Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma

Immune surveillance by cytotoxic lymphocytes against cancer has been postulated for decades, but direct evidence for the role of cytotoxic lymphocytes in protecting against spontaneous malignancy has been lacking. As the rejection of many experimental cancers by cytotoxic T lymphocytes and natural killer cells is dependent on the pore-forming protein perforin (pfp), we examined pfp-deficient mice for increased cancer susceptibility. Here we show that pfp-deficient mice have a high incidence of malignancy in distinct lymphoid cell lineages (T, B, NKT), indicating a specific requirement for pfp in protection against lymphomagenesis. The susceptibility to lymphoma was accentuated by simultaneous lack of expression of the p53 gene, mutations in which also commonly predispose to human malignancies, including lymphoma. In contrast, the incidence and age of onset of sarcoma was unaffected in p53-deficient mice. Pfp-deficient mice were at least 1,000-fold more susceptible to these lymphomas when transplanted, compared with immunocompetent mice in which tumor rejection was controlled by CD8(+) T lymphocytes. This study is the first that implicates direct cytotoxicity by lymphocytes in regulating lymphomagenesis

BAFF and MyD88 signals promote a lupuslike disease independent of T cells

Systemic lupus erythernatosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies. However, the underlying cause of disease appears to relate to defects in T cell tolerance or T cell help to 13 cells. Transgenic (Tg) mice over-expressing the cytokine 13 cell-activating factor of the tumor necrosis factor family (BAFF) develop an autoimmune disorder similar to SLE and show impaired B cell tolerance and altered T cell differentiation. We generated BAFF Tg mice that were completely deficient in T cells, and, surprisingly, these mice developed an SLE-like disease indistinguishable from that of BAFF Tg mice. Autoimmunity in BAFF Tg mice did, however, require 13 cell-intrinsic signals through the Toll-like receptor (TLR)-associated signaling adaptor MyD88, which controlled the production of proinflammatory autoantibody isotypes. TLR7/9 activation strongly up-regulated expression of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), which is a receptor for BAFF involved in 13 cell responses to T cell-independent antigens. Moreover, BAFF enhanced TLR7/9 expression on 13 cells and TLR-mediated production of autoantibodies. Therefore, autoirnmunity in BAFF Tg mice results from altered 13 cell tolerance, but requires TLR signaling and is independent of T cell help. It is possible that SLE patients with elevated levels of BAFF show a similar basis for disease

Differential Dependence on Cysteine from Transsulfuration versus Transport During T Cell Activation

The synthesis of glutathione, a major cellular antioxidant with a critical role in T cell proliferation, is limited by cysteine. In this study, we evaluated the contributions of the xC- cystine transporter and the transsulfuration pathway to cysteine provision for glutathione synthesis and antioxidant defense in naive versus activated T cells and in the immortalized T lymphocyte cell line, Jurkat. We show that the xC- transporter, although absent in naive T cells, is induced after activation, releasing T cells from their cysteine dependence on antigen-presenting cells. We also demonstrate the existence of an intact transsulfuration pathway in naive and activated T cells and in Jurkat cells. The flux through the transsulfuration pathway increases in primary but not in transformed T cells in response to oxidative challenge by peroxide. Inhibition of the transsulfuration pathway in both primary and transformed T cells decreases cell viability under oxidative-stress conditions. Antioxid. Redox Signal. 15, 39-47.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90472/1/ars-2E2010-2E3496.pd

Australia's coastal fisheries and farmed seafood: An ecological basis for determining sustainability

In response to consumer concerns about the sustainability of Australian-sourced seafood we derive a set of criteria within an explicit decision-process that can be used to determine whether locally farmed and wild-caught Australian seafood products meet standards of ecological sustainability and Ecologically Sustainable Development. These criteria substantially address the ecological deficiencies we identified in other systems commonly used for assessing seafood sustainability. The criteria address the issues that are relevant to local seafood production, and are populated with indicators (metrics) and benchmarks relevant to the Australian context. The indicators establish performance thresholds drawn from public domain data about the products, including observed empirical data and proxies, and include default decisions to be applied in the absence of adequate information. This decision structure is set within a peer-reviewed expert jury decision-making process. The criteria, decision process and decision outcomes from assessment of a number of pilot products were tested in a real seafood market (Melbourne), where we found a high level of producer, reseller and consumer acceptance of the judgements and ratings. The use of ecologically-derived standards results in several outcomes that differ from those of other seafood assessment systems, especially those assessments more focused on production standards, such as government, industry and NGO-supported programs, popularly used in Australia and worldwide. We conclude that despite high levels of uncertainty surrounding many of the population parameters, ecological patterns and processes, empirical cost-effective proxies can be used to reasonably estimate a form of sustainability that matches consumer interests/expectations for production of fresh local seafood. Despite the plethora of industry and government programs, there remains a significant but presently unmet consumer demand for ecologically-based, technically robust, independently derived, and readily available information about the local sustainability attributes of Australian wild-caught and farmed fresh seafood

Covering Problems for Partial Words and for Indeterminate Strings

We consider the problem of computing a shortest solid cover of an indeterminate string. An indeterminate string may contain non-solid symbols, each of which specifies a subset of the alphabet that could be present at the corresponding position. We also consider covering partial words, which are a special case of indeterminate strings where each non-solid symbol is a don't care symbol. We prove that indeterminate string covering problem and partial word covering problem are NP-complete for binary alphabet and show that both problems are fixed-parameter tractable with respect to $k$, the number of non-solid symbols. For the indeterminate string covering problem we obtain a $2^{O(k \log k)} + n k^{O(1)}$-time algorithm. For the partial word covering problem we obtain a $2^{O(\sqrt{k}\log k)} + nk^{O(1)}$-time algorithm. We prove that, unless the Exponential Time Hypothesis is false, no $2^{o(\sqrt{k})} n^{O(1)}$-time solution exists for either problem, which shows that our algorithm for this case is close to optimal. We also present an algorithm for both problems which is feasible in practice.Comment: full version (simplified and corrected); preliminary version appeared at ISAAC 2014; 14 pages, 4 figure

A critical analysis of the tumour immunosurveillance controversy for 3-MCA-induced sarcomas

The cancer immunoediting hypothesis has gained significant footing over the past decade as a result of work performed using sarcomas induced by 3-methylcholanthrene (3-MCA) in mice. Despite the progress made by several groups in establishing evidence for the three phases of immunoediting (elimination, equilibrium and escape), there continues to be active controversy on the nature of interaction between spontaneously formed tumour cells and the immune system during the early phases of tumourigenesis. At the root of this controversy is conflicting and unresolved evidence spanning back to the 1970s regarding the incidence and frequency of 3-MCA-induced sarcomas in immunocompetent mice as compared to immunodeficient mice. In this mini review we provide a critical analysis of both sides of this controversy

Copy Number Variation Analysis in Single-Suture Craniosynostosis: Multiple Rare Variants Including RUNX2 Duplication in Two Cousins With Metopic Craniosynostosis

Little is known about genes that underlie isolated single-suture craniosynostosis. In this study, we hypothesize that rare copy number variants (CNV) in patients with isolated single-suture craniosynostosis contain genes important for cranial development. Using whole genome array comparative genomic hybridization (CGH), we evaluated DNA from 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications. We identified a 1.1 Mb duplication encompassing RUNX2 in two affected cousins with metopic synostosis and hypodontia. Given that RUNX2 is required as a master switch for osteoblast differentiation and interacts with TWIST I, mutations in which also cause craniosynostosis, we conclude that the duplication in this family is pathogenic, albeit with reduced penetrance. In addition, we find that a total of 7.5% of individuals with single-suture synostosis in our series have at least one rare deletion or duplication that contains genes and that has not been previously reported in unaffected individuals. The genes within and disrupted by CNVs in this cohort are potential novel candidate genes for craniosynostosis. (C) 2010 Wiley-Liss, Inc

BeadArray Expression Analysis Using Bioconductor

Illumina whole-genome expression BeadArrays are a popular choice in gene profiling studies. Aside from the vendor-provided software tools for analyzing BeadArray expression data (GenomeStudio/BeadStudio), there exists a comprehensive set of open-source analysis tools in the Bioconductor project, many of which have been tailored to exploit the unique properties of this platform. In this article, we explore a number of these software packages and demonstrate how to perform a complete analysis of BeadArray data in various formats. The key steps of importing data, performing quality assessments, preprocessing, and annotation in the common setting of assessing differential expression in designed experiments will be covered

Comprehensive analysis of Arabidopsis expression level polymorphisms with simple inheritance

In Arabidopsis thaliana, gene expression level polymorphisms (ELPs) between natural accessions that exhibit simple, single locus inheritance are promising quantitative trait locus (QTL) candidates to explain phenotypic variability. It is assumed that such ELPs overwhelmingly represent regulatory element polymorphisms. However, comprehensive genome-wide analyses linking expression level, regulatory sequence and gene structure variation are missing, preventing definite verification of this assumption. Here, we analyzed ELPs observed between the Eil-0 and Lc-0 accessions. Compared with non-variable controls, 5′ regulatory sequence variation in the corresponding genes is indeed increased. However, ∼42% of all the ELP genes also carry major transcription unit deletions in one parent as revealed by genome tiling arrays, representing a >4-fold enrichment over controls. Within the subset of ELPs with simple inheritance, this proportion is even higher and deletions are generally more severe. Similar results were obtained from analyses of the Bay-0 and Sha accessions, using alternative technical approaches. Collectively, our results suggest that drastic structural changes are a major cause for ELPs with simple inheritance, corroborating experimentally observed indel preponderance in cloned Arabidopsis QTL