Beyond “Big Eaters”: The Versatile Role of Alveolar Macrophages in Health and Disease

Macrophages act as immune scavengers and are important cell types in the homeostasis of various tissues. Given the multiple roles of macrophages, these cells can also be found as tissue resident macrophages tightly integrated into a variety of tissues in which they fulfill crucial and organ-specific functions. The lung harbors at least two macrophage populations: interstitial and alveolar macrophages, which occupy different niches and functions. In this review, we provide the latest insights into the multiple roles of alveolar macrophages while unraveling the distinct factors which can influence the ontogeny and function of these cells. Furthermore, we will highlight pulmonary diseases, which are associated with dysfunctional macrophages, concentrating on congenital diseases as well as pulmonary infections and impairment of immunological pathways. Moreover, we will provide an overview about different treatment approaches targeting macrophage dysfunction. Improved knowledge of the role of macrophages in the onset of pulmonary diseases may provide the basis for new pharmacological and/or cell-based immunotherapies and will extend our understanding to other macrophage-related disorders.     

Simplified Monopalmitoyl Toll-like Receptor 2 Ligand Mini-UPam for Self-Adjuvanting Neoantigen-Based Synthetic Cancer Vaccines

Synthetic vaccines, based on antigenic peptides that comprise MHC−I and MHC-II T-cell epitopes expressed by tumors, show great promise for the immunotherapy of cancer. For optimal immunogenicity, the synthetic peptides (SPs) should be adjuvanted with suitable immunostimulatory additives. Previously, we have shown that improved immunogenicity in vivo is obtained with vaccine modalities in which an SP is covalently connected to an adjuvanting moiety, typically a ligand to Toll-like receptor 2 (TLR2). SPs were covalently attached to UPam, which is a derivative of the classic TLR2 ligand Pam₃CysSK₄. A disadvantage of the triply palmitoylated UPam is its high lipophilicity, which precludes universal adoption of this adjuvant for covalent modification of various antigenic peptides as it renders the synthetic vaccine insoluble in several cases. Here, we report a novel conjugatable TLR2 ligand, mini-UPam, which contains only one palmitoyl chain, rather than three, and therefore has less impact on the solubility and other physicochemical properties of a synthetic peptide. In this study, we used SPs that contain the clinically relevant neoepitopes identified in a melanoma patient who completely recovered after T-cell therapy. Homogeneous mini-UPam-SP conjugates have been prepared in good yields by stepwise solid-phase synthesis that employed a mini-UPam building block pre-prepared in solution and the standard set of Fmoc-amino acids. The immunogenicity of the novel mini-UPam-SP conjugates was demonstrated by using the cancer patient's T-cells.     

CMC jackets for metallic pipes – A novel approach to prevent the creep deformation of thermo-mechanically loaded metals

Steel materials suffer extensive creep by the application at temperatures of about 700?°C and pressures about 350?bar in a power plant environment. The presented concept overwraps a steel pipe with a ceramic matrix composite (CMC) jacket in order to support the steel pipe and provide high temperature strength. Finite Element simulations show the influence of the wall thickness of CMC jacket and the coefficient of thermal expansion (CTE) on circumferential stresses within the hybrid metal ceramic pipe. Suitable fiber and matrix materials were studied, composites fabricated and mechanical properties determined. Finally, a prototype was designed in order to confirm the feasibility of the concept. The lifetime of a pure steel pipe was increased by more than four-fold by the additional CMC jacket.     

An Organoid for Woven Bone

Bone formation (osteogenesis) is a complex process in which cellular differentiation and the generation of a mineralized organic matrix are synchronized to produce a hybrid hierarchical architecture. To study the mechanisms of osteogenesis in health and disease, there is a great need for functional model systems that capture in parallel, both cellular and matrix formation processes. Stem cell-based organoids are promising as functional, self-organizing 3D in vitro models for studying the physiology and pathology of various tissues. However, for human bone, no such functional model system is yet available. This study reports the in vitro differentiation of human bone marrow stromal cells into a functional 3D self-organizing co-culture of osteoblasts and osteocytes, creating an organoid for early stage bone (woven bone) formation. It demonstrates the formation of an organoid where osteocytes are embedded within the collagen matrix that is produced by the osteoblasts and mineralized under biological control. Alike in in vivo osteocytes, the embedded osteocytes show network formation and communication via expression of sclerostin. The current system forms the most complete 3D living in vitro model system to investigate osteogenesis, both in physiological and pathological situations, as well as under the influence of external triggers (mechanical stimulation, drug administration).     

Nanomaterials for environmental studies: Classification, reference material issues, and strategies for physico-chemical characterisation

NanoImpactNet is a European Commission Framework Programme 7 (FP7) funded project that provides a forum for the discussion of current opinions on nanomaterials in relation to human and environmental issues. In September 2008, in Zurich, a NanoImpactNet environmental workshop focused on three key questions:

1.

What properties should be characterised for nanomaterials used in environmental and ecotoxicology studies?

2.

What reference materials should be developed for use in environmental and ecotoxicological studies?

3.

Is it possible to group different nanomaterials into categories for consideration in environmental studies?

Such questions have been, at least partially, addressed by other projects/workshops especially in relation to human health effects. Such projects provide a useful basis on which this workshop was based, but in this particular case these questions were reformulated in order to focus specifically on environmental studies. The workshop participants, through a series of discussion and reflection sessions, generated the conclusions listed below.The physicochemical characterisation information identified as important for environmental studies included measures of aggregation/agglomeration/dispersability, size, dissolution (solubility), surface area, surface charge, surface chemistry/composition, with the assumption that chemical composition would already be known.There is a need to have test materials for ecotoxicology, and several substances are potentially useful, including TiO₂ nanoparticles, polystyrene beads labelled with fluorescent dyes, and silver nanoparticles. Some of these test materials could then be developed into certified reference materials over time.No clear consensus was reached regarding the classification of nanomaterials into categories to aid environmental studies, except that a chemistry-based classification system was a reasonable starting point, with some modifications. It was suggested, that additional work may be required to derive criteria that can be used to generate such categories, that would also include aspects of the material structure and physical behaviour.     

The continued retreat of non-profit housing providers in the Netherlands

After the abolishment of object subsidies for housing construction and renovation in the mid 1990s, Dutch housing associations, the main non-profit housing providers in the country, heavily relied on market activities, such as selling homes to owner occupiers, to generate income for their social activities and to contribute to urban development policies. This worked well, which was one of the main reasons that these housing providers could adopt a wide field of operations, including not only the management and development of affordable housing for low-income groups, but also housing in other market segments, plus activities regarding care, welfare, local economy, employment and education. Recent economic and political developments, however, have caused housing associations to return on this path. Central in this paper is a research among Dutch housing associations about their values, strategic positioning and strategies. The research was executed in two waves (conducted in 2010/2011 and in 2013/2014, respectively), each consisting of a panel survey and interviews with selected panellists. This paper presents the results of the second wave. It is expected that after the first wave of the research, new regulations, such as the national implementation of European rules on state support and the introduction of a new property tax, have resulted in a further retreat from non-social housing activities. The analysis shows that this is indeed the case, but that the main shifts in priorities have not taken place directly after the credit crunch, but in later years.     

High-speed single cable synchronization system for data-converters

A clock-cycle accurate synchronization technique for fully integrated data-converters is presented. Only a single cable is needed to distribute both the required synchronization signal and the converter clock. Different possible implementations, both to generate and decompose the distributed signal, are presented. A discrete component generator circuit is discussed. To avoid setup and hold time violations, on-chip signal reconstruction is unavoidable. A 40 nm CMOS recovery circuit was developed. Simulation results, including layout parasitics, show the wide frequency operating range of the proposed technique.