Bimodal alteration of cognitive accuracy for spintronic artificial neural networks.

Spintronics-based artificial neural networks (ANNs) exhibiting nonvolatile, fast, and energy-efficient computing capabilities are promising neuromorphic hardware for performing complex cognitive tasks of artificial intelligence and machine learning. Early experimental efforts focused on multistate device concepts to enhance synaptic weight precisions, albeit compromising on cognitive accuracy due to their low magnetoresistance. Here, we propose a hybrid approach based on the tuning of tunnel magnetoresistance (TMR) and the number of states in the compound magnetic tunnel junctions (MTJs) to improve the cognitive performance of an all-spin ANN. A TMR variation of 33-78% is controlled by the free layer (FL) thickness wedge (1.6-2.6 nm) across the wafer. Meanwhile, the number of resistance states in the compound MTJ is manipulated by varying the number of constituent MTJ cells (n = 1-3), generating n + 1 states with a TMR difference between consecutive states of at least 21%. Using MNIST handwritten digit and fashion object databases, the test accuracy of the compound MTJ ANN is observed to increase with the number of intermediate states for a fixed FL thickness or TMR. Meanwhile, the test accuracy for a 1-cell MTJ increases linearly by 8.3% and 7.4% for handwritten digits and fashion objects, respectively, with increasing TMR. Interestingly, a multifarious TMR dependence of test accuracy is observed with the increasing synaptic complexity in the 2- and 3-cell MTJs. By leveraging on the bimodal tuning of multilevel and TMR, we establish viable paths for enhancing the cognitive performance of spintronic ANN for in-memory and neuromorphic computing.

Multistate Compound Magnetic Tunnel Junction Synapses for Digital Recognition.

The quest to mimic the multistate synapses for bioinspired computing has triggered nascent research that leverages the well-established magnetic tunnel junction (MTJ) technology. Early works on the spin transfer torque MTJ-based artificial neural network (ANN) are susceptible to poor thermal reliability, high latency, and high critical current densities. Meanwhile, work on spin-orbit torque (SOT) MTJ-based ANN mainly utilized domain wall motion, which yields negligibly small readout signals differentiating consecutive states and has designs that are incompatible with technological scale-up. Here, we propose a multistate device concept built upon a compound MTJ consisting of multiple SOT-MTJs (number of MTJs, n = 1-4) on a shared write channel, mimicking the spin-based ANN. The n + 1 resistance states representing varying synaptic weights can be tuned by varying the voltage pulses (±1.5-1.8 V), pulse duration (100-300 ns), and applied in-plane fields (5.5-10.5 mT). A large TMR difference of more than 13.6% is observed between two consecutive states for the 4-cell compound MTJ, a 4-fold improvement from reported state-of-the-art spin-based synaptic devices. The ANN built upon the compound MTJ shows high learning accuracy for digital recognition tasks with incremental states and retraining, achieving test accuracy as high as 95.75% in the 4-cell compound MTJ. These results provide an industry-compatible platform to integrate these multistate SOT-MTJ synapses directly into neuromorphic architecture for in-memory and unconventional computing applications.

Chiral Interlayer Exchange Coupling for Asymmetric Domain Wall Propagation in Field-Free Magnetization Switching.

The discovery of chiral spin texture has unveiled many unusual yet extraordinary physical phenomena, such as the Néel type domain walls and magnetic skyrmions. A recent theoretical study suggests that a chiral exchange interaction is not limited to a single ferromagnetic layer; instead, three-dimensional spin textures can arise from an interlayer Dzyaloshinskii-Moriya interaction. However, the influence of chiral interlayer exchange coupling on the electrical manipulation of magnetization has rarely been addressed. Here, the coexistence of both symmetric and chiral interlayer exchange coupling between two orthogonally magnetized CoFeB layers in PtMn/CoFeB/W/CoFeB/MgO is demonstrated. Images from polar magneto-optical Kerr effect microscopy indicate that the two types of coupling act concurrently to induce asymmetric domain wall propagation, where the velocities of domain walls with opposite chiralities are substantially different. Based on this microscopic mechanism, field-free switching of the perpendicularly magnetized CoFeB is achieved with a wide range of W thicknesses of 0.6-4.5 nm. This work enriches the understanding of interlayer exchange coupling for spintronic applications.

Ethanol Extract of Rosa laevigata Michx. Fruit Inhibits Inflammatory Responses through NF-κB/MAPK Signaling Pathways via AMPK Activation in RAW 264.7 Macrophages.

The fruit of Rosa laevigata Michx. (FR), a traditional Chinese herb utilized for the treatment of a variety diseases, has notably diverse pharmacological activities including hepatoprotective, anti-oxidant, and anti-inflammatory effects. Despite ongoing research on illustrating the underlying anti-inflammatory mechanism of FR, the principal mechanism remained inadequately understood. In this study, we investigated in depth the molecular mechanism of the anti-inflammatory actions of the ethanol extract of FR (EFR) and its potential targets using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages in vitro. We showed that EFR effectively ameliorated the overproduction of inflammatory mediators and cytokines, as well as the expression of related genes. It was further demonstrated that LPS-induced activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) were significantly inhibited by pretreatment with EFR, accompanied by a concomitant decrease in the nuclear translocation of the p65 subunit of NF-κB and activator protein 1 (AP-1). In addition, EFR pretreatment potently prevented LPS-induced decreased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Our data also revealed that the activation of AMPK and subsequent inhibition of the mammalian target of the rapamycin (mTOR) signaling pathway was probably responsible for the inhibitory effect of EFR on LPS-induced inflammatory responses, evidenced by reverse changes observed under the condition of AMPK inactivation following co-treatment with the AMPK-specific inhibitor Compound C. Finally, the main components with an anti-inflammatory effect in EFR were identified as madecassic acid, ellagic acid, quinic acid, and procyanidin C1 by LC-MS and testified based on the inhibition of NO production and inflammatory mediator expression. Taken together, our results indicated that EFR was able to ameliorate inflammatory responses via the suppression of MAPKs/NF-κB signaling pathways following AMPK activation, suggesting the therapeutic potential of EFR for inflammatory diseases.

Electric-field control of nonlinear THz spintronic emitters.

Energy-efficient spintronic technology holds tremendous potential for the design of next-generation processors to operate at terahertz frequencies. Femtosecond photoexcitation of spintronic materials generates sub-picosecond spin currents and emission of terahertz radiation with broad bandwidth. However, terahertz spintronic emitters lack an active material platform for electric-field control. Here, we demonstrate a nonlinear electric-field control of terahertz spin current-based emitters using a single crystal piezoelectric Pb(Mg1/3Nb2/3)O3-PbTiO3 (PMN-PT) that endows artificial magnetoelectric coupling onto a spintronic terahertz emitter and provides 270% modulation of the terahertz field at remnant magnetization. The nonlinear electric-field control of the spins occurs due to the strain-induced change in magnetic energy of the ferromagnet thin-film. Results also reveal a robust and repeatable switching of the phase of the terahertz spin current. Electric-field control of terahertz spintronic emitters with multiferroics and strain engineering offers opportunities for the on-chip realization of tunable energy-efficient spintronic-photonic integrated platforms.

Visualizing the strongly reshaped skyrmion Hall effect in multilayer wire devices.

Magnetic skyrmions are nanoscale spin textures touted as next-generation computing elements. When subjected to lateral currents, skyrmions move at considerable speeds. Their topological charge results in an additional transverse deflection known as the skyrmion Hall effect (SkHE). While promising, their dynamic phenomenology with current, skyrmion size, geometric effects and disorder remain to be established. Here we report on the ensemble dynamics of individual skyrmions forming dense arrays in Pt/Co/MgO wires by examining over 20,000 instances of motion across currents and fields. The skyrmion speed reaches 24 m/s in the plastic flow regime and is surprisingly robust to positional and size variations. Meanwhile, the SkHE saturates at ∼22∘, is substantially reshaped by the wire edge, and crucially increases weakly with skyrmion size. Particle model simulations suggest that the SkHE size dependence - contrary to analytical predictions - arises from the interplay of intrinsic and pinning-driven effects. These results establish a robust framework to harness SkHE and achieve high-throughput skyrmion motion in wire devices.

Targeted Writing and Deleting of Magnetic Skyrmions in Two-Terminal Nanowire Devices.

Controllable writing and deleting of nanoscale magnetic skyrmions are key requirements for their use as information carriers for next-generation memory and computing technologies. While several schemes have been proposed, they require complex fabrication techniques or precisely tailored electrical inputs, which limits their long-term scalability. Here, we demonstrate an alternative approach for writing and deleting skyrmions using conventional electrical pulses within a simple, two-terminal wire geometry. X-ray microscopy experiments and micromagnetic simulations establish the observed skyrmion creation and annihilation as arising from Joule heating and Oersted field effects of the current pulses, respectively. The unique characteristics of these writing and deleting schemes, such as spatial and temporal selectivity, together with the simplicity of the two-terminal device architecture, provide a flexible and scalable route to the viable applications of skyrmions.

Anti-Inflammatory Effect of a Polyphenol-Enriched Fraction from Acalypha wilkesiana on Lipopolysaccharide-Stimulated RAW 264.7 Macrophages and Acetaminophen-Induced Liver Injury in Mice.

A polyphenol-enriched fraction (PEF) from Acalypha wilkesiana, whose leaves have been traditionally utilized for the treatment of diverse medical ailments, was investigated for the anti-inflammatory effect and molecular mechanisms by using lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages and acetaminophen- (APAP-) induced liver injury mouse model. Results showed that PEF significantly attenuated LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production and suppressed the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) in RAW 264.7 macrophages. PEF also reduced the secretion of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin- (IL-) 1ß, and IL-6 in LPS-stimulated RAW 264.7 macrophages. Moreover, PEF potently inhibited LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs) as well as the activation of nuclear factor-κB (NF-κB) by preventing the degradation of inhibitor κB-α (IκB-α). In vivo, PEF pretreatment ameliorated APAP-induced liver injury and hepatic inflammation, as presented by decreased hepatic damage indicators and proinflammatory factors at both plasma and gene levels. Additionally, PEF pretreatment remarkably diminished Toll-like receptor 3 (TLR3) and TLR4 expression and the subsequent MAPKs and NF-κB activation. HPLC analysis revealed that two predominantly polyphenolic compounds present in PEF were geraniin and corilagin. These results indicated that PEF has an anti-inflammatory effect, and its molecular mechanisms may be involved in the inactivation of the TLR/MAPK/NF-κB signaling pathway, suggesting the therapeutic potential of PEF for inflammatory diseases.

Hepatoprotective Effect of Polyphenol-Enriched Fraction from Folium Microcos on Oxidative Stress and Apoptosis in Acetaminophen-Induced Liver Injury in Mice.

Folium Microcos (FM), the leaves of Microcos paniculata L., shows various biological functions including antioxidant activity and α-glucosidase inhibitory effect. However, its therapeutic potential in acute liver injury is still unknown. This study investigated the hepatoprotective effect and underlying mechanisms of the polyphenol-enriched fraction (FMF) from Folium Microcos. FMF exhibited strong free radical scavenging activities and prevented HepG2/Hepa1-6 cells from hydrogen peroxide- (H2O2-) induced ROS production and apoptosis in vitro. Antioxidant activity and cytoprotective effects were further verified by alleviating APAP-induced hepatotoxicity in mice. Western blot analysis revealed that FMF pretreatment significantly abrogated APAP-mediated phosphorylation of MAPKs, activation of proapoptotic protein caspase-3/9 and Bax, and restored expression of antiapoptotic protein Bcl2. APAP-intoxicated mice pretreated with FMF showed increased nuclear accumulation of nuclear factor erythroid 2-related factor (Nrf2) and elevated hepatic expression of its target genes, NAD(P)H:quinine oxidoreductase 1 (NQO1) and hemeoxygenase-1(HO-1). HPLC analysis revealed the four predominantly phenolic compounds present in FMF: narcissin, isorhamnetin-3-O-ß-D-glucoside, isovitexin, and vitexin. Consequently, these findings indicate that FMF possesses a hepatoprotective effect against APAP-induced hepatotoxicity mainly through dual modification of ROS/MAPKs/apoptosis axis and Nrf2-mediated antioxidant response, which may be attributed to the strong antioxidant activity of phenolic components.

A versatile rotary-stage high frequency probe station for studying magnetic films and devices.

We present a rotary-stage microwave probe station suitable for magnetic films and spintronic devices. Two stages, one for field rotation from parallel to perpendicular to the sample plane (out-of-plane) and the other intended for field rotation within the sample plane (in-plane) have been designed. The sample probes and micro-positioners are rotated simultaneously with the stages, which allows the field orientation to cover θ from 0(∘) to 90(∘) and φ from 0(∘) to 360(∘). θ and φ being the angle between the direction of current flow and field in a out-of-plane and an in-plane rotation, respectively. The operation frequency is up to 40 GHz and the magnetic field up to 1 T. The sample holder vision system and probe assembly are compactly designed for the probes to land on a wafer with diameter up to 3 cm. Using homemade multi-pin probes and commercially available high frequency probes, several applications including 4-probe DC measurements, the determination of domain wall velocity, and spin transfer torque ferromagnetic resonance are demonstrated.

A novel synthetic novobiocin analog, FM-Nov17, induces DNA damage in CML cells through generation of reactive oxygen species.

OBJECTIVES: To investigate the cytotoxicity of FM-Nov17 against chronic myeloid leukemia (CML) cells, we explored its underlying mechanisms mediating the induction of DNA damage and apoptotic cell death by reactive oxygen species (ROS). METHODS: MTT assays were used to measure the proliferation-inhibition ratio of K562 and K562/G01 cells. Flow cytometry (FCM) was used to test the level of extracellular ROS, DNA damage, cell cycle progression and apoptosis. Western blotting was used to verify the amount of protein. RESULTS: FM-Nov17 significantly inhibited the proliferation of K562 cells, with an IC50 of 58.28±0.304µM, and K562/G01 cells, with an IC50 of 62.36±0.136µM. FM-Nov17 significantly stimulated the generation of intracellular ROS, followed by the induction of DNA damage and the activation of the ATM-p53-r-H2AX pathway and checkpoint-related signals Chk1/Chk2, which led to increased numbers of cells in the S and G2/M phases of the cell cycle. Furthermore, FM-Nov17 induced apoptotic cell death by decreasing mitochondrial membrane potential and activating caspase-3 and PARP. The above effects were all prevented by the ROS scavenger N-acetylcysteine. CONCLUSIONS: FM-Nov17-induces DNA damage and mitochondria-dependent cellular apoptosis in CML cells. The process is mediated by the generation of ROS.

Functional ferroelectric tunnel junctions on silicon.

The quest for solid state non-volatility memory devices on silicon with high storage density, high speed, low power consumption has attracted intense research on new materials and novel device architectures. Although flash memory dominates in the non-volatile memory market currently, it has drawbacks, such as low operation speed, and limited cycle endurance, which prevents it from becoming the "universal memory". In this report, we demonstrate ferroelectric tunnel junctions (Pt/BaTiO3/La0.67Sr0.33MnO3) epitaxially grown on silicon substrates. X-ray diffraction spectra and high resolution transmission electron microscope images prove the high epitaxial quality of the single crystal perovskite films grown on silicon. Furthermore, the write speed, data retention and fatigue properties of the device compare favorably with flash memories. The results prove that the silicon-based ferroelectric tunnel junction is a very promising candidate for application in future non-volatile memories.

A Novobiocin Derivative, XN4, Inhibits the Proliferation of Chronic Myeloid Leukemia Cells by Inducing Oxidative DNA Damage.

XN4 might induce DNA damage and apoptotic cell death through reactive oxygen species (ROS). The inhibition of proliferation of K562 and K562/G01 cells was measured by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide). The mRNA levels of NADPH oxidase 1-5 (Nox1-5) genes were evaluated by qRT-PCR. The levels of extracellular reactive oxygen species (ROS), DNA damage, apoptosis, and cell cycle progression were examined by flow cytometry (FCM). Protein levels were analyzed by immunoblotting. XN4 significantly inhibited the proliferation of K562 and K562/G01 cells, with IC50 values of 3.75±0.07 µM and 2.63±0.43 µM, respectively. XN4 significantly increased the levels of Nox4 and Nox5 mRNA, stimulating the generation of intracellular ROS, inducing DNA damage and activating ATM-γ-H2AX signaling, which increased the number of cells in the S and G2/M phase of the cell cycle. Subsequently, XN4 induced apoptotic cell death by activating caspase-3 and PARP. Moreover, the above effects were all reversed by the ROS scavenger N-acetylcysteine (NAC). Additionally, XN4 can induce apoptosis in progenitor/stem cells isolated from CML patients' bone marrow. In conclusion, XN4-induced DNA damage and cell apoptosis in CML cells is mediated by the generation of ROS.

Ultrathin BaTiO3-based ferroelectric tunnel junctions through interface engineering.

The ability to change states using voltage in ferroelectric tunnel junctions (FTJs) offers a route for lowering the switching energy of memories. Enhanced tunneling electroresistance in FTJ can be achieved by asymmetric electrodes or introducing metal-insulator transition interlayers. However, a fundamental understanding of the role of each interface in a FTJ is lacking and compatibility with integrated circuits has not been explored adequately. Here, we report an incisive study of FTJ performance with varying asymmetry of the electrode/ferroelectric interfaces. Surprisingly high TER (∼400%) can be achieved at BaTiO3 layer thicknesses down to two unit cells (∼0.8 nm). Further our results prove that band offsets at each interface in the FTJs control the TER ratio. It is found that the off state resistance (R(Off)) increases much more rapidly with the number of interfaces compared to the on state resistance (ROn). These results are promising for future low energy memories.

Dual inhibition of Bcr-Abl and Hsp90 by C086 potently inhibits the proliferation of imatinib-resistant CML cells.

PURPOSE: Although tyrosine kinase inhibitors (TKI) such as imatinib provide an effective treatment against Bcr-Abl kinase activity in the mature cells of patients with chronic myelogenous leukemia (CML), TKIs probably cannot eradicate the leukemia stem cell (LSC) population. Therefore, alternative therapies are required to target both mature CML cells with wild-type (WT) or mutant Bcr-Abl and LSCs. To investigate the effect of C086, a derivative of curcumin, on imatinib-resistant cells, we explored its underlying mechanisms of Bcr-Abl kinase and heat shock protein 90 (Hsp90) function inhibition. EXPERIMENTAL DESIGN: Biochemical assays were used to test ABL kinase activity; fluorescence measurements using recombinant NHsp90, Hsp90 ATPase assay, immunoprecipitation, and immunoblotting were applied to examine Hsp90 function. Colony-forming unit, long-term culture-initiating cells (LTC-IC), and flow cytometry were used to test CML progenitor and stem cells. RESULTS: Biochemical assays with purified recombinant Abl kinase confirmed that C086 can directly inhibit the kinase activity of Abl, including WT and the Q252H, Y253F, and T315I mutations. Furthermore, we identified C086 as a novel Hsp90 inhibitor with the capacity to disrupt the Hsp90 chaperone function in CML cells. Consequently, it inhibited the growth of both imatinib-sensitive and -resistant CML cells. Interestingly, C086 has the capacity to inhibit LTC-ICs and to induce apoptosis in both CD34(+)CD38(+) and CD34(+)CD38(-) cells in vitro. Moreover, C086 could decrease the number of CD45(+), CD45(+)CD34(+)CD38(+), and CD45(+)CD34(+)CD38(-) cells in CML NOD-SCID mice. CONCLUSIONS: Dual suppression of Abl kinase activity and Hsp90 chaperone function by C086 provides a new therapeutic strategy for treating Bcr-Abl-induced leukemia resistant to TKIs.

Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro.

AIM: To find new kinase inhibitors that overcome the imatinib resistance in treatment of chronic myeloid leukemia (CML), we synthesized C817, a novel derivative of curcumin, and tested its activities against wild-type (WT) and imatinib-resistant mutant Abl kinases, as well as in imatinib-sensitive and resistant CML cells in vitro. METHODS: 32D cells harboring WT or mutant Abl kinases (nucleotide binding P-loop mutants Q252H, Y253F, and imatinib contact residue mutant T315I), as well as K562/G01 cells (with whole Bcr-Abl gene amplication) were tested. Kinase activity was measured using Kinase-Glo Luminescent Kinase Assay Platform in recombinant WT and mutant (Q252H, Y253F, and T315I) Abl kinases. Cell proliferation and apoptosis were examined using MTT assay and flow cytometry, respectively. The phosphorylation levels of Bcr-Abl initiated signaling proteins were analyzed using Western blotting. Colony forming units (CFU) growth and long term culture-initiating cells (LTC-ICs) were used to test the effects of C817 on human leukemia progenitor/stem cells. RESULTS: C817 potently inhibited both WT and mutant (Q252H, Y253F, and T315I) Abl kinase activities in a non-ATP competitive manner with the values of IC50 at low nanomole levels. In consistent with above results, C817 suppressed the growth of both imatinib-sensitive and resistant CML cells, including wild-type K562, K562/G01, 32D-T315I, 32D-Q252H, and 32D-Y253F cells with the values of IC50 at low micromole levels. C817 (0.5 or 1 µmol/L) dose-dependently inhibited the phosphorylation of Bcr-Abl and downstream proteins STAT-5 and CrkL in imatinib-resistant K562/G01 cells. Furthermore, C817 significantly suppressed CFU growth and LTC-ICs, implicating that C817 could eradiate human leukemia progenitor/stem cells. CONCLUSION: C817 is a promising compound for treatment of CML patients with Bcr-Abl kinase domain mutations that confer imatinib resistance.