High-Performance Neuromorphic Computing and Logic Operation Based on a Self-Assembled Vertically Aligned Nanocomposite SrTiO3:MgO Film Memristor.

Neuromorphic computing based on memristors capable of in-memory computing is promising to break the energy and efficiency bottleneck of well-known von Neumann architectures. However, unstable and nonlinear conductance updates compromise the recognition accuracy and block the integration of neural network hardware. To this end, we present a highly stable memristor with self-assembled vertically aligned nanocomposite (VAN) SrTiO3:MgO films that achieve excellent resistive switching with low set/reset voltage variability (4.7%/-5.6%) and highly linear conductivity variation (nonlinearity = 0.34) by spatially limiting the conductive channels at the vertical interfaces. Various synaptic behaviors are simulated by continuously modulating the conductance. Especially, convolutional image processing using diverse crossbar kernels is demonstrated, and the artificial neural network achieves an overwhelming recognition accuracy of up to 97.50% for handwritten digits. Even under the perturbation of Poisson noise (λ = 10), 6% Salt and Pepper noise, and 5% Gaussian noise, the high recognition accuracies are retained at 95.43%, 94.56%, and 95.97%, respectively. Importantly, the logic memory function is proven experimentally based on the nonvolatile properties. This work provides a material system and design idea to achieve high-performance neuromorphic computing and logic operation.

Silicon based Bi0.9La0.1FeO3 ferroelectric tunnel junction memristor for convolutional neural network application.

Computing in memory (CIM) based on memristors is expected to completely solve the dilemma caused by von Neumann architecture. However, the performance of memristors based on traditional conductive filament mechanism is unstable. In this study, we report a nonvolatile high-performance memristor based on ferroelectric tunnel junction (FTJ) Pd/Bi0.9La0.1FeO3 (6.9 nm) (BLFO)/La0.67Sr0.33MnO3 (LSMO) on a silicon substrate. The conductance of this device was adjusted by different pulse stimulation parameter to achieve various synaptic functions because of ferroelectric polarization reversal. Based on the multiple conductance characteristics of the devices and the high linearity and symmetry of weight updating, image processing and VGG8 convolutional neural network (CNN) simulation based on the devices were realized. Excellent results of the image processing are demonstrated. The recognition accuracy of CNN offline learning reached an astonishing 92.07% based on Cifar-10 dataset. This provides a more feasible solution to break through the bottleneck of von Neumann architecture.

Ligand-Triggered Self-Assembly of Flexible Carbon Dot Nanoribbons for Optoelectronic Memristor Devices and Neuromorphic Computing.

Carbon dots (CDs) are widely utilized in sensing, energy storage, and catalysis due to their excellent optical, electrical and semiconducting properties. However, attempts to optimize their optoelectronic performance through high-order manipulation have met with little success to date. In this study, through efficient packing of individual CDs in two-dimensions, the synthesis of flexible CDs ribbons is demonstrated technically. Electron microscopies and molecular dynamics simulations, show the assembly of CDs into ribbons results from the tripartite balance of π-π attractions, hydrogen bonding, and halogen bonding forces provided by the superficial ligands. The obtained ribbons are flexible and show excellent stability against UV irradiation and heating. CDs ribbons offer outstanding performance as active layer material in transparent flexible memristors, with the developed devices providing excellent data storage, retention capabilities, and fast optoelectronic responses. A memristor device with a thickness of 8 µm shows good data retention capability even after 104 cycles of bending. Furthermore, the device functions effectively as a neuromorphic computing system with integrated storage and computation capabilities, with the response speed of the device being less than 5.5 ns. These properties create an optoelectronic memristor with rapid Chinese character learning capability. This work lays the foundation for wearable artificial intelligence.

Superlow Power Consumption Artificial Synapses Based on WSe2 Quantum Dots Memristor for Neuromorphic Computing.

As the emerging member of zero-dimension transition metal dichalcogenide, WSe2 quantum dots (QDs) have been applied to memristors and exhibited better resistance switching characteristics and miniaturization size. However, low power consumption and high reliability are still challenges for WSe2 QDs-based memristors as synaptic devices. Here, we demonstrate a high-performance, superlow power consumption memristor device with the structure of Ag/WSe2 QDs/La0.3Sr0.7MnO3/SrTiO3. The device displays excellent resistive switching memory behavior with a R OFF/R ON ratio of ~5 × 103, power consumption per switching as low as 0.16 nW, very low set, and reset voltage of ~0.52 V and~ -0.19 V with excellent cycling stability, good reproducibility, and decent data retention capability. The superlow power consumption characteristic of the device is further proved by the method of density functional theory calculation. In addition, the influence of pulse amplitude, duration, and interval was studied to gradually modulating the conductance of the device. The memristor has also been demonstrated to simulate different functions of artificial synapses, such as excitatory postsynaptic current, spike timing-dependent plasticity, long-term potentiation, long-term depression, and paired-pulse facilitation. Importantly, digit recognition ability based on the WSe2 QDs device is evaluated through a three-layer artificial neural network, and the digit recognition accuracy after 40 times of training can reach up to 94.05%. This study paves a new way for the development of memristor devices with advanced significance for future low power neuromorphic computing.

Nocathiacin, Thiazomycin, and Polar Analogs Are Highly Effective Agents against Toxigenic Clostridioides difficile.

Clostridioides difficile is a commensal Gram-positive gut bacterium that causes C. difficile-associated diarrhea. Currently available antibacterial therapeutic treatment options are effective except for the repeated recurrences significantly burdening the health care system and causing mortality. The development of new therapeutic modalities including new effective antibiotics with a low rate of recurrence has been unpredictive and exceedingly challenging, requiring continued profiling of many new classes of antibiotics. Nocathiacins and thiazomycins are a class of thiazolyl peptides exhibiting potent and selective broad-spectrum Gram-positive activity including activity against the anaerobe C. difficile. These compounds showed MIC values of 0.015-0.06 µg/mL against C. difficile with more than 100-200-fold selectivity versus commensurate Gram-negative Bacteroides fragilis. Nocathiacin I and one of its analogs exhibited potent in vivo efficacy in the gold-standard hamster model of C. difficile infection, providing 100% protection in this lethal model at 6.25 mg/kg orally twice daily. The efficacy was corroborated by robust reduction of cecum C. difficile burden and proportionate exposure of the compounds in the cecum contents without any systemic absorption. In this paper, details of the results of in vitro, in vivo, pharmacodynamics, and pharmacokinetic studies have been described.

A Robust Memristor Based on Epitaxial Vertically Aligned Nanostructured BaTiO3 -CeO2 Films on Silicon.

With the exploration of ferroelectric materials, researchers have a strong desire to explore the next generation of non-volatile ferroelectric memory with silicon-based epitaxy, high-density storage, and algebraic operations. Herein, a silicon-based memristor with an epitaxial vertically aligned nanostructures BaTiO3 -CeO2 film based on La0.67 Sr0.33 MnO3 /SrTiO3 /Si substrate is reported. The ferroelectric polarization reversal is optimized through the continuous exploring of growth temperature, and the epitaxial structure is obtained, thus it improves the resistance characteristic, the multi-value storage function of five states is achieved, and the robust endurance characteristic can reach 109 cycles. In the synapse plasticity modulated by pulse voltage process, the function of the spiking-time-dependent plasticity and paired-pulse facilitation is simulated successfully. More importantly, the algebraic operations of addition, subtraction, multiplication, and division are realized by using fast speed pulse of the width ≈50 ns. Subsequently, a convolutional neural network is constructed for identifying the CIFAR-10 dataset, to simulate the performance of the device; the online and offline learning recognition rate reach 90.03% and 92.55%, respectively. Overall, this study paves the way for memristors with silicon-based epitaxial ferroelectric films to realize multi-value storage, algebraic operations, and neural computing chip applications.

MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology.

The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound 5) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 7. Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.

Continuous and intermittent dosing of lonafarnib potentiates the therapeutic efficacy of docetaxel on preclinical human prostate cancer models.

Lonafarnib is a potent, selective farnesyltransferase inhibitor (FTI) undergoing clinical studies for the treatment of solid tumors and hematological malignancies. Preclinically, a number of FTIs, including lonafarnib, interact with taxanes to inhibit cancer cell growth in an additive/synergistic manner. These observations provided rationale for investigating the effects of combining lonafarnib and docetaxel on preclinical prostate cancer models. To date, docetaxel is the only chemotherapeutic agent in clinical use for hormone-refractory prostate cancer. In vitro experiments with 22Rv1, LNCaP, DU-145, PC3 and PC3-M prostate cancer cell lines showed significantly enhanced inhibition of cell proliferation and apoptosis when lonafarnib was added to docetaxel. In human tumor xenograft models, continuous coadministration of lonafarnib with docetaxel caused marked tumor regressions (24-47%) in tumors from all of the cell types as well as parental CWR22 xenografts. Intermittent dosing of lonafarnib (5 days on then 5 days off) coadministered with docetaxel produced similar regressions in hormone-refractory 22Rv1 tumors. 22Rv1 tumors progressing on docetaxel treatment also responded to treatment with intermittent lonafarnib (5 days on then 5 days off). Moreover, animals did not exhibit any signs of toxicity during coadministration of lonafarnib and docetaxel. In conclusion, coadministration of continuous and intermittent lonafarnib enhanced the antitumor activity of docetaxel in a panel of prostate cancer models. An intermittent dosing schedule of lonafarnib coadministered with docetaxel may allow enhanced efficacy to that of continuous dosing by improving the tolerability of higher doses of lonafarnib.

Combining the farnesyltransferase inhibitor lonafarnib with paclitaxel results in enhanced growth inhibitory effects on human ovarian cancer models in vitro and in vivo.

OBJECTIVES: To determine the effects of combining lonafarnib with paclitaxel on the growth of human ovarian cancer cells and tumor xenografts as well as to monitor a pharmacodynamic marker of farnesyltransferase inhibition (HDJ-2) in peripheral blood mononuclear cells (PBMCs) isolated from tumor-bearing animals after treatment with this combination. METHODS: Proliferation of A2780, PA-1, IGROV-1, and TOV-112D cells was assessed after treatment with lonafarnib and paclitaxel. Cell cycle progression was determined by flow cytometry, and apoptosis was evaluated by assaying for caspase-3 and cleaved PARP. The effects of lonafarnib and paclitaxel on the tumor growth of each model were determined in immunocompromised mice. Proteins extracted from cells, tumors, and PBMCs were assayed for HDJ-2 mobility shifts by Western blotting as well as for farnesyl protein transferase (FTase) enzyme activity by biochemical analyses. RESULTS: In A2780, PA-1, IGROV-1, and TOV-112D cells lonafarnib potentiated the growth inhibitory effects of paclitaxel. In each of the models lonafarnib enhanced paclitaxel-induced mitotic arrest and apoptosis. The combination of lonafarnib plus paclitaxel resulted in marked tumor regressions in A2780, TOV-112D, PA-1, and IGROV-1 tumor xenografts. Western blotting demonstrated that in PBMCs isolated from the animals, paclitaxel treatment suppressed lonafarnib-induced HDJ-2 mobility shifts. Paclitaxel did not affect lonafarnib inhibition of FTase enzyme activity levels in these PBMCs. CONCLUSIONS: Lonafarnib enhances the antiproliferative effects of paclitaxel on ovarian cancer cells in vitro and ovarian tumor xenografts in vivo. Measuring FTase enzyme activity levels rather than HDJ-2 shifts in PBMCs may be a more accurate biomarker to predict levels of farnesyltransferase inhibition in patients who are also receiving paclitaxel chemotherapy.

The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity.

Lonafarnib (SCH66336) is a farnesyl transferase inhibitor (FTI) that inhibits the post-translational lipid modification of H-Ras and other farnesylated proteins. K- and N-Ras are also substrates of farnesyl transferase; however, upon treatment with FTIs, they are alternatively prenylated by geranylgeranyl transferase-1. Despite the failure to abrogate prenylation of K- and N-Ras, growth of many tumors in preclinical models is inhibited by FTIs. This suggests that the anti-proliferative action of FTIs is dependent on blocking the farnesylation of other proteins. Rheb (Ras homologue enriched in brain) is a farnesylated small GTPase that positively regulates mTOR (mammalian target of rapamycin) signaling. We found that Rheb and Rheb2 mRNA were elevated in various tumor cell lines relative to normal cells. Peptides derived from the carboxyl termini of human Rheb and Rheb2 are in vitro substrates for farnesyl transferase but not geranylgeranyl transferase-1. Rheb prenylation in cell culture was completely inhibited by SCH66336, indicating a lack of alternative prenylation. SCH66336 treatment also inhibited the phosphorylation of S6 ribosomal protein, a downstream target of Rheb and mTOR signaling. SCH66336 did not inhibit S6 phosphorylation in cells expressing Rheb-CSVL, a mutant construct of Rheb designed to be geranylgeranylated. Importantly, expression of Rheb-CSVL also abrogated SCH66336 enhancement of tamoxifen- and docetaxel-induced apoptosis in MCF-7 breast cancer cells and ES-2 ovarian cancer cells, respectively. Further, inhibition of Rheb signaling by rapamycin treatment, small interfering RNA, or dominant negative Rheb enhanced tamoxifen- and docetaxel-induced apoptosis, similar to FTI treatment. These studies demonstrated that Rheb is modified by farnesylation, is not a substrate for alternative prenylation, and plays a role in SCH66336 enhancement of the anti-tumor response to other chemotherapeutics.

Farnesyltransferase inhibitors are potent lung cancer chemopreventive agents in A/J mice with a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf.

Mutations in the Kras2 gene are seen in both human and mouse lung adenocarcinomas. The protein product (p21ras) encoded by the Kras2 gene must be post-translationally modified at a terminal CAAX motif in order to be biologically active. In this study, we systematically investigated the chemopreventive efficacy of two different farnesyltransferase inhibitors (FTIs): one is a peptidomimetic (FTI-276) and the other is an imidazole (L778-123). Both FTIs are designed to inhibit the post-translational modification of p21ras proteins with a terminal CAAX motif. In a complete chemoprevention study, where the inhibitor was administered before carcinogen was given, and throughout the study, FTI-276 treatment significantly reduced both the tumor multiplicity by 41.7% (P<0.005), and the total tumor volume by 79.4% (P<0.0001). In the late treatment study, where mice were treated with an inhibitor 12 to 20 weeks after carcinogen administration, FTI-276 treatment resulted in a 60% reduction in tumor multiplicity and 58% reduction in tumor volume. Next, we examined the chemopreventive efficacy of a new FTI, L-778,123, on lung tumor development in A/J mice and transgenic mice with a dominant-negative p53 mutation and/or heterozygous deletion of Ink4a/Arf. Treatment of mice with L-778,123 for a period of 10 weeks from 20 weeks to 30 weeks post carcinogen initiation resulted in an approximately 50% decrease in tumor multiplicity in wild-type mice and mice with a dominant-negative p53 mutation and/or heterozygous deletion of the Ink4a/Arf tumor suppressor genes. Interestingly, tumor volume was decreased approximately 50% in wild-type mice and in mice with an Ink4a/Arf heterozygous deletion, while tumor volume was decreased approximately 75% in animals with a dominant-negative p53 and in mice with both a p53 mutation and heterozygous deletion of Ink4a/Arf. This result suggests that FTI exhibited a significantly (P<0.05) more efficacious chemopreventive effect in animals with alterations of p53 and Ink4a/Arf as contrasted with wild-type mice. Thus, FTIs are potent lung chemopreventive agents in both A/J mice and transgenic mice harboring a dominant-negative p53 and heterozygous deletion of Ink4a/Arf. In fact, L-778,123 is more effective in inhibiting primary lung progression in mice with a p53 mutation and/or an Ink4a/Arf deletion than in wild-type animals.

Fine mapping and identification of candidate pulmonary adenoma susceptibility 1 genes using advanced intercross lines.

In the present study, we used newly developed F(11) generation mouse advanced intercross lines (AIL) to fine map Pas1-3 quantitative trait loci (QTL). The (A/J x C57BL/6) F(11) AIL mouse population was created by crossing lung tumor-resistant C57BL/6 mice with lung tumor-susceptible A/J mice. By selectively genotyping 30% of the population, we have confirmed the Pas1 QTL and narrowed it to an interval of approximately 1.0 cM or 1.3 Mb in the vicinity of the Kras2 gene. The Pas2 QTL was detected by both ANOVA and regression analysis but not by MapMaker EXP/QTL software. In addition, an interaction between the Pas1 and Pas2 QTLs was revealed. However, the Pas3 QTL was not confirmed in this study. It was either lost during the development of the AIL or too weak to be detected using AIL. The Pas1 locus is now sufficiently fine-mapped that candidate gene(s) for the Pas1 locus can be characterized by positional cloning. In this study, all 27 of the known or predicted genes located in the Pas1 candidate region were characterized as possible candidate Pas genes. Six genes were selected for additional analyses because of their relevant function in tumorigenesis or allelic changes between A/J and C57BL/6 mice. The Lrmp gene bears amino acid polymorphisms among various mouse strains that are highly correlated with the Pas1 allele status. The Pas1c1 gene (RIKEN Ak016641), encoding an intermediate filament tail domain-containing protein, produces alternatively spliced transcripts across inbred strains of mice, and its splicing pattern cosegregates with the Pas1 allele. The genetic and expression data support these two genes as strong candidates for the Pas1 locus. Of the other four genes (Eca39, RIKEN Ak015530, mHoj-1, and Krag), no functional polymorphisms or differential gene expression were found in Eca39, mHoj-1, and Krag between lung tumor-susceptible and -resistant strains. The Ak015530 carries an amino acid polymorphism, but this polymorphism does not cosegregate with mouse lung tumor susceptibility. Thus, these 4 genes are less likely candidates for the Pas1 locus.

A strong candidate gene for the Papg1 locus on mouse chromosome 4 affecting lung tumor progression.

Lung cancer is the leading cause of cancer death among both men and women, accounting for more than 28% of all cancer deaths. In fact, more people die of lung cancer than of colon, breast, and prostate cancers combined. Although lung cancer is largely induced by smoking, there is strong evidence for genetic susceptibility and gene-environment interactions in the development of lung cancer. Inbred mouse models offer an effective means of identifying candidate lung cancer susceptibility loci since genetic heterogeneity and enormous variation in exposure levels to environmental agents make it difficult to identify lung cancer susceptibility loci in humans. Papg-1 (pulmonary adenoma progression 1) was previously mapped to a region on mouse chromosome 4. This locus contains a candidate gene, Cdkn2a also referred to as Ink4a/Arf, which dually encodes two established tumor suppressors p16(INK4a) and ARF. Cdkn2a became a primary candidate for Papg-1 for two reasons: (1) two haplotypes of mouse Cdkn2a were found to segregate with differential genetic susceptibility to lung tumor progression in mice; and (2) in vitro studies showed that the p16(INK4a) allele from the BALB/cJ mouse had a significantly decreased ability to bind and inhibit CDK6 and to suppress cell growth when compared with the p16(INK4a) allele from the A/J mouse. Here, we report that mice with a heterozygous deficiency for the A/J Cdkn2a allele were significantly more susceptible to lung tumor progression than mice with a heterozygous deficiency for a BALB/cJ Cdkn2a allele, when compared to their respective wild type mice. These results offer strong evidence that naturally occurring variation of p16(INK4a) influences susceptibility to enhance lung tumor progression making it a strong candidate for the lung tumor progression locus, Papg-1.