ILC1s in tissue inflammation and infection

Innate lymphoid cells (ILCs) are innate immune cells that provide an early source of cytokines to initiate and tailor the immune response to the type of the encountered pathogen or insult. The group 1 ILCs are comprised of conventional natural killer (cNK) cells and subsets of unconventional NK cells, termed ILC1s. Although cNK cells and ILC1s share many features, such as certain phenotypic markers and the ability to produce IFN-γ upon activation, it is now becoming apparent that these two subsets develop from different progenitors and show unique tissue distribution and functional characteristics. Recent studies have aimed at elucidating the individual contributions of cNK cells and ILC1s during protective host responses, as well as during chronic inflammation. This review provides an overview of the current knowledge of the developmental origins, as well as of the phenotypic and functional characteristics of ILC1s

Loss of DAP12 and FcRγ drives exaggerated IL-12 production and CD8(+) T cell response by CCR2(+) Mo-DCs

Dap12 and FcRγ, the two transmembrane ITAM-containing signaling adaptors expressed in dendritic cells (DC), are implicated in the regulation of DC function. Several activating and adhesion receptors including integrins require these chains for their function in triggering downstream signaling and effector pathways, however the exact role(s) for Dap12 and FcRγ remains elusive as their loss can lead to both attenuating and enhancing effects. Here, we report that mice congenitally lacking both Dap12 and FcRγ chains (DF) show a massively enhanced effector CD8(+) T cell response to protein antigen immunization or West Nile Virus (WNV) infection. Thus, immunization of DF mice with MHCI-restricted OVA peptide leads to accumulation of IL-12-producing monocyte-derived dendritic cells (Mo-DC) in draining lymph nodes, followed by vastly enhanced generation of antigen-specific IFNγ-producing CD8(+) T cells. Moreover, DF mice show increased viral clearance in the WNV infection model. Depletion of CCR2+ monocytes/macrophages in vivo by administration anti-CCR2 antibodies or clodronate liposomes completely prevents the exaggerated CD8+ T cell response in DF mice. Mechanistically, we show that the loss of Dap12 and FcRγ-mediated signals in Mo-DC leads to a disruption of GM-CSF receptor-induced STAT5 activation resulting in upregulation of expression of IRF8, a transcription factor. Consequently, Dap12- and FcRγ-deficiency exacerbates GM-CSF-driven monocyte differentiation and production of inflammatory Mo-DC. Our data suggest a novel cross-talk between DC-ITAM and GM-CSF signaling pathways, which controls Mo-DC differentiation, IL-12 production, and CD8(+) T cell responses

Modeling for nano risk assessment and management: The development of integrated governance tools and the potential role of technology assessment

In nano risk governance, we observe a trend toward coupling and integrating a variety of computational models into integrated risk governance tools. This article discusses the development and design of such integrated tools as ‘nano risk governance imaginaries in the making.’ Using an illustrative example, the SUNDS tool, we show how the tool manifests conceptual shifts from risk to innovation governance, a technocratic evidence culture based on the quantification of risks, and an envisioned application in industrial innovation management. This conceptualization runs the risk of narrowing the view of nano risks and cementing the widely lamented democratic deficit in risk governance. We therefore conclude that the development and application of integrated governance tools are highly relevant for technology assessment (TA) and TA should actively engage in their development processes

A Broad Phenotypic Screen Identifies Novel Phenotypes Driven by a Single Mutant Allele in Huntington’s Disease CAG Knock-In Mice

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing

UWB antenna design and ray tracing method for robot localization

This poster presents a new base station antenna design and preliminary results on electric field mapping for localizing a UWB-MICS robot in an arena. A batch of new base station antenna prototypes, was built and measured at EPFL - LEMA. A microstrip-fed compact monopole design, built in the inexpensive FR4 substrate, was chosen. Reflexion coefficient measurements and radiation pattern simulations meet the project specifications. The presented prototype is electrically small and therefore affected by the feeding and surroundings – the final revision will take the actual deployment points into account. An existing LEMA ray-tracing code was adapted for use in the project. A simple scenario was tested as proof-of-concept, estimating the electric field in the arena taking into account three reflections. The model will be improved by using the real radiation pattern from the base station antenna and improving the boundary conditions

Stereotactic Image-Guidance for Ablation of Malignant Liver Tumors

Stereotactic percutaneous ablation is a rapidly advancing modality for treatment of tumors in soft solid organs such as the liver. Each year, there are about 850,000 cases of primary liver cancer worldwide. Although surgical resection still is the gold standard for most cases, only 20–30% of patients are candidates for it, due to the advanced stage of the disease. Surgery can also be a huge burden to the patient and his/her quality of life might be temporarily severely reduced due to long hospital stays, complications, and slow recovery. To overcome these disadvantages, thermo-ablation of tumors of up to 3 cm has become a more viable alternative especially in the last decade, offering a potentially equally effective but minimally invasive and tissue sparing treatment alternative. In conjunction with improved CT imaging, stereotactic image-guidance techniques and image fusion technology were introduced to increase safety, efficacy, and accuracy of this treatment. Stereotactic image-guidance leads to a simple, fast, and accurate placement of the ablation probe into the liver tumor, which is a prerequisite for a complete destruction of the tumor by ablation. More and more physicians, including surgeons, consider ablation a viable alternative to resection whenever feasible. Patients undergoing such a minimally invasive treatment benefit from a shorter hospital stays, reduced complication rates, and faster recovery

Presenilin‐dependent γ‐secretase processing of β‐amyloid precursor protein at a site corresponding to the S3 cleavage of Notch

The presenilin (PS)-dependent site 3 (S3) cleavage of Notch liberates its intracellular domain (NICD), which is required for Notch signaling. The similar gamma-secretase cleavage of the beta-amyloid precursor protein (betaAPP) results in the secretion of amyloid beta-peptide (Abeta). However, little is known about the corresponding C-terminal cleavage product (CTFgamma). We have now identified CTFgamma in brain tissue, in living cells, as well as in an in vitro system. Generation of CTFgamma is facilitated by PSs, since a dominant-negative mutation of PS as well as a PS gene knock out prevents its production. Moreover, gamma-secretase inhibitors, including one that is known to bind to PS, also block CTFgamma generation. Sequence analysis revealed that CTFgamma is produced by a novel gamma-secretase cut, which occurs at a site corresponding to the S3 cleavage of Notch