IAPs Regulate Distinct Innate Immune Pathways to Co-ordinate the Response to Bacterial Peptidoglycans

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Pixel classification method in optical coherence tomography for tumor segmentation and its complementary usage with OCT microangiography

A novel machine‐learning method to distinguish between tumor and normal tissue in optical coherence tomography (OCT) has been developed. Pre‐clinical murine ear model implanted with mouse colon carcinoma CT‐26 was used. Structural‐image‐based feature sets were defined for each pixel and machine learning classifiers were trained using “ground truth” OCT images manually segmented by comparison with histology. The accuracy of the OCT tumor segmentation method was then quantified by comparing with fluorescence imaging of tumors expressing genetically encoded fluorescent protein KillerRed that clearly delineates tumor borders. Because the resultant 3D tumor/normal structural maps are inherently co‐registered with OCT derived maps of tissue microvasculature, the latter can be color coded as belonging to either tumor or normal tissue. Applications to radiomics‐based multimodal OCT analysis are envisioned.      

Inside Back Cover: The conformation of bovine serum albumin adsorbed to the surface of single all‐dielectric nanoparticles following light‐induced heating (J. Biophotonics 7/2018)

Germanium vs Silicon: All‐dielectric nanoparticles provides the heat resistance for proteins under light‐induced heating. Further details can be found in the article by Andrei A. Krasilin et al. ( e201700322 )

     

The conformation of bovine serum albumin adsorbed to the surface of single all‐dielectric nanoparticles following light‐induced heating

Interaction between nanoparticles and biomolecules leads to the formation of biocompatible or bioadverse complexes. Despite the rapid development of nanotechnologies for biology and medicine, relatively little is known about the structure of such complexes. Here, we report on the changes in conformation of a blood protein (bovine serum albumin) adsorbed on the surface of single all‐dielectric nanoparticles (silicon and germanium) following light‐induced heating to 640 K. This protein is considerably more resistant to heat when adsorbed on the nanoparticle than when in solution or in the solid state. Intriguingly, with germanium nanoparticles this heat resistance is more pronounced than with silicon. These observations will facilitate biocompatible usage of all‐dielectric nanoparticles.      

Informative and misinformative interactions in a school of fish

Quantifying distributed information processing is crucial to understanding collective motion in animal groups. Recent studies have begun to apply rigorous methods based on information theory to quantify such distributed computation. Following this perspective, we use transfer entropy to quantify dynamic information flows locally in space and time across a school of fish during directional changes around a circular tank, i.e., U-turns. This analysis reveals peaks in information flows during collective U-turns and identifies two different flows: an informative flow (positive transfer entropy) from fish that have already turned to fish that are turning, and a misinformative flow (negative transfer entropy) from fish that have not turned yet to fish that are turning. We also reveal that the information flows are related to relative position and alignment between fish and identify spatial patterns of information and misinformation cascades. This study offers several methodological contributions and we expect further application of these methodologies to reveal intricacies of self-organisation in other animal groups and active matter in general.     

Cytosolic aminoacyl-tRNA synthetases: Unanticipated relocations for unexpected functions

Prokaryotic and eukaryotic cytosolic aminoacyl-tRNA synthetases (aaRSs) are essentially known for their conventional function of generating the full set of aminoacyl-tRNA species that are needed to incorporate each organism's repertoire of genetically-encoded amino acids during ribosomal translation of messenger RNAs. However, bacterial and eukaryotic cytosolic aaRSs have been shown to exhibit other essential nonconventional functions. Here we review all the subcellular compartments that prokaryotic and eukaryotic cytosolic aaRSs can reach to exert either a conventional or nontranslational role. We describe the physiological and stress conditions, the mechanisms and the signaling pathways that trigger their relocation and the new functions associated with these relocating cytosolic aaRS. Finally, given that these relocating pools of cytosolic aaRSs participate to a wide range of cellular pathways beyond translation, but equally important for cellular homeostasis, we mention some of the pathologies and diseases associated with the dis-regulation or malfunctioning of these nontranslational functions.     

Extracellular matrix content and WNT/β-catenin levels of cartilage determine the chondrocyte response to compressive load

During osteoarthritis (OA)-development extracellular matrix (ECM) molecules are lost from cartilage, thus changing gene-expression, matrix synthesis and biomechanical competence of the tissue. Mechanical loading is important for the maintenance of articular cartilage; however, the influence of an altered ECM content on the response of chondrocytes to loading is not well understood, but may provide important insights into underlying mechanisms as well as supplying new therapies for OA. Objective here was to explore whether a changing ECM-content of engineered cartilage affects major signaling pathways and how this alters the chondrocyte response to compressive loading.Activity of canonical WNT-, BMP-, TGF-β- and p38-signaling was determined during maturation of human engineered cartilage and followed after exposure to a single dynamic compression-episode. WNT/β-catenin- and pSmad1/5/9-levels declined with increasing ECM-content of cartilage. While loading significantly suppressed proteoglycan-synthesis and ACAN-expression at low ECM-content this catabolic response then shifted to an anabolic reaction at high ECM-content. A positive correlation was observed between GAG-content and load-induced alteration of proteoglycan-synthesis. Induction of high β-catenin levels by the WNT-agonist CHIR suppressed load-induced SOX9- and GAG-stimulation in mature constructs. In contrast, the WNT-antagonist IWP-2 was capable of attenuating load-induced GAG-suppression in immature constructs.In conclusion, either ECM accumulation-associated or pharmacologically induced silencing of WNT-levels allowed for a more anabolic reaction of chondrocytes to physiological loading. This is consistent with the role of proteoglycans in sequestering WNT-ligands in the ECM, thus reducing WNT-activity and also provides a novel explanation of why low WNT-activity in cartilage protects from OA-development in mechanically overstressed cartilage.     

The 1.25 A crystal structure of sepiapterin reductase reveals its binding mode to pterins and brain neurotransmitters.

Sepiapterin reductase catalyses the last steps in the biosynthesis of tetrahydrobiopterin, the essential co-factor of aromatic amino acid hydroxylases and nitric oxide synthases. We have determined the crystal structure of mouse sepiapterin reductase by multiple isomorphous replacement at a resolution of 1.25 A in its ternary complex with oxaloacetate and NADP. The homodimeric structure reveals a single-domain alpha/beta-fold with a central four-helix bundle connecting two seven-stranded parallel beta-sheets, each sandwiched between two arrays of three helices. Ternary complexes with the substrate sepiapterin or the product tetrahydrobiopterin were studied. Each subunit contains a specific aspartate anchor (Asp258) for pterin-substrates, which positions the substrate side chain C1'-carbonyl group near Tyr171 OH and NADP C4'N. The catalytic mechanism of SR appears to consist of a NADPH-dependent proton transfer from Tyr171 to the substrate C1' and C2' carbonyl functions accompanied by stereospecific side chain isomerization. Complex structures with the inhibitor N-acetyl serotonin show the indoleamine bound such that both reductase and isomerase activity for pterins is inhibited, but reaction with a variety of carbonyl compounds is possible. The complex structure with N-acetyl serotonin suggests the possibility for a highly specific feedback regulatory mechanism between the formation of indoleamines and pteridines in vivo.     

Target choice determinants of the Tc1 transposon of Caenorhabditis elegans.

The Tc1 transposon of Caenorhabditis elegans always integrates into the sequence TA, but some TA sites are preferred to others. We investigated a TA target site from the gpa-2 gene of C.elegans that was previously found to be preferred (hot) for Tc1 integration in vivo . This site with its immediate flanks was cloned into a plasmid, and remained hot in vitro , showing that sequences immediately adjacent to the TA dinucleotide determine this target choice. Further deletion mapping and mutagenesis showed that a 4 bp sequence on one side of the TA is sufficient to make a site hot; this sequence nicely fits the previously identified Tc1 consensus sequence for integration. In addition, we found a second type of hot site: this site is only preferred for integration when the target DNA is supercoiled, not when it is relaxed. Excision frequencies were relatively independent of the flanking sequences. The distribution of Tc1 insertions into a plasmid was similar when we used nuclear extracts or purified Tc1 transposase in vitro , showing that the Tc1 transposase is the protein responsible for the target choice.