Synaptic metaplasticity with multi-level memristive devices

Deep learning has made remarkable progress in various tasks, surpassing human performance in some cases. However, one drawback of neural networks is catastrophic forgetting, where a network trained on one task forgets the solution when learning a new one. To address this issue, recent works have proposed solutions based on Binarized Neural Networks (BNNs) incorporating metaplasticity. In this work, we extend this solution to quantized neural networks (QNNs) and present a memristor-based hardware solution for implementing metaplasticity during both inference and training. We propose a hardware architecture that integrates quantized weights in memristor devices programmed in an analog multi-level fashion with a digital processing unit for high-precision metaplastic storage. We validated our approach using a combined software framework and memristor based crossbar array for in-memory computing fabricated in 130 nm CMOS technology. Our experimental results show that a two-layer perceptron achieves 97% and 86% accuracy on consecutive training of MNIST and Fashion-MNIST, equal to software baseline. This result demonstrates immunity to catastrophic forgetting and the resilience to analog device imperfections of the proposed solution. Moreover, our architecture is compatible with the memristor limited endurance and has a 15× reduction in memory footprint compared to the binarized neural network case

Nano Electro Mechanical Devices for Physical and Chemical Sensing

The emergence of MEMS in consumer applications has dramatically increased market perspectives but also puts very strong constraints on cost and integration issues. Addressing these issues through further size reduction is not always relevant as it does not allow maintaining a correct signal to noise ratio (SNR) for the ubiquitous capacitive MEMS sensors. Different solutions are presented here according to the nature of the signal to be sensed: For physical sensors a new concept mixing a micron sized proof mass and a nano-sized detection structure is described. For chemical sensors, the reduction in size actually presents some advantages in terms of high resonant frequency, reduced gas damping, and high sensitivity to applied forces or added mass. Application of nano-resonators to gaz sensing is depicted. Developed originally at the end of the 80's, Micro Electro Mechanical Systems (MEMS) have by now given rise to a mature industry generating this year almost a 10 billion US$ turnover: Silicon micromachining techniques made possible the realisation of ultra-miniature and low cost sensors that allowed the deployment of airbags in cars (MEMS accelerometers are used there to measure the deceleration related to an accident), and more recently, new functions in smart phones. This deployment in large volume applications has triggered interest from large semiconductor industries (STM, TI, Freescale…) and a strong competition towards lower cost and higher integration: The new Grail of the industry is the realization of a 9 Degrees of Freedom sensor, combining the measurement in the 3 directions of space of acceleration, rotation speed and earth magnetic field. As inspired by the semiconductor industry, an obvious answer to these needs is to further decrease the size of the sensors, from Micro to Nano Electro Mechanical Systems (NEMS). However, even taking apart the technological challenges, this is not that simple as physics laws are not always in favour of scaling down: A simple homothetic size reduction does not allow maintaining a correct signal to noise ratio (SNR). As it will be seen here, different types of sensors require different approaches. Nano size detection for physical sensors. As mentioned before, inertial sensors are becoming one of the most ubiquitous sensor today, with applications in industrial, automotive or consumer applications. Further miniaturization is highly sought, as it allows both to decrease the cost (proportional to the surface of silicon) and increase integration (mandatory in portable applications such as smartphones, tablets…). However simple reduction of the seismic mass affects the sensitivity and reduces the nominal capacitance (95% of commercial MEM

Change Is in the Air: The Hypoxic Induction of Phenotype Switching in Melanoma

Melanoma cells can switch from a highly proliferative, less invasive state to a highly invasive, less proliferative state, a phenomenon termed phenotype switching. This results in a highly heterogenous tumor, where a slow-growing, aggressive population of cells may resist tumor therapy, and it predicts tumor recurrence. Here we discuss the observation made by Widmer et al. that hypoxia may drive phenotype switching

Expanding the Repertoire of Natural Product-Inspired Ring Pairs for Molecular Recognition of DNA

A furan amino acid, inspired by the recently discovered proximicin natural products, was incorporated into the scaffold of a DNA-binding hairpin polyamide. While unpaired oligomers of 2,4-disubstituted furan amino acids show poor DNA-binding activity, furan (Fn) carboxamides paired with N-methylpyrrole (Py) and N-methylimidazole (Im) rings demonstrate excellent stabilization of duplex DNA as well as discrimination of noncognate sequences, consistent with function as a Py mimic according to the Py/Im polyamide pairing rules

Inkjet Metrology: High-Accuracy Mass Measurements of Microdroplets Produced by a Drop-on-Demand Dispenser

We describe gravimetric methods for measuring the mass of droplets generated by a drop-on-demand (DOD) microdispenser. Droplets are deposited, either continuously at a known frequency or as a burst of known number, into a cylinder positioned on a submicrogram balance. Mass measurements are acquired precisely by computer, and results are corrected for evaporation. Capabilities are demonstrated using isobutyl alcohol droplets. For ejection rates greater than 100 Hz, the repeatability of droplet mass measurements was 0.2%, while the combined relative standard uncertainty (uc) was 0.9%. When bursts of droplets were dispensed, the limit of quantitation was 72 μg (1490 droplets) with uc = 1.0%. Individual droplet size in a burst was evaluated by high-speed videography. Diameters were consistent from the tenth droplet onward, and the mass of an individual droplet was best estimated by the average droplet mass with a combined uncertainty of about 1%. Diameters of the first several droplets were anomalous, but their contribution was accounted for when dispensing bursts. Above the limits of quantitation, the gravimetric methods provided statistically equivalent results and permit detailed study of operational factors that influence droplet mass during dispensing, including the development of reliable microassays and standard materials using DOD technologies

Identification of a Novel Topoisomerase Inhibitor Effective in Cells Overexpressing Drug Efflux Transporters

BACKGROUND:Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology. METHOD AND FINDINGS:A library of natural products (NCI Natural Product set) was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine), an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo. CONCLUSIONS:The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids

A Unique Carrier for Delivery of Therapeutic Compounds beyond the Blood-Brain Barrier

BACKGROUND: Therapeutic intervention in many neurological diseases is thwarted by the physical obstacle formed by the blood-brain barrier (BBB) that excludes most drugs from entering the brain from the blood. Thus, identifying efficacious modes of drug delivery to the brain remains a "holy grail" in molecular medicine and nanobiotechnology. Brain capillaries, that comprise the BBB, possess an endogenous receptor that ferries an iron-transport protein, termed p97 (melanotransferrin), across the BBB. Here, we explored the hypothesis that therapeutic drugs "piggybacked" as conjugates of p97 can be shuttled across the BBB for treatment of otherwise inoperable brain tumors. APPROACH: Human p97 was covalently linked with the chemotherapeutic agents paclitaxel (PTAX) or adriamycin (ADR) and following intravenous injection, measured their penetration into brain tissue and other organs using radiolabeled and fluorescent derivatives of the drugs. In order to establish efficacy of the conjugates, we used nude mouse models to assess p97-drug conjugate activity towards glioma and mammary tumors growing subcutaneously compared to those growing intracranially. PRINCIPAL FINDINGS: Bolus-injected p97-drug conjugates and unconjugated p97 traversed brain capillary endothelium within a few minutes and accumulated to 1-2% of the injected by 24 hours. Brain delivery with p97-drug conjugates was quantitatively 10 fold higher than with free drug controls. Furthermore, both free-ADR and p97-ADR conjugates equally inhibited the subcutaneous growth of gliomas growing outside the brain. Evocatively, only p97-ADR conjugates significantly prolonged the survival of animals bearing intracranial gliomas or mammary tumors when compared to similar cumulated doses of free-ADR. SIGNIFICANCE: This study provides the initial proof of concept for p97 as a carrier capable of shuttling therapeutic levels of drugs from the blood to the brain for the treatment of neurological disorders, including classes of resident and metastatic brain tumors. It may be prudent, therefore, to consider implementation of this novel delivery platform in various clinical settings for therapeutic intervention in acute and chronic neurological diseases