Parallel convolutional processing using an integrated photonic tensor core.

With the proliferation of ultrahigh-speed mobile networks and internet-connected devices, along with the rise of artificial intelligence (AI)1, the world is generating exponentially increasing amounts of data that need to be processed in a fast and efficient way. Highly parallelized, fast and scalable hardware is therefore becoming progressively more important2. Here we demonstrate a computationally specific integrated photonic hardware accelerator (tensor core) that is capable of operating at speeds of trillions of multiply-accumulate operations per second (1012 MAC operations per second or tera-MACs per second). The tensor core can be considered as the optical analogue of an application-specific integrated circuit (ASIC). It achieves parallelized photonic in-memory computing using phase-change-material memory arrays and photonic chip-based optical frequency combs (soliton microcombs3). The computation is reduced to measuring the optical transmission of reconfigurable and non-resonant passive components and can operate at a bandwidth exceeding 14 gigahertz, limited only by the speed of the modulators and photodetectors. Given recent advances in hybrid integration of soliton microcombs at microwave line rates3-5, ultralow-loss silicon nitride waveguides6,7, and high-speed on-chip detectors and modulators, our approach provides a path towards full complementary metal-oxide-semiconductor (CMOS) wafer-scale integration of the photonic tensor core. Although we focus on convolutional processing, more generally our results indicate the potential of integrated photonics for parallel, fast, and efficient computational hardware in data-heavy AI applications such as autonomous driving, live video processing, and next-generation cloud computing services.

All-optical spiking neurosynaptic networks with self-learning capabilities.

Software implementations of brain-inspired computing underlie many important computational tasks, from image processing to speech recognition, artificial intelligence and deep learning applications. Yet, unlike real neural tissue, traditional computing architectures physically separate the core computing functions of memory and processing, making fast, efficient and low-energy computing difficult to achieve. To overcome such limitations, an attractive alternative is to design hardware that mimics neurons and synapses. Such hardware, when connected in networks or neuromorphic systems, processes information in a way more analogous to brains. Here we present an all-optical version of such a neurosynaptic system, capable of supervised and unsupervised learning. We exploit wavelength division multiplexing techniques to implement a scalable circuit architecture for photonic neural networks, successfully demonstrating pattern recognition directly in the optical domain. Such photonic neurosynaptic networks promise access to the high speed and high bandwidth inherent to optical systems, thus enabling the direct processing of optical telecommunication and visual data.

A self-resetting spiking phase-change neuron.

Neuromorphic, or brain-inspired, computing applications of phase-change devices have to date concentrated primarily on the implementation of phase-change synapses. However, the so-called accumulation mode of operation inherent in phase-change materials and devices can also be used to mimic the integrative properties of a biological neuron. Here we demonstrate, using physical modelling of nanoscale devices and SPICE modelling of associated circuits, that a single phase-change memory cell integrated into a comparator type circuit can deliver a basic hardware mimic of an integrate-and-fire spiking neuron with self-resetting capabilities. Such phase-change neurons, in combination with phase-change synapses, can potentially open a new route for the realisation of all-phase-change neuromorphic computing.

Memristive effects in oxygenated amorphous carbon nanodevices.

Computing with resistive-switching (memristive) memory devices has shown much recent progress and offers an attractive route to circumvent the von-Neumann bottleneck, i.e. the separation of processing and memory, which limits the performance of conventional computer architectures. Due to their good scalability and nanosecond switching speeds, carbon-based resistive-switching memory devices could play an important role in this respect. However, devices based on elemental carbon, such as tetrahedral amorphous carbon or ta-C, typically suffer from a low cycling endurance. A material that has proven to be capable of combining the advantages of elemental carbon-based memories with simple fabrication methods and good endurance performance for binary memory applications is oxygenated amorphous carbon, or a-CO x . Here, we examine the memristive capabilities of nanoscale a-CO x devices, in particular their ability to provide the multilevel and accumulation properties that underpin computing type applications. We show the successful operation of nanoscale a-CO x memory cells for both the storage of multilevel states (here 3-level) and for the provision of an arithmetic accumulator. We implement a base-16, or hexadecimal, accumulator and show how such a device can carry out hexadecimal arithmetic and simultaneously store the computed result in the self-same a-CO x cell, all using fast (sub-10 ns) and low-energy (sub-pJ) input pulses.

Genome-wide Scan of Dental Fear and Anxiety Nominates Novel Genes.

Dental care-related fear and anxiety (DFA) is prevalent, affects oral health care utilization, and is related to poor oral health and decreased quality of life. In addition to learned and cultural factors, genetics is hypothesized to contribute to DFA. Therefore, we performed a genome-wide association study to identify genetic variants contributing to DFA. Adult and adolescent participants were from 4 cohorts (3 from the US-based Center for Oral Health Research in Appalachia, n = 1,144, 1,164, and 535, and the UK-based Avon Longitudinal Study of Parents and Children [ALSPAC], n = 2,078). Two self-report instruments were used to assess DFA: the Dental Fear Survey (US cohorts) and Corah's Dental Anxiety Scale (ALSPAC). Genome-wide scans were performed for the DFA total scores and subscale scores (avoidance, physiological arousal, fear of dental treatment-specific stimuli), adjusting for age, sex, educational attainment, recruitment site, and genetic ancestry. Results across cohorts were combined using meta-analysis. Heritability estimates for DFA total and subscale scores were similar across cohorts and ranged from 23% to 59%. The meta-analysis revealed 3 significant (P < 5E-8) associations between genetic loci and 2 DFA subscales: physiological arousal and avoidance. Nearby genes included NTSR1 (P = 3.05E-8), DMRTA1 (P = 4.40E-8), and FAM84A (P = 7.72E-9). Of these, NTSR1, which was associated with the avoidance subscale, mediates neurotensin function, and its deficiency may lead to altered fear memory in mice. Gene enrichment analyses indicated that loci associated with the DFA total score and physiological arousal subscale score were enriched for genes associated with severe and persistent mental health (e.g., schizophrenia) and neurocognitive (e.g., autism) disorders. Heritability analysis indicated that DFA is partly explained by genetic factors, and our association results suggested shared genetic underpinnings with other psychological conditions.

Localized electro-thermal processing: a new route to the patterning of magnetic recording media.

Previous reports have detailed the fabrication of media able to support high density magnetic recording in both longitudinal and perpendicular formats by the global rapid thermal processing of sputtered non-magnetic precursor films. During processing in this manner a magnetic element is released from its nitride and agglomerates to form a random near mono-dispersion of magnetic nano-particles. Here we explore, primarily through modelling and simulation, the feasibility of processing similarly formulated precursor media not globally but locally. We investigate the potential of using conducting nano-probe tips to produce, via electro-thermal (Joule) heating, a nano-patterned recording medium in the form of regular arrays of magnetic islands in a non-magnetic host. In the first instance we concentrate on the simplest cobalt based precursor medium for which both initial simulation and experimental studies indicate the formation of magnetic islands with dimensions of the order of the tip diameter; this is relatively straightforward. The results signify that if practical production scenarios can be devised to produce technologically significant areas of recording media by the rapid multi-probe repetition of this technique, then processing in this manner offers a promising route to areal recording densities of perhaps 5 Terabit/in(2) even with the simplest cobalt media. We also note that the electro-thermal processing method is potentially extendable to the production of a wide variety of magnetic materials (e.g. PtCo, FeCo, NiFe alloys) and, applied via electrical nano-imprinting type techniques, to the production of a wide variety of patterned structures.

A new forest dwelling button spider from South Africa (Araneae, Theridiidae, Latrodectus).

The medically important spider genus Latrodectus Walckenaer 1805, commonly referred to as "button spiders" in South Africa, is represented by six species in the country. Using morphology and the COI barcoding gene we describe a new forest dwelling species, Latrodectus umbukwane n. sp. Wright, Wright, Lyle and Engelbrecht. Females have red markings on both the ventral and posterior dorsal surfaces of the abdomen, parallel spermathecae and three loops of the copulatory ducts. Males have an embolus with four loops and diagnostic white markings on the ventral surface of the abdomen that darken with age. Egg sacs are smooth, large, and bright purple when freshly laid, turning shiny grey with time. Latrodectus umbukwane n. sp. is known only from sand forest vegetation types in northern Zululand, KwaZulu-Natal, South Africa. A predicted geographic distribution for this species is provided based on cartographic mapping of known habitat and altitudinal preference, from which area of occupancy (AOO; 698 km2) and extent of occurrence (EOO; 4963 km2) were calculated to assess potential IUCN Red List status. Due to the uncertainty of the distribution of this species, a Red List status of Data Deficient (DD) is recommended. An updated key to the southern African species of Latrodectus is provided.

The effect of secretory leukocyte protease inhibitor (SLPI) on ischemia/reperfusion injury in cardiac transplantation.

We investigated the role of secretory leukocyte protease inhibitor (SLPI) in ischemia/reperfusion injury in cardiac transplantation. SLPI-/- mouse hearts and wild-type (WT) controls were transplanted immediately or after 10 h of cold ischemia (CI). Recombinant SLPI (rSLPI) was added to the preservation solution or given systemically. After evaluation of myocardial performance, grafts were investigated for histology, SLPI, TNF-alpha, TGF-beta, NF-kappaB and protease expression at indicated time points. Early myocardial contraction was profoundly impaired in SLPI-/- hearts exposed to CI and associated with high intra-graft protease expression. Systemic administration of rSLPI had no effect, however, when SLPI was added to the preservation solution, myocardial contraction was restored to normal. At 10 days, inflammation, myocyte vacuolization and necrosis were significantly more severe in SLPI-/- hearts. SLPI gene expression was detected in WT mice at 12 and 24 h and was significantly higher after CI. SLPI protein was observed at 24 h and 10 days. High intra-graft concentrations of SLPI after administration of rSLPI were inversely correlated with protease levels early and TGF-beta expression late after reperfusion. SLPI plays a crucial role in early myocardial performance and postischemic inflammation after cardiac transplantation. A dual inhibitory effect on protease and TGF-beta expression might be the underlying mechanism.

New routes to the functionalization patterning and manufacture of graphene-based materials for biomedical applications.

Graphene-based materials are being widely explored for a range of biomedical applications, from targeted drug delivery to biosensing, bioimaging and use for antibacterial treatments, to name but a few. In many such applications, it is not graphene itself that is used as the active agent, but one of its chemically functionalized forms. The type of chemical species used for functionalization will play a key role in determining the utility of any graphene-based device in any particular biomedical application, because this determines to a large part its physical, chemical, electrical and optical interactions. However, other factors will also be important in determining the eventual uptake of graphene-based biomedical technologies, in particular the ease and cost of manufacture of proposed device and system designs. In this work, we describe three novel routes for the chemical functionalization of graphene using oxygen, iron chloride and fluorine. We also introduce novel in situ methods for controlling and patterning such functionalization on the micro- and nanoscales. Our approaches are readily transferable to large-scale manufacturing, potentially paving the way for the eventual cost-effective production of functionalized graphene-based materials, devices and systems for a range of important biomedical applications.

Fear of Pain Questionnaire-9: Brief assessment of pain-related fear and anxiety.

BACKGROUND: Fear and anxiety are important considerations in both acute and chronic pain. Effectively and efficiently measuring fear and anxiety associated with pain in healthcare settings is critical for identifying vulnerable patients. The length and administration time of current measures of pain-related fear and anxiety inhibit their routine use, as screening tools and otherwise, suggesting the need for a shorter, more efficient instrument. METHODS: A 9-item shortened version of the Fear of Pain Questionnaire - III (FPQ-III), the Fear of Pain Questionnaire-9 (FPQ-9), was developed based upon statistical analyses of archival data from 275 outpatients with chronic pain and 275 undergraduates. Additionally, new data were collected from 100 outpatients with chronic pain and 190 undergraduates to directly compare the standard and short forms. Exploratory and confirmatory factor analyses, and other psychometric analyses, were conducted to examine and establish the FPQ-9 as a reliable and valid instrument. RESULTS: The original three-factor structure of the FPQ-III was retained in the shortened version; a confirmatory factor analysis produced good model fit (RMSEA = 0.00, CFI = 1.00, TLI = 1.00, SRMR = 0.03). Results suggested a high degree of correlation between the original FPQ-III and the new FPQ-9 (r = 0.77, p < 0.001). Measures of internal consistency for FPQ-9 subscales were high; correlations with other pain and anxiety instruments suggested concurrent, convergent and divergent validity. CONCLUSIONS: The FPQ-9 is a psychometrically sound alternative to longer instruments assessing fear and anxiety associated with pain, for use in both clinical and research situations that only allow brief screening. SIGNIFICANCE: The FPQ-9 has considerable potential for dissemination and utility for routine, brief screening, given its length (completion time ~2 min; scoring time ~1 min), reading level and psychometric properties.

Calculating with light using a chip-scale all-optical abacus.

Machines that simultaneously process and store multistate data at one and the same location can provide a new class of fast, powerful and efficient general-purpose computers. We demonstrate the central element of an all-optical calculator, a photonic abacus, which provides multistate compute-and-store operation by integrating functional phase-change materials with nanophotonic chips. With picosecond optical pulses we perform the fundamental arithmetic operations of addition, subtraction, multiplication, and division, including a carryover into multiple cells. This basic processing unit is embedded into a scalable phase-change photonic network and addressed optically through a two-pulse random access scheme. Our framework provides first steps towards light-based non-von Neumann arithmetic.

PEA3, Oct 1 and Oct 2 positively regulate the human ETS1 promoter.

The promoter of the human ETS1 gene contains binding site motifs for transcription factors Sp1, Ap1, Ap2, ETS, PEA3 and Oct. It has been shown previously that Ap1, Ap2, and ETS are positive regulators for the transcription of the ETS1 gene and that the ETS1 gene is autoregulated. In addition, two regions on the ETS1 promoter that contain negative regulatory sequences have also been identified. In this study, GST/PEA3 and GST/ets1 fusion proteins were used in gel mobility assays to analyse the interaction between these transcription factors with the binding motifs of PEA3 and ETS in the ETS1 promoter. Promoter constructs in which the binding site motifs are mutated were used to examine the effect of mutation on the activities of transcription factors PEA3, ets1 and Oct. Reporter plasmids containing different deletion mutants of the ETS1 promoter were used to examine the effect of different transcription factors (PEA3, Oct 1 and Oct 2) upon the expression of the ETS1 gene. The results of these studies indicate that PEA3 is a strong positive regulator of the ETS1 promoter and that other transcription factors increase the activity of the ETS1 promoter in an additive rather than synergistic fashion.

Thymoma: state of the art.

Thymoma is the most common tumor of the anterior mediastinum. This tumor is associated with unique paraneoplastic syndromes, such as myasthenia gravis, hypogammaglobulinemia, and pure red cell aplasia. The rarity of this tumor, however, has somewhat obscured the optimal treatment for this disease. For the majority of patients who present with localized tumor, surgical extirpation remains the standard of choice. Adjuvant radiotherapy seems to improve local control and survival. In more advanced disease, systemic therapy has been demonstrated to produce a 50% to 80% objective response rate. These observations have led to the development of multimodality therapy for the treatment of patients with advanced thymoma. In this article, we will review the current perspectives on the management of early stage and advanced thymoma.

Regulation of polymorphonuclear leukocyte membrane fluidity: effect of cytoskeletal modification.

We previously demonstrated that the f-actin cytoskeleton modulates oxygen radical production associated with polymorphonuclear leukocyte (PMN) oxidative burst activity. Given the close association of the actin and microtubule cytoskeletons with the plasma membrane and the transmembrane location of the PMN NADPH oxidase, it is likely cytoskeletal change may affect PMN membrane responses, such as cellular anisotropy. Changes in PMN membrane fluidity were therefore examined after PMN activation by the chemoattractant N-formyl-1-methionyl-1-leucyl-1-phenylalanine (fMLP) in the presence or absence of phalloidin or cytochalasin B (CB), agents that stabilize and disrupt f-actin, or taxol and vincristine, which stabilize and disrupt microtubules, respectively. Phalloidin and taxol treatment of PMN significantly decreased whereas CB and vincristine significantly increased membrane fluidity. Activation of PMN by fMLP (10(-6) M) resulted in a significant increase in membrane fluidity that was attenuated by PMN pretreatment with phalloidin or taxol. CB and vincristine pretreatment of PMN did not alter the fMLP response. These data suggest that stabilization of the f-actin or microtubule cytoskeleton may prevent increases in cellular membrane fluidity associated with PMN activation.

Inhibition of human neutrophil activation by the allergic mediator release inhibitor, CI-922: differential inhibition of responses to a variety of stimuli.

The allergic mediator release inhibitor 3,7-dimethoxy-4-phenyl-N-1H-tetrazol-5-yl-4H-furo[3,2-b]indole-2- carboxamide, L-arginate (CI-922) is a potent inhibitor of human neutrophil functions in vitro. Over a concentration range from 1 to 100 mumol CI-922 inhibits the chemotactic response of neutrophils to the synthetic chemotaxin N-formyl-methionyl-leucyl-phenylalanine (FMLP). CI-922 also inhibits respiratory and secretory responses of neutrophils in response to agents that stimulate phospholipase C-dependent phosphoinositide hydrolysis to generate the second messengers inositol 1,4,5, trisphosphate and 1,2 diacylglycerol, including: the plasma membrane receptor-specific ligands FMLP and C5a; serum-opsonized zymosan; concanavalin A; and the guanine nucleotide regulatory protein-specific stimulus guanosine-5'-0-(3-thiotriphosphate) (GTP gamma S). CI-922 also inhibits neutrophil functions stimulated by the calcium ionophore A23187. In contrast, CI-922 does not inhibit neutrophil responses to protein kinase C-specific stimuli such as phorbol 12-myristate 13-acetate (PMA) or L-alpha-1,2 dioctanoylglycerol (DiC8). CI-922 also fails to inhibit the synergistic activation of the respiratory burst by suboptimal concentrations of PMA and calcium ionophore A23187. The observation that CI-922 inhibits neutrophil responses to a variety of soluble and particulate stimuli, excluding protein kinase C-specific stimuli, allows us to postulate the site of action of the compound. We propose that CI-922 inhibits neutrophil activation at a site distal to signal transduction through the guanine nucleotide regulatory protein required for second messenger generation but proximal to phosphorylation reactions mediated by protein kinase C and calmodulin-dependent protein kinases.

Inhibition of human neutrophil activation by the allergic mediator release inhibitor, CI-949.

The allergic mediator release inhibitor Cl-949 [5-methoxy-3-(1-methylethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H -indole-2-carboxamide, L-arginine salt] was evaluated for its effects on human neutrophil functions. Cl-949 (100 microM) inhibited spontaneous migration and chemotaxis toward f-met-leu-phe (FMLP) by 49.1% and 45.8%, respectively. At the same concentration, Cl-949 inhibited the phagocytosis of serum-opsonized zymosan (SOZ) by 39.0%. Cl-949 inhibited leukotriene B4 and thromboxane B2 release in response to SOZ with IC50s of 2.0 microM and 3.3 microM, while inhibiting the response to FMLP with IC50s of 1.7 and 2.0 microM. Cl-949 also inhibited myeloperoxidase release from primary lysosomal granules in response to the following stimuli with the respective IC50s (microM): C5a (40.3); FMLP (34.4): SOZ (21.4); concanavalin A (Con A) 3.9); and calcium ionophore A23187 (91.2). In contrast, Cl-949 inhibited lysozyme release from secondary granules in response to SOZ and Con A with IC50s of 99.3 and 56.1 microM, while inhibiting the response to C5a, FMLP, and A23187 by 41.2%, 52.4%, and 10.0%, respectively, at 100 microM. Cl-949 (100 microM) had no inhibitory effect against lysozyme release in response to L-alpha-1,2 dioctanoylglycerol (DiC8), or phorbol 12-myristate 13-acetate (PMA). Cl-949 inhibited superoxide anion generation stimulated by FMLP and Con A with IC50s of 33.9 and 25.8 microM, while inhibiting the response to C5a, SOZ, and A23187 by 36.6%, 24.8%, and 14.1% and having no effect on the response to DiC8 or PMA at 100 microM. These results demonstrate preferential inhibition of arachidonic acid metabolism and degranulation of primary lysosomal granules by Cl-949 with selectivity for stimuli which promote intracellular calcium mobilization or calcium influx.

Selective regulation of human neutrophil functions by the cell activation inhibitor CI-959.

The cell activation inhibitor CI-959 [5-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-ylbenzo[ b]thiophene-2- carboxamide, monosodium salt] was evaluated for its effects on human neutrophil functions. CI-959 inhibited spontaneous migration and chemotaxis toward N-formyl-methionyl-L-leucyl-L-phenylalanine (fMLP) with 50% inhibition (IC50) values of 3.6 and 3.1 microM, respectively. CI-959 also inhibited superoxide anion generation in response to C5a, fMLP, serum-opsonized zymosan (SOZ), concanavalin A (Con A), and calcium ionophore A23187 with IC50 values of 2.5, 4.7, 14.5, 5.4, and 14.8 microM, respectively. In comparison, CI-959 inhibited myeloperoxidase microM, respectively. In comparison, CI-959 inhibited myeloperoxidase release in response to C5a, fMLP, SOZ, and Con A with IC50 values of 11.6, 16.1, 7.5, and < 1.0 microM, respectively, while inhibiting the response to A23187 by only 5.5% at 100 microM. At concentrations up to 100 microM, CI-959 had no effect on the respiratory burst or degranulation in response to L-alpha-1,2-dioctanoylglycerol (DiC8) or phorbol 12-myristate 13-acetate (PMA). In addition, the compound inhibited leukotriene B4 release stimulated by fMLP and SOZ (IC50 values 4.0 and 2.5 microM, respectively), while having less activity against the A23187-stimulated response (IC50 > 100 microM). These results demonstrate that CI-959 inhibits cellular responses to stimuli that mobilize intracellular calcium. For cellular responses to inophore-mediated calcium influx, only oxygen radical production was inhibited by CI-959. CI-959 was further evaluated for its effects on neutrophil stimulus-response coupling. At 100 microM, CI-959 had no effect on human neutrophil phospholipase C or protein kinase C. CI-959 inhibited fMLP-stimulated intracellular calcium mobilization and calcium influx with IC50 values of 16.7 and 3.1 microM, respectively, and exhibited less potent calmodulin antagonist activity (IC50 = 90.5 microM). These results indicate that CI-959 may exert its stimulus- and response-specific inhibitory effects on neutrophil functions, in part, through inhibition of calcium-regulated signalling mechanisms.

Master-equation approach to the study of phase-change processes in data storage media.

We study the dynamics of crystallization in phase-change materials using a master-equation approach in which the state of the crystallizing material is described by a cluster size distribution function. A model is developed using the thermodynamics of the processes involved and representing the clusters of size two and greater as a continuum but clusters of size one (monomers) as a separate equation. We present some partial analytical results for the isothermal case and for large cluster sizes, but principally we use numerical simulations to investigate the model. We obtain results that are in good agreement with experimental data and the model appears to be useful for the fast simulation of reading and writing processes in phase-change optical and electrical memories.

Esophageal cancer surgery in 2005.

Surgery for esophageal cancer remains a cornerstone for early stage disease. The treatment of more advanced locoregional disease is quite controversial. Efforts to improve survival in more advanced stages include using chemoradiotherapy alone without operation, using induction or adjuvant therapy in conjunction with resection, and performing a more radical resection by an en-bloc approach and/or a three-field lymph node dissection. The actual approach to esophagectomy in an individual patient is very controversial and seems to be mostly surgeon and institution dependent. There is a paucity of large, adequately powered randomized clinical trials to guide surgical care of patients with esophageal cancer. Accordingly, the numerous aspects of care of the patient are quite varied with little consensus reached among surgeons. There is increasing evidence that the care of the patient requiring an esophagectomy be performed in an institution and by a surgeon with a relatively high volume.