Accumulation of misfolded proteins in the endoplasmic reticulum (ER) induces the unfolded protein response (UPR), which alleviates protein overload in the secretory pathway. Although the UPR is activated under diverse pathological conditions, its physiological role during development and in adulthood has not been fully elucidated. Binding immunoglobulin protein (BiP) is an ER chaperone, which is central to ER function. We produced knock-in mice expressing a mutant BiP lacking the retrieval sequence to cause a defect in ER function without completely eliminating BiP. In embryonic fibroblasts, the UPR compensated for mutation of BiP. However, neonates expressing mutant BiP suffered respiratory failure due to impaired secretion of pulmonary surfactant by alveolar type II epithelial cells. Expression of surfactant protein (SP)-C was reduced and the lamellar body was malformed, indicating that BiP plays a critical role in the biosynthesis of pulmonary surfactant. Because pulmonary surfactant requires extensive post-translational processing in the secretory pathway, these findings suggest that in secretory cells, such as alveolar type II cells, the UPR is essential for managing the normal physiological ER protein overload that occurs during development. Moreover, failure of this adaptive mechanism may increase pulmonary susceptibility to environmental insults, such as hypoxia and ischemia, ultimately leading to neonatal respiratory failure.
We evaluated the expression of the FLK1, one of the lateral mesoderm early markers where cardiogenesis occurs, to characterize and isolate cardiac stem/progenitor cells from ES cells. Dissociated cells from embryoid bodies (EBs) on day 3, 4, or 5 were collected into two subpopulations with or without FLK1 expression and coculture on OP9 stromal cells was continued to examine whether contracting colonies came out or not. FLK1+ cells from EBs at days 3 and 4 formed spontaneous contracting colonies more efficiently than FLK1- cells on the same days, but not at day 5. Most contracting cardiac colonies derived from FLK1+cells mainly on day 4 were detected on endothelial cells along with hematopoietic cells. Further characterization of cells with these capabilities into three lineages revealed the FLK1+ CD31-VE-cadherin-phenotype. Our findings indicate that FLK1+cells, especially FLK1+ CD31-VE-cadherin-cells, could act as cardiohemangioblasts to form cardiac cells as well as endothelial cells and hematopoietic cells.
Mediator is a coregulatory complex that regulates transcription of Pol II-dependent genes. Previously, we showed that human Mediator subunit MED26 plays a role in the recruitment of Super Elongation Complex (SEC) or Little Elongation Complex (LEC) to regulate the expression of certain genes. MED26 plays a role in recruiting SEC to protein-coding genes including c-myc and LEC to small nuclear RNA (snRNA) genes. However, how MED26 engages SEC or LEC to regulate distinct genes is unclear. Here, we provide evidence that MED26 recruits LEC to modulate transcription termination of non-polyadenylated transcripts including snRNAs and mRNAs encoding replication-dependent histone (RDH) at Cajal bodies. Our findings indicate that LEC recruited by MED26 promotes efficient transcription termination by Pol II through interaction with CBC-ARS2 and NELF/DSIF, and promotes 3′ end processing by enhancing recruitment of Integrator or Heat Labile Factor to snRNA or RDH genes, respectively.
By injection of microwave power P EC near the electron cyclotron (EC) frequency into an Ohmically heated (OH) plasma in the WT-2 tokamak after OH power is shut off, the plasma current is sustained and ramped up by the EC wave only, without OH power. Here, EC-driven current is generated by EC heating of the suprathermal electron beam in OH plasma. Further, when P EC is injected into plasma sustained by lower-hybrid-(LH-) driven current, the plasma current and its rampup rate increase. Here, EC-driven current is generated by EC heating of the mildly relativistic electrons in LH-driven plasma.
A high current plasma electron emitter based on a miniature plasma source has been developed. The emitting plasma is created by a pulsed high current gas discharge. The electron emission current is 1 kA at 300 V with a pulse duration of 10 ms. The prototype injector described in this paper will be used for a 20 kA electrostatic current injection experiment in the Madison symmetric torus reversed-field pinch. The source will be replicated in order to attain this total current requirement. The source has a simple design and has proven to be very reliable in operation. A high emission current, small size (3.7 cm in diameter) and low impurity generation make the source suitable for a variety of fusion and technological applications.
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