Dlgh1 coordinates actin polymerization, synaptic T cell receptor and lipid raft aggregation, and effector function in T cells.

Lipid raft membrane compartmentalization and membrane-associated guanylate kinase (MAGUK) family molecular scaffolds function in establishing cell polarity and organizing signal transducers within epithelial cell junctions and neuronal synapses. Here, we elucidate a role for the MAGUK protein, Dlgh1, in polarized T cell synapse assembly and T cell function. We find that Dlgh1 translocates to the immune synapse and lipid rafts in response to T cell receptor (TCR)/CD28 engagement and that LckSH3-mediated interactions with Dlgh1 control its membrane targeting. TCR/CD28 engagement induces the formation of endogenous Lck-Dlgh1-Zap70-Wiskott-Aldrich syndrome protein (WASp) complexes in which Dlgh1 acts to facilitate interactions of Lck with Zap70 and WASp. Using small interfering RNA and overexpression approaches, we show that Dlgh1 promotes antigen-induced actin polymerization, synaptic raft and TCR clustering, nuclear factor of activated T cell activity, and cytokine production. We propose that Dlgh1 coordinates TCR/CD28-induced actin-driven T cell synapse assembly, signal transduction, and effector function. These findings highlight common molecular strategies used to regulate cell polarity, synapse assembly, and transducer organization in diverse cellular systems

The Degradome database: mammalian proteases and diseases of proteolysis

The degradome is defined as the complete set of proteases present in an organism. The recent availability of whole genomic sequences from multiple organisms has led us to predict the contents of the degradomes of several mammalian species. To ensure the fidelity of these predictions, our methods have included manual curation of individual sequences and, when necessary, direct cloning and sequencing experiments. The results of these studies in human, chimpanzee, mouse and rat have been incorporated into the Degradome database, which can be accessed through a web interface at http://degradome.uniovi.es. The annotations about each individual protease can be retrieved by browsing catalytic classes and families or by searching specific terms. This web site also provides detailed information about genetic diseases of proteolysis, a growing field of great importance for multiple users. Finally, the user can find additional information about protease structures, protease inhibitors, ancillary domains of proteases and differences between mammalian degradomes

Internet of Things for Sustainable Mining

The sustainable mining Internet of Things deals with the applications of IoT technology to the coupled needs of sustainable recovery of metals and a healthy environment for a thriving planet. In this chapter, the IoT architecture and technology is presented to support development of a digital mining platform emphasizing the exploration of rock–fluid–environment interactions to develop extraction methods with maximum economic benefit, while maintaining and preserving both water quantity and quality, soil, and, ultimately, human health. New perspectives are provided for IoT applications in developing new mineral resources, improved management of tailings, monitoring and mitigating contamination from mining. Moreover, tools to assess the environmental and social impacts of mining including the demands on dwindling freshwater resources. The cutting-edge technologies that could be leveraged to develop the state-of-the-art sustainable mining IoT paradigm are also discussed

Dendritic cell-specific delivery of Flt3L by coronavirus vectors secures induction of therapeutic antitumor immunity

Efficacy of antitumor vaccination depends to a large extent on antigen targeting to dendritic cells (DCs). Here, we assessed antitumor immunity induced by attenuated coronavirus vectors which exclusively target DCs in vivo and express either lymphocyte- or DC-activating cytokines in combination with a GFP-tagged model antigen. Tracking of in vivo transduced DCs revealed that vectors encoding for Fms-like tyrosine kinase 3 ligand (Flt3L) exhibited a higher capacity to induce DC maturation compared to vectors delivering IL-2 or IL-15. Moreover, Flt3L vectors more efficiently induced tumor-specific CD8(+) T cells, expanded the epitope repertoire, and provided both prophylactic and therapeutic tumor immunity. In contrast, IL-2- or IL-15-encoding vectors showed a substantially lower efficacy in CD8(+) T cell priming and failed to protect the host once tumors had been established. Thus, specific in vivo targeting of DCs with coronavirus vectors in conjunction with appropriate conditioning of the microenvironment through Flt3L represents an efficient strategy for the generation of therapeutic antitumor immunity

The Roles of Standardization, Certification and Assurance Services in Global Commerce

In this article we examine the rapid emergence and expansion of standardized product and process frameworks and a private-sector compliance and enforcement infrastructure that we believe may increasingly be providing a substitute for public and legal regulatory infrastructure in global commerce. This infrastructure is provided by a proliferation of performance codes and standards, many of which define acceptable social and environmental behavior, and a rapidly-growing number of privately-trained and authorized inspectors and certifiers that we call the third-party assurance industry. We offer reasons for this development, evidence of its scope and scale, and then describe the phenomenon in more detail by examining supply chain arrangements in two industries, food products and apparel, where the use of third-party standards and assurance services has expanded especially rapidly. We conclude with a discussion of the implications for the make or buy decision at the core of the theory of the firm. We argue that as quasi-regulatory standards are developed within various industries, and as performance to these standards can be systematically evaluated using third-party inspectors and certifiers, the costs of moving production outside of vertical firm hierarchies drop. We believe this may be an important factor in accelerating the shift to outsourcing that has been observed over the last two decades

Performance Assessment in Fingerprinting and Multi Component Quantitative NMR Analyses

An interlaboratory comparison (ILC) was organized with the aim to set up quality control indicators suitable for multicomponent quantitative analysis by nuclear magnetic resonance (NMR) spectroscopy. A total of 36 NMR data sets (corresponding to 1260 NMR spectra) were produced by 30 participants using 34 NMR spectrometers. The calibration line method was chosen for the quantification of a five-component model mixture. Results show that quantitative NMR is a robust quantification tool and that 26 out of 36 data sets resulted in statistically equivalent calibration lines for all considered NMR signals. The performance of each laboratory was assessed by means of a new performance index (named Qp-score) which is related to the difference between the experimental and the consensus values of the slope of the calibration lines. Laboratories endowed with a Qp-score falling within the suitable acceptability range are qualified to produce NMR spectra that can be considered statistically equivalent in terms of relative intensities of the signals. In addition, the specific response of nuclei to the experimental excitation/relaxation conditions was addressed by means of the parameter named NR. NR is related to the difference between the theoretical and the consensus slopes of the calibration lines and is specific for each signal produced by a well-defined set of acquisition parameters

Nurses' experiences, expectations, and preferences for mind-body practices to reduce stress

BACKGROUND: Most research on the impact of mind-body training does not ask about participants\u27 baseline experience, expectations, or preferences for training. To better plan participant-centered mind-body intervention trials for nurses to reduce occupational stress, such descriptive information would be valuable. METHODS: We conducted an anonymous email survey between April and June, 2010 of North American nurses interested in mind-body training to reduce stress. The e-survey included: demographic characteristics, health conditions and stress levels; experiences with mind-body practices; expected health benefits; training preferences; and willingness to participate in future randomized controlled trials. RESULTS: Of the 342 respondents, 96% were women and 92% were Caucasian. Most (73%) reported one or more health conditions, notably anxiety (49%); back pain (41%); GI problems such as irritable bowel syndrome (34%); or depression (33%). Their median occupational stress level was 4 (0 = none; 5 = extreme stress). Nearly all (99%) reported already using one or more mind-body practices to reduce stress: intercessory prayer (86%), breath-focused meditation (49%), healing or therapeutic touch (39%), yoga/tai chi/qi gong (34%), or mindfulness-based meditation (18%). The greatest expected benefits were for greater spiritual well-being (56%); serenity, calm, or inner peace (54%); better mood (51%); more compassion (50%); or better sleep (42%). Most (65%) wanted additional training; convenience (74% essential or very important), was more important than the program\u27s reputation (49%) or scientific evidence about effectiveness (32%) in program selection. Most (65%) were willing to participate in a randomized trial of mind-body training; among these, most were willing to collect salivary cortisol (60%), or serum biomarkers (53%) to assess the impact of training. CONCLUSIONS: Most nurses interested in mind-body training already engage in such practices. They have greater expectations about spiritual and emotional than physical benefits, but are willing to participate in studies and to collect biomarker data. Recruitment may depend more on convenience than a program\u27s scientific basis or reputation. Knowledge of participants\u27 baseline experiences, expectations, and preferences helps inform future training and research on mind-body approaches to reduce stress

Effect of B7.1 Costimulation on T-Cell Based Immunity against TAP-Negative Cancer Can Be Facilitated by TAP1 Expression

Tumors deficient in expression of the transporter associated with antigen processing (TAP) usually fail to induce T-cell-mediated immunity and are resistant to T-cell lysis. However, we have found that introduction of the B7.1 gene into TAP-negative (TAP−) or TAP1-transfected (TAP1+) murine lung carcinoma CMT.64 cells can augment the capacity of the cells to induce a protective immune response against wild-type tumor cells. Differences in the strength of the protective immune responses were observed between TAP− and TAP1+ B7.1 expressing CMT.64 cells depending on the doses of γ-irradiated cell immunization. While mice immunized with either high or low dose of B7.1-expressing TAP1+ cells rejected TAP− tumors, only high dose immunization with B7.1-expressing TAP− cells resulted in tumor rejection. The induced protective immunity was T-cell dependent as demonstrated by dramatically reduced antitumor immunity in mice depleted of CD8 or CD4 cells. Augmentation of T-cell mediated immune response against TAP− tumor cells was also observed in a virally infected tumor cell system. When mice were immunized with a high dose of γ-irradiated CMT.64 cells infected with vaccinia viruses carrying B7.1 and/or TAP1 genes, we found that the cells co-expressing B7.1 and TAP1, but not those expressing B7.1 alone, induced protective immunity against CMT.64 cells. In addition, inoculation with live tumor cells transfected with several different gene(s) revealed that only B7.1- and TAP1-coexpressing tumor cells significantly decreased tumorigenicity. These results indicate that B7.1-provoked antitumor immunity against TAP− cancer is facilitated by TAP1-expression, and thus both genes should be considered for cancer therapy in the future