Evaluating QBF Solvers: Quantifier Alternations Matter

We present an experimental study of the effects of quantifier alternations on the evaluation of quantified Boolean formula (QBF) solvers. The number of quantifier alternations in a QBF in prenex conjunctive normal form (PCNF) is directly related to the theoretical hardness of the respective QBF satisfiability problem in the polynomial hierarchy. We show empirically that the performance of solvers based on different solving paradigms substantially varies depending on the numbers of alternations in PCNFs. In related theoretical work, quantifier alternations have become the focus of understanding the strengths and weaknesses of various QBF proof systems implemented in solvers. Our results motivate the development of methods to evaluate orthogonal solving paradigms by taking quantifier alternations into account. This is necessary to showcase the broad range of existing QBF solving paradigms for practical QBF applications. Moreover, we highlight the potential of combining different approaches and QBF proof systems in solvers.Comment: preprint of a paper to be published at CP 2018, LNCS, Springer, including appendi

Controlling Cherenkov angles with resonance transition radiation

Cherenkov radiation provides a valuable way to identify high energy particles in a wide momentum range, through the relation between the particle velocity and the Cherenkov angle. However, since the Cherenkov angle depends only on material's permittivity, the material unavoidably sets a fundamental limit to the momentum coverage and sensitivity of Cherenkov detectors. For example, Ring Imaging Cherenkov detectors must employ materials transparent to the frequency of interest as well as possessing permittivities close to unity to identify particles in the multi GeV range, and thus are often limited to large gas chambers. It would be extremely important albeit challenging to lift this fundamental limit and control Cherenkov angles as preferred. Here we propose a new mechanism that uses constructive interference of resonance transition radiation from photonic crystals to generate both forward and backward Cherenkov radiation. This mechanism can control Cherenkov angles in a flexible way with high sensitivity to any desired range of velocities. Photonic crystals thus overcome the severe material limit for Cherenkov detectors, enabling the use of transparent materials with arbitrary values of permittivity, and provide a promising option suited for identification of particles at high energy with enhanced sensitivity.Comment: There are 16 pages and 4 figures for the manuscript. Supplementary information with 18 pages and 5 figures, appended at the end of the file with the manuscript. Source files in Word format converted to PDF. Submitted to Nature Physic

Anchor Side Chains of Short Peptide Fragments Trigger Ligand-Exchange of Class II MHC Molecules

Class II MHC molecules display peptides on the cell surface for the surveillance by CD4+ T cells. To ensure that these ligands accurately reflect the content of the intracellular MHC loading compartment, a complex processing pathway has evolved that delivers only stable peptide/MHC complexes to the surface. As additional safeguard, MHC molecules quickly acquire a ‘non-receptive’ state once they have lost their ligand. Here we show now that amino acid side chains of short peptides can bypass these safety mechanisms by triggering the reversible ligand-exchange. The catalytic activity of dipeptides such as Tyr-Arg was stereo-specific and could be enhanced by modifications addressing the conserved H-bond network near the P1 pocket of the MHC molecule. It affected both antigen-loading and ligand-release and strictly correlated with reported anchor preferences of P1, the specific target site for the catalytic side chain of the dipeptide. The effect was evident also in CD4+ T cell assays, where the allele-selective influence of the dipeptides translated into increased sensitivities of the antigen-specific immune response. Molecular dynamic calculations support the hypothesis that occupation of P1 prevents the ‘closure’ of the empty peptide binding site into the non-receptive state. During antigen-processing and -presentation P1 may therefore function as important “sensor” for peptide-load. While it regulates maturation and trafficking of the complex, on the cell surface, short protein fragments present in blood or lymph could utilize this mechanism to alter the ligand composition on antigen presenting cells in a catalytic way

United States Acculturation and Cancer Patients' End-of-Life Care

Background: Culture shapes how people understand illness and death, but few studies examine whether acculturation influences patients' end-of-life treatment preferences and medical care. Methods and Findings: In this multi-site, prospective, longitudinal cohort study of terminally-ill cancer patients and their caregivers (n = 171 dyads), trained interviewers administered the United States Acculturation Scale (USAS). The USAS is a 19-item scale developed to assess the degree of "Americanization" in first generation or non-US born caregivers of terminally-ill cancer patients. We evaluated the internal consistency, concurrent, criterion, and content validity of the USAS. We also examined whether caregivers' USAS scores predicted patients' communication, treatment preferences, and end-of-life medical care in multivariable models that corrected for significant confounding influences (e.g. education, country of origin, English proficiency). The USAS measure was internally consistent (Cronbach α = 0.98); and significantly associated with US birthplace (r = 0.66, P<0.0001). USAS scores were predictive of patients' preferences for prognostic information (AOR = 1.31, 95% CI:1.00-1.72), but not comfort asking physicians' questions about care (AOR 1.23, 95% CI:0.87-1.73). They predicted patients' preferences for feeding tubes (AOR = 0.68, 95% CI:0.49-0.99) and wish to avoid dying in an intensive care unit (AOR = 1.36, 95% CI:1.05-1.76). Scores indicating greater acculturation were also associated with increased odds of patient participation in clinical trials (AOR = 2.20, 95% CI:1.28-3.78), compared with lower USAS scores, and greater odds of patients receiving chemotherapy (AOR = 1.59, 95% CI:1.20-2.12). Conclusion: The USAS is a reliable and valid measure of "Americanization" associated with advanced cancer patients' end-of-life preferences and care. USAS scores indicating greater caregiver acculturation were associated with increased odds of patient participation in cancer treatment (chemotherapy, clinical trials) compared with lower scores. Future studies should examine the effects of acculturation on end-of-life care to identify patient and provider factors that explain these effects and targets for future interventions to improve care (e.g., by designing more culturally-competent health education materials). © 2013 Wright et al

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Collaborative planning approach to inform the implementation of a healthcare manager intervention for hispanics with serious mental illness: a study protocol

Background: This study describes a collaborative planning approach that blends principles of community-based participatory research (CBPR) and intervention mapping to modify a healthcare manager intervention to a new patient population and provider group and to assess the feasibility and acceptability of this modified intervention to improve the physical health of Hispanics with serious mental illness (SMI) and at risk for cardiovascular disease (CVD). Methods: The proposed study uses a multiphase approach that applies CBPR principles and intervention-mapping steps--an intervention-planning approach--to move from intervention planning to pilot testing. In phase I, a community advisory board composed of researchers and stakeholders will be assembled to learn and review the intervention and make initial modifications. Phase II uses a combination of qualitative methods--patient focus groups and stakeholder interviews--to ensure that the modifications are acceptable to all stakeholders. Phase III uses results from phase II to further modify the intervention, develop an implementation plan, and train two care managers on the modified intervention. Phase IV consists of a 12-month open pilot study (N = 30) to assess the feasibility and acceptability of the modified intervention and explore its initial effects. Lastly, phase V consists of analysis of pilot study data and preparation for future funding to develop a more rigorous evaluation of the modified intervention. Discussion: The proposed study is one of the few projects to date to focus on improving the physical health of Hispanics with SMI and at risk for CVD by using a collaborative planning approach to enhance the transportability and use of a promising healthcare manager intervention. This study illustrates how blending health-disparities research and implementation science can help reduce the disproportionate burden of medical illness in a vulnerable population

New dosing schedules of dasatinib for CML and adverse event management

Resistance to imatinib in patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has emerged as a significant clinical issue. Dasatinib is a tyrosine kinase inhibitor that has 325-fold greater in vitro activity against native BCR-ABL (breakpoint cluster region-Abelson leukemia virus) compared with imatinib and can overcome primary (intrinsic) and secondary (acquired) imatinib resistance. Here, we review the clinical profile of dasatinib in imatinib-resistant and -intolerant patients and share clinical approaches for managing adverse events (AEs) to ensure maximum patient benefit. References were obtained through literature searches on PubMed as well as from the Proceedings of Annual Meetings of the American Society of Clinical Oncology, the American Society of Hematology, and European Hematology Association. Phase II and III studies of dasatinib in patients with imatinib-resistant or -intolerant CML in any phase or Ph+ ALL were selected for discussion. Dasatinib is currently indicated for the treatment of patients with imatinib-resistant or -intolerant CML or Ph+ ALL. AEs associated with dasatinib are typically mild to moderate, and are usually resolved with temporary treatment interruption and/or dose adjustments. A Phase III dose optimization study showed that in patients with chronic phase (CP) CML, 100 mg once-daily dasatinib improves the safety profile, particularly pleural effusion and thrombocytopenia, while maintaining efficacy compared with the previously recommended dose of 70 mg twice-daily. Dasatinib has a manageable safety profile. For patients with CP CML, a new recommended starting dose of 100 mg once daily has recently been approved. The recommended dose for patients with advanced CML or Ph+ ALL remains 70 mg twice daily