrozyten auf externe Stimuli mit der gezielten Freisetzung von Gliotransmittern reagieren.
In kultivierten Astrozyten konnte Keil143 das TGN, bestehend aus Zisternen und Vesikeln, darstellen und mit anti-Rab6 identifizieren. Rab6 mit seinen Subtypen A und B gehört der Superfamilie der monomeren Ras-GTPasen an, die den intrazellulären Membran- und Vesikelverkehr regulieren. Rab6 spielt in HeLa-Zellen beim Transport vesikulärer Organellen vom TGN zur Zellmembran eine wichtige Rolle. Assoziationsanalysen von Rab6A mit vesikulären Glutamattransportern, Serinracemase und Markern der regulierten Exozytose in kultivierten Astrozyten143 deuten darauf hin, dass dieses Rab6A-Organellsystem die ultrastrukturelle Grundlage für die Freisetzung von Gliotransmittern wie D-Serin und Glutamat bildet.
Zur Untersuchung, ob Rab6A tatsächlich ein System der Glia-Neuron-Kommunikation im Gehirn darstellt, war es zunächst unabdingbar das Vorkommen von Rab6A in situ zu untersuchen. Die durchgeführten immunzytochemischen Färbungen an Hirnschnitten der Maus zeigen das gleichmäßige und ubiquitäre Vorkommen von Rab6A in allen untersuchten Hirnregionen. Durch verblindet durchgeführte Kolokalisationsanalysen von Rab6A mit den etablierten astrozytären Markern Glutaminsynthetase (GS), Glial fibrillary acidic protein (GFAP), Aldh1L1 und Sox9 konnte eine Lokalisation von Rab6A in allen Astrozyten gezeigt werden. Weitere Analysen schließen die Lokalisation von Rab6A in Mikroglia (Iba1), NG2-Zellen (NG2) und Oligodendrozyten (CNPase) aus. Die Astrozyten unterscheiden sich in Größe und subzellulärem Verteilungsmuster der Rab6A+ Strukturen, wonach eine Kategorisierung in vier Typen vorgenommen wurde. Anhand der Einteilung kann vermutet werden, dass größere Rab6A+ TGN-Zisternen bis weit in die Zellperipherie transportiert werden und kleine Rab6A+ Vesikel erst dort ausknospen und der Exozytose zugeführt werden. Zur Frage der möglichen astrozytären Subpopulationen konnte gezeigt werden, dass alle untersuchten Astrozyten GS+, Aldh1L1+, Sox9+ und Rab6A+ sind, jedoch nicht GFAP+.
Um die prinzipielle Übertragbarkeit der gewonnenen Befunde auf den Menschen zu überprüfen, wurde reseziertes Cortex-Gewebe von drei Patienten mit unterschiedlicher pathologischer Genese untersucht. Rab6A ist im massiven Ausmaß in humanen Astrozyten lokalisiert, was nahelegt, dass die zuvor an der Maus gewonnenen Ergebnisse auf den Menschen übertragbar sind.
Die mögliche funktionelle Bedeutung von astrozytärem Rab6A im Gehirn wurde an HFS-Schnitten untersucht. Die Untersuchung zeigt einen signifikanten Anstieg der Rab6A+ Intensität in der gesamten Molekularschicht der Fascia dentata der stimulierten im Vergleich zur unstimulierten Seite. Da die HFS ein etabliertes LTP-Modell darstellt, könnte es infolge dieser zu einer strukturellen, intrazellulären Veränderung der Astrozyten mit erhöhter Freisetzung von D-Serin oder Glutamat aus Rab6A+ Vesikeln kommen, was das Lernverhalten beeinflussen könnte. Die dargestellten Ergebnisse legen eine Auswirkung der HFS auf Rab6A nahe.
Zur Bestätigung der immunzytochemischen Untersuchungen wurde die mRNA-Expression von Rab6A in Astrozyten bereits publizierter Transkriptomanalysen untersucht. Die in den Publikationen verwendeten Genom-Chips treffen allenfalls indirekt eine Aussage zu Rab6A, da Rab6 allgemein und nur Rab6B spezifisch untersucht wurde, jedoch keine spezifische Rab6A Sonde erwähnt wird.
Zusammenfassend kann Rab6A als spezifisches und selektiv in Astrozyten vorkommendes Protein dargestellt und als neuer astrozytärer Marker etabliert werden, der auch Astrozyten des humanen Gewebes markiert. Durch die gewonnenen Befunde kann in nachfolgenden Studien die mögliche Bedeutung von Rab6A in neuropathologischen und neurophysiologischen Prozessen untersucht werden.
We have measured the γ-rays following neutron capture on 240Pu and 244 Cm at the n_TOF facility at CERN with the Total Absorption Calorimeter (TAC) and with C6D6 organic scintillators. The TAC is made of 40 BaF2 crystals operating in coincidence and covering almost the entire solid angle. This allows to obtain information concerning the energy spectra and the multiplicity of the measured capture γ-ray cascades. Additional information is also obtained from the C6D6 detectors. We have analyzed the measured data in order to draw conclusions about the Photon Strength Functions (PSFs) of 241Pu and 245Cm below their neutron separation energies. The analysis has been performed by fitting the PSFs to the experimental results, using the differential evolution method, in order to find neutron capture cascades capable of reproducing at the same time a great variety of deposited energy spectra.
Background: The health status, health awareness and health behavior of persons with a migration background often differ from the autochthonous population. Little is known about the proportion of patients with a migration background (PMB) that participate in primary care studies on oral antithrombotic treatment (OAT) in Germany, and whether the quality of their antithrombotic care differs from patients without a migration background. The aim of this paper was to use the results of a cluster-randomized controlled trial (PICANT) to determine the proportion of PMB at different stages of recruitment, and to compare the results in terms of sociodemographic characteristics and antithrombotic treatment.
Methods: This study used screening and baseline data from the PICANT trial on oral anticoagulation management in GP practices. For this analysis, we determined the proportion of PMB during the recruitment period at stage 1 (screening of potentially eligible patients), stage 2 (eligible patients invited to participate in the trial), and stage 3 (assessment of baseline characteristics of patients participating in the PICANT trial). In addition, we compared patients in terms of sociodemographic characteristics and quality of anticoagulant treatment. Statistical analysis comprised descriptive and bivariate analyses.
Results: The proportion of PMB at each recruitment stage declined from 9.1% at stage 1 to 7.9% at stage 2 and 7.3% at stage 3). A lack of German language skills led to the exclusion of half the otherwise eligible PMB. At stages 1 and 3, PMB were younger (stage 1: 70.7 vs. 75.0 years, p<0.001; stage 3: 70.2 vs. 73.5 years, p = 0.013), but did not differ in terms of gender. The quality of their anticoagulant care was comparable (100.0% vs. 99.1% were receiving appropriate OAT, 94.4% vs. 95.7% took phenprocoumon, or warfarin, and the most recent INR measurement of 60.8% vs. 69.3% was within their individual INR range).
Conclusions: In the potentially eligible population and among participants at baseline, the quality of anticoagulant care was high in all groups of patients, which is reassuring. To enable the inclusion of more PMB, future primary care research on OAT in Germany should address how best to overcome language barriers. This will be challenging, particularly because the heterogeneity of PMB means the resulting sample sizes for each specific language group are small.
Trial registration: Current Controlled Trials ISRCTN41847489.
High-risk rhabdomyosarcoma (RMS) occurring in childhood to young adulthood is associated with a poor prognosis; especially children above the age of 10 with advanced stage alveolar RMS still succumb to the disease within a median of 2 years. The advent of chimeric antigen receptor (CAR)-engineered T cells marked significant progress in the treatment of refractory B cell malignancies, but experience for solid tumors has proven challenging. We speculate that this is at least in part due to the poor quality of the patient's own T cells and therefore propose using CAR-modified cytokine-induced killer (CIK) cells as effector cells. CIK cells are a heterogeneous population of polyclonal T cells that acquire phenotypic and cytotoxic properties of natural killer (NK) cells through the cultivation process, becoming so-called T-NK cells. CIK cells can be genetically modified to express CARs. They are minimally alloreactive and can therefore be acquired from haploidentical first-degree relatives. Here, we explored the potential of ERBB2-CAR-modified random-donor CIK cells as a treatment for RMS in xenotolerant mice bearing disseminated high-risk RMS tumors. In otherwise untreated mice, RMS tumors engrafted 13–35 days after intravenous tumor cell injection, as shown by in vivo bioluminescence imaging, immunohistochemistry, and polymerase chain reaction for human gDNA, and mice died shortly thereafter (median/range: 62/56–66 days, n = 5). Wild-type (WT) CIK cells given at an early stage delayed and eliminated RMS engraftment in 4 of 6 (67%) mice, while ERBB2-CAR CIK cells inhibited initial tumor load in 8 of 8 (100%) mice. WT CIK cells were detectable but not as active as CAR CIK cells at distant tumor sites. CIK cell therapies during advanced RMS delayed but did not inhibit tumor progression compared to untreated controls. ERBB2-CAR CIK cell therapy also supported innate immunity as evidenced by selective accumulation of NK and T-NK cell subpopulations in disseminated RMS tumors, which was not observed for WT CIK cells. Our data underscore the power of heterogenous immune cell populations (T, NK, and T-NK cells) to control solid tumors, which can be further enhanced with CARs, suggesting ERBB2-CAR CIK cells as a potential treatment for high-risk RMS.
During the course of sepsis in critically ill patients, kidney dysfunction and damage are among the first events of a complex scenario toward multi-organ failure and patient death. Acute kidney injury triggers the release of lipocalin-2 (Lcn-2), which is involved in both renal injury and recovery. Taking into account that Lcn-2 binds and transports iron with high affinity, we aimed at clarifying if Lcn-2 fulfills different biological functions according to its iron-loading status and its cellular source during sepsis-induced kidney failure. We assessed Lcn-2 levels both in serum and in the supernatant of short-term cultured renal macrophages (MΦ) as well as renal tubular epithelial cells (TEC) isolated from either Sham-operated or cecal ligation and puncture (CLP)-treated septic mice. Total kidney iron content was analyzed by Perls’ staining, while Lcn-2-bound iron in the supernatants of short-term cultured cells was determined by atomic absorption spectroscopy. Lcn-2 protein in serum was rapidly up-regulated at 6 h after sepsis induction and subsequently increased up to 48 h. Lcn-2-levels in the supernatant of TEC peaked at 24 h and were low at 48 h with no change in its iron-loading. In contrast, in renal MΦ Lcn-2 was low at 24 h, but increased at 48 h, where it mainly appeared in its iron-bound form. Whereas TEC-secreted, iron-free Lcn-2 was associated with renal injury, increased MΦ-released iron-bound Lcn-2 was linked to renal recovery. Therefore, we hypothesized that both the cellular source of Lcn-2 as well as its iron-load crucially adds to its biological function during sepsis-induced renal injury.
The aim of this observational study was to follow-up patients with bedtime basal insulin (NPH insulin) added to metformin. In 285 patients with type 2 diabetes, a therapy with bedtime basal insulin added to metformin was started due to failure to achieve a glycaemic goal. Up until July 2019, 272 patients (95.4%) were followed-up (59.5 y, 92.6 kg, diabetes duration 6.6 y, HbA1c 8.4%/68.6 mmol/mol). HbA1c decreased by −1.2% and bodyweight by −1.7 kg after a duration of 31.7 ± 29.1 (range 2–133) months. Severe hypoglycaemia did not occur. In 144/272 patients (52.9%), the therapeutic goal for HbA1c was achieved over 32.7 months. In 69/272 patients (25.4%), the HbA1c target was achieved over 25.0 months (afterwards, therapy with basal insulin was discontinued because HbA1c was under target). In 36/272 patients (13.2%), the HbA1c goal was achieved until the submission of this manuscript (mean duration of treatment 57.4 ± 28.2 (range 13–121) months). Over 90% of patients with type 2 diabetes and failure of metformin reached their HbA1c goal with additional basal insulin at bedtime over several years in association with a reduction of bodyweight and without any event of severe hypoglycaemia.
Nature and its constituents are known to affect human well-being in positive and negative ways. Nature can be beneficial for humans by providing, for instance, food, recreation or inspiration. Natural disasters or transmitted diseases are, on the other hand, examples of nature’s detrimental or harmful contributions to human well-being. Such positive as well as negative effects have been termed Nature’s Contributions to People (NCP) by the Intergovernmental Science-Policy Platform for Biodiversity and Ecosystem Services (IPBES) and can be categorized into three different types of contributions: regulating, material and non-material NCP. While regulating and material NCP have been studied extensively, research on the non-material NCP is less common in comparison, especially regarding non-material NCP of biodiversity and wildlife. This dissertation therefore aims at shedding light on the non-material links between biodiversity, wildlife and human well-being. The thesis presents the results of three individual research studies in three separate chapters (CH1, 2 & 3).
In the first chapter (CH1) I conduct a systematic literature review on the non-material contributions of wildlife. Several previous reviews have published overviews on the non-material contributions of wildlife. However, only a few of these reviews examine both the positive and negative effects of wildlife in combination. These reviews usually cover few aspects of human well-being (e.g. recreation, health, psychological well-being) or just focus on a specific group of wildlife species (e.g. carnivores, scavengers). In addition, the pathways determining how wildlife affects human well-being are yet little understood. The aim of this review is therefore to create a holistic overview of the current knowledge on non-material contributions of wildlife (WCP), by summarising research on positive and negative effects and disentangling potential channels of human-wildlife experiences.
My results show that most studies in scientific literature report negative WCP. However, over the last decade the number of publications on positive WCP has increased, mainly in the Global North. This change in research focus, at the turn of the century, may be related to the newly emerging ideas and perspectives on nature during that time (e.g. Ecosystem Services and NCP). The results may also indicate different research interests across global regions and a focus on positive WCP (especially in the Global North). Surprisingly, the review identifies a lack of joint systematic assessments of positive and negative WCP across taxa, human well-being dimensions and ways (channels) of wildlife experiences. Studies show taxon-specific differences, with predominantly positive WCP reported for birds and predominantly negative WCP published for mammals and reptiles. Physical health was the most examined human well-being dimension, while many others, such as subjective well-being, social well-being, learning, identity or sense of place were rarely studied in comparison. The two channels of wildlife experiences that have been mainly studied or reported are Interaction and Knowing. While Interaction describes multisensory experiences in which people physically interact with wildlife. Knowing describes the metaphysical connection between humans and wildlife that arises through thinking or remembering experiences from wildlife encounters (including knowledge about wildlife).
To date, only few published studies examine the relationship between biodiversity and human well-being across larger spatial scales. For instance, little is known about how biodiversity is related to human well-being on the national or continental level. The second and third chapter (CH2 & 3) are thus comprised of two empirical case studies which examine the relationship between biodiversity and human well-being across Germany and Europe, respectively. As indicator for biodiversity, I use different species diversity measures including species richness and abundance. In the second chapter (CH2) I analyse the association between species richness and human health across Germany. The results demonstrate a significant positive relationship between plant and bird species richness and mental health while controlling for a multitude of socio-economic and demographic factors as well as other nature characteristics. In the third chapter (CH3) I conduct the first study on the relationship between species diversity and subjective well-being on the continental level. The results show that bird species richness (unlike mammal, megafauna and tree richness) is positively associated with life-satisfaction, a measure for subjective well-being across Europe. These results are robust while accounting for socio-economic and macro-economic factors. The results of both empirical studies are in correspondence with previous research, conducted on the local and national level.
Overall, my dissertation shows that wildlife and biodiversity greatly affect human well-being and provide substantial non-material NCP.
...
Nature affects human well-being in multiple ways. However, the association between species diversity and human well-being at larger spatial scales remains largely unexplored. Here, we examine the relationship between species diversity and human well-being at the continental scale, while controlling for other known drivers of well-being. We related socio-economic data from more than 26,000 European citizens across 26 countries with macroecological data on species diversity and nature characteristics for Europe. Human well-being was measured as self-reported life-satisfaction and species diversity as the species richness of several taxonomic groups (e.g. birds, mammals and trees). Our results show that bird species richness is positively associated with life-satisfaction across Europe. We found a relatively strong relationship, indicating that the effect of bird species richness on life-satisfaction may be of similar magnitude to that of income. We discuss two, non-exclusive pathways for this relationship: the direct multisensory experience of birds, and beneficial landscape properties which promote both bird diversity and people's well-being. Based on these results, this study argues that management actions for the protection of birds and the landscapes that support them would benefit humans. We suggest that political and societal decision-making should consider the critical role of species diversity for human well-being.
We show that the metrisability of an oriented projective surface is equivalent to the existence of pseudo-holomorphic curves. A projective structure p and a volume form σ on an oriented surface M equip the total space of a certain disk bundle Z→M with a pair (Jp,Jp,σ) of almost complex structures. A conformal structure on M corresponds to a section of Z→M and p is metrisable by the metric g if and only if [g]:M→Z is a pseudo-holomorphic curve with respect to Jp and Jp,dAg.
Locomotor activity patterns of laboratory mice are widely used to analyze circadian mechanisms, but most investigations have been performed under standardized laboratory conditions. Outdoors, animals are exposed to daily changes in photoperiod and other abiotic cues that might influence their circadian system. To investigate how the locomotor activity patterns under outdoor conditions compare to controlled laboratory conditions, we placed 2 laboratory mouse strains (melatonin-deficient C57Bl and melatonin-proficient C3H) in the garden of the Dr. Senckenbergische Anatomie in Frankfurt am Main. The mice were kept singly in cages equipped with an infrared locomotion detector, a hiding box, nesting material, and with food and water ad libitum. The locomotor activity of each mouse was recorded for 1 year, together with data on ambient
temperature, light, and humidity. Chronotype, chronotype stability, total daily activity, duration of the activity period, and daily diurnality indices were determined from the actograms. C3H mice showed clear seasonal differences in the chronotype, its stability, the total daily activity, and the duration of the activity period. These pronounced seasonal differences were not observed in the C57Bl. In both strains, the onset of the main activity period was mainly determinedby the evening dusk, whereas the offset was influenced by the ambient temperature. The actograms did not reveal infra-, ultradian, or lunar rhythms or a weekday/weekend pattern. Under outdoor conditions, the 2 strains retained their nocturnal locomotor identity as observed in the laboratory. Our results indicate that the chronotype displays a seasonal plasticity that may depend on the melatoninergic system. Photoperiod and ambient temperature are the most potent abiotic entraining cues. The timing of the evening dusk mainly affects the onset of the activity period; the ambient temperature during this period influences the latter’s duration. Humidity, overall light intensities, and human activities do not affect the locomotor behavior.
The bacteriophage ΦX174 causes large pore formation in Escherichia coli and related bacteria. Lysis is mediated by the small membrane-bound toxin ΦX174-E, which is composed of a transmembrane domain and a soluble domain. The toxin requires activation by the bacterial chaperone SlyD and inhibits the cell wall precursor forming enzyme MraY. Bacterial cell wall biosynthesis is an important target for antibiotics; therefore, knowledge of molecular details in the ΦX174-E lysis pathway could help to identify new mechanisms and sites of action. In this study, cell-free expression and nanoparticle technology were combined to avoid toxic effects upon ΦX174-E synthesis, resulting in the efficient production of a functional full-length toxin and engineered derivatives. Pre-assembled nanodiscs were used to study ΦX174-E function in defined lipid environments and to analyze its membrane insertion mechanisms. The conformation of the soluble domain of ΦX174-E was identified as a central trigger for membrane insertion, as well as for the oligomeric assembly of the toxin. Stable complex formation of the soluble domain with SlyD is essential to keep nascent ΦX174-E in a conformation competent for membrane insertion. Once inserted into the membrane, ΦX174-E assembles into high-order complexes via its transmembrane domain and oligomerization depends on the presence of an essential proline residue at position 21. The data presented here support a model where an initial contact of the nascent ΦX174-E transmembrane domain with the peptidyl-prolyl isomerase domain of SlyD is essential to allow a subsequent stable interaction of SlyD with the ΦX174-E soluble domain for the generation of a membrane insertion competent toxin.
The aim of this study is to provide a systematic assessment of the influence of the position on the arterial input function (AIF) for perfusion quantification. In 39 patients with a wide range of left ventricular function the AIF was determined using a diluted contrast bolus of a cardiac magnetic resonance imaging in three left ventricular levels (basal, mid, apex) as well as aortic sinus (AoS). Time to peak signal intensities, baseline corrected peak signal intensity and upslopes were determined and compared to those obtained in the AoS. The error induced by sampling the AIF in a position different to the AoS was determined by Fermi deconvolution. The time to peak signal intensity was strongly correlated (r2 > 0.9) for all positions with a systematic earlier arrival in the basal (− 2153 ± 818 ms), the mid (− 1429 ± 928 ms) and the apical slice (− 450 ± 739 ms) relative to the AoS (all p < 0.001). Peak signal intensity as well as upslopes were strongly correlated (r2 > 0.9 for both) for all positions with a systematic overestimation in all positions relative to the AoS (all p < 0.001 and all p < 0.05). Differences between the positions were more pronounced for patients with reduced ejection fraction. The error of averaged MBF quantification was 8%, 13% and 27% for the base, mid and apex. The location of the AIF significantly influences core parameters for perfusion quantification with a systematic and ejection fraction dependent error. Full quantification should be based on obtaining the AIF as close as possible to the myocardium to minimize these errors.
Standard monitoring of heart rate, blood pressure and arterial oxygen saturation during endoscopy is recommended by current guidelines on procedural sedation. A number of studies indicated a reduction of hypoxic (art. oxygenation < 90% for > 15 s) and severe hypoxic events (art. oxygenation < 85%) by additional use of capnography. Therefore, U.S. and the European guidelines comment that additional capnography monitoring can be considered in long or deep sedation. Integrated Pulmonary Index® (IPI) is an algorithm-based monitoring parameter that combines oxygenation measured by pulse oximetry (art. oxygenation, heart rate) and ventilation measured by capnography (respiratory rate, apnea > 10 s, partial pressure of end-tidal carbon dioxide [PetCO2]). The aim of this paper was to analyze the value of IPI as parameter to monitor the respiratory status in patients receiving propofol sedation during PEG-procedure. Patients reporting for PEG-placement under sedation were randomized 1:1 in either standard monitoring group (SM) or capnography monitoring group including IPI (IM). Heart rate, blood pressure and arterial oxygen saturation were monitored in SM. In IM additional monitoring was performed measuring PetCO2, respiratory rate and IPI. Capnography and IPI values were recorded for all patients but were only visible to the endoscopic team for the IM-group. IPI values range between 1 and 10 (10 = normal; 8–9 = within normal range; 7 = close to normal range, requires attention; 5–6 = requires attention and may require intervention; 3–4 = requires intervention; 1–2 requires immediate intervention). Results on capnography versus standard monitoring of the same study population was published previously. A total of 147 patients (74 in SM and 73 in IM) were included in the present study. Hypoxic events occurred in 62 patients (42%) and severe hypoxic events in 44 patients (29%), respectively. Baseline characteristics were equally distributed in both groups. IPI = 1, IPI < 7 as well as the parameters PetCO2 = 0 mmHg and apnea > 10 s had a high sensitivity for hypoxic and severe hypoxic events, respectively (IPI = 1: 81%/81% [hypoxic/severe hypoxic event], IPI < 7: 82%/88%, PetCO2: 69%/68%, apnea > 10 s: 84%/84%). All four parameters had a low specificity for both hypoxic and severe hypoxic events (IPI = 1: 13%/12%, IPI < 7: 7%/7%, PetCO2: 29%/27%, apnea > 10 s: 7%/7%). In multivariate analysis, only SM and PetCO2 = 0 mmHg were independent risk factors for hypoxia. IPI (IPI = 1 and IPI < 7) as well as the individual parameters PetCO2 = 0 mmHg and apnea > 10 s allow a fast and convenient conclusion on patients’ respiratory status in a morbid patient population. Sensitivity is good for most parameters, but specificity is poor. In conclusion, IPI can be a useful metric to assess respiratory status during propofol-sedation in PEG-placement. However, IPI was not superior to PetCO2 and apnea > 10 s.