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This Week in PNAS: Apr 21, 2010

In PNAS this week, researchers in Pittsburgh report their findings that modification of ubiquitin carboxyl-terminal hydrolase L1 by cyclopentenone prostaglandins causes unfolding and aggregation of neurofribillary tangles. A single thiol group on Cys152 reacts with the α,β-unsaturated carbonyl center in the cyclopentenone ring of prostaglandins, resulting in a covalent adduct, the researchers write. Their work also shows that the I93M mutant of UCH-L1 associated with Parkinson's disease is "well-folded, structurally similar to the wild-type protein, and aggregates upon conjugation by cyclopentenone prostaglandins." The team suggests there is a possible mechanistic link between UCH-L1 modification by cyclopentenone prostaglandins and the etiology of neurodegeneration.

Also in PNAS this week, a research team from Georgia reports that expression of the RNA biding protein HuR in human umbilical vein endothelial cells is regulated by stress and statin treatment. In turn, the team writes, HuR regulates other stress-sensitive genes such as Klf2, eNOS, and BMP-4. "We found that siRNA knockdown of HuR inhibited inflammatory responses in endothelial cells, including ICAM-1 and VCAM-1 up-regulation, NFκB phosphorylation, and adhesion of monocytes," the researchers say. In addition, tissue staining of a mouse aorta showed increased HuR expression in the lesser curvature region of the arch that is exposed to disturbed flow, the team writes. "Taken together, these results suggest that HuR plays a critical role in inducing inflammatory response of endothelial cells under mechanical and biochemical stresses," they conclude.

In PNAS, researchers from Ohio report results from a murine ischemic wound model meant to elucidate the role microRNAs may play in limiting wound re-epithelialization under hypoxia. "In vivo imaging showed massive hypoxia inducible factor-1α (HIF-1α) stabilization in ischemic wounds, where HIF-1α induced miR-210 expression that, in turn, silenced its target E2F3, which was markedly down-regulated in the wound-edge tissue of ischemic wounds," the researchers write. Forced stabilization of HIF-1α using Ad-VP16- HIF-1α under normoxic conditions up-regulated miR-210 expression, down-regulated E2F3, and limited cell proliferation, the team adds.

In the PNAS Early Edition this week, researchers in Philadelphia report their findings that the microRNA17/20 cluster is shown to use heterotypic secreted signals to govern cellular migration and invasion of nearby cells. Cell-conditioned medium from microRNA17/20–overexpressing noninvasive breast cancer cell MCF7 was sufficient to inhibit MDA-MB-231 cell migration and invasion through inhibiting secretion of a subset of cytokines, and suppressing plasminogen activation via inhibition of the secreted plasminogen activators, the researchers write, adding, that "these findings not only reveal an anti-invasive function of miR-17/20 in breast cancer, but also identify a heterotypic secreted signal that mediates the microRNA regulation of tumor metastasis."

The Scan

Genome Sequences Reveal Range Mutations in Induced Pluripotent Stem Cells

Researchers in Nature Genetics detect somatic mutation variation across iPSCs generated from blood or skin fibroblast cell sources, along with selection for BCOR gene mutations.

Researchers Reprogram Plant Roots With Synthetic Genetic Circuit Strategy

Root gene expression was altered with the help of genetic circuits built around a series of synthetic transcriptional regulators in the Nicotiana benthamiana plant in a Science paper.

Infectious Disease Tracking Study Compares Genome Sequencing Approaches

Researchers in BMC Genomics see advantages for capture-based Illumina sequencing and amplicon-based sequencing on the Nanopore instrument, depending on the situation or samples available.

LINE-1 Linked to Premature Aging Conditions

Researchers report in Science Translational Medicine that the accumulation of LINE-1 RNA contributes to premature aging conditions and that symptoms can be improved by targeting them.