Predicting Antigen Presentation-What Could We Learn From a Million Peptides?

Antigen presentation lies at the heart of immune recognition of infected or malignant cells. For this reason, important efforts have been made to predict which peptides are more likely to bind and be presented by the human leukocyte antigen (HLA) complex at the surface of cells. These predictions have become even more important with the advent of next-generation sequencing technologies that enable researchers and clinicians to rapidly determine the sequences of pathogens (and their multiple variants) or identify non-synonymous genetic alterations in cancer cells. Here, we review recent advances in predicting HLA binding and antigen presentation in human cells. We argue that the very large amount of high-quality mass spectrometry data of eluted (mainly self) HLA ligands generated in the last few years provides unprecedented opportunities to improve our ability to predict antigen presentation and learn new properties of HLA molecules, as demonstrated in many recent studies of naturally presented HLA-I ligands. Although major challenges still lie on the road toward the ultimate goal of predicting immunogenicity, these experimental and computational developments will facilitate screening of putative epitopes, which may eventually help decipher the rules governing T cell recognition

A Functional Elaboration Theory Perspective on Management Accounting in Small Firms

We note a lack of theoretical explanations in a recent review of small-firm management accounting research and draw on recent organizational research (functional elaboration theory and theory of asymmetric effects of misfit, specifically) that may further illuminate findings in some small-firm management accounting studies. After briefly discussing how the functional elaboration process model in Wilkerson and Seers (2019) may be adapted to small-firm management accounting research, we offer recommendations for questionnaire measures of management accounting’s qualitative functional elaboration and underfit in small firms. Finally, we discuss implications for practice and entrepreneurship education

Adapting V-ISA Technology: Driver Behaviour along Interchange Ramp and Merging/Diverging Terminals

An original in-vehicle Intelligent Speed Adaptation System for Visibility (V-ISA) was designed to promote compliance with real-time speed management. The functionality of V-ISA is based on the prevailing sight conditions along the road, and operates in two variants: (i) providing visual information, and (ii) vehicle speed intervention. A road scenario with the driver performing merging and diverging manoeuvres in a motorway section was designed. A within-subject experiment involved 32 participants and a vehicle equipped with the two variants and the system off (baseline condition) under two traffic flow conditions. V-ISA had a significant positive effect on the drivers' longitudinal performance along ramps. This change in behaviour along ramps had no effect on merging and diverging manoeuvres. V-ISA had a positive impact on driver speed behaviour in such complex road environment and assisted drivers to modulate the operating speed towards the safe dynamic limits

'Hotspots' of Antigen Presentation Revealed by Human Leukocyte Antigen Ligandomics for Neoantigen Prioritization.

The remarkable clinical efficacy of the immune checkpoint blockade therapies has motivated researchers to discover immunogenic epitopes and exploit them for personalized vaccines. Human leukocyte antigen (HLA)-binding peptides derived from processing and presentation of mutated proteins are one of the leading targets for T-cell recognition of cancer cells. Currently, most studies attempt to identify neoantigens based on predicted affinity to HLA molecules, but the performance of such prediction algorithms is rather poor for rare HLA class I alleles and for HLA class II. Direct identification of neoantigens by mass spectrometry (MS) is becoming feasible; however, it is not yet applicable to most patients and lacks sensitivity. In an attempt to capitalize on existing immunopeptidomics data and extract information that could complement HLA-binding prediction, we first compiled a large HLA class I and class II immunopeptidomics database across dozens of cell types and HLA allotypes and detected hotspots that are subsequences of proteins frequently presented. About 3% of the peptidome was detected in both class I and class II. Based on the gene ontology of their source proteins and the peptide's length, we propose that their processing may partake by the cellular class II presentation machinery. Our database captures the global nature of the in vivo peptidome averaged over many HLA alleles, and therefore, reflects the propensity of peptides to be presented on HLA complexes, which is complementary to the existing neoantigen prediction features such as binding affinity and stability or RNA abundance. We further introduce two immunopeptidomics MS-based features to guide prioritization of neoantigens: the number of peptides matching a protein in our database and the overlap of the predicted wild-type peptide with other peptides in our database. We show as a proof of concept that our immunopeptidomics MS-based features improved neoantigen prioritization by up to 50%. Overall, our work shows that, in addition to providing huge training data to improve the HLA binding prediction, immunopeptidomics also captures other aspects of the natural in vivo presentation that significantly improve prediction of clinically relevant neoantigens

Life cycle economic and environmental impacts of cdw recycled aggregates in roadway construction and rehabilitation

The use of recycled materials in roadway construction and rehabilitation can achieve significant benefits in saving natural resources, reducing energy, greenhouse gas emissions and costs. Construction and demolition waste (CDW) recycled aggregate as an alternative to natural one can enhance sustainability benefits in roadway infrastructure. The objective of this study was to quantitatively assess the life cycle economic and environmental benefits when alternative stabilizedCDW aggregates are used in pavement construction. Comparative analysis was conducted on a pavement project representative of typical construction practices in northern Italy so as to quantify such benefits. The proposed alternative sustainable construction strategies considered CDW aggregates stabilized with both cement and cement kiln dust (CKD) for the base layer of the roadway. The life cycle assessment results indicate that using CDW aggregate stabilized with CKD results in considerable cost savings and environmental benefits due to (i) lower energy consumption and emissions generation during material processing and (ii) reduction in landfill disposal. The benefits illustrated in this analysis should encourage the wider adoption of stabilized CDW aggregate in roadway construction and rehabilitation. In terms of transferability, the analysis approach suggested in this study can be used to assess the economic and environmental benefits of these and other recycled materials in roadway infrastructure elsewhere

Swift-XRT observation of 34 new INTEGRAL/IBIS AGNs: discovery of Compton thick and other peculiar sources

For a significant number of the sources detected at high energies (>10 keV) by the INTEGRAL/IBIS and Swift/BAT instruments there is either a lack information about them in the 2-10 keV range or they are totally unidentified. Herein, we report on a sample of 34 IBIS AGN or AGN candidate objects for which there is X-ray data in the Swift/XRT archive. Thanks to these X-ray follow up observations, the identification of the gamma ray emitters has been possible and the spectral shape in terms of photon index and absorption has been evaluated for the first time for the majority of our sample sources. The sample, enlarged to include 4 more AGN already discussed in the literature, has been used to provide photon index and column density distribution. We obtain a mean value of 1.88 with a dispersion of 0.12, i.e. typical of an AGN sample. Sixteen objects (47%) have column densities in excess of 10^{22} cm^{-2} and, as expected, a large fraction of the absorbed sources are within the Sey 2 sample. We have provided a new diagnostic tool (NH versus F(2-10)keV/F(20-100)keV softness ratio) to isolate peculiar objects; we find at least one absorbed Sey 1 galaxy, 3 Compton thick AGN candidates; and one secure example of a "true" type 2 AGN. Within the sample of 10 still unidentified objects, 3 are almost certainly AGN of type 2; 3 to 4 have spectral slopes typical of AGN; and two are located high on the galactic plane and are strong enough radio emitters so that can be considered good AGN candidates.Comment: 15 pages, 5 figures, ApJ accepte

Acetyl-L-carnitine is an anti-angiogenic agent targeting the VEGFR2 and CXCR4 pathways

Carnitines play an important role in the energy exchange in cells, involved in the transport of fatty acids across the inner mitochondrial membrane. L-Acetylcarnitine (ALCAR) is an acetic acid ester of carnitine that has higher bioavailability than carnitine and is considered a fat-burning energizer supplement. We previously found that in serum samples from prostate cancer (PCa) patients, 3 carnitine family members were significantly decreased, suggesting a potential protective role of carnitine against PCa. Several studies support beneficial effects of carnitines on cancer, no study has investigated the activities of carnitine on tumor angiogenesis. We examined whether ALCAR act as an \u201cangiopreventive\u201d compound and studied the molecular mechanisms involved. We found that ALCAR was able to limit inflammatory angiogenesis by reducing stimulated endothelial cell and macrophage infiltration in vitro and in vivo. Molecularly, we showed that ALCAR downregulates VEGF, VEGFR2, CXCL12, CXCR4 and FAK pathways. ALCAR blocked the activation of NF-\u3baB and ICAM-1 and reduced the adhesion of a monocyte cell line to endothelial cells. This is the first study showing that ALCAR has anti-angiogenesis and anti-inflammatory properties and might be attractive candidate for cancer angiopreventionCarnitines play an important role in the energy exchange in cells, and are involved in the transport of fatty acids across the inner mitochondrial membrane. L-Acetylcarnitine (ALCAR) is an acetic acid ester of carnitine that has higher bioavailability and is considered a fat-burning energizer supplement. We previously found that in serum samples from prostate cancer (PCa) patients, 3 carnitine family members were significantly decreased, suggesting a potential protective role of carnitine against PCa. Several studies support beneficial effects of carnitines on cancer, no study has investigated the activities of carnitine on tumor angiogenesis. We examined whether ALCAR acts as an \u201cangiopreventive\u201d compound and studied the molecular mechanisms involved. We found that ALCAR was able to limit inflammatory angiogenesis by reducing stimulated endothelial cell and macrophage infiltration in vitro and in vivo. Molecularly, we show that ALCAR downregulates VEGF, VEGFR2, CXCL12, CXCR4 and FAK pathways. ALCAR blocked the activation of NF-\u3baB and ICAM-1 and reduced the adhesion of a monocyte cell line to endothelial cells. This is the first study showing that ALCAR has anti-angiogenic and anti-inflammatory properties and might be an attractive candidate for cancer angioprevention

BATSE Observations of the Piccinotti Sample of AGN

BATSE Earth occultation data have been used to search for emission in the 20-100 keV band from all sources in the Piccinotti sample, which represents to date the only complete 2-10 keV survey of the extragalactic sky down to a limiting flux of 3.1 x 10^(-11) erg cm^(-2)$ s^(-1). Nearly four years of observations have been analyzed to reach a 5sigma sensitivity level of about 7.8x 10^(-11) erg cm^(-2) s^(-1) in the band considered. Of the 36 sources in the sample, 14 have been detected above 5sigma confidence level while marginal detection (3<sigma<5) can be claimed for 13 sources; for 9 objects 2sigma upper limits are reported. Comparison of BATSE results with data at higher energies is used to estimate the robustness of our data analysis: while the detection level of each source is reliable, the flux measurement maybe overestimated in some sources by as much as 35%, probably due to incomplete data cleaning. Comparison of BATSE fluxes with X-ray fluxes, obtained in the 2-10 keV range and averaged over years, indicates that a canonical power law of photon index 1.7 gives a good description of the broad band spectra of bright AGNs and that spectral breaks preferentially occur above 100 keV.Comment: 18 pages, 1 figure. Accepted for publication on Apj

Theory of Umklapp-assisted recombination of bound excitons in Si:P

We present the calculations for the oscillator strength of the recombination of excitons bound to phosphorous donors in silicon. We show that the direct recombination of the bound exciton cannot account for the experimentally measured oscillator strength of the no-phonon line. Instead, the recombination process is assisted by an umklapp process of the donor electron state. We make use of the empirical pseudopotential method to evaluate the Umklapp-assisted recombination matrix element in second-order perturbation theory. Our result is in excellent agreement with the experiment. We also present two methods to improve the optical resolution of the optical detection of the spin state of a single nucleus in silicon.Comment: 9 pages, 6 EPS figures, Revtex