Critical role of interleukin 5 and eosinophils in concanavalin A-induced hepatitis in mice.

BACKGROUND & AIMS: Eosinophils are observed in several liver diseases, but their contribution in the pathogenesis of these disorders remains poorly investigated. Concanavalin A (Con A)-induced hepatitis is an experimental model of immune-mediated liver injury in which natural killer T (NKT) cells play a critical role through the production of interleukin (IL)-4 and the expression of Fas ligand (FasL). Because activated NKT cells also produce IL-5, a critical cytokine for eosinophil maturation and function, the role of IL-5 was investigated in this model. METHODS: IL-5-deficient mice, eosinophil depletion in wild-type (WT) mice, and NKT cell transfer from WT- or IL-5-deficient mice into NKT cell-deficient mice were used to assess the role of IL-5 and eosinophils. RESULTS: Liver eosinophil infiltrate and IL-5 production were observed after Con A challenge. Liver injury was dramatically reduced in IL-5-deficient or eosinophil-depleted mice. In addition, residual hepatitis observed in Fas-deficient mice was abolished after IL-5 neutralization. Finally, we showed that NKT cells constituted a critical source of IL-5. Indeed, transfer of WT NKT cells to mice lacking NKT cells restored liver injury, whereas transfer of IL-5-deficient NKT cells did not. CONCLUSIONS: These observations highlight the pathologic role of IL-5 and eosinophils in experimental immune-mediated hepatitis.

Bound on quantum computation time: Quantum error correction in a critical environment

We obtain an upper bound on the time available for quantum computation for a given quantum computer and decohering environment with quantum error correction implemented. First, we derive an explicit quantum evolution operator for the logical qubits and show that it has the same form as that for the physical qubits but with a reduced coupling strength to the environment. Using this evolution operator, we find the trace distance between the real and ideal states of the logical qubits in two cases. For a super-Ohmic bath, the trace distance saturates, while for Ohmic or sub-Ohmic baths, there is a finite time before the trace distance exceeds a value set by the user. © 2010 The American Physical Society.

Physical activity in US Blacks: a systematic review and critical examination of self-report instruments.

BACKGROUND: Physical activity self-report instruments in the US have largely been developed for and validated in White samples. Despite calls to validate existing instruments in more diverse samples, relatively few instruments have been validated in US Blacks. Emerging evidence suggests that these instruments may have differential validity in Black populations. PURPOSE: This report reviews and evaluates the validity and reliability of self-reported measures of physical activity in Blacks and makes recommendations for future directions. METHODS: A systematic literature review was conducted to identify published reports with construct or criterion validity evaluated in samples that included Blacks. Studies that reported results separately for Blacks were examined. RESULTS: The review identified 10 instruments validated in nine manuscripts. Criterion validity correlations tended to be low to moderate. No study has compared the validity of multiple instruments in a single sample of Blacks. CONCLUSION: There is a need for efforts validating self-report physical activity instruments in Blacks, particularly those evaluating the relative validity of instruments in a single sample.

Direct TLR2 signaling is critical for NK cell activation and function in response to vaccinia viral infection.

Natural killer (NK) cells play an essential role in innate immune control of poxviral infections in vivo. However, the mechanism(s) underlying NK cell activation and function in response to poxviruses remains poorly understood. In a mouse model of infection with vaccinia virus (VV), the most studied member of the poxvirus family, we identified that the Toll-like receptor (TLR) 2-myeloid differentiating factor 88 (MyD88) pathway was critical for the activation of NK cells and the control of VV infection in vivo. We further showed that TLR2 signaling on NK cells, but not on accessory cells such as dendritic cells (DCs), was necessary for NK cell activation and that this intrinsic TLR2-MyD88 signaling pathway was required for NK cell activation and played a critical role in the control of VV infection in vivo. In addition, we showed that the activating receptor NKG2D was also important for efficient NK activation and function, as well as recognition of VV-infected targets. We further demonstrated that VV could directly activate NK cells via TLR2 in the presence of cytokines in vitro and TLR2-MyD88-dependent activation of NK cells by VV was mediated through the phosphatidylinositol 3-kinase (PI3K)-extracellular signal-regulated kinase (ERK) pathway. Taken together, these results represent the first evidence that intrinsic TLR signaling is critical for NK cell activation and function in the control of a viral infection in vivo, indicate that multiple pathways are required for efficient NK cell activation and function in response to VV infection, and may provide important insights into the design of effective strategies to combat poxviral infections.

Genetic Studies Identify Critical Biomarkers and Refine the Classification of Malignant Gliomas

Gliomagenesis is driven by a complex network of genetic alterations and while the glioma genome has been a focus of investigation for many years; critical gaps in our knowledge of this disease remain. The identification of novel molecular biomarkers remains a focus of the greater cancer community as a method to improve the consistency and accuracy of pathological diagnosis. In addition, novel molecular biomarkers are drastically needed for the identification of targets that may ultimately result in novel therapeutics aimed at improving glioma treatment. Through the identification of new biomarkers, laboratories will focus future studies on the molecular mechanisms that underlie glioma development. Here, we report a series of genomic analyses identifying novel molecular biomarkers in multiple histopathological subtypes of glioma and refine the classification of malignant gliomas. We have completed a large scale analysis of the WHO grade II-III astrocytoma exome and report frequent mutations in the chromatin modifier, alpha thalassemia mental retardation x-linked (ATRX), isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), and mutations in tumor protein 53 (TP53) as the most frequent genetic mutations in low grade astrocytomas. Furthermore, by analyzing the status of recurrently mutated genes in 363 brain tumors, we establish that highly recurrent gene mutational signatures are an effective tool in stratifying homogeneous patient populations into distinct groups with varying outcomes, thereby capable of predicting prognosis. Next, we have established mutations in the promoter of telomerase reverse transcriptase (TERT) as a frequent genetic event in gliomas and in tissues with low rates of self renewal. We identify TERT promoter mutations as the most frequently mutated gene in primary glioblastoma. Additionally, we show that TERT promoter mutations in combination with IDH1 and IDH2 mutations are able to delineate distinct clinical tumor cohorts and are capable of predicting median overall survival more effectively than standard histopathological diagnosis alone. Taken together, these data advance our understanding of the genetic alterations that underlie the transformation of glial cells into neoplasms and we provide novel genetic biomarkers and multi – gene mutational signatures that can be utilized to refine the classification of malignant gliomas and provide opportunity for improved diagnosis.

PHILIPPE ROGIER (c.1561-1596): MISSA INCLITA STIRPS JESSE. A CRITICAL AND PERFORMING EDITION WITH PERFORMANCE COMMENTARY

The dissertation comprises two parts: (a) a musical edition and (b) a performance given on 3 July, 2008 of Philippe Rogier’s Missa Inclita stirps Jesse. The dissertation explores some of the editorial decisions required, how the demands of performers and musicologists differ, and whether they can be reconciled in one single edition. The commentary explains the preparation and realization of the edition. A video recording of the concert performance is attached to the dissertation. The Mass: The Missa Inclita stirps Jesse was published in Madrid in 1598 in a collection entitled Missae Sex. The mass setting is for four voices, except the Agnus Dei, which is for five, and is based on musical material in the motet Inclita stirps Jesse by Jacobus Clemens non Papa (c. 1510-15 – c.1556-6). Rogier’s choice and use of musical material from the motet (published in 1549) are discussed in the dissertation. The Edition: The edition is made from a microfilm copy of the Missae Sex held in the Biblioteca del Conservatorio de Musica “Giuseppe Verdi” in Milan. The Missae Sex was originally dedicated to King Philip II of Spain (1527-1598, reg. 1556-1598), whom Rogier had served as chorister and then maestro de capilla. Both Rogier and King Philip died before the volume was ready for publication. One of Rogier’s pupils, Géry de Ghersem, prepared the volume, which was printed in 1598, dedicated to King Philip III. The Performance: The mass was performed at a concert of Spanish Renaissance music in St. Matthew’s Cathedral, Washington, DC, on 3 July 2008, sung by the ensemble Orpheus directed by Philip Cave as part of the Chorworks summer workshop entitled Kings and Conquistadors: Music of Old and New Spain.

The upstream enhancer elements of the G6PC promoter are critical for optimal G6PC expression in murine glycogen storage disease type Ia.

Glycogen storage disease type-Ia (GSD-Ia) patients deficient in glucose-6-phosphatase-α (G6Pase-α or G6PC) manifest impaired glucose homeostasis characterized by fasting hypoglycemia, growth retardation, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic acidemia. Two efficacious recombinant adeno-associated virus pseudotype 2/8 (rAAV8) vectors expressing human G6Pase-α have been independently developed. One is a single-stranded vector containing a 2864-bp of the G6PC promoter/enhancer (rAAV8-GPE) and the other is a double-stranded vector containing a shorter 382-bp minimal G6PC promoter/enhancer (rAAV8-miGPE). To identify the best construct, a direct comparison of the rAAV8-GPE and the rAAV8-miGPE vectors was initiated to determine the best vector to take forward into clinical trials. We show that the rAAV8-GPE vector directed significantly higher levels of hepatic G6Pase-α expression, achieved greater reduction in hepatic glycogen accumulation, and led to a better toleration of fasting in GSD-Ia mice than the rAAV8-miGPE vector. Our results indicated that additional control elements in the rAAV8-GPE vector outweigh the gains from the double-stranded rAAV8-miGPE transduction efficiency, and that the rAAV8-GPE vector is the current choice for clinical translation in human GSD-Ia.

Safety-critical medical device development using the UPP2SF model translation tool

Software-based control of life-critical embedded systems has become increasingly complex, and to a large extent has come to determine the safety of the human being. For example, implantable cardiac pacemakers have over 80,000 lines of code which are responsible for maintaining the heart within safe operating limits. As firmware-related recalls accounted for over 41% of the 600,000 devices recalled in the last decade, there is a need for rigorous model-driven design tools to generate verified code from verified software models. To this effect, we have developed the UPP2SF model-translation tool, which facilitates automatic conversion of verified models (in UPPAAL) to models that may be simulated and tested (in Simulink/Stateflow). We describe the translation rules that ensure correct model conversion, applicable to a large class of models. We demonstrate how UPP2SF is used in themodel-driven design of a pacemaker whosemodel is (a) designed and verified in UPPAAL (using timed automata), (b) automatically translated to Stateflow for simulation-based testing, and then (c) automatically generated into modular code for hardware-level integration testing of timing-related errors. In addition, we show how UPP2SF may be used for worst-case execution time estimation early in the design stage. Using UPP2SF, we demonstrate the value of integrated end-to-end modeling, verification, code-generation and testing process for complex software-controlled embedded systems. © 2014 ACM.

The second round of Critical Assessment of Automated Structure Determination of Proteins by NMR: CASD-NMR-2013

The second round of the community-wide initiative Critical Assessment of automated Structure Determination of Proteins by NMR (CASD-NMR-2013) comprised ten blind target datasets, consisting of unprocessed spectral data, assigned chemical shift lists and unassigned NOESY peak and RDC lists, that were made available in both curated (i.e. manually refined) or un-curated (i.e. automatically generated) form. Ten structure calculation programs, using fully automated protocols only, generated a total of 164 three-dimensional structures (entries) for the ten targets, sometimes using both curated and un-curated lists to generate multiple entries for a single target. The accuracy of the entries could be established by comparing them to the corresponding manually solved structure of each target, which was not available at the time the data were provided. Across the entire data set, 71 % of all entries submitted achieved an accuracy relative to the reference NMR structure better than 1.5 Å. Methods based on NOESY peak lists achieved even better results with up to 100 % of the entries within the 1.5 Å threshold for some programs. However, some methods did not converge for some targets using un-curated NOESY peak lists. Over 90 % of the entries achieved an accuracy better than the more relaxed threshold of 2.5 Å that was used in the previous CASD-NMR-2010 round. Comparisons between entries generated with un-curated versus curated peaks show only marginal improvements for the latter in those cases where both calculations converged.

A critical examination of node-similarity based graph matching algorithms

In this paper, we shall critically examine a special class of graph matching algorithms that follow the approach of node-similarity measurement. A high-level algorithm framework, namely node-similarity graph matching framework (NSGM framework), is proposed, from which, many existing graph matching algorithms can be subsumed, including the eigen-decomposition method of Umeyama, the polynomial-transformation method of Almohamad, the hubs and authorities method of Kleinberg, and the kronecker product successive projection methods of Wyk, etc. In addition, improved algorithms can be developed from the NSGM framework with respects to the corresponding results in graph theory. As the observation, it is pointed out that, in general, any algorithm which can be subsumed from NSGM framework fails to work well for graphs with non-trivial auto-isomorphism structure.

A critical analysis of polymer cure modeling for microelectronics applications

A review of polymer cure models used in microelectronics packaging applications reveals no clear consensus of the chemical rate constants for the cure reactions, or even of an effective model. The problem lies in the contrast between the actual cure process, which involves a sequence of distinct chemical reactions, and the models, which typically assume only one, (or two with some restrictions on the independence of their characteristic constants.) The standard techniques to determine the model parameters are based on differential scanning calorimetry (DSC), which cannot distinguish between the reactions, and hence yields results useful only under the same conditions, which completely misses the point of modeling. The obvious solution is for manufacturers to provide the modeling parameters, but failing that, an alternative experimental technique is required to determine individual reaction parameters, e.g. Fourier transform infra-red spectroscopy (FTIR).