Training and operation of an integrated neuromorphic network based on metal-oxide memristors.

Despite much progress in semiconductor integrated circuit technology, the extreme complexity of the human cerebral cortex, with its approximately 10(14) synapses, makes the hardware implementation of neuromorphic networks with a comparable number of devices exceptionally challenging. To provide comparable complexity while operating much faster and with manageable power dissipation, networks based on circuits combining complementary metal-oxide-semiconductors (CMOSs) and adjustable two-terminal resistive devices (memristors) have been developed. In such circuits, the usual CMOS stack is augmented with one or several crossbar layers, with memristors at each crosspoint. There have recently been notable improvements in the fabrication of such memristive crossbars and their integration with CMOS circuits, including first demonstrations of their vertical integration. Separately, discrete memristors have been used as artificial synapses in neuromorphic networks. Very recently, such experiments have been extended to crossbar arrays of phase-change memristive devices. The adjustment of such devices, however, requires an additional transistor at each crosspoint, and hence these devices are much harder to scale than metal-oxide memristors, whose nonlinear current-voltage curves enable transistor-free operation. Here we report the experimental implementation of transistor-free metal-oxide memristor crossbars, with device variability sufficiently low to allow operation of integrated neural networks, in a simple network: a single-layer perceptron (an algorithm for linear classification). The network can be taught in situ using a coarse-grain variety of the delta rule algorithm to perform the perfect classification of 3 × 3-pixel black/white images into three classes (representing letters). This demonstration is an important step towards much larger and more complex memristive neuromorphic networks.

Genetic predictors of cardiovascular morbidity in Bardet-Biedl syndrome.

Bardet-Biedl syndrome is a rare ciliopathy characterized by retinal dystrophy, obesity, intellectual disability, polydactyly, hypogonadism and renal impairment. Patients are at high risk of cardiovascular disease. Mutations in BBS1 and BBS10 account for more than half of those with molecular confirmation of the diagnosis. To elucidate genotype-phenotype correlations with respect to cardiovascular risk indicators 50 patients with mutations in BBS1 were compared with 19 patients harbouring BBS10 mutations. All patients had truncating, missense or compound missense/truncating mutations. The effect of genotype and mutation type was analysed. C-reactive protein was higher in those with mutations in BBS10 and homozygous truncating mutations (p = 0.013 and p = 0.002, respectively). Patients with mutations in BBS10 had higher levels of C peptide than those with mutations in BBS1 (p = 0.043). Triglyceride levels were significantly elevated in patients with homozygous truncating mutations (p = 0.048). Gamma glutamyl transferase was higher in patients with homozygous truncating mutations (p = 0.007) and heterozygous missense and truncating mutations (p = 0.002) than those with homozygous missense mutations. The results are compared with clinical cardiovascular risk factors. Patients with missense mutations in BBS1 have lower biochemical cardiovascular disease markers compared with patients with BBS10 and other BBS1 mutations. This could contribute to stratification of the clinical service.

Impact ionization-induced bistability in CMOS transistors at cryogenic temperatures for capacitorless memory applications.

Cryogenic operation of complementary metal oxide semiconductor (CMOS) silicon transistors is crucial for quantum information science, but it brings deviations from standard transistor operation. Here, we report on sharp current jumps and stable hysteretic loops in the drain current as a function of gate voltage V G for both n- and p-type commercial-foundry 180-nm-process CMOS transistors when operated at voltages exceeding 1.3 V at cryogenic temperatures. The physical mechanism responsible for the device bistability is impact ionization charging of the transistor body, which leads to effective back-gating of the inversion channel. This mechanism is verified by independent measurements of the body potential. The hysteretic loops, which have a >107 ratio of high to low drain current states at the same V G, can be used for a compact capacitorless single-transistor memory at cryogenic temperatures with long retention times.

Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by multiple clinical features that include pigmentary retinal dystrophy, polydactyly, obesity, developmental delay, and renal defects. BBS is considered an autosomal recessive disorder, and recent positional cloning efforts have identified two BBS genes (BBS2 and BBS6). We screened our cohort of 163 BBS families for mutations in both BBS2 and BBS6 and report the presence of three mutant alleles in affected individuals in four pedigrees. In addition, we detected unaffected individuals in two pedigrees who carry two BBS2 mutations but not a BBS6 mutation. We therefore propose that BBS may not be a single-gene recessive disease but a complex trait requiring three mutant alleles to manifest the phenotype. This triallelic model of disease transmission may be important in the study of both Mendelian and multifactorial disorders.

Electron beam-based metrology after CMOS.

The magnitudes of the challenges facing electron-based metrology for post-CMOS technology are reviewed. Directed selfassembly, nanophotonics/plasmonics, and resistive switches and selectors, are examined as exemplars of important post-CMOS technologies. Materials, devices, and architectures emerging from these technologies pose new metrology requirements: defect detection, possibly subsurface, in soft materials, accurate measurement of size, shape, and roughness of structures for nanophotonic devices, contamination-free measurement of surface-sensitive structures, and identification of subtle structural, chemical, or electronic changes of state associated with switching in non-volatile memory elements. Electron-beam techniques are examined in the light of these emerging requirements. The strong electron-matter interaction provides measurable signal from small sample features, rendering electron-beam methods more suitable than most for nanometer-scale metrology, but as is to be expected, solutions to many of the measurement challenges are yet to be demonstrated. The seeds of possible solutions are identified when they are available.

Corrigendum: A multiply-add engine with monolithically integrated 3D memristor crossbar/CMOS hybrid circuit.

This corrects the article DOI: 10.1038/srep42429.

A multiply-add engine with monolithically integrated 3D memristor crossbar/CMOS hybrid circuit.

Silicon (Si) based complementary metal-oxide semiconductor (CMOS) technology has been the driving force of the information-technology revolution. However, scaling of CMOS technology as per Moore's law has reached a serious bottleneck. Among the emerging technologies memristive devices can be promising for both memory as well as computing applications. Hybrid CMOS/memristor circuits with CMOL (CMOS + "Molecular") architecture have been proposed to combine the extremely high density of the memristive devices with the robustness of CMOS technology, leading to terabit-scale memory and extremely efficient computing paradigm. In this work, we demonstrate a hybrid 3D CMOL circuit with 2 layers of memristive crossbars monolithically integrated on a pre-fabricated CMOS substrate. The integrated crossbars can be fully operated through the underlying CMOS circuitry. The memristive devices in both layers exhibit analog switching behavior with controlled tunability and stable multi-level operation. We perform dot-product operations with the 2D and 3D memristive crossbars to demonstrate the applicability of such 3D CMOL hybrid circuits as a multiply-add engine. To the best of our knowledge this is the first demonstration of a functional 3D CMOL hybrid circuit.

Self-Adaptive Spike-Time-Dependent Plasticity of Metal-Oxide Memristors.

Metal-oxide memristors have emerged as promising candidates for hardware implementation of artificial synapses - the key components of high-performance, analog neuromorphic networks - due to their excellent scaling prospects. Since some advanced cognitive tasks require spiking neuromorphic networks, which explicitly model individual neural pulses ("spikes") in biological neural systems, it is crucial for memristive synapses to support the spike-time-dependent plasticity (STDP). A major challenge for the STDP implementation is that, in contrast to some simplistic models of the plasticity, the elementary change of a synaptic weight in an artificial hardware synapse depends not only on the pre-synaptic and post-synaptic signals, but also on the initial weight (memristor's conductance) value. Here we experimentally demonstrate, for the first time, an STDP behavior that ensures self-adaptation of the average memristor conductance, making the plasticity stable, i.e. insensitive to the initial state of the devices. The experiments have been carried out with 200-nm Al2O3/TiO2-x memristors integrated into 12 × 12 crossbars. The experimentally observed self-adaptive STDP behavior has been complemented with numerical modeling of weight dynamics in a simple system with a leaky-integrate-and-fire neuron with a random spike-train input, using a compact model of memristor plasticity, fitted for quantitatively correct description of our memristors.

Evidence for a direct action of insulin to increase renal reabsorption of calcium and for an irreversible defect in renal ability to conserve calcium due to prolonged absence of insulin.

Male rats were injected with streptozotocin (STZ), 60 mg/kg, i.p., on 2 successive days. Six hours after the last STZ injection, some STZ-diabetic rats began receiving daily injections of insulin that were insufficient to control blood glucose. Another group of STZ-diabetic rats received insulin injections after 2 wk duration of untreated diabetes. Still other STZ-diabetic rats received no insulin treatment. Under sodium pentobarbital anesthesia, kidneys from each treatment group were isolated and perfused with an artificial "plasma" containing 45Ca. As urine was collected, urine-to-perfusate ultrafiltrate (U/P) ratios for 45Ca were determined. The results of the studies showed that: STZ diabetes reduced 45Ca reabsorption by the kidney; the increased urinary excretion of calcium was not due to an osmotic effect or to a direct nephrotoxic action of STZ; and insulin therapy instituted early, but insufficient to control blood glucose, reduced the diabetes-induced calcium loss via a direct action on the kidney, whereas insulin therapy instituted late failed to reverse renal loss of calcium.

Effectiveness of insulin therapy on altered renal calcium transport in diabetic rats.

The uptake of 45Ca was measured in slices of kidney cortex from normal rats, streptozotocin-diabetic rats, and streptozotocin-diabetic rats treated early and late with insulin. Insulin therapy was performed such that blood glucose levels were controlled in half the treated diabetic animals but not in the others. Considerably earlier than evidence of nephropathy (i.e., proteinuria and increased BUN levels) in streptozotocin-diabetic rats, there was a significant decrease in active uptake of calcium by the kidney. Insulin therapy, begun immediately upon diagnosis of diabetes, maintained normal calcium transport even when blood glucose levels were not controlled. On the other hand, insulin therapy, begun 1 mo after diabetes was confirmed but before evidence of nephropathy, did not restore calcium transport to normal whether or not blood glucose was controlled. We conclude that this biochemical mechanism, which possibly may be implicated in the pathophysiology of diabetic nephropathy, is clearly influenced by duration of insulin deficiency and not by the degree in hyperglycemia.

Time-resolved equatorial X-ray diffraction studies of skinned muscle fibres during stretch and release.

Equatorial X-ray diffraction patterns were recorded from small bundles of one to three chemically skinned frog sartorius muscle fibres (time resolution 250 microseconds) during rapid stretch and subsequent release. In the relaxed state, the dynamic A-band lattice spacing change as a result of a 2 % step stretch (determined from the positions of the 10 and 11 reflections) resulted in a 21 % increase in lattice volume, while static studies of spacing and sarcomere length indicated than an increase in volume of >/=50 % for the same length change. In rigor, stretch caused a lattice volume decrease which was reversed by a subsequent release. In activated fibres (pCa 4.5) exposed to 10 mM 2,3-butanedione 2-monoxime (BDM), stretch was accompanied by a lattice compression exceeding that of constant volume behaviour, but during tension recovery, compression was partially reversed to leave a net spacing change close to that observed in the relaxed fibre. In the relaxed state, spacing changes were correlated with the amplitude of the length step, while in rigor and BDM states, spacing changes correlated more closely with axial force. This behaviour is explicable in terms of two components of radial force, one due to structural constraints as seen in the relaxed state, and an additional component arising from cross-bridge formation. The ratio of axial to radial force for a single thick filament resulting from a length step was four in rigor and BDM, but close to unity for the relaxed state.

Age-induced differentiation of morphine's effect on cyclic nucleotide metabolism.

Male ICR mice, immature (25 days old), mature adult (3 months old) and aged (22 months old), were injected with morphine sulfate (10 mg/kg, SC) or were implanted with morphine pellets (75 mg). Age-matched controls received saline injections or placebo pellets. One hour after injections and 72 hours after pellet implantation (when tolerance to morphine had occurred), the mice were decapitated and the frontal cortex and cerebellum were removed. Basal activities of adenylate cyclase, guanylate cyclase, cyclic AMP phosphodiesterase and cyclic GMP phosphodiesterase were determined in both brain regions. Results showed that there are age- and region-differentiated effects of morphine on these enzymes.

Opiate receptor characteristics in brains from young, mature and aged mice.

Age-related differences in opiate receptors were determined using young (1 month old), mature (3 and 8 months old) and aged (20 months old) mice. 3H-Dihydromorphine binding to mu-receptors in brain synaptic membranes consisted of two components: one with high affinity and one with low affinity. High affinity mu binding sites in membranes from young and aged mice had significantly less receptor densities and higher affinities than the mature mice. In the membranes from aged mouse brain, the affinity of low affinity binding sites for 3H-dihydromorphine was also significantly increased when compared to those in membranes from the 8-month-old group. Membranes from the young and aged groups revealed significantly higher affinity for binding of the kappa ligand, 3H-(-)ethylketocylazocine, than mature mice, which was not accompanied by any change in the density of the receptors. There was no change in either the number or affinity of the binding sites for 3H-(D-Ser2-Leu5)-enkephalinyl-Thr, the delta receptor ligand, among young mature and aged groups.

Hyperkalemic periodic paralysis. Effects of potassium, exercise, glucose, and acetazolamide on blood chemistry.

Effects of strenous exercise, followed by rest, and of potassium administration on blood chemistry values were studied in two patients with hyperkalemic periodic paralysis and in normal volunteers. These procedures produced attacks of flaccid paralysis that occurred concomitantly with rapid rises in serum potassium concentrations and decreases in blood glucose and inorganic phosphate levels. With the exception of the serum potassium level which rose following exercise and potassium administration, there were no changes in the blood chemistry values of the normal volunteers. During the induced attacks of paralysis, the expired breath of the patients had a very strong odor of ketosis. Results of subsequent glucose tolerance tests were abnormal. Following 24 hour administration of acetazolamide, the studies were repeated. The drug appeared to cause lesser effects of stimuli on serum potassium levels and a stabilizing effect on blood glucose levels.

Changes in activities of calmodulin-mediated enzymes in rat brain during aging.

Components of the calmodulin system, (i.e. calmodulin levels and activities of the following calmodulin-dependent enzymes: (Ca2+ + Mg2+)-ATPase, adenylate and guanylate cyclases, cyclic AMP and cyclic GMP phosphodiesterases, and Ca2+-dependent protein kinase) were studied in brains from rats of three different ages: 3 weeks old, 3 months old and 1 year old. With the exception of adenylate cyclase activity, all components measured were found to significantly decrease with increasing age. Adenylate cyclase activity was significantly higher in brains from the 3-month-old rats than in those from 3-week-old rats. Brains from year-old rats had adenylate cyclase activity that was intermediate between the two younger ages and was significantly different from both groups. The study provides evidence for important changes in the activity of this fundamental cell regulatory system in the central nervous system during the aging process.

Effects of maturation and aging on calmodulin and calmodulin-regulated enzymes in various regions of mouse brain.

Components of the calmodulin system (i.e., calmodulin levels and activities of the following calmodulin-dependent enzymes: Ca2+ + Mg2+-ATPase, adenylate and guanylate cyclases, cyclic AMP and cyclic GMP phosphodiesterases, and Ca2+-dependent protein kinase were studied in the following brain regions from immature (25-day-old), mature (3-month-old) and aged (22-month-old) mice: striatum, cortex, cerebellum, diencephalon and medulla + pons. Both maturation and advanced aging were associated with significant changes in calmodulin content and in enzyme activities. The study provides evidence for important changes in the activity of this fundamental cell regulatory system in the brain during the processes of maturation and aging.

Behavioral and neurochemical effects of continuous infusion of cocaine in rats.

The ability of continuous intravenous infusion of cocaine (60 mg/kg per day for 11 or 12 days; by osmotic minipump) to alter responses to acute injection of cocaine (20 mg/kg, i.p.; given 24 hr after termination of the infusion by minipump) was tested in conscious, tethered Sprague-Dawley rats. Extracellular levels of cocaine, dopamine and metabolites of dopamine in the striatum were determined by in vivo microdialysis. Locomotor activity and stereotyped behavior were evaluated simultaneously during dialysis sampling. Prior infusion of cocaine blunted the ability of acute challenge with cocaine to increase the efflux of dopamine in the striatum, locomotor activity and stereotypy. Increases in extracellular levels of homovanillic acid in the striatum were significantly greater in cocaine-infused rats than vehicle-infused controls, both prior to and after acute injections of cocaine. However, no differences between these two groups were observed in levels of cocaine in the striatum after acute challenge. Extracellular levels of dopamine in the striatum correlated significantly (P less than 0.05) with stereotypy in both groups but with locomotor activity only in cocaine-infused rats. The results indicate that behavioral tolerance occurred after continuous intravenous infusions of cocaine, that this was correlated with neurochemical tolerance to acute cocaine challenge and that alterations in the metabolism of cocaine did not account for the observed behavioral responses.

Antagonism of the toxicity of cocaine by MK-801: differential effects in spontaneously hypertensive and Wistar-Kyoto rats.

A putative role for endogenous excitatory amino acid systems in the mediation of the cardiovascular and toxic responses to acute administration of cocaine, was examined in spontaneously hypertensive and normal Wistar-Kyoto rats. Conscious, restrained, male hypertensive and normal rats (12 weeks of age) received either the non-competitive excitatory amino acid receptor antagonist, MK-801 (0.01-10 mg/kg, i.v.) or vehicle, 30 min prior to initiation of infusion of cocaine hydrochloride (1.25 mg/kg min, i.v.). Administration of MK-801 produced increases in mean blood pressure and heart rate in both hypertensive and normal rats. Resting rectal temperature was reduced by MK-801 only at the largest dose tested (10 mg/kg). Infusion of cocaine caused convulsions and death at doses of 27.8 +/- 2.3 and 48.2 +/- 5.7 mg/kg, respectively in the normals, and 21.2 +/- 2.5 (P < 0.05) and 31.1 +/- 3.4 (P < 0.05) in the hypertensive rats. Pretreatment with MK-801 abolished the enhanced sensitivity of the hypertensive rats to the toxicity of cocaine. The doses of cocaine required to cause death were significantly increased, in the hypertensive rats at doses > or = 0.05 mg/kg, an effect which was not evident, at any dose, in the normals. The maximally effective dose of MK-801 (0.5 mg/kg) increased the dose of cocaine required to cause lethality by 272% (P < 0.05) in the hypertensive rats; the increase produced by MK-801 in the normals (163%) was not significant. Cocaine-induced convulsions were abolished in both hypertensive and control rats with doses of MK-801 > 0.1 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective inhibitory effect of organophosphates on UDP-glucuronyl transferase activities in rat liver microsomes.

The effects of acute and subacute administration of diisopropylfluorophosphate (DFP) and acute administration of Soman, Sarin and Tabun on UDP-glucuronyltransferase (GT) activity towards 4-nitrophenol, 4-methylumbelliferone, phenolphthalein and testosterone in rat liver microsomes were investigated. Twenty-four hours after a single injection of DFP, the activity of GT towards 4-nitrophenol and 4-methylumbelliferone was inhibited, and the inhibitory effect continued for 3 days. The activity had recovered by 7 days after injection. The activity of GT towards phenolphthalein and testosterone was not affected at any time after injection. Soman, Sarin and Tabun showed the same effect as DFP after a single injection. After daily DFP injections, the activity of GT towards 4-nitrophenol and 4-methylumbelliferone was decreased to the same level as found following acute treatment with DFP. The in vitro addition of DFP to liver microsomes did not affect GT activity towards 4-nitrophenol. It is suggested that these changes are not due to a direct effect of DFP. Furthermore, the effects of two enzyme inducers on GT activity in the presence and absence of DFP were investigated. In the 3-methylcholanthrene (MC) pretreatment group, DFP inhibited only the GT activity towards 4-nitrophenol and 4-methylumbelliferone. On the other hand, in the phenobarbital (PB) pretreatment group, DFP did not inhibit the GT activity towards 4-nitrophenol and 4-methylumbelliferone. It was also demonstrated that MC pretreatment increased the mortality in the DFP-treated rats but that PB pretreatment suppressed it. These results suggest that DFP and other organophosphorus agents may be useful agents for studies on the heterogeneity of GT.

Enhancement of the rate of GTP hydrolysis in rat brain by repeated kappa-opioid treatment.

To investigate the G protein and protein kinase C (PKC) systems during the initial state of kappa-opioid tolerance, the low Km GTPase and PKC activities were measured following repeated treatment of rat with the kappa-agonist, U-50,488. In behavioral studies, antinociceptive tolerance to U-50,488 was developed following 7-day treatment with U-50,488. Under these conditions, repeated administration of U-50,488 significantly enhanced the basal low Km GTPase activity in the pons/medulla but not in the cortex and midbrain regions. On the other hand, repeated U-50,488 treatment had no effect on PKC activity in cytosol and membrane fractions under the calcium-chelating conditions. These results indicate that repeated administration of kappa-agonist, U-50,488, increases in the basal hydrolysis of GTP to GDP in rat pons/medulla but not PKC activity which was observed in the case of repeated administration with morphine in rats.