PubMed · 14110921
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T KAWAMURA, S NISHIYAMA, S IKEDA, K TAJIMA. 1964. THE HUMAN HAARSCHEIBE, ITS STRUCTURE AND FUNCTION.. https://doi.org/10.1038/jid.1964.17
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Marine picocyanobacteria of the genera Prochlorococcus and Synechococcus, the two most abundant phototrophs on Earth, thrive in oligotrophic oceanic regions. While it is well known that specific lineages are exquisitely adapted to prevailing in situ light and temperature regimes, much less is known of the molecular machinery required to facilitate occupancy of these low-nutrient environments. Here, we describe a hitherto unknown alkaline phosphatase, Psip1, that has a substantially higher affinity for phosphomonoesters than other well-known phosphatases like PhoA, PhoX, or PhoD and is restricted to clade III Synechococcus and a subset of high light I-adapted Prochlorococcus strains, suggesting niche specificity. We demonstrate that Psip1 has undergone convergent evolution with PhoX, requiring both iron and calcium for activity and likely possessing identical key residues around the active site, despite generally very low sequence homology. Interrogation of metagenomes and transcriptomes from TARA oceans and an Atlantic Meridional transect shows that psip1 is abundant and highly expressed in picocyanobacterial populations from the Mediterranean Sea and north Atlantic gyre, regions well recognized to be phosphorus (P)-deplete. Together, this identifies psip1 as an important oligotrophy-specific gene for P recycling in these organisms. Furthermore, psip1 is not restricted to picocyanobacteria and is abundant and highly transcribed in some α-proteobacteria and eukaryotic algae, suggesting that such a high-affinity phosphatase is important across the microbial taxonomic world to occupy low-P environments.
Hepatitis C virus (HCV) encodes a polyprotein that needs to be processed proteolytically by cellular and viral proteases into mature functional proteins. One of the viral proteins, NS3/4A, has serine protease activity that is critical for virus maturation. The generation and characterization of an engineered HCV replicon cell line (Ava5) is described which constitutively expresses EGdelta4AB)SEAP reporter protein and the cell line was designated as Ava5-EG(delta4AB)SEAP. EG(delta4AB)SEAP is a fusion protein in which Enhanced Green Fluorescent Protein (EGFP) was fused to SEcreted Alkaline Phosphatase (SEAP) through the NS3/4A protease decapeptide recognition sequence, delta4AB, which spans the NS4A and NS4B junction region. The secretion of SEAP into culture medium has been shown to depend on the cleavage of delta4AB by HCV NS3/4A protease. It is demonstrated that the amount of NS3/4A in Ava5-EG(delta4AB)SEAP cells correlated well with the copy numbers of HCV subgenomic RNA. It is also shown that replication of HCV subgenomic RNA inside cells is reflected by the alkaline phosphatase (SEAP) levels in culture medium. SEAP activity in the culture medium of Ava5-EG(delta4AB)SEAP was approximately 50-fold higher than the parental Ava5 cells. Ava5-EG(delta4AB)SEAP was validated as a drug screening system since several known HCV inhibitors were shown to reduce SEAP activities in culture media of Ava5-EG(delta4AB)SEAP cells. In conclusion, Ava5-EG(delta4AB)SEAP cells can be used to monitor HCV sub-genomic replication and the assay can be readily adapted to high throughput screening format to identify prospective anti-HCV drugs.
Longitudinal growth of endochondral bones is accomplished through the co-ordinated proliferation and hypertrophic differentiation of growth plate chondrocytes. The molecular mechanisms and signalling cascades controlling these processes are not well understood. To analyse the expression and roles of p38 mitogen-activated protein kinases in this process, we have established a micromass system for the reproducible hypertrophic differentiation of mouse mesenchymal limb bud cells. Our results show that all four mammalian p38 kinase genes are expressed during the chondrogenic programme, as well as their upstream regulators MKK3 (mitogen-activated protein kinase kinase 3) and MKK6. Treatment of micromass cultures with pharmacological inhibitors of p38 results in a marked delay in hypertrophic differentiation in micromass cultures, indicating a requirement for p38 signalling in chondrocyte differentiation. Inhibition of p38 kinase activity leads to reduced and delayed induction of alkaline phosphatase activity and matrix mineralization. In addition, p38 inhibition causes reduced expression of hypertrophic marker genes such as collagen X, matrix metalloproteinase 13 and bone sialoprotein. The function of p38 in hypertrophic differentiation appears to be mediated, at least in part, by the transcription factor myocyte enhancer factor 2C. In summary, we have demonstrated a novel requirement for p38 signalling in hypertrophic differentiation of chondrocytes and identified myocyte enhancer factor 2C as an important regulator of chondrocyte gene expression.