bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive characterization of the DNA amplification at 13q34 in human breast cancer reveals TFDP1 and CUL4A as likely candidate target genes
Authors: Melchor Lorenzo , Saucedo-Cuevas Laura Paula , Muñoz-Repeto Iván , Rodríguez-Pinilla Socorro María , Honrado Emiliano , Campoverde Alfredo , Palacios Jose , Nathanson Katherine L , García María José , Benítez Javier
Published: December 2009

Introduction

Breast cancer subtypes exhibit different genomic aberration patterns with a tendency for high-level amplifications in distinct chromosomal regions. These genomic aberrations may drive carcinogenesis through the upregulation of proto-oncogenes. We have characterized DNA amplification at the human chromosomal region 13q34 in breast cancer.

Methods

A set of 414 familial and sporadic breast cancer cases was studied for amplification at region 13q34 by fluorescence in situ hybridization (FISH) analysis on tissue microarrays. Defining the minimal common region of amplification in those cases with amplification at 13q34 was carried out using an array-based comparative genomic hybridization platform. We performed a quantitative real-time - polymerase chain reaction (qRT-PCR) gene expression analysis of 11 candidate genes located within the minimal common region of amplification. Protein expression levels of two of these genes (TFDP1 and CUL4A) were assessed by immunohistochemical assays on the same tissue microarrays used for FISH studies, and correlated with the expression of a panel of 33 antibodies previously analyzed.

Results

We have found 13q34 amplification in 4.5% of breast cancer samples, but the frequency increased to 8.1% in BRCA1-associated tumors and to 20% in basal-like tumors. Tumors with 13q34 amplification were associated with high grade, estrogen receptor negativity, and expression of EGFR, CCNE, CK5, and P-Cadherin, among other basal cell markers. We have defined a 1.83 megabases minimal common region of genomic amplification and carried out mRNA expression analyses of candidate genes located therein, identifying CUL4A and TFDP1 as the most likely target genes. Moreover, we have confirmed that tumors with 13q34 amplification significantly overexpress CUL4A and TFDP1 proteins. Tumors overexpressing either CUL4A or TFDP1 were associated with tumor proliferation and cell cycle progression markers.

Conclusions

We conclude that 13q34 amplification may be of relevance in tumor progression of basal-like breast cancers by inducing overexpression of CUL4A and TFDP1, which are both important in cell cycle regulation. Alternatively, as these genes were also overexpressed in non-basal-like tumor samples, they could play a wider role in cancer development by inducing tumor proliferation.
Robust train formation planning
Authors: Shafia M A , Sadjadi S J , Jamili A
Published: December 2009

Train formation planning models determine the routing and frequency of trains and assign the wagons to trains. In this article, a new robust mixed integer model for the train formation problems is proposed where the input data are subject to uncertainty. The optimal solution of the proposed model of this article is believed to be difficult to determine and a heuristic approach to find the near-optimal solution is presented. The implementation of the proposed model of this article is demonstrated for a real-world case study and the results are discussed.
Fuzzy supervisor approach on logic-based switching H2/H∞
Authors: Jamshidi F , Fakharian A , Beheshti M T H
Published: December 2009

In this paper the synthesis of a logic-based switching H2/ H∞ state-feedback controller for continuous-time linear time-invariant (LTI) singular perturbation systems is considered which achieves a minimum limit on the H2 performance level, while satisfying the H∞ performance. The proposed hybrid control scheme is based on a fuzzy supervisor, which manages the combination of controllers. A convex linear matrix inequality (LMI)-based formulation of the fast and slow subsystem controllers leads to a ε-independent structure which ensures a good performance in both the transient phase and the steady-state phase. The stability analysis uses the Lyapunov technique, inspired from switching system theory, to prove that the system with the proposed controller remains globally stable, despite the configuration (controller) changing. Simulations show that the proposed non-linear scheme composed of two low-order controllers improves the performance in comparison with the linear optimal scheme with higher order designed for a full-order system.
Investment in Schooling and the Marriage Market
Authors: Chiappori Pierre-André , Iyigun Murat , Weiss Yoram
Published: December 2009

We present a model in which investment in schooling generates two kinds of returns: the labor-market return, resulting from higher wages, and a marriage-market return, defined as the impact of schooling on the marital surplus share one can extract. Men and women may have different incentives to invest in schooling because of different market wages or household roles. This asymmetry can yield a mixed equilibrium with some educated individuals marrying uneducated spouses. When the labor-market return to schooling rises, home production demands less time, and the traditional spousal labor division norms weaken, more women may invest in schooling than men. (JEL I21, J12, J24, J31)
Adaptation and Vertical Integration in the Airline Industry
Authors: Forbes Silke Januszewski , Lederman Mara
Published: December 2009

We explore patterns of vertical integration in the US airline industry. Major airlines subcontract portions of their network to regional partners, which may or may not be owned. We investigate if ownership economizes on ex post renegotiation costs. We estimate whether airlines are more likely to use owned regionals on city pairs with adverse weather (which makes adaptation decisions more frequent) and on city pairs that are more integrated into the major's network (which raises the costs of having adaptation decisions resolved suboptimally). Our results suggest a robust empirical relationship between adaptation and vertical integration in this setting. (JEL L14, L22, L24, L93)
Naked Exclusion: An Experimental Study of Contracts with Externalities
Authors: Landeo Claudia M. , Spier Kathryn E.
Published: December 2009

This paper reports the results of an experiment on exclusive contracts. We replicate the strategic environment described by Rasmusen, Ramseyer, and Wiley (1991) and Segal and Whinston (2000). Our findings are as follows. First, when the buyers can communicate, discrimination raises the likelihood of exclusion. Second, when the incumbent seller is unable to discriminate and must make the same offers to the buyers, communication reduces the likelihood of exclusion. Communication also induces more generous offers when the seller cannot discriminate, and divide-and-conquer offers when the seller can discriminate. Third, when communication is allowed, payoff endogeneity increases the likelihood of exclusion. (JEL C72, C91, D62, D86, K12, K21, L12, L42)
The Relative Performance of Real Estate Marketing Platforms: MLS versus FSBOMadison.com
Authors: Hendel Igal , Nevo Aviv , Ortalo-Magné François
Published: December 2009

We compare house sales on a For-Sale-By-Owner (FSBO) platform to Multiple Listing Service (MLS) sales and find that FSBO precommission prices are no lower, but that FSBO is less effective in terms of time to sell and probability of a sale. We do not find direct evidence of the importance of network size as a reason for the lower effectiveness of FSBO. We do find evidence of endogenous platform differentiation: patient sellers use FSBO while patient buyers transact more often on the MLS (where they avoid patient sellers). We discuss the implications for platform competition, two-sided markets, and welfare. (JEL L85, M31, R31)
Innovation Diffusion in Heterogeneous Populations: Contagion, Social Influence, and Social Learning
Authors: Young H. Peyton
Published: December 2009

New ideas, products, and practices take time to diffuse, a fact that is often attributed to some form of heterogeneity among potential adopters. This paper examines three broad classes of diffusion models—contagion, social influence, and social learning—and shows how to incorporate heterogeneity into each at a high level of generality without losing analytical tractability. Each type of model leaves a characteristic “footprint” on the shape of the adoption curve which provides a basis for discriminating empirically between them. The approach is illustrated using the classic study of Ryan and Gross (1943) on the diffusion of hybrid corn. (JEL D83, O33, Q16, Z13)
A Theory of Demand Shocks
Authors: Lorenzoni Guido
Published: December 2009

This paper presents a model of business cycles driven by shocks to consumer expectations regarding aggregate productivity. Agents are hit by heterogeneous productivity shocks, they observe their own productivity and a noisy public signal regarding aggregate productivity. The public signal gives rise to “noise shocks,” which have the features of aggregate demand shocks: they increase output, employment, and inflation in the short run and have no effects in the long run. Numerical examples suggest that the model can generate sizable amounts of noise-driven volatility. (JEL D83, D84, E21, E23, E32)
Intra-Industry Foreign Direct Investment
Authors: Alfaro Laura , Charlton Andrew
Published: December 2009

We use a new firm-level dataset that establishes the location, ownership, and activity of 650,000 multinational subsidiaries. Using a combination of four-digit-level information and input-output tables, we find the share of vertical FDI (subsidiaries that provide inputs to their parent firms) to be larger than commonly thought, even within developed countries. Most subsidiaries are not readily explained by the comparative advantage considerations whereby multinationals locate activities abroad to take advantage of factor cost differences. Instead, multinationals tend to own the stages of production proximate to their final production, giving rise to a class of high-skill, intra-industry vertical FDI. (JEL G11, J32)
Media Markets and Localism: Does Local News en Español Boost Hispanic Voter Turnout?
Authors: Oberholzer-Gee Felix , Waldfogel Joel
Published: December 2009

In the past decade Americans have increasingly turned their attention to nonlocal information sources, raising concerns about disengagement from local communities. Regulation sometimes seeks to curtail the integration of media markets through the promotion of “localism.” This paper examines the role of local media. We make use of the rapid growth of Hispanic communities in the United States to test whether the presence of local television news affects local civic behavior. We find that Hispanic voter turnout increased by 5 to 10 percentage points, relative to non-Hispanic turnout, in markets where Spanish-language local television news became available. (JEL D72, J15, L82)
Departure Times in Y-Shaped Traffic Networks with Multiple Bottlenecks
Authors: Daniel Terry E. , Gisches Eyran J. , Rapoport Amnon
Published: December 2009

We study the departure time decisions of commuters traversing a traffic network with the goal of arriving at a common destination at a specified time. There are costs associated with arriving either too early or too late, and with delays experienced at bottlenecks. Our main hypothesis, based on the Nash equilibrium distribution of departure times, implies that, for certain parameter values, expanding the capacity of an upstream bottleneck can increase the total travel costs in the network. We report the results of a large-group laboratory experiment, which are strongly supportive of this counterintuitive hypothesis, and we discuss the implications. (JEL D85, R41)
Technology, International Trade, and Pollution from US Manufacturing
Authors: Levinson Arik
Published: December 2009

Pollution emitted by US manufacturers declined markedly over the past several decades, even as real manufacturing output increased. I first show that most of the decline in US manufacturing pollution has resulted from changing production processes (“technology”), rather than changes in the mix of goods produced. I then show that increased net imports of polluting goods (“international trade”) accounts for only a small portion of the pollution reductions from the changing mix of goods. Together, these two findings demonstrate that shifting polluting industries overseas explains only a minor part—less than 10 percent—of the cleanup of US manufacturing. (JEL F18, L23, L60, O30, Q52, Q53)
The Retirement Consumption Puzzle: Evidence from a Regression Discontinuity Approach
Authors: Battistin Erich , Brugiavini Agar , Rettore Enrico , Weber Guglielmo
Published: December 2009

We investigate the size of the consumption drop at retirement in Italy by exploiting pension eligibility information to correct for endogenous retirement. We take a regression discontinuity approach and assume that spending would be smooth around pension eligibility if individuals did not retire. We estimate a 9.8 percent drop associated to retirement. This fall is not driven by liquidity problems for the less well off and can be accounted for by drops in work-related expenses. Retirement also induces a significant drop in the number of grown children living with their parents and this explains most of the retirement consumption drop. (JEL D91, E21, J26, J31)
Direct Democracy and Public Employees
Authors: Matsusaka John G.
Published: December 2009

In the public sector, employment may be inefficiently high because of patronage, and wages may be inefficiently high because of public employee interest groups. This paper explores whether the initiative process, a direct democracy institution of growing importance, ameliorates these political economy problems. In a sample of 650+ cities, I find that when public employees cannot bargain collectively and patronage could be a problem, initiatives appear to cut employment but not wages. When public employees bargain collectively, driving up wages, the initiative appears to cut wages but not employment. The employment-cutting result is robust; the wage-cutting result survives some but not all robustness tests. (JEL D72, J31, J45, J52)
A Comment on the Economics of Labor Adjustment: Mind the Gap: Evidence from a Monte Carlo Experiment
Authors: Bayer Christian
Published: December 2009

This comment addresses a point raised in Russell Cooper and Jonathan Willis (2003, 2004), which discusses whether the “gap approach” is appropriate to describe the adjustment of production factors. They show that this approach to labor adjustment as applied in Ricardo J. Caballero, Eduardo Engel, and John C. Haltiwanger (1997) and Caballero and Engel (1993) can falsely generate evidence in favor of nonconvex adjustment costs, even if costs are quadratic. Simulating a dynamic model of firm-level employment decisions with quadratic adjustment costs and estimating a gap model from the simulated data, they identify two factors producing this spurious evidence: approximating dynamic adjustment targets by static ones, and estimating the static targets themselves. This comment reassesses whether the first factor indeed leads to spurious evidence in favor of fixed adjustment costs. We show that the numerical approximation of the productivity process is pivotal for Cooper and Willis's finding. With more precise approximations of the productivity process, it becomes rare to falsely reject the quadratic adjustment cost model due to the approximation of dynamic targets by static ones. (JEL E24, J3)
Series Jackson Networks and Noncrossing Probabilities
Authors: Dieker A. B. , Warren J.
Published: December 2009

This paper studies the queue-length process in series Jackson networks with external input to the first station only. We show that its Markov transition probabilities can be written as a finite sum of noncrossing probabilities, so that questions on time-dependent queueing behavior are translated to questions on noncrossing probabilities. This makes previous work on noncrossing probabilities relevant to queueing systems and allows new queueing results to be established. To illustrate the latter, we prove that the relaxation time (i.e., the reciprocal of the “spectral gap”) of a positive recurrent system equals the relaxation time of an M/M/1 queue with the same arrival and service rates as the network's bottleneck station. This resolves a conjecture of Blanc that he proved for two queues in series.
A Plant Location Guide for the Unsure: Approximation Algorithms for Min-Max Location Problems
Authors: Anthony Barbara , Goyal Vineet , Gupta Anupam , Nagarajan Viswanath
Published: December 2009

This paper studies an extension of the k-median problem under uncertain demand. We are given an n-vertex metric space (V, d) and m client sets [Formula: see text]. The goal is to open a set of k facilities F such that the worst-case connection cost over all the client sets is minimized, i.e., [Formula: see text] where for any [Formula: see text], [Formula: see text]. This is a “min-max” or “robust” version of the k-median problem. Note that in contrast to the recent papers on robust and stochastic problems, we have only one stage of decision-making where we select a set of k facilities to open. Once a set of open facilities is fixed, each client in the uncertain client-set connects to the closest open facility. We present a simple, combinatorial O(log n + log m)-approximation algorithm for the robust k-median problem that is based on reweighting/Lagrangean-relaxation ideas. In fact, we give a general framework for (minimization) k-facility location problems where there is a bound on the number of open facilities. We show that if the location problem satisfies a certain “projection” property, then both the robust and stochastic versions of the location problem admit approximation algorithms with logarithmic ratios. We use our framework to give the first approximation algorithms for robust and stochastic versions of several location problems such as k-tree, capacitated k-median, and fault-tolerant k-median.
An Integrated Solver for Optimization Problems
Authors: Yunes Tallys , Aron Ionuţ D. , Hooker J. N.
Published: December 2009

One of the central trends in the optimization community over the past several years has been the steady improvement of general-purpose solvers. A logical next step in this evolution is to combine mixed-integer linear programming, constraint programming, and global optimization in a single system. Recent research in the area of integrated problem solving suggests that the right combination of different technologies can simplify modeling and speed up computation substantially. Nevertheless, integration often requires special-purpose coding, which is time consuming and error prone. We present a general-purpose solver, SIMPL, that allows its user to replicate (and sometimes improve on) the results of custom implementations with concise models written in a high-level language. We apply SIMPL to production planning, product configuration, machine scheduling, and truss structure design problems on which customized integrated methods have shown significant computational advantage. We obtain results that either match or surpass the original codes at a fraction of the implementation effort.
Capacity Rationing in Stochastic Rental Systems with Advance Demand Information
Authors: Papier Felix , Thonemann Ulrich W.
Published: December 2009

Many companies have started segmenting customers to better match their products and services to the needs of the customers. We support this development by presenting a stochastic model of a rental system with two customer classes that was motivated by the operations of one of Europe's leading logistics companies. At the company, customers can choose between premium and classic service. Under premium service, customers provide advance demand information (ADI) by reserving cars ahead of the time when they need them, and they receive a service guarantee in return. Under classic service, customers do not make a reservation and do not receive a service guarantee. Because both demand classes access a common pool of cars, the company must decide which demands to fill and which to reject. The admission decision must be made without knowing the rental duration, which is an exponentially distributed random variable. We model the system as a multiserver loss system and prove that the optimal admission policy is a threshold policy. Because computing the parameters of the policy is computationally intractable, we propose an ADI policy that can be implemented and executed with moderate effort. We analyze the performance of our ADI policy by analytically deriving upper and lower bounds on the optimal expected profit and by performing numerical experiments using data from the logistics company that motivated our research. The numerical experiments indicate that the potential benefit of using ADI is significant and that our ADI policy performs close to optimal. Finally, we extend our model to a different cost structure and to multiple ADI classes.
Rescheduling for Job Unavailability
Authors: Hall Nicholas G. , Potts Chris N.
Published: December 2009

This paper considers scheduling problems where the processing of a set of jobs has been scheduled (i.e., planned) to minimize a classical cost objective, under the assumption that the jobs are all available at the start of the planning horizon. Before processing starts, however, the availability of a subset of the jobs is delayed. Therefore, the decision maker needs to adjust the existing schedule to allow for the initial unavailability of those jobs, but without causing excessive disruption to the schedule and expensive resource reallocations. The limit on allowable disruption is measured by the maximum time disruption to any job, between the original and adjusted schedules. For the classical sum of weighted completion times scheduling objective, we provide a computationally efficient optimal algorithm and an intractability proof showing that such an algorithm is the best possible type of result. Also, we provide a linear time approximate solution procedure, show that its worst-case performance ratio is a small constant, and demonstrate computationally that its average performance is very close to optimal. Finally, we provide a fully polynomial time approximation scheme. We also summarize analogous results for three other classical scheduling objectives. Our work is among the first to develop optimal algorithms, heuristics with guaranteed performance bounds, and approximation schemes, for rescheduling problems.
Peripheral Blood Stem Cell Mobilization Tactics
Authors: Rosenbeck Lindsay L , Srivastava Shivani , Kiel Patrick J
Published: December 2009

OBJECTIVE

To evaluate the methods and collection techniques currently used in stem cell mobilization for patients undergoing autologous transplantation.

DATA SOURCES

Literature search was performed through PubMed (1948-August 2009) and MEDLINE (1977-August 2009). Reference citations from publications identified were also reviewed.

STUDY SELECTION AND DATA EXTRACTION

All literature identified was reviewed for inclusion. Original research and retrospective cohorts, along with previously published systematic reviews of stem cell mobilization and growth factors, were evaluated. Abstract data on plerixafor were also reviewed.

DATA SYNTHESIS

Successful mobilization of an adequate number of progenitor cells can help ensure and improve time to neutrophil and platelet engraftment. A variety of methods have been studied to find the safest and most predictable mobilization of CD34+ progenitor cells, including use of single agents or the combinations of hematopoietic growth factors, chemotherapy, and a novel chemokine receptor 4 antagonist. Currently, granulocyte colony-stimulating factor (G-CSF) 10 Mg/kg daily started 4 days prior to apheresis remains the standard of care for initial mobilization therapy. In patients who fail to mobilize or who are at high risk for mobilization failure, cyclophosphamide in conjunction with G-CSF may be used. Plerixafor, a novel chemokine receptor antagonist, in combination with G-CSF has demonstrated superiority for achieving collection goals compared to G-CSF alone in 2 Phase 3 trials.

CONCLUSIONS

The optimal mobilization strategy is still unknown; however, colony-stimulating factors remain the most commonly used mobilization agents. Currently, chemotherapy or plerixafor in combination with G-CSF is a reasonable option in heavily pretreated and hard-to-mobilize patients with non-Hodgkin's lymphoma and multiple myeloma.
Nonnucleoside Reverse Transcriptase Inhibitor Resistance and the Role of the Second-Generation Agents
Authors: Adams Jessica , Patel Nimish , Mankaryous Nancy , Tadros Mariam , Miller Christopher D
Published: December 2009

OBJECTIVE

To review the current state of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance, discuss the promising role of second-generation NNRTIs, and provide insight into their clinical utility.

DATA SOURCES

Articles were identified through searches of MEDLINE (May 2000-August 2009) and International Pharmaceutical Abstracts (May 1998-August 2009), using the key words etravirine, rilpivirine, TMC125, TMC278, diarylpyrimidine, NNRTI, and resistance.

STUDY SELECTION AND DATA EXTRACTION

Clinical trials, resistance studies, and pharmacokinetic data were selected for review.

DATA SYNTHESIS

NNRTIs are an integral class of antiretroviral agents utilized for the treatment of HIV-1 infection. These agents have become preferred therapy options for treatment-naïve individuals per treatment guideline recommendations and have gained increased popularity over protease inhibitor-based antiretroviral therapy. However, available NNRTIs possess inherent characteristics, such as low genetic barrier to resistance and high degree of cross-resistance, that limit their use in HIV therapy. Due to the growing utilization of this highly efficacious antiretroviral class and the increased capability for resistance development, many HIV-infected patients have experienced treatment failure of an NNRTI. Cross-resistance makes other first-generation NNRTI agents unavailable for future use. Etravirine and rilpivirine are second-generation NNRTIs that are not significantly hampered by cross-resistance and possess potent antiretroviral activity against current NNRTI-resistant viral strains. These agents provide new and important therapy options for many HIV-infected patients.

CONCLUSIONS

NNRTI resistance is an increasing problem that may impair the chances for therapeutic success in HIV-infected patients. Novel agents such as etravirine and rilpivirine provide new, sensitive options for patients and significantly improve the rate of virologic suppression when appropriately applied.
Olfactory Impairment Predicts Brain Atrophy in Parkinson's Disease: Figure 1.
Authors: Wattendorf Elise , Welge-Lüssen Antje , Fiedler Klaus , Bilecen Deniz , Wolfensberger Markus , Fuhr Peter , Hummel Thomas , Westermann Birgit
Published: December 2009

Olfactory dysfunction is a frequent nonmotor symptom in idiopathic Parkinson's disease (PD) and may be considered as an early clinical feature of the disease preceding motor symptoms by years. According to recent neuropathological staging concepts, impaired olfaction is assumed to indicate an early pathological process and might be associated with structural changes in the brain. A morphometric analysis of magnetic resonance images [voxel-based morphometry (VBM)] was used to investigate gray matter atrophy related to psychophysically measured scores of olfactory function in early PD patients (n= 15, median Hoehn and Yahr stage 1.5), moderately advanced PD patients (n= 12, median Hoehn and Yahr stage 2.5), and age-matched healthy controls (n= 17). In PD patients, but not in controls, cortical atrophy in olfactory-related brain regions correlated specifically with olfactory dysfunction. Positive correlations between olfactory performance and gray matter volume were observed in the right piriform cortex in early PD patients and in the right amygdala in moderately advanced patients. The results provided first evidence that olfactory dysfunction in PD is related to atrophy in olfactory-eloquent regions of the limbic and paralimbic cortex. In addition, olfactory-correlated atrophy in these brain regions is consistent with the assumption that olfactory impairment as an early symptom of PD is likely to be associated with extranigral pathology.
cAMP-Dependent Axon Guidance Is Distinctly Regulated by Epac and Protein Kinase A
Authors: Murray Andrew J. , Tucker Steven J. , Shewan Derryck A.
Published: December 2009

cAMP is a key mediator of a number of molecules that induce growth cone chemotaxis, including netrin-1 and myelin-associated glycoprotein (MAG). Endogenous neuronal cAMP levels decline during development, and concomitantly axonal growth cones switch their response to cAMP-dependent guidance cues from attraction to repulsion. The mechanisms by which cAMP regulates these polarized growth cone responses are unknown. We report that embryonic growth cone attraction to gradients of cAMP, netrin-1, or MAG is mediated by Epac. Conversely, the repulsion conferred by MAG or netrin-1 on adult growth cones is mediated by protein kinase A (PKA). Furthermore, fluorescence resonance energy transfer reveals that netrin-1 distinctly activates Epac in embryonic growth cones but PKA in postnatal neurons. Our results suggest that cAMP mediates growth cone attraction or repulsion by distinctly activating Epac or PKA, respectively. Moreover, we propose that the developmental switch in growth cone response to gradients of cAMP-dependent guidance cues from attraction to repulsion is the result of a switch from Epac- to PKA-mediated signaling pathways.
Altered Sleep Homeostasis after Restraint Stress in5-HTTKnock-Out Male Mice: A Role for Hypocretins
Authors: Rachalski Adeline , Alexandre Chloé , Bernard Jean-François , Saurini Françoise , Lesch Klaus-Peter , Hamon Michel , Adrien Joëlle , Fabre Véronique
Published: December 2009

Restraint stress produces changes in the sleep pattern that are mainly characterized by a delayed increase in rapid eye movement sleep (REMS) amounts. Because the serotonin (5-HT) and the hypocretin (hcrt) systems that regulate REMS are interconnected, we used mutant mice deficient in the 5-HT transporter (5-HTT−/−) to examine the role of 5-HT and hcrt neurotransmissions in the sleep response to stress.

In contrast to wild-type mice, restraint stress did not induce a delayed increase in REMS amounts in5-HTT−/−mice, indicating impaired sleep homeostasis in mutants. However, pharmacological blockade of the hcrt type 1 receptor (hcrt-R1) before restraint stress restored the REMS increase in5-HTT−/−mice. In line with this finding,5-HTT−/−mutants displayed after restraint stress higher long-lasting activation of hypothalamic preprohcrt neurons than wild-type mice and elevated levels of the hcrt-1 peptide and the hcrt-R1 mRNA in the anterior raphe area. Thus, hypocretinergic neurotransmission was enhanced by stress in5-HTT−/−mice. Furthermore, in5-HTT−/−but not wild-type mice, hypothalamic levels of the 5-HT metabolite 5-hydroxyindole acetic acid significantly increased after restraint stress, indicating a marked enhancement of serotonergic neurotransmission in mutants.

Altogether, our data show that increased serotonergic -and in turn hypocretinergic- neurotransmissions exert an inhibitory influence on stress-induced delayed REMS. We propose that the direct interactions between hcrt neurons in the hypothalamus and 5-HT neurons in the anterior raphe nuclei account, at least in part, for the adaptive sleep–wakefulness regulations triggered by acute stress.
No Nogo66- and NgR-Mediated Inhibition of Regenerating Axons in the Zebrafish Optic Nerve
Authors: Abdesselem Houari , Shypitsyna Aleksandra , Solis Gonzalo P. , Bodrikov Vsevolod , Stuermer Claudia A. O.
Published: December 2009

In contrast to mammals, lesioned axons in the zebrafish (ZF) optic nerve regenerate and restore vision. This correlates with the absence of the NogoA-specific N-terminal domains from the ZFnogo/rtn-4(reticulon-4) gene that inhibits regeneration in mammals. However, mammaliannogo/rtn-4carries a second inhibitory C-terminal domain, Nogo-66, being 70% identical with ZF-Nogo66. The present study examines, (1) whether ZF-Nogo66 is inhibitory and effecting similar signaling pathways upon Nogo66-binding to the Nogo66 receptor NgR and its coreceptors, and (2) whether Rat-Nogo66 on fish, and ZF-Nogo66 on mouse neurons, cause inhibition via NgR. Our results from “outgrowth, collapse and contact assays” suggest, surprisingly, that ZF-Nogo66 is growth-permissive for ZF and mouse neurons, quite in contrast to its Rat-Nogo66 homolog which inhibits growth. The opposite effects of ZF- and Rat-Nogo66 are, in both fish and mouse, transmitted by GPI (glycosylphosphatidylinositol)-anchored receptors, including NgR. The high degree of sequence homology in the predicted binding site is consistent with the ability of ZF- and mammalian-Nogo66 to bind to NgRs of both species. Yet, Rat-Nogo66 elicits phosphorylation of the downstream effector cofilin whereas ZF-Nogo66 has no influence on cofilin phosphorylation—probably because of significantly different Rat- versus ZF-Nogo66 sequences outside of the receptor-binding region effecting, by speculation, recruitment of a different set of coreceptors or microdomain association of NgR. Thus, not only was the NogoA-specific domain lost in fish, but Nogo66, the second inhibitory domain in mammals, and its signaling upon binding to NgR, was modified so that ZF-Nogo/RTN-4 does not impair axon regeneration.
NFIL3 and cAMP Response Element-Binding Protein Form a Transcriptional Feedforward Loop that Controls Neuronal Regeneration-Associated Gene Expression
Authors: MacGillavry Harold D. , Stam Floor J. , Sassen Marion M. , Kegel Linde , Hendriks William T. J. , Verhaagen Joost , Smit August B. , van Kesteren Ronald E.
Published: December 2009

Successful regeneration of damaged neurons depends on the coordinated expression of neuron-intrinsic genes. At present however, there is no comprehensive view of the transcriptional regulatory mechanisms underlying neuronal regeneration. We used high-content cellular screening to investigate the functional contribution of 62 transcription factors to regenerative neuron outgrowth. Ten transcription factors are identified that either increase or decrease neurite outgrowth. One of these, NFIL3, is specifically upregulated during successful regenerationin vivo. Paradoxically however, knockdown of NFIL3 and overexpression of dominant-negative NFIL3 both increase neurite outgrowth. Our data show that NFIL3, together with CREB, forms an incoherent feedforward transcriptional regulatory loop in which NFIL3 acts as a negative regulator of CREB-induced regeneration-associated genes.
Dramatic Reduction of PrPCLevel and Glycosylation in Peripheral Nerves following PrP Knock-Out from Schwann Cells Does Not Prevent Transmissible Spongiform Encephalopathy Neuroinvasion
Authors: Bradford Barry M. , Tuzi Nadia L. , Feltri M. Laura , McCorquodale Caroline , Cancellotti Enrico , Manson Jean C.
Published: December 2009

Expression of the prion protein (PrPC) is a requirement for host susceptibility to the transmissible spongiform encephalopathies (TSEs) and thought to be necessary for the replication and transport of the infectious agent. The mechanism of TSE neuroinvasion is not fully understood, although the routing of infection has been mapped through the peripheral nervous system (PNS) and Schwann cells have been implicated as a potential conduit for transport of the TSE infectious agent. To address whether Schwann cells are a requirement for spread of the TSE agent from the site of infection to the CNS, PrPCexpression was selectively removed from Schwann cellsin vivo. This dramatically reduced total PrPCwithin peripheral nerves by 90%, resulting in the selective loss of glycosylated PrPCspecies. Despite this, 139A and ME7 mouse-passaged scrapie agent strains were efficiently replicated and transported to the CNS following oral and intraperitoneal exposure. Thus, the myelinating glial cells within the PNS do not appear to play a significant role in TSE neuroinvasion.
Functional Excitatory Microcircuits in Neonatal Cortex Connect Thalamus and Layer 4
Authors: Zhao Cuiping , Kao Joseph P. Y. , Kanold Patrick O.
Published: December 2009

The functional connectivity of the cerebral cortex is shaped by experience during development, especially during a critical period early in life. In the prenatal and neonatal cortex, transient neuronal circuits are formed by a population of subplate neurons (SPNs). However, SPNs are absent in the adult cortex. While SPNs are crucial for normal development of the cerebral cortex and of thalamocortical synapses, little is known about how they are integrated in the developing thalamocortical circuit. We therefore investigated SPNsin vitroin thalamocortical slices of A1 and medial geniculate nucleus (MGN) in mouse from postnatal day 1 (P1) to P13. We found that SPNs can fire action potentials at P1 and that their intrinsic membrane properties are mature after P5. We find that SPNs receive functional excitatory inputs from the MGN as early as P2. The MGN projections to SPNs strengthen between P2 and P13 and are capable of inducing action potentials in SPNs. Selective activation of SPNs by photostimulation produced EPSCs in layer 4 neurons, demonstrating a functional excitatory connection. Thus, SPNs are tightly integrated into the developing thalamocortical circuit and would be a reliable relay of early spontaneous and sound-evoked activity. The role of SPNs in development likely results from their strong excitatory projection to layer 4, which might function to regulate activity-dependent processes that enable mechanisms required for the functional maturation and plasticity of the developing cortex and thereby contribute to the development of normal cortical organization.
Distinct Dose-Dependent Cortical Neuronal Migration and Neurite Extension Defects inLis1andNdel1Mutant Mice
Authors: Youn Yong Ha , Pramparo Tiziano , Hirotsune Shinji , Wynshaw-Boris Anthony
Published: December 2009

Haploinsufficiency of LIS1 results in lissencephaly, a human neuronal migration disorder. LIS1 is a microtubule- (MT) and centrosome- [microtubule organizing center (MTOC)] associated protein that regulates nucleokinesis via the regulation of dynein motor function and localization. NDEL1 (NudE isoform, NudE like) interacts with LIS1/dynein complex, and is phosphorylated by CDK5/P35. Previous reports using siRNA-mediated knock-down demonstrated similar critical roles for LIS1 and NDEL1 during neuronal migration, but neuronal migration has not been studied in genetic mutants forLis1andNdel1where protein levels are uniform in all cells. Brains from mice with complete loss ofLis1andNdel1displayed severe cortical layering and hippocampal defects, butLis1mutants had more severe defects. Neuronal migration speed was reduced and neurite lengths were elongated in proportion to the reduction of LIS1 and NDEL1 protein levels in embryonic day 14.5 mutant cortical slices compared to wild type, using two-photon confocal time lapse videomicroscopy. Additionally, mice with 35% of wild-type NDEL1 levels displayed diverse branched migration modes with multiple leading processes, suggesting defects in adhesion and/or polarity. Complete loss ofLis1orNdel1resulted in the total inhibition of nuclear movement in cortical slice assays, and in neurosphere assays, the percentage of migrating neurons with correctly polarized MTOC location was significantly reduced while nuclear-centrosomal distance was extended. Neurite lengths were increased after complete lossNdel1but reduced after complete loss ofLis1. Thus,Lis1andNdel1are essential for normal cortical neuronal migration, neurite outgrowth, and function of the MTOC in a dose-dependent manner.
Diagnostic utility of the glucagon stimulation test in comparison to the insulin tolerance test in patients following pituitary surgery
Authors: Berg Christian , Meinel Timo , Lahner Harald , Yuece Ali , Mann Klaus , Petersenn Stephan
Published: December 2009

Objective

The glucagon stimulation test (GST) like the insulin tolerance test (ITT) stimulates both ACTH and GH secretion. However, there are limited data with modern assays on sensitivity and specificity for GST in comparison to ITT. The aim of this study was to evaluate the diagnostic utility of the GST for GH deficiency (GHD) and adrenal insufficiency (AI) in patients following pituitary surgery.

Design and patients

ITT and GST were performed within 7 days in 49 patients at least 3 months after transsphenoidal surgery. Serum GH and cortisol were measured by Immulite 2000 assay (Siemens AG). Receiver-operating characteristic (ROC) analysis was performed to identify the thresholds for GST.

Results

In ITT, 18/49 cases were classified as AI. ROC analysis revealed a peak cortisol value >599 nmol/l in GST for adrenal sufficiency with 100% specificity and 32% sensitivity, and a peak cortisol <277 nmol/l with >95% specificity and 72% sensitivity for AI. Of the 49 subjects, 25 (51%) demonstrated levels between these cut-offs and could not be diagnosed by GST alone with sufficient accuracy. Regarding GHD, 21/49 cases were classified as insufficient by ITT. ROC analysis revealed a cut-off of 2.5 ng/ml with 95% sensitivity and 79% specificity. Of the 49 cases, seven (14%) were discordant in terms of defining GHD, with six subjects being treated for GHD according to GST although being sufficient in ITT.

Conclusion

In our prospective series of patients with pituitary disease, GST is a potential alternative test for the assessment of GH reserve, but is a poor test for ACTH reserve. Test-specific cut-offs should be applied to avoid misinterpretation.
Immunoprotective Sertoli cells: making allogeneic and xenogeneic transplantation feasible
Authors: Mital Payal , Kaur Gurvinder , Dufour Jannette M
Published: December 2009

The testis as an immune-privileged site allows long-term survival of allogeneic and xenogeneic transplants. Testicular Sertoli cells (SCs) play a major role in this immunoprotection and have been used to create an ectopic immune-privileged environment that prolongs survival of co-transplanted allogeneic and xenogeneic cells, including pancreatic islets and neurons. Extended survival of such grafts testifies to the immunoprotective properties of SCs. However, there is still variability in the survival rates of the co-grafted cells and rarely are 100% of the grafts protected. This emphasizes the need to learn more about what is involved in creating the optimal immunoprotective milieu. Several parameters including organization of the SCs into tubule-like structures and the production of immunomodulatory factors by SCs, specifically complement inhibitors, cytokines, and cytotoxic lymphocyte inhibitors, are likely important. In addition, an intricate interplay between several of these factors may be responsible for providing the most ideal environment for protection of the co-transplants by SCs. In this review, we will also briefly describe a novel use for the immune-privileged abilities of SCs; engineering them to deliver therapeutic proteins for the treatment of diseases like diabetes and Parkinson's disease. In conclusion, further studies and more detailed analysis of the mechanisms involved in creating the immune-protective environment by SCs may make their application in co-transplantation and as engineered cells clinically feasible.
Endoscopic management of postoperative biliary injuries
Authors: Völgyi Zoltán , Fischer Tünde , Szenes Mária , Gasztonyi Beáta
Published: December 2009

Korábban a posztoperatív epeúti sérüléseket sebészi úton kezelték, azonban a 90-es évektől a sérülések ellátását az endoszkópos módszerek vették át. Ezen szövődmények elsősorban a laparoszkópos műtéteket követően fordulnak elő. Amennyiben epeúti sérülésre van gyanú, a szoros endoszkópos és sebészi együttműködés elengedhetetlen. Az epeutak mielőbbi endoszkópos vizualizációja szükséges a sérülések igazolására, illetve a lokalizáció megítélésére. Többfajta endoszkópos módszer is hatásos az epeműtét utáni sérülés kezelésére. A döntő tényező a duodenalis és a biliaris nyomás kiegyenlítése, ezáltal az epe elfolyásának biztosítása és a sérülés gyógyulásának elősegítése. Az önmagában végzett endoszkópos sphincterectomia vagy az endoszkópos sphincterectomia és az azt követő stentbehelyezés alkalmas erre. Epeúti szűkületek megoldására többszörös stentelés javasolt, amelynek hosszú távú hatásai is jó eredménnyel kecsegtetnek.
Modification of the Newton-Kantorovich Iteration Procedure for Piecewise-Constant Real Permittivity Profile Reconstruction
Authors: Alexin S. G. , Drobakhin O. O. , Tkachenko V. O.
Published: December 2009

The general Newton-Kantorovich method and its new modification for piecewise-constant real permittivity profile reconstruction on the basis of multifrequency reflectometry data are described. The method of spectral analysis based on the chain-fraction approximation is proposed to be used as stage of the modified Newton-Kantorovich method and is also described. Some results of numerical simulation are presented.
Method for Detection and Exclusion of Abnormal Values of the Sample Obtained from a Homogeneous General Population
Authors: Zakharov Ivan S. , Urazbachtin A. I.
Published: December 2009

The procedure for optimal detection and exclusion of abnormal observations from population of experimental data is proposed. Optimization is reached through maximization of the closeness of the homogeneous population parameter to the mean value of the censored sample.
Development of the Earth Remote Sensing Methods at IRE NAS of Ukraine
Authors: Ivanov V. K. , Yatsevich S. Ye.
Published: December 2009

History of development of radiophysical methods of remote sensing of terrain from aerospace facilities in A. Usikov Institute of Radio Physics and Electronics of NAS of Ukraine in the second half of the 20th century is considered. Main features of spacecraft and airborne side-looking radars are presented. Obtained results and prospects of development of remote sensing methods are discussed.