Functional determinants for general self-adjoint extensions of Laplace-type operators resulting from the generalized cone

In this article we consider the zeta regularized determinant of Laplace-type operators on the generalized cone. For {\it arbitrary} self-adjoint extensions of a matrix of singular ordinary differential operators modelled on the generalized cone, a closed expression for the determinant is given. The result involves a determinant of an endomorphism of a finite-dimensional vector space, the endomorphism encoding the self-adjoint extension chosen. For particular examples, like the Friedrich's extension, the answer is easily extracted from the general result. In combination with \cite{BKD}, a closed expression for the determinant of an arbitrary self-adjoint extension of the full Laplace-type operator on the generalized cone can be obtained.Comment: 27 pages, 2 figures; to appear in Manuscripta Mathematic

A Weak Neutralizing Antibody Response to Hepatitis C Virus Envelope Glycoprotein Enhances Virus Infection

We have completed a phase 1 safety and immunogenicity trial with hepatitis C virus (HCV) envelope glycoproteins, E1 and E2, with MF59 adjuvant as a candidate vaccine. Neutralizing activity to HCV genotype 1a was detected in approximately 25% of the vaccinee sera. In this study, we evaluated vaccinee sera from poor responders as a potential source of antibody dependent enhancement (ADE) of HCV infection. Sera with poor neutralizing activity enhanced cell culture grown HCV genotype 1a or 2a, and surrogate VSV/HCV pseudotype infection titer, in a dilution dependent manner. Surrogate pseudotypes generated from individual HCV glycoproteins suggested that antibody to the E2 glycoprotein; but not the E1 glycoprotein, was the principle target for enhancing infection. Antibody specific to FcRII expressed on the hepatic cell surface or to the Fc portion of Ig blocked enhancement of HCV infection by vaccinee sera. Together, the results from in vitro studies suggested that enhancement of viral infectivity may occur in the absence of a strong antibody response to HCV envelope glycoproteins

Dualism in the Labor Market: A Perspective on the Lewis Model After Half a Century

This paper asks how the Lewis model might be viewed from the perspective of economic science half a century later. Many of the core propositions remain intact, some might be amplified, and a small number might be revised

Angular Momentum and the Formation of Stars and Black Holes

The formation of compact objects like stars and black holes is strongly constrained by the requirement that nearly all of the initial angular momentum of the diffuse material from which they form must be removed or redistributed during the formation process. The mechanisms that may be involved and their implications are discussed for (1) low-mass stars, most of which probably form in binary or multiple systems; (2) massive stars, which typically form in clusters; and (3) supermassive black holes that form in galactic nuclei. It is suggested that in all cases, gravitational interactions with other stars or mass concentrations in a forming system play an important role in redistributing angular momentum and thereby enabling the formation of a compact object. If this is true, the formation of stars and black holes must be a more complex, dynamic, and chaotic process than in standard models. The gravitational interactions that redistribute angular momentum tend to couple the mass of a forming object to the mass of the system, and this may have important implications for mass ratios in binaries, the upper stellar IMF in clusters, and the masses of supermassive black holes in galaxies.Comment: Accepted by Reports on Progress in Physic

A General Framework for Architecture Composability

Architectures depict design principles: paradigms that can be understood by all, allow thinking on a higher plane and avoiding low-level mistakes. They provide means for ensuring correctness by construction by enforcing global properties characterizing the coordination between components. An architecture can be considered as an operator A that, applied to a set of components B, builds a composite component A(B) meeting a characteristic property Φ. Architecture composability is a basic and common problem faced by system designers. In this paper, we propose a formal and general framework for architecture composability based on an associative, commutative and idempotent architecture composition operator ⊕. The main result is that if two architectures A1 and A2 enforce respectively safety properties Φ1 and Φ2 , the architecture A1 ⊕ A2 enforces the property Φ1 ∧ Φ2 , that is both properties are preserved by architecture composition. We also establish preservation of liveness properties by architecture composition. The presented results are illustrated by a running example and a case study

Managing patients with ICD shocks and programming tachycardia therapies during acute heart failure syndromes

We review the pharmacologic, interventional and device programming treatment options for patients with implantable cardioverter-defibrillators who present with acute heart failure and implantable cardioverter-defibrillator shocks

Estimating EQ-5D utilities based on the Short-Form Long Term Conditions Questionnaire (LTCQ-8)

Purpose: The aim of this work was to develop a mapping algorithm for estimating EuroQoL 5 Dimension (EQ-5D) utilities from responses to the Long-Term Conditions Questionnaire (LTCQ), thus increasing LTCQ’s potential as a comprehensive outcome measure for evaluating integrated care initiatives. Methods: We combined data from three studies to give a total sample of 1334 responses. In each of the three datasets, we randomly selected 75% of the sample and combined the selected random samples to generate the estimation dataset, which consisted of 1001 patients. The unselected 25% observations from each dataset were combined to generate an internal validation dataset of 333 patients. We used direct mapping models by regressing responses to the LTCQ-8 directly onto EQ-5D-5L and EQ-5D-3L utilities as well as response (or indirect) mapping to predict the response level that patients selected for each of the five EQ-5D-5L domains. Several models were proposed and compared on mean squared error and mean absolute error. Results: A two-part model with OLS was the best performing based on the mean squared error (0.038) and mean absolute error (0.147) when estimating the EQ-5D-5L utilities. A multinomial response mapping model using LTCQ-8 responses was used to predict EQ-5D-5L responses levels. Conclusions: This study provides a mapping algorithm for estimating EQ-5D utilities from LTCQ responses. The results from this study can help broaden the applicability of the LTCQ by producing utility values for use in economic analyses

Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer

Towards a Synthetic Chloroplast

The evolution of eukaryotic cells is widely agreed to have proceeded through a series of endosymbiotic events between larger cells and proteobacteria or cyanobacteria, leading to the formation of mitochondria or chloroplasts, respectively. Engineered endosymbiotic relationships between different species of cells are a valuable tool for synthetic biology, where engineered pathways based on two species could take advantage of the unique abilities of each mutualistic partner.We explored the possibility of using the photosynthetic bacterium Synechococcus elongatus PCC 7942 as a platform for studying evolutionary dynamics and for designing two-species synthetic biological systems. We observed that the cyanobacteria were relatively harmless to eukaryotic host cells compared to Escherichia coli when injected into the embryos of zebrafish, Danio rerio, or taken up by mammalian macrophages. In addition, when engineered with invasin from Yersinia pestis and listeriolysin O from Listeria monocytogenes, S. elongatus was able to invade cultured mammalian cells and divide inside macrophages.Our results show that it is possible to engineer photosynthetic bacteria to invade the cytoplasm of mammalian cells for further engineering and applications in synthetic biology. Engineered invasive but non-pathogenic or immunogenic photosynthetic bacteria have great potential as synthetic biological devices