The Rise and Fall of the Legal Expert System

Those very few of us who were critical of the rise of legal expert systems in the early 1980s probably wonder, in idle moments, whether there is a possibility of rejuvenation of an approach which was once multi¬various and is now obscure and esoteric. Is it possible that after rising and falling, that legal expert system research programme could rise again? What were the conditions which gave impetus to the field and could they be repeated? In this article I want to return, with a personal viewpoint, on the rise of expert systems and why – despite their failure – the appeal of commoditising legal expertise continues to allure the unwary.

Characterization of a thymidylate synthase (TS)-inducible cell line: a model system for studying sensitivity to TS- and non-TS-targeted chemotherapies

Thymidylate synthase (TS) is responsible for the de novo synthesis of thymidylate, which is required for DNA synthesis and repair and which is an important target for fluoropyrimidines such as 5-fluorouracil (5-FU), and antifolates such as Tomudex (TDX), ZD9331, and multitargeted antifolate (MTA). To study the importance of TS expression in determining resistance to these agents, we have developed an MDA435 breast cancer-derived cell line with tetracycline-regulated expression of TS termed MTS-5. We have demonstrated that inducible expression of TS increased the IC(50) dose of the TS-targeted therapeutic agents 5-FU, TDX, and ZD9331 by 2-, 9- and 24-fold respectively. An IC(50) dose for MTA was unobtainable when TS was overexpressed in these cells, which indicated that MTA toxicity is highly sensitive to increased TS expression levels. The growth inhibitory effects of the chemotherapeutic agents CPT-11, cisplatin, oxaliplatin, and Taxol were unaffected by TS up-regulation. Cell cycle analyses revealed that IC(50) doses of 5-FU, TDX and MTA caused an S-phase arrest in cells that did not overexpress TS, and this arrest was overcome when TS was up-regulated. Furthermore, the S-phase arrest was accompanied by 2- to 4-fold increased expression of the cell cycle regulatory genes cyclin E, cyclin A, and cyclin dependent kinase 2 (cdk2). These results indicate that acute increases in TS expression levels play a key role in determining cellular sensitivity to TS-directed chemotherapeutic drugs by modulating the degree of S-phase arrest caused by these agents. Moreover, CPT-11, cisplatin, oxaliplatin, and Taxol remain highly cytotoxic in cells that overexpress TS.

Banking in Crisis: The Rise and Fall of British Banking Stability, 1800 to the Present

Can the lessons of the past help us to prevent another banking collapse in the future? This is the first book to tell the story of the rise and fall of British banking stability in the past two centuries, and it sheds new light on why banking systems crash and the factors underpinning banking stability. John Turner shows that there were only two major banking crises in Britain during this time: the crisis of 1825–6 and the Great Crash of 2007–8. Although there were episodic bouts of instability in the interim, the banking system was crisis-free. Why was the British banking system stable for such a long time and why did the British banking system implode in 2008? In answering these questions, the book explores the long-run evolution of bank regulation, the role of the Bank of England, bank rescues and the need to hold shareholders to account.

The Type VI secretion system of Burkholderia cenocepacia affects multiple Rho family GTPases disrupting the actin cytoskeleton and the assembly of NADPH oxidase complex in macrophages

Burkholderia cenocepacia is a Gram-negative opportunistic pathogen of patients with cystic fibrosis and chronic granulomatous disease. The bacterium survives intracellularly in macrophages within a membrane-bound vacuole (BcCV) that precludes the fusion with lysosomes. The underlying cellular mechanisms and bacterial molecules mediating these phenotypes are unknown. Here, we show that intracellular B. cenocepacia expressing a type VI secretion system (T6SS) affects the activation of the Rac1 and Cdc42 RhoGTPase by reducing the cellular pool of GTP-bound Rac1 and Cdc42. The T6SS also increases the cellular pool of GTP-bound RhoA and decreases cofilin activity. These effects lead to abnormal actin polymerization causing collapse of lamellipodia and failure to retract the uropod. The T6SS also prevents the recruitment of soluble subunits of the NADPH oxidase complex including Rac1 to the BcCV membrane, but is not involved in the BcCV maturation arrest. Therefore, T6SS-mediated deregulation of Rho family GTPases is a common mechanism linking disruption of the actin cytoskeleton and delayed NADPH oxidase activation in macrophages infected with B. cenocepacia.

Burkholderia cenocepacia Type VI Secretion System Mediates Escape of Type II Secreted Proteins into the Cytoplasm of Infected Macrophages

Burkholderia cenocepacia is an opportunistic pathogen that survives intracellularly in macrophages and causes serious respiratory infections in patients with cystic fibrosis. We have previously shown that bacterial survival occurs in bacteria-containing membrane vacuoles (BcCVs) resembling arrested autophagosomes. Intracellular bacteria stimulate IL-1ß secretion in a caspase-1-dependent manner and induce dramatic changes to the actin cytoskeleton and the assembly of the NADPH oxidase complex onto the BcCV membrane. A Type 6 secretion system (T6SS) is required for these phenotypes but surprisingly it is not required for the maturation arrest of the BcCV. Here, we show that macrophages infected with B. cenocepacia employ the NLRP3 inflammasome to induce IL-1ß secretion and pyroptosis. Moreover, IL-1ß secretion by B. cenocepacia-infected macrophages is suppressed in deletion mutants unable to produce functional Type VI, Type IV, and Type 2 secretion systems (SS). We provide evidence that the T6SS mediates the disruption of the BcCV membrane, which allows the escape of proteins secreted by the T2SS into the macrophage cytoplasm. This was demonstrated by the activity of fusion derivatives of the T2SS-secreted metalloproteases ZmpA and ZmpB with adenylcyclase. Supporting this notion, ZmpA and ZmpB are required for efficient IL-1ß secretion in a T6SS dependent manner. ZmpA and ZmpB are also required for the maturation arrest of the BcCVs and bacterial intra-macrophage survival in a T6SS-independent fashion. Our results uncover a novel mechanism for inflammasome activation that involves cooperation between two bacterial secretory pathways, and an unanticipated role for T2SS-secreted proteins in intracellular bacterial survival.

Evolutionary Requirements for Next-Generation Dataflow-Based FPGA System Design

The use of dataflow digital signal processing system modelling
and synthesis techniques has been a fruitful research theme for many years and has yielded many powerful rapid system synthesis and optimisation capabilities. However, recent years have seen the spectrum of languages and techniques splinter in an application specific manner, resulting in an ad-hoc design process which is increasingly dependent on the particular application under development. This poses a major problem for automated toolflows attempting to provide rapid system synthesis for a wide ranges of applications. By analysing a number of dataflow FPGA implementation case studies, this paper shows that despit ethis common traits may be found in current techniques, which fall largely into three classes. Further, it exposes limitations pertaining to their ability to adapt algorith models to implementations for different operating environments and target platforms.

Assessment of the impedance cardiogram recorded by an automated external defibrillator during clinical cardiac arrest

OBJECTIVE: To assess the impedance cardiogram recorded by an automated external defibrillator during cardiac arrest to facilitate emergency care by lay persons. Lay persons are poor at emergency pulse checks (sensitivity 84%, specificity 36%); guidelines recommend they should not be performed. The impedance cardiogram (dZ/dt) is used to indicate stroke volume. Can an impedance cardiogram algorithm in a defibrillator determine rapidly circulatory arrest and facilitate prompt initiation of external cardiac massage?

DESIGN: Clinical study.

SETTING: University hospital.

PATIENTS: Phase 1 patients attended for myocardial perfusion imaging. Phase 2 patients were recruited during cardiac arrest. This group included nonarrest controls.

INTERVENTIONS: The impedance cardiogram was recorded through defibrillator/electrocardiographic pads oriented in the standard cardiac arrest position.

MEASUREMENTS AND MAIN RESULTS: Phase 1: Stroke volumes from gated myocardial perfusion imaging scans were correlated with parameters from the impedance cardiogram system (dZ/dt(max) and the peak amplitude of the Fast Fourier Transform of dZ/dt between 1.5 Hz and 4.5 Hz). Multivariate analysis was performed to fit stroke volumes from gated myocardial perfusion imaging scans with linear and quadratic terms for dZ/dt(max) and the Fast Fourier Transform to identify significant parameters for incorporation into a cardiac arrest diagnostic algorithm. The square of the peak amplitude of the Fast Fourier Transform of dZ/dt was the best predictor of reduction in stroke volumes from gated myocardial perfusion imaging scans (range = 33-85 mL; p = .016). Having established that the two pad impedance cardiogram system could detect differences in stroke volumes from gated myocardial perfusion imaging scans, we assessed its performance in diagnosing cardiac arrest. Phase 2: The impedance cardiogram was recorded in 132 "cardiac arrest" patients (53 training, 79 validation) and 97 controls (47 training, 50 validation): the diagnostic algorithm indicated cardiac arrest with sensitivities and specificities (+/- exact 95% confidence intervals) of 89.1% (85.4-92.1) and 99.6% (99.4-99.7; training) and 81.1% (77.6-84.3) and 97% (96.7-97.4; validation).

CONCLUSIONS: The impedance cardiogram algorithm is a significant marker of circulatory collapse. Automated defibrillators with an integrated impedance cardiogram could improve emergency care by lay persons, enabling rapid and appropriate initiation of external cardiac massage.

The impedance cardiogram recorded through two electrocardiogram/defibrillator pads as a determinant of cardiac arrest during experimental studies

OBJECTIVE: Laypersons are poor at emergency pulse checks (sensitivity 84%, specificity 36%). Guidelines indicate that pulse checks should not be performed. The impedance cardiogram (dZ/dt) is used to assess stroke volume. Can a novel defibrillator-based impedance cardiogram system be used to distinguish between circulatory arrest and other collapse states?

DESIGN: Animal study.

SETTING: University research laboratory.

SUBJECTS: Twenty anesthetized, mechanically ventilated pigs, weight 50-55 kg.

INTERVENTIONS: Stroke volume was altered by right ventricular pacing (160, 210, 260, and 305 beats/min). Cardiac arrest states were then induced: ventricular fibrillation (by rapid ventricular pacing) and, after successful defibrillation, pulseless electrical activity and asystole (by high-dose intravenous pentobarbitone).

MEASUREMENTS AND MAIN RESULTS: The impedance cardiogram was recorded through electrocardiogram/defibrillator pads in standard cardiac arrest positions. Simultaneously recorded electro- and impedance cardiogram (dZ/dt) along with arterial blood pressure tracings were digitized during each pacing and cardiac arrest protocol. Five-second epochs were analyzed for sinus rhythm (20 before ventricular fibrillation, 20 after successful defibrillation), ventricular fibrillation (40), pulseless electrical activity (20), and asystole (20), in two sets of ten pigs (ten training, ten validation). Standard impedance cardiogram variables were noncontributory in cardiac arrest, so the fast Fourier transform of dZ/dt was assessed. During ventricular pacing, the peak amplitude of fast Fourier transform of dZ/dt (between 1.5 and 4.5 Hz) correlated with stroke volume (r2 = .3, p < .001). In cardiac arrest, a peak amplitude of fast Fourier transform of dZ/dt of < or = 4 dB x ohm x rms indicated no output with high sensitivity (94% training set, 86% validation set) and specificity (98% training set, 90% validation set).

CONCLUSIONS: As a powerful clinical marker of circulatory collapse, the fast Fourier transformation of dZ/dt (impedance cardiogram) has the potential to improve emergency care by laypersons using automated defibrillators.

The Kepler-454 system: a small, not-rocky inner planet, a Jovian world, and a distant companion

Kepler-454 (KOI-273) is a relatively bright (V = 11.69 mag), Sun-like star that hosts a transiting planet candidate in a 10.6 day orbit. From spectroscopy, we estimate the stellar temperature to be 5687 ± 50 K, its metallicity to be [m/H] = 0.32 ± 0.08, and the projected rotational velocity to be v sin i <2.4 km s^-1. We combine these values with a study of the asteroseismic frequencies from short cadence Kepler data to estimate the stellar mass to be , the radius to be 1.066 ± 0.012 R_o, and the age to be Gyr. We estimate the radius of the 10.6 day planet as 2.37 ± 0.13 R_⊕. Using 63 radial velocity observations obtained with the HARPS-N spectrograph on the Telescopio Nazionale Galileo and 36 observations made with the HIRES spectrograph at the Keck Observatory, we measure the mass of this planet to be 6.8 ± 1.4 M_⊕. We also detect two additional non-transiting companions, a planet with a minimum mass of 4.46 ± 0.12 M_J in a nearly circular 524 day orbit and a massive companion with a period >10 years and mass >12.1 M_J. The 12 exoplanets with radii ⊕ and precise mass measurements appear to fall into two populations, with those ⊕ following an Earth-like composition curve and larger planets requiring a significant fraction of volatiles. With a density of 2.76 ± 0.73 g cm^-3, Kepler-454b lies near the mass transition between these two populations and requires the presence of volatiles and/or H/He gas.