Multi-terminal memtransistors from polycrystalline monolayer molybdenum disulfide.

Memristors are two-terminal passive circuit elements that have been developed for use in non-volatile resistive random-access memory and may also be useful in neuromorphic computing. Memristors have higher endurance and faster read/write times than flash memory and can provide multi-bit data storage. However, although two-terminal memristors have demonstrated capacity for basic neural functions, synapses in the human brain outnumber neurons by more than a thousandfold, which implies that multi-terminal memristors are needed to perform complex functions such as heterosynaptic plasticity. Previous attempts to move beyond two-terminal memristors, such as the three-terminal Widrow-Hoff memristor and field-effect transistors with nanoionic gates or floating gates, did not achieve memristive switching in the transistor. Here we report the experimental realization of a multi-terminal hybrid memristor and transistor (that is, a memtransistor) using polycrystalline monolayer molybdenum disulfide (MoS2) in a scalable fabrication process. The two-dimensional MoS2 memtransistors show gate tunability in individual resistance states by four orders of magnitude, as well as large switching ratios, high cycling endurance and long-term retention of states. In addition to conventional neural learning behaviour of long-term potentiation/depression, six-terminal MoS2 memtransistors have gate-tunable heterosynaptic functionality, which is not achievable using two-terminal memristors. For example, the conductance between a pair of floating electrodes (pre- and post-synaptic neurons) is varied by a factor of about ten by applying voltage pulses to modulatory terminals. In situ scanning probe microscopy, cryogenic charge transport measurements and device modelling reveal that the bias-induced motion of MoS2 defects drives resistive switching by dynamically varying Schottky barrier heights. Overall, the seamless integration of a memristor and transistor into one multi-terminal device could enable complex neuromorphic learning and the study of the physics of defect kinetics in two-dimensional materials.

Reconfigurable MoS2 Memtransistors for Continuous Learning in Spiking Neural Networks.

Artificial intelligence and machine learning are growing computing paradigms, but current algorithms incur undesirable energy costs on conventional hardware platforms, thus motivating the exploration of more efficient neuromorphic architectures. Toward this end, we introduce here a memtransistor with gate-tunable dynamic learning behavior. By fabricating memtransistors from monolayer MoS2 grown on sapphire, the relative importance of the vertical field effect from the gate is enhanced, thereby heightening reconfigurability of the device response. Inspired by biological systems, gate pulses are used to modulate potentiation and depression, resulting in diverse learning curves and simplified spike-timing-dependent plasticity that facilitate unsupervised learning in simulated spiking neural networks. This capability also enables continuous learning, which is a previously underexplored cognitive concept in neuromorphic computing. Overall, this work demonstrates that the reconfigurability of memtransistors provides unique hardware accelerator opportunities for energy efficient artificial intelligence and machine learning.

Discovery of novel heat shock protein (Hsp90) inhibitors based on luminespib with potent antitumor activity.

A series of isosteric surrogates of the 4-phenyl group in luminespib were investigated as new scaffolds of the Hsp90 inhibitor for the discovery of novel antitumor agents. Among the synthesized surrogates of isoxazole and pyrazole, compounds 4a, 5e and 12b exhibited potent Hsp90 inhibition in ATPase activity and Her2 degradation assays and significant antitumor activity in A2780 and HCT116 cell lines. Animal studies indicated that compared to luminespib, their activities were superior in A2780 or NCI-H1975 tumor xenograft models. A molecular modeling study demonstrated that compound 4a could fit nicely into the N-terminal ATP binding pocket.

Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer.

BACKGROUND: The IDF-11774, a novel clinical candidate for cancer therapy, targets HSP70 and inhibits mitochondrial respiration, resulting in the activation of AMPK and reduction in HIF-1α accumulation. METHODS: To identify genes that have synthetic lethality to IDF-11774, RNA interference screening was conducted, using pooled lentiviruses expressing a short hairpin RNA library. RESULTS: We identified ATP6V0C, encoding the V0 subunit C of lysosomal V-ATPase, knockdown of which induced a synergistic growth-inhibitory effect in HCT116 cells in the presence of IDF-11774. The synthetic lethality of IDF-11774 with ATP6V0C possibly correlates with IDF-11774-mediated autolysosome formation. Notably, the synergistic effect of IDF-11774 and the ATP6V0C inhibitor, bafilomycin A1, depended on the PIK3CA genetic status and Bcl-2 expression, which regulates autolysosome formation and apoptosis. Similarly, in an experiment using conditionally reprogramed cells derived from colorectal cancer patients, synergistic growth inhibition was observed in cells with low Bcl-2 expression. CONCLUSIONS: Bcl-2 is a biomarker for the synthetic lethal interaction of IDF-11774 with ATP6V0C, which is clinically applicable for the treatment of cancer patients with IDF-11774 or autophagy-inducing anti-cancer drugs.

Identification of Targets of the HIF-1 Inhibitor IDF-11774 Using Alkyne-Conjugated Photoaffinity Probes.

We developed a hypoxia-inducible factor-1 (HIF-1) inhibitor, IDF-11774, as a clinical candidate for cancer therapy. To understand the mechanism of action of IDF-11774, we attempted to isolate target proteins of IDF-11774 using bioconjugated probes. Multifunctional chemical probes containing sites for click conjugation and photoaffinity labeling were designed and synthesized. After fluorescence and photoaffinity labeling of proteins, two-dimensional electrophoresis (2DE) was performed to isolate specific molecular targets of IDF-11774. Heat shock protein (HSP) 70 was identified as a target protein of IDF-11774. We revealed that IDF-11774 inhibited HSP70 chaperone activity by binding to its allosteric pocket, rather than the ATP-binding site in its nucleotide-binding domain (NBD). Moreover, IDF-11774 reduced the oxygen consumption rate (OCR) and ATP production, thereby increasing intracellular oxygen tension. This result suggests that the inhibition of HSP70 chaperone activity by IDF-11774 suppresses HIF-1α refolding and stimulates HIF-1α degradation. Taken together, these findings indicate that IDF-11774-derived chemical probes successfully identified IDF-11774's target molecule, HSP70, and elucidated the mode of action of IDF-11774 in inhibiting HSP70 chaperone activity and stimulating HIF-1α degradation in cancer cells.

Identification of novel aminopiperidine derivatives for antibacterial activity against Gram-positive bacteria.

We have previously reported amidopiperidine derivatives as a novel peptide deformylase (PDF) inhibitor and evaluated its antibacterial activity against Gram-positive bacteria, but poor pharmacokinetic profiles have resulted in low efficacy in in vivo mouse models. In order to overcome these weaknesses, we newly synthesized aminopiperidine derivatives with remarkable antimicrobial properties and oral bioavailability, and also identified their in vivo efficacy against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and penicillin-resistant Streptococcus pneumoniae (PRSP).

Evaluation of a ferroelectric tunnel junction by ultraviolet-visible absorption using a removable liquid electrode.

Ferroelectric memristors offer a significant alternative to their redox-based analogs in resistive random access memory because a ferroelectric tunnel junction (FTJ) exhibits a memristive effect that induces resistive switching (RS) regardless of the operating current level. This RS results from a change in the ferroelectric polarization direction, allowing the FTJ to overcome the restriction encountered in redox-based memristors. Herein, the memristive effect of an FTJ was investigated by ultraviolet-visible (UV-Vis) absorption spectroscopy using a removable mercury (Hg) top electrode (TE), BaTiO3 (BTO) ferroelectric tunnel layer, La0.7Sr0.3MnO3 (LSMO) semiconductor bottom electrode, and wide-bandgap quartz (100) single-crystal substrate to determine the low-resistance state (LRS) and high-resistance state (HRS) of the FTJ. A BTO (110)/LSMO (110) polycrystal memristor involving a Hg TE showed a small memristive effect (switching ratio). This effect decreased with increasing read voltage because of a small potential barrier height. The LRS and HRS of the FTJ showed quasi-similar UV-Vis absorption spectra, consistent with the small energy difference between the valence-band maximum of BTO and Fermi level of LSMO near the interface between the LRS and HRS. This energy difference stemmed from the ferroelectric polarization and charge-screening effect of LSMO based on an electrostatic model of the FTJ.

Manganite based hetero-junction structure of La0.7Sr(0.7-x)CaxMnO3 and CaMnO(3-δ) for cross-point arrays.

Resistive random access memory and the corresponding cross-point array (CPA) structure have received a great deal of attention for high-density next generation non-volatile memory. However, the cross-talk issue of CPA structure by sneak current should be overcome to realize the highest density integration. To accomplish this, the sneak current can be minimized by high, nonlinear characteristic behaviors of resistive switching (RS). Therefore this study fabricated pnp bipolar hetero-junction structure using the perovskite manganite family, such as La0.7Sr(0.3-x)CaxMnO3 (LSCMO) and CaMnO(3-δ) (CMO), to obtain nonlinear RS behavior. The pnp structure not only shows nonlinear characteristics, but also a tunable characteristic with Ca substitution.

Achalasia in Korea: an epidemiologic study using a national healthcare database.

Owing to the rarity of the disease, epidemiologic information on achalasia is limited. This study aimed to investigate the epidemiology and treatment patterns of achalasia in the population of Korea using a national healthcare database. The diagnostic code K22.0 of the International Classification of Diseases was used to identify cases of achalasia between 2007 and 2011. Treatment modalities for achalasia were identified using the electronic data interchange codes Q7642 or Q7641 for balloon dilation and QA421 or QA422 for esophago-cardiomyotomy. A total of 3,105 patients with achalasia (1,447 men; mean age, 52.5 yr) were identified between 2007 and 2011, indicating a prevalence of 6.29/100,000 (95% confidence interval [CI], 4.94-7.66) during this 5-yr period. A total of 191 incident cases of achalasia (82 men; mean age, 49.5 yr), which were not diagnosed as achalasia in the previous 4 yr, were detected in 2011, indicating an incidence of 0.39/100,000 (95% CI, 0.15-0.63) for that year. During the study period, balloon dilation therapy was performed a total of 975 times in 719 patients, and surgical esophago-cardiomyotomy was performed once per patient in 17 patients. This is the first population-based epidemiologic study of achalasia in Korea.

Study on the Sodium-Doped Titania Interface-Type Memristor.

Memristors integrated into a crossbar-array architecture (CAA) are promising candidates for analog in-memory computing accelerators. However, the relatively low reliability of the memristor device and sneak current issues in CAA remain the main obstacles. Alkali ion-based interface-type memristors are promising solutions for implementing highly reliable memristor devices and neuromorphic hardware. This interface-type device benefits from self-rectifying and forming-free resistive switching (RS), and exhibits relatively low variation from device to device and cycle to cycle. In a previous report, we introduced an in situ grown Na/TiO2 memristor using atomic layer deposition (ALD) and proposed a RS mechanism from experimentally measured Schottky barrier modulation. Self-rectifying RS characteristics were observed by the asymmetric distribution of Na dopants and oxygen vacancies as the Ti metal used as the adhesion layer for the bottom electrode diffuses over the Pt electrode at 250 °C during the ALD process and is doped into the TiO2 layer. Here, we theoretically verify the modulation of the Schottky barrier at the TiO2/Pt electrode interface by Na ions. This study fabricated a Pt/Na/TiO2/Pt memristor device and confirmed its self-rectifying RS characteristics and stable retention characteristics for 24 h at 85 °C. Additionally, this device exhibited relative standard deviations of 27 and 7% in the high and low resistance states, respectively, in terms of cycle-to-cycle variation. To verify the RS mechanism, we conducted density functional theory simulations to analyze the impact of Na cations at interstitial sites on the Schottky barrier. Our findings can contribute to both fundamental understanding and the design of high-performance memristor devices for neuromorphic computing.

High-Reliability and Self-Rectifying Alkali Ion Memristor through Bottom Electrode Design and Dopant Incorporation.

Ionic memristor devices are crucial for efficient artificial neural network computations in neuromorphic hardware. They excel in multi-bit implementation but face challenges like device reliability and sneak currents in crossbar array architecture (CAA). Interface-type ionic memristors offer low variation, self-rectification, and no forming process, making them suitable for CAA. However, they suffer from slow weight updates and poor retention and endurance. To address these issues, the study demonstrated an alkali ion self-rectifying memristor with an alkali metal reservoir formed by a bottom electrode design. By adopting Li metal as the adhesion layer of the bottom electrode, an alkali ion reservoir was formed at the bottom of the memristor layer by diffusion occurring during the atomic layer deposition process for the Na:TiO2 memristor layer. In addition, Al dopant was used to improve the retention characteristics by suppressing the diffusion of alkali cations. In the memristor device with optimized Al doping, retention characteristics of more than 20 h at 125 °C, endurance characteristics of more than 5.5 × 105, and high linearity/symmetry of weight update characteristics were achieved. In reliability tests on 100 randomly selected devices from a 32 × 32 CAA device, device-to-device and cycle-to-cycle variations showed low variation values within 81% and 8%, respectively.

Sodium-Doped Titania Self-Rectifying Memristors for Crossbar Array Neuromorphic Architectures.

Memristors integrated into a crossbar-array architecture (CAA) are promising candidates for nonvolatile memory elements in artificial neural networks. However, the relatively low reliability of memristors coupled with crosstalk and sneak currents in CAAs have limited the realization of the full potential of this technology. Here, high-reliability Na-doped TiO2  memristors grown in situ by atomic layer deposition (ALD) are demonstrated, where reversible Na migration underlies the resistive-switching mechanism. By employing ALD growth with an aqueous NaOH reactant in deionized water, uniform implantation of Na dopants is achieved in the crystallized TiO2  thin films at 250 °C without post-annealing. The resulting Na-doped TiO2  memristors show electroforming-free and self-rectifying resistive-switching behavior, and they are ideally suited for selectorless CAAs. Effective addressing of selectorless nodes is demonstrated via electrical measurement of individual memristors in a 6 × 6 crossbar using a read current of less than 1 µA with negligible sneak current at or below the noise level of ≈100 pA. Finally, the long-term potentiation and depression synaptic behavior from these Na-doped TiO2  memristors achieves greater than 99.1% accuracy for image-recognition tasks using a convolutional neural network based on the selectorless of crossbar arrays.

Filamentary and Interface-Type Memristors Based on Tantalum Oxide for Energy-Efficient Neuromorphic Hardware.

To implement artificial neural networks (ANNs) based on memristor devices, it is essential to secure the linearity and symmetry in weight update characteristics of the memristor, and reliability in the cycle-to-cycle and device-to-device variations. This study experimentally demonstrated and compared the filamentary and interface-type resistive switching (RS) behaviors of tantalum oxide (Ta2O5 and TaO2)-based devices grown by atomic layer deposition (ALD) to propose a suitable RS type in terms of reliability and weight update characteristics. Although Ta2O5 is a strong candidate for memristor, the filament-type RS behavior of Ta2O5 does not fit well with ANNs demanding analog memory characteristics. Therefore, this study newly designed an interface-type TaO2 memristor and compared it to a filament type of Ta2O5 memristor to secure the weight update characteristics and reliability. The TaO2-based interface-type memristor exhibited gradual RS characteristics and area dependency in both high- and low-resistance states. In addition, compared to the filamentary memristor, the RS behaviors of the TaO2-based interface-type device exhibited higher suitability for the neuromorphic, symmetric, and linear long-term potentiation (LTP) and long-term depression (LTD). These findings suggest better types of memristors for implementing ionic memristor-based ANNs among the two types of RS mechanisms.

Linear and Symmetric Li-Based Composite Memristors for Efficient Supervised Learning.

Emerging energy-efficient neuromorphic circuits are based on hardware implementation of artificial neural networks (ANNs) that employ the biomimetic functions of memristors. Specifically, crossbar array memristive architectures are able to perform ANN vector-matrix multiplication more efficiently than conventional CMOS hardware. Memristors with specific characteristics, such as ohmic behavior in all resistance states in addition to symmetric and linear long-term potentiation/depression (LTP/LTD), are required in order to fully realize these benefits. Here, we demonstrate a Li-based composite memristor (LCM) that achieves these objectives. The LCM consists of three phases: Li-doped TiO2 as a Li reservoir, Li4Ti5O12 as the insulating phase, and Li7Ti5O12 as the metallic phase, where resistive switching correlates with the change in the relative fraction of the metallic and insulating phases. The LCM exhibits a symmetric and gradual resistive switching behavior for both set and reset operations during a full bias sweep cycle. This symmetric and linear weight update is uniquely enabled by the symmetric bidirectional migration of Li ions, which leads to gradual changes in the relative fraction of the metallic phase in the film. The optimized LCM in ANN simulation showed that exceptionally high accuracy in image classification is realized in fewer training steps compared to the nonlinear behavior of conventional memristors.

Pharmacokinetics and tolerability of IDP-73152 mesylate after a single oral administration under fasted and fed conditions in healthy volunteers.

BACKGROUND AND OBJECTIVE: IDP-73152 mesylate is a peptide deformylase inhibitor under investigation for the treatment of complicated skin and respiratory tract infections. The objective of this study was to investigate the pharmacokinetic (PK) profile and tolerability of IDP-73152 and the effect of food after a single oral administration. METHODS: A dose block-randomized, double-blind, placebo-controlled, dose-escalation study was conducted. A total of 56 healthy volunteers received IDP-73152 mesylate in a single oral dose of 40, 80, 160, 320, 640, or 1280 mg in the fasted and fed (640 mg only) states. Blood and urine samples for PK analysis were collected up to 48 h post dose. RESULTS: The area under the plasma concentration-time curve (AUC0-t) of IDP-73152 increased in a dose-proportional manner in the range of 40-320 mg. The mean terminal half-life decreased from 10.7 to 6.2 hrs as the dose increased. The fraction excreted unchanged in the urine ranged from 0.05 to 0.12. In the 640-mg dose group, food delayed the median time to peak concentration (t max) from 0.9 to 3.5 hrs. Furthermore, the maximum plasma concentration (Cmax) were decreased by 36.2%; however, AUC0-t was not generally affected. No serious adverse event or clinically significant findings were observed. CONCLUSIONS: The systemic exposure of IDP-73152 proportionally increased as the dose increased up to 320 mg. The rate of absorption and extent of exposure were reduced by food intake. IDP-73152 was well tolerated without clinically significant adverse effects after a single oral administration.

Production of teicoplanin from Actinoplanes teichomyceticus ID9303 by adding proline.

We evaluated the influence of amino acids in improving teicoplanin productivity. Arginine, lysine, and proline were selected for better productivity among 20 amino acids in Erlenmeyer flasks. Proline was finally chosen as the additive for maximum teicoplanin productivity in a 5-liter fermenter. We obtained the highest teicoplanin productivity, 3.12 g/l, on the eighth d in a 75-liter pilot fermenter.

Extensive intracellular accumulation of ID-6105, a novel anthracycline, in SK-OV-3 ovarian cancer cells.

We investigated the anticancer activity of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, on weakly doxorubicin (Dox)-resistant SK-OV-3 ovarian cancer cells, and elucidated the relationship between its anticancer activity and accumulation in cells compared with those of Dox. Accumulation of ID-6105 in the cells was time-and concentration-dependent, a result of drug-induced cytotoxicity in the cells. SK-OV-3 cells were preloaded with ID-6105 or Dox for 12 h at concentrations ranging from 100 to 2000 nM and then incubated with drug-free medium for 0-48 h. Cell viability was measured using a proliferation-based assay (XTT assay). The inhibitory effects of ID-6105 on cell viability were more pronounced than those of Dox. The IC(50) values of ID-6105 after 24-and 48-h incubation with drug-free medium were 1.58 and 0.084 microM, while those of Dox were 2 and 0.334 microM, respectively. To investigate the relationship between the intracellular levels and the cytotoxic effects of the drugs, we preloaded SKOV-3 cells with ID-6105 or Dox (100-2000 nM) for 12 h and then measured the intracellular levels of drugs by HPLC in drug-free medium for 0-48 h. After preloading the drugs, the intracellular concentrations of ID-6105 at time 0 were 1.3-, 1.8-, and 1.4-fold larger than those of Dox at initial concentrations of 500, 1000, and 2000 nM, respectively. The extent of ID-6105 accumulation in the cells was more pronounced than that of Dox. These findings suggest that ID-6105 effluxed less from the cells than Dox, resulting in its extensive cytotoxicity compared with that of Dox. These results show that accumulation of ID-6105 within tumor cells may be important for the inhibitory effects of this drug in cancer cells. ID-6105 has an antiproliferative effect on SK-OV-3 cells that is due to its cytotoxicity. This effect is more pronounced than that of Dox, and may be attributed to extensive accumulation of ID-6105 in the cells.

Chemical composition and antimicrobial activity of essential oil from cones of Pinus koraiensis.

The essential oil from the cones of Pinus koraiensis was prepared after removing the seeds, and its chemical composition analyzed using gas chromatography-mass spectrometry (GC-MS). Hydrodistillation of the P. koraiensis cones yielded 1.07% (v/w) of essential oil, which was almost three times the amount of essential oil extracted from the needles of the same plant. Moreover, the antimicrobial activities of the oil against the growth of Gram-positive bacteria, Gram-negative bacteria, and fungi were evaluated using the agar disc diffusion method and broth microdilution method. Eighty-seven components, comprising about 96.8% of the total oil, were identified. The most abundant oil components were limonene (27.90%), alpha-pinene (23.89%), beta-pinene (12.02%), 3-carene (4.95%), beta-myrcene (4.53%), isolongifolene (3.35%), (-)-bornyl acetate (2.02%), caryophyllene (1.71%), and camphene (1.54%). The essential oil was confirmed to have significant antimicrobial activities, especially against pathogenic fungal strains such as Candida glabrata YFCC 062 and Cryptococcus neoformans B 42419. Therefore, the present results indicate that the essential oil from the cones of Pinus koraiensis can be used in various ways as a nontoxic and environmentally friendly disinfectant.

Quantification of IDP-73152, a novel antibiotic, in plasma from mice, rats and humans using an ultra-high performance liquid chromatography/tandem mass spectrometry method for use in pharmacokinetic studies.

IDP-73152, a novel inhibitor of a bacterial peptide deformylase, was recently approved as a new, investigational drug in Korea for the clinical management of infections caused by Gram positive bacteria. The objective of this study was to develop/validate a simple and robust analytical method for the determination of IDP-73152 in plasma samples from rodents and humans, and to assess the feasibility of the assay for use in pharmacokinetic studies using animal models. Plasma samples were processed using a standard method for protein precipitation and an aliquot of the extract then injected onto an UHPLC-MS/MS system. The drug and IDP-117293, an internal standard, were analyzed in the positive ion-mode by electrospray ionization and quantified by monitoring the transition at m/z 555.2→245.2 for IDP-73152 and 563.3→253.1 for the internal standard, respectively. The lower and upper limit of the assay was determined to be 5 and 10000ng/ml, respectively, with an acceptable linearity (R>0.999) in the response-concentration relationship. Validation parameters, including accuracy, precision, dilution, recovery, matrix effect and stability were found to be within the acceptable ranges recommended by the assay validation guidelines of the United States FDA. The method was successfully applied to the quantification of IDP-73152 in plasma from mice/rats that had received a single oral administration of 80mg/kg IDP-73152, in the form of the mesylate salt. These findings suggest that the validated assay can be used in preclinical and clinical pharmacokinetic studies of IDP-73152.