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Heute weiß fast jeder, dass ein hoher Blutcholesterinspiegel ein Risikofaktor für Herz-Kreislauf-Erkrankungen ist. Inzwischen gibt es wirksame Therapien, die den Cholesterinstoffwechsel wieder in Gang setzen. Doch die Herzgesundheit hängt von so viel mehr ab als von Cholesterin. Zu den bekannten Mediatoren für Herz-Kreislauf-Erkrankungen sind neue hinzugekommen. Alle können durch Ernährung beeinflusst werden.
In der Tat sind Herz-Kreislauf-Erkrankungen häufig multikausal. Neben Risikofaktoren wie Bluthochdruck, Diabetes, Nikotinmissbrauch spielen die genetische Veranlagung, familiäre und soziale Einflüsse sowie Umweltfaktoren eine Rolle, auch eigene psychische Erkrankungen und die Persönlichkeit. Ein einzelner Faktor hat in der Regel nur einen kleinen Einfluss, aber mehrere können durch Akkumulation zur Erkrankung führen. ...
Transforming growth factor-β (TGF-β) suppresses innate and adaptive immune responses via multiple mechanisms. TGF-β also importantly contributes to the formation of an immunosuppressive tumor microenvironment thereby promoting tumor growth. Amongst others, TGF-β impairs tumor recognition by cytotoxic lymphocytes via NKG2D. NKG2D is a homodimeric C-type lectin-like receptor expressed on virtually all human NK cells and cytotoxic T cells, and stimulates their effector functions upon engagement by NKG2D ligands (NKG2DL). While NKG2DL are mostly absent from healthy cells, their expression is induced by cellular stress and malignant transformation, and, accordingly, frequently detected on various tumor cells. Hence, the NKG2D axis is thought to play a decisive role in cancer immunosurveillance and, obviously, often is compromised in clinically apparent tumors. There is mounting evidence that TGF-β, produced by tumor cells and immune cells in the tumor microenvironment, plays a key role in blunting the NKG2D-mediated tumor surveillance. Here, we review the current knowledge on the impairment of NKG2D-mediated cancer immunity through TGF-β and discuss therapeutic approaches aiming at counteracting this major immune escape pathway. By reducing tumor-associated expression of NKG2DL and blinding cytotoxic lymphocytes through down-regulation of NKG2D, TGF-β is acting upon both sides of the NKG2D axis severely compromising NKG2D-mediated tumor rejection. Consequently, novel therapies targeting the TGF-β pathway are expected to reinvigorate NKG2D-mediated tumor elimination and thereby to improve the survival of cancer patients.
Introduction and Objectives: Surgical techniques such as preservation of the full functional-length of the urethral sphincter (FFLU) have a positive impact on postoperative continence rates. Thereby, data on very early continence rates after radical prostatectomy (RP) are scarce. The aim of the present study was to analyze very early continence rates in patients undergoing FFLU during RP.
Materials and Methods: Very early-continence was assessed by using the PAD-test within 24 h after removal of the transurethral catheter. The PAD-test is a validated test that measures the amount of involuntary urine loss while performing predefined physical activities within 1 h (e.g., coughing, walking, climbing stairs). Full continence was defined as a urine loss below 1 g. Mild, moderate, and severe incontinence was defined as urine loss of 1–10 g, 11–50 g, and >50 g, respectively.
Results: 90 patients were prospectively analyzed. Removal of the catheter was performed on the 6th postoperative day. Proportions for no, mild, moderate and severe incontinence were 18.9, 45.5, 20.0, and 15.6%, respectively. In logistic regression younger age was associated with significant better continence (HR 2.52, p = 0.04), while bilateral nerve-sparing (HR 2.56, p = 0.057) and organ-confined tumor (HR 2.22, p = 0.078) showed lower urine loss, although the effect was statistically not significant. In MVA, similar results were recorded.
Conclusion: Overall, 64.4% of patients were continent or suffered only from mild incontinence at 24 h after catheter removal. In general, reduced urine loss was recorded in younger patients, patients with organ-confined tumor and in patients with bilateral nerve sparing. Severe incontinence rates were remarkably low with 15.6%.
Differential games of common resources that are governed by linear accumulation constraints have several applications. Examples include political rent-seeking groups expropriating public infrastructure, oligopolies expropriating common resources, industries using specific common infrastructure or equipment, capital-flight problems, pollution, etc. Most of the theoretical literature employs specific parametric examples of utility functions. For symmetric differential games with linear constraints and a general time-separable utility function depending only on the player’s control variable, we provide an exact formula for interior symmetric Markovian-strategies. This exact solution, (a) serves as a guide for obtaining some new closed-form solutions and for characterizing multiple equilibria, and (b) implies that, if the utility function is an analytic function, then the Markovian strategies are analytic functions, too. This analyticity property facilitates the numerical computation of interior solutions of such games using polynomial projection methods and gives potential to computing modified game versions with corner solutions by employing a homotopy approach.
Protein quality control (PQC) machinery is in charge of ensuring protein homeostasis in the cell, i.e. proteostasis. Chaperones assist polypeptides throughout their maturation until functionality is achieved. This process might be disrupted in the presence of mutations or external damaging agents that affect the folding and stability of proteins. In this case, proteins can be efficiently recognized and targeted for degradation in a controlled manner. Ubiquitylation refers to the covalent attachment of one or more ubiquitin moieties to faulty proteins, thus triggering their degradation by the 26S proteasome.
More than 30% of proteins need cofactor molecules. Lack of cofactors renders proteins non-functional. We wanted to understand how the PQC deals with wild-type proteins in the absence of their cofactors. Several studies have indicated the importance of the riboflavin-derived cofactor FAD in the stability of individual flavoproteins, and hence we assumed that loss of flavin should mediate a targeted degradation of this group of proteins. Indeed, our mass spectrometry experiments showed that flavoproteome levels decreased under riboflavin starvation. The oxidoreductase NQO1 was used as a model enzyme to further investigate the mechanism of flavoproteome targeting by the PQC. We showed that cofactor loading determines ubiquitylation of NQO1 by the co-chaperone CHIP, both in vivo and in vitro. Furthermore, subtle changes in the C-terminus of NQO1 in the absence of FAD seemed to be crucial for this recognition event. ApoNQO1 interactome differed from holoNQO1. Chaperones and degradation factors were enriched on NQO1 upon cofactor withdrawal, probably to support maturation and prevent aggregation of the enzyme.
Loss of protein folding and stability, even to a small extent, can enhance the aggregating behavior of proteins. Proper loading with FAD reduced the co-aggregation of NQO1 with Aβ1-42 peptide. We assumed that the flavoproteome might represent aggregating-prone species under riboflavin deprivation. Supportingly, reversible apoNQO1 aggregates were observed in vivo in the absence of cofactor. General amyloidogenesis in vivo also increased under these conditions, apparently as a result of flavoproteome destabilization. In this context, we think that our data might have important implications considering the onset and development of conformational diseases.
This work has shed some light on the therapeutic implications of riboflavin deficiency as well. The sensitivity of melanoma cells towards the alkylating agent methyl methanesulfonate (MMS) increased under riboflavin starvation. Subsequent analyses indicated that a complex metabolic reorganization, mostly affecting proliferation and energy metabolism, occurs in response to starvation. What we suggest to call “flavoaddiction” can be understood as the dependence of melanoma cells on the flavoproteome structural and functional intactness to survive chemotherapy. Understanding this cellular reprogramming in detail might reveal new possibilities for future therapies.
The marginalization of the hijra identity in postcolonial Pakistan perpetuates the inequalities that have dogged the transgender community since the colonial era. Although Pakistan has since ratified all concerned UN treaties aimed at protecting transgender people and preventing human rights violations against them, the country’s gender-variant population nevertheless remains vulnerable to these transgressions. As such, this study aims to explore the following inquiry: “What are the lifeways of the hijra community and how do hijra people face human rights violations in their daily life activities?”
The identity construction of the hijra is a complex process. Pakistan is a patriarchal society that determines gender based on biological sex. While a genitally ambiguous child is generally recognized as intersexed, the family usually obscures this circumstance or tries to enforce a predominantly male identity onto the child. To some degree, an intersexed child is allowed to perform feminine roles, particularly when compared to a biologically male individual who is inclined toward femininity. They may partake in “girls’ games” or in “women’s chores” like cooking; they may opt to don feminine clothing and jewelry or practice walking and talking “like a girl.” Many family members and relatives consider such actions a threat to family honor and/or an indication of weakness, which in turn renders the child vulnerable to sexual or physical assault. Abuse also causes some gender-variant children to drop out of school. As adults, many hijras do not see childhood sexual encounters as assault, particularly because they considered themselves to be feminine even from a young age. Nevertheless, experiences of isolation, abuse, and exclusion often compel a gender-variant child to seek company outside of his/her family of orientation.
Many transgender individuals see redemption in joining the hijra community: there, a new identity is defined and shaped. New members mirror themselves after more senior hijras. In the community, relationships are solidified through similar childhood experiences and interests as well as a shared freedom to express the outer reflection of an “inner feminine soul.” Here, they accept the childhood label affixed to them by heteronormative society: hijra. In fact, the identity now becomes the key to economic viability and socialization.
The predominant livelihood strategies within the hijra community are dancing and prostitution. New members must adhere to stringent norms and rules; they risk (sometimes severe) punishment if they do not. For example, a new hijra must adopt a very strict feminine appearance; if she does not appear feminine enough she may be socially isolated or physically punished. Similarly, a hijra is required to remain passive during sex. In fact, because hijras are stereotyped as passive and vulnerable, many clients physically exploit or even rape them. If she tries to resist, a hijra may face physical violence and, in extreme circumstances, death. Reporting abuse to law enforcement authorities often leads to further exploitation. As such, whether dancing or performing sexually, hijras are encouraged to do whatever is asked of them.
In the last decade, the Supreme Court of Pakistan has taken significant steps to ensure the rights of transgender people. The Court has similarly compelled local governments to amend existing legislation in order to protect the transgender community. Nevertheless, discrepancies exist in legislative and judicial interpretations of the transgender identity, which continues to impede the struggle for basic rights. Indeed, there is a long way to go in the effort to incorporate transgender people into the folds of mainstream Pakistani society.
Die Extrauteringravidität (EUG) ist eine relativ häufige und bei zu spätem Erkennen schwerwiegende bis tödliche Anomalie der Schwangerschaft. Rund 2 % aller Schwangerschaften befinden sich extrauterin, z. B. im Eileiter, im Eierstock oder in der Bauchhöhle. Das Symptomspektrum kann vielfältig sein und reicht u. a. von Symptomfreiheit bis hin zu Schockzuständen durch innere Blutungen. Die maternale Sterblichkeit lag zu Beginn des letzten Jahrhunderts noch sehr hoch, da die Diagnose nicht oder zu spät gestellt wurde bzw. keine adäquate Therapie verfügbar war. Durch sensible Schwangerschaftstest, welche die β-Untereinheit des hCGs nachweisen, und den transvaginalen Ultraschall können heute pathologische Schwangerschaftsverläufe früh detektiert und ebenso früh interveniert werden. Je nach Fortschritt und Lokalisation der EUG stehen verschiedene Therapiemöglichkeiten zu Verfügung. Ambulant kann eine einmalige Methotrexatinjektion erfolgen. Auch chirurgische Methoden sind eine Therapieoption.
In dieser Arbeit wurden die 8.040 Publikationen, die zwischen 1900 und 2012 zum Thema EUG erschienen sind und ins Web of Science aufgenommen wurden, szientometrisch analysiert, um quantitative und qualitative Aussagen bezüglich der Publikationen und dem Forschungsverhalten treffen zu können. Quantitativ wurden u. a. die Publikationsleistung einzelner Länder, Autoren und Fachzeitschriften sowie verschiedene Kooperationen evaluiert. Die qualitative Beurteilung betrachtete neben Zitationszahlen, Zitationsraten und modifizierten H-Indizes auch Impact-Faktoren (IF). Eine derartige Untersuchung existiert zum jetzigen Zeitpunkt nicht.
Im betrachteten Zeitraum sind die Publikations- und Zitationszahlen stetig gestiegen. Dies lässt auf ein gestiegenes wissenschaftliches Interesse für EUGen schließen. Außerdem ist über die Jahre auch die Anzahl der Autoren pro Publikation gestiegen, was auf eine vermehrte Zusammenarbeit zwischen Autoren, Institutionen und Ländern hindeutet. Als meistpublizierend kristallisierten sich die USA heraus. Auch bezüglich des modifizierten H-Index`, der erhaltenen Zitierungen und der meisten Institutionen, die das Thema EUG beforschen, sind die USA führend. Im Gegensatz dazu ist Israel mit einem weitaus geringeren BIP unter den 5 meistpublizierenden Ländern zu finden. Israels Publikationszahl pro BIP zeigt, dass die Forschung einen hohen Stellen¬wert hat, aus der qualitativ hochwertige Ergebnisse resultieren, was durch die hohe Zitationsrate und den modifizierten H-Index untermauert wird. Unter den Zeitschriften sind Fertility and Sterility, American Journal of Obstetrics & Gynecology und Obstetrics & Gynecology quantitativ die Spitzenreiter. Werden jedoch qualitative Parameter wie der IF betrachtet, siedeln sich die genannten Periodika im hinteren Drittel ein. Im Gegensatz zu Journalen mit hohen IF, wie das New England Journal of Medicine (IF = 51,658) und The Lancet (IF = 39,060) haben die meistpublizierenden Journale ein eingeschränktes Themengebiet, was erheblichen Einfluss auf den IF hat. Unter den 15 meistpublizierenden Fachjournalen werden 14 in englischer Sprache veröffentlicht. Nur die Fachzeitschrift Geburtshilfe und Frauenheilkunde publiziert deutschsprachige Fachbeiträge. Parallel dazu sind mehr als 92 % der Veröffentlichungen in Englisch publiziert worden. Ursächlich hierfür sind unter anderem die Vorauswahl, die vom WoS getroffen wird und die Anerkennung der englischen Sprache als Sprache der Wissenschaft. Mit Abstand die meisten Publikationen wurden im Themengebiet Obstetrics & Gynecology veröffentlicht. Da die EUG ein gynäkologisches Krankheitsbild ist, ist dies wenig verwunderlich. Weltweit führende Institution hinsichtlich der Publikationen ist die University of London. Mit 168 Publikationen reihen sich die weltbekannten amerikanischen Universitäten aus Pennsylvania, Yale und die Harvard University hinter der britischen Einrichtung ein. Hinsichtlich der Zahl der Zitierungen liegt die Londoner Universität hinter dem Center for Disease Control, das in den USA angesiedelt ist. Unter den Autoren genießt der Amerikaner Kurt T. Barnhart (81 Publikationen) großes Ansehen. Diese Veröffentlichungen wurden über 1.000 Mal zitiert. Sein modifizierter H-Index von 19 wird von Hervé Fernandez (mod. H-Index 24) noch übertroffen. Mit 79 Publikationen reiht er sich hinter Barnhart ein. Durch die Genderanalyse wird ersichtlich, dass weitaus weniger Frauen als Autoren in Erscheinung treten, wobei nur ca. 22 % der Autorennamen ihrem Geschlecht zugeordnet werden konnten.
Diese szientometrische Analyse zum Thema EUG liefert einen Überblick über die quantitative und qualitative Entwicklung der internationalen Forschung zeigt die wissenschaftliche Anerkennung auf, interpretiert Ergebnisse und hinterfragt sie kritisch.
The present thesis is primarily concerned with the application of the functional renormalization group (FRG) to spin systems. In the first part, we study the critical regime close to the Berezinskii-Kosterlitz-Thouless (BKT) transition in several systems. Our starting point is the dual-vortex representation of the two-dimensional XY model, which is obtained by applying a dual transformation to the Villain model. In order to deal with the integer-valued field corresponding to the dual vortices, we apply the lattice FRG formalism developed by Machado and Dupuis [Phys. Rev. E 82, 041128 (2010)]. Using a Litim regulator in momentum space with the initial condition of isolated lattice sites, we then recover the Kosterlitz-Thouless renormalization group equations for the rescaled vortex fugacity and the dimensionless temperature. In addition to our previously published approach based on the vertex expansion [Phys. Rev. E 96, 042107 (2017)], we also present an alternative derivation within the derivative expansion. We then generalize our approach to the O(2) model and to the strongly anisotropic XXZ model, which enables us to show that weak amplitude fluctuations as well as weak out-of-plane fluctuations do not change the universal properties of the BKT transition.
In the second part of this thesis, we develop a new FRG approach to quantum spin systems. In contrast to previous works, our spin functional renormalization group (SFRG) does not rely on a mapping to bosonic or fermionic fields, but instead deals directly with the spin operators. Most importantly, we show that the generating functional of the irreducible vertices obeys an exact renormalization group equation, which resembles the Wetterich equation of a bosonic system. As a consequence, the non-trivial structure of the su(2) algebra is fully taken into account by the initial condition of the renormalization group flow. Our method is motivated by the spin-diagrammatic approach to quantum spin system that was developed more than half a century ago in a seminal work by Vaks, Larkin, and Pikin (VLP) [Sov. Phys. JETP 26, 188 (1968)]. By embedding their ideas in the language of the modern renormalization group, we avoid the complicated diagrammatic rules while at the same time allowing for novel approximation schemes. As a demonstration, we explicitly show how VLP's results for the leading corrections to the free energy and to the longitudinal polarization function of a ferromagnetic Heisenberg model can be recovered within the SFRG. Furthermore, we apply our method to the spin-S Ising model as well as to the spin-S quantum Heisenberg model, which allows us to calculate the critical temperature for both a ferromagnetic and an antiferromagnetic exchange interaction. Finally, we present a new hybrid formulation of the SFRG, which combines features of both the pure and the Hubbard-Stratonovich SFRG that were published recently [Phys. Rev. B 99, 060403(R) (2019)].
Epigenetic mechanisms largely influence how genetic information on DNA level is translated into different phenotypes. DNA methylations and histone post-translational modifications make up what is referred to as "epigenetic landscape", an interconnected pattern that regulates access to genes and serves as platform for specific binding partners. The epigenetic landscape is maintained by "writers", which add the modifications, "erasers", which delete the modifications and "readers" which specifically bind modifications and mediate their location to other proteins connected to transcription. In the context of acetylations, which are the focus of this thesis, the writers are called histone acetyl transferases (HATs), the erasers are called histone deacetylases (HDACs) and the readers comprise Bromodomains (BRDs) as well as Yaf9, ENL, AF9, Taf14, Sas5 (YEATS) domains. An aberrant epigenetic landscape and mutated forms of epigenetic readers can lead to diseases including cancer and inflammatory diseases, making epigenetic reader domains attractive drug targets.
The focus of this thesis were YEATS domains and the development of inhibitors for this new class of epigenetic readers. Eleven-nineteen-leukemia protein (ENL) and ALL1-fused gene from chromosome 9 protein (AF9) are also part of the super elongation complex and are common fusion partners of mixed lineage leukemia protein (MLL) in acute myeloid leukemia (AML) (Wan et al., 2017, Erb et al., 2017). In this thesis, the first ligand-free crystal structure of ENL YEATS revealed an inherent flexibility of the Y78 side chain in the aromatic triad and two conserved water molecules. Soaking experiments led to the first co-crystal structures between a YEATS domain and small molecule inhibitors and defined prerequisites for ENL YEATS inhibitor scaffolds. The discovered inhibitory fragments had a central amide bond in common, which replaced one of the two conserved water molecules to form beta-sheet-like hydrogen bonds between the loop 6 backbone and the S58 side chain. The amide bond was flanked by two aromatic moieties, of which one stacks with H56 in the front pocket and the other interacts with the aromatic triad in the rear pocket. The development of the first chemical probe for ENL/AF9, SGC-iMLLT, show that the affinity is increased to low nanomolar levels if the rear flanking aromatic moiety forms additional hydrogen bonds with loop 6 and the side chain of E75 (Moustakim et al., 2018). In case of the probe, this is achieved with a 2-methyl-pyrrolidine-benzimidazole moiety. The probe binds with high affinity to ENL (129 nM) and AF9 (77 nM) and shows no significant affinity towards other human YEATS domains or BRDs. Target engagement was shown by fluorescence recovery after photobleaching (FRAP), cellular thermal shift assay (CETSA) and in case of AF9 also with NanoBRET. The probe changed the expression of three AML-related genes (MYC, dendrin and CD86) in MV4;11 cells, encouraging application of this probe in more AML cell lines.
Eine qualitative und quantitative Studie zum Einsatz der virtuellen Mikroskopie in der Schule
(2019)
Das Mikroskop stellt in der Alltagswelt ein Sinnbild für naturwissenschaftliches Arbeiten dar (Coleman 2009, Paulsen 2010). Im Bereich der Lehre eröffnet dieses Laborgerät das Eintauchen in die mikroskopische Dimension und besitzt eine wesentliche Rolle bei der damit verbundenen Erkenntnisgewinnung, insbesondere von funktionsmorphologischen Konzepten (Gropengießer & Kattmann 2008, Kremer 2002). Jedoch wird die Durchführung der klassischen Mikroskopie und damit die aktive Auseinandersetzung mit mikroskopischen Präparaten im schulischen (Biologie-)Unterricht durch verschiedene Faktoren erschwert. Zu den Limitierungen gehören beispielsweise die Verfügbarkeit geeigneter Mikroskope und Dauerpräparate, die aufwendige Vor- und Nachbereitungszeit sowie der zeitliche Aufwand bei der Herstellung hochwertiger mikroskopischer Frischpräparate. Die virtuelle Mikroskopie könnte diese Schwierigkeiten umgehen. Das virtuelle Mikroskop kann als eine Simulation verstanden werden, bei der die bildanalytischen Vorgehensweisen bei mikroskopischen Präparaten analog zur klassischen Mikroskopie nachvollzogen werden können (Gu & Oglivie 2005, Hentschel 2009). Hierbei umfasst das virtuelle Mikroskop ein Akquisitionssystem zum Einscannen und Digitalisieren mikroskopischer Präparate, einen Server zum Speichern und Bereitstellen der entstandenen virtuellen hochauflösenden Aufnahmen (WSI) sowie eine Bildbetrachtungssoftware auf einem Anwendungsrechner (Kalinski et al. 2006). Basierend auf einer Nutzerbefragung wurde eine Betrachtungssoftware programmiert, die hinsicht¬lich ihrer Benutzerfreundlichkeit und ihren Eigenschaften auf den schulischen Einsatz angepasst wurde. Um die Relevanz in diesem Anwendungsfeld zu testen, wurden die Untersuchungen der vorliegenden Arbeit sowohl im Schülerlabor Goethe BioLab als auch in der universitären Lehre der Abteilung für Didaktik der Biowissen¬schaften der Goethe–Universität Frankfurt am Main durchgeführt. Der Schülerlabortag „Blut und das virtuelle Mikroskop“ wurde entwickelt, um die computerbasierte virtuelle Mikroskopie mit Schülern ergänzend zur klassischen Mikroskopie in einem fachlichen Kontext anzuwenden und zu erforschen.
Beruhend auf der Vergleichbarkeit beider Mikroskopiemethoden (Paulsen et al. 2010) lagen die Forschungsschwerpunkte neben der Nutzung der Software durch Schülerinnen und Schülern auf einer gegenüberstellenden Beurteilung beider mikroskopischer Verfahren von Schülern und Lehramtsstudierenden. Es wurden in diesem Zusammenhang drei zentrale Forschungsfragen formuliert.
Die erste Forschungsfrage untersucht das Nutzerverhalten der Schüler (n = 123) bei der virtuellen Mikroskopie mittels automatisch generierter Datensätze während der Anwendung der Bildbetrachtungssoftware. Die Analyse der Anwendungsdaten zeigt, dass das mikroskopische Sehen, insbesondere das Fokussieren auf relevante Bildbereiche, im virtuellen Humanblutausstrich angewandt wurde.
Die zweite Forschungsfrage untersuchte das aktuelle Interesses bei Schülern (n = 293) im direkten Vergleich zwischen virtueller und klassischer Mikroskopie. Dabei wurde das aktuelle Interesse aufgrund des engen Zusammenhangs zum Lernen (vgl. Krapp 1992a) als Indikator der Lernwirksamkeit gewählt. Die Erhebung erfolgte mittels eines Fragebogens. Die Ergebnisse dieser Untersuchung zeigen, dass der Einsatz beider mikroskopischer Verfahren das aktuelle Interesse fördert, das emotionale und das wertbezogene Merkmal sich jedoch zugunsten der klassischen Mikroskopie signifikant unterscheiden.
Im Rahmen der dritten Forschungsfrage erfolgte eine Beurteilung der Vorteile virtueller Mikroskopie gegenüber der klassischen Mikroskopie von Schülern (n = 504) sowie Lehramtsstudierenden (n = 247). Hierbei diente ebenfalls ein Fragebogen als Grundlage der Erhebung. Die Auswertung zeigt, dass sowohl die Schüler als auch die Studierenden die Vorteile der virtuellen Mikroskopie klar erkennen. Es liegen jedoch signifikante Unterschiede zwischen den Versuchsgruppen vor. Die Schüler bewerten die Vorteile betreffend der Förderung von Lernprozessen, des Erkennens von Strukturen und des mikroskopischen Zeichnens höher.
Zusammenfassend bestärken die Ergebnisse dieser Studie die Ansicht, dass das virtuelle Mikroskop nicht als Ersatz, sondern als sinnvolle Ergänzung zu der klassischen Lichtmikroskopie angesehen werden sollte (Bloodgood et al. 2006, Berg et al. 2016, Braun & Kearns 2008, Hufnagl et al. 2012, Mione et al. 2013, Santiago 2018, Scoville & Buskirk 2007). Dabei sollte die vorliegende Arbeit als Einstieg verstanden werden, um bestehende Forschungslücken zu verkleinern, damit ein Transfer der virtuellen Mikroskopie in den schulischen Kontext möglichst lernwirksam erfolgen kann.
Die Neurowissenschaften sind in Forschungsarbeiten für Schüler und Studierende immer wieder als eines der schwierigsten Teilgebiete der Biologie angeführt. Die Inhalte werden überwiegend nicht verstanden. Als mögliche Ursache gelten die seltenen praktischen Zugänge für die Lernenden aufgrund limitierter Ressourcen. Diese Ursache konnte in der vorliegenden Arbeit durch eine Befragung der Lehrkräfte zu ihren Praxisumsetzungen bestätigt werden. 70 % der Lehrkräfte gaben an, dass sie keine Experimente in der Schule zum Thema Nervenzellen anbieten. Experimente zur Verhaltensbiologie führen 65 % der Lehrkräfte nicht durch.
Um Schülern die Möglichkeit zu geben, sich experimentell mit den Themenfeldern der Neuro- und Verhaltensbiologie auseinanderzusetzen, wurden im Rahmen der vorliegenden Arbeit Schülerlabortage auf dem Feld der Neurowissenschaften konzipiert. Die Konzepte wurden schülerorientiert umgesetzt und neurowissenschaftliche Forschung durch den eigenen Umgang mit modernen Forschungsapparaturen erfahrbar gemacht. Die drei Labortage für die Sekundarstufe II wurden wissenschaftlich begleitet: 1) Verhaltensbiologie, 2) systemische Ebene der Elektrophysiologie, 3) elektrophysiologische Forschungsmethoden. Um die Qualität und Wirksamkeit der Labortage beurteilen zu können, wurden sie mit Feedbackerhebungen begleitet. Die drei Labortage wurden sowohl von den Lehrkräften als auch von den Schülern bezüglich ihrer Qualität positiv bewertet. Für die Schüler konnte gezeigt werden, dass die Beurteilung weitgehend unabhängig von einem zugrunde liegenden Interesse an Biologie und Forschung ausfällt. Anhand einer retrospektiven Erhebung wird außerdem gezeigt, dass alle drei Labortage eine höchst signifikante, selbsteingeschätzte Steigerung des „Wissens“, der „Anwendungszuversicht“ und des „Interesses“ bewirken. Schüler mit niedrigen Ausgangswerten zeigen einen besonders hohen Anstieg. Für das Interesse kann weiter gezeigt werden, dass auch Schüler mit hohem Ausgangswert eine große Interessenssteigerung durch den Labortag aufweisen. Das Interesse für den verhaltensbiologischen Labortag liegt etwas niedriger – die Labortage mit elektrophysiologischen Inhalten zeigen dagegen für die Anwendungszuversicht etwas niedrigere Werte.
Der Fokus der fachdidaktischen Forschung lag auf der Betrachtung des experimentellen Zugangs zur Elektrophysiologie über ein entwickeltes „EPhys-Setup“. Dabei handelt es sich um einen quasi-realen Messaufbau. Die Umsetzung kombiniert dazu Komponenten eines realen Elektrophysiologie-Setups (Hands-on Komponenten) mit einer speziell entwickelten schülerfreundlichen Software (Neurosimulation) und einem virtuellen Nervensystem in Form einer Platine. Als Modellnervensystem werden für diese Umsetzung Ganglien von Hirudo medicinalis verwendet – der Neurosimulation liegen originale elektrophysiologische Messspuren des Ganglions zugrunde. Experimentelle Vermittlungsansätze für die Elektrophysiologie finden sich kaum für den Schulbereich. Dem Bedarf einer entsprechenden Beforschung wurde mit verschiedenen Testinstrumenten nachgegangen, um den Vermittlungsansatz mit dem EPhys-Setup bewerten zu können. Dafür fand eine Wirksamkeitsanalyse über die Erhebung der Motivation der Schüler statt (Lab Motivation Scale; Dohn et al. 2016). Von Bedeutung war auch, inwiefern gegenüber der Umsetzung eine Technologieakzeptanz vorliegt (Technology Acceptance Model; Davis 1989), die im Schulkontext ausgehend von der steigenden Einbindung von Technologien einen entsprechenden Forschungsbedarf aufweist. Weiter wurde untersucht, ob sich die Bewertung des EPhys-Setups von der Bewertung einer Kontrollgruppe unterscheidet. Für die Kontrollgruppe wurde die Neurosimulation von den Hands-on Komponenten gelöst und die Schüler arbeiteten ausschließlich PC-basiert. Die Ergebnisse zeigen, dass beide Umsetzungen die Motivation förderten und eine Technologieakzeptanz bei den Schülern aufwiesen. Der Unterschied der Untersuchungsgruppen fällt gering aus. Die Abhängigkeiten, die für die verwendete Simulationsumsetzung gefunden wurden, beziehen sich ausschließlich auf Komponenten der „Freude“. Somit wird der intrinsische Bereich von den Schülern die am EPhys-Setup gearbeitet haben höher bewertet. Zur weiteren Analyse der Testinstrumente wurde auch eine Abhängigkeit der Bewertung vom zugrunde liegenden Biologieinteresse sowie von den Computerfähigkeiten vergleichend betrachtet. Der Einfluss auf die Bewertungen der drei Testskalen ist in vielen Fällen höher als der Einfluss der verwendeten Simulation. Vom individuellen Biologieinteresse der Schüler zeigen alle untersuchten Komponenten eine Abhängigkeit. Die größeren Effekte beziehen sich auf die Komponenten der „Lernwirksamkeit“ oder der „Freude“. Von den individuellen Computerfähigkeiten der Schüler zeigen Komponenten zur „Zuversicht bezüglich der Methoden und der Inhalte“ eine Abhängigkeit.
Autophagy has important functions in maintaining energy metabolism under conditions of starvation and to alleviate stress by removal of damaged and potentially harmful cellular components. Therefore, autophagy represents a pro-survival stress response in the majority of cases. However, the role of autophagy in cell survival and cell death decisions is highly dependent on its extent, duration, and on the respective cellular context. An alternative pro-death function of autophagy has been consistently observed in different settings, in particular, in developmental cell death of lower organisms and in drug-induced cancer cell death. This cell death is referred to as autophagic cell death (ACD) or autophagy-dependent cell death (ADCD), a type of cellular demise that may act as a backup cell death program in apoptosis-deficient tumors. This pro-death function of autophagy may be exerted either via non-selective bulk autophagy or excessive (lethal) removal of mitochondria via selective mitophagy, opening new avenues for the therapeutic exploitation of autophagy/mitophagy in cancer treatment.
Health-related preferences of older patients with multimorbidity: the protocol for an evidence map
(2019)
Introduction: Interaction of conditions and treatments, complicated care needs and substantial treatment burden make patient–physician encounters involving multimorbid older patients highly complex. To optimally integrate patients’ preferences, define and prioritise realistic treatment goals and individualise care, a patient-centred approach is recommended. However, the preferences of older patients, who are especially vulnerable and frequently multimorbid, have not been systematically investigated with regard to their health status. The purpose of this evidence map is to explore current research addressing health-related preferences of older patients with multimorbidity, and to identify the knowledge clusters and research gaps.
Methods and analysis: To identify relevant research, we will conduct searches in the electronic databases MEDLINE, EMBASE, PsycINFO, PSYNDEX, CINAHL, Social Science Citation Index, Social Science Citation Index Expanded and the Cochrane library from their inception. We will check reference lists of relevant articles and carry out cited reference research (forward citation tracking). Two independent reviewers will screen titles and abstracts, check full texts for eligibility and extract the data. Any disagreement will be resolved and consensus reached with the help of a third reviewer. We will include both qualitative and quantitative studies, and address preferences from the patients’ perspectives in a multimorbid population of 60 years or older. There will be no restrictions on the publication language. Data extraction tables will present study and patient characteristics, aim of study, methods used to identify preferences and outcomes (ie, type of preferences). We will summarise the data using tables and figures (ie, bubble plot) to present the research landscape and to describe clusters and gaps.
Ethics and dissemination: Due to the nature of the proposed evidence map, ethics approval will not be required. Results from our research will be disseminated by means of specifically prepared materials for patients, at relevant (inter)national conferences and via publication in peer-reviewed journals.
Background: Cannabis proofed to be effective in pain relief, but one major side effect is its influence on memory in humans. Therefore, the role of memory on central processing of nociceptive information was investigated in healthy volunteers.
Methods: In a placebo-controlled cross-over study including 22 healthy subjects, the effect of 20 mg oral Δ9-tetrahydrocannabinol (THC) on memory involving nociceptive sensations was studied, using a delayed stimulus discrimination task (DSDT). To control for nociceptive specificity, a similar DSDT-based study was performed in a subgroup of thirteen subjects, using visual stimuli.
Results: For each nociceptive stimulus pair, the second stimulus was associated with stronger and more extended brain activations than the first stimulus. These differences disappeared after THC administration. The THC effects were mainly located in two clusters comprising the insula and inferior frontal cortex in the right hemisphere, and the caudate nucleus and putamen bilaterally. These cerebral effects were accompanied in the DSDT by a significant reduction of correct ratings from 41.61% to 37.05% after THC administration (rm-ANOVA interaction "drug" by "measurement": F (1,21) = 4.685, p = 0.042). Rating performance was also reduced for the visual DSDT (69.87% to 54.35%; rm-ANOVA interaction of "drug" by "measurement": F (1,12) = 13.478, p = 0.003) and reflected in a reduction of stimulus-related brain deactivations in the bilateral angular gyrus.
Conclusions: Results suggest that part of the effect of THC on pain may be related to memory effects. THC reduced the performance in DSDT of nociceptive and visual stimuli, which was accompanied by significant effects on brain activations. However, a pain specificity of these effects cannot be deduced from the data presented.
SAFE Newsletter : 2019, Q4
(2019)
Objectives: The present randomized clinical trial assesses the six-month outcomes following surgical regenerative therapy of periimplantitis lesions using either an electrolytic method (EC) to remove biofilms or a combination of powder spray and electrolytic method (PEC).
Materials and Methods: 24 patients with 24 implants suffering from peri-implantitis with any type of bone defect were randomly treated by EC or PEC. Bone defects were augmented with a mixture of natural bone mineral and autogenous bone and left for submerged healing. The distance from implant shoulder to bone was assessed at six defined points at baseline (T0) and after six months at uncovering surgery (T1) by periodontal probe and standardized x-rays.
Results: One implant had to be removed at T1 because of reinfection and other obstacles. None of the other implants showed signs of inflammation. Bone gain was 2.71 ± 1.70 mm for EC and 2.81 ± 2.15 mm for PEC. No statistically significant difference between EC and PEC was detected. Significant clinical bone fill was observed for all 24 implants. Complete regeneration of bone was achieved in 12 implants. Defect morphology impacted the amount of regeneration.
Conclusion: EC needs no further mechanical cleaning by powder spray. Complete re-osseointegration in peri-implantitis cases is possible.
Background: Critical incident reporting systems (CIRS) can be an important tool for the identification of organisational safety needs and thus to improve patient safety. In German primary care, CIRS use is obligatory but remains rare. Studies on CIRS implementation in primary care are lacking, but those from secondary care recommend involving management personnel.
Objective: This project aimed to increase CIRS use in 69 practices belonging to a local practice network.
Methods: The intervention consisted of the provision of a web-based CIRS, accompanying measures to train practice teams in error management and CIRS, and the involvement of the network’s management. Three measurements were used: (1) number of incident reports and user access rates to the web-based CIRS were recorded, (2) staff were given a questionnaire addressing incident reporting, error management and safety climate and (3) qualitative reflection conferences were held with network management.
Results: Over 20 months, 17 critical incidents were reported to the web-based CIRS. The number of staff intending to report the next incident online decreased from 42% to 20% of participants. In contrast, the number of practices using an offline CIRS (eg, incident book) increased from 23% to 49% of practices. Practices also began proactively approaching network management for help with incidents. After project completion, participants scored higher in the patient safety climate factor ‘perception of causes of errors’. For many practices, the project provided the first contact with structured error management.
Conclusion: Specific measures to improve the use of CIRS in primary care should focus on network management and practice owners. Practices need basic training on safety culture and error management. Continuing, practices should implement an offline CIRS, before they can profit from the exchange of reports via web-based CIRS. It is crucial that practices receive feedback on incidents, and trained network management personnel can provide such support.
Classical Hodgkin lymphoma (cHL) is one of the most common malignant lymphomas in Western Europe. The nodular sclerosing subtype of cHL (NS cHL) is characterized by a proliferation of fibroblasts in the tumor microenvironment, leading to fibrotic bands surrounding the lymphoma infiltrate. Several studies have described a crosstalk between the tumour cells of cHL, the Hodgkin- and Reed-Sternberg (HRS) cells, and cancer-associated fibroblasts. However, to date a deep molecular characterization of these fibroblasts is lacking. Thus, the aim of the present study is a comprehensive characterization of these fibroblasts. Gene expression profiling and methylation profiles of fibroblasts isolated from primary lymph node suspensions revealed persistent differences between fibroblasts obtained from NS cHL and lymphadenitis. NS cHL derived fibroblasts exhibit a myofibroblastic phenotype characterized by myocardin (MYOCD) expression. Moreover, TIMP3, an inhibitor of matrix metalloproteinases, was strongly upregulated in NS cHL fibroblasts, likely contributing to the accumulation of collagen in sclerotic bands of NS cHL. As previously shown for other types of cancer-associated fibroblasts, treatment by luteolin could reverse this fibroblast phenotype and decrease TIMP3 secretion. NS cHL fibroblasts showed enhanced proliferation when they were exposed to soluble factors released from HRS cells. For HRS cells, soluble factors from fibroblasts were not sufficient to protect them from Brentuximab-Vedotin induced cell death. However, HRS cells adherent to fibroblasts were protected from Brentuximab-Vedotin induced injury. In summary, we confirm the importance of fibroblasts for HRS cell survival and identify TIMP3 which probably contributes as a major factor to the typical fibrosis observed in NS cHL.
The title co-crystal, 1,3,5,7-tetraazatricyclo[3.3.1.13,7]decane (HMTA, 1)–4-fluorophenol (4-FP) (1/1), C6H12N4·C6H5FO, shows an unusual asymmetric unit that comprises eight independent molecules (Z′′ = 8), four for each component, with four formula units per asymmetric unit (Z′ = 4). In the molecular packing, each HMTA molecule bridges one 4-FP molecule via an O−H···N hydrogen bond to form a two-molecule aggregate. Differences can be observed between the bond lengths and angles of the independent HMTA and 4-FP molecules and those of the molecules in the aggregate. The C−N bonds exhibit different bond lengths in the tetrahedral cage-like structure of the HMTA molecules, but the largest differences between the molecular aggregates are in the bond lengths in the 4-fluorophenol ring. In the crystal, the HMTA and 4-FP molecules form two hydrogen-bonded (O−H···N, C−H···F and C−H···O) dimers of HMTA and 4-FP molecules, A···D and B···C inversion dimers, which generate enlarged R88(34) ring motifs in both supramolecular structures. In both structures, the crystal packing also features additional C−H···F and C−H···O interactions. The A···D and B···C dimers are linked by additional C−H···F and C−H···O hydrogen bonds, forming columns along the a and b axes, respectively. The importance of the C−H···F interaction to the structure and crystal packing has been demonstrated.
Introduction: Pediatric pneumococcal pneumonia complicated by parapneumonic pleural effusion/empyema (PPE/PE) remains a major concern despite general immunization with pneumococcal conjugate vaccines (PCVs).
Methods: In a nationwide pediatric hospital surveillance study in Germany we identified 584 children <18 years of age with bacteriologically confirmed PPE/PE from October 2010 to June 2018. Streptococcus pneumoniae was identified by culture and/or PCR of blood samples and/or pleural fluid and serotyped.
Results: S. pneumoniae was identified in 256 of 584 (43.8%) children by culture (n = 122) and/or PCR (n = 207). The following pneumococcal serotypes were detected in 114 children: serotype 3 (42.1%), 1 (25.4%), 7F (12.3%), 19A (7.9%), other PCV13 serotypes (4.4%) and non-PCV13 serotypes (7.9%). Between October 2010 and June 2014 serotype 1 (38.1%) and serotype 3 (25.4%) were most prevalent, whereas between July 2014 and June 2018 serotype 3 (62.7%) and non-PCV13 serotypes (15.7%) were dominant. Compared to children with other pneumococcal serotypes, children with serotype 3 associated PPE/PE were younger (median 3.2 years [IQR 2.1–4.3 years] vs. median 5.6 years [IQR 3.8–8.2 years]; p < 0.001) and more frequently admitted to intensive care (43 [89.6%] vs. 48 [73.8%]; p = 0.04). Seventy-six of 114 (66.7%) children with pneumococcal PPE/PE had been vaccinated with pneumococcal vaccines. Thirty-nine of 76 (51.3%) had received a vaccine covering the serotype detected. Thirty of these 39 breakthrough cases were age-appropriately vaccinated with PCV13 and considered vaccine failures, including 26 children with serotype 3, three children with serotype 19A and one child with serotype 1.
Conclusion: Following the introduction of PCV13 in general childhood vaccination we observed a strong emergence of serotype 3 associated PPE/PE in the German pediatric population, including a considerable number of younger children with serotype 3 vaccine breakthrough cases and failures. Future PCVs should not only cover newly emerging serotypes, but also include a more effective component against serotype 3.
Transdisciplinary research is research not only on, but also for and, most of all, with practitioners. In the research framework of transdisciplinarity, scholars and practitioners collaborate throughout research projects with the aim of mutual learning. This paper shows the value transdisciplinarity can add to media linguistics. It does so by investigating the digital literacy shift in journalism: the change, in the last two decades, from the predominance of a writing mode that we have termed focused writing to a mode we have called writing-by-the-way. Large corpora of writing process data have been generated and analyzed with the multimethod approach of progression analysis in order to combine analytical depth with breadth. On the object level of doing writing in journalism, results show that the general trend towards writing-by-the-way opens up new niches for focused writing. On a meta level of doing research, findings explain under what conditions transdisciplinarity allows for deeper insights into the medialinguistic object of investigation.
Recent studies have proven that Dimethylfumarate (DMF) has a marked anti-proliferative impact on diverse cancer entities e.g., on malignant melanoma. To explore its anti-tumorigenic potential, we examined the effects of DMF on human colon carcinoma cell lines and the underlying mechanisms of action. Human colon cancer cell line HT-29 and human colorectal carcinoma cell line T84 were treated with or without DMF. Effects of DMF on proliferation, cell cycle progression, and apoptosis were analyzed mainly by Bromodeoxyuridine (BrdU)- and Lactatdehydrogenase (LDH)-assays, caspase activation, flowcytometry, immunofluorescence, and immunoblotting. In addition, combinational treatments with radiation and chemotherapy were performed. DMF inhibits cell proliferation in both cell lines. It was shown that DMF induces a cell cycle arrest in G0/G1 phase, which is accompanied by upregulation of p21 and downregulation of cyclin D1 and Cyclin dependent kinase (CDK)4. Furthermore, upregulation of autophagy associated proteins suggests that autophagy is involved. In addition, the activation of apoptotic markers provides evidence that apoptosis is involved. Our results show that DMF supports the action of oxaliplatin in a synergetic manner and failed synergy with radiation. We demonstrated that DMF has distinct anti-tumorigenic, cell dependent effects on colon cancer cells by arresting cell cycle in G0/G1 phase as well as activating both the autophagic and apoptotic pathways and synergizes with chemotherapy.
Adipose-derived mesenchymal stem cells (ASCs) are considered to be a useful tool for regenerative medicine, owing to their capabilities in differentiation, self-renewal, and immunomodulation. These cells have become a focus in the clinical setting due to their abundance and easy isolation. However, ASCs from different depots are not well characterized. Here, we analyzed the functional similarities and differences of subcutaneous and visceral ASCs. Subcutaneous ASCs have an extraordinarily directed mode of motility and a highly dynamic focal adhesion turnover, even though they share similar surface markers, whereas visceral ASCs move in an undirected random pattern with more stable focal adhesions. Visceral ASCs have a higher potential to differentiate into adipogenic and osteogenic cells when compared to subcutaneous ASCs. In line with these observations, visceral ASCs demonstrate a more active sonic hedgehog pathway that is linked to a high expression of cilia/differentiation related genes. Moreover, visceral ASCs secrete higher levels of inflammatory cytokines interleukin-6, interleukin-8, and tumor necrosis factor α relative to subcutaneous ASCs. These findings highlight, that both ASC subpopulations share multiple cellular features, but significantly differ in their functions. The functional diversity of ASCs depends on their origin, cellular context and surrounding microenvironment within adipose tissues. The data provide important insight into the biology of ASCs, which might be useful in choosing the adequate ASC subpopulation for regenerative therapies.
IL-27 regulates inflammatory diseases by exerting a pleiotropic impact on immune cells. In cancer, IL-27 restricts tumor growth by acting on tumor cells directly, while its role in the tumor microenvironment is still controversially discussed. To explore IL-27 signaling in the tumor stroma, we used a mammary carcinoma syngraft approach in IL27Rα-deficient mice. Tumor growth in animals lacking IL27Rα was markedly reduced. We noticed a decrease in immune cell infiltrates, enhanced tumor cell death, and fibroblast accumulation. However, most striking changes pertain the tumor vasculature. Tumors in IL27Rα-deficient mice were unable to form functional vessels. Blocking IL-27-STAT1 signaling in endothelial cells in vitro provoked an overshooting migration/sprouting of endothelial cells. Apparently, the lack of the IL-27 receptor caused endothelial cell hyper-activation via STAT1 that limited vessel maturation. Our data reveal a so far unappreciated role of IL-27 in endothelial cells with importance in pathological vessel formation.
Chemotherapy, nerve injuries, or diseases like multiple sclerosis can cause pathophysiological processes of persistent and neuropathic pain. Thereby, the activation threshold of ion channels is reduced in peripheral sensory neurons to normally noxious stimuli like heat, cold, acid, or mechanical due to sensitization processes. This leads to enhanced neuronal activity, which can result in mechanical allodynia, cold allodynia, thermal hyperalgesia, spontaneous pain, and may initiate persistent and neuropathic pain. The treatment options for persistent and neuropathic pain patients are limited; for about 50% of them, current medication is not efficient due to severe side effects or low response to the treatment. Therefore, it is of special interest to find additional treatment strategies. One approach is the control of neuronal sensitization processes. Herein, signaling lipids are crucial mediators and play an important role during the onset and maintenance of pain. As preclinical studies demonstrate, lipids may act as endogenous ligands or may sensitize transient receptor potential (TRP)-channels. Likewise, they can cause enhanced activity of sensory neurons by mechanisms involving G-protein coupled receptors and activation of intracellular protein kinases. In this regard, oxidized metabolites of the essential fatty acid linoleic acid, 9- and 13-hydroxyoctadecadienoic acid (HODE), their dihydroxy-metabolites (DiHOMEs), as well as epoxides of linoleic acid (EpOMEs) and of arachidonic acid (EETs), as well as lysophospholipids, sphingolipids, and specialized pro-resolving mediators (SPMs) have been reported to play distinct roles in pain transmission or inhibition. Here, we discuss the underlying molecular mechanisms of the oxidized linoleic acid metabolites and eicosanoids. Furthermore, we critically evaluate their role as potential targets for the development of novel analgesics and for the treatment of persistent or neuropathic pain.
Introduction: MRI-targeted biopsy (TB) increases overall prostate-cancer (PCa) detection-rates and decreases the risk of insignificant PCa detection. However, the impact of these findings on the definite pathology after radical prostatectomy (RP) is under debate.
Materials and Methods: Between 01/2014 and 12/2018, 366 patients undergoing prostate biopsy and RP were retrospectively analyzed. The correlation between biopsy Gleason-score (highest Gleason-score in a core) and the RP Gleason-score in patients undergoing systematic biopsy (SB-group) (n = 221) or TB+SB (TB-group, n = 145) was tested using the ISUP Gleason-group grading (GGG, scale 1–5). Sub analyses focused on biopsy GGG 1 and GGG ≥ 2.
Results: Proportions of biopsy GGG 1–5 in the SB-group and TB-group were 24.4, 37.6, 19, 10.9, 8.1% and 13.8, 43.4, 24.2, 13.8, 4.8%, respectively (p = 0.07). Biopsy and pathologic GGG were concordant in 108 of 221 (48.9%) in SB- and 74 of 145 (51.1%) in TB-group (p = 0.8). Gleason upgrading was recorded in 33.5 and 31.7% in SB- vs. TB-group (p = 0.8). Patients with biopsy GGG 1 undergoing RP showed an upgrading in 68.5%(37/54) in SB- and 75%(15/20) in TB-group (p = 0.8). In patients with biopsy GGG ≥ 2 concordance increased for both biopsy approaches (54.5 vs. 55.2% for SB- vs. TB-group, p = 0.9).
Discussion: Irrespective of differences in PCa detection-rates between TB- and SB-groups, no significant differences in GGG concordance and upgrading between patients of both groups undergoing biopsy, followed by RP, were recorded. Concordance rates increased in men with biopsy GGG ≥ 2. TB seems to detect more patients with PCa without a difference in concordance with final pathology.
Video and image data are regularly used in the field of benthic ecology to document biodiversity. However, their use is subject to a number of challenges, principally the identification of taxa within the images without associated physical specimens. The challenge of applying traditional taxonomic keys to the identification of fauna from images has led to the development of personal, group, or institution level reference image catalogues of operational taxonomic units (OTUs) or morphospecies. Lack of standardisation among these reference catalogues has led to problems with observer bias and the inability to combine datasets across studies. In addition, lack of a common reference standard is stifling efforts in the application of artificial intelligence to taxon identification. Using the North Atlantic deep sea as a case study, we propose a database structure to facilitate standardisation of morphospecies image catalogues between research groups and support future use in multiple front-end applications. We also propose a framework for coordination of international efforts to develop reference guides for the identification of marine species from images. The proposed structure maps to the Darwin Core standard to allow integration with existing databases. We suggest a management framework where high-level taxonomic groups are curated by a regional team, consisting of both end users and taxonomic experts. We identify a mechanism by which overall quality of data within a common reference guide could be raised over the next decade. Finally, we discuss the role of a common reference standard in advancing marine ecology and supporting sustainable use of this ecosystem.
Fibrogenesis is a progressive scarring event resulting from disrupted regular wound healing due to repeated tissue injury and can end in organ failure, like in liver cirrhosis. The protagonists in this process, either liver-resident cells or patrolling leukocytes attracted to the site of tissue damage, interact with each other by soluble factors but also by direct cell-cell contact mediated by cell adhesion molecules. Since cell adhesion molecules also support binding to the extracellular matrix, they represent excellent biosensors, which allow cells to modulate their behavior based on changes in the surrounding microenvironment. In this review, we focus on selectins, cadherins, integrins and members of the immunoglobulin superfamily of adhesion molecules as well as some non-classical cell adhesion molecules in the context of hepatic fibrosis. We describe their liver-specific contributions to leukocyte recruitment, cell differentiation and survival, matrix remodeling or angiogenesis and touch on their suitability as targets in antifibrotic therapies.
Acetylcholine (ACh) is the major excitatory neurotransmitter in the insect central nervous system (CNS). However, besides the neuronal expression of ACh receptors (AChR), the existence of non-neuronal AChR in honeybees is plausible. The cholinergic system is a popular target of insecticides because the pharmacology of insect nicotinic acetylcholine receptors (nAChRs) differs substantially from their vertebrate counterparts. Neonicotinoids are agonists of the nAChR and are largely used in crop protection. In contrast to their relatively high safety for humans and livestock, neonicotinoids pose a threat to pollinating insects such as bees. In addition to its effects on behavior, it becomes increasingly evident that neonicotinoids affect developmental processes in bees that appear to be independent of neuronal AChRs. Brood food (royal jelly, worker jelly, or drone jelly) produced in the hypopharyngeal glands of nurse bees contains millimolar concentrations of ACh, which is required for proper larval development. Neonicotinoids reduce the secreted ACh-content in brood food, reduce hypopharyngeal gland size, and lead to developmental impairments within the colony. We assume that potential hazards of neonicotinoids on pollinating bees occur neuronally causing behavioral impairments on adult individuals, and non-neuronally causing developmental disturbances as well as destroying gland functioning.
Background: Recent research has shown an increased risk of accidents and injuries in ADHD patients, which could potentially be reduced by stimulant treatment. Therefore, the first aim of our study was to evaluate the prevalence of adult ADHD in a trauma surgery population. The second aim was to investigate accident mechanisms and circumstances which could be specific to ADHD patients, in comparison to the general population.
Methods: We screened 905 accident victims for ADHD using the ASRS 18-item self-report questionnaire. The basic demographic data and circumstances of the accidents were also assessed.
Results: Prevalence of adult ADHD was found to be 6.18% in our trauma surgery patient sample. ADHD accident victims reported significantly higher rates of distraction, stress and overconfidence in comparison to non-ADHD accident victims. Overconfidence and being in thoughts as causal mechanisms for the accidents remained significantly higher in ADHD patients after correction for multiple comparison. ADHD patients additionally reported a history of multiple accidents.
Conclusion: The majority of ADHD patients in our sample had not previously been diagnosed and were therefore not receiving treatment. The results subsequently suggest that general ADHD screening in trauma surgery patients may be useful in preventing further accidents in ADHD patients. Furthermore, psychoeducation regarding specific causal accident mechanisms could be implemented in ADHD therapy to decrease accident incidence rate.
Cerebral radiation necrosis is a common complication of the radiotherapy of brain tumours that can cause significant mortality. Corticosteroids are the standard of care, but their efficacy is limited and the consequences of long-term steroid therapy are problematic, including the risk of adrenal insufficiency (AI). Off-label treatment with the vascular endothelial growth factor A antibody bevacizumab is highly effective in steroid-resistant radiation necrosis. Both the preservation of neural tissue integrity and the cessation of steroid therapy are key goals of bevacizumab treatment. However, the withdrawal of steroids may be impossible in patients who develop AI. In order to elucidate the frequency of AI in patients with cerebral radiation necrosis after treatment with corticosteroids and bevacizumab, we performed a retrospective study at our institution’s brain tumour centre. We obtained data on the tumour histology, age, duration and maximum dose of dexamethasone, radiologic response to bevacizumab, serum cortisol, and the need for hydrocortisone substitution for AI. We identified 17 patients with cerebral radiation necrosis who had received treatment with bevacizumab and had at least one available cortisol analysis. Fifteen patients (88%) had a radiologic response to bevacizumab. Five of the 17 patients (29%) fulfilled criteria for AI and required hormone substitution. Age, duration of dexamethasone treatment, and time since radiation were not statistically associated with the development of AI. In summary, despite the highly effective treatment of cerebral radiation necrosis with bevacizumab, steroids could yet not be discontinued due to the development of AI in roughly one-third of patients. Vigilance to spot the clinical and laboratory signs of AI and appropriate testing and management are, therefore, mandated.
Attractiveness ratings for musicians and non-musicians: An evolutionary-psychology perspective
(2019)
From an evolutionary perspective, musical behavior such as playing an instrument can be considered as part of an individual’s courting behavior. Playing a musical instrument or singing might fulfill a function similar to that of a bird’s colored feathers: attracting attention. Therefore, musicians may be rated as more attractive than non-musicians. In an online survey, 137 volunteers (95 female) with ages ranging from 16 to 39 years rated the attractiveness of fictitious persons of the opposite sex described in short verbal profiles. These profiles differed with respect to whether the described person made music or not. Additionally, the musicians’ profiles varied with regard to whether the described person played music or sang in public or in private only. Results show that musicians’ profiles were not generally rated as more attractive than non-musicians’, but attractiveness did vary according to setting: private musicians were rated as most attractive, followed by non-musicians and public musicians. Furthermore, results indicate that participants who played a musical instrument or sang themselves gave higher ratings to profiles of musicians. But for participants who do not make music themselves, higher attractiveness ratings for musicians playing instruments or sing in private settings were found. These results indicate that the impression of sharing a common interest (making music) and furthermore making music in private instrumental settings seems to make people attractive to other people. No additional support for the sexual selection hypotheses for the evolution of music was provided by the current results. The musical status of the rater affected his or her judgements, with musicians rating other people as more attractive if they share the common interest in making music. Not the display of being a musician seems to be critical for attractiveness ratings but the perceived or imagined similarity by the rater created by information on musicality, fostering the theoretical significance of the communication aspect of music.
Neurobiological systems rely on hierarchical and modular architectures to carry out intricate computations using minimal resources. A prerequisite for such systems to operate adequately is the capability to reliably and efficiently transfer information across multiple modules. Here, we study the features enabling a robust transfer of stimulus representations in modular networks of spiking neurons, tuned to operate in a balanced regime. To capitalize on the complex, transient dynamics that such networks exhibit during active processing, we apply reservoir computing principles and probe the systems' computational efficacy with specific tasks. Focusing on the comparison of random feed-forward connectivity and biologically inspired topographic maps, we find that, in a sequential set-up, structured projections between the modules are strictly necessary for information to propagate accurately to deeper modules. Such mappings not only improve computational performance and efficiency, they also reduce response variability, increase robustness against interference effects, and boost memory capacity. We further investigate how information from two separate input streams is integrated and demonstrate that it is more advantageous to perform non-linear computations on the input locally, within a given module, and subsequently transfer the result downstream, rather than transferring intermediate information and performing the computation downstream. Depending on how information is integrated early on in the system, the networks achieve similar task-performance using different strategies, indicating that the dimensionality of the neural responses does not necessarily correlate with nonlinear integration, as predicted by previous studies. These findings highlight a key role of topographic maps in supporting fast, robust, and accurate neural communication over longer distances. Given the prevalence of such structural feature, particularly in the sensory systems, elucidating their functional purpose remains an important challenge toward which this work provides relevant, new insights. At the same time, these results shed new light on important requirements for designing functional hierarchical spiking networks.
Gravitational waves, electromagnetic radiation, and the emission of high energy particles probe the phase structure of the equation of state of dense matter produced at the crossroad of the closely related relativistic collisions of heavy ions and of binary neutron stars mergers. 3 + 1 dimensional special- and general relativistic hydrodynamic simulation studies reveal a unique window of opportunity to observe phase transitions in compressed baryon matter by laboratory based experiments and by astrophysical multimessenger observations. The astrophysical consequences of a hadron-quark phase transition in the interior of a compact star will be focused within this article. Especially with a future detection of the post-merger gravitational wave emission emanated from a binary neutron star merger event, it would be possible to explore the phase structure of quantum chromodynamics. The astrophysical observables of a hadron-quark phase transition in a single compact star system and binary hybrid star merger scenario will be summarized within this article. The FAIR facility at GSI Helmholtzzentrum allows one to study the universe in the laboratory, and several astrophysical signatures of the quark-gluon plasma have been found in relativistic collisions of heavy ions and will be explored in future experiments.
Within the last decades, western democracies have experienced a rise of inequality, with the gap between lower and upper class citizens steadily increasing and a widespread sentiment of growing inequalities also in the political sphere. Against this background, and in the context of the current “crisis of democracy”, democratic innovations such as direct democratic instruments are discussed as a very popular means to bring citizens back in. However, research on direct democracy has produced rather inconsistent results with regard to the question of which effects referenda and initiatives have on equality. Studies in this field are often limited to single countries and certain aspects of equality. Moreover, most existing studies look at the mere availability of direct democratic instruments instead of actual bills that are put to a vote. This paper aims to take a first step to fill these gaps by giving an explorative overview of the outputs of direct democratic bills on multiple equality dimensions, analyzing all national referenda and initiatives in European democracies between 1990 and 2015. How many pro- and contra-equality bills have been put to a vote, how many of those succeeded at the ballot, and are there differences between country groups? Our findings show that a majority of direct democratic bills was not related to equality at all. Regarding the successful bills, we detect some regional differences along with the general tendency that there are more pro- than contra-equality bills. Our paper sheds new light on the question if direct democracy can serve as an appropriate means to complement representative democracy and to shape democratic institutions in the future. The potential of direct democracy in fostering or impeding equality should be an important criterion for the assessment of claims to extend decision-making by citizens.
Organized running events have gained substantial popularity. This study aimed to elucidate the prevalence of musculoskeletal pain, knowledge about injury prevention as well as the attitudes and motivations of individuals participating in the JP Morgan Corporate Challenge in Frankfurt (Germany). A total of 720 recreational runners completed a digital questionnaire immediately prior to the start. The majority of them displayed low to moderate physical activity levels and were rather unambitious regarding targeted finishing time. One quarter (25.3%) participated for the first time in an organized race. The most stated reasons to register were team building (76.4%) and experiencing the run’s atmosphere (50.6%). In contrast, improving health played a minor role (19.4%). More than one in five individuals (n = 159 runners) reported pain, with the most common locations being the knee and lower back. Both at rest (3.2/10 on a numerical rating scale) and during activity (4.7/10), average pain intensity was clinically relevant. Almost three thirds of the participants believed that stretching and wearing appropriate shoes would be effective for injury prevention while other methods such as resistance training, balance exercise or wearing of orthoses were rarely named. Musculoskeletal pain is a significant burden in runners participating in an urban mass event. In view of the poor knowledge about injury prevention, organizers and coaches may consider offering structured preparation programs as well as tailored running-related health education.
We investigate the default probability, recovery rates and loss distribution of a portfolio of securitised loans granted to Italian small and medium enterprises (SMEs). To this end, we use loan level data information provided by the European DataWarehouse platform and employ a logistic regression to estimate the company default probability. We include loan-level default probabilities and recovery rates to estimate the loss distribution of the underlying assets. We find that bank securitised loans are less risky, compared to the average bank lending to small and medium enterprises.
Detection of antihypertensive drugs in biological samples is an important tool to assess the adherence of hypertensive patients. Urine and serum/plasma screenings based on qualitative results may lead to misinterpretations regarding drugs with a prolonged detectability. The aim of the present study was to develop a method that can be used for therapeutic drug monitoring (TDM) of antihypertensive drugs with focus on adherence assessment. Therefore, a method for quantification of four diuretics and four β-blockers using high-performance liquid chromatography-mass spectrometric analysis (LC-MS/MS) of combined acidic and basic serum extracts was developed and validated. The method was applied to 40 serum samples from 20 patients in a supervised medication setting (trough and peak serum samples). Literature data on therapeutic concentration ranges, as well as dose-related drug concentrations (calculated from data of pharmacokinetic studies) were used to evaluate adherence assessment criteria. Concentrations were measured for bisoprolol (n = 9 patients), metoprolol (n = 7), nebivolol (n = 1), canrenone (n = 2, metabolite of spironolactone), hydrochlorothiazide (n = 10) and torasemide (n = 8). The measured concentrations were within the therapeutic reference ranges, except for 24% of the samples (mainly β-blockers). In contrast, all measured concentrations were above the lower dose-related concentration (DRC), which appears superior in evaluating adherence. In conclusion, the quantitative analysis of antihypertensive drugs in serum samples and its evaluation on the basis of the individually calculated lower DRC is a promising tool to differentially assess adherence. This method could possibly detect a lack of adherence or other causes of insufficient therapy more reliably than qualitative methods.
Five hundred years ago, Hernán Cortés launched his invasion of Mexico (1519–1521), which culminated in the fall of Tenochtitlán. A little over a decade later, the Inca realm was destroyed by Francisco Pizarro’s clan in Peru (1532–1533). The decisive factors and myths of the Spanish "conquests" are treated in the pertinent historiography. Recent literature has had less to say on the subsequent phase of early colonial history, when the Castilian Crown and its representatives in the "New World" tried to reinforce their dominance – essentially against the interests of the first generation of conquistadores. This tumultuous period is the subject of Gregorio Salinero’s book, which re-examines disobediences, political trials and governance in Spanish America, as the subtitle reads. It is an augmented version of Salinero’s La trahison de Cortés (Paris 2014), now skillfully translated into Spanish by Manuela Águeda García Garrido. The author, professor of history at the Université Paris 1 Panthéon-Sorbonne, is well known for his research on transatlantic relations between Spain and Spanish America. ...
Konstitutionalisierung, Europäisierung, Internationalisierung … So viele bestehende oder sich abzeichnende Tendenzen, die durch ihre Neuheit bestechen und durch ihre Dynamik Interesse erwecken. Doch, wie Jean-Claude Gautron gerne seinen Doktoranden zu verstehen gibt, "nicht alles, was glänzt, ist Gold", eine Einstellung, die sich auch in seiner eigenen Haltung der "kritischen Betrachtung Europas durch einen Europarechtler" widerspiegelt. Ihn durch den Versuch zu würdigen, die Verwendung bestimmter Begriffe zu beleuchten, ist daher nicht unangemessen. ...
Gezielte Früherkennung am Beispiel des Deutschen Konsortiums Familiärer Brust- und Eierstockkrebs / Rita Schmutzler
Modelle für eine erfolgreiche, risikoadaptierte Therapie –
am Beispiel der akuten lymphatischen Leukämie / Nicola Gökbuget
Modelle für eine erfolgreiche, risikoadaptierte Therapie –
am Beispiel des Hodgkin-Lymphoms / Andreas Engert
Modelle für eine erfolgreiche, risikoadaptierte Therapie –
am Beispiel der Keimzelltumoren des Mannes / Carsten Bokemeyer