Fog Computing (FC) was introduced to offer resources closer to the users. Researchers propose different solutions to make FC mature and use simulators for evaluating their solutions at early stages. ...In this paper, we compare different FC simulators based on their technical and non-technical characteristics. In addition, a practical comparison is conducted to compare the three main FC simulators based on their performance such as execution time, CPU, and memory usage for running different applications. The analysis can be helpful for researchers to select the appropriate simulator and platform to evaluate their solutions on different use cases. Furthermore, open issues and challenges for FC simulators are discussed that require attention and need to be addressed in the future.
The precise identification of Human Leukocyte Antigen class I (HLA-I) binding motifs plays a central role in our ability to understand and predict (neo-)antigen presentation in infectious diseases ...and cancer. Here, by exploiting co-occurrence of HLA-I alleles across ten newly generated as well as forty public HLA peptidomics datasets comprising more than 115,000 unique peptides, we show that we can rapidly and accurately identify many HLA-I binding motifs and map them to their corresponding alleles without any a priori knowledge of HLA-I binding specificity. Our approach recapitulates and refines known motifs for 43 of the most frequent alleles, uncovers new motifs for 9 alleles that up to now had less than five known ligands and provides a scalable framework to incorporate additional HLA peptidomics studies in the future. The refined motifs improve neo-antigen and cancer testis antigen predictions, indicating that unbiased HLA peptidomics data are ideal for in silico predictions of neo-antigens from tumor exome sequencing data. The new motifs further reveal distant modulation of the binding specificity at P2 for some HLA-I alleles by residues in the HLA-I binding site but outside of the B-pocket and we unravel the underlying mechanisms by protein structure analysis, mutagenesis and in vitro binding assays.
Predictions of epitopes presented by class II human leukocyte antigen molecules (HLA-II) have limited accuracy, restricting vaccine and therapy design. Here we combined unbiased mass spectrometry ...with a motif deconvolution algorithm to profile and analyze a total of 99,265 unique peptides eluted from HLA-II molecules. We then trained an epitope prediction algorithm with these data and improved prediction of pathogen and tumor-associated class II neoepitopes.
A number of studies from Tel Aviv date the rise of the pork taboo in Israel as early as the Iron Age I in order to salvage the notion that the taboo was a reaction to the pork-consuming habits of the ...hated Philistines. Though neither DNA analysis nor pig bone ratios support this scenario, these studies explain how the abhorrence of Iron Age Israelites for pork was eventually canonised in the Persian era. The present paper challenges the validity of each stage of the proposed scenario, arguing that the Hellenistic-era ethnic differentiation based on pork consumption cannot be pushed as far back as the Iron Age.
Land, Credit and Crisis presents a new understanding of the financial culture of the Bible. Biblical Palestine was characterized by an over-abundance of arable land combined with a chronic lack of ...manpower and agricultural credit - circumstances which lead to much prophetic fulminating against merchants and the rich. The book reveals how the financial instruments and institutions of the time reflected a tough economic realism and argues that the image of the biblical prophet as a champion of social justice must be revised.
HLA-I molecules bind short peptides and present them for recognition by CD8
T cells. The length of HLA-I ligands typically ranges from 8 to 12 aa, but variability is observed across different HLA-I ...alleles. In this study we collected recent in-depth HLA peptidomics data, including 12 newly generated HLA peptidomes (31,896 unique peptides) from human meningioma samples, to analyze the peptide length distribution and multiple specificity across 84 different HLA-I alleles. We observed a clear clustering of HLA-I alleles with distinct peptide length distributions, which enabled us to study the structural basis of peptide length distributions and predict peptide length distributions from HLA-I sequences. We further identified multiple specificity in several HLA-I molecules and validated these observations with binding assays. Explicitly modeling peptide length distribution and multiple specificity improved predictions of naturally presented HLA-I ligands, as demonstrated in an independent benchmarking based on the new human meningioma samples.
Immunotherapy directed against private tumor neo-antigens derived from non-synonymous somatic mutations is a promising strategy of personalized cancer immunotherapy. However, feasibility in low ...mutational load tumor types remains unknown. Comprehensive and deep analysis of circulating and tumor-infiltrating lymphocytes (TILs) for neo-epitope specific CD8
T cells has allowed prompt identification of oligoclonal and polyfunctional such cells from most immunotherapy-naive patients with advanced epithelial ovarian cancer studied. Neo-epitope recognition is discordant between circulating T cells and TILs, and is more likely to be found among TILs, which display higher functional avidity and unique TCRs with higher predicted affinity than their blood counterparts. Our results imply that identification of neo-epitope specific CD8
T cells is achievable even in tumors with relatively low number of somatic mutations, and neo-epitope validation in TILs extends opportunities for mutanome-based personalized immunotherapies to such tumors.
Animal models of skin disease are used to evaluate therapeutics to alleviate disease. One common clinical dermatological complaint is pruritus (itch), but there is a lack of standardization in the ...characterization of pre-clinical models and scratching behavior, a key itch endpoint, is often neglected. One such model is the widely used imiquimod (IMQ) mouse model of psoriasis. However, it lacks characterized behavioral attributes like scratching, nor has widely expanded to other species like rats. We demonstrate that the IMQ model can be reproduced in rats, including their genetically modified derivatives, and how scratching can be used as a key behavioral endpoint. We systemically delivered an anti-PAR2 antibody (P24E1102) which reversed scratching bouts--validating this behavioral methodology and have shown its feasibility and value in identifying effective antipruritic drugs.
Recruitment and activation of CD8 T cells occur through specific triggering of T cell receptor (TCR) by peptide-bound human leucocyte antigen (HLA) ligands. Within the generated trimeric ...TCR-peptide:HLA complex, the molecular binding affinities between peptide and HLA, and between TCR and peptide:HLA both impact T cell functional outcomes. However, how their individual and combined effects modulate immunogenicity and overall T cell responsiveness has not been investigated systematically. Here, we established two panels of human tumor peptide variants differing in their affinity to HLA. For precise characterization, we developed the "blue peptide assay", an upgraded cell-based approach to measure the peptide:HLA affinity. These peptide variants were then used to investigate the cross-reactivity of tumor antigen-specific CD8 T cell clonotypes derived from blood of cancer patients after vaccination with either the native or an affinity-optimized Melan-A/MART-1 epitope, or isolated from tumor infiltrated lymph nodes (TILNs). Vaccines containing the native tumor epitope generated T cells with better functionality, and superior cross-reactivity against potential low affinity escape epitopes, as compared to T cells induced by vaccines containing an HLA affinity-optimized epitope. Comparatively, Melan-A/MART-1-specific TILN cells displayed functional and cross-reactive profiles that were heterogeneous and clonotype-dependent. Finally, we took advantage of a collection of T cells expressing affinity-optimized NY-ESO-1-specific TCRs to interrogate the individual and combined impact of peptide:HLA and TCR-pHLA affinities on overall CD8 T cell responses. We found profound and distinct effects of both biophysical parameters, with additive contributions and absence of hierarchical dominance. Altogether, the biological impact of peptide:HLA and TCR-pHLA affinities on T cell responses was carefully dissected in two antigenic systems, frequently targeted in human cancer immunotherapy. Our technology and stepwise comparison open new insights into the rational design and selection of vaccine-associated tumor-specific epitopes and highlight the functional and cross-reactivity profiles that endow T cells with best tumor control capacity.
New Teaching Perspectives from Working with Young People with Hearing Disabilities. Language is not a particular case of the semiotic function. That is why it seems possible to me, even if there is ...no strict historical coincidence, to postulate a convergence not yet noticed between the evolutions of the two manifestations of the semiotic function, the image and the language representations. To do that, I will refer to the structural evolution of languages proposed by Gustave Guillaume, with its three linguistic areas, and to that of the balancing forms of Jean Piaget’s genetic epistemology with its three stages. The research field is a vast one. Here I will limit myself to trying to show that language and its grammar are, for the discourse of a speaker of a tertiary language, what perspective is for the figurative image (painted or drawn) of an artist of the Western world. More precisely, perspective and grammar ensure the same function of knowing how to allow prominence to the vision of the one expressing himself/herself and by doing so they can both introduce space into representation.
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