bluuebunny/crossref_metadata_2025 huggingface dataset:
Moldovan Media Talk in the Aftermath of the 2015 Riga Eastern Partnership Summit
Authors: Colăcel Onoriu
Published: February 2016

The delegation of the European Union to Moldova takes upon itself the task of making the case for the Association Agenda between the country and the EU. The European foreign policy in the borderlands of the Union is carried out against the background of the war in Eastern Ukraine. A war of words is being fought in Moldovan media as well. Mostly on Romanian-speaking TV, Pirkka Tapiola, the EU ambassador, is among those who lead the way. At a time of renewed Western concern about Eastern Europe, the media presence of the EU in Moldova reveals anxieties about the future: once again, the former Soviet republic seems to be teetering on the brink of Russian control. The breakaway region of Trans-Dniester and the prospect of default are the two main concerns that the EU mission has to address while speaking the language of European politics in a country battered by corruption, high inflation, and unemployment. The discourse of Pirkka Tapiola, Head of the EU delegation, is an exercise in spokesmanship, which seems to underplay the seriousness of the situation. According to opinion polls conducted recently, the avowedly pro-Russian parties would win the next election. In hindsight, it is possible to surmise that the pro-EU parties pulled off a political coup by deferring the costs incurred during the mandates of the previous government coalitions. Parties whose constituencies are declining stayed in power, while better alternatives have developed: the new names that can be found on the right wing of the Moldovan political spectrum show that their electorate is ready to embrace the goal of European accession once again.
E-government Policy and its Implementation in the Czech Republic: Selected Shortcomings
Authors: Špaček David
Published: February 2016

The paper summarizes the specifics and challenges of e-government policy, and then discusses the apparent shortcomings of policy implementation and challenges for further development in the Czech Republic. It draws attention to problems in national e-government policy and in practical policy implementation (instability of governance, low quality of evaluation, low involvement of stakeholders in project design, and public procurement issues).
Health policy in the Czech Republic: General character and selected interesting aspects
Authors: Nemec Juraj , Pavlík Marek , Malý Ivan , Kotherová Zuzana
Published: February 2016

Transformation of the health care system was a task faced by all formerly socialist Central and Eastern European countries. The years of changes revealed a large number of problems, including those induced by the limited capacity of governments to formulate and implement health care reforms. The goal of this article is to reflect the Czech situation. We start by summarizing the historical development of the Czech health care system in the context of government capacity for implementing health policy. In the core parts of this article, we highlight the main features of Czech health policy making and implementation and present an in-depth analysis of two selected country-specific issues - a low level of patient co-payments and a pluralistic insurance-based financing of health services.
Dropout Policy in Czech Higher Education: Can Universities Serve Several Masters?
Authors: Švec Václav , Vlk Aleš , Stiburek Šimon
Published: February 2016

The purpose of this study is to explore the way higher education institutions adapt to environmental pressures. These pressures can be represented either by various demands or by specific policies. Dropout policy is examined on a Czech case study in order to demonstrate that at the end of the day, higher education institutions respond mainly to the most pressing challenges of an economic nature in the most rational way. As a result, their traditional mission (teaching, research, the third mission), and mainly the social function of the higher education system, may be at stake. At the same time, this study illustrates how difficult it is to introduce any higher education policy without thorough evaluation of other policies in place and of various factors affecting institutional behaviour.
Moral Foundations of Welfare Attitudes: The Role of Moral Intuition and Reasoning in Pursuing Social Justice
Authors: Findor Andrej
Published: February 2016

The article interconnects the research on welfare attitudes and welfare chauvinism with moral psychology in order to develop an interdisciplinary analytical approach designed for studying attitudes to welfare policies and potentially overcoming the divisions prevalent in many European democracies. It introduces Moral Foundations Theory (MFT) - an empirical approach to analysing intuitions, reasoning, and emotions constituting moral judgment - and outlines its understanding of competing versions of fairness and distributive justice. The potential contributions of MFT are exemplified on a case study situated in contemporary Slovakia which deals with two conflicting conceptions of fairness, as equity and as equality, embodied in the diverging attitudes towards an amendment to the Act on the Assistance in Material Need (2013). The article argues that MFT and related research programmes are irreplaceable components in an interdisciplinary study of the plurality of welfare policy attitudes. It also highlights the transformative potential of MFT and related research programmes in devising interventions aimed at changing (political) attitudes to welfare and reducing their polarisation.
Providing Public Sport Facilities in Post-Socialist Times: The Case of the Czech Republic
Authors: Popelka Jakub
Published: February 2016

The paper aims to investigate current approaches to the management of public sport facilities by local governments. In the Czech Republic, local clubs traditionally played a key role in providing sport to the public. With decreasing participation in organized sport, a significant number of clubs have been forced to transfer their facilities to local governments and the sport position of local authorities has strengthened considerably in recent years. In consequence, there have been alterations in the management of public sport facilities. The findings of statistical analysis emphasize an increasing role of specialized organizations at the expense of in-house management or external provision (facilities hired out to sport clubs). Moreover, local population and type of facility were found to be the possible reasons for different approaches. In-house management is associated with smaller municipalities whereas most of their facilities have the character of public goods. In contrast, publicly funded organizations and municipal enterprises appear in municipalities with larger populations providing sport facilities of regional importance in the form of mixed goods. Finally, clubs, as representatives of external provision, mostly provide sport facilities primarily intended for their own purposes - club goods. In the context of recent works and contemporary trends in sport participation, the research findings indicate that different forms of management may have significant effects not only on efficiency of public budgets but also on conditions for sport at local level - especially on targeting those who would participate in sport if they had access to new opportunities or leisure programs.
Human dipeptidyl peptidase III regulates G-protein coupled receptor-dependent Ca2+ concentration in human embryonic kidney 293T cells
Authors: Prajapati Subhash C. , Singh Ratnakar , Chauhan Shyam S.
Published: February 2016

The precise biological function of human dipeptidyl peptidase III (hDPP III) is poorly understood. Using luciferase reporter constructs responsive to change in Ca2+ and/or cAMP and Fura 2-AM fluorometric assay, we show a significant decrease in intracellular Ca2+ following hDPP III overexpression and angiotensin II stimulation in angiotensin II type 1 receptor (G-protein coupled receptor, GPCR) expressing HEK293T cells. Silencing the expression of hDPP III by siRNA reversed the effect of hDPP III overexpression with a concomitant increase in Ca2+. These results, for the first time, show involvement of hDPP III in GPCR dependent Ca2+ regulation in HEK293T cells.
Assessing Capabilities of Commercial WiMAX Networks for Deliverling Real-Time Surveillance Video Traffic in Uplink
Authors: Flizikowski Adam , Półcienniczak Mateusz , Rybicki Maciej , Hołubowicz Witold , Podyma Maciej
Published: February 2016

Streaming video in uplink is an interesting opportunity for network operators for capitalizing unused part of bandwidth (due to Internet asymmetry). The uplink seems not optimized nowadays due to lack of business cases. The main challenge however is bursty and unpredictable nature of wireless channel observed especially as mobility comes into play in current broadband networks. That is why in this paper, we have approached the diagnosis of commercial mobile WiMAX network towards the capabilities of assuring real-time video in uplink direction. We present results of drive tests showing that delay in WiMAX networks for LOS-NLOS (Line of sight - No n line of sight) mobile conditions is largely contributed by uplink direction (60-90% of RTT (Round trip time)) whereas downlink directions hardly ever exceeds 40ms. We show that enabling MIMO-A(Multiple Input Multiple Output) can decrease delays by 100ms in NLOS conditions and decrease delay variation by up to 90%. For each of tests we have presented exact probabilities of particular modulations involved based on channel realizations.
A New Idea of Fast Three-Dimensional Median Filtering for Despeckling of Optical Coherence Tomography Images
Authors: Gocławski Jarosław , Sekulska-Nalewajko Joanna
Published: February 2016

Median filtering has been widely used in image processing for noise removal because it can significantly reduce the power of noise while limiting edge blurring. This filtering is still a challenging task in the case of three-dimensional images containing up to a billion of voxels, especially for large size filtering windows. The authors encountered the problem when applying median filter to speckle noise reduction in optical coherence tomography images acquired by the Spark OCT systems. In the paper a new approach to the GPU (Graphics Processing Unit) based median smoothing has been proposed, which uses two-step evaluation of local intensity histograms stored in the shared memory of a graphic device. The solution is able to output about 50 million voxels per second while processing the neighbourhood of 125 voxels by Quadro K6000 graphic card configured on the Kepler architecture.
3D Reconstruction of Funnel Flow Boundary Using Automatic Point Set Extraction
Authors: Waktola Selam , Grudzien Krzysztof , Babout Laurent
Published: February 2016

The paper presents an automatic point set extraction method for reconstructing 3D tomography images of funnel flow boundary. The method clearly shows the boundary between the funnel flow and stagnant zone during silo discharging process. After adjusting the contrast of the original X-ray CT image and applying filter function, the intensity profile of the image shows a high jump corresponding to the local flow boundary position at a specific height of the silo model. By extracting and connecting those jump points gave us a boundary line of the funnel flow from the stagnant. The outcome of segmented image opens a door for analysing further about funnel flow in 3D images.
Pituitary gigantism: a retrospective case series
Authors: Creo Ana L. , Lteif Aida N.
Published: February 2016

Pituitary gigantism (PG) is a rare pediatric disease with poorly defined long-term outcomes. Our aim is to describe the longitudinal clinical course in PG patients using a single-center, retrospective cohort study.

Patients younger than 19 years diagnosed with PG were identified. Thirteen cases were confirmed based on histopathology of a GH secreting adenoma or hyperplasia and a height >2 SD for age and gender. Laboratory studies, initial pathology, and imaging were abstracted.

Average age at diagnosis was 13 years with an average initial tumor size of 7.4×3.8 mm. Initial transsphenoidal surgery was curative in 3/12 patients. Four of the nine patients who failed the initial surgery required a repeat procedure. Octreotide successfully normalized GH levels in 1/6 patients with disease refractory to surgery (1/6). Two out of five patients received pegvisomant after failing octreotide but only one patient responded to treatment. Five patients were ultimately treated with radiosurgery or radiation patients were followed for an average of 10 years.

PG is difficult to treat. In most patients, the initial transsphenoidal surgery failed to normalize GH levels. If the initial surgery was unsuccessful, repeat surgery was unlikely to control GH secretion. Treatment with octreotide or pegvisomant was successful in less than half the patients failing surgery. Radiosurgery was curative, but is not an optimal treatment for pediatric patients. Despite the small sample, our study suggests that the treatment outcome of pediatric PG may be different than adults.
Effect of Storage on Residue Levels of Enrofloxacin in Muscle of Rainbow Trout (Oncorhynchus mykiss) and Common Carp (Cyprinus carpio)
Authors: Kyuchukova Ralica , Milanova Anelia , Daskalova Aleksandra , Stratev Deyan , Lashev Lubomir , Pavlov Alexander
Published: February 2016

Since fluoroquinolones are one of the most commonly used antibacterial drugs in aquaculture, there is a risk of their residues to be found in the treated fish. The objective of this study was to examine the changes in enrofloxacin and ciprofloxacin levels during storage of rainbow trout and common carp muscle at −18 °C. The trout and carp were treated orally with a single dose of 10 mg/kg of enrofloxacin. Tissue samples were collected 24 h after the treatment and stored at −18 °C for 270 days either as a whole fish or as precut muscle samples. Results for trout revealed that in the precut samples enrofloxacin concentration decreased significantly only after 9 months of storage, whereas a significant decline in the ciprofloxacin level was observed much earlier (after 3 months). After 9 months of storage, the trout stored without being sliced and eviscerated showed significantly higher levels of both quinolones as compared to the precut muscle samples. The enrofloxacin levels in the carp musculature decreased considerably after 3 months of storage and stayed almost unchanged up to the end of the study, whereas the ciprofloxacin concentration continued to drop even after this period and after 270 days constituted 1/6 of the initial values.
An explicit representation of the transition densities of the skew Brownian motion with drift and two semipermeable barriers
Authors: Dereudre David , Mazzonetto Sara , Roelly Sylvie
Published: February 2016

In this paper, we obtain an explicit representation of the transition density of the one-dimensional skew Brownian motion with (a constant drift and) two semipermeable barriers. Moreover, we propose a rejection sampling method to simulate this density in an exact way.
Crystal structure of diaqua-bis(μ3-2-methyl-6-oxidopyridinium-4-carboxylato-κ3
O:O′:O′′)neodymium(III) chloride, C14H16ClN2O8Nd
Authors: Li Rong-Fang , Li Jin , Wang Ke-Qiang , Huo Su Zhen
Published: February 2016

C14H14ClN2O8Nd, Tetragonal, I41/a, a = 10.3597(15) Å, b = 10.3597(15) Å, c = 32.729(10) Å, V = 3512.6(12) Å3, Z = 8, R
gt
(F) = 0.0243, wR
ref(F
2) = 0.0620, T = 296(2) K.
Crystal structure of N,N-diethyl-2-(2-(6-(4-methoxybenzyl)-7-oxo-7H-thiazolo[3,3-b][1,2,4]triazin-3-yl)phenoxy)acetamide, C25H26N4O4S
Authors: Liu Si-Jie , Shang Ruo-Feng , Jia PengFei , Wang Xin , Song Yu-Pin
Published: February 2016

The structure of C25H26N4O4S, triclinic, P1̅ (no. 2), a = 8.6698(17) Å, b = 9.4692(19) Å, c = 14.855(3) Å, β = 76.32(3)°, V = 1158.5(4) Å3, Z = 2, R
gt
(F) = 0.0429, wR
ref
(F
2
) = 0.1192, T = 113 K.
Crystal structure of methyl 8-hydroxy-3-isopropyl-5a,8-dimethyl-2,3,4,5,5a,6,7,8,10a,10b-decahydrocyclohepta[e]indene-3a(1H)-carboxylate, C21H34O3
Authors: Brito Iván , Bórquez Jorge , Simirgiotis Mario , Cárdenas Alejandro , Molina-Salinas Gloria M. , Jerz Gerold , Peña-Rodriguez Luis Manuel , Winterhalter Peter
Published: February 2016

C21H34O3, orthorhombic, P212121 (no. 19), a = 7.5420(7) Å, b = 11.6929(11) Å, c = 22.657(2) Å, V = 1998.1(3) Å3, Z = 4, R
gt
(F) = 0.0383, wR
ref
(F
2
) = 0.113, T = 293(2) K.
Changing exposures in a changing world: models for reducing the burden of disease
Authors: Suk William A. , Mishamandani Sara
Published: February 2016

Environmental exposures are changing dramatically in location, intensity, and frequency. Many developing countries are undergoing a transition in which they face the double burden of infectious diseases as well as chronic diseases. Noncommunicable diseases have emerged as the leading cause of death and disability in developing countries. Globally, pollution is insufficiently appreciated and inadequately quantified as a cause of disease. The health burden from both noninfectious diseases and infectious disease, especially parasites, is high among exposed people. Mothers and children are particularly vulnerable to pollution-related diseases in developing countries. Exposures to pollution can cause protracted noncommunicable diseases across their life span. A global initiative to promote human health sciences and technologies would enhance collaborations and communications amongst investigators and public environmental health officials. Existing models that facilitate the transfer of information and research results exist and can provide insight into building such an international network, allowing better prediction of disease risk and provide ways to reduce exposure to environmental contaminants. A global network would bring together scientists from multiple disciplines and countries to work toward a better understanding of the double burden of disease, especially in low and middle income countries, and promote ways to improve public health.
Semidiscrete approximations for the stationary radiative–conductive heat transfer problem in a two-dimensional system of plates
Authors: Amosov Andrey A. , Maslov Dmitry A.
Published: February 2016

Special semidiscrete approximations, namely, basic, first, and second semidiscrete problems are proposed for a boundary value problem describing a stationary radiative–conductive heat transfer in a two-dimensional system of heat-conductive plates of width
Preconditioners for hierarchical matrices based on their extended sparse form
Authors: Sushnikova Darya A. , Oseledets Ivan V.
Published: February 2016

In this paper we consider linear systems with dense-matrices which arise from numerical solution of boundary integral equations. Such matrices can be well-approximated with ℋ
Discontinuous Galerkin method for wave propagation in elastic media with inhomogeneous inclusions
Authors: Voroshchuk Denis N. , Miryaha Vladislav A. , Petrov Igor B. , Sannikov Alexander V.
Published: February 2016

A discontinuous Galerkin method on unstructured grids is adapted and implemented for simulation of wave response of subvertical fractured systems in carbonate rocks for numerical solution of direct problems of seismic exploration. The present paper compares seismic responses for several mechanical-mathematical models of a fractured reservoir. The models of collectors differ in the presence and location of media interfaces relative to the collector and also in a way of its specification, namely, an explicit selection of fractures with the parameters of the medium in the domain of collector coinciding with the host medium, or differing from it. We indicate the ability to take into account inter-fracture interactions with the use of the model of a fractured layer presented in the paper and study wave processes formed as the result of interaction of seismic pulses with fractured reservoirs.
Conceptualizing Stakeholders’ Perceptions of Ecosystem Services: A Participatory Systems Mapping Approach
Authors: Lopes Rita , Videira Nuno
Published: February 2016

A participatory system dynamics modelling approach is advanced to support conceptualization of feedback processes underlying ecosystem services and to foster a shared understanding of leverage intervention points. The process includes systems mapping workshop and follow-up tasks aiming at the collaborative construction of causal loop diagrams. A case study developed in a natural area in Portugal illustrates how a stakeholder group was actively engaged in the development of a conceptual model depicting policies for sustaining the climate regulation ecosystem service.
HMM-DM: identifying differentially methylated regions using a hidden Markov model
Authors: Yu Xiaoqing , Sun Shuying
Published: February 2016

DNA methylation is an epigenetic modification involved in organism development and cellular differentiation. Identifying differential methylations can help to study genomic regions associated with diseases. Differential methylation studies on single-CG resolution have become possible with the bisulfite sequencing (BS) technology. However, there is still a lack of efficient statistical methods for identifying differentially methylated (DM) regions in BS data. We have developed a new approach named HMM-DM to detect DM regions between two biological conditions using BS data. This new approach first uses a hidden Markov model (HMM) to identify DM CG sites accounting for spatial correlation across CG sites and variation across samples, and then summarizes identified sites into regions. We demonstrate through a simulation study that our approach has a superior performance compared to BSmooth. We also illustrate the application of HMM-DM using a real breast cancer dataset.
Reliability Analysis of Bearing Capacity of Square Footing on Soil with Strength Anisotropy Due to Layered Microstructure
Authors: Kawa Marek
Published: February 2016

The paper deals with reliability analysis of square footing on soil with strength anisotropy. The strength of the soil has been described with identified anisotropic strength criterion dedicated to geomaterials with layered microstructure. The analysis assumes dip angle α and azimuth angle β which define direction of lamination of the structure to be random variables with given probability density functions. Bearing capacity being a function of these variables is approximated based on results of deterministic simulations obtained for variety of orientations. The weighted regression method by Kaymaz and McMahon within the framework of Response Surface Method is used for the approximation. As a result of analysis, global factor of safety that corresponds to assumed value of probability of failure is determined. The value of the safety factor denotes the ratio between the value of the design load and the mean value of bearing capacity which is needed to reduce the probability of failure to the acceptable level. The procedure of calculating the factor has been presented for two different cases. In the first case, no information about lamination direction of the soil has been provided and thus all the orientations are assumed to be equally probable (uniform distribution). In the second case, statistical information including mean, variance and assumed probability distribution for both α and β angle is known. For the latter case, using results obtained for few different values of mean of angle α, also the influence of strength anisotropy on the value of global factor of safety is shown.
Analysis of the Foundation Slab Settlement of the “Africa Pavilion” Facility in Wrocław
Authors: Sawicki Eugeniusz , Strzelecki Tomasz
Published: February 2016

This article presents the results of numerical calculations of soil consolidation underneath the “Africa Pavilion” structure in Wrocław Zoo, Poland. To determine the deformations of the baseplate of the “Africa Pavilion” and deformations of the subsoil, Biot’s consolidation theory for two-phase medium was applied. The calculations were carried out using the professional program FlexPDE v.6, which is based on the Finite Element Method. Numerical calculations performed were used to evaluate the design assumptions allowing for the laying of hydraulic conduits under the slab.
Comparison Between Two Methods for Estimating the Vertical Scale of Fluctuation for Modeling Random Geotechnical Problems
Authors: Pieczyńska-Kozłowska Joanna M.
Published: February 2016

The design process in geotechnical engineering requires the most accurate mapping of soil. The difficulty lies in the spatial variability of soil parameters, which has been a site of investigation of many researches for many years. This study analyses the soil-modeling problem by suggesting two effective methods of acquiring information for modeling that consists of variability from cone penetration test (CPT). The first method has been used in geotechnical engineering, but the second one has not been associated with geotechnics so far. Both methods are applied to a case study in which the parameters of changes are estimated. The knowledge of the variability of parameters allows in a long term more effective estimation, for example, bearing capacity probability of failure.
Influence of legume crops on content of organic carbon in sandy soil
Authors: Hajduk Edmund , Właśniewski Stanisław , Szpunar-Krok Ewa
Published: February 2016

The paper presents the results of a 3-year field experiment designed to evaluate the content of organic carbon in brown soil (Haplic Cambisol Dystric) developed from a light loamy sand under legumes cultivation. Experimental factors were: species of legume crop (colorful-blooming pea(Pisum sativum), chickling vetch(Lathyrus sativus), narrow-leafed lupin(Lupinus angustifolius), methods of legumes tillage (legumes in pure culture and in mixture with naked oats) and mineral N fertilization (0, 30, 60, 90 kg N·ha−1). Cultivation of legumes on sandy soil did not result in an increase of organic carbon content in the soil after harvest as compared to the initial situation, i.e. 7.39 vs. 7.76 g·kg−1dry matter (DM), on average, respectively. However, there was the beneficial effect of this group of plants on soil abundance in organic matter, the manifestation of which was higher content of organic carbon in soils after legume harvest as compared to soils with oats grown (7.21 g·kg−1DM, on average). Among experimental crops, cultivation of pea exerted the most positive action to organic carbon content (7.58 g·kg−1, after harvest, on average), whereas narrow-leaved lupin had the least effect on organic carbon content (7.23 g·kg−1, on average). Pure culture and greater intensity of legume cultivation associated with the use of higher doses of mineral nitrogen caused less reduction in organic carbon content in soils after harvest.
Selected physical and water properties of soils located in the vicinity of proposed opencast lignite mine “Drzewce” (middle Poland)
Authors: Gajewski Piotr , Kaczmarek Zbigniew , Owczarzak Wojciech , Mocek Andrzej , Glina Bartłomiej
Published: February 2016

The paper presents physical and water properties of six soils located in the areas directly adjacent to “Drzewce” lignite open cast mine (KWB Konin). The conducted works included preparation of pits of various soil types in points characteristic to large and representative soil allotments. The selected soil types represented mineral and organic soils. Samples of disturbed and undisturbed structure were taken from various genetic horizons for laboratory analysis. Such properties as content of total carbon, texture, specific density, bulk density, total and drainage porosity, moisture, saturated hydraulic conductivity, the potential of water bonding, total and readily available water, and total retention were determined in the samples from the horizons of 0–100 cm. The investigated soils showed mostly sandy texture with few local loam insertions. Texture and the content of organic matter were the most important parameters which influenced all analyzed properties. Morphology and the properties of the examined soils as well as deep level of soil – ground water were decisive factors when categorizing them as a precipitation-water type. Such soils will not undergo degradation caused by the dehydrating depression cone of open cast mine.
Importance of Unit Cells in Accurate Evaluation of the Characteristics of Graphene
Authors: Sabzyan Hassan , Sadeghpour Narges
Published: February 2016

Effects of the size of the unit cell on energy, atomic charges, and phonon frequencies of graphene at the Γ point of the Brillouin zone are studied in the absence and presence of an electric field using density functional theory (DFT) methods (LDA and DFT-PBE functionals with Goedecker–Teter–Hutter (GTH) and Troullier–Martins (TM) norm-conserving pseudopotentials). Two types of unit cells containing nC=4–28 carbon atoms are considered. Results show that stability of graphene increases with increasing size of the unit cell. Energy, atomic charges, and phonon frequencies all converge above nC=24 for all functional-pseudopotentials used. Except for the LDA-GTH calculations, application of an electric field of 0.4 and 0.9 V/nm strengths does not change the trends with the size of the unit cell but instead slightly decreases the binding energy of graphene. Results of this study show that the choice of unit cell size and type is critical for calculation of reliable characteristics of graphene.
Tau-Driven Neuronal and Neurotrophic Dysfunction in a Mouse Model of Early Tauopathy
Authors: Mazzaro Nadia , Barini Erica , Spillantini Maria Grazia , Goedert Michel , Medini Paolo , Gasparini Laura
Published: February 2016

Tauopathies are neurodegenerative diseases characterized by intraneuronal inclusions of hyperphosphorylated tau protein and abnormal expression of brain-derived neurotrophic factor (BDNF), a key modulator of neuronal survival and function. The severity of both these pathological hallmarks correlate with the degree of cognitive impairment in patients. However, how tau pathology specifically modifies BDNF signaling and affects neuronal function during early prodromal stages of tauopathy remains unclear. Here, we report that the mild tauopathy developing in retinal ganglion cells (RGCs) of the P301S tau transgenic (P301S) mouse induces functional retinal changes by disrupting BDNF signaling via the TrkB receptor. In adult P301S mice, the physiological visual response of RGCs to pattern light stimuli and retinal acuity decline significantly. As a consequence, the activity-dependent secretion of BDNF in the vitreous is impaired in P301S mice. Further, in P301S retinas, TrkB receptors are selectively upregulated, but uncoupled from downstream extracellular signal-regulated kinase (ERK) 1/2 signaling. We also show that the impairment of TrkB signaling is triggered by tau pathology and mediates the tau-induced dysfunction of visual response. Overall our results identify a neurotrophin-mediated mechanism by which tau induces neuronal dysfunction during prodromal stages of tauopathy and define tau-driven pathophysiological changes of potential value to support early diagnosis and informed therapeutic decisions.

SIGNIFICANCE STATEMENTThis work highlights the potential molecular mechanisms by which initial tauopathy induces neuronal dysfunction. Combining clinically used electrophysiological techniques (i.e., electroretinography) and molecular analyses, this work shows that in a relevant model of early tauopathy, the retina of the P301S mutant human tau transgenic mouse, mild tau pathology results in functional changes of neuronal activity, likely due to selective impairment of brain-derived neurotrophic factor signaling via its receptor, TrkB. These findings may have important translational implications for early diagnosis in a subset of Alzheimer's disease patients with early visual symptoms and emphasize the need to clarify the pathophysiological changes associated with distinct tauopathy stages to support informed therapeutic decisions and guide drug discovery.
Impaired Dendritic Development and Memory inSorbs2Knock-Out Mice
Authors: Zhang Qiangge , Gao Xian , Li Chenchen , Feliciano Catia , Wang Dongqing , Zhou Dingxi , Mei Yuan , Monteiro Patricia , Anand Michelle , Itohara Shigeyoshi , Dong Xiaowei , Fu Zhanyan , Feng Guoping
Published: February 2016

Intellectual disability is a common neurodevelopmental disorder characterized by impaired intellectual and adaptive functioning. Both environmental insults and genetic defects contribute to the etiology of intellectual disability. Copy number variations ofSORBS2have been linked to intellectual disability. However, the neurobiological function ofSORBS2in the brain is unknown. TheSORBS2gene encodes ArgBP2 (Arg/c-Abl kinase binding protein 2) protein in non-neuronal tissues and is alternatively spliced in the brain to encode nArgBP2 protein. We found nArgBP2 colocalized with F-actin at dendritic spines and growth cones in cultured hippocampal neurons. In the mouse brain, nArgBP2 was highly expressed in the cortex, amygdala, and hippocampus, and enriched in the outer one-third of the molecular layer in dentate gyrus. Genetic deletion ofSorbs2in mice led to reduced dendritic complexity and decreased frequency of AMPAR-miniature spontaneous EPSCs in dentate gyrus granule cells. Behavioral characterization revealed thatSorbs2deletion led to a reduced acoustic startle response, and defective long-term object recognition memory and contextual fear memory. Together, our findings demonstrate, for the first time, an important role for nArgBP2 in neuronal dendritic development and excitatory synaptic transmission, which may thus inform exploration of neurobiological basis ofSORBS2deficiency in intellectual disability.

SIGNIFICANCE STATEMENTCopy number variations of theSORBS2gene are linked to intellectual disability, but the neurobiological mechanisms are unknown. We found that nArgBP2, the only neuronal isoform encoded bySORBS2, colocalizes with F-actin at neuronal dendritic growth cones and spines. nArgBP2 is highly expressed in the cortex, amygdala, and dentate gyrus in the mouse brain. Genetic deletion ofSorbs2in mice leads to impaired dendritic complexity and reduced excitatory synaptic transmission in dentate gyrus granule cells, accompanied by behavioral deficits in acoustic startle response and long-term memory. This is the first study ofSorbs2function in the brain, and our findings may facilitate the study of neurobiological mechanisms underlyingSORBS2deficiency in the development of intellectual disability.
Live Imaging of Kv7.2/7.3 Cell Surface Dynamics at the Axon Initial Segment: High Steady-State Stability and Calpain-Dependent Excitotoxic Downregulation Revealed
Authors: Benned-Jensen Tau , Christensen Rasmus Kordt , Denti Federico , Perrier Jean-Francois , Rasmussen Hanne Borger , Olesen Søren-Peter
Published: February 2016

The voltage-gated K+channels Kv7.2 and Kv7.3 are located at the axon initial segment (AIS) and exert strong control over action potential generation. Therefore, changes in their localization or cell surface numbers are likely to influence neuronal signaling. However, nothing is known about the cell surface dynamics of Kv7.2/7.3 at steady state or during short-term neuronal stimulation. This is primarily attributable to their membrane topology, which hampers extracellular epitope tagging. Here we circumvent this limitation by fusing an extra phluorin-tagged helix to the N terminus of human Kv7.3. This seven transmembrane chimera, named super ecliptic phluorin (SEP)–TAC-7.3, functions and traffics as a wild-type (WT) channel. We expressed SEP–TAC-7.3 in dissociated rat hippocampal neurons to examine the lateral mobility, surface numbers, and localization of AIS Kv7.2/7.3 heteromers using live imaging. We discovered that they are extraordinarily stable and exhibit a very low surface mobility both during steady state and neuronal stimulation. In the latter case, we also found that neither localization nor cell surface numbers were changed. However, at high glutamate loads, we observed a rapid irreversible endocytosis of Kv7.2/7.3, which required the activation of NR2B-containing NMDA receptors, Ca2+influx, and calpain activation. This excitotoxic mechanism may be specific to ankyrin G-bound AIS proteins because Nav1.2 channels, but not AIS GABAAreceptors, were also endocytosed. In conclusion, we have, for the first time, characterized the cell surface dynamics of a full-length Kv7 channel using a novel chimeric strategy. This approach is likely also applicable to other Kv channels and thus of value for the additional characterization of this ion channel subfamily.

SIGNIFICANCE STATEMENTThe voltage-gated K+channels Kv7.2 and Kv7.3 exert strong control over action potential generation, but little is known about their cell surface dynamics. Using a novel phluorin-based approach, we here show that these channels are highly stable at steady state and different types of neuronal stimulation. However, at high glutamate loads, they undergo a rapid calpain-dependent endocytosis that likely represents an early response during excitotoxic states.
Perceptual Learning at a Conceptual Level
Authors: Wang Rui , Wang Jie , Zhang Jun-Yun , Xie Xin-Yu , Yang Yu-Xiang , Luo Shu-Han , Yu Cong , Li Wu
Published: February 2016

Humans can learn to abstract and conceptualize the shared visual features defining an object category in object learning. Therefore, learning is generalizable to transformations of familiar objects and even to new objects that differ in other physical properties. In contrast, visual perceptual learning (VPL), improvement in discriminating fine differences of a basic visual feature through training, is commonly regarded as specific and low-level learning because the improvement often disappears when the trained stimulus is simply relocated or rotated in the visual field. Such location and orientation specificity is taken as evidence for neural plasticity in primary visual cortex (V1) or improved readout of V1 signals. However, new training methods have shown complete VPL transfer across stimulus locations and orientations, suggesting the involvement of high-level cognitive processes. Here we report that VPL bears similar properties of object learning. Specifically, we found that orientation discrimination learning is completely transferrable between luminance gratings initially encoded in V1 and bilaterally symmetric dot patterns encoded in higher visual cortex. Similarly, motion direction discrimination learning is transferable between first- and second-order motion signals. These results suggest that VPL can take place at a conceptual level and generalize to stimuli with different physical properties. Our findings thus reconcile perceptual and object learning into a unified framework.

SIGNIFICANCE STATEMENTTraining in object recognition can produce a learning effect that is applicable to new viewing conditions or even to new objects with different physical properties. However, perceptual learning has long been regarded as a low-level form of learning because of its specificity to the trained stimulus conditions. Here we demonstrate with new training tactics that visual perceptual learning is completely transferrable between distinct physical stimuli. This finding indicates that perceptual learning also operates at a conceptual level in a stimulus-invariant manner.
Cell-Type Specific Phase Precession in Layer II of the Medial Entorhinal Cortex
Authors: Reifenstein Eric T. , Ebbesen Christian L. , Tang Qiusong , Brecht Michael , Schreiber Susanne , Kempter Richard
Published: February 2016

The identity of phase-precessing cells in the entorhinal cortex is unknown. Here, we used a classifier derived from cell-attached recordings to separate putative pyramidal cells and putative stellate cells recorded extracellularly in layer II of the medial entorhinal cortex in rats. Using a novel method to identify single runs as temporal periods of elevated spiking activity, we find that both cell types show phase precession but putative stellate cells show steeper slopes of phase precession and larger phase ranges. As the two classes of cells have different projection patterns, phase precession is differentially passed on to different subregions of the hippocampal formation.

SIGNIFICANCE STATEMENTIt is a great challenge for neuroscience to reveal the cellular basis of cognitive functions. One such function is the ability to learn and recollect temporal sequences of events. The representation of sequences in the brain is thought to require temporally structured activity of nerve cells. How different types of neurons generate temporally structured activity is currently unknown. In the present study, we use a computational classification procedure to separate different cell types and find that a subpopulation of cells, so-called stellate neurons, exhibits clear temporal coding. Contrary to the stellate cells, pyramidal cells show weaker temporal coding. This discovery sheds light on the cellular basis of temporal coding in the brain.
Histone Modification ofNedd4Ubiquitin Ligase Controls the Loss of AMPA Receptors and Cognitive Impairment Induced by Repeated Stress
Authors: Wei Jing , Xiong Zhe , Lee Janine B. , Cheng Jia , Duffney Lara J. , Matas Emmanuel , Yan Zhen
Published: February 2016

Stress and the major stress hormone corticosterone induce profound influences in the brain. Altered histone modification and transcriptional dysfunction have been implicated in stress-related mental disorders. We previously found that repeated stress caused an impairment of prefrontal cortex (PFC)-mediated cognitive functions by increasing the ubiquitination and degradation of AMPA-type glutamate receptors via a mechanism depending on the E3 ubiquitin ligase Nedd4. Here, we demonstrated that in PFC of repeatedly stressed rats, active glucocorticoid receptor had the increased binding to the glucocorticoid response element of histone deacetylase 2 (HDAC2) promoter, resulting in the upregulation of HDAC2. Inhibition or knock-down of HDAC2 blocked the stress-induced impairment of synaptic transmission, AMPAR expression, and recognition memory. Furthermore, we found that, in stressed animals, the HDAC2-dependent downregulation of histone methyltransferase Ehmt2 (G9a) led to the loss of repressive histone methylation at theNedd4-1promoter and the transcriptional activation of Nedd4. These results have provided an epigenetic mechanism and a potential treatment strategy for the detrimental effects of chronic stress.

SIGNIFICANCE STATEMENTProlonged stress exposure can induce altered histone modification and transcriptional dysfunction, which may underlie the profound influence of stress in regulating brain functions. We report an important finding about the epigenetic mechanism controlling the detrimental effects of repeated stress on synaptic transmission and cognitive function. First, it has revealed the stress-induced alteration of key epigenetic regulators HDAC2 and Ehmt2, which determines the synaptic and behavioral effects of repeated stress. Second, it has uncovered the stress-induced histone modification of the target gene Nedd4, an E3 ligase that is critically involved in the ubiquitination and degradation of AMPA receptors and cognition. Third, it has provided the epigenetic approach, HDAC2 inhibition or knock-down, to rescue synaptic and cognitive functions in stressed animals.
Distorted Tonotopic Coding of Temporal Envelope and Fine Structure with Noise-Induced Hearing Loss
Authors: Henry Kenneth S. , Kale Sushrut , Heinz Michael G.
Published: February 2016

People with cochlear hearing loss have substantial difficulty understanding speech in real-world listening environments (e.g., restaurants), even with amplification from a modern digital hearing aid. Unfortunately, a disconnect remains between human perceptual studies implicating diminished sensitivity to fast acoustic temporal fine structure (TFS) and animal studies showing minimal changes in neural coding of TFS or slower envelope (ENV) structure. Here, we used general system-identification (Wiener kernel) analyses of chinchilla auditory nerve fiber responses to Gaussian noise to reveal pronounced distortions in tonotopic coding of TFS and ENV following permanent, noise-induced hearing loss. In basal fibers with characteristic frequencies (CFs) >1.5 kHz, hearing loss introduced robust nontonotopic coding (i.e., at the wrong cochlear place) of low-frequency TFS, while ENV responses typically remained at CF. As a consequence, the highest dominant frequency of TFS coding in response to Gaussian noise was 2.4 kHz in noise-overexposed fibers compared with 4.5 kHz in control fibers. Coding of ENV also became nontonotopic in more pronounced cases of cochlear damage. In apical fibers, more classical hearing-loss effects were observed, i.e., broadened tuning without a significant shift in best frequency. Because these distortions and dissociations of TFS/ENV disrupt tonotopicity, a fundamental principle of auditory processing necessary for robust signal coding in background noise, these results have important implications for understanding communication difficulties faced by people with hearing loss. Further, hearing aids may benefit from distinct amplification strategies for apical and basal cochlear regions to address fundamentally different coding deficits.

SIGNIFICANCE STATEMENTSpeech-perception problems associated with noise overexposure are pervasive in today's society, even with modern digital hearing aids. Unfortunately, the underlying physiological deficits in neural coding remain unclear. Here, we used innovative system-identification analyses of auditory nerve fiber responses to Gaussian noise to uncover pronounced distortions in coding of rapidly varying acoustic temporal fine structure and slower envelope cues following noise trauma. Because these distortions degrade and diminish the tonotopic representation of temporal acoustic features, a fundamental principle of auditory processing, the results represent a critical advancement in our understanding of the physiological bases of communication disorders. The detailed knowledge provided by this work will help guide the design of signal-processing strategies aimed at alleviating everyday communication problems for people with hearing loss.
Determinants of RNA metabolism in the Schizosaccharomyces pombe genome
Authors: Eser Philipp , Wachutka Leonhard , Maier Kerstin C , Demel Carina , Boroni Mariana , Iyer Srignanakshi , Cramer Patrick , Gagneur Julien
Published: February 2016

To decrypt the regulatory code of the genome, sequence elements must be defined that determine the kinetics of RNA metabolism and thus gene expression. Here, we attempt such decryption in an eukaryotic model organism, the fission yeast S. pombe. We first derive an improved genome annotation that redefines borders of 36% of expressed mRNAs and adds 487 non‐coding RNAs (ncRNAs). We then combine RNA labeling in vivo with mathematical modeling to obtain rates of RNA synthesis and degradation for 5,484 expressed RNAs and splicing rates for 4,958 introns. We identify functional sequence elements in DNA and RNA that control RNA metabolic rates and quantify the contributions of individual nucleotides to RNA synthesis, splicing, and degradation. Our approach reveals distinct kinetics of mRNA and ncRNA metabolism, separates antisense regulation by transcription interference from RNA interference, and provides a general tool for studying the regulatory code of genomes.