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Somite-Derived Retinoic Acid Regulates Zebrafish Hematopoietic Stem Cell Formation
Hematopoietic stem cells (HSCs) are multipotent progenitors that generate all vertebrate adult blood lineages. Recent analyses have highlighted the importance of somite-derived signaling factors in regulating HSC specification and emergence from dorsal aorta hemogenic endothelium. However, these factors remain largely uncharacterized. We provide evidence that the vitamin A derivative retinoic acid (RA) functions as an essential regulator of zebrafish HSC formation. Temporal analyses indicate that RA is required for HSC gene expression prior to dorsal aorta formation, at a time when the predominant RA synthesis enzyme, aldh1a2, is strongly expressed within the paraxial mesoderm and somites. Previous research implicated the Cxcl12 chemokine and Notch signaling pathways in HSC formation. Consequently, to understand how RA regulates HSC gene expression, we surveyed the expression of components of these pathways in RA-depleted zebrafish embryos. During somitogenesis, RA-depleted embryos exhibit altered expression of jam1a and jam2a, which potentiate Notch signaling within nascent endothelial cells. RA-depleted embryos also exhibit a severe reduction in the expression of cxcr4a, the predominant Cxcl12b receptor. Furthermore, pharmacological inhibitors of RA synthesis and Cxcr4 signaling act in concert to reduce HSC formation. Our analyses demonstrate that somite-derived RA functions to regulate components of the Notch and Cxcl12 chemokine signaling pathways during HSC formation.
Journal Article
Correction: Somite-Derived Retinoic Acid Regulates Zebrafish Hematopoietic Stem Cell Formation
[This corrects the article DOI: 10.1371/journal.pone.0166040.].
Journal Article
Petrogenesis of Middle Triassic Volcaniclastic Rocks from Balochistan, Pakistan： Implications for the Break-Up of Gondwanaland
Basaltic volcanic conglomerates near the Wulgai village in Balochistan occur in the undivided sedimentary rock unit of the Bagh complex which is the mélange zone beneath the Muslim Bagh ophiolite. The presence of Middle Triassic grey radiolarian chert within the upper and lower horizon of the conglomerates suggests that the lavas, from which these conglomerates were principally derived, were eroded and re-deposited in the Middle Triassic. The Wulgai conglomerate contains several textural and mineralogical varieties of volcanic rocks, such as porphyritic, glomerophyric, intersertal and vitrophyric basalts. The main minerals identified in these samples are augite, olivine, plagioclase（An35–78） leucite and nosean, with apatite ilmenite, magnetite and hematite occurring as accessory minerals. These rocks are mildly to strongly-alkaline with low Mg~# and low Cr, Ni and Co contents suggesting that their parent magma had undergone considerable fractionation prior to eruption. Trace element-enriched mantle-normalized patterns with marked positive Nb anomalies are consistent with 10%–15% melting of an enriched mantle source in a within-plate tectonic setting. It is proposed that this Middle Triassic intra-plate volcanism may represent mantle plume-derived melts related to the Late Triassic rifting of micro-continental blocks（including Afghan, Iran, Karakorum and Lhasa） from the northern margin of Gondwana.
Journal Article
On Earth
While bouncing through Earth's prehistory in a malfunctioning time machine, Andrew, his cousin Judy, and Thudd the robot meet Dr. KronTox's nephew, Beeper, and nearly lose the Time-a-Tron in a tsunami.5
Book
Cancer Stem Cell Signaling during Repopulation in Head and Neck Cancer
The aim of the study was to investigate cancer stem signaling during the repopulation response of a head and neck squamous cell cancer (HNSCC) xenograft after radiation treatment. Xenografts were generated from low passage HNSCC cells and were treated with either sham radiation or 15 Gy in one fraction. At different time points, days 0, 3, and 10 for controls and days 4, 7, 12, and 21, after irradiation, 3 tumors per group were harvested for global gene expression, pathway analysis, and immunohistochemical evaluation. 316 genes were identified that were associated with a series of stem cell-related genes and were differentially expressed ( p ≤ 0.01 and 1.5-fold) at a minimum of one time point in UT-SCC-14 xenografts after radiation. The largest network of genes that showed significant changes after irradiation was associated with CD44, NOTCH1, and MET. c-MET and ALDH1A3 staining correlated with the changes in gene expression. A clear pattern emerged that was consistent with the growth inhibition data in that genes associated with stem cell pathways were most active at day 7 and day 12 after irradiation. The MET/CD44 axis seemed to be an important component of the repopulation response.
Journal Article
With the dinosaurs
When Beeper accidentally releases the escape hatch to the Time-a-Tron, the time travelers must protect themselves from the world's most fearsome creature, Tyrannosaurus rex.
Book
“Scanning mutagenesis” of the amino acid sequences flanking phosphorylation site 1 of the mitochondrial pyruvate dehydrogenase complex
The mitochondrial pyruvate dehydrogenase complex (mtPDC) is regulated by reversible seryl-phosphorylation of the E1α subunit by a dedicated, intrinsic kinase. The phospho-complex is reactivated when dephosphorylated by an intrinsic PP2C-type protein phosphatase. Both the position of the phosphorylated Ser-residue and the sequences of the flanking amino acids are highly conserved. We have used the synthetic peptide-based kinase client (KiC) assay plus recombinant pyruvate dehydrogenase E1α and E1α-kinase to perform \"scanning mutagenesis\" of the residues flanking the site of phosphorylation. Consistent with the results from \"phylogenetic analysis\" of the flanking sequences, the direct peptide-based kinase assays tolerated very few changes. Even conservative changes such as Leu, Ile, or Val for Met, or Glu for Asp, gave very marked reductions in phosphorylation. Overall the results indicate that regulation of the mtPDC by reversible phosphorylation is an extreme example of multiple, interdependent instances of co-evolution.
Journal Article