Weak managers and the plight of white-collar workers

Far too many employees are unhappy at work. Today, one of the major problems - resulting from weak, callous, dispassionate, greedy managers and leaders - is the great number of workers, including white-collar ones, who are grossly underemployed, underpaid, and maltreated by management

Mapping spaces in Quasi-categories

We apply the Dwyer-Kan theory of homotopy function complexes in model categories to the study of mapping spaces in quasi-categories. Using this, together with our work on rigidification from [DS1], we give a streamlined proof of the Quillen equivalence between quasi-categories and simplicial categories. Some useful material about relative mapping spaces in quasi-categories is developed along the way

A curious example of two model categories and some associated differential graded algebras

The paper gives a new proof that the model categories of stable modules for the rings Z/(p^2) and (Z/p)[\epsilon]/(\epsilon^2) are not Quillen equivalent. The proof uses homotopy endomorphism ring spectra. Our considerations lead to an example of two differential graded algebras which are derived equivalent but whose associated model categories of modules are not Quillen equivalent. As a bonus, we also obtain derived equivalent dgas with non-isomorphic K-theories

Rigidification of quasi-categories

We give a new construction for rigidifying a quasi-category into a simplicial category, and prove that it is weakly equivalent to the rigidification given by Lurie. Our construction comes from the use of necklaces, which are simplicial sets obtained by stringing simplices together. As an application of these methods, we use our model to reprove some basic facts from Lurie's "Higher Topos Theory" regarding the rigidification process.Comment: 26 page

Duality and Pro-Spectra

Cofiltered diagrams of spectra, also called pro-spectra, have arisen in diverse areas, and to date have been treated in an ad hoc manner. The purpose of this paper is to systematically develop a homotopy theory of pro-spectra and to study its relation to the usual homotopy theory of spectra, as a foundation for future applications. The surprising result we find is that our homotopy theory of pro-spectra is Quillen equivalent to the opposite of the homotopy theory of spectra. This provides a convenient duality theory for all spectra, extending the classical notion of Spanier-Whitehead duality which works well only for finite spectra. Roughly speaking, the new duality functor takes a spectrum to the cofiltered diagram of the Spanier-Whitehead duals of its finite subcomplexes. In the other direction, the duality functor takes a cofiltered diagram of spectra to the filtered colimit of the Spanier-Whitehead duals of the spectra in the diagram. We prove the equivalence of homotopy theories by showing that both are equivalent to the category of ind-spectra (filtered diagrams of spectra). To construct our new homotopy theories, we prove a general existence theorem for colocalization model structures generalizing known results for cofibrantly generated model categories.Comment: Published by Algebraic and Geometric Topology at http://www.maths.warwick.ac.uk/agt/AGTVol4/agt-4-34.abs.htm

Obstruction Theory in Model Categories

Many examples of obstruction theory can be formulated as the study of when a lift exists in a commutative square. Typically, one of the maps is a cofibration of some sort and the opposite map is a fibration, and there is a functorial obstruction class that determines whether a lift exists. Working in an arbitrary pointed proper model category, we classify the cofibrations that have such an obstruction theory with respect to all fibrations. Up to weak equivalence, retract, and cobase change, they are the cofibrations with weakly contractible target. Equivalently, they are the retracts of principal cofibrations. Without properness, the same classification holds for cofibrations with cofibrant source. Our results dualize to give a classification of fibrations that have an obstruction theory.Comment: 17 pages. v3 includes improved introduction and several other minor improvement

Alphavirus Replicon Particles Expressing TRP-2 Provide Potent Therapeutic Effect on Melanoma through Activation of Humoral and Cellular Immunity

Malignant melanoma is the deadliest form of skin cancer and is refractory to conventional chemotherapy and radiotherapy. Therefore alternative approaches to treat this disease, such as immunotherapy, are needed. Melanoma vaccine design has mainly focused on targeting CD8+ T cells. Activation of effector CD8+ T cells has been achieved in patients, but provided limited clinical benefit, due to immune-escape mechanisms established by advanced tumors. We have previously shown that alphavirus-based virus-like replicon particles (VRP) simultaneously activate strong cellular and humoral immunity against the weakly immunogenic melanoma differentiation antigen (MDA) tyrosinase. Here we further investigate the antitumor effect and the immune mechanisms of VRP encoding different MDAs.VRP encoding different MDAs were screened for their ability to prevent the growth of the B16 mouse transplantable melanoma. The immunologic mechanisms of efficacy were investigated for the most effective vaccine identified, focusing on CD8+ T cells and humoral responses. To this end, ex vivo immune assays and transgenic mice lacking specific immune effector functions were used. The studies identified a potent therapeutic VRP vaccine, encoding tyrosinase related protein 2 (TRP-2), which provided a durable anti-tumor effect. The efficacy of VRP-TRP2 relies on a novel immune mechanism of action requiring the activation of both IgG and CD8+ T cell effector responses, and depends on signaling through activating Fcγ receptors.This study identifies a VRP-based vaccine able to elicit humoral immunity against TRP-2, which plays a role in melanoma immunotherapy and synergizes with tumor-specific CD8+ T cell responses. These findings will aid in the rational design of future immunotherapy clinical trials

Phenotype-genotype association grid: a convenient method for summarizing multiple association analyses

BACKGROUND: High-throughput genotyping generates vast amounts of data for analysis; results can be difficult to summarize succinctly. A single project may involve genotyping many genes with multiple variants per gene and analyzing each variant in relation to numerous phenotypes, using several genetic models and population subgroups. Hundreds of statistical tests may be performed for a single SNP, thereby complicating interpretation of results and inhibiting identification of patterns of association. RESULTS: To facilitate visual display and summary of large numbers of association tests of genetic loci with multiple phenotypes, we developed a Phenotype-Genotype Association (PGA) grid display. A database-backed web server was used to create PGA grids from phenotypic and genotypic data (sample sizes, means and standard errors, P-value for association). HTML pages were generated using Tcl scripts on an AOLserver platform, using an Oracle database, and the ArsDigita Community System web toolkit. The grids are interactive and permit display of summary data for individual cells by a mouse click (i.e. least squares means for a given SNP and phenotype, specified genetic model and study sample). PGA grids can be used to visually summarize results of individual SNP associations, gene-environment associations, or haplotype associations. CONCLUSION: The PGA grid, which permits interactive exploration of large numbers of association test results, can serve as an easily adapted common and useful display format for large-scale genetic studies. Doing so would reduce the problem of publication bias, and would simplify the task of summarizing large-scale association studies

Multifactor dimensionality reduction for graphics processing units enables genome-wide testing of epistasis in sporadic ALS

Motivation: Epistasis, the presence of gene–gene interactions, has been hypothesized to be at the root of many common human diseases, but current genome-wide association studies largely ignore its role. Multifactor dimensionality reduction (MDR) is a powerful model-free method for detecting epistatic relationships between genes, but computational costs have made its application to genome-wide data difficult. Graphics processing units (GPUs), the hardware responsible for rendering computer games, are powerful parallel processors. Using GPUs to run MDR on a genome-wide dataset allows for statistically rigorous testing of epistasis

Agonist Anti-GITR Monoclonal Antibody Induces Melanoma Tumor Immunity in Mice by Altering Regulatory T Cell Stability and Intra-Tumor Accumulation

In vivo GITR ligation has previously been shown to augment T-cell-mediated anti-tumor immunity, yet the underlying mechanisms of this activity, particularly its in vivo effects on CD4+ foxp3+ regulatory T cells (Tregs), have not been fully elucidated. In order to translate this immunotherapeutic approach to the clinic it is important gain better understanding of its mechanism(s) of action. Utilizing the agonist anti-GITR monoclonal antibody DTA-1, we found that in vivo GITR ligation modulates regulatory T cells (Tregs) directly during induction of melanoma tumor immunity. As a monotherapy, DTA-1 induced regression of small established B16 melanoma tumors. Although DTA-1 did not alter systemic Treg frequencies nor abrogate the intrinsic suppressive activity of Tregs within the tumor-draining lymph node, intra-tumor Treg accumulation was significantly impaired. This resulted in a greater Teff:Treg ratio and enhanced tumor-specific CD8+ T-cell activity. The decreased intra-tumor Treg accumulation was due both to impaired infiltration, coupled with DTA-1-induced loss of foxp3 expression in intra-tumor Tregs. Histological analysis of B16 tumors grown in Foxp3-GFP mice showed that the majority of GFP+ cells had lost Foxp3 expression. These “unstable” Tregs were absent in IgG-treated tumors and in DTA-1 treated TDLN, demonstrating a tumor-specific effect. Impairment of Treg infiltration was lost if Tregs were GITR−/−, and the protective effects of DTA-1 were reduced in reconstituted RAG1−/− mice if either the Treg or Teff subset were GITR-negative and absent if both were negative. Our results demonstrate that DTA-1 modulates both Teffs and Tregs during effective tumor treatment. The data suggest that DTA-1 prevents intra-tumor Treg accumulation by altering their stability, and as a result of the loss of foxp3 expression, may modify their intra-tumor suppressive capacity. These findings provide further support for the continued development of agonist anti-GITR mAbs as an immunotherapeutic strategy for cancer