Does Epileptiform Activity Represent a Failure of Neuromodulation to Control Central Pattern Generator-Like Neocortical Behavior?

Rhythmic motor patterns in invertebrates are often driven by specialized "central pattern generators" (CPGs), containing small numbers of neurons, which are likely to be "identifiable" in one individual compared with another. The dynamics of any particular CPG lies under the control of modulatory substances, amines, or peptides, entering the CPG from outside it, or released by internal constituent neurons; consequently, a particular CPG can generate a given rhythm at different frequencies and amplitudes, and perhaps even generate a repertoire of distinctive patterns. The mechanisms exploited by neuromodulators in this respect are manifold: Intrinsic conductances (e.g., calcium, potassium channels), conductance state of postsynaptic receptors, degree of plasticity, and magnitude and kinetics of transmitter release can all be affected. The CPG concept has been generalized to vertebrate motor pattern generating circuits (e.g., for locomotion), which may contain large numbers of neurons - a construct that is sensible, if there is enough redundancy: that is, the large number of neurons consists of only a small number of classes, and the cells within any one class act stereotypically. Here we suggest that CPG and modulator ideas may also help to understand cortical oscillations, normal ones, and particularly transition to epileptiform pathology. Furthermore, in the case illustrated, the mechanism of the transition appears to be an exaggerated form of a normal modulatory action used to influence sensory processing

Leakage Current Mechanisms in SiGe HBTs Fabricated Using Selective and Nonselective Epitaxy

SiGe heterojunction bipolar transistors (HTBs) have been fabricated using selective epitaxy for the Si collector, followed in the same growth step by nonselective epitaxy for the p+ SiGe base and n-Si emitter cap. DC electrical characteristics are compared with cross-section TEM images to identify the mechanisms and origins of leakage currents associated with the epitaxy in two different types of transistor . In the first type, the polysilicon emitter is smaller than the collector active area, so that the extrinsic base implant penetrates into the single-crystal Si and SiGe around the perimeter of the emitter and the polycrystalline Si and SiGe exrtrinsic base. In these transistors, the Bummel plots are near-ideal and there is no evidence of emitter/collector leakage. In the second type, the collector active area is smaller than the polysilicon emitter, so the extrinsic base implant only penetrates into the polysilicon extrinsic base. In these transistors, the leakage currents observed depend on the base doping level. In transistors with a low doped base, emitter/collector and emitter/base leakage is observed, whereas in transistors with a high doped base only emitter/base leakage is observed. The emitter/collector leakage is explained by punch through o fhte base caused by thinning of the SiGe base at the emitter perimeter. The emitter/base leakeage is shown to be due to Poole-Frenkel mechanism and is explained by penetration of the emitter/base depletion region into the p+ polysilicon extrinsic base at the emitter periphery. Variable collector/base reverse leakage currents are observed and a variety of mechanisms are observed, including Shockley-Read-Hall recombination, trap assisted tunneling, Poole Frenkel and band to band tunneling. These result s are explained by the presence of polysilicon grains on the sidewalls of the field oxide at the collector perimeter

Raman spectroscopy and X‐ray diffraction responses when measuring health‐related micrometre and nanometre particle size fractions of crystalline quartz and the measurement of quartz in dust samples from the cutting and polishing of natural and artificial stones

Abstract: Around 560 000 workers in Great Britain are potentially exposed to respirable crystalline silica (RCS), which can cause disabling diseases, such as silicosis and lung cancer. These experiments assessed the performance of a new Raman spectroscopy method for measuring RCS, in samples of pure quartz powder with different median aerodynamic particle diameters and stone dusts from variety of natural and artificial stones. The relationship between the Raman response and particle size was characterised by measuring subfractions of the respirable quartz standard A9950 collected using the Sioutas impactor. Bulk samples of quartz standards A9950 and Quin B that provided the highest median particle size diameters were also measured. Health‐related thoracic and respirable particle size fractions, and the environmental monitoring fractions of PM10, PM2.5, PM1 and PM0.5, were also collected during the powered cutting and polishing of sandstone and diorite (granite), engineered and sintered stones. All Raman spectroscopy results were compared with those from X‐ray diffraction (XRD), which was used as the reference technique. The Raman spectroscopy response closely followed the predicted crystallinity of RCS for different particle diameters. Raman spectroscopy obtained slightly higher percentages than XRD for particle size fractions below 1 μm. The Raman spectroscopy and XRD results were highly correlated for the thoracic, respirable and impactor fractions. The coefficients of determination were between 0.98 and 0.95. The slope coefficients for the correlation were 1.11 for the respirable fraction and 1.07 for the thoracic fraction. Raman spectroscopy is a promising alternative to XRD for measurement of RCS with a much lower limit of detection of 0.21 μg compared with 1 μg

Sea level fall during glaciation stabilized atmospheric CO2 by enhanced volcanic degassing

Paleo-climate records and geodynamic modelling indicate the existence of complex interactions between glacial sea level changes, volcanic degassing and atmospheric CO2, which may have modulated the climate system’s descent into the last ice age. Between ∼85 and 70 kyr ago, during an interval of decreasing axial tilt, the orbital component in global temperature records gradually declined, while atmospheric CO2, instead of continuing its long-term correlation with Antarctic temperature, remained relatively stable. Here, based on novel global geodynamic models and the joint interpretation of paleo-proxy data as well as biogeochemical simulations, we show that a sea level fall in this interval caused enhanced pressure-release melting in the uppermost mantle, which may have induced a surge in magma and CO2 fluxes from mid-ocean ridges and oceanic hotspot volcanoes. Our results reveal a hitherto unrecognized negative feedback between glaciation and atmospheric CO2 predominantly controlled by marine volcanism on multi-millennial timescales of ∼5,000–15,000 years

Recent developments in vertical MOSFETs and SiGe HBTs, Journal of Telecommunications and Information Technology, 2004, nr 1

There is a well recognised need to introduce new materials and device architectures to Si technology to achieve the objectives set by the international roadmap. This paper summarises our work in two areas: vertical MOSFETs, which can allow increased current drive per unit area of Si chip and SiGe HBT's in silicon-on-insulator technology, which bring together and promise to extend the very high frequency performance of SiGe HBT's with SOI-CMOS

Tofacitinib, an oral janus kinase inhibitor: pooled efficacy and safety analyses in an Australian rheumatoid arthritis population

In Australia, there is an unmet need for improved treatments for rheumatoid arthritis (RA). Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. To provide an overview of key study outcomes for tofacitinib in Australian patients, we analyzed the efficacy and safety of tofacitinib in the Australian subpopulation of global RA phase III and long-term extension (LTE) studies. Data were pooled from the Australian subpopulation of four phase III studies and one LTE study (database not locked at cut-off date: January 2016). Patients in the phase III studies received tofacitinib 5 or 10 mg twice daily (BID), placebo (advancing to tofacitinib at months 3 or 6), or adalimumab, with background methotrexate or conventional synthetic disease-modifying antirheumatic drugs. Patients in the LTE study received tofacitinib 5 or 10 mg BID. Efficacy endpoints were American College of Rheumatology (ACR) 20/50/70 response rates, and change from baseline in the Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)] and Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Safety endpoints included incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs. AEs of special interest and laboratory parameters were analyzed in the LTE study. Across phase III studies (N = 100), ACR response rates and improvements in DAS28-4(ESR) and HAQ-DI scores were numerically greater with tofacitinib vs. placebo at month 3, and increased until month 12. The results were sustained in the LTE study (N = 99) after 60 months' observation. In general, the efficacy and safety profiles of tofacitinib were similar to those of the global RA population. In Australian patients with RA, tofacitinib therapy demonstrated sustained efficacy and consistent safety over ae 60 months' treatment. Pfizer Inc. NCT00960440; NCT00847613; NCT00856544; NCT00853385; NCT00413699

The putative mevalonate diphosphate decarboxylase from Picrophilus torridus is in reality a mevalonate-3-kinase with high potential for bioproduction of isobutene

Mevalonate diphosphate decarboxylase (MVD) is an ATP-dependent enzyme that catalyzes the phosphorylation/decarboxylation of (R)-mevalonate-5-diphosphate to isopentenyl pyrophosphate in the mevalonate (MVA) pathway.MVD is a key enzyme in engineered metabolic pathways for bioproduction of isobutene, since it catalyzes the conversion of 3-hydroxyisovalerate (3-HIV) to isobutene, an important platform chemical. The putative homologue from Picrophilus torridus has been identified as a highly efficient variant in a number of patents, but its detailed characterization has not been reported. In this study, we have successfully purified and characterized the putative MVD from P. torridus. We discovered that it is not a decarboxylase per se but an ATP-dependent enzyme, mevalonate-3-kinase (M3K), which catalyzes the phosphorylation of MVA to mevalonate-3-phosphate. The enzyme’s potential in isobutene formation is due to the conversion of 3-HIV to an unstable 3-phosphate intermediate that undergoes consequent spontaneous decarboxylation to form isobutene. Isobutene production rates were as high as 507 pmol min-1 g cells-1 using Escherichia coli cells expressing the enzyme and 2,880 pmol min-1 mg protein-1 with the purified histidine-tagged enzyme, significantly higher than reported previously. M3K is a key enzyme of the novel MVA pathway discovered very recently in Thermoplasma acidophilum. We suggest that P. torridus metabolizes MVA by the same pathway

The Problem with Big Data: Operating on Smaller Datasets to Bridge the Implementation Gap

Big datasets have the potential to revolutionize public health. However, there is a mismatch between the political and scientific optimism surrounding big data and the public’s perception of its benefit. We suggest a systematic and concerted emphasis on developing models derived from smaller datasets to illustrate to the public how big data can produce tangible benefits in the long term. In order to highlight the immediate value of a small data approach, we produced a proof-of-concept model predicting hospital length of stay. The results demonstrate that existing small datasets can be used to create models that generate a reasonable prediction, facilitating health-care delivery. We propose that greater attention (and funding) needs to be directed toward the utilization of existing information resources in parallel with current efforts to create and exploit “big data.

Sequencing the genome of the Burmese python (Python molurus bivittatus) as a model for studying extreme adaptations in snakes

The Consortium for Snake Genomics is in the process of sequencing the genome and creating transcriptomic resources for the Burmese python. Here, we describe how this will be done, what analyses this work will include, and provide a timeline