Mode shifting between storage and recall based on novelty detection in oscillating hippocampal circuits.

ABSTRACT: It has been suggested that hippocampal mode shifting between a storage and a retrieval state might be under the control of acetylcholine (ACh) levels, as set by an autoregulatory hippocampo-septohippocampal loop. The present study investigates how such a mechanism might operate in a large-scale connectionist model of this circuitry that takes into account the major hippocampal subdivisions, oscillatory population dynamics and the time scale on which ACh exerts its effects in the hippocampus. The model assumes that hippocampal mode shifting is regulated by a novelty signal generated in the hippocampus. The simulations suggest that this signal originates in the dentate. Novel patterns presented to this structure lead to brief periods of depressed firing in the hippocampal circuitry. During these periods, an inhibitory influence of the hippocampus on the septum is lifted, leading to increased firing of cholinergic neurons. The resulting increase in ACh release in the hippocampus produces network dynamics that favor learning over retrieval. Resumption of activity in the hippocampus leads to the reinstatement of inhibition. Despite theta-locked rhythmic firing of ACh neurons in the septum, ACh modulation in the model fluctuates smoothly on a time scale of seconds. It is shown that this is compatible with the time scale on which memory processes take place. A number of strong predictions regarding memory function are derived from the model. © 2004 Wiley-Liss, Inc. KEY WORDS: acetylcholine; computational modeling; hippocampus; medial septum; memor

Temporal transcriptome changes induced by MDV in marek's disease-resistant and -susceptible inbred chickens

<p>Abstract</p> <p>Background</p> <p>Marek's disease (MD) is a lymphoproliferative disease in chickens caused by Marek's disease virus (MDV) and characterized by T cell lymphoma and infiltration of lymphoid cells into various organs such as liver, spleen, peripheral nerves and muscle. Resistance to MD and disease risk have long been thought to be influenced both by genetic and environmental factors, the combination of which contributes to the observed outcome in an individual. We hypothesize that after MDV infection, genes related to MD-resistance or -susceptibility may exhibit different trends in transcriptional activity in chicken lines having a varying degree of resistance to MD.</p> <p>Results</p> <p>In order to study the mechanisms of resistance and susceptibility to MD, we performed genome-wide temporal expression analysis in spleen tissues from MD-resistant line 6₃, susceptible line 7₂and recombinant congenic strain M (RCS-M) that has a phenotype intermediate between lines 6₃and 7₂after MDV infection. Three time points of the MDV life cycle in chicken were selected for study: 5 days post infection (dpi), 10dpi and 21dpi, representing the early cytolytic, latent and late cytolytic stages, respectively. We observed similar gene expression profiles at the three time points in line 6₃and RCS-M chickens that are both different from line 7₂. Pathway analysis using Ingenuity Pathway Analysis (IPA) showed that MDV can broadly influence the chickens irrespective of whether they are resistant or susceptible to MD. However, some pathways like cardiac arrhythmia and cardiovascular disease were found to be affected only in line 7₂; while some networks related to cell-mediated immune response and antigen presentation were enriched only in line 6₃and RCS-M. We identified 78 and 30 candidate genes associated with MD resistance, at 10 and 21dpi respectively, by considering genes having the same trend of expression change after MDV infection in lines 6₃and RCS-M. On the other hand, by considering genes with the same trend of expression change after MDV infection in lines 7₂and RCS-M, we identified 78 and 43 genes at 10 and 21dpi, respectively, which may be associated with MD-susceptibility.</p> <p>Conclusions</p> <p>By testing temporal transcriptome changes using three representative chicken lines with different resistance to MD, we identified 108 candidate genes for MD-resistance and 121 candidate genes for MD-susceptibility over the three time points. Genes included in our resistance or susceptibility genes lists that are also involved in more than 5 biofunctions, such as <it>CD8α</it>, <it>IL8</it>, <it>USP18</it>, and <it>CTLA4</it>, are considered to be important genes involved in MD-resistance or -susceptibility. We were also able to identify several biofunctions related with immune response that we believe play an important role in MD-resistance.</p

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

FACTOR DEMAND IN THE SAWMILL INDUSTRY OF THE LAKE STATES

This study examined the production structure of the sawmilling industry of the Lake States (Michigan, Minnesota and Wisconsin) in order to determine elasticities of substitution and elasticities of demand. A homogeneous translog cost function was estimated using pooled time-series data for the period 1963-1996 with inputs labor, materials and capital. Based on the model selection process, the estimated model imposes constant returns to scale and allows for nonunitary elasticities of substitution amongst the inputs. The hypothesis of constant returns to scale could not be rejected at the 1% level. This was common for studies of the sawmill industry but seems particularly common to regions where the industry was made up primarily of small mills. Constant returns to scale in a mature sawmill industry would lead to the outcome of mills of similar size as all economies of scale have been exhausted and the industry has settled into an equilibrium firm size near the minimum of the long run average cost curve. Nevertheless, this does not explain why the average mill size in the Lake States is small compared to the Pacific Northwest and Southeastern U.S. Results for the Allen Partial Elasticity of Substitution (AES) indicate that labor and materials were inelastic substitutes with an elasticity of 0.76 while labor and capital were elastic complements with an elasticity of -1.38. Materials and capital were also inelastic substitutes and had an elasticity of substitution of 0.80. The labor/materials elasticity of substitution is high compared to almost all studies of softwood lumber producing regions. The Morishima Elasticity of Substitution (MES) results indicate that labor/materials, materials/labor, materials/capital, capital/materials and labor/capital were inelastic substitutes with the greatest substitutability between labor/materials. The MES for capital/labor was -0.017 indicating a complementary relationship. The own-price elasticities of demand were all inelastic and negative indicating downward sloping demand curves. All other elasticities were inelastic and indicate that materials was a substitute for labor and capital but labor and capital were complements. Changes in the price of materials had a relatively large, but inelastic, effect on the demand for capital with a cross-price elasticity of 0.51. Changes in the price of labor also had a relatively large effect on the demand for capital, but in a complementary fashion, with an elasticity of -0.44. Changes in the price of materials had a greater effect on the demand for labor than the other way around with cross-price elasticities of 0.48 and 0.24, respectively

Effects of tax incentives on long-run capital formation and total factor productivity growth in the Canadian sawmilling industry

The goal of this study was to analyze effects of tax incentives on long-run dynamics of total factor productivity (TFP) growth and capital formation in the Canadian sawmilling industry over a 40-year period (1961-2000). Simulated tax incentives involved increasing capital cost allowance and investment tax credit and reducing corporate income tax. The production technology was specified as a function of capital, labor, energy, sawlogs, and a time dependent technological progress variable. A translog multilateral index number model was applied to measure and analyze TFP. Two analytical phases were followed. In the first phase, without the tax incentives, we analyzed annual levels and growth rates of TFP1; and parametrically examined effects of output growth and time dependent technology on the growth of TFP1. Over the study period, the average annual growth rate of TFP1 was 2%; and the parametric results revealed that the marginal effects of each of output growth and technological progress on TFP1 growth were highly significant. The second phase involved recalculation of the rental price of capital to estimate effects of the simulated tax incentives on capital formation and growth of TFP (= TFP2). As expected, the average annual share of capital in total cost with the tax incentives rose to 12% from 9% without the tax incentives. The average annual capital intensity also rose to real $15,263.70 with the incentives from real$10,402.91 without the incentives. Most importantly, higher capital formation, motivated by the tax incentives, raised aggregate quantity of the inputs significantly, leading to a slightly lower TFP2 than TFP1, because output was unchanged. In short, the data validated the hypothesis that tax incentives do indeed spur capital formation and TFP growth.Tax incentives Capital intensity Technological progress Technical efficiency Competitiveness

FACTOR DEMAND IN THE SAWMILL INDUSTRY OF THE LAKE STATES

This study examined the production structure of the sawmilling industry of the Lake States (Michigan, Minnesota and Wisconsin) in order to determine elasticities of substitution and elasticities of demand. A homogeneous translog cost function was estimated using pooled time-series data for the period 1963-1996 with inputs labor, materials and capital. Based on the model selection process, the estimated model imposes constant returns to scale and allows for nonunitary elasticities of substitution amongst the inputs. The hypothesis of constant returns to scale could not be rejected at the 1% level. This was common for studies of the sawmill industry but seems particularly common to regions where the industry was made up primarily of small mills. Constant returns to scale in a mature sawmill industry would lead to the outcome of mills of similar size as all economies of scale have been exhausted and the industry has settled into an equilibrium firm size near the minimum of the long run average cost curve. Nevertheless, this does not explain why the average mill size in the Lake States is small compared to the Pacific Northwest and Southeastern U.S. Results for the Allen Partial Elasticity of Substitution (AES) indicate that labor and materials were inelastic substitutes with an elasticity of 0.76 while labor and capital were elastic complements with an elasticity of -1.38. Materials and capital were also inelastic substitutes and had an elasticity of substitution of 0.80. The labor/materials elasticity of substitution is high compared to almost all studies of softwood lumber producing regions. The Morishima Elasticity of Substitution (MES) results indicate that labor/materials, materials/labor, materials/capital, capital/materials and labor/capital were inelastic substitutes with the greatest substitutability between labor/materials. The MES for capital/labor was -0.017 indicating a complementary relationship. The own-price elasticities of demand were all inelastic and negative indicating downward sloping demand curves. All other elasticities were inelastic and indicate that materials was a substitute for labor and capital but labor and capital were complements. Changes in the price of materials had a relatively large, but inelastic, effect on the demand for capital with a cross-price elasticity of 0.51. Changes in the price of labor also had a relatively large effect on the demand for capital, but in a complementary fashion, with an elasticity of -0.44. Changes in the price of materials had a greater effect on the demand for labor than the other way around with cross-price elasticities of 0.48 and 0.24, respectively.Agribusiness,