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Eukaryotic translation initiation factor 2 alpha (eIF2α), which is a component of the eukaryotic translation initiation complex, functions in cell death and survival under various stress conditions. In this study, we investigated the roles of eIF2α phosphorylation in cell death using the breast cancer cell lines MCF-7 and MCF-7/ADR. MCF- 7/ADR cells are MCF-7-driven cells that have acquired resistance to doxorubicin (ADR). Treatment of doxorubicin reduced the viability and induced apoptosis in both cell lines, although susceptibility to the drug was very different. Treatment with doxorubicin induced phosphorylation of eIF2α in MCF-7 cells but not in MCF-7/ADR cells. Basal expression levels of Growth Arrest and DNA Damage 34 (GADD34), a regulator of eIF2α, were higher in MCF-7/ADR cells compared to MCF-7 cells. Indeed, treatment with salubrinal, an inhibitor of GADD34, resulted in the upregulation of eIF2α phosphorylation and enhanced doxorubicinmediated apoptosis in MCF-7/ADR cells. However, MCF-7 cells did not show such synergic effects. These results suggest that dephosphorylation of eIF2α by GADD34 plays an important role in doxorubicin resistance in MCF-7/ADR cells. [ABSTRACT FROM AUTHOR]

Enteropathy-associated T-cell lymphoma (EATL) is a rare extranodal T-cell lymphoma arising from the intestine. Two types of EATL have been reported. In contrast to the classic EATL type I, EATL type II occurs sporadically, is unrelated to celiac disease, and comprises 10% to 20 % of all EATL cases. A total of five cases of EATL type II were diagnosed at our clinic from January 2009 to September 2012. Four of the five patients were diagnosed with the help of endoscopy. Among the four patients, two of the cases involved both the small and large intestines, whereas in the other two patients, EATL was limited to the small intestine. Common endoscopic findings included innumerable fine granularities (also called mosaic mucosal patterns) and diffuse thickening of the mucosa with a semicircular shallow ulceration in the lesions of the small bowel. In contrast, the endoscopic findings of the colon were nonspecific and could not distinguish EATL type II from other diseases. There are only few published reports regarding the representative endoscopic findings of EATL. Here, we present the clinical and endoscopic findings of four cases of EATL type II diagnosed by endoscopy. [ABSTRACT FROM AUTHOR]

Background Codman's paradox reveals a misunderstanding of geometry in orthopedic practice. Physicians often encounter situations that cannot be understood intuitively during orthopedic interventions such as corrective osteotomy. Occasionally, unexpected angular or rotational deformity occurs during surgery. This study aimed to draw the attention of orthopedic surgeons toward the concepts of orientation and rotation and demonstrate the potential for unexpected deformity after orthopedic interventions. This study focused on three situations: shoulder arthrodesis, femoral varization derotational osteotomy, and femoral derotation osteotomy. Methods First, a shoulder model was generated to calculate unexpected rotational deformity to demonstrate Codman's paradox. Second, femoral varization derotational osteotomy was simulated using a cylinder model. Third, a reconstructed femoral model was used to calculate unexpected angular or rotational deformity during femoral derotation osteotomy. Results Unexpected external rotation was found after forward elevation and abduction of the shoulder joint. In the varization and derotation model, closed-wedge osteotomy and additional derotation resulted in an unexpected extension and valgus deformity, namely, undercorrection of coxa valga. After femoral derotational osteotomy, varization and extension of the distal fragment occurred, although the extension was negligible. Conclusions Surgeons should be aware of unexpected angular deformity after surgical procedure involving bony areas. The degree of deformity differs depending on the context of the surgical procedure. However, this study reveals that notable deformities can be expected during orthopedic procedures such as femoral varization derotational osteotomy. [ABSTRACT FROM AUTHOR]

In spite of the fact that hacking is a widely used term, it is still not legally established. Moreover, the definition of the concept of hacking has been deployed in a wide variety of ways in national literature. This ambiguity has led to various side effects. Recently in the United States, reforms collectively known as Aaron's Law were proposed as intended amendments to the Computer Fraud and Abuse Act (CFAA).Most experts expect that this change will put the brakes on the CFAA as a severe punishment policy, and result in a drop in controversial court decisions. In this study, we analyze the definitions and the penalties for hacking for each country and compare them with the national law and then make suggestions through more specific legislation. We expect it will reduce legal controversy and prevent excessive punishment [ABSTRACT FROM AUTHOR]

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates an intracellular signal transduction program termed the unfolded protein response (UPR). In mammalian cells, the UPR is signaled in part through dimerization of ER membrane-localized IRE1α to activate its protein kinase and endoribonuclease activities. Activated IRE1α cleaves XBP1 mRNA at two sites to initiate an unconventional splicing reaction. The 5′ and 3′ fragments are subsequently joined by an RNA ligase activity, thereby removing a 26-base intron. This splicing reaction creates a translational frameshift to produce a functional XBP1 transcription factor. However, the cellular location and physiological processes required for splicing of XBP1 mRNA are not well characterized. To study these processes, XBP1 mRNAs were engineered in which translation of enhanced green fluorescence protein or luciferase required splicing of the XBP1 intron. Using cell lines that continuously or transiently express these reporter constructs, we show that cytoplasmic unspliced XBP1 mRNA is efficiently spliced by activated IRE1α and requires ongoing cellular transcription but not active translation. The XBP1 intron was effectively removed from RNA substrates transcribed from T7 RNA polymerase or delivered directly to the cytoplasm by RNA transfection, thus indicating that the splicing reaction does not require nuclear processing of the RNA substrate. Analysis of nuclear and cytoplasmic RNA fractions demonstrated that XBP1 mRNA splicing occurs in the cytoplasm. Moreover, an artificial Fv-IRE1αΔN was engineered that was able to splice XBP1 mRNA upon chemical-induced dimerization. These findings demonstrate that IRE1α dimerization is sufficient to activate XBP1 mRNA splicing in the absence of the UPR. We propose that XBP1 mRNA cytoplasmic splicing provides a novel mechanism to rapidly induce translation of a transcription factor in response to a specific stimulus. [ABSTRACT FROM AUTHOR]

An improved bipolar transistor model considering heterojunction barrier effect (HBE) in SiGe double heterojunction bipolar transistors is developed. The effect of barrier formation due to high level injection, which is related to the rapid degradations of the dc current gain (β) and cutoff frequency (ƒT), is carefully investigated and analyzed. As the collector current becomes high, the conduction band barrier is induced and increased. It causes the saturation of collector current (JC) due to the blocking of carrier transport, the sharp increase of base transit time (τB) due to the additional charge storage, the increase of base current (JB) due to the increased recombination, and the decrease of intrinsic base resistance (Rbi) due to the increased charge and base pushout. Those phenomena are included into a vertical bipolar intercompany model (VBIC) compact model by employing a unified model of the HBE on JC, JB, τB, and Rbi. Furthermore, portions of τB and Rbi from the Kirk effect itself are modeled according to the high current model description and the new formulation of widened base, respectively. A full extraction of parameters has been performed and the modified VBIC model is applied. The modeling accuracy is significantly improved at the high current region for the dc and RF characteristics. [ABSTRACT FROM AUTHOR]

An improved direct parameter extraction method of SiGe heteroj unction bipolar transistors (HBTs) for the vertical bipolar intercompany (VBIC)-type hybrid-π model is developed. All the equivalent circuit elements are extracted analytically from S-parameter data only and without any numerical optismization. The proposed technique of the parameter extraction, differing from the previous ones, focuses on correcting the pad de-embedding error for an accurate and invariant extraction of intrinsic base resistance (Rbi), formulating a new parasitic substrate network, and improving the extraction procedure of transconductance (gm), dynamic base-emitter resistance (rπ), and basc-emitter capacitance (Cπ) using the accurately extracted Rbbi. The extracted parameters are frequency-independent and reliable due to elimination of any de-embedding errors. The agreements between the measured and model-calculated data are excellent in the frequency range of 0.2-10.2 GHz over a wide range of bias points. Therefore, we believe that the proposed extraction method is a simple and reliable routine applicable to the optimization of transistor design, process control, and the improvement of VBIC compact model, especially for SiGe HBTs. [ABSTRACT FROM AUTHOR]

A novel structure distributed active transformer (DAT), which significantly reduces the coupling from the DAT to the feed line is demonstrated. A grounded, guard line is implemented to isolate the feed line from the magnetic field of the DAT. The measured result of the DAT on a GaAs substrate shows a 10.5-dB reduction in the coupling. To reduce DAT loss, an air-bridge connected double primary DAT structure is implemented. The DAT at 2 GHz shows a 0.7-dB loss reduction in comparison to the conventional DAT. The improved DAT performance is related to the reduced metal resistance and closer coupling between the primary and secondary loops without any increase in the DAT area. [ABSTRACT FROM AUTHOR]

Reports that the unfolded protein response (UPR) is required for haploid tolerance in yeast. Transcription factor that mediates the UPR in Saccharomyces cerevisiae; Novel function for HAC1 in haploid tolerance; Autodiploidization of hac1 spore clones occurring after germinations.

Analyzes the nonlinear behavior of power heterojunction bipolar transistors (HBT). Development of an analytical nonlinear HBT model; Use of the Volterra-series analysis; Consideration of several nonlinear components; Dependence of the third-order intermodulation on the terminations of the source second harmonic impedances.

InP-based single heterojunction bipolar transistors (SHBTs) for high-speed circuit applications were developed. Typical common emitter dc current gain (β) and BV[sub CEO] were about 17 and 10 V, respectively. Maximum extrapolated f[sub max] of 478 GHz with f[sub T] of 154 GHz was achieved for 0.5 × 10 µm² emitter size devices at 300 kA/cm² collector current density and 1.5 V collector bias. This is the highest f[sub max] ever reported for any nontransferred substrate HBTs, as far as the authors know. This paper highlights the optimized conventional process, and the authors have great hopes for the process that offers inherent advantages for the direct implementation to high-speed electronic circuit fabrication. [ABSTRACT FROM AUTHOR]

A link exists between endoplasmic reticulum (ER) biogenesis and the unfolded protein response (UPR), a complex set of signaling mechanisms triggered by increased demands on the protein folding capacity of the ER. The UPR transcriptional activator X-box binding protein 1 (XBP1) regulates the expression of proteins that function throughout the secretory pathway and is necessary for development of an expansive ER network. We previously demonstrated that overexpression of XBP1(S), the active form of XBP1 generated by UPR-mediated splicing of Xbp1 mRNA, augments the activity of the cytidine diphosphocholine (CDP-choline) pathway for biosynthesis of phosphatidylcholine (PtdCho) and induces ER biogenesis. Another UPR transcriptional activator, activating transcription factor 6α (ATF6α), primarily regulates expression of ER resident proteins involved in the maturation and degradation of ER client proteins. Here, we demonstrate that enforced expression of a constitutively active form of ATF6α drives ER expansion and can do so in the absence of XBP1(S). Overexpression of active ATF6α induces PtdCho biosynthesis and modulates the CDP-choline pathway differently than does enforced expression of XBP1(S). These data indicate that ATF6α and XBP1(S) have the ability to regulate lipid biosynthesis and ER expansion by mechanisms that are at least partially distinct. These studies reveal further complexity in the potential relationships between UPR pathways, lipid production and ER biogenesis. [ABSTRACT FROM AUTHOR]

Examines the regulation of the unfolded protein response by the complementary signaling pathway. Requirement of the complementary signaling pathways for Caenorhabditis elegans; Presence of the unfolded protein within the endoplasmic reticulum; Use of protein kinase for the mediation of translation attenuation.

Background: Reactive oxygen species (ROS) produce different lesions in DNA by ROS-induced DNA damage. Detection and quantification of 8-oxo-7,8-dihydroguanine (8-oxoG) within cells are important for study. Human ribosomal protein S3 (hRpS3) has a high binding affinity to 8-oxoG. In this study, we developed an imaging probe to detect 8-oxoG using a specific peptide from hRpS3. Transactivator (TAT) proteins are known to have cellpenetrating properties. Therefore, we developed a TAT-S3 probe by attaching a TAT peptide to our imaging probe. Results: A DNA binding assay was conducted to confirm that our probe bound to 8-oxoG and apurinic/apyrimidinic (AP) sites. We confirmed that the TAT-S3 probe localized in the mitochondria, without permeabilization, and fluoresced in H2O2-treated HeLa cells and zebrafish embryos. Treatment with Mitoquinone (MitoQ), a mitochondria-targeted antioxidant, reduced TAT-S3 probe fluorescence. Additionally, treatment with O8, an inhibitor of OGG1, increased probe fluorescence. A competition assay was conducted with an aldehyde reaction probe (ARP) and methoxyamine (MX) to confirm binding of TAT-S3 to the AP sites. The TAT-S3 probe showed competitive binding to AP sites with ARP and MX. Conclusions: These results revealed that the TAT-S3 probe successfully detected the presence of 8-oxoG and AP sites in damaged cells. The TAT-S3 probe may have applications for the detection of diseases caused by reactive oxygen species. [ABSTRACT FROM AUTHOR]