A Double Error Dynamic Asymptote Model of Associative Learning

In this paper a formal model of associative learning is presented which incorporates representational and computational mechanisms that, as a coherent corpus, empower it to make accurate predictions of a wide variety of phenomena that so far have eluded a unified account in learning theory. In particular, the Double Error Dynamic Asymptote (DDA) model introduces: 1) a fully-connected network architecture in which stimuli are represented as temporally clustered elements that associate to each other, so that elements of one cluster engender activity on other clusters, which naturally implements neutral stimuli associations and mediated learning; 2) a predictor error term within the traditional error correction rule (the double error), which reduces the rate of learning for expected predictors; 3) a revaluation associability rate that operates on the assumption that the outcome predictiveness is tracked over time so that prolonged uncertainty is learned, reducing the levels of attention to initially surprising outcomes; and critically 4) a biologically plausible variable asymptote, which encapsulates the principle of Hebbian learning, leading to stronger associations for similar levels of cluster activity. The outputs of a set of simulations of the DDA model are presented along with empirical results from the literature. Finally, the predictive scope of the model is discussed

The Innovation Performance of Foreign Affiliates: Evidence from Dutch Manufacturing Firms

innovation, performance, manufacturing, firms

The shadow economy in Colombia: size and effects on economic growth

Using the currency demand approach size and development of the Colombian shadow economy are estimated over the period from 1976 to 2002. In the 70s the size fluctuated around 20% of official GDP and rose to 50% in the 90s. The most important factors driving the shadow economy are unemployment and taxation. Analyzing the interaction between shadow and official economy, the shadow economy has a positive effect on the official one. Average growth rate of real per capita GDP is 1.11% between 1976 and 2002 and the shadow economy "explains" on average between 0.09 and 0.27 of this growth.Colombian shadow economy; currency demand method; taxation; unemployment; interaction between the shadow and official economy

Measuring service outcomes for adaptive preventive maintenance

Services account for an increasing share of economic activity in the western world. As part of this, preventive maintenance (PM) service volumes are constantly growing as a result of a growing (and aging) asset population and maintenance outsourcing. While the pursuit of improved service productivity is in the interest of both firms and nations, the challenges of measuring service performance, and more specifically service outcomes, persist. This paper presents an outcome-based measure for fleet PM, which has far-reaching implications considering service productivity and performance measurement. We develop a statistical process control based measure that utilizes data typically available in PM. The measure is grounded in reliability theory, which enables generalization of the measure within PM services but also outlines the limitations of its application. Finally we apply the measure in a PM field service process of a servitized equipment manufacturer. Based on actual maintenance records we show that the service provider could reduce their service output by at least 5–10% without significantly affecting the aggregate service outcome. The developed measure and control process form the basis for adaptive preventive maintenance, which is expected to facilitate the transition towards outcome-based contracts through complementing condition-based maintenance. One of the key benefits of the approach is that it provides a cost-effective way of revealing the scarcely studied phenomenon of service overproduction. Based on our case, we conclude that there are significant productivity gains in making sure that you meet required standards for service output but do not exceed them

Skill-Biased Technological Change: Evidence from a Firm-Level Survey

Siegel provides evidence that technology adoption is associated with downsizing, skill upgrading, greater employee empowerment, and a widening wage gap. Unlike previous studies that use industry-level data, Siegel collected firm-level data on technology usage and labor composition which enable him to link the magnitude of labor market outcomes for six classes of workers to the types of technologies implemented.https://research.upjohn.org/up_press/1065/thumbnail.jp

Pharmacokinetic and Pharmacodynamic Studies of a Novel Spectinamide Series of Antituberculosis Agents

Spectinamides are novel amide derivatives of the antibiotic spectinomycin that have emerged as a new class of agents to treat tuberculosis. These agents showed potent in vitro activity against Mycobacterium tuberculosis (MTB) compared to spectinomycin and in a preliminary in vivo study in interferon gamma (IFN‑γ) knockout mice, spectinamide Lee1329 reduced the lung bacillary load of TB comparable to streptomycin. We hypothesized that the application of an iterative pharmacokinetics and pharmacodynamics (PK/PD) guided approach would facilitate the optimization of these lead compounds suitable for further development. A series of in vitro experiments including parallel artificial membrane permeability assay (PAMPA), microsomal metabolic stability using rat liver microsomes and protein binding assay were designed to characterize the in vivo biopharmaceutic and pharmacokinetic behavior. Drug uptake studies into Mycobacterium bovis BCG and into J774 murine macrophages were performed to understand reasons for improved activity of spectinamides and to evaluate their potential to target primary TB infection that resides in macrophages. In vivo pharmacokinetic studies were carried out in rats by intravenous (10 mg/Kg) and oral administration (100 mg/Kg) of the compounds. LC‑MS/MS assays were developed to quantify concentrations in test samples obtained from these studies. Spectinamides exhibit low to intermediate plasma protein binding and were found to be metabolically stable. Following intravenous administration, spectinamides were relatively widely distributed (0.36 to 1.15 L/Kg) with short half‑lives (0.43 to 0.62 hr). Mean systemic clearance ranged between 0.36 and 0.89 L/hr/Kg with a significant fraction of drug eliminated unchanged in urine (0.46 to 1.0). Spectinamides exhibited a renal excretion ratio greater than one indicating filtration and active secretion as the net renal elimination process. In the uptake experiments, the spectinamides exhibited 3‑4 times higher uptake into murine macrophages compared to streptomycin and showed nearly four times higher uptake into M. bovis BCG compared to spectinomycin, which may in part explain their increased activity compared to spectinomycin. In a previously reported in vitro PK/PD system, PK concentration‑time profiles were simulated on the basis of the in vivo clearance of rats obtained from the PK studies and different daily doses of 0.4, 2, 10 and 50 mg/Kg/day of Lee1445 were added as QD, BID or TID regimens. The time‑kill effect of these regimens was studied on the growing M. bovis BCG present in the system. A semi‑mechanistic model incorporating a logistic function for growth of mycobacteria in the absence of drug and an inhibitory sigmoidal Emax model with a delay function for the time‑kill effect of the drug was fit to the data and the in vitro PK/PD parameters were determined. Since the in vivo efficacy model of tuberculosis infection was the gamma knock‑out (GKO) mice, a PK bridging study was performed in mice following intraperitoneal administration of 20 mg/Kg Lee1445. Simulations for various dosing regimens were performed using the obtained mouse PK parameters and the in vitro PK/PD parameters that were incorporated into a combined PK/PD model to predict the efficacy in terms of reduction of bacterial counts measured in log CFU/mL. Based on the results of the simulations, an optimal dose was chosen for the in vivo efficacy study. The results from the in vitro PK/PD studies showed that QD was marginally effective. The same total daily dose administered BID showed a marked reduction in mycobacterial counts. TID dosing did not show a significant difference in time‑kill compared to BID regimen. The maximum growth rate constant (K0) was estimated as 0.0274 hr-1 which corresponds to a maximum doubling time of 25.3 hr that is consistent with the commonly observed in vitro doubling times of 20‑24 hr. A maximum bacterial kill rate (Imax) was calculated as 0.0566 hr-1. The free drug concentration required to produce half‑maximum inhibition (IC50) was calculated as 2.62 mg/L. The delay rate constant for the initial kill was found to be 0.0245 hr-1. The PK bridging study showed that the Lee1445 half‑life was shorter in mice (0.25 hr) compared to rats (0.43 hr). Simulations based on the parameters obtained from the mouse PK bridging study and the in vitro PK/PD model suggested that a total daily dose of 200 mg/Kg/day and 400 mg/Kg/day administered BID would be optimal and result in approximately 2 and 3 log reduction in bacterial counts respectively after seven days of therapy and hence were chosen for in vivo efficacy studies in mice. In summary, we have successfully developed a series of biopharmaceutic, PK and PD experiments that help in an iterative PK/PD guided approach for development of spectinamides, a novel class of antituberculosis agents. The in vivo PK and in vitro PK/PD parameters obtained from these studies provide a basis for optimal compound as well as dose selection

Particulate inorganic carbon flux and sediment transport dynamics in karst: Significance to landscape evolution and the carbon cycle.

Research focused on three areas of karst hydrogeology and sediment transport that have been poorly studied in the past: the role of particulate inorganic carbon transport in calculating carbon sink rates in karst; rapid changes in surface vs. subsurface sediment mixing in karst conduits; and comparison of landscape denudation calculations using dissolved carbonate load vs. total dissolved/sediment load. Carbonate bedrock weathering is a significant component of the atmospheric carbon sink. Particulate inorganic carbon (PIC) in bed and suspended sediment load of karst waters is frequently dismissed as insignificant for calculating denudation and carbon transport/sink rates, but PIC flux has not been adequately studied. PIC fluxes were quantified in fluviokarst settings using RFID-tagged cobbles and gravel to track subsurface bed load flux, along with remote loggers and lab analysis of sediment and water chemistry for suspended and dissolved loads. PIC contributed about 10.3 percent annually to total inorganic carbon removal and additional carbon sequestration at Blowing Cave basin. Cosmogenic and fallout radionuclides 7Be and 137Cs were also utilized to develop a better understanding of rapid, short-term changes in sediment flux and transport through karst aquifers. The ratio of surface-derived sediment to stored and remobilized subsurface sediment in cave streams was estimated by tracking isotopic changes across storm runoff events. During a large storm event, approximately 34% of the total sediment flux during the 4-day runoff event originated from surface erosion. Landscape denudation rates in karst settings have been calculated using a number of different methods. The most widely applied basin-wide method is measurement of dissolved carbonate load at base-level springs, calculating denudation using the area of exposed carbonate outcrop, and assuming other outcrop types are in equilibrium. In mixed carbonate/noncarbonate lithologies (which includes most fluviokarst settings), much of the landscape is also eroded by transport of sediments through conduits. The basin average rate of landscape denudation (aggregating both carbonate and non-carbonate areas) was 48.5 mm/ka, but denudation rates for carbonate and non-carbonate outcrop areas were not in equilibrium