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Ziel dieser Arbeit war, mittels einer (n,γ)-Aktivierung, 129Te zu erzeugen und eine Teilchenzahlbestimmung durchzuführen. Aktivierung der Probe am Forschungsreaktor TRIGA und Spektrenaufnahme mittels eines HPGe-Detektors erfolgten im Mai 2014 am Institut für Kernchemie der Johannes Gutenberg Universität in Mainz.
Die Teilchenzahl des Tochternuklids 129I kann anhand der Teilchenzahlen des Isomers und des Grundzustandes von 129Te berechnet werden. In den Aktivierungen #2 bis #6 wurden (14.27 ± 0.53)x10exp12 Iodnuklide erzeugt. Angegeben ist die maximal mögliche Anzahl von Iodteilchen bei unendlich langer Wartezeit und vollständigem Zerfall aller Tellurnuklide.
Beobachtet werden konnte die Abnahme der Grundzustandsaktivität bis zum Erreichen des Gleichgewichts aus Nachbevölkerung durch das Isomer und Zerfall. Die Grundzustandslinien der Energien von 459.60 keV, 487 keV, 1083 KeV und 1111 keV konnten zu dieser Untersuchung herangezogen werden. Diese 4 Linien erfüllen die erforderten Konsistenzkriterien bezüglich der Systematik und können daher zur Teilchenzahlbestimmung des Grundzustandes verwendet werden (Seite 31).
Der Einfluss der Eigenabsorption ist noch zu untersuchen, da die genaue Position der Probe im Polyethylenbehältnis nicht bestimmt werden konnte. Weiterhin ist die Datenanalyse der ersten Aktivierung aufgrund des Detektorwechsels noch nicht erfolgt. Der Austausch war wegen technischer Probleme notwendig. Ziel weiterführender Untersuchungen ist, eine erneute Halbwertszeitbestimmung des radioaktiven 129I vorzunehmen. Sie ist von Interesse, angesichts des Widerspruchs zweier Veröffentlichungen. Die Halbwertszeit des 129I kann Aufschluss über stellare Bedingungen des s-Prozesses geben.
The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0–T1: +3.37±2.17%), while non-responders further decreased in methylation (−2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02–0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.
Microsurgical free flap reconstruction in acute burn care offers the option of reconstructing even challenging defects in a single stage procedure. Due to altered rheological and hemodynamic conditions in severely burned patients, it bears the risk of a higher complication rate compared to microsurgical reconstruction in other patients. To avoid failure, appropriate indications for free flap reconstruction should be reviewed thoroughly. Several aspects concerning timing of the procedure, individual flap choice, selection and preparation of the recipient vessels, and perioperative measures must be considered. Respecting these specific conditions, a low complication rate, comparable to those seen in microsurgical reconstruction of other traumatic limb defects, can be observed. Hence, the free flap procedure in acute burn care is a relatively safe and reliable tool in the armamentarium of acute burn surgery. In reconstructive burn care, microsurgical tissue transfer is routinely used to treat scar contractures. Due to the more robust perioperative condition of patients, even lower rates of complication are seen in microsurgical reconstruction.
Streitpunkt Hochschulranking
(2012)
Seit den 90er Jahren werden auch in Deutschland Hochschulen und Fakultäten in Form von Rankings bewertet. Dabei werden anhand bestimmter Kriterien – z.B. Leistungen in Forschung und Lehre, Ausstattung oder Entwicklungsperspektiven – Ranglisten erstellt.
Hochschulrankings sind als Informationsquellen für Studierende, Wissenschaftler, Unternehmen und Hochschulpolitik immer wichtiger geworden. Zugleich schwelt seit einiger Zeit ein heftiger Streit über die generelle Aussagekraft von Rankings. Methodische Mängel und unzulässige Interpretationen der Daten seien zu beklagen, so die Kritiker. Einige Fakultäten und sogar ganze Hochschulen haben sich bereits aus bestimmten Rankings ausgeklinkt. Die Befürworter der Rankings wiederum sehen in diesen Austritten eine Gefahr für die Wettbewerbsfähigkeit der deutschen Hochschulen.
Wir haben speziell zu einem der wichtigsten Rankings zwei Standpunkte eingeholt. Frank Ziegele, Geschäftsführer des Centrum für Hochschulentwicklung (CHE), verteidigt das CHE Hochschulranking, Prof. Sighard Neckel, Soziologe an der Goethe-Universität, kontert mit seiner Kritik.
Anfang Februar veröffentlichte die Pressestelle der Goethe-Universität die Meldung „In der Stadt bauen Kaninchen dichter: Große Bauten für die ländliche Großfamilie, kleine Bauten für das städtische Pärchen.“ Die Meldung beruhte auf einem Fachartikel der Arbeitsgruppe Ökologie und Evolution im Journal of Zoology. Rasend schnell verbreitete sich die Meldung in den Medien – wir haben Madlen Ziege, Doktorandin in der Arbeitsgruppe Ökologie und Evolution einmal danach befragt, wie die Forschung mit populären oder besser: popularisierten Meldungen umgeht.
Unter ökonomischen Gesichtspunkten ist die Mainmetropole ein etablierter Global Player, nun will sie auch in Sachen Klimaschutz eine Vorreiterrolle einnehmen. Ziel ist es, die städtische Energieversorgung in den nächsten vier Jahrzehnten komplett aus erneuerbaren Ressourcen sicherzustellen. Dabei ist Frankfurt bereits jetzt auf einem guten Weg. Neben Kopenhagen und Bristol schaffte es die größte Stadt Hessens in die Finalrunde um den Titel „Europäische Grüne Hauptstadt 2014“.
Importance of latrine communication in European rabbits shifts along a rural–to–urban gradient
(2016)
Background: Information transfer in mammalian communication networks is often based on the deposition of excreta in latrines. Depending on the intended receiver(s), latrines are either formed at territorial boundaries (between-group communication) or in core areas of home ranges (within-group communication). The relative importance of both types of marking behavior should depend, amongst other factors, on population densities and social group sizes, which tend to differ between urban and rural wildlife populations. Our study is the first to assess (direct and indirect) anthropogenic influences on mammalian latrine-based communication networks along a rural-to-urban gradient in European rabbits (Oryctolagus cuniculus) living in urban, suburban and rural areas in and around Frankfurt am Main (Germany).
Results: The proportion of latrines located in close proximity to the burrow was higher at rural study sites compared to urban and suburban ones. At rural sites, we found the largest latrines and highest latrine densities close to the burrow, suggesting that core marking prevailed. By contrast, latrine dimensions and densities increased with increasing distance from the burrow in urban and suburban populations, suggesting a higher importance of peripheral marking.
Conclusions: Increased population densities, but smaller social group sizes in urban rabbit populations may lead to an increased importance of between-group communication and thus, favor peripheral over core marking. Our study provides novel insights into the manifold ways by which man-made habitat alterations along a rural-to-urban gradient directly and indirectly affect wildlife populations, including latrine-based communication networks.
The process of urbanization is one of the major causes of the global loss of biodiversity; however, cities nowadays also have the potential to serve as new habitats for wildlife. The European rabbit (Oryctolagus cuniculus, L. 1758) is a typical example of a wildlife species that reaches stable population densities in cities. Due to intense plant and soil damages, German city authorities aim to control high rabbit densities through the application of a yearly hunting regime (e. g., in Munich, Berlin or Frankfurt am Main). In contrast, population densities of O. cuniculus are on decline in German rural areas, i. e., numbers of yearly hunting bags decreased. The aim of my doctoral thesis was to answer the following research questions: Do population densities of the European rabbit correlate with the intensity of urbanization in and around Frankfurt am Main and if so, which factors play a role in varying densities? How are burrow construction behaviors and group sizes, daytime activity patterns and anti-predator behaviors as well as communication behaviors of this mammal affected by urbanization?
In my first study, I focused on population dynamics across 17 different study sites in and around Frankfurt. As one of yet few studies, I invented an approach that quantified the intensity of urbanization (degree of urbanity) of each study site base on four variables: (1) intensity of anthropogenic disturbance per min and ha, (2) number of residents within a radius of 500 m, (3) proportion of artificial ground cover and (4) numbers of anthropogenic objects per ha. Spearman rank correlations confirmed that with increasing degree of urbanity also rabbit and burrow densities increased. The access to dense shrubs, bushes etc. as suitable sites for burrow construction is the most determining factor for rabbit abundances, and therefore I presumed different densities along the rural-to-urban gradient to be driven by shifts in the availability of thick vegetation.
In the second study, I calculated two indices that in both cases classified burrows to be either accumulated, evenly or randomly distributed within study sites. Additionally, in cooperation with local hunters the number of burrow entrances and animals that occupy the same burrow had been determined during the hunting season. With increasing degree of urbanity burrow distribution patterns shifted from accumulated in rural areas towards more evenly distributed within the city center of Frankfurt. This is a clear sign for an increasing access to sites suitable for burrow construction along the rural to-urban gradient. Additional Spearman rank correlations revealed that the external dimensions of burrows decreased (shorter distances between entrances) and that burrows became less complex (fewer entrances) along the rural-to-urban gradient. In accordance, the number of rabbits that commonly shared the same burrow system was highest within rural areas, whereas I found mainly pairs and single individuals within highly urbanized study sites.
In the last study I compared activity patterns, burrow use and percentages of anti-predator behaviors from one hour before sunrise until one hour after sunset of rural, suburban and urban rabbit groups. A linear mixed model (LMM) and Spearman rank correlations confirmed that rabbits located at urban and suburban sites spent more time outside their protective burrows compared to their rural conspecifics. At suburban sites, individuals invested the least amount of time in anti-predator behavior. Results of this third study gave evidence that suburban rabbit populations on one hand benefit from less predation pressure by natural predators in comparison to rural sites, whereas on the other hand are exposed to less intense disturbance by humans compared to urban study sites.
The last study focused on the effects that urbanization had on the latrine-based communication behavior of rabbits. As many other mammals, O. cuniculus exchange information via the deposition of excreta in latrines, and depending on the intended receiver(s), latrines are either formed in central areas for within-group communication or at territorial boundaries, e. g., for between-group communication. The relative importance of within- vs. between-group communication depends on, amongst other factors, population densities and group sizes which I proved both to shift along the considered rural-to-urban gradient. I determined latrine sizes, latrine densities and latrine utilization frequencies relative to their distance to the nearest burrow at 15 different study sites. Latrine densities and utilization frequencies increased with increasing distance from the burrow in suburban and urban populations whereas at rural sites, largest latrines and those containing the most fecal pellets were close to the burrow, suggesting that within-group communication prevailed.
To sum up, for the first time, I was able to relate shifts in the ecology and behavior of the European rabbit as adaptations to a gradual anthropogenic habitat alteration that are typical for “urban exploiters”. Especially the suburban habitat provides high landscape heterogeneity (“edge habitat“) which is essential for high and stable rabbit populations. Moreover, here, comparably low human disturbance and predation pressure are given in contrast to the agriculturally transformed, open landscapes which are nowadays typical for most rural areas in central Europe. I argue that this mainly leads to the observed behavioral changes along the rural-to-urban gradient. Future plans for rural land management actions should aim to increase refuge availability by generating networks of ecotones. This would also benefit species that depend on similar ecosystem structures as the European rabbit and are on decline in Germany.
This article uses survey data from the German Socio-Economic Panel (GSOEP) to analyze the persistence of educational attainment across three generations in Germany. I obtain evidence of a robust effect of grandparents’ education on respondents’ own educational attainment in West Germany, net of parental class, education, occupational status, family income, parents’ relationship history, and family size. I also test whether the grandparent effect results from resource compensation or cumulative advantage and find empirical support for both mechanisms. In comparison, the intergenerational association between grandparents’ and respondents’ education is considerably weaker in East Germany and is also mediated completely by parental education. There are hardly any gender differences in the role of grandparents for respondents’ educational attainment, except for the fact that resource compensation is found to be exclusively relevant for women’s attainment in both West Germany and in East Germany after German reunification and the associated transition to an open educational system.
Proton-pumping complex I of the mitochondrial respiratory chain is among the largest and most complex membrane protein complexes. The enzyme contributes substantially to oxidative energy-conversion in eukaryotic cells. Its malfunctions are implicated in many hereditary and degenerative disorders. Here, we report the X-ray structure of mitochondrial complex I at 3.6- 3.9 Å resolution describing in detail the central subunits that execute the bioenergetic function. A continuous axis of basic and acidic residues running centrally through the membrane arm connects the ubiquinone reduction site in the hydrophilic arm to four putative proton-pumping units. The binding position for a substrate analogous inhibitor and blockage of the predicted ubiquinone binding site provide a model for the ‘deactive’ form of the enzyme. The proposed transition into the active form is based on a concerted structural rearrangement at the ubiquinone reduction site rendering support for a two-state stabilization-change mechanism of protonpumping.
Membrane-bound complex I (NADH:ubiquinone oxidoreductase) of the respiratory chain is considered the main site of mitochondrial radical formation and plays a major role in many mitochondrial pathologies. Structural information is scarce for complex I, and its molecular mechanism is not known. Recently, the 49-kDa subunit has been identified as part of the "catalytic core" conferring ubiquinone reduction by complex I. We found that the position of the 49-kDa subunit is clearly separated from the membrane part of complex I, suggesting an indirect mechanism of proton translocation. This contradicts all hypothetical mechanisms discussed in the field that link proton translocation directly to redox events and suggests an indirect mechanism of proton pumping by redox-driven conformational energy transfer.
Artificial Intelligence (AI) has the potential to greatly improve the delivery of healthcare and other services that advance population health and wellbeing. However, the use of AI in healthcare also brings potential risks that may cause unintended harm. To guide future developments in AI, the High-Level Expert Group on AI set up by the European Commission (EC), recently published ethics guidelines for what it terms “trustworthy” AI. These guidelines are aimed at a variety of stakeholders, especially guiding practitioners toward more ethical and more robust applications of AI. In line with efforts of the EC, AI ethics scholarship focuses increasingly on converting abstract principles into actionable recommendations. However, the interpretation, relevance, and implementation of trustworthy AI depend on the domain and the context in which the AI system is used. The main contribution of this paper is to demonstrate how to use the general AI HLEG trustworthy AI guidelines in practice in the healthcare domain. To this end, we present a best practice of assessing the use of machine learning as a supportive tool to recognize cardiac arrest in emergency calls. The AI system under assessment is currently in use in the city of Copenhagen in Denmark. The assessment is accomplished by an independent team composed of philosophers, policy makers, social scientists, technical, legal, and medical experts. By leveraging an interdisciplinary team, we aim to expose the complex trade-offs and the necessity for such thorough human review when tackling socio-technical applications of AI in healthcare. For the assessment, we use a process to assess trustworthy AI, called 1Z-Inspection® to identify specific challenges and potential ethical trade-offs when we consider AI in practice.
Co-design of a trustworthy AI system in healthcare: deep learning based skin lesion classifier
(2021)
This paper documents how an ethically aligned co-design methodology ensures trustworthiness in the early design phase of an artificial intelligence (AI) system component for healthcare. The system explains decisions made by deep learning networks analyzing images of skin lesions. The co-design of trustworthy AI developed here used a holistic approach rather than a static ethical checklist and required a multidisciplinary team of experts working with the AI designers and their managers. Ethical, legal, and technical issues potentially arising from the future use of the AI system were investigated. This paper is a first report on co-designing in the early design phase. Our results can also serve as guidance for other early-phase AI-similar tool developments.
Jeden Tag werden 2,5 Trillionen Bytes an Daten generiert. Diese enorme Menge an Daten wird beispielsweise durch digitale Bilder, Videos, Beiträge in den sozialen Medien, intelligente Sensoren, Einzelhandels- und Finanztransaktionen und GPS-Signale von Handys erzeugt. Das ist Big Data. Es besteht kein Zweifel daran, dass Big Data und das, was wir damit tun, das Potential hat, ein signifikanter Treiber für Innovationen und Wertschöpfung zu werden.
Justice, not development : Sen and the hegemonic framework for ameliorating global inequality
(2014)
Starting from the merits of Sen's "Development as freedom", the article also explores its shortcomings. It argues that they are related to an uncritical adoption of the discourse of "development", which is the hegemonic framework for ameliorating global inequality today. This discourse implies certain limitations of thought and action, and the article points out three areas where urgent questions of global justice have been largely ignored by development theory and policy as a consequence. Struggles for justice on a global scale, this is the conclusion, should not take the detour of "development".
Fluorescently labeled nanoparticles are widely used for evaluating their distribution in the biological environment. However, dye leakage can lead to misinterpretations of the nanoparticles’ biodistribution. To better understand the interactions of dyes and nanoparticles and their biological environment, we explored PLGA nanoparticles labeled with four widely used dyes encapsulated (coumarin 6, rhodamine 123, DiI) or bound covalently to the polymer (Cy5.5.). The DiI label was stable in both aqueous and lipophilic environments, whereas the quick release of coumarin 6 was observed in model media containing albumin (42%) or liposomes (62%), which could be explained by the different affinity of these dyes to the polymer and lipophilic structures and which we also confirmed by computational modeling (log PDPPC/PLGA: DiI—2.3, Cou6—0.7). The importance of these factors was demonstrated by in vivo neuroimaging (ICON) of the rat retina using double-labeled Cy5.5/Cou6-nanoparticles: encapsulated Cou6 quickly leaked into the tissue, whereas the stably bound Cy.5.5 label remained associated with the vessels. This observation is a good example of the possible misinterpretation of imaging results because the coumarin 6 distribution creates the impression that nanoparticles effectively crossed the blood–retina barrier, whereas in fact no signal from the core material was found beyond the blood vessels.
Highlights
• Deletion of SPPL3 promotes resistance of malignant B cells to NK cell cytotoxicity
• Loss of SPPL3 blocks ligand binding to NK receptors via increased N-glycosylation
• B3GNT2 deletion reduces LacNAc addition and restores SPPL3-KO cell sensitivity to NK cells
• SPPL3-deficient cells are enriched in tetra-antennary N-glycans with LacNAc elongations
Summary
Natural killer (NK) cells are primary defenders against cancer precursors, but cancer cells can persist by evading immune surveillance. To investigate the genetic mechanisms underlying this evasion, we perform a genome-wide CRISPR screen using B lymphoblastoid cells. SPPL3, a peptidase that cleaves glycosyltransferases in the Golgi, emerges as a top hit facilitating evasion from NK cytotoxicity. SPPL3-deleted cells accumulate glycosyltransferases and complex N-glycans, disrupting not only binding of ligands to NK receptors but also binding of rituximab, a CD20 antibody approved for treating B cell cancers. Notably, inhibiting N-glycan maturation restores receptor binding and sensitivity to NK cells. A secondary CRISPR screen in SPPL3-deficient cells identifies B3GNT2, a transferase-mediating poly-LacNAc extension, as crucial for resistance. Mass spectrometry confirms enrichment of N-glycans bearing poly-LacNAc upon SPPL3 loss. Collectively, our study shows the essential role of SPPL3 and poly-LacNAc in cancer immune evasion, suggesting a promising target for cancer treatment.
A metal–organic framework (MOF) material, [Zn2(adc)2(dabco)] (adc = anthracene-9,10-dicarboxylate, dabco = 1,4-diazabicyclo[2.2.2]octane), the fluorescence of which depends on the loading of its nanopores, was synthesized in two forms: as free-flowing nanocrystals with different shapes and as surface-attached MOFs (SURMOFs). For the latter, we used self-assembled monolayers (SAMs) bearing functional groups, such as carboxylate and pyridyl groups, capable of coordinating to the constituents of the MOF. It could be demonstrated that this directed coordination also orients the nanocrystals deposited at the surface. Using two different patterning methods, i.e., microcontact printing and electron-beam lithography, the lateral distribution of the functional groups could be determined in such a way that the highly localized deposition of the SURMOF films became possible.
Metallorganische Netzwerke (engl. metal-organic frameworks, MOFs) sind eine neuartige Klasse mikro/mesoporöser Materialien, für die eine Vielzahl von möglichen Anwendungen demonstriert werden konnte. Das Ziel dieser Arbeit besteht in der Synthese von MOF Mikro/Nanopartikeln sowie der Herstellung von sogenannten Oberflächen-deponierten MOFs (engl. surface-attached metal-organic frameworks, SURMOFs). MOF Partikel mit kontrollierbarer Morphologie und Größe wurden unter milden Bedingungen synthetisiert. Um MOFs als Sensoren, intelligente Membrane, oder in nanotechnologischen Bauelementen verwenden zu können, ist die Integration auf der jeweiligen Oberfläche wichtig. Daher beschäftigt sich der Großteil dieser Arbeit mit der kontrollierten Abscheidung von SURMOFs auf verschiedenartigen Trägermaterialien. Etliche interessante Eigenschaften (z.B. die Fluoreszenz in Abhängigkeit von der Gegenwart von Gastmolekülen und die dynamische Gasadsorptionskapazität) der SURMOFs wurden untersucht.
Formalin‐fixed, paraffin‐embedded (FFPE ), biobanked tissue samples offer an invaluable resource for clinical and biomarker research. Here, we developed a pressure cycling technology (PCT )‐SWATH mass spectrometry workflow to analyze FFPE tissue proteomes and applied it to the stratification of prostate cancer (PC a) and diffuse large B‐cell lymphoma (DLBCL ) samples. We show that the proteome patterns of FFPE PC a tissue samples and their analogous fresh‐frozen (FF ) counterparts have a high degree of similarity and we confirmed multiple proteins consistently regulated in PC a tissues in an independent sample cohort. We further demonstrate temporal stability of proteome patterns from FFPE samples that were stored between 1 and 15 years in a biobank and show a high degree of the proteome pattern similarity between two types of histological regions in small FFPE samples, that is, punched tissue biopsies and thin tissue sections of micrometer thickness, despite the existence of a certain degree of biological variations. Applying the method to two independent DLBCL cohorts, we identified myeloperoxidase, a peroxidase enzyme, as a novel prognostic marker. In summary, this study presents a robust proteomic method to analyze bulk and biopsy FFPE tissues and reports the first systematic comparison of proteome maps generated from FFPE and FF samples. Our data demonstrate the practicality and superiority of FFPE over FF samples for proteome in biomarker discovery. Promising biomarker candidates for PC a and DLBCL have been discovered.
Within this thesis, an experimental study of the photo double ionization (PDI) and the simultaneous ionization-excitation is performed for lithium in different initial states Li (1s22l) (l = s, p). The excess energy of the linearly polarized VUV-light is between 4 and 12 eV above the PDI-threshold. Three forefront technologies are combined: a magneto-optical trap (MOT) for lithium generating an ultra-cold and, by means of optical pumping, a state-prepared target; a reaction microscope (ReMi), enabling the momentum resolved detection of all reaction fragments with high-resolution and the free-electron laser in Hamburg (FLASH), providing an unprecedented brilliant photon beam at favourable time structure to access small cross sections. Close to threshold the total as well as differential PDI cross sections are observed to critically depend on the excitation level and the symmetry of the initial state. For the excited state Li (1s22p) the PDI dynamics strongly depends on the alignment of the 2p-orbital with respect to the VUV-light polarization and, thus, from the population of the magnetic substates (mp = 0, ±1). This alignment sensitivity decreases for increasing excess energy and is completely absent for ionization-excitation. Time-dependent close-coupling calculations are able to reproduce the experimental total cross sections with deviations of at most 30%. All the experimental observations can be consistently understood in terms of the long range electron correlation among the continuum electrons which gives rise to their preferential back-to-back emission. This alignment effect, which is observed here for the first time, allows controlling the PDI dynamics through a purely geometrical modification of the target initial state without changing its internal energy.
Beam test of the direct plasma injection scheme (DPIS) is carried out successfully for the first time in China, by setting up a comprehensive test and research platform of RFQ and laser ion source. The C6+ beam is accelerated successfully, and the peak beam current reaches more than 6mA which is measured by a Faraday cup of unique structure. The RF power coupled into the RFQ cavity is also examined, and results reveal that it is the RF power of about 195kW that can produce the peak beam current.
Structural and functional characterization of the dimerization region of soluble guanylyl cyclase
(2004)
Soluble guanylyl cyclase (sGC) is a ubiquitous enzyme that functions as a receptor for nitric oxide. Despite the obligate heterodimeric nature of sGC, the sequence segments mediating subunit association have remained elusive. Our initial screening for relevant interaction site(s) in the most common sGC isoenzyme, α1 β1, identified two regions in each subunit, i.e. the regulatory domains and the central regions, contributing to heterodimer formation. To map the relevant segments in the β1 subunit precisely, we constructed multiple N- and C-terminal deletion variants and cotransfected them with full-length α1 in COS cells. Immunoprecipitation revealed that a sequence segment spanning positions 204–408 mediates binding of β1 to α1 The same region of β1[204–408] was found to promote β /β1 homodimerization. Fusion of [204 β1–408] to enhanced green fluorescent protein conferred binding activity to the recipient protein. Coexpression of β1[204–408] with α1 or β1 targeted the sGC subunits for proteasomal degradation, suggesting that β1[204–408] forms structurally deficient complexes with α1 and β1. Analysis of deletion constructs lacking portions of the β1 dimerization region identified two distinct segments contributing to α1 binding, i.e. an N-terminal site covering positions 204–244 and a C-terminal site at 379–408. Both sites are crucial for sGC function because deletion of either site rendered sGC dimerization-deficient and thus functionally inactive. We conclude that the dimerization region of β1 extends over 205 residues of its regulatory and central domains and that two discontinuous sites of 41 and 30 residues, respectively, facilitate binding of β1 to the α1 subunit of sGC.
Sustainable biosynthesis of chemicals and efforts to create new molecules of interest require efficient enzymes and pathways as well as comprehensive tools and technologies to implement this rewiring. Enzymes are the key components for construction of efficient biosynthetic pathways, enzyme characterization and engineering can help to identify key enzymes and regulatory factors for construction of biosynthetic pathways, as well as improve enzyme performance; Pathway engineering can help construct biosynthetic pathways and balance metabolic network to improve biosynthetic efficiency; Tools and technologies facilitate the engineering of enzymes, pathways, and whole cells. This special issue focusing on “Pathway and Protein Engineering for Biosynthesis” comprises eight review articles and nine original research articles, which highlight and showcase current progress on Pathway and Protein Engineering and their application for biosynthesis.
Xenorhabdus and Photorhabdus bacteria are gaining more and more attention as a subject of research because of their unique yet similar life cycle with nematodes and insects. This work focused on the secondary metabolites that are produced by Xenorhabdus and Photorhabdus. With the help of modern HPLC-MS methodologies and increasingly available bacterial genome sequences, the structures of unknown secondary metabolites could be elucidated and thus their biosynthesis pathways could be proposed, too.
The first paper reported 17 depsipeptides termed xentrivalpeptides produced by the bacterium Xenorhabdus sp. 85816. Xentrivalpeptide A could be isolated from the bacterial culture as the main component. The structure of xentrivalpeptide A was elucidated by NMR and the Marfey´s method. The remaining xentrivalpeptides were exclusively identified by feeding experiments and MS fragmentation patterns.
The second paper described the discovery and isolation of xenoamicin A from Xenorhabdus mauleonii DSM17908. Additionally, other xenoamicin derivatives from Xenorhabdus doucetiae DSM17909 were analyzed by means of feeding experiments and MS fragmentation patterns. The xenoamicin biosynthesis gene cluster was identified in Xenorhabdus doucetiae DSM17909.
The manuscript for publication focused on the biosynthesis of anthraquinones in Photorhabdus luminescens. The Type II polyketide synthase for the biosynthesis of anthraquinone derivatives was discovered in P. luminescens in a previous publication by the Bode group,1 in which a partial reaction mechanism for the biosynthesis has been proposed. The manuscript reported in this thesis however elucidated the biosynthetic mechanisms in a greater detail as compared to the previous publication. Particularly, the biosynthetic mechanism was deciphered through heterologous expression of anthraquinone biosynthesis (ant) genes in E. coli. Additionally, deactivation of the genes antG encoding a putative CoA ligase and antI encoding a putative hydrolase, was performed in P. luminescens. Selected ant genes were over-expressed in E. coli as well as the corresponding proteins purified for in vitro assays. Model compounds were chemically synthesized as possible substrates of AntI and were used for in vitro assays. Here, it was revealed that the CoA ligase AntG played an essential role in the activation of the ACP AntF. Furthermore, a chain shortening mechanism by the hydrolase AntI was identified and was further confirmed by in vitro assays using model compounds. Additionally, this chain shortening mechanism was supported by homology based structural modeling of AntI.
In this proceeding we review our recent work using supervised learning with a deep convolutional neural network (CNN) to identify the QCD equation of state (EoS) employed in hydrodynamic modeling of heavy-ion collisions given only final-state particle spectra ρ(pT, Ф). We showed that there is a traceable encoder of the dynamical information from phase structure (EoS) that survives the evolution and exists in the final snapshot, which enables the trained CNN to act as an effective “EoS-meter” in detecting the nature of the QCD transition.
We investigate charmonium production in Pb + Pb collisions at LHC beam energy Elab=2.76A TeV at fixed-target experiment (√sNN = 72 GeV). In the frame of a transport approach including cold and hot nuclear matter effects on charmonium evolution, we focus on the antishadowing effect on the nuclear modification factors RAA and rAA for the J/ψ yield and transverse momentum. The yield is more suppressed at less forward rapidity (ylab ≃ 2) than that at very forward rapidity (ylab ≃ 4) due to the shadowing and antishadowing in different rapidity bins.
We study the effect of thermal charm production on charmonium regeneration in high energy nuclear collisions. By solving the kinetic equations for charm quark and charmonium distributions in Pb+Pb collisions, we calculate the global and differential nuclear modification factors RAA(Npart) and RAA(pt) for J/ψ s. Due to the thermal charm production in hot medium, the charmonium production source changes from the initially created charm quarks at SPS, RHIC and LHC to the thermally produced charm quarks at Future Circular Collider (FCC), and the J/ψ suppression (RAA<1) observed so far will be replaced by a strong enhancement (RAA>1) at FCC at low transverse momentum.
Thioredoxin 1 and thioredoxin 2 have opposed regulatory functions on hypoxia-inducible factor-1α
(2007)
Hypoxia inducible factor 1 (HIF-1), a key regulator for adaptation to hypoxia, is composed of HIF-1alpha and HIF-1beta. In this study, we present evidence that overexpression of mitochondria-located thioredoxin 2 (Trx2) attenuated hypoxia-evoked HIF-1alpha accumulation, whereas cytosolic thioredoxin 1 (Trx1) enhanced HIF-1alpha protein amount. Transactivation of HIF-1 is decreased by overexpression of Trx2 but stimulated by Trx1. Inhibition of proteasomal degradation of HIF-1alpha in Trx2-overexpressing cells did not fully restore HIF-1alpha protein levels, while HIF-1alpha accumulation was enhanced in Trx1-overexpressing cells. Reporter assays showed that cap-dependent translation is increased by Trx1 and decreased by Trx2, whereas HIF-1alpha mRNA levels remained unaltered. These data suggest that thioredoxins affect the synthesis of HIF-1alpha. Trx1 facilitated synthesis of HIF-1alpha by activating Akt, p70S6K, and eIF-4E, known to control cap-dependent translation. In contrast, Trx2 attenuated activities of Akt, p70S6K, and eIF-4E and provoked an increase in mitochondrial reactive oxygen species production. MitoQ, a mitochondria specific antioxidant, reversed HIF-1alpha accumulation as well as Akt activation under hypoxia in Trx2 cells, supporting the notion of translation control mechanisms in affecting HIF-1alpha protein accumulation.
Cardiovascular disease (CVD) remains the leading cause of cardiac morbidity and mortality in the entire world population. Heart failure (HF) is the fastest growing cardiac diagnosis, with an annual incidence of 10 cases per 1000 people in individuals older than 65 [1]. This is partly a reflection of an aging population and success of treatment of acute coronary syndromes with reduced premature mortality due to ischaemic heart disease (IHD), as well as increasing ability to recognise non-ischaemic - intrinsic myocardial processes- due to advances in genetics and imaging. The conventional imaging predictors of outcome in CVD patients primarily include left ventricular ejection fraction (LVEF) and late gadolinium enhancement (LGE) using cardiovascular magnetic resonance (CMR). LVEF represents the main universal, as well as the multimodality biomarker of risk stratification. ...
Philosophy is essentially dialectical. One gets into a dialectic by a puzzle, an aporia in thought and understanding. The point of philosophizing is not (necessarily) to get hold of the ultimate, objective, and immutably correct answers. The point is rather to come to be able to see one’s way out of the aporia, and to understand how one got into it in the first place.
The essay that follows – which I am submitting as my dissertation – is dialectical in two senses. As a piece of philosophizing, the essay is guided by a problem, the problem of understanding how laws of nature are possible, and how it is possible for us to know them. The movement of thought generated by attempts to get out of the problem then yields some ideas that do not stay in the original context in which the problem was felt to exist. Two important ones are, first, perceptual experience is not the only ultimate source of warrant we have for empirical knowledge claims, and second, perceptual experience is not the only epistemically significant experience we can have. Both are consequences of the idea that the mastery of skills is a form of interaction with nature that provides epistemic warrant for nomological claims. I shall leave it to the epilogue to examine how this view of skills contrasts with the ways skills are ordinarily thought of in philosophy and the implication of it for empiricism.
The other sense in which the essay is dialectical is more interesting, and it has to do with the way in which I approach the problem that got me into started, namely, by paying special attention to the dialectic exchange between the realists and the antirealists about the laws of nature. Antirealism about the lawfulness of nature has experienced something like a post-Humean revival since the publication of van Fraassen’s The Scientific Image. Most, including me, have strong realist intuitions about nomological “connections” in nature. Philosophical positions that are strongly counterintuitive have mostly not ended well in history. So it becomes something of a puzzle why antirealism about laws of nature manages to enjoy popularity every now and then.
Spermatogonial stem cells (SSCs) are adult stem cells that are slowly cycling and self-renewing. The pool of SSCs generates very large numbers of male gametes throughout the life of the individual. SSCs can be cultured in vitro for long periods of time, and established SSC lines can be manipulated genetically. Upon transplantation into the testes of infertile mice, long-term cultured mouse SSCs can differentiate into fertile spermatozoa, which can give rise to live offspring. Here, we show that the testicular soma of mice with a conditional knockout (conKO) in the X-linked gene Tsc22d3 supports spermatogenesis and germline transmission from cultured mouse SSCs upon transplantation. Infertile males were produced by crossing homozygous Tsc22d3 floxed females with homozygous ROSA26-Cre males. We obtained 96 live offspring from six long-term cultured SSC lines with the aid of intracytoplasmic sperm injection. We advocate the further optimization of Tsc22d3-conKO males as recipients for testis transplantation of SSC lines.
The transient receptor potential (TRP) ankyrin type 1 (TRPA1) channel is highly expressed in a subset of sensory neurons where it acts as an essential detector of painful stimuli. However, the mechanisms that control the activity of sensory neurons upon TRPA1 activation remain poorly understood. Here, using in situ hybridization and immunostaining, we found TRPA1 to be extensively co-localized with the potassium channel Slack (KNa1.1, Slo2.2, or Kcnt1) in sensory neurons. Mice lacking Slack globally (Slack−/−) or conditionally in sensory neurons (SNS-Slack−/−) demonstrated increased pain behavior after intraplantar injection of the TRPA1 activator allyl isothiocyanate. By contrast, pain behavior induced by the TRP vanilloid 1 (TRPV1) activator capsaicin was normal in Slack-deficient mice. Patch-clamp recordings in sensory neurons and in a HEK cell line transfected with TRPA1 and Slack revealed that Slack-dependent potassium currents (IKS) are modulated in a TRPA1-dependent manner. Taken together, our findings highlight Slack as a modulator of TRPA1-mediated, but not TRPV1-mediated, activation of sensory neurons.
Keywords: TRPA1; slack; dorsal root ganglia; pain; mice
Slack (sequence like a Ca2+ -activated K + channel; also termed Slo2.2, Kcnt1, or KNa 1.1) is a Na+ -activated K + channel that is highly expressed in the peripheral and central nervous system. Previous studies have shown that Slack is enriched in the isolectin B4binding, non-peptidergic subpopulation of C-fiber sensory neurons and that Slack controls the sensory input in neuropathic pain. Recent single-cell RNA-sequencing studies suggested that Slack is highly co-expressed with transient receptor potential (TRP) ankyrin 1 (TRPA1) in sensory neurons. By using in situ hybridization and immunostaining we confirmed that Slack is highly co-localized with TRPA1 in sensory neurons, but only to a minor extent with TRP vanilloid 1. Mice lacking Slack globally or conditionally in sensory neurons (SNS-Slack─/─ ), but not mice lacking Slack conditionally in neurons of the spinal dorsal horn (Lbx1-Slack─/─ ), displayed increased pain behavior after intraplantar injection of the TRPA1 activator allyl isothiocyanate. Patch-clamp recordings with cultured primary neurons and in a HEK-293 cell line transfected with TRPA1 and Slack revealed that Slack-dependent K + currents are modulated in a TRPA1-dependent manner. Taken together, these findings highlight Slack as a modulator of TRPA1-mediated activation of sensory neurons.
Furthermore, we investigated the contribution of Slack in the spinal dorsal horn to pain processing. Lbx1-Slack ─/─ mice demonstrated normal basal pain sensitivity and Complete Freund’s Adjuvant-induced inflammatory pain. Interestingly, we observed a significantly increased spared nerve injury (SNI)-induced neuropathic pain hypersensitivity in Lbx1-Slack ─/─ mutants compared to control littermates. Moreover, we tested the effects of pharmacological Slack activation in the SNI model. Systemic and intrathecal, but not intraplantar administration of the Slack opener loxapine significantly alleviated SNI-induced hypersensitivity in control mice, but only slightly in Lbx1Slack ─/─ mice, further supporting the inhibitory function of Slack in spinal dorsal horn neurons in neuropathic pain processing.
Altogether, our data suggest that Slack in sensory neurons controls TRPA1-induced pain, whereas Slack in spinal dorsal horn neurons inhibits peripheral nerve injury induced neuropathic pain. These data provide further insights into the molecular mechanisms of pain sensation.
We have built quasi-equilibrium models for uniformly rotating quark stars in general relativity. The conformal flatness approximation is employed and the Compact Object CALculator (cocal) code is extended to treat rotating stars with surface density discontinuity. In addition to the widely used MIT bag model, we have considered a strangeon star equation of state (EoS), suggested by Lai and Xu, that is based on quark clustering and results in a stiff EoS. We have investigated the maximum mass of uniformly rotating axisymmetric quark stars. We have also built triaxially deformed solutions for extremely fast rotating quark stars and studied the possible gravitational wave emission from such configurations.
Extending the carotenoid pathway to astaxanthin in plants is of scientific and industrial interest. However, expression of a microbial beta-carotene ketolase (BKT) that catalyses the formation of ketocarotenoids in transgenic plants typically results in low levels of astaxanthin. The low efficiency of BKTs in ketolating zeaxanthin to astaxanthin is proposed to be the major limitation for astaxanthin accumulation in engineered plants. To verify this hypothesis, several algal BKTs were functionally characterized using an Escherichia coli system and three BKTs were identified, with high (up to 85%), moderate (~38%), and low (~1%) conversion rate from zeaxanthin to astaxanthin from Chlamydomonas reinhardtii (CrBKT), Chlorella zofingiensis (CzBKT), and Haematococcus pluvialis (HpBKT3), respectively. Transgenic Arabidopsis thaliana expressing the CrBKT developed orange leaves which accumulated astaxanthin up to 2 mg g -1 dry weight with a 1.8-fold increase in total carotenoids. In contrast, the expression of CzBKT resulted in much lower astaxanthin content (0.24 mg g -1 dry weight), whereas HpBKT3 was unable to mediate synthesis of astaxanthin in A. thaliana. The none-native astaxanthin was found mostly in a free form integrated into the light-harvesting complexes of photosystem II in young leaves but in esterified forms in senescent leaves. The alteration of carotenoids did not affect chlorophyll content, plant growth, or development significantly. The astaxanthin-producing plants were more tolerant to high light as shown by reduced lipid peroxidation. This study advances a decisive step towards the utilization of plants for the production of high-value astaxanthin. Keywords: Arabidopsis thaliana, astaxanthin, beta-carotene ketolase, carotenoid, Haematococcus pluvialis
Mannan-induced Nos2 in macrophages enhances IL-17–driven psoriatic arthritis by innate lymphocytes
(2018)
Previous identification of the inducible nitric oxide synthase (NOS2) gene as a risk allele for psoriasis (Ps) and psoriatic arthritis (PsA) suggests a possible pathogenic role of nitric oxide (NO). Using a mouse model of mannan-induced Ps and PsA (MIP), where macrophages play a regulatory role by releasing reactive oxygen species (ROS), we found that NO was detectable before disease onset in mice, independent of a functional nicotinamide adenine dinucleotide phosphate oxidase 2 complex. MIP was suppressed by either deletion of Nos2 or inhibition of NO synthases with NG-nitro-L-arginine methyl ester, demonstrating that Nos2-derived NO is pathogenic. NOS2 expression was also up-regulated in lipopolysaccharide- and interferon-γ–stimulated monocyte subsets from patients with PsA compared to healthy controls. Nos2-dependent interleukin-1α (IL-1α) release from skin macrophages was essential for arthritis development by promoting IL-17 production of innate lymphoid cells. We conclude that Nos2-derived NO by tissue macrophages promotes MIP, in contrast to the protective effect by ROS.
Clinical application of transcranial Doppler for detection of cerebral emboli during cardiac surgery
(2010)
Objective: Neurologic injury is one of the most damaging complications for cardiac surgery. How to decrease neurologic impairment by improving perioperative monitoring remains a challenge for both cardiac surgeons and anesthetists. For this reason, transcranial doppler (TCD) has been widely used in cerebral monitoring during cardiac surgery. In this study, two experiments of clinical application of TCD for detection of cerebral emboli during cardiac surgery were to be done. One was “Solid and gaseous cerebral emboli during valvular surgery are significantly reduced with axillary artery cannulation”. The other was “Do intraoperative cerebral embolic signals differ between valvular surgery (VS) and CABG”. Methods: In experiment one, 20 valve and combined procedures with aortic cannulation (AoC group) were compared to 18 procedures with axillary cannulation (AxC group) in a prospective non-randomized study. In experiment two, 18 VS patients and 18 CABG patients were matched by extracorporeal circulation (ECC) time retrospectively. Intraoperative monitoring of both middle cerebral arteries was performed with TCD discriminating between solid and gaseous embolic signals (ES). Results: In experiment one, the AxC group had less solid ES than the AoC group (38±22 vs 55±25, P<0.05), but no significant difference was found in gaseous (501±271 vs 538±333, P>0.05) and total (539 ± 279 vs 593 ± 350, P>0.05) ES. The AxC group had less solid ES during arterial cannulation (2.1±1.5 vs 6.6±3.6, P<0.05) and during aortic cross-clamp time (4.4 ±3.1 vs 10.2 ± 5.1, P<0.05) than the AoC group. During ECC, gaseous ES was not significantly different between groups (398±210 vs 448±291, P>0.05). However, AxC showed less gaseous ES (85±68 vs 187±148, P<0.05) and less gaseous ES per minute (1.8±1.5 vs 4.5±3.2, P<0.05) during weaning off extracorporeal circulation than the AoC group. No significant difference in gaseous ES (313±163 vs 261±189, P>0.05) and gaseous ES per minute (3.1±2.2 vs 2.8±2.2, P>0.05) was found between groups from bypass start to aortic declamping. No neurologic complications occurred. In experiment two, no significant difference was found in solid (38±20 vs 40±26, P>0.05) or gaseous (457±263 vs 412±157, P>0.05) ES between the VS and CABG group during the whole recording time. During ECC, solid ES (20±10 vs 24±19, P>0.05) and gaseous ES (368±230 vs 317±157, P>0.05) were comparable between groups. Specifically, during weaning off ECC, the VS group had more gaseous ES/min (5.6±3.6 vs 3.1±1.2, P<0.05) than the CABG group. But this difference in gaseous ES/min was not significant during the period from bypass start to aortic declamping (2.5±1.8 vs 3.0±1.8, P>0.05). Conclusion: Cerebral embolization does occur during cardiac surgery. Through these two experiments, we demonstrated the feasibility and importance of clinical application of transcranial doppler for detection of cerebral emboli during cardiac surgery. Due to the diversity in clinical application of TCD, it is impossible to compare the number of ES between different research centers. More unified standards should be drawn in order to make wider clinical application possible. Up till now, no robust evidence shows the correlation between intraoperative ES and postoperative neurological impairment. The research on intraoperative ES and postoperative neurological impairment should rely on a complete concept.
Background: We evaluated the sensitivity of the D-statistic, a parsimony-like method widely used to detect gene flow between closely related species. This method has been applied to a variety of taxa with a wide range of divergence times. However, its parameter space and thus its applicability to a wide taxonomic range has not been systematically studied. Divergence time, population size, time of gene flow, distance of outgroup and number of loci were examined in a sensitivity analysis.
Result: The sensitivity study shows that the primary determinant of the D-statistic is the relative population size, i.e. the population size scaled by the number of generations since divergence. This is consistent with the fact that the main confounding factor in gene flow detection is incomplete lineage sorting by diluting the signal. The sensitivity of the D-statistic is also affected by the direction of gene flow, size and number of loci. In addition, we examined the ability of the f-statistics, fˆGf^G and fˆhomf^hom, to estimate the fraction of a genome affected by gene flow; while these statistics are difficult to implement to practical questions in biology due to lack of knowledge of when the gene flow happened, they can be used to compare datasets with identical or similar demographic background.
Conclusions: The D-statistic, as a method to detect gene flow, is robust against a wide range of genetic distances (divergence times) but it is sensitive to population size. The D-statistic should only be applied with critical reservation to taxa where population sizes are large relative to branch lengths in generations.
Reciprocal t(9;22) ABL/BCR fusion proteins: leukemogenic potential and effects on B cell commitment
(2009)
Background: t(9;22) is a balanced translocation, and the chromosome 22 breakpoints (Philadelphia chromosome – Ph+) determine formation of different fusion genes that are associated with either Ph+ acute lymphatic leukemia (Ph+ ALL) or chronic myeloid leukemia (CML). The "minor" breakpoint in Ph+ ALL encodes p185BCR/ABL from der22 and p96ABL/BCR from der9. The "major" breakpoint in CML encodes p210BCR/ABL and p40ABL/BCR. Herein, we investigated the leukemogenic potential of the der9-associated p96ABL/BCR and p40ABL/BCR fusion proteins and their roles in the lineage commitment of hematopoietic stem cells in comparison to BCR/ABL. Methodology: All t(9;22) derived proteins were retrovirally expressed in murine hematopoietic stem cells (SL cells) and human umbilical cord blood cells (UCBC). Stem cell potential was determined by replating efficiency, colony forming - spleen and competitive repopulating assays. The leukemic potential of the ABL/BCR fusion proteins was assessed by in a transduction/transplantation model. Effects on the lineage commitment and differentiation were investigated by culturing the cells under conditions driving either myeloid or lymphoid commitment. Expression of key factors of the B-cell differentiation and components of the preB-cell receptor were determined by qRT-PCR. Principal Findings: Both p96ABL/BCR and p40ABL/BCR increased proliferation of early progenitors and the short term stem cell capacity of SL-cells and exhibited own leukemogenic potential. Interestingly, BCR/ABL gave origin exclusively to a myeloid phenotype independently from the culture conditions whereas p96ABL/BCR and to a minor extent p40ABL/BCR forced the B-cell commitment of SL-cells and UCBC. Conclusions/Significance: Our here presented data establish the reciprocal ABL/BCR fusion proteins as second oncogenes encoded by the t(9;22) in addition to BCR/ABL and suggest that ABL/BCR contribute to the determination of the leukemic phenotype through their influence on the lineage commitment.
The information processing abilities of neural circuits arise from their synaptic connection patterns. Understanding the laws governing these connectivity patterns is essential for understanding brain function. The overall distribution of synaptic strengths of local excitatory connections in cortex and hippocampus is long-tailed, exhibiting a small number of synaptic connections of very large efficacy. At the same time, new synaptic connections are constantly being created and individual synaptic connection strengths show substantial fluctuations across time. It remains unclear through what mechanisms these properties of neural circuits arise and how they contribute to learning and memory. In this study we show that fundamental characteristics of excitatory synaptic connections in cortex and hippocampus can be explained as a consequence of self-organization in a recurrent network combining spike-timing-dependent plasticity (STDP), structural plasticity and different forms of homeostatic plasticity. In the network, associative synaptic plasticity in the form of STDP induces a rich-get-richer dynamics among synapses, while homeostatic mechanisms induce competition. Under distinctly different initial conditions, the ensuing self-organization produces long-tailed synaptic strength distributions matching experimental findings. We show that this self-organization can take place with a purely additive STDP mechanism and that multiplicative weight dynamics emerge as a consequence of network interactions. The observed patterns of fluctuation of synaptic strengths, including elimination and generation of synaptic connections and long-term persistence of strong connections, are consistent with the dynamics of dendritic spines found in rat hippocampus. Beyond this, the model predicts an approximately power-law scaling of the lifetimes of newly established synaptic connection strengths during development. Our results suggest that the combined action of multiple forms of neuronal plasticity plays an essential role in the formation and maintenance of cortical circuits.
Background: Prostate cancer is a major health concern in aging men. Paralleling an aging society, prostate cancer prevalence increases emphasizing the need for efcient diagnostic algorithms.
Methods: Retrospectively, 106 prostate tissue samples from 48 patients (mean age,
66 ± 6.6 years) were included in the study. Patients sufered from prostate cancer (n = 38) or benign prostatic hyperplasia (n = 10) and were treated with radical prostatectomy or Holmium laser enucleation of the prostate, respectively. We constructed tissue microarrays (TMAs) comprising representative malignant (n = 38) and benign (n = 68) tissue cores. TMAs were processed to histological slides, stained, digitized and assessed for the applicability of machine learning strategies and open–source tools in diagnosis of prostate cancer. We applied the software QuPath to extract features for shape, stain intensity, and texture of TMA cores for three stainings, H&E, ERG, and PIN-4. Three machine learning algorithms, neural network (NN), support vector machines (SVM), and random forest (RF), were trained and cross-validated with 100 Monte Carlo random splits into 70% training set and 30% test set. We determined AUC values for single color channels, with and without optimization of hyperparameters by exhaustive grid search. We applied recursive feature elimination to feature sets of multiple color transforms.
Results: Mean AUC was above 0.80. PIN-4 stainings yielded higher AUC than H&E and
ERG. For PIN-4 with the color transform saturation, NN, RF, and SVM revealed AUC of 0.93 ± 0.04, 0.91 ± 0.06, and 0.92 ± 0.05, respectively. Optimization of hyperparameters improved the AUC only slightly by 0.01. For H&E, feature selection resulted in no increase of AUC but to an increase of 0.02–0.06 for ERG and PIN-4.
Conclusions: Automated pipelines may be able to discriminate with high accuracy between malignant and benign tissue. We found PIN-4 staining best suited for classifcation. Further bioinformatic analysis of larger data sets would be crucial to evaluate the reliability of automated classifcation methods for clinical practice and to evaluate potential discrimination of aggressiveness of cancer to pave the way to automatic precision medicine.
"High-aluminous coal" is an important coal kind and widely distributed in North China in age of Permo-Carboniferous period. To explore their occurrence state, a total of 15 harmful elements (Li, Ga, In, Cd, Cr, Pb, Be, Mn, Zn, Ag, Co, Ni, Cu, Ba and U) in the No.9 coal and No.11 coal collected from Pingshuo mining district were determined by inductively coupled plasma mass spectrometry (ICP-MS) and scanning electron microscope with energy spectrum (SEM-EDX). The results showed that the content of Li, Ga, In, Pb, Ag and U were all exceed the world hard coal. In view of the result of clustering analysis within trace elements, it was found that Co, Ni, Zn, Cu, Ag and Cr were mainly associated with sulfide minerals due to their common sulfophilic property. Manganese was mainly occurred in carbonate minerals, while Ba, Cd and U were mainly associated with total minerals. In addition, Pb was related to sulfides and Be is mainly distributed in clay minerals. The enrichment of such harmful elements in Pingshuo coal was caused by the combined effect of transgression and input of terrestrial materials in the peat accumulation stage. Li, Ga, In and Ag have reached the harmful grade.
A new cyclic lipopeptide, phototemtide A (1), was isolated from Escherichia coli expressing the biosynthetic gene cluster pttABC from Photorhabdus temperata Meg1. The structure of 1 was elucidated by HR‐ESI‐MS and NMR experiments. The absolute configurations of amino acids and 3‐hydroxyoctanoic acid in 1 were determined by using the advanced Marfey's method and comparison after total synthesis of 1, respectively. Additionally, three new minor derivatives, phototemtides B–D (2–4), were identified by detailed HPLC–MS analysis. Phototemtide A (1) showed weak antiprotozoal activity against Plasmodium falciparum, with an IC50 value of 9.8 μm. The biosynthesis of phototemtides A–D (1–4) was also proposed.
The glidobactin-like natural products (GLNPs) glidobactin A and cepafungin I have been reported to be potent proteasome inhibitors and are regarded as promising candidates for anticancer drug development. Their biosynthetic gene cluster (BGC) plu1881–1877 is present in entomopathogenic Photorhabdus laumondii but silent under standard laboratory conditions. Here we show the largest subset of GLNPs, which are produced and identified after activation of the silent BGC in the native host and following heterologous expression of the BGC in Escherichia coli. Their chemical diversity results from a relaxed substrate specificity and flexible product release in the assembly line of GLNPs. Crystal structure analysis of the yeast proteasome in complex with new GLNPs suggests that the degree of unsaturation and the length of the aliphatic tail are critical for their bioactivity. The results in this study provide the basis to engineer the BGC for the generation of new GLNPs and to optimize these natural products resulting in potential drugs for cancer therapy.
The application of natural products (NPs) as drugs and lead compounds has greatly improved human health over the past few decades. Despite their success, we still need to find new NPs that can be used as drugs to combat increasing drug resistance via new modes of action and to develop safer treatments with less side effects.
Entomopathogenic bacteria of Xenorhabdus and Photorhabdus that live in mutualistic symbiosis with nematodes are considered as promising producers of NPs, since more than 6.5% of their genomes are assigned to biosynthetic gene clusters (BGCs) responsible for production of secondary metabolites. The investigation on NPs from Xenorhabdus and Photorhabdus can not only provide new compounds for drug discovery but also help to understand the biochemical basis involved in mutualistic and pathogenic symbiosis of bacteria, nematode host and insect prey.
Nonribosomal peptides (NRPs) are a large class of NPs that are mainly found in bacteria and fungi. They are biosynthesized by nonribosomal peptide synthetases (NRPSs) and display diverse functions, representing more than 20 clinically used drugs. Although a large number of NRPs have been identified in Xenorhabdus and Photorhabdus, the advanced genome sequencing and bioinformatic analysis indicate that these bacteria still have many unknown NRPS-encoding gene clusters for NRP production that are worth to explore. Therefore, this thesis focuses on the discovery, biosynthesis, structure identification, and biological functions of new NRPs from Xenorhabdus and Photorhabdus.
The first publication describes the isolation and structure elucidation of seven new rhabdopeptide/xenortide-like peptides (RXPs) from X. innexi, incorporating putrescine or ammonia as the C-terminal amines. Bioactivity testing of these RXPs revealed potent antiprotozoal activity against the causative agents of sleeping sickness (Trypanosoma brucei rhodesiense) and malaria (Plasmodium falciparum), making them the most active RXP derivatives known to date. Biosynthetically, the initial NRPS module InxA might act iteratively with a flexible methyltransferase activity to catalyze the incorporation of the first five or six N-methylvaline/valine to these peptides.
The second publication focuses on the structure elucidation of seven unusual methionine-containing RXPs that were found as minor products in E. coli carrying the BGC kj12ABC from Xenorhabdus KJ12.1. To confirm the proposed structures from detailed HPLC-MS analysis, a solid-phase peptide synthesis (SPPS) method was developed for the synthesis of these partially methylated RXPs. These RXPs also exhibited good effects against T. brucei rhodesiense and P. falciparum, suggesting RXPs might play a role in protecting insect cadaver from soil-living protozoa to support the symbiosis with nematodes.
The third publication presents the identification of a new peptide library, named photohexapeptide library, which occurred after the biosynthetic gene phpS was activated in P. asymbiotica PB68.1 via promoter exchange. The chemical diversity of the photohexapeptides results from unusual promiscuous specificity of five out of six adenylation (A) domains being an excellent example of how to create compound libraries in nature. Furthermore, photohexapeptides enrich the family of the rare linear D-/L-peptide NPs.
The fourth publication concentrates on the structure elucidation of a new cyclohexapeptide, termed photoditritide, which was produced by P. temperata Meg1 after the biosynthetic gene pdtS was activated via promoter exchange. Photoditritide so far is the only example of a peptide from entomopathogenic bacteria that contains the uncommon amino acid homoarginine. The potent antimicrobial activity of photoditritide against Micrococcus luteus implies that photoditritide can protect the insect cadaver from food competitor bacteria in the complex life cycle of nematode and bacteria.
The last publication reports a new family of cyclic lipopeptides (CLPs), named phototemtides, which were obtained after the BGC pttABC from P. temperata Meg1 was heterologously expressed in E. coli. The gene pttA encodes an MbtH protein that was required for the biosynthesis of phototemtides in E. coli. To determine the absolute configurations of the hydroxy fatty acids, a total synthesis of the major compound phototemtide A was performed. Although the antimalarial activity of phototemtide A is only weak, it might be a starting point towards a selective P. falciparum compound, as it shows no activity against any other tested organisms.
We present the first very long baseline interferometric (VLBI) observations of the blazar OJ 287 carried out jointly with the Global Millimeter VLBI Array (GMVA) and the phased Atacama Large Millimeter/submillimeter Array (ALMA) at 3.5 mm on 2017 April 2. The participation of phased ALMA has not only improved the GMVA north–south resolution by a factor of ∼3, but has also enabled fringe detections with signal-to-noise ratios up to 300 at baselines longer than 2 Gλ. The high sensitivity has motivated us to image the data with newly developed regularized maximum likelihood imaging methods, revealing the innermost jet structure with unprecedentedly high angular resolution. Our images reveal a compact and twisted jet extending along the northwest direction, with two bends within the inner 200 μas, resembling a precessing jet in projection. The component at the southeastern end shows a compact morphology and high brightness temperature, and is identified as the VLBI core. An extended jet feature that lies at ∼200 μas northwest of the core shows a conical shape, in both total and linearly polarized intensity, and a bimodal distribution of the linear polarization electric vector position angle. We discuss the nature of this feature by comparing our observations with models and simulations of oblique and recollimation shocks with various magnetic field configurations. Our high-fidelity images also enabled us to search for possible jet features from the secondary supermassive black hole (SMBH) and test the SMBH binary hypothesis proposed for this source.