Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer.

Head and neck cancer constitutes the 6th most common malignancy worldwide and affects the crucial anatomical structures and physiological functions of the upper aerodigestive tract. Classical therapeutic strategies such as surgery and radiotherapy carry substantial toxicity and functional impairment. Moreover, the loco-regional control rates as well as overall survival still need to be improved in subgroups of patients. The scatter-factor/hepatocyte growth factor receptor tyrosine kinase MET is an established effector in the promotion, maintenance and progression of malignant transformation in a wide range of human malignancies, and has been gaining considerable interest in head and neck cancer over the last 15 years. Aberrant MET activation due to overexpression, mutations, tumor-stroma paracrine loops, and cooperative/redundant signaling has been shown to play prominent roles in epithelial-to-mesenchymal transition, angiogenesis, and responses to anti-cancer therapeutic modalities. Accumulating preclinical and translational evidence highly supports the increasing interest of MET as a biomarker for lymph node and distant metastases, as well as a potential marker of stratification for responses to ionizing radiation. The relevance of MET as a therapeutic molecular target in head and neck cancer described in preclinical studies remains largely under-evaluated in clinical trials, and therefore inconclusive. Also in the context of anti-cancer targeted therapy, a large body of preclinical data suggests a central role for MET in treatment resistance towards multiple therapeutic modalities in malignancies of the head and neck region. These findings, as well as the potential use of combination therapies including MET inhibitors in these tumors, need to be further explored.

Reconstructing Arguments: Formalization and Reflective Equilibrium

Traditional logical reconstruction of arguments aims at assessing the validity of ordinary language arguments. It involves several tasks: extracting argumentations from texts, breaking up complex argumentations into individual arguments, framing arguments in standard form, as well as formalizing arguments and showing their validity with the help of a logical formalism. These tasks are guided by a multitude of partly antagonistic goals, they interact in various feedback loops, and they are intertwined with the development of theories of valid inference and adequate formalization. This paper explores how the method of reflective equilibrium can be used for modelling the complexity of such reconstructions and for justifying the various steps involved. The proposed approach is illustrated and tested in a detailed reconstruction of the beginning of Anselm’s De casu diaboli.

From Framework to Action: The DESIRE Approach to Combat Desertification

It has become increasingly clear that desertification can only be tackled through a multi-disciplinary approach that not only involves scientists but also stakeholders. In the DESIRE project such an approach was taken. As a first step, a conceptual framework was developed in which the factors and processes that may lead to land degradation and desertification were described. Many of these factors do not work independently, but can reinforce or weaken one another, and to illustrate these relationships sustainable management and policy feedback loops were included. This conceptual framework can be applied globally, but can also be made site-specific to take into account that each study site has a unique combination of bio-physical, socio-economic and political conditions. Once the conceptual framework was defined, a methodological framework was developed in which the methodological steps taken in the DESIRE approach were listed and their logic and sequence were explained. The last step was to develop a concrete working plan to put the project into action, involving stakeholders throughout the process. This series of steps, in full or in part, offers explicit guidance for other organizations or projects that aim to reduce land degradation and desertification.

Supersymmetric quantum mechanics on the lattice: I. Loop formulation

Simulations of supersymmetric field theories on the lattice with (spontaneously) broken supersymmetry suffer from a fermion sign problem related to the vanishing of the Witten index. We propose a novel approach which solves this problem in low dimensions by formulating the path integral on the lattice in terms of fermion loops. For N=2 supersymmetric quantum mechanics the loop formulation becomes particularly simple and in this paper – the first in a series of three – we discuss in detail the reformulation of this model in terms of fermionic and bosonic bonds for various lattice discretisations including one which is Q-exact.

Catching Reality or Bowing Disciplines: How to Move the Study of Citizenship

In his contribution, Joppke justifies his selection of foundational scholars by linking each to what he sees as the three key facets of citizenship: status, rights and identity. Maarten Vink explicitly links his research agenda to the first, status, and outlines why it is so important. In identifying three facets of citizenship, Joppke acknowledges that some academics would include political participation, but he ultimately decides against it. But here we can, and should, broaden citizenship studies by bringing in insights from the behavioral politics tradition in domestic politics - when and why people engage in political acts - and from the social movements literature in sociology. I believe that the American debate on immigration reform, admittedly stalled, would not have advanced as far as it has without the social movement activism of DREAMers - unauthorized young people pushing for a path to citizenship - and the belief that Barack Obama won re-election in part because of the Latino vote. Importantly, one type of political activism demands formal citizenship, the other does not. As many contributors note, the “national models” approach has had a significant impact on citizenship studies. Whether one views such models through a cultural, institutional or historical lens, this tends to be a top-down, macro-level framework. What about immigrants’ agency? In Canada, although the ruling Conservative government is shifting citizenship discourse to a more traditional language - as Winter points out - it has not reduced immigration, ended dual citizenship, or eliminated multiculturalism, all goals of the Reform Party that the current prime minister once helped build. “Lock-in” effects (or policy feedback loops) based on high immigrant naturalization and the coming of age of a second-generation with citizenship also d emands study, in North America and elsewhere. Much of the research thus far suggests that political decisions over citizenship status and rights do not seem linked to immigrants’ political activism. State-centered decision-making may have characterized policy in the early post-World War II period in Europe (and East Asia?), but does it continue to hold today? Majority publics and immigrant-origin residents are increasingly politicized around citizenship and immigration. Does immigrant agency extend citizenship status, rights and identity to those born outside the polity? Is electoral power key, or is protest necessary? How is citizenship practiced, and contested, irrespective of formal status? These are important and understudied empirical questions, ones that demand theoretical creativity - across sub-fields and disciplines - in conceptualizing and understanding citizenship in contemporary times.

Infrared regime of SU(2) with one adjoint Dirac flavor

SU(2) gauge theory with one Dirac flavor in the adjoint representation is investigated on a lattice. Initial results for the gluonic and mesonic spectrum, static potential from Wilson and Polyakov loops, and the anomalous dimension of the fermionic condensate from the Dirac mode number are presented. The results found are not consistent with conventional confining behavior, pointing instead tentatively towards a theory lying within or very near the onset of the conformal window, with the anomalous dimension of the fermionic condensate in the range 0.9≲γ∗≲0.95. The implications of our work for building a viable theory of strongly interacting dynamics beyond the standard model are discussed.

Psychomotor symptoms of schizophrenia map on the cerebral motor circuit

Schizophrenia is a devastating disorder thought to result mainly from cerebral pathology. Neuroimaging studies have provided a wealth of findings of brain dysfunction in schizophrenia. However, we are still far from understanding how particular symptoms can result from aberrant brain function. In this context, the high prevalence of motor symptoms in schizophrenia such as catatonia, neurological soft signs, parkinsonism, and abnormal involuntary movements is of particular interest. Here, the neuroimaging correlates of these motor symptoms are reviewed. For all investigated motor symptoms, neural correlates were found within the cerebral motor system. However, only a limited set of results exists for hypokinesia and neurological soft signs, while catatonia, abnormal involuntary movements and parkinsonian signs still remain understudied with neuroimaging methods. Soft signs have been associated with altered brain structure and function in cortical premotor and motor areas as well as cerebellum and thalamus. Hypokinesia is suggested to result from insufficient interaction of thalamocortical loops within the motor system. Future studies are needed to address the neural correlates of motor abnormalities in prodromal states, changes during the course of the illness, and the specific pathophysiology of catatonia, dyskinesia and parkinsonism in schizophrenia.

Size does matter: 18 amino acids at the N-terminal tip of an amino acid transporter in Leishmania determine substrate specificity

Long N-terminal tails of amino acid transporters are known to act as sensors of the internal pool of amino acids and as positive regulators of substrate flux rate. In this study we establish that N-termini of amino acid transporters can also determine substrate specificity. We show that due to alternative trans splicing, the human pathogen Leishmania naturally expresses two variants of the proline/alanine transporter, one 18 amino acid shorter than the other. We demonstrate that the longer variant (LdAAP24) translocates both proline and alanine, whereas the shorter variant (∆18LdAAP24) translocates just proline. Remarkably, co-expressing the hydrophilic N-terminal peptide of the long variant with ∆18LdAAP24 was found to recover alanine transport. This restoration of alanine transport could be mediated by a truncated N-terminal tail, though truncations exceeding half of the tail length were no longer functional. Taken together, the data indicate that the first 18 amino acids of the negatively charged N-terminal LdAAP24 tail are required for alanine transport and may facilitate the electrostatic interactions of the entire negatively charged N-terminal tail with the positively charged internal loops in the transmembrane domain, as this mechanism has been shown to underlie regulation of substrate flux rate for other transporters.

Nonperturbative results for two-index conformal windows

Via large and small N c relations we derive nonperturbative results about the conformal window of two-index theories. Using Schwinger-Dyson methods as well as four-loops results we estimate subleading corrections and show that naive large number of colors extrapolations are unreliable when N c is less than about six. Nevertheless useful nonper-turbative inequalities for the size of the conformal windows, for any number of colors, can be derived. By further observing that the adjoint conformal window is independent of the number of colors we argue, among other things, that: the large N c two-index conformal window is twice the conformal window of the adjoint representation (which can be determined at small N c) expressed in terms of Dirac fermions; lattice results for adjoint matter can be used to provide independent information on the conformal dynamics of two-index theories such as SU(N c) with two and four symmetric Dirac flavors.

3' end processing of mouse histone pre-mRNA: evidence for additional base-pairing between U7 snRNA and pre-mRNA.

We have analysed the extent of base-pairing interactions between spacer sequences of histone pre-mRNA and U7 snRNA present in the trans-acting U7 snRNP and their importance for histone RNA 3' end processing in vitro. For the efficiently processed mouse H4-12 gene, a computer analysis revealed that additional base pairs could be formed with U7 RNA outside of the previously recognised spacer element (stem II). One complementarity (stem III) is located more 3' and involves nucleotides from the very 5' end of U7 RNA. The other, more 5' located complementarity (stem I) involves nucleotides of the Sm binding site of U7 RNA, a part known to interact with snRNP structural proteins. These potential stem structures are separated from each other by short internal loops of unpaired nucleotides. Mutational analyses of the pre-mRNA indicate that stems II and III are equally important for interaction with the U7 snRNP and for processing, whereas mutations in stem I have moderate effects on processing efficiency, but do not impair complex formation with the U7 snRNP. Thus nucleotides near the processing site may be important for processing, but do not contribute to the assembly of an active complex by forming a stem I structure. The importance of stem III was confirmed by the ability of a complementary mutation in U7 RNA to suppress a stem III mutation in a complementation assay using Xenopus laevis oocytes. The main role of the factor(s) binding to the upstream hairpin loop is to stabilise the U7-pre-mRNA complex. This was shown by either stabilising (by mutation) or destabilising (by increased temperature) the U7-pre-mRNA base-pairing under conditions where hairpin factor binding was either allowed or prevented (by mutation or competition). The hairpin dependence of processing was found to be inversely related to the strength of the U7-pre-mRNA interaction.

Experiences with a voluntary surveillance system for early detection of equine diseases in Switzerland

Clinical observations made by practitioners and reported using web- and mobile-based technologies may benefit disease surveillance by improving the timeliness of outbreak detection. Equinella is a voluntary electronic reporting and information system established for the early detection of infectious equine diseases in Switzerland. Sentinel veterinary practitioners have been able to report cases of non-notifiable diseases and clinical symptoms to an internet-based platform since November 2013. Telephone interviews were carried out during the first year to understand the motivating and constraining factors affecting voluntary reporting and the use of mobile devices in a sentinel network. We found that non-monetary incentives attract sentinel practitioners; however, insufficient understanding of the reporting system and of its relevance, as well as concerns over the electronic dissemination of health data were identified as potential challenges to sustainable reporting. Many practitioners are not yet aware of the advantages of mobile-based surveillance and may require some time to become accustomed to novel reporting methods. Finally, our study highlights the need for continued information feedback loops within voluntary sentinel networks.