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The World Health Organization recently highlighted the serious worldwide problem of the emergence of antibiotic-resistant or antibiotic multidrug-resistant bacteria. Carbapenem-resistant Enterobacterales, including carbapenemase-producing Enterobacterales (CPE), are major antibiotic-resistant bacteria that can be identified by various methods, including antibiotic susceptibility testing, PCR, and immunologic assays. However, there is a need for a faster, more accurate, low-cost, and easy method to detect CPE strains. We previously developed an osmotic shock matrix-assisted laser desorption/ionization mass spectrometry (OS-MALDI MS) method for directly detecting intact Klebsiella pneumoniae carbapenemase (KPC) using osmotic shock cell lysis. In this study, we evaluated the OS-MALDI MS method and compared it with two other methods (octyl-glucoside-aided direct KPC detection method [OG-MALDI MS] and Bruker's MBT subtyping module indirect method [MBT-SM MALDI MS]). We first completed an analytical performance evaluation of the OS-MALDI MS method according to Clinical and Laboratory Standards Institute guidelines. Clinical testing was performed with 437 clinical isolates, including 292 KPC-producing bacteria and 145 non-KPC-producing bacteria. The OS-MALDI MS method exhibited 95.9% sensitivity, 100.0% specificity, and 100.0% precision for detecting KPC. Accuracy of the OS-MALDI MS, OG-MALDI MS, and MBT-SM MALDI MS methods was 97.3%, 55.9%, and 50.2%, respectively. In conclusion, the OS-MALDI MS method clearly outperformed the other methods, exhibiting the highest accuracy and sensitivity of the three methods. We propose the OS-MALDI MS method as a practical, useful method for clinic environments, which may help guide appropriate antibiotic treatment and contribute to the prevention of the spread of CPE.

Apolipoprotein monitoring is useful for diagnosing cardiovascular diseases, as they are risk factors of arteriosclerosis and other neutral fat-related diseases. LC-MS/MS is advantageous for simultaneous apolipoprotein quantification, differentiation, and standardization including their isoforms. However, fast and straightforward sample preparation that retains quantification accuracy remains challenging in clinical MS.We developed a simultaneous assay for serum apolipoprotein A-I, apolipoprotein B100 family, and apolipoprotein C-III using a high-throughput LC-MS/MS platform coupled with a BRAVO system. The assay was simplified by using sodium deoxycholate and trypsin/lys-C without reduction and alkylation steps.Simple sample preparation reduced turnaround time by 1.5 h and neat goat serum was chosen as an optimal calibration matrix for accurate protein quantification. Assay precision, linearity, correlation, accuracy, LOD, LLOQ, and carryover were validated according to CLSI guidelines over 41 days using more than 100 human serum samples. Good correlation compared with TIA was observed by Deming regression for all analytes.A high-throughput LC-MS/MS and BRAVO assay for simultaneous apolipoprotein analysis was validated using a simple preparation method with a human serum calibrator in goat serum matrix. The assay is readily expandable to include other target serum proteins and/or their isoforms. This article is protected by copyright. All rights reserved.

All living beings on earth are influenced by the circadian rhythm, the rising and the setting of the sun. The ubiquitous effect of exercise is widely believed to maximize health benefits but has not been formally investigated for cardiac responses in the exercise-induced circadian rhythms. We hypothesized that the exercise-related proteome is differentially influenced by circadian rhythm and analyzed the differences between the effects of morning and evening exercise. Twenty-four Sprague-Dawley rats were randomly divided into four groups (n = 6 per group): morning control, morning exercise, evening control, and evening exercise groups. The exercise groups were subjected to 12-week treadmill exercise (5 days/week) performed either during daytime or nighttime. After 12 weeks, the physiological characteristics (e.g., body weight, heart weight, visceral fat, and blood metabolites), cardiovascular capacity (ejection fraction (%) and fractional shortening (%)), circadian gene expression levels (clock, ball1, per1, per2, cry1, and cry2), and the proteomic data were obtained and subjected to univariate and multivariate analysis. The mRNA levels of per1 and cry2 increased in the evening group compared with those in the morning group. We also found that per2 decreased and cry2 increased in the evening exercise groups. The evening exercise groups showed more decreased triacylglycerides and increased blood insulin levels than the morning exercise group. The principal component analysis, partial least squares discriminant analysis, and orthogonal partial least squares discriminant analysis indicated that the circadian rhythm differently influenced the protein networks of the exercise groups. In the morning exercise group, the transcription-translation feedback loop (TTFL) (clock, per1, per2, cry1, and cry2) formed a protein-protein interaction network with Nme2, Hint1, Ddt, Ndufb8, Ldha, and Eef1a2. In contrast, the TTFL group appeared close to Maoa, Hist2h4, and Macrod1 in the evening exercise group. Interestingly, the evening exercise group decreased the mRNA level of per2 but not per1. Per1 and Per2 are known to transport Cry1 and Cry2 into the nucleus. Taken together, we summarized the characteristics of enriched proteins in the aspect of their molecular function, cellular component, and biological process. Our results might provide a better understanding of the circadian effect on exercise-related proteins.

A tumorigenic factor, AIMP2 lacking exon 2 (AIMP2-DX2), is often upregulated in many cancers. However, how its cellular level is determined is not understood. Here, we report heat-shock protein HSP70 as a critical determinant for the level of AIMP2-DX2. Interaction of the two factors was identified by interactome analysis and structurally determined by X-ray crystallography and NMR analyses. HSP70 recognizes the amino (N)-terminal flexible region, as well as the glutathione S-transferase domain of AIMP2-DX2, via its substrate-binding domain, thus blocking the Siah1-dependent ubiquitination of AIMP2-DX2. AIMP2-DX2-induced cell transformation and cancer progression in vivo was further augmented by HSP70. A positive correlation between HSP70 and AIMP2-DX2 levels was shown in various lung cancer cell lines and patient tissues. Chemical intervention in the AIMP2-DX2-HSP70 interaction suppressed cancer cell growth in vitro and in vivo. Thus, this work demonstrates the importance of the interaction between AIMP2-DX2 and HSP70 on tumor progression and its therapeutic potential against cancer.

We propose to use cRFP (common Repository of FBS Proteins) in the MS (mass spectrometry) raw data search of cell secretomes. cRFP is a small supplementary sequence list of highly abundant fetal bovine serum proteins added to the reference database in use. The aim behind using cRFP is to prevent the contaminant FBS proteins from being misidentified as other proteins in the reference database, just as we would use cRAP (common Repository of Adventitious Proteins) to prevent contaminant proteins present either by accident or through unavoidable contacts from being misidentified as other proteins. We expect it to be widely used in experiments where the proteins are obtained from serum-free media after thorough washing of the cells, or from a complex media such as SILAC, or from extracellular vesicles directly.

Glycyl‐tRNA synthetase 1 (GARS1), a cytosolic enzyme secreted from macrophages, promotes apoptosis in cancer cells. However, the mechanism underlying GARS1 secretion has not been elucidated. Here, we report that GARS1 is secreted through unique extracellular vesicles (EVs) with a hydrodynamic diameter of 20–58 nm (mean diameter: 36.9 nm) and a buoyant density of 1.13–1.17 g/ml. GARS1 was anchored to the surface of these EVs through palmitoylated C390 residue. Proteomic analysis identified 164 proteins that were uniquely enriched in the GARS1‐containing EVs (GARS1‐EVs). Among the identified factors, insulin‐like growth factor II receptor, and vimentin also contributed to the anti‐cancer activity of GARS1‐EVs. This study identified the unique secretory vesicles containing GARS1 and various intracellular factors that are involved in the immunological defence response against tumorigenesis.

PURPOSE Clinical mass spectrometry requires a simple step process for sample preparation. This study aims to optimize the method for isolating periplasmic protein from Gram-negative bacteria and apply to clinical mass spectrometry. EXPERIMENTAL DESIGN The Klebsiella pneumoniae carbapenemase (KPC)-producing E. coli standard cells were used for optimizing the osmotic shock (OS) lysis method. The supernatant from OS lysis was analysed by LC-MS/MS and MALDI-TOF MS. The effectiveness of the OS lysis method for KPC-2-producing Enterobacteriaceae clinical isolates were then confirmed by MALDI-TOF MS. RESULTS The optimized OS lysis using KPC-2 producing E. coli standard cells showed a high yield of KPC-2 protein and enriches periplasmic proteins. Compared with other lysis methods, the detection sensitivity of KPC-2 protein significantly increased in MALDI-TOF MS analysis. Nineteen clinical isolates were validated by MALDI-TOF MS using the OS method, which also showed higher detection sensitivity compared to other lysis method (e.g., 1.5% n-octyl-β-D-glucopyranoside) (p

A fundamental question in biology is how vertebrates evolved and differ from invertebrates, and little is known about differences in the regulation of translation in the two systems. Herein, we identify a threonyl-tRNA synthetase (TRS)-mediated translation initiation machinery that specifically interacts with eIF4E homologous protein, and forms machinery that is structurally analogous to the eIF4F-mediated translation initiation machinery via the recruitment of other translation initiation components. Biochemical and RNA immunoprecipitation analyses coupled to sequencing suggest that this machinery emerged as a gain-of-function event in the vertebrate lineage, and it positively regulates the translation of mRNAs required for vertebrate development. Collectively, our findings demonstrate that TRS evolved to regulate vertebrate translation initiation via its dual role as a scaffold for the assembly of initiation components and as a selector of target mRNAs. This work highlights the functional significance of aminoacyl-tRNA synthetases in the emergence and control of higher order organisms., The initiation of translation is a highly regulated process that contributes to specific gene expression programs. Here the authors find that, in vertebrate, threonyl-tRNA synthetase (TRS) can act as a scaffold for the initiation machinery to stimulate the translation of a specific set of mRNAs.

Established fear memory becomes vulnerable to disruption after memory retrieval and extinction; this labile state is critical for inhibiting the return of fear memory. However, the labile state has a very narrow time window after retrieval, and underlying molecular mechanisms are not well known. To that end, we isolated the hippocampus immediately after fear memory retrieval and performed proteomics. We identified Neurobeachin (NBEA), an autism-related regulator of synaptic protein trafficking, to be upregulated after contextual fear memory retrieval. NBEA protein expression was rapid and transient after fear memory retrieval at the synapse. Nbea mRNA was enriched at the synapses, and the rapid induction of NBEA expression was blocked by inhibition of the mammalian target of rapamycin (mTOR)-dependent signaling pathway. Mice with cornu ammonis 1 (CA1)-specific Nbea shRNA knockdown showed normal fear acquisition and contextual fear memory but impaired extinction, suggesting an important role of Nbea in fear memory extinction processes. Consistently, Nbea heterozygotes showed normal fear acquisition and fear memory recall but showed impairment in extinction. Our data suggest that NBEA is necessary either for induction of memory lability or for the physiological process of memory extinction.

A tRNA synthase in metabolic control Leucyl-tRNA synthetase 1 (LARS1), which covalently couples leucine to its cognate transfer RNAs (tRNAs), appears to have broader roles in the control of leucine metabolism. The enzyme also serves as a leucine sensor for the mechanistic target of rapamycin complex 1 (mTORC1), which regulates protein synthesis, metabolism, autophagy, and cell growth. Yoon et al. show that in cells deprived of glucose, LARS1 is phosphorylated by Unc-51 like autophagy activating kinase 1 (see the Perspective by Lehman and Abraham). This phosphorylation decreases leucine binding to LARS1 and, in turn, should decrease translation, reduce activation of mTORC1, and perhaps free up leucine for use in the generation of adenosine triphosphate in glucose-starved cells. Science , this issue p. 205 ; see also p. 146

Procollagen type I carboxy-terminal propeptide (PICP), derived from type I procollagen, has been identified as an indicator of type I collagen synthesis in bone matrix formation and skin recovery. PICP is a heterotrimeric glycoprotein consisting of two α1 chains (PICPα1) and one α2 chain (PICPα2). Here, we report the recombinant expression of human PICP using a mammalian expression system. Co-expression of PICPα1 and PICPα2 in HEK293F cells resulted in the production of functional PICP in the correctly assembled heterotrimeric form. Using the recombinant PICP as an antigen, we isolated PICP-specific human monoclonal antibodies from phage-displayed antibody libraries and raised rabbit polyclonal antibodies. Using those antibodies, we then developed a sandwich ELISA for PICP with a limit of detection of 1 ng/mL and a measurable range of 1–640 ng/mL. Both intra- and inter-assay imprecision values were

Small cell lung cancer (SCLC) is an aggressive type of lung cancer, and the detection of SCLCs at an early stage is necessary for successful therapy and for improving cancer survival rates. Fucosylation is one of the most common glycosylation-based modifications. Increased levels of fucosylation have been reported in a number of pathological conditions, including cancers. In this study, we aimed to identify and validate the aberrant and selective fucosylated glycoproteins in the sera of patients with SCLC. Fucosylated glycoproteins were enriched by the Aleuria aurantia lectin column after serum albumin and IgG depletion. In a narrowed down and comparative data analysis of both label-free proteomics and isobaric peptide-tagging chemistry iTRAQ approaches, the fucosylated glycoproteins were identified as up- or down-regulated in the sera of limited disease and extensive disease stage patients with SCLC. Verification was performed by multiple reaction monitoring-mass spectrometry to select reliable markers. Four fucosylated proteins, APCS, C9, SERPINA4, and PON1, were selected and subsequently validated by hybrid A. aurantia lectin ELISA (HLE) and Western blotting. Compared with Western blotting, the HLE analysis of these four proteins produced more optimal diagnostic values for SCLC. The PON1 protein levels were significantly reduced in the sera of patients with SCLC, whereas the fucosylation levels of PON1 were significantly increased. Fucosylated PON1 exhibited an area under curve of 0.91 for the extensive disease stage by HLE, whereas the PON1 protein levels produced an area under curve of 0.82 by Western blot. The glycan structural analysis of PON1 by MS/MS identified a biantennary fucosylated glycan modification consisting of a core + 2HexNAc + 1Fuc at increased levels in the sera of patients with SCLC. In addition, the PON1 levels were decreased in the sera of the Lewis lung carcinoma lung cancer mouse model that we examined. Our data suggest that fucosylated protein biomarkers, such as PON1, and their fucosylation levels and patterns can serve as diagnostic and prognostic serological markers for SCLC.

Although doxorubicin (Doxo) and docetaxel (Docet) in combination are widely used in treatment regimens for a broad spectrum of breast cancer patients, a major obstacle has emerged in that some patients are intrinsically resistant to these chemotherapeutics. Our study aimed to discover potential prediction markers of drug resistance in needle-biopsied tissues of breast cancer patients prior to neoadjuvant chemotherapy. Tissues collected before chemotherapy were analyzed by mass spectrometry. A total of 2,331 proteins were identified and comparatively quantified between drug sensitive (DS) and drug resistant (DR) patient groups by spectral count. Of them, 298 proteins were differentially expressed by more than 1.5-fold. Some of the differentially expressed proteins (DEPs) were further confirmed by Western blotting. Bioinformatic analysis revealed that the DEPs were largely associated with drug metabolism, acute phase response signaling, and fatty acid elongation in mitochondria. Clinical validation of two selected proteins by immunohistochemistry found that FKBP4 and S100A9 might be putative prediction markers in discriminating the DR group from the DS group of breast cancer patients. The results demonstrate that a quantitative proteomics/bioinformatics approach is useful for discovering prediction markers of drug resistance, and possibly for the development of a new therapeutic strategy.

Background: Fatty acid-bearing albumin [FA(+) albumin] exerts more deleterious effects in tubular cells than albumin alone. We investigated the effect of FA(+) albumin on the vascular cell adhesion molecule-1 (VCAM-1) expression and elucidated the underlying signaling pathways. We further examined the effect of L-carnitine, since it was known to modulate intracellular fatty acid concentration. Methods: Activation of AP-1 and NF-ĸB was assessed by electrophoretic mobility shift assay. Phosphorylation of protein kinase was examined by Western blot analysis. VCAM-1 mRNA and protein expression were measured by Northern blot analysis and cell ELISA. Results: FA(+) albumin induced VCAM-1 expression via activation of AP-1 and NF-ĸB, which was mediated through activation of c-Src kinase, followed by MAP kinases (p38, ERK 1/2, JNK-1) and IĸB kinase and IĸB-α, respectively. Inhibitors of protein kinase C and tyrosine kinase, anti-oxidants and intracellular calcium chelator suppressed the FA(+) albumin-induced activation of c-Src kinase. L-Carnitine suppressed the FA(+) albumin-induced VCAM-1 expression via inhibition of c-Src kinase. Conclusions: VCAM-1 expression with activation of c-Src kinase-AP-1/NFĸB pathways might be one of the possible mechanisms that linked FA(+) albumin to tubulointerstitial injury. L-Carnitine might be beneficial in attenuating FA(+) albumin-induced tubular injury.

Aminoacyl-tRNA synthetases (ARSs) acylate transfer (t)RNAs with amino acids. Charging tRNAs with the right amino acids is the first step in translation; therefore, the accurate and error-free functioning of ARSs is an essential prerequisite for translational fidelity. A recent study found that methionine (Met) can be incorporated into non-Met residues of proteins through methionylation of non-cognate tRNAs under conditions of oxidative stress. However, it was not understood how this mis-methionylation is achieved. Here, we report that methionyl-tRNA synthetase (MRS) is phosphorylated at Ser209 and Ser825 by extracellular signal-related kinase (ERK1/2) under conditions of stress caused by reactive oxygen species (ROS), and that this phosphorylated MRS shows increased affinity for non-cognate tRNAs with lower affinity for tRNAMet, leading to an increase in Met residues in cellular proteins. The expression of a mutant MRS containing the substitutions S209D and S825D, mimicking dual phosphorylation, reduced ROS levels and cell death. This controlled inaccuracy of MRS seems to serve as a defense mechanism against ROS-mediated damage at the cost of translational fidelity.

Electrical and reliability characteristics of several Si/Al2O3 (barrier layer)/Si capacitor structures have been investigated. Al2O3 film was deposited by atomic layer deposition (ALD). ALD Al2O3 was found to be a good chemical oxide barrier layer which is important for achieving thin oxide thickness. Formation of a metallic Al cluster was observed at the Al2O3/n+-doped Si interface layer. SiO2 formed by O2 flushing at 400°C for 10 min was found to be very effective to prevent the formation of a metallic Al cluster and to reduce the leakage current to less than 1×10−15 A/μm2 at an applied voltage of 2.0 V. In situ stress–temperature measurement of Al2O3/SiO2/n+-doped poly Si was carried out to evaluate the residual stain of the film. Average interband oscillator energy of the Al2O3 film on SiO2 is greater than that of Al2O3 film on Si(100) by 1.162 eV. Al2O3 films exhibited excellent interface quality, dielectric reliability, and shrinkability. The capacitor using Al2O3 film satisfied the requirement for cell capacitance of 25 fF/cell in 0.30-μm pitched DRAMs.

We successfully obtained vertically aligned multiwalled carbon nanotubes on different nickel-coated substrates by plasma enhanced hot filament chemical vapor deposition at low temperatures below 650°C. Acetylene and ammonia gas were used as the carbon source and a catalyst. The surface roughness of the nickel layer increased as NH3 etching time increased. The diameters of the nanotubes decreased and the density of nanotubes increased as NH3 etching time increased. The diameter of the nanotubes was 30–70 nm. A nickel cap was observed on the top of the grown nanotube and a very thin amorphous-carbon-like layer was found on the nickel cap. The morphology and microstructure of carbon nanotubes were measured using scanning electron microscopy and transmission electron microscopy.

In this letter, we report the effects of gate notching on the performance characteristics of short-channel NMOS transistor with the gate oxide thickness of 32 /spl Aring/. The significant gate-notching defect into channel region brings about the serious degradation of such transistor performances as transconductance (G/sub m/) characteristic and subthreshold swing (S/sub t/), resulting in increases of threshold voltage (V/sub TH/) and leakage current (I/sub OFF/) and the considerable reduction of drive current (I/sub ON/). We will suggest the local thickening of gate oxide as a main mechanism of its effects and show that lack of gate-to-source/drain extension (SDE) overlap may be an additional reason for the degradation of I/sub ON/ with increasing the notch depth.

The standby current at device off-state is investigated against the measuring mode in 6-T and low-power static random access memory (SRAM) device with short gate length of 0.12 µm and high density of 32 M-bit. It can be found that there is the difference of the standby currents between initial and D0 modes and this discrepancy in the standby current is closely related to the leakage current of cell n-type metal-oxide semiconductor field-effect transistor (NMOSFET), especially pull-down transistor. This discrepancy in the standby currents among the measuring modes can be explained with the characteristic of the cell latch using its dependence on the leakage current of pull-down transistor and it will be shown that the cell spontaneously moves to minimize the standby current.

A new double offset-implanted (DOI) technology, which can effectively suppress the gate-induced drain-leakage (GIDL) current of buried-channel PMOS transistor in small-size CMOS devices, is proposed and developed with a 0.12-/spl mu/m single-gate low-power SRAM device. The DOI scheme is characterized by the usage of the silicon nitride etch-stopper for the formation of borderless W-contact as offset spacer without supplementing auxiliary processes at p+ source/drain (S/D) implantation process after the n+ S/D one. It is assured that the DOI technology makes the gate-to-S/D overlap controllable, so that the GIDL current of PMOS transistor can remarkably be reduced. Furthermore, the enhancement of CMOS transistor performance was possible by reducing the sidewall reoxidation thickness of the gate-poly Si and optimizing the implantation conditions with this technology.

Vertically well-aligned multiwall carbon nanotubes (MWNTs) were grown on nickel-coated glass substrates by plasma-enhanced chemical vapor deposition at low temperatures, below 600 °C, with and without hot filament. Acetylene and ammonia gas were used as the carbon source and a catalyst. Effects of growth parameters, such as plasma intensity, filament current, and substrate temperature, on the growth characteristics of MWNTs were investigated. Plasma intensity was found to be the most critical parameter controlling the growth of MWNTs. Field emission from the MWNTs was obtained using a phosphor anode with an onset electric field of 1.5 V/μm.

Fatty acid-bearing albumin [FA(+) albumin] exerts more deleterious effects in tubular cells than albumin alone. We investigated the effect of FA(+) albumin on the vascular cell adhesion molecule-1 (VCAM-1) expression and elucidated the underlying signaling pathways. We further examined the effect of L-carnitine, since it was known to modulate intracellular fatty acid concentration.Activation of AP-1 and NF-kappaB was assessed by electrophoretic mobility shift assay. Phosphorylation of protein kinase was examined by Western blot analysis. VCAM-1 mRNA and protein expression were measured by Northern blot analysis and cell ELISA.FA(+) albumin induced VCAM-1 expression via activation of AP-1 and NF-kappaB, which was mediated through activation of c-Src kinase, followed by MAP kinases (p38, ERK 1/2, JNK-1) and IkappaB kinase and IkappaB-alpha, respectively. Inhibitors of protein kinase C and tyrosine kinase, anti-oxidants and intracellular calcium chelator suppressed the FA(+) albumin-induced activation of c-Src kinase. L-Carnitine suppressed the FA(+) albumin-induced VCAM-1 expression via inhibition of c-Src kinase.VCAM-1 expression with activation of c-Src kinase-AP-1/NFkappaB pathways might be one of the possible mechanisms that linked FA(+) albumin to tubulointerstitial injury. L-Carnitine might be beneficial in attenuating FA(+) albumin-induced tubular injury.

The native state of alpha(1)-antitrypsin (alpha(1)AT), a member of the serine protease inhibitor (serpin) family, is considered a kinetically trapped folding intermediate that converts to a more stable form upon complex formation with a target protease. Although previous structural and mutational studies of alpha(1)AT revealed the structural basis of the native strain and the kinetic trap, the mechanism of how the native molecule overcomes the kinetic barrier to reach the final stable conformation during complex formation remains unknown. We hypothesized that during complex formation, a substantial portion of the molecule undergoes unfolding, which we dubbed functional unfolding. Hydrogen-deuterium exchange coupled with ESI-MS was used to analyze this serpin in three forms: native, complexing, and complexed with bovine beta-trypsin. Comparing the deuterium content at the corresponding regions of these three samples, we probed the unfolding of alpha(1)AT during complex formation. A substantial portion of the alpha(1)AT molecule unfolded transiently during complex formation, including not only the regions expected from previous structural studies, such as the reactive site loop, helix F, and the following loop, but also regions not predicted previously, such as helix A, strand 6 of beta-sheet B, and the N terminus. Such unfolding of the native interactions may elevate the free energy level of the kinetically trapped native serpin sufficiently to cross the transition state during complex formation. In the current study, we provide evidence that protein unfolding has to accompany functional execution of the protein molecule.

One of the most important issues for DRAM development is the control of data retention time. A negatively-biased off-state level of the word line (NWL) was introduced to the memory cell design to improve cell transistor "on" current and to maintain "off current sufficiently low. This paper discusses a method to design cell transistor and NWL bias level to improve the data retention time in DRAM with NWL.

We integrate FinFET DRAM in sub-60nm feature size. To avoid severe passing gate effects in FinFET cell array, we introduce a local damascene gate structure. Threshold voltage control of the ultra thin body transistors is successfully achieved by adopting p+ boron in-situ doped poly-silicon gate on the FinFET cells. As a result, very stable and uniform operation of FinFET cells is realized. The local damascene FinFET with p+ gate can become a highly feasible mainstream DRAM technology for sub-60nm low-power high-speed devices

The effects of gate notching profile defects on transistor performance in cell NMOSFETs of low-power SRAM devices with 0.12 /spl mu/m channel length were investigated. Experimentally, it was found that gate notching profile defects cause serious degradation of the transconductance and the transistor drive current. TSUPREM4 simulations showed that the degradation of transistor characteristics is related to the penetration of the gate notching into the channel region over the source/drain (S/D) extension region and the rapid reduction of gate electric field. Moreover, we found that the degradation of transistor performance is more sensitive to notch depth than notch height.

A novel integration technology with capacitor over metal (COM) for 0.15 /spl mu/m stand-alone and embedded DRAMs is developed using a self-aligned dual damascene (SADD) process, which offers great breakthroughs. First, many back-end metallization issues encountered in conventional COB (capacitor over bit line) DRAMs are simply overcome because the capacitor is formed after the metal lines. Secondly, memory cell capacitors can be integrated much more simply and easily compared to those of conventional COB technology because the memory cell contact and storage node are formed simultaneously. Furthermore, transistor performance can be greatly improved because a novel poly-Si/Al/sub 2/O/sub 3//poly-Si capacitor is integrated at temperatures below 400/spl deg/C.

This paper presents the properties for CoSi/sub 2/ junction used to realize embedded DRAM and logic (EDL). In high thermal processes for EDL, TiN capping shows considerably better junction leakage and device characteristics than Ti capping.

A 1.8 V 4 Gb DDR SDRAM for low voltage and high speed at full density has reduced inter-bitline coupling noise in the twisted open bit line architecture. Amplifier sensitivity and sensing margin are improved by gain-controlled pre-sensing and active calibration of the bitline reference voltage. For noise-immune power-stabilized operation, three circuit schemes suitable for the SDRAM are presented: (i) twisted open bitline (TOB) architecture; (ii) gain-controlled pre-sensing (GCP); and (iii) reference bitline calibration (RBC). The TOB scheme eliminates the coupling noise between adjacent BLs by holding neighboring bitlines stable at the reference voltage with the open readout and sensing using a reference BL from the adjacent block. The GCP scheme increases the sensing margin and speed by employing transconductance-matched pre-amplification. The RBC scheme actively mimics the cell data retention characteristics and yields an optimal voltage level for the reference BL from the charge-shared voltage from replica BL pairs. Together with a chip-size-efficient core signal repeating architecture, these schemes ensure reliable low-voltage and high-speed cell and core operation.

Lipocortin-1, a 37-kDa member of the annexin family of proteins, originally evoked interest as one of the second messengers for the anti-inflammatory actions of glucocorticoids. Studies showed that glucocorticoids inhibited the proliferation of various cell types and lipocortin-1 mediated growth inhibition of glucocorticoids in a human lung adenocarcinoma cell line. The presence of specific lipocortin-1-binding sites (receptor-like molecules) on monocytic cells has been demonstrated. This study was performed to evaluate the effects of hydrocortisone and recombinant human lipocortin-1 on cultured human mesangial cells (CHMC), and the effects of anti-lipocortin-1 antibody on the hydrocortisone-induced inhibition of CHMC proliferation. The existence of specific binding sites for lipocortin-1 was also investigated. Lipocortin-1 inhibited CHMC proliferation in a dose-dependent manner as determined by [3H]thymidine uptake and cell count. Growth of CHMC was inhibited to 18% of the control in the presence of 5 micrograms/ml of lipocortin-1. Similar growth-inhibitory activity by lipocortin-1 was observed in CHMC activated by platelet-derived growth factor. Hydrocortisone also inhibited cell proliferation in a dose-dependent manner. One to 5,000 dilution of anti-lipocortin-1 antibody reversed hydrocortisone-induced inhibition of CHMC proliferation partially, whereas concentrations over 1:1,000 reversed the inhibition completely. Flow cytometry analysis as well as indirect immunofluorescent microscopy revealed specific binding sites on the surface of CHMC. These results support the hypothesis that corticosteroids act by inducing CHMC to synthesize or secrete lipocortin-1, and that lipocortin-1 generates proliferation-suppressive signal(s) through specific binding sites on CHMC.