The concept of quasi-integrability for modified non-linear Schrodinger models

We consider modifications of the nonlinear Schrodinger model (NLS) to look at the recently introduced concept of quasi-integrability. We show that such models possess an in finite number of quasi-conserved charges which present intriguing properties in relation to very specific space-time parity transformations. For the case of two-soliton solutions where the fields are eigenstates of this parity, those charges are asymptotically conserved in the scattering process of the solitons. Even though the charges vary in time their values in the far past and the far future are the same. Such results are obtained through analytical and numerical methods, and employ adaptations of algebraic techniques used in integrable field theories. Our findings may have important consequences on the applications of these models in several areas of non-linear science. We make a detailed numerical study of the modified NLS potential of the form V similar to (vertical bar psi vertical bar(2))(2+epsilon), with epsilon being a perturbation parameter. We perform numerical simulations of the scattering of solitons for this model and find a good agreement with the results predicted by the analytical considerations. Our paper shows that the quasi-integrability concepts recently proposed in the context of modifications of the sine-Gordon model remain valid for perturbations of the NLS model.

Individualisierte Krebstherapie : präklinischer „proof of concept“ einer mutationsspezifischen Immuntherapie

Da nicht-synonyme tumorspezifische Punktmutationen nur in malignen Geweben vorkommen und das veränderte Proteinprodukt vom Immunsystem als „fremd“ erkannt werden kann, stellen diese einen bisher ungenutzten Pool von Zielstrukturen für die Immuntherapie dar. Menschliche Tumore können individuell bis zu tausenden nicht-synonymer Punktmutationen in ihrem Genom tragen, welche nicht der zentralen Immuntoleranz unterliegen. Ziel der vorliegenden Arbeit war die Hypothese zu untersuchen, dass das Immunsystem in der Lage sein sollte, mutierte Epitope auf Tumorzellen zu erkennen und zu klären, ob auf dieser Basis eine wirksame mRNA (RNA) basierte anti-tumorale Vakzinierung etabliert werden kann. Hierzu wurde von Ugur Sahin und Kollegen, das gesamte Genom des murinen B16-F10 Melanoms sequenziert und bioinformatisch analysiert. Im Rahmen der NGS Sequenzierung wurden mehr als 500 nicht-synonyme Punktmutationen identifiziert, von welchen 50 Mutationen selektiert und durch Sanger Sequenzierung validiert wurden. rnNach der Etablierung des immunologischen Testsysteme war eine Hauptfragestellung dieser Arbeit, die selektierten nicht-synonyme Punktmutationen in einem in vivo Ansatz systematisch auf Antigenität zu testen. Für diese Studien wurden mutierte Sequenzen in einer Länge von 27 Aminosäuren genutzt, in denen die mutierte Aminosäure zentral positioniert war. Durch die Länge der Peptide können prinzipiell alle möglichen MHC Klasse-I und -II Epitope abgedeckt werden, welche die Mutation enthalten. Eine Grundidee des Projektes Ansatzes ist es, einen auf in vitro transkribierter RNA basierten oligotopen Impfstoff zu entwickeln. Daher wurden die Impfungen naiver Mäuse sowohl mit langen Peptiden, als auch in einem unabhängigen Ansatz mit peptidkodierender RNA durchgeführt. Die Immunphänotypisierung der Impfstoff induzierten T-Zellen zeigte, dass insgesamt 16 der 50 (32%) mutierten Sequenzen eine T-Zellreaktivität induzierten. rnDie Verwendung der vorhergesagten Epitope in therapeutischen Vakzinierungsstudien bestätigten die Hypothese das mutierte Neo-Epitope potente Zielstrukturen einer anti-tumoralen Impftherapie darstellen können. So wurde in therapeutischen Tumorstudien gezeigt, dass auf Basis von RNA 9 von 12 bestätigten Epitopen einen anti-tumoralen Effekt zeigte.rnÜberaschenderweise wurde bei einem MHC Klasse-II restringierten mutiertem Epitop (Mut-30) sowohl in einem subkutanen, als auch in einem unabhängigen therapeutischen Lungenmetastasen Modell ein starker anti-tumoraler Effekt auf B16-F10 beobachtet, der dieses Epitop als neues immundominantes Epitop für das B16-F10 Melanom etabliert. Um den immunologischen Mechanismus hinter diesem Effekt näher zu untersuchen wurde in verschieden Experimenten die Rolle von CD4+, CD8+ sowie NK-Zellen zu verschieden Zeitpunkten der Tumorentwicklung untersucht. Die Analyse des Tumorgewebes ergab, eine signifikante erhöhte Frequenz von NK-Zellen in den mit Mut-30 RNA vakzinierten Tieren. Das NK Zellen in der frühen Phase der Therapie eine entscheidende Rolle spielen wurde anhand von Depletionsstudien bestätigt. Daran anschließend wurde gezeigt, dass im fortgeschrittenen Tumorstadium die NK Zellen keinen weiteren relevanten Beitrag zum anti-tumoralen Effekt der RNA Vakzinierung leisten, sondern die Vakzine induzierte adaptive Immunantwort. Durch die Isolierung von Lymphozyten aus dem Tumorgewebe und deren Einsatz als Effektorzellen im IFN-γ ELISPOT wurde nachgewiesen, dass Mut-30 spezifische T-Zellen das Tumorgewebe infiltrieren und dort u.a. IFN-γ sekretieren. Dass diese spezifische IFN-γ Ausschüttung für den beobachteten antitumoralen Effekt eine zentrale Rolle einnimmt wurde unter der Verwendung von IFN-γ -/- K.O. Mäusen bestätigt.rnDas Konzept der individuellen RNA basierten mutationsspezifischen Vakzine sieht vor, nicht nur mit einem mutations-spezifischen Epitop, sondern mit mehreren RNA-kodierten Mutationen Patienten zu impfen um der Entstehung von „escape“-Mutanten entgegenzuwirken. Da es nur Erfahrung mit der Herstellung und Verabreichung von Monotop-RNA gab, also RNA die für ein Epitop kodiert, war eine wichtige Fragestellungen, inwieweit Oligotope, welche die mutierten Sequenzen sequentiell durch Linker verbunden als Fusionsprotein kodieren, Immunantworten induzieren können. Hierzu wurden Pentatope mit variierender Position des einzelnen Epitopes hinsichtlich ihrer in vivo induzierten T-Zellreaktivitäten charakterisiert. Die Experimente zeigten, dass es möglich ist, unabhängig von der Position im Pentatop eine Immunantwort gegen ein Epitop zu induzieren. Des weiteren wurde beobachtet, dass die induzierten T-Zellfrequenzen nach Pentatop Vakzinierung im Vergleich zur Nutzung von Monotopen signifikant gesteigert werden kann.rnZusammenfassend wurde im Rahmen der vorliegenden Arbeit präklinisch erstmalig nachgewiesen, dass nicht-synonyme Mutationen eine numerisch relevante Quelle von Zielstrukturen für die anti-tumorale Immuntherapie darstellen. Überraschenderweise zeigte sich eine dominante Induktion MHC-II restringierter Immunantworten, welche partiell in der Lage waren massive Tumorabstoßungsreaktionen zu induzieren. Im Sinne einer Translation der gewonnenen Erkenntnisse wurde ein RNA basiertes Oligotop-Format etabliert, welches Eingang in die klinische Testung des Konzeptes fand.rn

Development of the Heat and Energy Concept Inventory: Preliminary Results on the Prevalence and Persistence of Engineering Students' Misconceptions

BACKGROUND Students frequently hold a number of misconceptions related to temperature, heat and energy. There is not currently a concept inventory with sufficiently high internal reliability to assess these concept areas for research purposes. Consequently, there is little data on the prevalence of these misconceptions amongst undergraduate engineering students. PURPOSE (HYPOTHESIS) This work presents the Heat and Energy Concept Inventory (HECI) to assess prevalent misconceptions related to: (1) Temperature vs. Energy, (2) Temperature vs. Perceptions of Hot and Cold, (3) Factors that affect the Rate vs. Amount of Heat Transfer and (4) Thermal Radiation. The HECI is also used to document the prevalence of misconceptions amongst undergraduate engineering students. DESIGN/METHOD Item analysis, guided by classical test theory, was used to refine individual questions on the HECI. The HECI was used in a one group, pre-test-post-test design to assess the prevalence and persistence of targeted misconceptions amongst a population of undergraduate engineering students at diverse institutions. RESULTS Internal consistency reliability was assessed using Kuder-Richardson Formula 20; values were 0.85 for the entire instrument and ranged from 0.59 to 0.76 for the four subcategories of the HECI. Student performance on the HECI went from 49.2% to 54.5% after instruction. Gains on each of the individual subscales of the HECI, while generally statistically significant, were similarly modest. CONCLUSIONS The HECI provides sufficiently high estimates of internal consistency reliability to be used as a research tool to assess students' understanding of the targeted concepts. Use of the instrument demonstrates that student misconceptions are both prevalent and resistant to change through standard instruction.

Internet based multicenter study for thoracolumbar injuries: a new concept and preliminary results

This article reports about the internet based, second multicenter study (MCS II) of the spine study group (AG WS) of the German trauma association (DGU). It represents a continuation of the first study conducted between the years 1994 and 1996 (MCS I). For the purpose of one common, centralised data capture methodology, a newly developed internet-based data collection system ( http://www.memdoc.org ) of the Institute for Evaluative Research in Orthopaedic Surgery of the University of Bern was used. The aim of this first publication on the MCS II was to describe in detail the new method of data collection and the structure of the developed data base system, via internet. The goal of the study was the assessment of the current state of treatment for fresh traumatic injuries of the thoracolumbar spine in the German speaking part of Europe. For that reason, we intended to collect large number of cases and representative, valid information about the radiographic, clinical and subjective treatment outcomes. Thanks to the new study design of MCS II, not only the common surgical treatment concepts, but also the new and constantly broadening spectrum of spine surgery, i.e. vertebro-/kyphoplasty, computer assisted surgery and navigation, minimal-invasive, and endoscopic techniques, documented and evaluated. We present a first statistical overview and preliminary analysis of 18 centers from Germany and Austria that participated in MCS II. A real time data capture at source was made possible by the constant availability of the data collection system via internet access. Following the principle of an application service provider, software, questionnaires and validation routines are located on a central server, which is accessed from the periphery (hospitals) by means of standard Internet browsers. By that, costly and time consuming software installation and maintenance of local data repositories are avoided and, more importantly, cumbersome migration of data into one integrated database becomes obsolete. Finally, this set-up also replaces traditional systems wherein paper questionnaires were mailed to the central study office and entered by hand whereby incomplete or incorrect forms always represent a resource consuming problem and source of error. With the new study concept and the expanded inclusion criteria of MCS II 1, 251 case histories with admission and surgical data were collected. This remarkable number of interventions documented during 24 months represents an increase of 183% compared to the previously conducted MCS I. The concept and technical feasibility of the MEMdoc data collection system was proven, as the participants of the MCS II succeeded in collecting data ever published on the largest series of patients with spinal injuries treated within a 2 year period.

[Implant-supported bridges in the edentulous jaw. Clinical aspects of a simple treatment concept]

Clinical aspects of a simple treatment concept with fixed prostheses in the edentulous jaw are described. Fixed implant-supported reconstructions in the edentulous jaw require multiple implants, are technically complex, aesthetically demanding and metal-ceramic solutions are expensive. Specific surgical techniques to enhance the hard and soft tissue conditions become often necessary. Thus the bar-supported overdenture may be preferred, because problems with aesthetics and alveolar ridge deficiencies can be solved more easily and the number of implants is reduced. Both, the "All-on-Four" technique and the "Procera implant bridge" are simple type of fixed prostheses, comparable to overdentures or complete dentures with regard to design and technology. They present a cost-effective alternative, with predictable aesthetics and optimum passive fit.

Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies.

A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a "cosmopolitan" tagging approach to capture the genetic diversity across approximately 2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions.

Do Cognitive and behavioral assessments of executive functions measure the same concept in children born very preterm?

Aims: This study investigated whether children aged between 8 - 12 years born very preterm (VPT) and/or at very low birth weight (VLBW) performed lower than same-aged term-born controls in cognitive and behavioral aspects of three executive functions: inhibition, working memory, and shifting. Special attention was given to sex differences. Methods: Fifty-two VPT/VLBW children (26 girls) born in the cohort of 1998–2003 at the Children’s University Hospital in Bern, Switzerland, and 36 same-aged term-born controls (18 girls) were recruited. As cognitive measures, children completed tasks of inhibition (Colour-Word Interference Test, D-KEFS), working memory (digit span backwards, WISC-IV) and shifting (Trail Making Test, number-letter switching, D-KEFS). As behavioral measures, mothers completed the Behavior Rating Inventory of Executive Function (BRIEF), assessing executive functions in everyday life.

First-in-Human Proof-of-Concept Study: Intralesional Administration of BQ788, an Endothelin Receptor B Antagonist, to Melanoma Skin Metastases

BACKGROUND This first-in-human proof-of-concept study aimed to check whether safety and preclinical results obtained by intratumoral administration of BQ788, an endothelin receptor B (EDNRB) antagonist, can be repeated in human melanoma patients. METHODS Three patients received a single intralesional BQ788 application of 3 mg. After 3-7 days, the lesions were measured and removed for analysis. The administered dose was increased to a cumulative dosage of 8 mg in patient 4 (4 × 2.0 mg, days 0-3; lesion removed on day 4) and to 10 mg in patient 5 (3 × 3.3 mg, days 0, 3, and 10; lesion removed after 14 days). Control lesions were simultaneously treated with phosphate-buffered saline (PBS). All samples were processed and analyzed without knowledge of the clinical findings. RESULTS No statistical evaluation was possible because of the number of patients (n = 5) and the variability in the mode of administration. No adverse events were observed, regardless of administered dose. All observations were in accordance with results obtained in preclinical studies. Accordingly, no difference in degree of tumor necrosis was detected between BQ788- and PBS-treated samples. In addition, both EDNRB and Ki67 showed decreased expression in patients 2 and 5 and, to a lesser extent, in patient 1. Similarly, decreased expression of EDNRB mRNA in patients 2 and 5 and of BCL2A1 and/or PARP3 in patients 2, 3, and 5 was found. Importantly, semiquantitatively scored immunohistochemistry for CD31 and CD3 revealed more blood vessels and lymphocytes, respectively, in BQ788-treated tumors of patients 2 and 4. Also, in all patients, we observed inverse correlation in expression levels between EDNRB and HIF1A. Finally, in patient 5 (the only patient treated for longer than 1 week), we observed inhibition in lesion growth, as shown by size measurement. CONCLUSION The intralesional applications of BQ788 were well tolerated and showed signs of directly and indirectly reducing the viability of melanoma cells.

Towards the foundation of a global modes concept

A contribution is presented, intended to provide theoretical foundations for the ongoing efforts to employ global instability theory for the analysis of the classic boundary-layer flow, and address the associated issue of appropriate inflow/outflow boundary conditions to close the PDE-based global eigenvalue problem in open flows. Starting from a theoretically clean and numerically simple application, in which results are also known analytically and thus serve as a guidance for the assessment of the performance of the numerical methods employed herein, a sequence of issues is systematically built into the target application, until we arrive at one representative of open systems whose instability is presently addressed by global linear theory applied to open flows, the latter application being neither tractable theoretically nor straightforward to solve by numerical means. Experience gained along the way is documented. It regards quantification of the depar- ture of the numerical solution from the analytical one in the simple problem, the generation of numerical boundary layers at artificially truncated boundaries, no matter how far the latter are placed from the region of highest flow gradients and, ultimately the impracti- cally large number of (direct and adjoint) modes necessary to project an arbitrary initial perturbation and follow its temporal evolution by a global analysis approach, a finding which may question the purported robustness reported in the literature of the recovery of optimal perturbations as part of global analyses yielding under-resolved eigenspectra.

Telomeres in the mouse have large inter-chromosomal variations in the number of T2AG3 repeats

The ultra-long telomeres that have been observed in mice are not in accordance with the concept that critical telomere shortening is related to aging and immortalization. Here, we have used quantitative fluorescence in situ hybridization to estimate (T2AG3)n lengths of individual telomeres in various mouse strains. Telomere lengths were very heterogeneous, but specific chromosomes of bone marrow cells and skin fibroblasts from individual mice had similar telomere lengths. We estimate that the shortest telomeres are around 10 kb in length, indicating that each mouse cell has a few telomeres with (T2AG3)n lengths within the range of human telomeres. These short telomeres may be critical in limiting the replicative potential of murine cells.

An Introduction to Conservation Easements in the United States: A Simple Concept and a Complicated Mosaic of Law

The idea of a conservation easement – restrictions on the development and use of land designed to protect the land’s conservation or historic values – can be relatively easily understood. More significant and more challenging is the complex body of state and federal laws that shapes the creation, funding, tax treatment, enforcement, modification, and termination of conservation easements. The explosion in the number of conservation easements over the past four decades has made them one of the most popular land protection mechanisms in the United States. The National Conservation Easement Database estimates that the total number of acres encumbered by conservation easements exceeds 40 million.Because conservation easements are both novel and ubiquitous, understanding how they actual work is essential for practicing lawyers, policymakers, land trust professionals, and students of conservation. This article provides a “quick tour” through some of the most important aspects of the developing mosaic of conservation easement law. It gives the reader a sense of the complex inter-jurisdictional dynamics that shape conservation transactions and disputes about conservation easements. Professors of property law, environmental law, tax law, and environmental studies who wish to cover conservation easements in the context of a more general course can use the article to provide their students with a broad but comprehensive overview of the relevant legal and policy issues.

Ukraine’s wartime nationalism. OSW COMMENTARY NUMBER 179, 28.08.2015

From the Introduction. The Euromaidan revolution and the war in Donbas that followed it have brought about deep changes in the way Ukrainian citizens think and have led to a rapid transformation of how people view the concept of national community. It began to be increasingly common for proponents of nationalism to refer to solidarity with the state instead of referring to the nation understood as an ethnic community, as they had previously done. This is due to the fact that an entire young generation has matured which takes the Ukrainian state for granted, but also because in the Russian-Ukrainian conflict most Russian-speaking citizens of Ukraine have opted for Ukraine.

The vacuous concept of dignity

Rights talk dominates contemporary moral discourse. It is also having a growing impact on the development of legal principle and doctrine. One of the best known general arguments in support of rights-based moral theories is the one given by John Rawls, who claims that only rights-based theories take seriously the distinction between human beings; only they can be counted on to protect certain rights and interests that are so paramount that they are beyond the demands of net happiness (Rawls 1971). Charges and assertions of this nature have been extremely influential. After the Second World War, there was an immense increase in rights talk, both in the sheer volume of that talk and in the number of supposed rights being claimed. Rights doctrine has progressed a long way since its original modest aim of providing “a legitimization of … claims against tyrannical or exploiting regimes” (Benn 1978: 61). As Tom Campbell points out: The human rights movement is based on the need for a counter-ideology to combat the abuses and misuses of political authority by those who invoke, as a justification for their activities, the need to subordinate the particular interests of individuals to the general good (Campbell 1996: 13).

Concept-based document readability in domain specific information retrieval

Domain specific information retrieval has become in demand. Not only domain experts, but also average non-expert users are interested in searching domain specific (e.g., medical and health) information from online resources. However, a typical problem to average users is that the search results are always a mixture of documents with different levels of readability. Non-expert users may want to see documents with higher readability on the top of the list. Consequently the search results need to be re-ranked in a descending order of readability. It is often not practical for domain experts to manually label the readability of documents for large databases. Computational models of readability needs to be investigated. However, traditional readability formulas are designed for general purpose text and insufficient to deal with technical materials for domain specific information retrieval. More advanced algorithms such as textual coherence model are computationally expensive for re-ranking a large number of retrieved documents. In this paper, we propose an effective and computationally tractable concept-based model of text readability. In addition to textual genres of a document, our model also takes into account domain specific knowledge, i.e., how the domain-specific concepts contained in the document affect the document’s readability. Three major readability formulas are proposed and applied to health and medical information retrieval. Experimental results show that our proposed readability formulas lead to remarkable improvements in terms of correlation with users’ readability ratings over four traditional readability measures.

Ontology ranking based on the analysis of concept structures

In view of the need to provide tools to facilitate the re-use of existing knowledge structures such as ontologies, we present in this paper a system, AKTiveRank, for the ranking of ontologies. AKTiveRank uses as input the search terms provided by a knowledge engineer and, using the output of an ontology search engine, ranks the ontologies. We apply a number of metrics in an attempt to investigate their appropriateness for ranking ontologies, and compare the results with a questionnaire-based human study. Our results show that AKTiveRank will have great utility although there is potential for improvement.