An analysis of the relationship of school entrance age to mental age and school achievement in grade one.

Thesis (Ed.M.)--Boston Universit

Accelerated epigenetic aging in Werner syndrome.

Individuals suffering from Werner syndrome (WS) exhibit many clinical signs of accelerated aging. While the underlying constitutional mutation leads to accelerated rates of DNA damage, it is not yet known whether WS is also associated with an increased epigenetic age according to a DNA methylation based biomarker of aging (the "Epigenetic Clock"). Using whole blood methylation data from 18 WS cases and 18 age matched controls, we find that WS is associated with increased extrinsic epigenetic age acceleration (p=0.0072) and intrinsic epigenetic age acceleration (p=0.04), the latter of which is independent of age-related changes in the composition of peripheral blood cells. A multivariate model analysis reveals that WS is associated with an increase in DNA methylation age (on average 6.4 years, p=0.011) even after adjusting for chronological age, gender, and blood cell counts. Further, WS might be associated with a reduction in naïve CD8+ T cells (p=0.025) according to imputed measures of blood cell counts. Overall, this study shows that WS is associated with an increased epigenetic age of blood cells which is independent of changes in blood cell composition. The extent to which this alteration is a cause or effect of WS disease phenotypes remains unknown

"You are too much mistaken in this king"

Henry V., das berühmte Stück Shakespeares wurde im Laufe des 20. Jahrhunderts von zwei namhaften Regisseuren verfilmt, nämlich Laurence Olivier (1944) und Kenneth Branagh (1989). Auf der Analyse beider Filme lag der Schwerpunkt dieser Arbeit, gefolgt von einem Überblick über die historischen Begebenheiten zu Beginn des 15. Jahrhunderts zur Zeit dieses englischen Königs. Das Originalstück des Autors enthielt schon zu seiner Entstehungszeit einige Ungereimtheiten, zum Beispiel der Anspruch auf den französischen Thron oder der Kampf verschiedener Nationen gegen einen gemeinsamen Feind, die maßgeblich von der Tudor-Geschichtsschreibung beeinflusst wurden. Olivier hält sich an Shakespeares Vorgaben und präsentiert uns die Hauptfigur als fehlerfreien, christlichen König, der zu keiner Zeit Zweifel an seinem Vorhaben hat. Er ist ein verantwortungsvoller Anführer seiner Truppen und weiß genau, wie die Franzosen zu schlagen sind. Dass Olivier dabei einige Szenen des Stückes kürzt, um diese einwandfreie Darstellung zu erreichen, ist im Film nicht ersichtlich. Seine Interpretation der Schlacht widerspricht vielen historischen Aufzeichnungen, die uns überlieferten, dass kurz vor Beginn der Schlacht schlechtes Wetter und starker Regen herrschte, der das Schlachtfeld zu einer Art Sumpf werden ließ und somit die Ausgangslage für die Franzosen verschlechterte. In dieser Verfilmung findet sich jedoch kein Wölkchen am Himmel und auch die Kampfszenen sind sehr sauber und mit wenig Verletzten und Toten dargestellt, obwohl wir wissen, dass die Schlacht tausende Opfer forderte. Der Film von 1944 orientiert sich sehr stark an einer Theaterproduktion im Globe Theatre z.B. der Blick hinter die Kulissen. Olivier nimmt wenig Rücksicht auf eventuelle historische Begebenheiten, sondern kreiert seine eigene makellose Interpretation des englischen Königs. Oliviers Heinrich entspricht somit der Geschichtsschreibung zur Zeit Shakespeares, die Heinrich als christlichen und fehlerfreien Anführer darstellt, der sich gegen die zahlenmäßig überlegenen Franzosen durchsetzen kann. Kenneth Branaghs Film ist im Vergleich zu Oliviers eine düstere Mittelalter- Verfilmung, die uns einen von Zweifeln gezeichneten, empfindlichen Heinrich präsentiert. Aber auch er hält sich nicht genau an den Originaltext, sondern kürzt an verschiedenen Stellen. Branaghs Heinrich entspricht hierbei weniger den Vorstellungen der Geschichtsschreibung, die von einem entschlossenen König ausgeht, der zwar anfangs keine konkreten Pläne hat, aber sich durchaus bewusst war, auf welches Vorhaben er sich einlässt. Aufgrund seiner Erfahrung aus Jugendjahren war die geplante Invasion für den König nichts Neues, da er bereits in jungen Jahren einige Feldzüge angeführt hatte. Zwar finden wir im Stück von Shakespeare Anspielungen auf Zweifel des Königs, die sich aber nicht direkt auf die Umsetzung seiner Pläne beziehen, sondern auf die Opfer, die dieser Feldzug mit sich bringen würde. Dafür ist Branaghs Darstellungsweise der Schlacht von Agincourt viel näher an jenen Erzählungen, die uns sowohl von englischer, als auch von französischer Seite aus der damaligen Zeit erhalten sind. Wir wissen heute, dass es damals geregnet hatte und der Boden des Schlachtfeldes aufgeweicht war. Die Erzählungen aus dem 15. Jahrhundert sprechen von einer Vielzahl an Opfern, vor allem auf französischer Seite. Branaghs Schlacht kommt den Beschreibungen sehr nahe, da er uns viel Blut, Verletzte, Tote und auch viel Matsch und Dreck präsentiert. Beide Filme legen bei der Umsetzung der Schlachtszenen großen Wert, die Bedeutung der englischen Bogenschützen hervorzuheben und folgen somit den historischen Gegebenheiten, da auch die Geschichtsschreibung den Bogenschützen eine wichtige Rolle zuschreibt. Bei der Darstellung der Franzosen unterscheiden sich die beiden Produktionen allerdings wieder. Olivier zeigt uns arrogante und überhebliche Franzosen, deren geistig verwirrter König nicht mehr viel zu befehlen hat. Es fehlt den Franzosen an Organisation und Zusammenhalt, da jeder nur an sein eigenes Wohl zu denken scheint. Man weiß heute, dass Karl VI., der französische König, zu Wutausbrüchen neigte und eine sehr zerstreute und unsichere Persönlichkeit war. Auch der Streit unter den Franzosen entsprach der damaligen innerpolitischen Situation. Diese beiden Aspekte trugen zu jener Zeit unter anderem zu Heinrichs Erfolg bei. Bei Branaghs Interpretation ist die Geisteskrankheit Karls VI. für den Zuschauer nicht wahrnehmbar und die Gegner des englischen Volkes erscheinen als rational und vernünftig denkend. Allgemein ist zu sagen, dass sich beide Filme, trotz Änderungen, sehr stark am Stück Shakespeares orientieren. Beide Produktionen unterliegen Textkürzungen, aber an verschiedenen Textstellen. Branagh und Olivier nehmen zwar Rücksicht auf etwaige historische Begebenheiten, jedoch an unterschiedlichen Stellen des Films. Hierbei ist auch anzumerken, dass die beiden Filme von den eigenen historischen Ereignissen während der Entstehung maßgeblich beeinflusst wurden. Vor allem Oliviers Film, der gegen Ende des 2. Weltkriegs herausgebracht wurde und vom englischen Informationsministerium mitfinanziert wurde, wurde maßgeblich von den politischen Umständen zu jener Zeit geprägt. Bei Branagh war es der Falkland-Krieg und die daraus resultierende Frage ob er nun einen Kriegs- oder Antikriegsfilm produziert hatte. Zusammenfassend lässt sich feststellen, dass es schwierig ist aufgrund der unterschiedlichen technischen Möglichkeiten und historischen Hintergründe während der Entstehung, beide Verfilmungen miteinander zu vergleichen. Interessant sind dabei auch die verschiedenen Interpretationsweisen mit denen beide Regisseure den Film umsetzen, aber gerade dieser Aspekt machte meine Untersuchungen auch so spannend.My diploma thesis deals with the two film adaptations by Laurence Olivier (1944) and Kenneth Branagh (1989) of Shakespeare’s Henry V. The main focus lies on the analysis of the two movies followed by an overview of the historical events at the beginning of the 15th century during the reign of this prominent English king. The original play was already full of various inconsistencies by the time Shakespeare wrote it e.g. the questionable claim on the French throne or the fight of different nations against one enemy. The Tudor history writing had been responsible for most of these ambiguities. In his production, just released before D-Day in 1944, Laurence Olivier tries to keep partly to Shakespeare’s original. Henry is represented as an accurate, Christian King who has never had any doubts about his plan. So the passages where the audience might get doubts about his Christianity e.g. when he orders the murder of the French soldiers, were cut. In Olivier’s movie the English king takes responsibility for his actions and knows exactly how to beat the French in battle. Although his presentation of the king is close to historical accounts Olivier’s version of the battle of Agincourt appears rather artificial. It is generally known that just before the battle began bad weather and rain had made conditions worse on the field especially for the French. We also know that a great number of soldiers, mainly on the French side, died or were wounded, which cannot be found in Olivier’s film. His film takes the Globe Theatre in London as a role model. So the whole film reminds the viewers much more of a theatre production than of an actual movie. Olivier didn’t take the historical details very much into consideration but rather created his own perfect and clean interpretation of the king. His representation of Henry corresponds much more to Tudor history writing which has been responsible for the positive and admirable image of the king. In comparison to the former Kenneth Branagh’s production is a rather dark and mysterious film about the Middle Ages because of the gloomy props and the big amount of blood the viewers come across. Branagh also does not keep to the original text but shortens and changes several passages. In contrast to his predecessor his Henry is interpreted differently as the king is much more sensitive and in doubts about his plans. The director shows us a king that is not so sure about his plans. This does not follow the general assumption of most historians nowadays. Henry had already acquired some experience during several campaigns in his teens. So the invasion planned was not something completely new for him. Although we find some hints in Shakespeare’s play about various doubts they were more concerned with the tragic consequences of warfare and did not directly affect his plans. Still his presentation of the battle is much more realistic than Olivier’s. He takes into account the various circumstances e.g. the weather that several narrators who were present at the battle scene report. In addition he shows a lot of blood, lots of wounded and dead soldiers which also follows the 15th century accounts. Both Olivier and Branagh try to emphasize the importance of the archers during the fighting. It is known that the archers contributed largely to the victory of the English. In general Branagh delivers the audience a more realistic and rational presentation of the battle. Considering the portrayal of the French the two films contract each other again. Olivier shows us arrogant and bigheaded French soldiers who are confident about their victory. Charles VI., the French king, is a rather weak and absent-minded character. There is no unity among the French who are more concerned with their own welfare. This follows the general historical accounts that inform us about a confused king who tended to have outbursts of fury quite often. This mental disease cannot be found in Branagh’s production. Instead he presents us a worthy enemy who knows what he is doing and acts reasonably and rationally. In general it can be said that both films follow Shakespeare’s original play but cut out several scenes and passages. Especially Olivier cuts those scenes in which Henry shows some hardness e.g. the killing of his friend Bardolph or the order to cut the French soldier’s throat. He does that in order to keep the Christian and accurate picture of the English king. Branagh and Olivier try to follow historical facts but do this at different points in the film. It also has to be taken into consideration that both films have been influenced by the historical circumstances at the time of the production. Especially Olivier’s film was affected by the general spirit at the end of World War II: His intention was to encourage the English soldiers with the help of the film which was released just a short time after D-Day. Branagh’s production, which was released at the end of the 1980s, was associated with the Falkland-War. Critics could not decide if they should interpret his version as a war- or antiwar film. Considering all the various aspects of both films it had been difficult to compare them due to the different methods of production and political backgrounds. Both creators use divergent means of interpretation in order to realize their ideas. This makes both films nearly non-comparable although if you have seen both you automatically start to evaluate and draw comparisons. Still this was the hardest but most interesting point during my whole research

Impact of Short-Term Isoflavone Intervention in Polycystic Ovary Syndrome (PCOS) Patients on Microbiota Composition and Metagenomics

Background: Polycystic ovary syndrome (PCOS) affects 5–20% of women of reproductive age worldwide and is associated with disorders of glucose metabolism. Hormone and metabolic signaling may be influenced by phytoestrogens, such as isoflavones. Their endocrine effects may modify symptom penetrance in PCOS. Equol is one of the most active isoflavone metabolites, produced by intestinal bacteria, and acts as a selective estrogen receptor modulator. Method: In this interventional study of clinical and biochemical characterization, urine isoflavone levels were measured in PCOS and control women before and three days after a defined isoflavone intervention via soy milk. In this interventional study, bacterial equol production was evaluated using the log(equol: daidzein ratio) and microbiome, metabolic, and predicted metagenome analyses were performed. Results: After isoflavone intervention, predicted stool metagenomic pathways, microbial alpha diversity, and glucose homeostasis in PCOS improved resembling the profile of the control group at baseline. In the whole cohort, larger equol production was associated with lower androgen as well as fertility markers. Conclusion: The dynamics in our metabolic, microbiome, and predicted metagenomic profiles underline the importance of external phytohormones on PCOS characteristics and a potential therapeutic approach or prebiotic in the future

Harnessing Dendritic Cells for Poly (D,L-lactide-co-glycolide) Microspheres (PLGA MS)—Mediated Anti-tumor Therapy

With emerging success in fighting off cancer, chronic infections, and autoimmune diseases, immunotherapy has become a promising therapeutic approach compared to conventional therapies such as surgery, chemotherapy, radiation therapy, or immunosuppressive medication. Despite the advancement of monoclonal antibody therapy against immune checkpoints, the development of safe and efficient cancer vaccine formulations still remains a pressing medical need. Anti-tumor immunotherapy requires the induction of antigen-specific CD8+ cytotoxic T lymphocyte (CTL) responses which recognize and specifically destroy tumor cells. Due to the crucial role of dendritic cells (DCs) in initiating anti-tumor immunity, targeting tumor antigens to DCs has become auspicious in modern vaccine research. Over the last two decades, micron- or nanometer-sized particulate delivery systems encapsulating tumor antigens and immunostimulatory molecules into biodegradable polymers have shown great promise for the induction of potent, specific and long-lasting anti-tumor responses in vivo. Enhanced vaccine efficiency of the polymeric micro/nanoparticles has been attributed to controlled and continuous release of encapsulated antigens, efficient targeting of antigen presenting cells (APCs) such as DCs and subsequent induction of CTL immunity. Poly (D, L-lactide-co-glycolide) (PLGA), as one of these polymers, has been extensively studied for the design and development of particulate antigen delivery systems in cancer therapy. This review provides an overview of the current state of research on the application of PLGA microspheres (PLGA MS) as anti-tumor cancer vaccines in activating and potentiating immune responses attempting to highlight their potential in the development of cancer therapeutics

Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca2+ signalling

Retraction of mesenchymal stromal cells supports the invasion of colorectal cancer cells (CRC) into the adjacent compartment. CRC-secreted 12(S)-HETE enhances the retraction of cancer-associated fibroblasts (CAFs) and therefore, 12(S)-HETE may enforce invasivity of CRC. Understanding the mechanisms of metastatic CRC is crucial for successful intervention. Therefore, we studied pro-invasive contributions of stromal cells in physiologically relevant three-dimensional in vitro assays consisting of CRC spheroids, CAFs, extracellular matrix and endothelial cells, as well as in reductionist models. In order to elucidate how CAFs support CRC invasion, tumour spheroid-induced CAF retraction and free intracellular Ca2+ levels were measured and pharmacological-or siRNA-based inhibition of selected signalling cascades was performed. CRC spheroids caused the retraction of CAFs, generating entry gates in the adjacent surrogate stroma. The responsible trigger factor 12(S)-HETE provoked a signal, which was transduced by PLC, IP3, free intracellular Ca2+, Ca(2+)calmodulin-kinase-II, RHO/ROCK and MYLK which led to the activation of myosin light chain 2, and subsequent CAF mobility. RHO activity was observed downstream as well as upstream of Ca2+ release. Thus, Ca2+ signalling served as central signal amplifier. Treatment with the FDA-approved drugs carbamazepine, cinnarizine, nifedipine and bepridil HCl, which reportedly interfere with cellular calcium availability, inhibited CAF-retraction. The elucidation of signalling pathways and identification of approved inhibitory drugs warrant development of intervention strategies targeting tumour-stroma interaction

High-throughput bioprinting of the nasal epithelium using patient-derived nasal epithelial cells.

Progenitor human nasal epithelial cells (hNECs) are an essential cell source for the reconstruction of the respiratory pseudostratified columnar epithelium composed of multiple cell types in the context of infection studies and disease modeling. Hitherto, manual seeding has been the dominant method for creating nasal epithelial tissue models through biofabrication. However, this approach has limitations in terms of achieving the intricate three-dimensional (3D) structure of the natural nasal epithelium. 3D bioprinting has been utilized to reconstruct various epithelial tissue models, such as cutaneous, intestinal, alveolar, and bronchial epithelium, but there has been no attempt to use of 3D bioprinting technologies for reconstruction of the nasal epithelium. In this study, for the first time, we demonstrate the reconstruction of the nasal epithelium with the use of primary hNECs deposited on Transwell inserts via droplet-based bioprinting (DBB), which enabled high-throughput fabrication of the nasal epithelium in Transwell inserts of 24-well plates. DBB of progenitor hNECs ranging from one-tenth to one-half of the cell seeding density employed during the conventional cell seeding approach enabled a high degree of differentiation with the presence of cilia and tight-junctions over a 4 weeks air-liquid interface culture. Single cell RNA sequencing of these cultures identified five major epithelial cells populations, including basal, suprabasal, goblet, club, and ciliated cells. These cultures recapitulated the pseudostratified columnar epithelial architecture present in the native nasal epithelium and were permissive to respiratory virus infection. These results denote the potential of 3D bioprinting for high-throughput fabrication of nasal epithelial tissue models not only for infection studies but also for other purposes, such as disease modeling, immunological studies, and drug screening