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The human immunodeficiency virus (HIV) is currently ranked sixth in the worldwide causes of death [1]. One treatment approach is to inhibit reverse transcriptase (RT), an enzyme essential for reverse transcription of viral RNA into DNA before integration into the host genome [2]. By using non-nucleoside RT inhibitors (NNRTIs) [3], which target an allosteric binding site, major side effects can be evaded. Unfortunately, high genetic variability of HIV in combination with selection pressure introduced by drug treatment enables the virus to develop resistance against this drug class by developing point mutations. This situation necessitates treatment with alternative NNRTIs that target the particular RT mutants encountered in a patient.
Previously, proteochemometric approaches have demonstrated some success in predicting binding of particular NNRTIs to individual mutants; however a structurebased approach may help to further improve the predictive success of such models. Hence, our aim is to rationalize the experimental activity of known NNRTIs against a variety of RT mutants by combining molecular modeling, long-timescale atomistic molecular dynamics (MD) simulation sampling and ensemble docking. Initial control experiments on known inhibitor-RT mutant complexes using this protocol were successful, and the predictivity for further complexes is currently being evaluated. In addition to predictive power, MD simulations of multiple RT mutants are providing fundamental insight into the dynamics of the allosteric NNRTI binding site which is useful for the design of future inhibitors. Overall, work of this type is hoped to contribute to the development of predictive efficacy models for individual patients, and hence towards personalized HIV treatment options.
This paper seeks to analyse the debate on equality between women and men found in the claims against the subjects related to Education for Citizenship. These claims were resolved in the Spanish Supreme Court and High Courts of the Autonomous Communities. In this debate, there is a strong rejection of antidiscrimination law assumptions, namely that the different roles and social roles of women and men have a cultural and social base and it is unnatural, as evidenced by the concept of gender. But many appellants and judgments defend the difference between women and men as if it was informed and legitimated on human nature. Hence gender is considered an ideology, that is, a category of analysis by means of which the reality of true human nature can be concealed or distorted. But these arguments are opposed to recent legal reforms since they are questioning its normative value, by prioritizing certain moral principles against these laws. We are talking about the Organic Law for Effective Equality between Women and Men, the Law on Integrated Protection Measures against Gender Violence and the Law on Education. However their arguments are not fully justified.
New technologies generate risks, for the evaluation of which various mechanisms have been developed; the most frequent of these mechanisms consists of advice from committees of experts to the bodies whose role is to decide whether a new technology should be implemented or not. Such committees try to measure the magnitude of the threats that accompany the introduction of a new technology in order that the policy-makers may take their decisions in the light of the reports of the experts. The legitimacy of such reports is not only found in the technical capacity of its authors, but also in the impartiality of their recommendations. On numerous occasions, nevertheless, the effective presence of this evaluation finds itself today under suspicion. There are various methods that can be employed to try to resolve this problem. Firstly by reinforcing the mechanisms on which the technocratic evaluation of the risk are based; for example, through transparency in the selection of the experts. Secondly, by means of the incorporation of democratic mechanisms in the scientific-technological policy. The exposure of the internal conditions to the dynamics of the technological change that make possible the institutionalised involvement of society in the control of risk, as well as of the mechanisms to realise it are the principal subjects of this work.
Germany is the focus of this paper, owing to the fact that since 1938 it has had the strictest laws on compulsory schooling worldwide. As a result, homeschooling in Germany has become virtually impossible. There are interesting divergences between policy and practice in the German setting, both in the country’s educational history and present educational problems. The Länder (federal states) have the responsibility for education, and they are taking a much stricter line against homeschoolers than a decade ago, especially by depriving parents of the custody of their homeschooled children at an early stage. The laws relied upon, however, were never intended to deal with such educational matters; they were designed to punish parents who abuse or neglect their children. The present, highly questionable legal action succeeds only because of the consent of state schools, state social welfare offices, and courts. The same laws are not used against the parents of the approximately 250,000 teens who are truant. The functioning of the legal and sociological machinery in Germany is being employed aggressively to stamp out homeschooling, while at the same time it ignores the crucial issue of parents who allow their children to skip school—thus depriving them of an adequate education at home or elsewhere. At the same time, the number of specialists in law and education, as well as politicians and governmental experts who argue in favor of homeschooling is growing, and media reports on homeschooling are much more positive than they were a decade ago.
The aim of this contribution is to introduce and outline a third theory of rights. Concentrating on claim-rights, it proposes to approach this aim via the concept of a directed duty. This approach is justified by the widely shared presupposition that an entity has a right if and only if a duty is owed to this entity. Unlike some prominent other proposals, this contribution does not contrast directed duties with undirected ones. It contrasts two ways a duty can be related to an entity. On the one hand, a duty can be owed to an entity. In this case it is directed to this entity. On the other hand, a duty can concern an entity. There is no reason to presuppose that they exclude each other, on the contrary. Theories of rights have to reconstruct the difference between these two ways a duty can be related to an entity. After having introduced the starting point for a theory of rights in that way, the two classic theories of rights will be rejected, the will theory and the interest theory. The main focus lies on the shortcomings of the different versions of the interest theory. This criticism helps to formulate the conditions a convincing theory of rights has to meet. In the last part, the status theory of rights will be outlined.
Axiomatic method and the law
(2012)
The process of finding evidence of what truthfully happened in a conflictive situation interests jurists and journalists but in different ways. When the work of journalists and judges are concerned the paradox is at stake. Both categories must tell a story about a conflict must listen to all involved, must inform what happened to the general public. Although both categories must use the freedom must use the freedom of speech their point of view about something with objectivity, their timing is different as well as the process and the effect of fulfilling their task. That question that should be made is what happen to law when it becomes the subject matter to the news in the world of full information? In what measurement journalists also pass judgements and how this affects the formal processes of law? The effort to answer these questions and the ones related to them is important to understand some of the problems that must be approached in order to establish the ways of law and of the mass media technological society.
In assessing the aftermath of the fraudulent presidential election of 2009 in Iran, one question has received less critical analysis than other complexities of this event: What can explain the remarkable non-violent character of the Green Movement in Iran? I propose that the answer, inter alia, lies with the following three learning experiences: 1) The experience of loss brought about by the Iran/Iraq war; 2) the experience of relative opening during Khatami’s presidency; and 3) the experience of modernization of faith in the work of the post-Islamist thinkers that aimed to make political Islam compatible with democracy. Together, these learning processes fostered a new mode of thinking that is civil and non-violent in character.
The development of laboratory animal science and animal care of legislation and the consummation
(2012)
Laboratory animal science is the use of non-human animals in experiments to obtain new knowledge and new technologies in biomedical research and testing. In order to develop science and technology, the human carried out a large number of animal experiments, these experiments greatly expanded the vision of related research field, and make a great contribution to human beings. Meanwhile, animal experiments also bring us a certain extent of negative effects. Countries around the world have adopted legislative measures to regulate behavior of animal experiments, but in the process of legislation and enforcement are not wholly satisfactory. On the basis of present situation of laboratory animal science and existing problems, with the comparison of animal welfare act between Europe and China, the author puts forward the ideas of perfecting experimental animals’ laws and its enforcement proposals.
The improvement of accident prevention technology in many fields of social life has spurred new challenges to the doctrinal tools of fault and strict based civil liability in the law of torts. Amid these challenges lies the identification of the proper scope of the respective criteria of liability in a changing factual environment, their suitability as doctrinal tools, as well as their actual application to concrete cases given the amount of information which would be needed to render adequate judgments. Precedents and old laws should be assessed with caution, taking into account the tacit cost-benefit analysis embedded in them, for they may or may not serve the interests of welfare maximization in an environment with constantly renewed accident prevention technology.
In this paper I demonstrate the utility of a Values in Design (VID) perspective for the assessment, the design and development of e-democracy tools. In the first part, I give some background information on Values in Design and Value-Sensitive Design and their relevance in the context of e-democracy. In part 2, I analyze three different e-democracy tools from a VID-perspective. The paper ends with some conclusions concerning the merits of VID for e-democracy as well as some considerations concerning the dual tasks of philosophers in assessing and promoting value-sensitive technology design.
Some advances in legal practical reason: for a progressive dialogue with contemporary hermeneutics
(2012)
This paper intends to critically discuss some points of the contemporary thesis concerning constitutional hermeneutics and methodology of law. Once identified some authors and the lines of argumentation affiliated grosso modo to the linguistic turn and rhetoric, as well as the core of the transcendental powers of communication (v.g. N. MacCormick, R. Alexy, K. Günther), the objective is to identify some dialogue with economics and political science, enlightened by recent researches about Hegel-Marx interpretations of social life. Of course the discussion inevitably passes through methodological questions, opposing analytics vs. dialectics, idealistic vs. realists standpoints. In a effort to foment the inclusive dialogue between points of view concerning the concept of law that may create (not necessarily) radical opponents, the lines of conclusion intents to revisit some foundations of Hegelian "method" (so to speak) and intends to give a modest contribution to a more profound analysis of the relations between sein and sollen categories, in order to enrich the discussions about technology and social life, specially the life of the law nowadays.
Einleitung: Lokoregionäre Rezidivtumore der Kopf-Hals-Region können häufig nicht mehr kurativ operativ oder radiotherapeutisch behandelt werden, so dass neue Therapiekonzepte erforderlich sind. Es konnte gezeigt werden, dass statische Magnetfelder (SMF) Tumorwachstum und -angiogenese signifikant beeinflussen und zu einem intratumoralen Ödem führen. Das Ziel der vorliegenden Studie war die Evaluation des Effektes von SMF auf die Permeabilität von Tumorblutgefäßen und die therapeutische Nutzbarkeit in Kombination mit einer konventionellen Chemotherapie.
Methoden: Zellen eines syngenen amelanotischen Melanoms wurden in transparente Rückenhautkammern bei Goldhamstern implantiert. Unter SMF-Exposition von 587 mT wurde fluoreszenzmikroskopisch die Extravasation von rhodaminmarkiertem Albumin zur Errechnung der Gefäßpermeabilität gemessen und intratumorale Leukozyten-Endothelzell-Interaktionen quantifiziert. Für die anschließende Therapiestudie wurden die antitumoralen Effekte einer Kombinationstherapie von Paclitaxel und SMF-Exposition verglichen mit drei Kontrollgruppen (Glucose, Paclitaxel allein, SMF allein; je n=6).
Ergebnisse: SMF führen zu einer signifikanten Erhöhung der Tumorblutgefäßpermeabilität bei unveränderten Leukozyten-Endothelzell-Interaktionen. Die Kombinationstherapie von SMF und Paclitaxel ist – bezogen auf Tumorwachstum und Angiogenese – Monotherapien überlegen.
Schlussfolgerung: Eine SMF-induzierte Steigerung der Gefäßpermeabilität kann die Blut-Tumor-Schranke beeinflussen und somit die Effektivität einer Chemotherapie mit kleinmolekularen Substanzen wie Paclitaxel deutlich steigern. Bei Verwendung von Kopfspulen erscheint eine derartige adjuvante Kombinationstherapie für lokoregionäre Karzinomrezidive der Kopf-Hals-Region besonders geeignet.
Free riders play fair
(2012)
After the demise of the social contract theory, the argument from fair play, which employs the principle of fair play, has been widely acknowledged as one of the most promising ways of justifying political obligation. First, I articulate the most promising version of the principle of fair play. Then, I show that free riders play fair, that is, that their moral fault lies not in unfairness but in the violation of a rule by appealing to the example of three-in-a-boat. Finally, I conclude that even the most promising version is false because those who have accepted benefits from a social cooperative scheme do not owe an obligation of fair play.
Principles can be directly expressed by law or may be found in jurisprudence, philosophy or literature. Often the principles are contradictory, as in the case of transparency and the taboo of state information disclosure. At the individual level, transparency and taboo, the sense and purpose of privacy may compliment each other. Moreover the rise of cyberspace has blurred the distinction between privacy and public. The taboo is widening. The development of the internet and of the social networks can alter the once apparently stable legal situation, bringing a new dynamic into play in both state and individual spheres. In the context of the internet it is as though the secret workings of the state are projected on its "walls and facades", reminding us of Plato's "Myth of the Cave". As Plato described, disillusionment and reflexive defensiveness can follow.
We study the implications on compact star properties of a soft nuclear equation of state determined from kaon production at subthreshold energies in heavy-ion collisions. On one hand, we apply these results to study radii and moments of inertia of light neutron stars. Heavy-ion data provides constraints on nuclear matter at densities relevant for those stars and, in particular, to the density dependence of the symmetry energy of nuclear matter. On the other hand, we derive a limit for the highest allowed neutron star mass of three solar masses. For that purpouse, we use the information on the nucleon potential obtained from the analysis of the heavy-ion data combined with causality on the nuclear equation of state.
Background: Undergoing systemic inflammation, the innate immune system releases excessive proinflammatory mediators, which finally can lead to organ failure. Pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs), form the interface between bacterial and viral toxins and innate immunity. During sepsis, patients with diagnosed adrenal gland insufficiency are at high risk of developing a multiorgan dysfunction syndrome, which dramatically increases the risk of mortality. To date, little is known about the mechanisms leading to adrenal dysfunction under septic conditions. Here, we investigated the sepsis-related activation of the PRRs, cell inflammation, and apoptosis within adrenal glands.
Methods: Two sepsis models were performed: the polymicrobial sepsis model (caecal ligation and puncture (CLP)) and the LTA-induced intoxication model. All experiments received institutional approval by the Regierungspräsidium Darmstadt. CLP was performed as previously described [1], wherein one-third of the caecum was ligated and punctured with a 20-gauge needle. For LTA-induced systemic inflammation, TLR2 knockout (TLR2-/-) and WT mice were injected intraperitoneally with pure LTA (pLTA; 1 mg/kg) or PBS for 2 hours. To detect potential direct adrenal dysfunction, mice were additionally injected with adrenocorticotropic hormone (ACTH; 100 μg/kg) 1 hour after pLTA or PBS. Adrenals and plasma samples were taken. Gene expressions in the adrenals (rt-PCR), cytokine release (multiplex assay), and the apoptosis rate (TUNEL assay) within the adrenals were determined.
Results: In both models, adrenals showed increased mRNA expression of TLR2 and TLR4, various NLRs, cytokines as well as inflammasome components, NADPH oxidase subunits, and nitric oxide synthases (data not shown). In WT mice, ACTH alone had no effect on inflammation, while pLTA or pLTA/ACTH administration showed increased levels of the cytokines IL-1β, IL-6, and TNFα. TLR2-/- mice indicated no response as expected (Figure 1, left). Interestingly, surviving CLP mice showed no inflammatory adrenal response, whereas nonsurvivors had elevated cytokine levels (Figure 1, right). Additionally, we identified a marked increase in apoptosis of both chromaffin and steroid-producing cells in adrenal glands obtained from mice with sepsis as compared with their controls (Figure 2).
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Conclusion: Taken together, sepsis-induced activation of the PRRs may contribute to adrenal impairment by enhancing tissue inflammation, oxidative stress and culminate in cellular apoptosis, while mortality seems to be associated with adrenal inflammation.
The bare life and (the) modern law : a journey to some key concepts or conceptions of Agamben
(2012)
This text is imitating a journey which tries to explore what is completely unknown. It starts Homo Sacer and traces some key concepts namely der Muselmann, bare life, state of exception, sovereignty and nihilism in law. Doing so, it hopes to reach a general picture of biopolitics or biopower according to Agamben. So, first part of this text generally tries to clarify some fundamental concepts or conceptions in order to use them for its aim. The second part suggests an alternative reading of Agamben, centered around his concept of der Muselmann which is the ultimate figure defined by Primo Levi and Agamben chooses the term because of its resemblance to or representation of Homo Sacer. Der Muselmann was a derogatory term in its origin and very meaning has still been unclear today. So, the second part tries to clarify the meaning of der Muselmann (and unbaptized babies) from a different outlook, not from outside but inside of the referred concept. It tries to show a Muslim’s image of a non Muslim world in order to reveal what are the very meanings of sovereignty, law and biopolitics. So at the end of the journey, this text hopes to reach a different picture of modern life and a modern law.
We present and compare new types of algorithms for lattice QCD with staggered fermions in the limit of infinite gauge coupling. These algorithms are formulated on a discrete spatial lattice but with continuous Euclidean time. They make use of the exact Hamiltonian, with the inverse temperature beta as the only input parameter. This formulation turns out to be analogous to that of a quantum spin system. The sign problem is completely absent, at zero and non-zero baryon density. We compare the performance of a continuous-time worm algorithm and of a Stochastic Series Expansion algorithm (SSE), which operates on equivalence classes of time-ordered interactions. Finally, we apply the SSE algorithm to a first exploratory study of two-flavor strong coupling lattice QCD, which is manageable in the Hamiltonian formulation because the sign problem can be controlled.