bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dissociable regulation of instrumental action within mouse prefrontal cortex
Authors: Gourley Shannon L. , Lee Anni S. , Howell Jessica L. , Pittenger Christopher , Taylor Jane R. 
Published: October 2010

AbstractEvaluation of the behavioral ‘costs’, such as effort expenditure relative to the benefits of obtaining reward, is a major determinant of goal‐directed action. Neuroimaging evidence suggests that the human medial orbitofrontal cortex (mOFC) is involved in this calculation and thereby guides goal‐directed and choice behavior, but this region’s functional significance in rodents is unknown despite extensive work characterizing the role of the lateral OFC in cue‐related response inhibition processes. We first tested mice with mOFC lesions in an instrumental reversal task lacking discrete cues signaling reinforcement; here, animals were required to shift responding based on the location of the reinforced aperture within the chamber. Mice with mOFC lesions acquired the reversal but failed to inhibit responding on the previously reinforced aperture, while mice with prelimbic prefrontal cortex lesions were unaffected. When tested on a progressive ratio schedule of reinforcement, mice with prelimbic cortical lesions were unable to maintain responding, resulting in declining response levels. Mice with mOFC lesions, by contrast, escalated responding. Neither lesion affected sensitivity to satiety‐specific outcome devaluation or non‐reinforcement (i.e. extinction), and neither had effects when placed after animals were trained on a progressive ratio response schedule. Lesions of the ventral hippocampus, which projects to the mOFC, resulted in similar response patterns, while lateral OFC and dorsal hippocampus lesions resulted in response acquisition, though not inhibition, deficits in an instrumental reversal. Our findings thus selectively implicate the rodent mOFC in braking reinforced goal‐directed action when reinforcement requires the acquisition of novel response contingencies.
Feed‐forward control of preshaping in the rat is mediated by the corticospinal tract
Authors: Carmel Jason B. , Kim Sangsoo , Brus‐Ramer Marcel , Martin John H. 
Published: October 2010

AbstractRats are used to model human corticospinal tract (CST) injury and repair. We asked whether rats possess the ability to orient their paw to the reaching target and whether the CST mediates this skill, as it does in primates. To test this ability, called preshaping, we trained rats to reach for pieces of pasta oriented either vertically or horizontally. We measured paw angle relative to the target and asked whether rats used target information attained before contact to preshape the paw, indicating feed‐forward control. We also determined whether preshaping improved with practice. We then selectively lesioned the CST in the medullary pyramid contralateral to the reaching forepaw to test whether preshaping relies on the CST. Rats significantly oriented their paw to the pasta orientation before contact, demonstrating feed‐forward control. Both preshaping and reaching efficiency improved with practice, while selective CST lesion abrogated both. The loss of preshaping was greatest for pasta oriented vertically, suggesting loss of supination, as seen with human CST injury. The degree of preshaping loss strongly correlated with the amount of skill acquired at baseline, suggesting that the CST mediates the learned component of preshaping. Finally, the amount of preshaping lost after injury strongly correlated with reduced retrieval success, showing an important functional consequence for preshaping. We have thus demonstrated, for the first time, preshaping in the rat and dependence of this skill on the CST. Understanding the basis for this skill and measuring its recovery after injury will be important for studying higher‐level motor control in rats.
MRI predictors of long‐term evolution in amyotrophic lateral sclerosis
Authors: Agosta Federica , Pagani Elisabetta , Petrolini Melissa , Sormani Maria P. , Caputo Domenico , Perini Michele , Prelle Alessandro , Salvi Fabrizio , Filippi Massimo 
Published: October 2010

AbstractWe investigated whether conventional and diffusion tensor (DT) magnetic resonance imaging (MRI) features of the corticospinal tract (CST) contribute to the prediction of the long‐term clinical evolution in patients with amyotrophic lateral sclerosis (ALS). Brain conventional and DT MRI were obtained from 18 healthy subjects and 24 patients with sporadic ALS. Mean diffusivity (MD) and fractional anisotropy (FA) of the CST were obtained. Patients were scanned at baseline, then entered a longitudinal clinical follow‐up. The ALS Functional Rating scale (ALSFRS) progression rate during follow‐up was estimated. Patients were followed up prospectively for a median period of 3.4 years. Two patients were lost at follow‐up and eight died during the observation period. The mean ALSFRS progression rate was 0.7/month (range = 0.0–2.0/month). At baseline, ALS patients showed significantly increased MD and decreased FA of the CST compared with controls. CST FA was associated with ALSFRS progression rate. ALSFRS deterioration rate and CST FA were independent predictors of survival in ALS patients. Survival at year 3 was 42% in patients with CST FA ≤ 0.56 compared with 90% in patients with CST FA > 0.56. This study shows that more severe CST DT MRI abnormalities predict a poorer long‐term clinical outcome in ALS patients. DT MRI of the brain has the potential to offer in vivo markers of disease severity.
Maximum Likelihood Estimation of a Multi-Dimensional Log-Concave Density
Authors: Cule Madeleine , Samworth Richard , Stewart Michael 
Published: October 2010

SummaryLet X1,…,Xn be independent and identically distributed random vectors with a (Lebesgue) density f. We first prove that, with probability 1, there is a unique log-concave maximum likelihood estimator f^n of f. The use of this estimator is attractive because, unlike kernel density estimation, the method is fully automatic, with no smoothing parameters to choose. Although the existence proof is non-constructive, we can reformulate the issue of computing f^n in terms of a non-differentiable convex optimization problem, and thus combine techniques of computational geometry with Shor’s r-algorithm to produce a sequence that converges to f^n. An R version of the algorithm is available in the package LogConcDEAD—log-concave density estimation in arbitrary dimensions. We demonstrate that the estimator has attractive theoretical properties both when the true density is log-concave and when this model is misspecified. For the moderate or large sample sizes in our simulations, f^n is shown to have smaller mean integrated squared error compared with kernel-based methods, even when we allow the use of a theoretical, optimal fixed bandwidth for the kernel estimator that would not be available in practice. We also present a real data clustering example, which shows that our methodology can be used in conjunction with the expectation–maximization algorithm to fit finite mixtures of log-concave densities.
A Geometric Characterization of Optimal Designs for Regression Models with Correlated Observations
Authors: Holland-Letz Tim , Dette Holger , Pepelyshev Andrey 
Published: October 2010

SummaryWe consider the problem of optimal design of experiments for random-effects models, especially population models, where a small number of correlated observations can be taken on each individual, whereas the observations corresponding to different individuals are assumed to be uncorrelated. We focus on c-optimal design problems and show that the classical equivalence theorem and the famous geometric characterization of Elfving from the case of uncorrelated data can be adapted to the problem of selecting optimal sets of observations for the n individual patients. The theory is demonstrated by finding optimal designs for a linear model with correlated observations and a non-linear random-effects population model, which is commonly used in pharmaco-kinetics.
Modelling Non-Homogeneous Poisson Processes with Almost Periodic Intensity Functions
Authors: Shao Nan , Lii Keh-Shin 
Published: October 2010

SummaryWe propose a model for the analysis of non-stationary point processes with almost periodic rate of occurrence. The model deals with the arrivals of events which are unequally spaced and show a pattern of periodicity or almost periodicity, such as stock transactions and earthquakes. We model the rate of occurrence of a non-homogeneous Poisson process as the sum of sinusoidal functions plus a baseline. Consistent estimates of frequencies, phases and amplitudes which form the sinusoidal functions are constructed mainly by the Bartlett periodogram. The estimates are shown to be asymptotically normally distributed. Computational issues are discussed and it is shown that the frequency estimates must be resolved with order o(T−1) to guarantee the asymptotic unbiasedness and consistency of the estimates of phases and amplitudes, where T is the length of the observation period. The prediction of the next occurrence is carried out and the mean-squared prediction error is calculated by Monte Carlo integration. Simulation and real data examples are used to illustrate the theoretical results and the utility of the model.
Viewing Tax Policy Through Party-Colored Glasses: What German Politicians Believe
Authors: Heinemann Friedrich , Janeba Eckhard 
Published: October 2010

AbstractThe process of globalization has an important impact on national tax policies. Most of the literature does not focus directly on the political decision-making process and assumes that the desired tax policy is responding to objective underlying tradeoffs. Based on an original survey of members of the German national parliament (Bundestag) in 2006/07, we document a strong ideological bias among policy-makers with respect to the perceived mobility of international tax bases (real capital and paper profits). Ideology also influences, directly and indirectly, the perceived national autonomy in tax setting and preferences for a European Union minimum tax for companies. There seems little consensus as to what the efficiency costs of capital taxation in open economies are, even though our survey falls in a period of extensive debate about, and actual adoption of, a company tax reform bill in Germany.
PACAP‐regulated phenylethanolamineN‐methyltransferase gene expression
Authors: Tai Tze Chun , Wong‐Faull David C. , Claycomb Robert , Aborn Jennifer L. , Wong Dona Lee 
Published: October 2010

J. Neurochem.(2010)115, 1195–1205.AbstractPituitary adenylate cyclase activating polypeptide (PACAP) induces the proximal −893 bp of rat phenylethanolamineN‐methyltransferase (PNMT) gene promoter in PC12 cells via PACAP type I receptors. Deletion mutation analysis suggested that the initial −392 bp of promoter, containing early growth response protein (Egr‐1), specificity protein 1 (Sp1) and activator protein 2 (AP‐2) binding sites (−165, −168 and −103 bp, respectively), was sufficient for PACAP activation. Egr‐1 and AP‐2 involvement was supported by PACAP induction of their mRNA and protein. Mutation of the Egr‐1, Sp1 and AP‐2 elements showed that the Egr‐1 site was essential for PACAP stimulation. Mutation of the −103 bp AP‐2 site partially reduced PACAP activation of the promoter. Mutation of two upstream AP‐2 sites at −573 and −650 bp, separately or in tandem, also prevented promoter induction by PACAP. siRNA knock‐down of Egr‐1 and AP‐2 suppressed promoter activation for the −893 bp construct. Egr‐1 siRNA knock‐down also eliminated the residual activation observed for the −103 bp AP‐2 mutant construct, suggesting that Egr‐1 and AP‐2 through respective −165 and −650/−573/−103 bp sites cooperatively stimulate the promoter. PACAP responses appear orchestrated through cAMP‐protein kinase A and phospholipase C signaling as MDL12,330A, H89 and U73122, respectively, inhibited promoter induction by PACAP and reduced PACAP‐stimulation of Egr‐1, AP‐2 and PNMT mRNA and protein and Egr‐1 and AP‐2 protein/DNA complex formation. Findings are the first to show that PACAP stimulates PNMT promoter‐driven gene expression via PACAP type I receptors and cAMP‐protein kinase A and phospholipase C signaling, recruiting Egr‐1 and AP‐2 as cooperative regulators, and the first to associate the transcription factor AP‐2 to PACAP‐mediated gene induction.
Interferon‐β induces apoptosis in human SH‐SY5Y neuroblastoma cells through activation of JAK–STAT signaling and down‐regulation of PI3K/Akt pathway
Authors: Dedoni Simona , Olianas Maria C. , Onali Pierluigi 
Published: October 2010

J. Neurochem. (2010) 115, 1421–1433.AbstractType I interferons (IFNs) are known to cause neuropsychiatric side effects, which have been proposed to be mediated by either peripheral actions or activation of glial cells. In the present study, we have investigated whether these cytokines could act directly on neuronal cells and regulate signaling pathways involved in cell death. In human SH‐SY5Y neuroblastoma cells, type I IFNs rapidly stimulated tyrosine phosphorylation of Janus kinase and signal transducer and activator of transcription (STAT) through type I IFN receptor. Prolonged exposure to IFN‐β induced apoptotic cell death accompanied by cytochrome C release, cleavage of caspases 9, 7, 3 and poly‐(ADP ribose) polymerase and DNA fragmentation. Janus kinase inhibition reduced IFN‐β‐stimulated TyK2 and STAT1 phosphorylation, STAT1 transcriptional activity, induction of double‐stranded RNA‐activated protein kinase (PKR) and caspase cleavage. PKR induction was associated with enhanced PKR activity and chemical inhibition of PKR reduced IFN‐stimulated caspase activation. Moreover, long‐term IFN‐β treatment led to down‐regulation of phosphatidylinositol 3‐kinase/Akt signaling and IFN‐β‐induced apoptosis was attenuated in cells expressing constitutively active Akt. Similarly, in mouse primary neurons IFN‐β induced STAT phosphorylation, caspase 3 cleavage and inhibition of Akt signaling. Thus, type I IFNs can directly impair neuronal survival by regulating multiple signaling molecules promoting the intrinsic apoptotic pathway. This effect may contribute to the cytokine neurotoxicity.
Regulation of protein phosphatase 2A methylation by LCMT1 and PME‐1 plays a critical role in differentiation of neuroblastoma cells
Authors: Sontag Jean‐Marie , Nunbhakdi‐Craig Viyada , Mitterhuber Martina , Ogris Egon , Sontag Estelle 
Published: October 2010

J. Neurochem. (2010) 115, 1455–1465.AbstractNeuritic alterations are a major feature of many neurodegenerative disorders. Methylation of protein phosphatase 2A (PP2A) catalytic C subunit by the leucine carboxyl methyltransferase (LCMT1), and demethylation by the protein phosphatase methylesterase 1, is a critical PP2A regulatory mechanism. It modulates the formation of PP2A holoenzymes containing the Bα subunit, which dephosphorylate key neuronal cytoskeletal proteins, including tau. Significantly, we have reported that LCMT1, methylated C and Bα expression levels are down‐regulated in Alzheimer disease‐affected brain regions. In this study, we show that enhanced expression of LCMT1 in cultured N2a neuroblastoma cells, which increases endogenous methylated C and Bα levels, induces changes in F‐actin organization. It promotes serum‐independent neuritogenesis and development of extended tau‐positive processes upon N2a cell differentiation. These stimulatory effects can be abrogated by LCMT1 knockdown and S‐adenosylhomocysteine, an inhibitor of methylation reactions. Expression of protein phosphatase methylesterase 1 and the methylation‐site L309Δ C subunit mutant, which decrease intracellular methylated C and Bα levels, block N2a cell differentiation and LCMT1‐mediated neurite formation. Lastly, inducible and non‐inducible knockdown of Bα in N2a cells inhibit process outgrowth. Altogether, our results establish a novel mechanistic link between PP2A methylation and development of neurite‐like processes.
Regulation and role of cyclin‐dependent kinase activity in neuronal survival and death
Authors: Hisanaga Shin‐ichi , Endo Ryo 
Published: October 2010

J. Neurochem. (2010) 115, 1309–1321.AbstractCyclin‐dependent kinase (Cdk)5 is a proline‐directed Ser/Thr protein kinase that functions mainly in neurons and is activated by binding to a regulatory subunit, p35 or p39. Kinase activity is mainly determined by the amount of p35 available, which is controlled by a balance between synthesis and degradation. Kinase activity is also regulated by Cdk5 phosphorylation, but the activity of phosphorylated Cdk5 is in contrast to that of cycling Cdks. Cdk5 is a versatile protein kinase that regulates multiple neuronal activities including neuronal migration and synaptic signaling. Further, Cdk5 plays a role in both survival and death of neurons. Long‐term inactivation of Cdk5 triggers cell death, and the survival activity of Cdk5 is apparent when neurons suffer from stress. In contrast, hyper‐activation of Cdk5 by p25 promotes cell death, probably by reactivating cell‐cycle machinery in the nucleus. The pro‐death activity is suppressed by membrane association of Cdk5 via myristoylation of p35. Appropriate activity, localization, and regulation of Cdk5 may be critical for long‐term survival of neurons, which is more than 80 years in the case of humans.
A Mock Circulatory System With Physiological Distribution of Terminal Resistance and Compliance: Application for Testing the Intra‐Aortic Balloon Pump
Authors: Kolyva Christina , Biglino Giovanni , Pepper John R. , Khir Ashraf W. 
Published: October 2010

AbstractA mock circulatory system (MCS) was designed to replicate a physiological environment for in vitro testing and was assessed with the intra‐aortic balloon pump (IABP). The MCS was comprised of an artificial left ventricle (LV), connected to a 14‐branch polyurethane‐compound aortic model. Physiological distribution of terminal resistance and compliance according to published data was implemented with capillary tubes of different sizes and syringes of varying air volume, respectively, fitted at the outlets of the branches. The ends of the aortic branches were connected to a common tube representing the venous system and an overhead reservoir provided atrial pressure. An IABP operating a 40‐cc balloon was set to counterpulsate with the LV. Total arterial compliance of the system was 0.94 mL/mm Hg and total arterial resistance was 20.3 ± 3.3 mm Hg/L/min. At control, physiological flow distribution was achieved and both mean and phasic aortic pressure and flow were physiological. With the IABP, aortic pressure exhibited the major features of counterpulsation: diastolic augmentation during inflation, inflection point at onset of deflation, and end‐diastolic reduction at the end of deflation. The contribution of balloon inflation and deflation was also evident on the aortic flow pattern. This MCS was verified to be suitable for IABP testing and with further adaptations it could be used for studying other hemodynamic problems and ventricular assist devices.
Total Migraine Freedom, a Potential Primary Endpoint to Assess Acute Treatment in Migraine: Comparison to the Current FDA Requirement Using the Complete Rizatriptan Study Database
Authors: Rodgers Anthony J. , Hustad Carolyn M. , Cady Roger K. , Martin Vincent T. , Winner Paul , Ramsey Karen E. , Ho Tony W. 
Published: October 2010

Objective.— To examine total migraine freedom (TMF), defined as pain freedom and absence of associated symptoms, using rizatriptan clinical trial data and to explore advantages of TMF as a single primary composite efficacy endpoint.Background.— The FDA has set a higher regulatory hurdle for registration of new migraine agents requiring both pain freedom (or relief) and absence of each associated symptom (phonophobia, photophobia, and nausea).Methods.— Twelve studies representing phase III + efficacy/safety studies of rizatriptan 10 mg in adults treating migraine were included in the meta‐analysis. The percentage of patients achieving TMF at 2 hours by study and combined by treatment group was summarized by treatment paradigm (early/mild pain, moderate/severe, menstrual migraine). To demonstrate the impact of the strict migraine regulatory hurdle on clinical trial design and to compare it to TMF, simulation via bootstrap sampling was used.Results.— Odds ratios (rizatriptan vs placebo, all P < .001) for TMF were 6.2 (95% CI: [4.9, 7.7]) for moderate/severe, 2.7 (95% CI: [1.8, 4.0]) for menstrual, and 3.1 (95% CI: [2.4, 4.0]) for early/mild. Most with moderate/severe migraine reported photophobia and/or phonophobia at baseline, but only half had nausea. Simulation results showed a substantial loss of power analyzing absence of pain and each symptom compared with the composite TMF endpoint across all treatment paradigms.Conclusion.— Rizatriptan 10 mg was superior to placebo in achieving TMF at 2 hours post‐dose across all treatment paradigms. Given that the majority of patients with migraine do not exhibit all 3 associated symptoms, the TMF endpoint has significant advantages vs establishing efficacy on pain and each symptom individually.
Life Cycle Assessment of Water Supply Plans in Mediterranean Spain
Authors: Muñoz Ivan , Milà‐i‐Canals Llorenç , Fernández‐Alba Amadeo R. 
Published: October 2010

SummaryLife cycle assessment (LCA) was used to compare the current water supply planning in Mediterranean Spain, the so‐called AGUA Programme, with its predecessor, the Ebro river water transfer (ERWT). Whereas the ERWT was based on a single interbasin transfer, the AGUA Programme excludes new transfers and focuses instead on different types of resources, including seawater and brackish water desalination and wastewater reuse, among others. The study includes not only water supply but the whole anthropic cycle of water, from water abstraction to wastewater treatment. In addition to standard LCA impact categories, a specific impact category focusing on freshwater resources is included, which takes into account freshwater scarcity in the affected water catchments. In most impact categories the AGUA Programme obtains similar or even lower impact scores than ERWT. Concerning impacts on freshwater resources, the AGUA Programme obtains an impact score 49% lower than the ERWT. Although the current water planning appears to perform better in many impact categories than its predecessor, this study shows that water supply in Spanish Mediterranean regions is substantially increasing its energy intensity and that Mediterranean basins suffer a very high level of water stress due to increasing demand and limited resources.
A High‐Resolution Statistical Model of Residential Energy End Use Characteristics for the United States
Authors: Min Jihoon , Hausfather Zeke , Lin Qi Feng 
Published: October 2010

SummaryThe absence of detailed information on residential energy end use characteristics for the United States has in the past presented an impediment to the effective development and targeting of residential energy efficiency programs. This article presents a framework for modeling space heating, cooling, water heating, and appliance energy end uses, fuels used, and carbon emissions at a zip code–level resolution for the entire United States. It combines a regression‐based statistical model derived from Residential Energy Consumption Survey data with U.S. census 2000 five‐digit zip code level information, climate division–level temperature data, and other sources. The results show large variations in energy use characteristics both between and within different regions of the country, with particularly notable differences in the magnitude of and distribution by fuel of residential energy use in urban and rural areas. The results are validated against residential energy sales data and have useful implications for both residential energy efficiency planning and further study of variations in use patterns.