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.     

Structure-conductivity relationship of PrBaMnMoO6-δ through in-situ measurements: A neutron diffraction study

The structural and electrochemical properties of the double perovskite-type oxide, PrBaMnMoO_6-δ, was investigated using neutron diffraction with in-situ conductivity measurement under a dry Argon atmosphere from 25 °C to 700 °C. A Rietveld refinement of the neutron diffraction data confirmed monoclinic symmetry in the P2₁/n space group. Rietveld refinement also confirms the unit cell parameters of a = 5.6567 (1) Å, b = 5.6065 (2) Å, c = 7.9344 (1) Å and β = 84.43° with reliable atomic positions and refinement factors (R-factors). Neutron diffraction data refinement shows two minor phases (<5%), an orthorhombic AB₂O₅ type phase of PrMn₂O₅ in the Pbam (No. 32) space group with unit cell parameters, a = 7.9672 (1) Å, b = 8.9043 (2) Å and c = 5.8540 (1) Å and a scheelite phase of BaMoO₄ in the tetragonal I4₁/a (88) space group with the unit cell parameters, a = b = 5.9522 (1) Å, and c = 12.3211 (2) Å. Morphological images revealed a porous and intertwined microstructure. In-situ conductivity measurement shows that the total conductivity of this material was 130.84 Scm^?1 at 700 °C.     

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).     

Inductive System for Reliable Magnesium Level Detection in a Titanium Reduction Reactor

Metallurgical and Materials Transactions B - The determination of the Magnesium level in a Titanium reduction retort by inductive methods is often hampered by the formation of Titanium sponge rings...     

Climate Protection

The voice of the social sciences in climate research and in climate policy discussions, except for interventions from economists mainly about the costs associated with policy options driven by climate science research, has been muted if not altogether absent. The absence of the social sciences from climate research and policy not surprisingly has coloured climate discourse in peculiar ways. We are making the case for a greater involvement and importance of the social sciences in interdisciplinary climate research.

It is not space but the structuring that comes from the soul that has social significance. Georg Simmel ([1908] 1992)

Soil and climate together determine the natural fertility of a country and of its people who are led either to indolence or to activity. Werner Sombart (1938)

     

Liquid chromatography with accurate mass measurement on a triple quadrupole mass-spectrometer for the identification and quantification of N-lactoyl ethanolamine in wine

In this study a specific taste-modulating flavor ingredient, N-lactoyl ethanolamine, was determined in two Beerenauslese wines using preparative LC, as a first isolation and concentration step, followed by LC-MS/MS on a triple quadrupole in accurate mass (AM) mode. The accurate masses of the analyte and three characteristic fragments were determined with mass accuracies between 8 and 20 ppm. N-lactoyl ethanolamine concentrations in the wines were 0.4 and 2.5 mg/L.     

Photothermal self-phase-modulation technique for absorption measurements on high-reflective coatings

We propose and demonstrate a new measurement technique for the optical absorption of high-reflection coatings. Our technique is based on photothermal self-phase modulation and exploits the deformation of cavity Airy peaks that occurs due to coating absorption of intracavity light. The mirror whose coating is under investigation needs to be the input mirror of a high-finesse cavity. Our example measurements were performed on a high-reflection SiO2-Ta2O5 coating in a three-mirror ring-cavity setup at a wavelength of 1064 nm. The optical absorption of the coating was determined to be α=(23.9±2.0)·10(-6) per coating. Our result is in excellent agreement with an independently performed laser calorimetry measurement that gave a value of α=(24.4±3.2)·10(-6) per coating. Since the self-phase modulation in our coating-absorption measurement affects mainly the propagation through the cavity input mirror, our measurement result is practically uninfluenced by the optical absorption of the other cavity mirrors.     

Interface micromechanics of transverse sections from retrieved cemented hip reconstructions: an experimental and finite element comparison

In finite element analysis (FEA) models of cemented hip reconstructions, it is crucial to include the cement-bone interface mechanics. Recently, a micromechanical cohesive model was generated which reproduces the behavior of the cement-bone interface. The goal was to investigate whether this cohesive model was directly applicable on a macro level. From transverse sections of retrieved cemented hip reconstructions, two FEA-models were generated. The cement-bone interface was modeled with cohesive elements. A torque was applied and the cement-bone interface micromotions, global stiffness and stem translation were monitored. A sensitivity analysis was performed to investigate whether the cohesive model could be improved. All results were compared with experimental findings. That the original cohesive model resulted in a too compliant macromechanical response; the motions were too large and the global stiffness too small. When the cohesive model was modified, the match with the experimental response improved considerably.     

All-conjugated block copolymers

All-conjugated block copolymers of the rod-rod type came into the focus of interest because of their unique and attractive combination of nanostructure formation and electronic activity. Potential applications in a next generation of organic polymer materials for photovoltaic devices ("bulk heterojunction"-type solar cells) or (bio)sensors have been proposed. Combining the fascinating self-assembly properties of block copolymers with the active electronic and/or optical function of conjugated polymers in all-conjugated block copolymers is, therefore, a very challenging goal of synthetic polymer chemistry. First examples of such all-conjugated block copolymers from a couple of research groups all over the world demonstrate possible synthetic approaches and the rich application potential in electronic devices. A crucial point in such a development of novel polymer materials is a rational control over their nanostructure formation. All-conjugated di- or triblock copolymers may allow for an organization of the copolymer materials into large-area ordered arrays with a length scale of nanostructure formation of the order of the exciton diffusion length of organic semiconductors (typically ca. 10 nm). Especially for amphiphilic, all-conjugated copolymers the formation of well-defined supramolecular structures (vesicles) has been observed. However, intense further research is necessary toward tailor-made, all-conjugated block copolymers for specific applications. The search for optimized block copolymer materials should consider the electronic as well as the morphological (self-assembly) properties.