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Recent structural studies have shown that the carboxyl-terminus of many TRP channels, including TRPC3, are folded into a horizontal rib helix that is connected to the vertical pole helix, which play roles in inter-structural interactions and multimerization. In a previous work we identified I807 located in the pole helix with a role in regulation of TRPC3 by STIM1 (Lee et al., 2014, Liu et al., 2022). To further determine the role of the pole helix in TRPC3 function, here we identified key hydrophobic residues in the pole helix that form tight tunnel-like structure and used mutations to probe their role in TRPC3 regulation by Ca

Obesity is implicated in cardiovascular disease and heart failure. When fatty acids are transported to and not adequately oxidized in cardiac cells, they accumulate, causing lipotoxicity in the heart. Since hepatic progesterone receptor membrane component 1 (Pgrmc1) suppressed de novo lipogenesis in a previous study, it was questioned whether cardiac Pgrmc1 protects against lipotoxicity. Hence, we focused on the role of cardiac Pgrmc1 in basal (Resting), glucose-dominant (Refed) and lipid-dominant high-fat diet (HFD) conditions. Pgrmc1 KO mice showed high FFA levels and low glucose levels compared to wild-type (WT) mice. Pgrmc1 KO mice presented low number of mitochondrial DNA copies in heart, and it was concomitantly observed with low expression of TCA cycle genes and oxidative phosphorylation genes. Pgrmc1 absence in heart presented low fatty acid oxidation activity in all conditions, but the production of acetyl-CoA and ATP was in pronounced suppression only in HFD condition. Furthermore, HFD Pgrmc1 KO mice resulted in high cardiac fatty acyl-CoA levels and TG level. Accordingly, HFD Pgrmc1 KO mice were prone to cardiac lipotoxicity, featuring high levels in markers of inflammation, endoplasmic reticulum stress, oxidative stress, fibrosis, and heart failure. In vitro study, it was also confirmed that Pgrmc1 enhances rates of mitochondrial respiration and fatty acid oxidation. This study is clinically important because mitochondrial defects in Pgrmc1 KO mice hearts represent the late phase of cardiac failure.

Prunus japonica var. nakaii is used in traditional Korean medicine to treat various conditions; however, it has not been investigated for treating male infertility. In this study, we investigated the in vitro effects of the ethanolic extract of P. japonica seeds on human sperm motility and identified its mechanism of action. Eleven male volunteers were selected, and the effects of the extract on human spermatozoa were assessed through a computer-assisted semen analysis. The P. japonica seed extract increased the percentage of total and progressive motility of spermatozoa. To understand the mechanism of action, we monitored intracellular alkalization using flow cytometry and obtained electrophysiological recordings of human voltage-gated proton channels hHv1 that were overexpressed in HEK-293 cells. The extract shifted the activation curves in a concentration-dependent manner. Two major constituents of the extract, linoleic acid and oleic acid, exhibited proton channel activity. Our in vitro experiments suggested that P. japonica seed extract could be potentially used to rescue sperm motility in idiopathic infertility patients via pharmacological modulation of the proton channels during capacitation. Therefore, our results indicate the therapeutic potential of P. japonica seed extract for treating male infertility.

Hepatic gluconeogenesis is the main pathway for blood glucose maintenance activated during fasting. Retardation of insulin action, such as in diabetes mellitus, activates gluconeogenesis during the fed state. While the role of progesterone (P4) in diabetes is controversial, the P4 receptor, progesterone receptor membrane component 1 (PGRMC1), is known to stimulate pancreatic insulin secretion. We investigated the role of P4, via hepatic PGRMC1, during gluconeogenesis. The PGRMC1 binding chemical, AG-205, induced PGRMC1 monomer (25 kDa) abundance, and increased PEPCK expression and glucose production in parallel with cyclic AMP (cAMP) induction in Hep3B cells. PGRMC1-mediated cyclic AMP was inhibited by an adenylate cyclase inhibitor (MDL-12,330A). PEPCK suppression in Pgrmc1 KO hepatocyte was not observed after treatment of MDL-12,330A. PGRMC1 knockdown or overexpression systems in Hep3B cells confirmed that PGRMC1 mediates PEPCK expression via phosphorylation of cAMP-response element binding protein (CREB). CREB phosphorylation and PEPCK expression in primary hepatocytes were greater than that in PGRMC1 knock-out hepatocytes. Progesterone increased PGRMC1 expression, which induced cAMP and PEPCK induction and glucose production. In vivo, P4 suppressed gluconeogenesis following plasma insulin induction under normal conditions in a mouse model. However, P4 increased blood glucose via gluconeogenesis in parallel with increases in PGRMC1 and PEPCK expression in mice in both insulin-deficient and insulin-resistant conditions. We conclude that P4 increases hepatic glucose production via PGRMC1, which may exacerbate hyperglycaemia in diabetes where insulin action is limited.

Benign prostate hyperplasia (BPH) is a common disease in old-age males, accounting for approximately 77% of morbidity within the age range of 40 to 70 years. It has been shown that morbidity increases with social graying. Quisqualis indica linn (QI) has been used to treat inflammation, stomach pain, and digestion problems. In this study, we evaluated the symptom-regulating effects of QI extract on a testosterone-induced BPH rat model. After inducing BPH in rats using testosterone propionate (TP) injection, we assessed basal intraurethral pressure (IUP) and increments of IUP elicited by electrical field stimulation (5 V, 5, 10, or 20 Hz) or phenylephrine (Phe) (0.01, 0.03, 0.1 mg/kg IV). To induce BPH, 8-week-old rats were subjected to a daily subcutaneous TP (3 mg/kg) injection for 4 weeks. Finasteride (Fina) (10 mg/kg PO) was administered to the rats in the first treatment, while QI (150 mg/kg PO) was administered to those in the second group. Blood pressure was measured together with IUP, after which low urinary tract (LUT), ventral prostate (VP), testicle, and corpus spongiosum were isolated and weighed. Basal IUPs for the Fina- and QI-treated groups were 87.6 and 86.8%, respectively.LUT and VP organ weights in the QI group were lower than those in the Fina group. However, the QI group showed significantly reduced electrical stimulated or Phe-induced IUP increment compared to the Fina and BPH groups. These results proved that QI can be beneficial for BPH symptoms by inhibiting 5α-reductase and consequently decreasing prostate and releasing urinary pressure.

Benign prostatic hyperplasia (BPH) is an age-related disease characterized by prostatic enlargement and is the most common urologic symptoms in elderly men 60 years of age and older. Previously, we documented that 70% ethanol (EtOH) seed extract of Quisqualis indica (QI) attenuates pathological condition of testosterone propionate (TP)-induced BPH rat model via modulation of proliferation and apoptosis of prostate cells. Based on this potential of QI, we produced standardized seed extract of QI (HU-033) in order to prove further mechanisms. In this study, we aimed to suggest further mechanisms underlying the relationship between BPH and HU-033. Through not only cellular and nuclear receptor functional assays, but TP-mediated BPH rat model treated with HU-033, we demonstrated that HU-033 exerted antagonist effect on α1A- and α1D-adrenergic receptors in vitro and inhibitory effect on protein expression of androgen receptor and estrogen receptor alpha in vivo. Taken together, these results suggest that HU-033 is a novel candidate for the management of BPH.

This paper presents a low-random noise of 2.6 e-rms, a low-power of 116.2 mW at video rate, and a high-speed up to 960 fps 2-mega pixels global-shutter type CMOS image sensor (CIS) using an advanced DRAM technology. To achieve a high performance global-shutter CIS, we proposed a novel architecture for the digital pixel sensor which is a remarkable global-shutter operation CIS with a pixel-wise ADC and an in-pixel digital memory. Each pixel has two small-pitch Cu-to-Cu interconnectors for the wafer-level stacking, and the pitch of each unit pixel is less than 5 μm which is the world’s smallest pixel embedding both pixel-level ADC and 22-bit memories.

This study characterized the antimicrobial substances produced by the radiation-resistant bacterium Nibribacter radioresistens. The antimicrobial substances showed activity against Salmonella Gallinarum, pathogenic Escherichia coli, Bacillus cereus, Streptococcus iniae, and Saccharomyces cerevisiae. The substances showed higher activity against Gram-positive bacteria than against Gram-negative bacteria and yeast. N. radioresistens showed the best growth rate in LB liquid medium at 37oC; however, production of the antimicrobial substances was not associated with growth. Since the activity of the antimicrobial substances was affected by proteinase K and EDTA, the substances were presumed to be antimicrobial peptides (AMPs). The antimicrobial substances produced by N. radioresistens were unstable at higher temperatures and in acidic and basic pH ranges, and most of the activity was attributed to either low ( 30 kDa) molecules. When S. Gallinarum was treated with the antimicrobial substances, the cell destruction was acted on the cell envelope. Therefore, we concluded that N. radioresistens produces broad-spectrum and very unstable antimicrobial substances that mostly consist of low- and high-molecular weight peptides.

Skeletal muscle is responsible for free fatty acid (FFA) disposal via mitochondrial respiration and fatty acid oxidation (FAO). Obesity triggers high levels of circulating FFAs, which can cause intramuscular lipid (IMCL) deposition. Diverse phytochemicals, including crude Castanea crenata inner shell extract (CCE), have been shown to possess an anti-obesity effect.We aimed to demonstrate whether the aqueous fraction of CCE (ACCE) provides an anti-obesity effect with a decrease in plasma FFAs and reduces IMCL.High-fat-fed C57BL/6 mice received ACCE via water intake. A204 cells incubated with fatty acids were treated with ACCE. Lipid accumulation and mitochondrial metabolism were assessed using histological and molecular techniques.ACCE possessed a notably higher gallic acid content than CCE among the constituents. ACCE-administered mice exhibited reduced plasma FFA levels, adiposity, and IMCL. Muscle lipotoxicity was suppressed, including apoptosis, ER stress, and inflammation. The anti-lipid effect of ACCE was observed with the induction of mitochondrial respiration and fatty acid oxidation in muscle.ACCE increases mitochondrial respiration and FAO in skeletal muscle and protects muscle from IMCL and lipotoxicity, reducing plasma FFA and adiposity.

As the automotive and AI industries are expanding rapidly, global-shutter (GS) image sensors are playing a more significant role in the perception system. More specifically, GS image sensors are required in various fields involving IR, including the face-ID in mobile devices, the driver monitoring system in automotive applications, and factory automation. GS image sensors are necessary for these applications because they can capture freeze-frame images without motion distortion due to their advantage in the pixel operation method. The simultaneous pixel exposure and in-pixel storing capability allow GS image sensors to achieve high-quality imaging, while the sequential pixel exposure and readout of rolling-shutter (RS) image sensors results in image distortion known as the jello effect. For mobile and automotive applications, a small form factor while maintaining a low parasitic light sensitivity (PLS) and low noise is crucial. In conventional backside illuminated (BSI) charge-domain GS image sensors, a light-shielding structure over the storage area must be formed in order to suppress the influence of parasitic light during the readout operation. Therefore, the introduction of such a light-shielding structure reduces the effective photodiode area, which results in a loss of full-well capacity (FWC), light sensitivity of the sensor, and pixel scalability.

As the smart mobile device market continues to grow and the number of cameras per device rapidly increases, demand for CMOS image sensors (CIS) also increases. Two major trends in mobile device cameras are: (1) adopting smaller pixels that enable greater pixel count at similar optical format, and (2) bigger pixels for higher image quality. To be more specific, front-facing cameras have a trend towards smaller pixels, while rear main cameras have a trend towards both smaller and bigger pixels. The optical format of front-facing cameras is especially limited due to existing bezel-less or border-less display designs, yet higher resolution still-shot and video (such as 4K UHD) recording is desired. To implement greater pixel count in a limited camera module size, scaling of pixel size is required. The main challenges are to maintain acceptable photodiode full-well capacity (FWC) and sensitivity, while suppressing optical crosstalk [1]. To completely eliminate both electrical and optical crosstalk, deep-trench isolation (DTI) has evolved from early BDTI (Back-side DTI) to current FDTI (Front-side DTI) technology, which is also called full-depth DTI. In this paper, a 44Mpixel CIS with 0.7µm pixels using full-depth DTI is demonstrated.

A 35nm node 4Gbit LPDDR3 prototype with high-k metal gate (HKMG) peripheral transistors is implemented for the first time using processes that are fully compatible with those of conventional commercial DRAMs with poly/SiON (PSiON) transistors. This paper describes that the HKMG transistors in the peripheral circuits drastically reduce operating voltage from 1.2V to less than 0.95V. At the same time, both retention time and tRDL are improved due to >30% reduction of the threshold voltage (Vth) mismatch in sense amplifiers which is majorly induced by random dopant fluctuation (RDF) phenomenon. Lastly, chip size can be reduced as the increase of drivability allows the gate width of transistors to be scaled down.

Objective To evaluate nafamostat mesilate (NM) as an alternative anticoagulant agent for intermittent hemodialysis (IHD). Design Prospective randomized study. Setting University teaching hospital. Animals Eighteen healthy Beagle dogs. Interventions In group 1 (n = 6), NM was administered at a dose of 0.5 mg/kg/h during IHD for 5 hours. In group 2 (n = 6), NM was administered at a low dose of 0.25 mg/kg/h during IHD. In group 3 (n = 6), which was the control group, unfractionated heparin (UFH) was administered during IHD. The evaluated parameters included: the amount of residual blood clots in the blood chamber and arterial side of the dialyzer; the levels of hemoglobin, hematocrit, and platelets; and the prothrombin time (PT), activated partial thromboplastin time (aPTT), and activated clotting time (ACT). Measurements and main results Groups 1 and 2 successfully completed IHD without serious coagulation in the extracorporeal circulation. The residual blood clotting in the blood chamber and arterial side of the dialyzer did not significantly differ in groups 1 and 2 compared to group 3 (group 1 vs group 3, P = 1.000; and group 2 vs group 3, P = 1.000). No significant differences were observed between pre- and posttreatment PTs in groups 1 (P = 0.476) and 2 (P = 0.597), between pre- and posttreatment aPTTs in groups 1 (P = 0.983) and 2 (P = 0.977), and between pre- and posttreatment ACT in groups 1 (P = 0.282) and 2 (P = 0.401). In group 3, a significant elevation of ACT was observed at the posttest (P Conclusions The results of this study in healthy Beagle dogs suggest that NM at 0.25 mg/kg/h may be a valid alternative to UFH for IHD. Further studies are needed in patients at high risk of bleeding.

Thromboembolic complications are increasing in veterinary medicine. Thromboelastography (TEG) is a more comprehensive method for assessing the clotting process than standard plasma-based coagulation tests. This study compared the ability of TEG and standard coagulation tests to analyze the overall hemostatic state of dogs. The study involved 40 dogs with underlying diseases that predispose to hypercoagulability, including neoplasia, hyperadrenocorticism, immune-mediated diseases, gastrointestinal diseases, and protein-losing nephropathies and enteropathies, and 20 healthy dogs. Their overall hemostatic functional state was evaluated by TEG and routine coagulation assays, including activated partial thromboplastin time, prothrombin time, platelet count, and D-dimer concentration. TEG analysis showed significant differences in clot formation time, α angle, and maximum amplitude (MA) between diseased and control dogs (P ＜ 0.001 each). Increased MA was the most frequent abnormality on TEG and was indicative of hypercoagulability. TEG was useful in detecting hemostatic dysfunction in dogs with diseases associated with hypercoagulability. Dogs with TEG tracings indicative of hypercoagulability are likely to be in procoagulant states. Future prospective studies are needed to evaluate whether TEG tracings indicative of hypercoagulability are predictive of thrombosis in dogs.

Context: Fructus Psoralea, Psoralea corylifolia L. (Leguminosae), has been widely used in traditional medicines for the treatment of dermatitis, leukoderma, asthma and osteoporosis. Objectives: In this study, we sought to study mechanisms underlying the vasoactive properties of Psoralea corylifolia extract (PCE) and its active ingredients. Materials and methods: To study mechanisms underlying the vasoactive properties of PCE prepared by extracting dried seeds of Psoralea corylifolia with 70% ethanol, isometric tension recordings of rat aortic rings and the ionic currents through TRPC3 (transient receptor potential canonical 3) channels were measured with the cumulative concentration (10–600 μg/mL) of PCE or its constituents. Results: Cumulative treatment with PCE caused the relaxation of pre-contracted aortic rings in the presence and absence of endothelium with EC50 values of 61.27 ± 3.11 and 211.13 ± 18.74 μg/mL, respectively. Pretreatment with inhibitors of nitric oxide (NO) synthase, guanylate cyclase, or cyclooxygenase and pyrazole 3, a selective TRPC3 channel blocker, significantly decreased PCE-induced vasorelaxation (p

Heterogeneously integrated single-λ and λtunable light sources on bulk-silicon platform are presented. A high wall plug efficiency of 8% up to 70°C is achieved due to efficient heat dissipation capability of bulk-silicon platform.

Heterogeneously integrated single $-\lambda$ and $\lambda$ -tunable light sources on bulk-silicon platform are presented. Thanks to the thermal advantage of the bulk-silicon platform, the single- $\lambda$ source showed WPE of 8% up to 70°C, feasibility of 25Gb/s direct modulation, and 70°C MTTF of ∼46000h. The $\lambda$ -tunable source showed 42.2nm tuning range. This result completes the optical device library suite for the bulk-silicon platform used in most semiconductor products.

In this paper, germanium pre-amorphization implantation (PAI) and carbon co-implantation (Ge + C co-IIP) were applied to suppress boron diffusion. The corresponding characteristics were investigated in terms of the dopant diffusion, device performance, and its application to dynamic random access memory (DRAM). A shallow dopant profile was indicated and the threshold voltage (VTH) was reduced by approximately 45 mV by Ge + C co-IIP. In the DRAM device, the VTH mismatch of the sense amplifier NMOS pairs was reduced by approximately 15% and the write characteristics were improved two-fold.

In this paper, to suppress transient enhanced dopant diffusion and improve short channel effects, cold implantation (cold-IIP) was applied to contact PLUG implantation in P-channel metal oxide semiconductor field effect transistors (PMOSFETs). A shallow dopant profile was formed by the suppression of transient enhanced diffusion (TED) due to the reduction of end-of-range (EOR) defects. Threshold voltage roll-off and off current (Ioff) increment, which are caused by a reduction in the distance between the gate and contact, were improved compared with room temperature implantation (RT-IIP). Additionally, the drain induced barrier lowering was improved, and the on-current improvement was attributed to reducing the contact resistance through the reduction of EOR defects. The contact resistance was reduced by ∼6% of the RT-IIP. In the DRAM device, the standby current at a short propagation delay time (tPD) was reduced effectively due to the decrease in the Ioff and contact resistance for the cold-IIP case.

Meropenem, a second carbapenem antimicrobial agent with a broad spectrum of activity, is used to treat sepsis and resistant-bacterial infections in veterinary medicine. The objective of this study was to identify the pharmacokinetics of meropenem in dogs receiving intermittent hemodialysis (IHD) and to determine the proper dosing in renal failure patients receiving IHD. Five healthy beagle dogs were given a single i.v. dose of 24 mg/kg of meropenem and received IHD. The blood flow rate, dialysate flow, and ultrafiltration rate were maintained at 40 mL/min, 300 mL/min, and 40 mL/h, respectively. Blood samples were collected for 24 h from the jugular vein and from the extracorporeal arterial and venous line. Urine samples and dialysate were also collected. The concentrations of meropenem were assayed using HPLC/MS/MS determination. The peak plasma concentration was 116 ± 37 μg/mL at 15 min. The systemic clearance was 347 ± 117 mL/h/kg, and the steady-state volume of distribution was 223 ± 67 mL/kg. Dialysis clearance was 71.1 ± 34.3 mL/h/kg, and the extraction ratio by hemodialysis was 0.455 ± 0.150. The half-life (T1/2 ) in dogs with IHD decreased compared with those without IHD, and the reduction in T1/2 was greater in renal failure patients than in normal patients. Sixty-nine percent and 21% of the administered drug were recovered by urine and dialysate in the unchanged form, respectively. In conclusion, additional dosing of 24 mg/kg of meropenem after dialysis could be necessary according to the residual renal function of the patient based on the simulated data.

Transient receptor potential canonical (TRPC) family contains a non-selective cation channel, and four TRPC subunits form a functional tetrameric channel. TRPC4/5 channels form not only the homotetrameric channel but also a heterotetrameric channel with TRPC1. We investigated the interaction domain required for TRPC1/4 or TRPC1/5 heteromultimeric channels using FRET and the patch-clamp technique. TRPC1 only localized at the plasma membrane (PM) when it was coexpressed with TRPC4 or TRPC5. The TRPC1/4 or TRPC1/5 heteromultimeric showed the typical outward rectifying I/V curve. When TRPC1 and TRPC4 form a heteromeric channel, the N-terminal coiled-coil domain (CCD) and C-terminal 725-745 region of TRPC1 interact with the N-terminal CCD and C-terminal 700-728 region of TRPC4. However, when TRPC1 and TRPC5 form a heteromeric channel, the N-terminal CCD and C-terminal 673-725 region of TRPC1 interact with the N-terminal CCD and C-terminal 707-735 region of TRPC5. In conclusion, the N-terminal CCD of TRPC channels is essential for the heteromultimeric structure of TRPC channels, whereas specific C-terminal regions are required for unique heteromerization between subgroups of TRPC channels.

Transient receptor potential canonical (TRPC) 4 channels are calcium-permeable, nonselective cation channels and are widely expressed in mammalian tissue, especially in the GI tract and brain. TRPC4 channels are known to be involved in neurogenic contraction of ileal smooth muscle cells via generating cationic current after muscarinic stimulation (muscarinic cationic current (mIcat)). Polyamines exist in numerous tissues and are believed to be involved in cell proliferation, differentiation, scar formation, wound healing, and carcinogenesis. Besides, physiological polyamines are essential to maintain inward rectification of cardiac potassium channels (Kir2.1). At membrane potentials more positive than equilibrium potential, intracellular polyamines plug the cytosolic surface of the Kir2.1 so that potassium ions cannot pass through the pore. Recently, it was reported that polyamines inhibit not only cardiac potassium channels but also nonselective cation channels that mediate the generation of mIcat. Here, we report that TRPC4, a definite mIcat mediator, is inhibited by intracellular spermine with great extent. The inhibition was specific to TRPC4 and TRPC5 channels but was not effective to TRPC1/4, TRPC1/5, and TRPC3 channels. For this inhibition to occur, we found that glutamates at 728th and 729th position of TRPC4 channels are essential whereby we conclude that spermine blocks the TRPC4 channel with electrostatic interaction between negative amino acids at the C-terminus of the channel.

Ethnopharmacological relevance Stauntonia hexaphylla (Lardizabalaceae, S. hexaphylla) is traditionally used as a folk remedy for alleviating fever and for its anti– inflammatory and analgesic properties. In Korea and China, S. hexaphylla has been used as a traditional medicine that acts as diuretic and analgesic. S. hexaphylla has also been reported to inhibit osteoporosis and aldose reductase activity. Aim of the study The study aimed to evaluate the therapeutic effects of an extract of S. hexaphylla on testosterone induced benign prostate hyperplasia (BPH) models and to observe its mechanism of action. Materials and methods To induce a BPH model in vitro and in vivo, a testosterone-treated LNCaP cell line and Sprague Dawley (SD) rats were used, respectively. Androgen receptors (ARs) and prostate-specific antigens (PSA), which are typical BPH-related proteins, were evaluated using western blotting. Prostate weights and dihydrotestosterone (DHT) levels were measured in vivo, and histopathology of the prostate examined using hematoxylin and eosin staining. Proliferating cell nuclear antigen (PCNA) and 5α-reductase type 2 were also evaluated via immunohistochemistry (IHC). In addition, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining and LC3 staining of IHC were performed to evaluate apoptosis and autophagy. Results S. hexaphylla reduced prostates weights and the thickness of prostate epithelial cells. In vivo and in vitro, PSA and ARs were downregulated following S. hexaphylla treatment. The S. hexaphylla extracts also reduced DHT and 5α-reductase type 2 expression. In addition, the expression of PCNA was reduced, and in the TUNEL staining and IHC of LC3, the number of positive cells was increased in the groups treated with S. hexaphylla. Conclusions It was observed that extracts of S. hexaphylla inhibited both 5α -reductase type 2 and ARs. The results indicate that the use of S. hexaphylla extract in BPH is probably beneficial through 5α-reductase inhibition and α-adrenergic receptor blockade. In addition, apoptosis and autophagy were induced, and PCNA was downregulated after S. hexaphylla treatment. Therefore, it can be concluded that S. hexaphylla has a therapeutic effect on BPH.

Background: With continuous decrease in the technology node of dynamic random access memories (DRAMs) down to sub-20 nm, the self-aligned double patterning (SADP) is an effective approach to generate two-dimensional (2-D) patterns, particularly contact arrays. Aim: We demonstrate a patterning scheme using the SADP technique to produce active trim contacts with anisotropic pattern pitches. Approach: The proposed scheme uses two consecutive spacer-formation processes. Results: By making the ellipsoidal core pillars and minimizing the spacer thickness, 2-D critical dimensions (CDs) for self-generated contacts match well with those for core contacts. In addition, an interesting cross-dependence of X -CD and Y -CD variations for the core and self-generated contacts is observed. Conclusion: This patterning approach is useful for forming active trim contacts in sub-20 nm DRAMs using fewer numbers of ArF immersion photolithography steps.

An O-band DFB laser heterogeneously integrated on bulk-silicon platform is presented. A high wall plug efficiency of over 8% up to 70°C is achieved due to efficient heat dissipation from III/V active region to silicon platform. The single-mode operation is maintained in a wide current range with side-mode suppression ratio over 45dB. This result completes the optical device library suite for the bulk-silicon platform used in most semiconductor products.

Store-operated calcium entry (SOCE), an important mechanism of Ca2+ signaling in a wide range of cell types, is mediated by stromal interaction molecule (STIM), which senses the depletion of endoplasmic reticulum Ca2+ stores and binds and activates Orai channels in the plasma membrane. This inside-out mechanism of Ca2+ signaling raises an interesting question about the evolution of SOCE: How did these two proteins existing in different cellular compartments evolve to interact with each other? We investigated the gating mechanism of Caenorhabditis elegans Orai channels. Our analysis revealed a mechanism of Orai gating by STIM binding to the intracellular 2-3 loop of Orai in C. elegans that is radically different from Orai gating by STIM binding to the N and C termini of Orai in mammals. In addition, we found that the conserved hydrophobic amino acids in the 2-3 loop of Orai1 are important for the oligomerization and gating of channels and are regulated via an intramolecular interaction mechanism mediated by the N and C termini of Orai1. This study identifies a previously unknown SOCE mechanism in C. elegans and suggests that, while the STIM-Orai interaction is conserved between invertebrates and mammals, the gating mechanism for Orai channels differs considerably.

Protein phosphatase 1 (PP1) is involved in various signal transduction mechanisms as an extensive regulator. The PP1 catalytic subunit (PP1c) recognizes and binds to PP1-binding consensus residues (FxxR/KxR/K) in NBCe1-B. Consequently, we focused on identifying the function of the PP1-binding consensus residue, 922FMDRLK927, in NBCe1-B. Using site-directed mutagenesis and co-immunoprecipitation assays, we revealed that in cases where the residues were substituted (F922A, R925A, and K927A) or deleted (deletion of amino acids 922-927), NBCe1-B mutants inhibited PP1 binding to NBCe1-B. Additionally, by recording the intracellular pH, we found that PP1-binding consensus residues in NBCe1-B were not only critical for NBCe1-B activity, but also relevant to its surface expression level. Therefore, we reported that NBCe1-B, as a substrate of PP1, contains these residues in the C-terminal region and that the direct interaction between NBCe1-B and PP1 is functionally critical in controlling the regulation of the HCO3- transport. These results suggested that like IRBIT, PP1 was another novel regulator of HCO3- secretion in several types of epithelia.

NAND flash memory is evolving from 2D to 3D structure since 2D NAND flash faced its limitation of size reduction. In this paper, the limitations of 2D planar technology and the development history of 3D NAND flash will be reviewed. Finally, we will discuss the problems to overcome in order to succeed the development of 3D NAND flash.

To a major candidate and beyond, directed self-assembly (DSA) lithography is investigated on DRAM contact-hole fabrication. We perform a systematic study about behavior of asymmetric PS-b-PMMA block copolymers (BCP) within pillar confinement for DSA and find that selectively removed PMMA contact domain has a different morphology according to chemically modified pillar surfaces. We calculate the perturbation of PMMA contacts by pillar diameter using free energy magnitude model. This established model provides practical engineering insight for present pillar scheme and future graphoepitaxial self-assembly techniques for semiconductor DSA procedure.

As Transistor length shrink, many unexpected short channel effects occur under 20nm size. Among these short channel effects, this paper explains about reliability problem of FN degradation and its improvement in 3-Dimension Transistor. The graph of Fig.1 demonstrates that there was threshold voltage(Vth) shift after reliability test(High voltage, High temperature, Long time condition). Of course, the original black curve must be maintained its value despite of reliability stress. This phenomenon caused serious reliability problem in the device. Above all the easiest method to solve this problem was that we increased the thickness of the oxide. However this method had serious demerit that we must endured the current decrease [1]. Therefore the following two methods were considered for solving this problem. The first method was that we changed the profile of FIN to reduce the leakage current. The electric fields were crowded at the sharp point and degradation could occur well in Fig.2 (a) profile-1. Therefore we made the sharp point be rounded like Fig.2 (b) profile-2 by changing FIN shape. This was good solution to protect charge converging on cusp and to reduce FN degradation. In the graph of Fig.4 we could confirm that profile-2 was better than profile-1. However this method must be applied carefully in device because it generated side effects that were caused by decreased margin of Gate to Active isolation. The second method was that we reduced fixed charges generation by adjusting the grain size of metal gate. The grain size of metal gate was more lager after all integration than just deposition status. This grain growth acted as (+) charge formation factor in the condition of reliability stress. In other words, at the interface of Si and metal gate the following reaction happened lively (TiN + SiO2 -> TiON + SiO+ ). Therefore we must reduce the grain growth to improve the FN degradation. We knew that the grain size was changed by temperature of TiN deposition through many experiments [2]. In Fig.3 (a), the grain size grew approximately 0.8nm per 30 degrees of TiN deposition temperature. As the TiN deposition temperature increased, gap of grain growth became smaller than low temperature status. It noted that the grain size after all integration is almost same as the grain size of just deposition status like Fig.3 (b) which is real grain TEM image in condition of 660°C. In conclusion, to confirm enhancement we verified the result of FIN profile optimization and TiN deposition temperature experiment by measuring Vth shift. In Fig.4, Vth shift and residual stress became smaller and smaller as we applied improvement condition. References [1] Fundamentals of Modern VLSI Devices, by Yuan Taur and Tak H.Ning [2] Hsyi-En Cheng, Wen-Jen Lee, C.-M. Hsu, Thin Solid Films Volume 485, Issues 1–2, 1 August 2005, Pages 59–65

Transient receptor potential canonical (TRPC) channels mediate a critical part of the receptor-evoked Ca(2+) influx. TRPCs are gated open by the endoplasmic reticulum Ca(2+) sensor STIM1. Here we asked which stromal interaction molecule 1 (STIM1) and TRPC domains mediate the interaction between them and how this interaction is used to open the channels. We report that the STIM1 Orai1-activating region domain of STIM1 interacts with the TRPC channel coiled coil domains (CCDs) and that this interaction is essential for opening the channels by STIM1. Thus, disruption of the N-terminal (NT) CCDs by triple mutations eliminated TRPC surface localization and reduced binding of STIM1 to TRPC1 and TRPC5 while increasing binding to TRPC3 and TRPC6. Single mutations in TRPC1 NT or C-terminal (CT) CCDs reduced interaction and activation of TRPC1 by STIM1. Remarkably, single mutations in the TRPC3 NT CCD enhanced interaction and regulation by STIM1. Disruption in the TRPC3 CT CCD eliminated regulation by STIM1 and the enhanced interaction caused by NT CCD mutations. The NT CCD mutations converted TRPC3 from a TRPC1-dependent to a TRPC1-independent, STIM1-regulated channel. TRPC1 reduced the FRET between BFP-TRPC3 and TRPC3-YFP and between CFP-TRPC3-YFP upon stimulation. Accordingly, knockdown of TRPC1 made TRPC3 STIM1-independent. STIM1 dependence of TRPC3 was reconstituted by the TRPC1 CT CCD alone. Knockout of Trpc1 and Trpc3 similarly inhibited Ca(2+) influx, and inhibition of Trpc3 had no further effect on Ca(2+) influx in Trpc1(-/-) cells. Cell stimulation enhanced the formation of Trpc1-Stim1-Trpc3 complexes. These findings support a model in which the TRPC3 NT and CT CCDs interact to shield the CT CCD from interaction with STIM1. The TRPC1 CT CCD dissociates this interaction to allow the STIM1 Orai1-activating region within STIM1 access to the TRPC3 CT CCD and regulation of TRPC3 by STIM1. These studies provide evidence that the TRPC channel CCDs participate in channel gating.

Scaling limitations in planar-NAND cell are discussed, including the depletion of floating gate and anomalous programming behavior. It is inevitable to have a paradigm shift to 3D-NAND due to numerous scaling limitations of planar NAND. However, the process complexity also increases in 3D-NAND as the mold height goes up in an exponential trend. Thus, scaling down of mold pitch is required, which degrades the cell characteristics. COP (Cell over Peripheral) 3D-NAND architecture has been developed as an area-scaling technology. CSL (Common-Source Line) junction leakage and p+ junction leakage at peripheral transistors have been improved by increasing the grain size and the thickness of barrier metal, respectively.

Plasma membrane hyperpolarization associated with activation of Ca2+-activated K+ channels plays an important role in sperm capacitation during fertilization. Although Slo3 (slowpoke homologue 3), together with the auxiliary γ2-subunit, LRRC52 (leucine-rich-repeat–containing 52), is known to mediate the pH-sensitive, sperm-specific K+ current KSper in mice, the molecular identity of this channel in human sperm remains controversial. In this study, we tested the classical BKCa activators, NS1619 and LDD175, on human Slo3, heterologously expressed in HEK293 cells together with its functional interacting γ2 subunit, hLRRC52. As previously reported, Slo3 K+ current was unaffected by iberiotoxin or 4-aminopyridine, but was inhibited by ~50% by 20 mM TEA. Extracellular alkalinization potentiated hSlo3 K+ current, and internal alkalinization and Ca2+ elevation induced a leftward shift its activation voltage. NS1619, which acts intracellularly to modulate hSlo1 gating, attenuated hSlo3 K+ currents, whereas LDD175 increased this current and induced membrane potential hyperpolarization. LDD175-induced potentiation was not associated with a change in the half-activation voltage at different intracellular pHs (pH 7.3 and pH 8.0) in the absence of intracellular Ca2+. In contrast, elevation of intracellular Ca2+ dramatically enhanced the LDD175-induced leftward shift in the half-activation potential of hSlo3. Therefore, the mechanism of action does not involve pH-dependent modulation of hSlo3 gating; instead, LDD175 may modulate Ca2+-dependent activation of hSlo3. Thus, LDD175 potentially activates native KSper and may induce membrane hyperpolarization-associated hyperactivation in human sperm.

Sperm function and male fertility are closely related to pH dependent K+ current (KSper) in human sperm, which is most likely composed of Slo3 and its auxiliary subunit leucine-rich repeat-containing protein 52 (LRRC52). Onion peel extract (OPE) and its major active ingredient quercetin are widely used as fertility enhancers; however, the effect of OPE and quercetin on Slo3 has not been elucidated. The purpose of this study is to investigate the effect of quercetin on human Slo3 channels. Human Slo3 and LRRC52 were co-transfected into HEK293 cells and pharmacological properties were studied with the whole cell patch clamp technique. We successfully expressed and measured pH sensitive and calcium insensitive Slo3 currents in HEK293 cells. We found that OPE and its key ingredient quercetin inhibit Slo3 currents. Inhibition by quercetin is dose dependent and this degree of inhibition decreases with elevating internal alkalization and internal free calcium concentrations. Functional moieties in the quercetin polyphenolic ring govern the degree of inhibition of Slo3 by quercetin, and the composition of such functional moieties are sensitive to the pH of the medium. These results suggest that quercetin inhibits Slo3 in a pH and calcium dependent manner. Therefore, we surmise that quercetin induced depolarization in spermatozoa may enhance the voltage gated proton channel (Hv1), and activate non-selective cation channels of sperm (CatSper) dependent calcium influx to trigger sperm capacitation and acrosome reaction.

The ubiquitous transient receptor potential canonical (TRPC) channels function as non-selective, Ca(2+)-permeable channels. TRPC channels are activated by stimulation of Gαq-PLC-coupled receptors. Here, we report that TRPC4/TRPC5 can be activated by Gαi. We studied the essential role of Gαi subunits in TRPC4 activation and investigated changes in ion selectivity and pore dilation of the TRPC4 channel elicited by the Gαi2 subunit. Activation of TRPC4 by Gαi2 increased Ca2+ permeability and Ca2+ influx through TRPC4 channels. Co-expression of the muscarinic receptor (M2) and TRPC4 in HEK293 cells induced TRPC4-mediated Ca2+ influx. Moreover, both TRPC4β and the TRPC4β-Gαi2 signaling complex induced inhibition of neurite growth and arborization in cultured hippocampal neurons. Cells treated with KN-93, a CaMKII inhibitor, prevented TRPC4- and TRPC4-Gαi2(Q205L)-mediated inhibition of neurite branching and growth. These findings indicate an essential role of Gαi proteins in TRPC4 activation and extend our knowledge of the functional role of TRPC4 in hippocampal neurons.

In this research we have confirmed that Nand flash cell current increases by optimization of contact barrier metal (BM) deposition and plug implantation (IIP) doping condition, which result in improved contact resistance (Rc) and cell leakage. Plug IIP dopant, BF2, which has been applied to P-type Transistor (Tr) for lowering Rc sacrifices contact process margin in cell area of n-type occurred by cell leakage. We could dramatically improve P-type Contact Rc and contact process margin by lowering BM deposition process temperature and adopting plug IIP doping with phosphorous (Ph.) respectively

The effects of shallow trench isolation (STI) gapfilling process deposited by high density plasma chemical vapor deposition (HDP-CVD) were investigated by comparing with TEOS+O3 undoped silicate glass (USG) process in NAND flash memory. HDP CVD oxide has been widely used for STI process because of its excellent gap-filling capability in relatively low temperature. However, it is well known that HDP-CVD process has problems caused by plasma-induced damage (PID) [1]. Thus thin thermal oxide was introduced as a buffer layer in order to minimize the plasma charging effect. In addition, there is also hydrogen related problem which is dissociated from SiH4 precursor in plasma. Hydrogen has both beneficial and deleterious effect to the gate integration [2]. The comparative sub-threshold swing degradation of the cell after F-N current stress of 0.13C/cm [3] is shown in Fig. 1. Initial swing is almost the same which indicates that PID during process is not dominant since the direct plasma damage was shielded by buffer oxide under layer. However, after stress, the swing of HDP-CVD gap-filled device is 20% more degraded than USG. The calculated interface state density (Dit) of the HDP-CVD is also 23% more than USG. It is insufficient to explain only with PID model. It was reported that hydrogen ions in plasma penetrate into underlying thermal oxide and they are drifted into the Si substrate by high electric field [4]. Although TEOS+O3 USG process also contains hydrogen species in precursor, the hydrogen atoms or ions have little kinetic energy to penetrate into underlying layers since there is no applied electric field or RF bias. Fig. 2. shows the hydrogen contents in both devices confirmed by thermal desorption spectroscopy (TDS) spectra after field recess process. HDP-CVD gap-filled device contains 50% more hydrogen concentration. It is well known that the role of atomic hydrogen is passivation of the Si dangling bonds in the Si/SiO2 interface (Si· + H2 → Si-H + H0) during the forming gas annealing (FGA) process. Simultaneously, the atomic hydrogen also depassivate the Si-H bonding (Si-H + H0 → Si· + H2) at room temperature [5,6]. As a results interface trap generation by atomic hydrogen depends on the ratio of passivation and depassivation. The HDP-CVD gap-filled device contains a large amount of hydrogen as we measured, and they can easily diffuse to tunnel oxide and degrade the cell transistors in flash memory. Fig. 3. shows average Vth shift of 64M cell array according to P/E cycling stress. The vth of HDP-CVD gap-filled device shifted 15% more than USG due to the oxide trap and interface trap generation by F-N current stress [7]. It is consistent with the swing degradation and the hydrogen depassivation model. We have demonstrated the effect of the plasmadeposited HDP-CVD STI gap-fill process which contains hydrogen species in the precursor and confirmed the degradation mechanism of the cell in flash memory. References

Ca(2+) is a critical factor in the regulation of signal transduction and Ca(2+) homeostasis is altered in different human diseases. The level of Ca(2+) in cells is highly regulated through a diverse class of regulators. Among them is the transient receptor potential vanilloid 6 (TRPV6), which is a Ca(2+) selective channel that absorbs Ca(2+) in the small intestine. TRPV6 is overexpressed in some cancers and exhibits oncogenic potential, but its exact mechanism is still poorly understood. The Numb protein is a cell fate determinant that functions in endocytosis and as a tumor suppressor via the stabilization of p53. Numb protein consisted of four isoforms. Here, we showed a novel function of Numb1, which negatively regulates TRPV6 activity. The expression of Numb1 decreased cytosolic Ca(2+) concentrations in TRPV6-transfected HEK293 cells. When all the isoforms of Numb were depleted using siRNA in a TRPV6 stable cell line, the levels of cytosolic Ca(2+) increased. We observed an interaction between Numb1 and TRPV6 using co-immunoprecipitation. We confirmed this interaction using Fluorescence Resolution Energy Transfer (FRET). We identified the TRPV6 and Numb1 binding site using TRPV6 C-terminal truncation mutants and Numb1 deletion mutants. The binding site in TRPV6 was an aspartic acid at amino acid residue 716, and that binding site in Numb1 was arginine at amino acid residue 434. A Numb1 mutant, lacking TRPV6 binding activity, failed to inhibit TRPV6 activity. Every isoform of Numb knockdown, using an siRNA-based approach in MCF-7 breast cancer cells, not only showed enhanced TRPV6 expression but also both the cytosolic Ca(2+) concentration and cell proliferation were increased. The down-regulated expression of TRPV6 using siRNA increased Numb protein expression; however, the cytosolic influx of Ca(2+) and proliferation of the cell were decreased. To examine downstream signaling during Ca(2+) influx, we performed Western blotting analysis on TRPV6 upregulated cancer cells (MCF-7, PC-3). Taken together, these results demonstrated that Numb1 interacts with TRPV6 through charged residues and inhibits its activity via the regulation of protein expression. Moreover, we provided evidence for a Ca(2+)-regulated cancer cell signaling pathway and that the Ca(2+) channel is a target of cancer cells.

Summary Onion (Allium cepa L.) and quercetin protect against oxidative damage and have positive effects on multiple functional parameters of spermatozoa, including viability and motility. However, the associated underlying mechanisms of action have not yet been identified. The aim of this study was to investigate the effect of onion peel extract (OPE) on voltage-gated proton (Hv1) channels, which play a critical role in rapid proton extrusion. This process underlies a wide range of physiological processes, particularly male fertility. The whole-cell patch-clamp technique was used to record the changes in Hv1 currents in HEK293 cells transiently transfected with human Hv1 (HVCN1). The effects of OPE on human sperm motility were also analyzed. OPE significantly activated the outward-rectifying proton currents in a concentration-dependent manner, with an EC50 value of 30 μg/mL. This effect was largely reversible upon washout. Moreover, OPE induced an increase in the proton current amplitude and decreased the time constant of activation at 0 mV from 4.9 ± 1.7 to 0.6 ± 0.1 sec (n = 6). In the presence of OPE, the half-activation voltage (V1/2) shifted in the negative direction, from 20.1 ± 5.8 to 5.2 ± 8.7 mV (n = 6), but the slope was not significantly altered. The OPE-induced current was profoundly inhibited by 10 μm Zn2+, the most potent Hv1 channel inhibitor, and was also inhibited by treatment with GF109203X, a specific protein kinase C (PKC) inhibitor. Furthermore, sperm motility was significantly increased in the OPE-treated groups. OPE exhibits protective effects on sperm motility, at least partially via regulation of the proton channel. Moreover, similar effects were exerted by quercetin, the major flavonoid in OPE. These results suggest OPE, which is rich in the potent Hv1 channel activator quercetin, as a possible new candidate treatment for human infertility.

An analysis on the degradation of DRAM performance caused by the NBTI degradation of p-MOSFET is first to be reported. To improve the NBTI immunity, three candidates are examined. First, minimizing Si-H bonds at Si/SiON interface through controlling the heat-budget at BEOL shows a promising result in NBTI lifetime, but it is not appropriate for DRAM process since it decreases the refresh time. Next, the buried SiGe channel p-MOSFET, which has 1.2 times higher NBTI immunity, is considered but difficult to adopt in DRAM peripheral circuit due to extra manufacturing cost. Finally, a deuterium annealing seems to be the right candidate for DRAM process since it improves the NBTI immunity without the refresh time penalty. This NBTI gain, however, varies depending on the amount of deuterium atom at Si/SiON interface and the probability of Si-D bond replacement with Si-H bond. Thus, selecting a right process sequence and an annealing condition is crucial.

Memory industry has been pursuing endless shrinking technology which increases fabrication complexity. It poses problems between adjacent layers as well as within a single layer. To verify the interlayer design, we have developed the interlayer design verification methodology using contour image. Our methodology makes it possible to verify interlayer design visually by extracting the contour image from the real patterns. And we can verify interlayer design even during the fabrication process and conduct a non-destructive inspection. Also this methodology provides a statistical analysis of massive measured data. Through this methodology, we can calculate the margin of current interlayer design and suggest the requirement of design.