Identification of a Gene Regulatory Network Necessary for the Initiation of Oligodendrocyte Differentiation

Differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes requires extensive changes in gene expression, which are partly mediated by post-translational modifications of nucleosomal histones. An essential modification for oligodendrocyte differentiation is the removal of acetyl groups from lysine residues which is catalyzed by histone deacetylases (HDACs). The transcriptional targets of HDAC activity within OPCs however, have remained elusive and have been identified in this study by interrogating the oligodendrocyte transcriptome. Using a novel algorithm that allows clustering of gene transcripts according to expression kinetics and expression levels, we defined major waves of co-regulated genes. The initial overall decrease in gene expression was followed by the up-regulation of genes involved in lipid metabolism and myelination. Functional annotation of the down-regulated gene clusters identified transcripts involved in cell cycle regulation, transcription, and RNA processing. To define whether these genes were the targets of HDAC activity, we cultured rat OPCs in the presence of trichostatin A (TSA), an HDAC inhibitor previously shown to inhibit oligodendrocyte differentiation. By overlaying the defined oligodendrocyte transcriptome with the list of ‘TSA sensitive’ genes, we determined that a high percentage of ‘TSA sensitive’ genes are part of a normal program of oligodendrocyte differentiation. TSA treatment increased the expression of genes whose down-regulation occurs very early after induction of OPC differentiation, but did not affect the expression of genes with a slower kinetic. Among the increased ‘TSA sensitive’ genes we detected several transcription factors including Id2, Egr1, and Sox11, whose down-regulation is critical for OPC differentiation. Thus, HDAC target genes include clusters of co-regulated genes involved in transcriptional repression. These results support a de-repression model of oligodendrocyte lineage progression that relies on the concurrent down-regulation of several inhibitors of differentiation

The authority of next-of-kin in explicit and presumed consent systems for deceased organ donation: an analysis of 54 nations

Background. The degree of involvement by the next-of-kin in deceased organ procurement worldwide is unclear. We investigated the next-of-kin’s authority in the procure-ment process in nations with either explicit or presumed consent. Methods. We collected data from 54 nations, 25 with presumed consent and 29 with explicit consent. We char-acterized the authority of the next-of-kin in the decision to donate deceased organs. Specifically, we examined whether the next-of-kin’s consent to procure organs was always required and whether the next-of-kin were able to veto procurement when the deceased had expressed a wish to donate. Results. The next-of-kin are involved in the organ procure-ment process in most nations regardless of the consent principle and whether the wishes of the deceased to be a donor were expressed or unknown. Nineteen of the 25 nations with presumed consent provide a method for individuals to express a wish to be a donor. However, health professionals in only four of these nations responded that they do not override a deceased’s expressed wish because of a family’s objection. Similarly, health profes-sionals in only four of the 29 nations with explicit consent proceed with a deceased’s pre-existing wish to be a donor and do not require next-of-kin’s consent, but caveats still remain for when this is done. Conclusions. The next-of-kin have a considerable influ-ence on the organ procurement process in both presumed and explicit consent nations

Treating Diet-Induced Diabetes and Obesity with Human Embryonic Stem Cell-Derived Pancreatic Progenitor Cells and Antidiabetic Drugs

Human embryonic stem cell (hESC)-derived pancreatic progenitor cells effectively reverse hyperglycemia in rodent models of type 1 diabetes, but their capacity to treat type 2 diabetes has not been reported. An immunodeficient model of type 2 diabetes was generated by high-fat diet (HFD) feeding in SCID-beige mice. Exposure to HFDs did not impact the maturation of macroencapsulated pancreatic progenitor cells into glucose-responsive insulin-secreting cells following transplantation, and the cell therapy improved glucose tolerance in HFD-fed transplant recipients after 24 weeks. However, since diet-induced hyperglycemia and obesity were not fully ameliorated by transplantation alone, a second cohort of HFD-fed mice was treated with pancreatic progenitor cells combined with one of three antidiabetic drugs. All combination therapies rapidly improved body weight and co-treatment with either sitagliptin or metformin improved hyperglycemia after only 12 weeks. Therefore, a stem cell-based therapy may be effective for treating type 2 diabetes, particularly in combination with antidiabetic drugs

Graffiti, drawing, St. Anne's Church, Little Fogo Island

Drawing on the wall of St. Anne's Churc

Plant size, latitude, and phylogeny explain within-population variability in herbivory

Interactions between plants and herbivores are central in most ecosystems, but their strength is highly variable. The amount of variability within a system is thought to influence most aspects of plant-herbivore biology, from ecological stability to plant defense evolution. Our understanding of what influences variability, however, is limited by sparse data. We collected standardized surveys of herbivory for 503 plant species at 790 sites across 116° of latitude. With these data, we show that within-population variability in herbivory increases with latitude, decreases with plant size, and is phylogenetically structured. Differences in the magnitude of variability are thus central to how plant-herbivore biology varies across macroscale gradients. We argue that increased focus on interaction variability will advance understanding of patterns of life on Earth