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.
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.
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.
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.
Amphibians provide an ideal model to study the actions of thyroid hormone (TH) in animal development because TH signaling via two TH receptors, TRα and TRβ, is indispensable for amphibian metamorphosis. However, specific roles for the TRβ isoform in metamorphosis are poorly understood. To address this issue, we generated trβ-disrupted Xenopus tropicalis tadpoles using the CRISPR-Cas system. We first established a highly efficient and rapid workflow for gene disruption in the founder generation (F0) by injecting sgRNA and Cas9 ribonucleoprotein. Most embryos showed severe mutant phenotypes carrying high somatic mutation rates. Utilizing this founder analysis system, we examined the role of trβ in metamorphosis. trβ-disrupted pre-metamorphic tadpoles exhibited mixed responsiveness to exogenous TH. Specifically, gill resorption and activation of several TH-response genes, including trβ itself and two protease genes, were impaired. However, hind limb outgrowth and induction of the TH-response genes, klf9 and fra-2, were not affected by loss of trβ. Surprisingly, trβ-disrupted tadpoles were able to undergo spontaneous metamorphosis normally, except for a slight delay in tail resorption. These results indicate TRβ is not required but contributes to the timing of resorptive events of metamorphosis.
To evaluate species- and isoform-specific responses to dioxins and related compounds (DRCs) via aryl hydrocarbon receptor (AHR) in the red seabream ( Pagrus major ), we constructed a reporter gene assay system. Each expression plasmid of red seabream AHR1 (rsAHR1) and AHR2 (rsAHR2) together with a reporter plasmid containing red seabream CYP1A 5'-flanking region were transfected into COS-7 cells. The cells were treated with graded concentrations of seven DRC congeners including 2,3,7,8-TCDD, 1,2,3,7,8-PeCDD, 1,2,3,4,7,8-HxCDD, 2,3,7,8-TCDF, 2,3,4,7,8-PeCDF, 1,2,3,4,7,8-HxCDF, and PCB126. Both rsAHR1 and rsAHR2 exhibited dose-dependent responses for all the tested congeners. The rsAHR isoform-specific TCDD induction equivalency factors (rsAHR1- and rsAHR2-IEFs) were calculated on the basis of 2,3,7,8-TCDD relative potency derived from the dose-response of each congener. The rsAHR1-IEFs of PeCDD, HxCDD, TCDF, PeCDF, and HxCDF were estimated as 0.17, 0.29, 2.5, 1.5, and 0.27, respectively. For PCB126, no rsAHR1-IEF was given because of less than 10% 2,3,7,8-TCDD maximum response. The rsAHR2-IEFs of PeCDD, HxCDD, TCDF, PeCDF, HxCDF, and PCB126 were estimated as 0.38, 0.13, 1.5, 0.93, 0.20, and 0.0085, respectively. The rsAHR1/2-IEF profiles were different from WHO toxic equivalency factors for fish. In silico docking simulations supported that both rsAHRs have potentials to bind to these congeners. These results suggest that dioxin toxicities may be mediated by both rsAHRs in red seabreams.
In WT-3, lower hybrid waves are injected into a microwave discharge at the electron cyclotron resonance frequency to initiate the toroidal plasma current IP and to sustain it by radiofrequency (RF) power alone without Ohmic heating power (this is called the ‘RF tokamak’). First, fast electrons in the range of several kilo-electronvolts are generated by electron cyclotron and lower hybrid power which initiate a weak toroidal plasma current. Then, fast electrons above 100 keV are produced by the lower hybrid waves, and IP increases rapidly (ΔIp/Δt ∼ 780 kA·s−1) to almost 13 kA. Subsequently the toroidal plasma current is ramped up slowly (ΔIp/Δt ∼ 180 kA·s−1) to > 25 kA for low densities (n̄e < 6 × 1018 m−3). The fraction ∈R (≤8%) of injected lower hybrid power is converted into poloidal magnetic field energy. For high densities (n̄e = (6−12) × 1018 m−3), a quasi-steady-state discharge is obtained with IP = 7−20 kA, and the figure of merit ηCD is about 0.05 × 1019 A·m−2·W−1. The experimental values of ∈R and ηCD are explained by the direct loss of fast electrons.
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