Providing relatives of patients who are dying in the ICU with a brochure on bereavement and using a proactive communication strategy that includes longer conferences and more time for family members to talk may lessen the burden of bereavement. (ClinicalTrials.gov number, NCT00331877.)

Pattern lormation in the dorsal region of the Drosophila embryo depends on the activity of a small group of zygotically acting genes, dpp, a key gene in this group, encodes a TGF-p-like product (Dpp) that has been proposed to function as a morphogen with peak levels of Dpp-specifying amnioserosa, the dorsal-most cell type, and lower Dpp levels specifying dorsal ectoderm. The short gastrulation gene also contributes to patterning the dorsal region, but unlike the other genes involved in this process, sog activity is only required in ventral cells. Genetic evidence indicates that sog functions to antagonize dpp activity. In this report we present further phenotypic characterization of sog mutant embryos in dorsal and lateral regions and describe the cloning of the sog locus, sog is expressed in a broad lateral stripe of cells that abuts the dorsal territory of dfpp-expressing cells, sog is predicted to encode a protein with an internal signal sequence and a large extracellular domain containing four repeats of a novel motif defined by the spacing of 10 cysteine residues that is distantly related to domains present in thrombospondin and procollagen. We propose that one or more of these cysteine repeats can be liberated by proteolytic cleavage of the primary Sog protein. These putative soluble Sog peptides may then diffuse into the dorsal region to antagonize the activity of Dpp, leading to the subdivision of the dorsal territory into amnioserosa and dorsal ectoderm.[

A personalized and standardized APA is acceptable, effective and safe in patients awaiting LT. It positively influences the index of fitness and quality of life. Its promising impact on the posttransplantation period, duration of hospitalization, and 6-month survival needs to be prospectively evaluated in a large randomized study.

The short gastrulation (sog) gene is expressed in broad lateral stripes comprising the neuroectoderm of the Drosophila blastoderm embryo, sog encodes a predicted secreted protein that functions nonautonomously to antagonize the activity of the TGF-~-like Decapentaplegic (Dpp) signaling pathway in the dorsal region of the embryo. Recently, it has been shown that sog and dpp are functionally equivalent to their respective Xenopus homologs chordin and BMP-4. In this report we provide the first direct evidence that sog plays a local role in the lateral region of the blastoderm embryo to oppose Dpp activity in the neuroectoderm. In the dorsal region, Dpp signaling both suppresses neurogenesis and maintains expression of genes that promote dorsal cell fates (dorsalization). We show that Dpp also can perform both of these functions in the neuroectoderm. In wild-type embryos, the ability of Dpp to induce expression of dorsal markers including itself (autoactivation) in the neuroectoderm is blocked by sog. We propose that Sog protects the neuroectoderm from an invasive positive feedback loop created by Dpp diffusion and autoactivation. We show that the two functions of Dpp signaling, neural suppression and dorsalization, are triggered by distinct thresholds of Dpp activity. Epistasis experiments reveal that all observed sog activity can be accounted for by Sog functioning as a dedicated Dpp antagonist. Finally, we provide evidence that Sog functions as a diffusible morphogen in the blastoderm embryo. These data strongly support the view that the primary phylogenetically conserved function of the Drosophila sog and dpp genes and the homologous Xenopus chordin and BMP-4 genes is to subdivide the primitive embryonic ectoderm into neural versus non-neural domains.

Accidental extubation but not self-extubation or reintubation after weaning increased the risk of nosocomial pneumonia. These 3 events may deserve evaluation as an indicator for quality-of-care studies.

The transfer of exosomes containing both genetic and protein materials is necessary for the control of the cancer cell microenvironment to promote tumor angiogenesis. The nature and function of proteins found in the exosomal cargo, and the mechanism of their action in membrane transport and related signaling events are not clearly understood. In this study, we demonstrate, in human lung cancer A549 cells, that the exosome release mechanism is closely linked to the multifaceted receptor sortilin (also called neurotensin receptor 3). Sortilin is already known to be important for cancer cell function. Here, we report for the first time its role in the assembly of a tyrosine kinase complex and subsequent exosome release. This new complex (termed the TES complex) is found in exosomes and results in the linkage of the two tyrosine kinase receptors TrkB (also known as NTRK2) and EGFR with sortilin. Using in vitro models, we demonstrate that this sortilin-containing complex exhibits a control on endothelial cells and angiogenesis activation through exosome transfer.

No abstract

Members of the bone morphogenetic protein-1/tolloid (BMP-1/Tld) family of metalloproteinases, also known as procollagen C-proteinases (PCPs), control multiple biological events (including matrix assembly, cross-linking, cell adhesion/migration and pattern formation) through enzymatic processing of several extracellular substrates. PCP activities on fibrillar procollagens can be stimulated by another family of extracellular proteins, PCP enhancers (PCPE-1, PCPE-2), which lack intrinsic enzymatic activity. While PCPs have multiple substrates, the extent to which PCPEs is involved in the processing of proteins other than fibrillar procollagens is unknown. In the experiments reported here, PCPE-1 was found to have no effect on the in vitro BMP-1 processing of procollagen VII, the procollagen V N-propeptide, the laminin 5 ␥2 chain, osteoglycin, prolysyl oxidase, or chordin. In contrast, PCPE-1 enhanced C-terminal processing of human fibrillar procollagen III but only when this substrate was in its native, disulfidebonded conformation. Surprisingly, processing of procollagen III continued to be enhanced when essentially all the triple-helical region was removed. These and previous results (Ricard-Blum, S., Bernocco, S., Font, B., Moali, C., Eichenberger, D., Farjanel, J., Burchardt, E. R., van der Rest, M., Kessler, E., and Hulmes, D. J. S. In recent years, it has become clear that members of the tolloid family of metalloproteinases (BMP-1, 1 mTld, mTLL-1, mTLL-2) are key players in morphogenesis through their ability to control and synchronize the processing of multiple extracellular substrates (1-25). Also called procollagen C-proteinases, tolloid proteinases trigger collagen fibril formation in the extracellular matrix (26) by cleaving the C-propeptide regions from the major fibrillar procollagens (I, II, and III). They are also involved in precursor processing of the minor fibrillar collagens V and XI, necessary for the regulation of heterotypic fibril assembly, in both the N-and C-propeptide regions (8,15,17,19,23,27). Tolloid proteinases also cleave precursor forms of small leucine-rich proteoglycans such as biglycan (13) and osteoglycin (24). While some of these proteoglycans have been shown to modulate the kinetics of assembly as well as fibril diameter (28), functional differences between mature and precursor forms are not yet clearly established (24). Biglycan is also important for bone formation (29) and more recently, dentin matrix protein-1, a protein involved in mineralization, has been found to be a substrate for tolloid proteinases (22).Another important function early attributed to tolloid proteinases is the maturation of the precursor form of lysyl oxidase (LOX) (5, 30), the enzyme responsible for the stabilization of collagen and elastin networks through the formation of covalent cross-links. This tolloid-dependent processing has recently gained in significance with the demonstration that the cleaved propeptide of proLOX accounts for the ras-recision gene activity of this protein (31). In addition, ...