bluuebunny/crossref_metadata_2025 huggingface dataset:
Alterations in Platelet Activity and Elastic Modulus of Healthy Subjects, Carriers of G20210A Polymorphism in the Prothrombin Gene
Authors: Komsa-Penkova Regina , Todinova Svetla J. , Andreeva Tonya D. , Krumova Sashka B. , Taneva Stefka G. , Golemanov Georgi M. , Georgieva Galia A. , Mihaylova Nikolina M. , Tchorbanov Andrey I. , Tonchev Pencho T.
Published: December 2016

Platelet activation is a complex process in which platelet reorganization takes place associated with changes in the cell shape, topology, membrane elasticity and microparticle production. The aim of this study was to investigate the changes/aberrations in the platelet activity, elasticity and morphology in healthy subjects, carriers of A allele of prothrombin G20210A polymorphism. Blood samples from 18 healthy subjects were used for platelet analysis by force-mode atomic force microscopy. Restriction analysis was used to investigate the carriage of G20210A polymorphism in the prothrombin gene. Flow- cytometry was applied to evaluate platelet activation. Young’s modulus of the plasma membranes of platelets derived from healthy subjects, carriers of variant A allele of prothrombin 20210G>A polymorphism (407±69 kPa) is two times higher than the one determined for non­carriers (195.4±48.7 kPa; p<0.05). The background activity of platelets measured as an interrelation of Cd41/Cd61 and CD62 by flow cytometry was also higher in carriers of variant A allele of prothrombin 20210G>A polymorphism (5.0%) than in non-carriers (1.3%). Platelets isolated from healthy carriers of variant A allele of prothrombin 20210G>A polymorphism exhibited a higher level of activity and a higher degree of stiffness at the stage of spreading as compared to platelets from non­carriers.
Ovarian Brenner Tumors Revisited: Do We Have Space for Malignant Tumorsvand Methanol
Authors: Ivanova Vesela , Karaivanov Milen P. , Dikov Tihomir I.
Published: December 2016

We present a case of a 75-year-old female who underwent a total abdominal hysterectomy with bilateral salpingooophorectomy for an ovarian tumor. Hematoxylin-eosin- stained slides from tumor specimen revealed 1) focci of benign Brenner tumor; 2) mucinous cysts and 3) intracystic papillary projections resembling low-grade papillary transitional cell carcinoma (Grade 1-2) with squamous differentiation and comedo-type necrosis; 4) focal areas resembling noninvasive papillary transitional cell carcinoma Grade 3. Immunohistochemical investigation with a panel of antibodies (p63, p53, Ki-67, Wilms Tumor 1 - WT1, pi 6) was initiated. Areas resembling urothelial carcinoma showed diffuse nuclear positive reaction for p63 and wild-type expression of p53. Ki-67-nuclear positivity varied from less than 5% up to 30% in areas resembling high-grade urothelial carcinoma. WT1 expression was not seen. Weak but still exceeding background staining was observed in predominantly cytoplasmic fashion with few scattered positive nuclei in transitional cell nest of the benign component. No reactivity, however, was seen within the proliferative component. The histopathological diagnosis was a borderline/atypical proliferative Brenner tumor.

The patient has been regularly followed up and is at present disease-free 5 years after diagnosis. In this paper, the authors describe the morphological characteristics of Brenner tumors and address some debatable issues in the light of recent immunohistochemical and molecular studies.
Well-Differentiated Liposarcoma of The Larynx: A Case Report and Review of Literature
Authors: Mateva Svetlana A. , Nikolova Margarita R. , Valkov Alexandar V. , Nikolova Margarita R.
Published: December 2016

Liposarcoma is one of the most common soft tissue sarcomas in adults with a relative incidence amongst other sarcomas ranging from 9.8% to 16%. It usually locates in the limbs and retroperitoneum. Primary liposarcomas of the larynx and hypopharynx are rare, comprising less than 20% of all head and neck liposarcomas. According to World Health Organization, these tumors are divided into four histologic types, and well-differentiated liposarcoma is the most common one. It is a tumor of low-grade malignancy that may recur locally, but does not metastasize. We present a case of laryngopharyngeal well- differentiated liposarcoma in an old patient with two previous removals. We also discuss recently published cases with this unusual location of liposarcoma.
A Review on Strategic Positioning of Bottleneck around the Customer Order Decoupling Point and Issues on Production Planning in Supply Chain
Authors: Saeed Muhammad , Loya Samiya , Loya Adil
Published: December 2016

The decoupling point separates part of the supply chain oriented towards customer orders from the part based on forecast planning. This paper focuses on identification of bottlenecks and their positioning with respect to customer order decoupling point (CODP) in supply chain continuum. The research is based on a conceptual model that separates engineer to order (ETO), make to order (MTO), assemble to order (ATO) and make to stock (MTS) by a decoupling point. The important feature of this paper is that supply, demand and operational constraints are allocated in specific part of the supply chain, making it more versatile. Shifting bottleneck concepts, including impact of bottleneck position and issues concerning production and capacity planning, are studied extensively to stabilize the supply chain and reduce its complexity.
A Slag Management Toolset for Determining Optimal Coal Gasification Temperatures
Authors: Kwong Kyei‐Sing , Bennett James P.
Published: December 2016

Gasifier operation is an intricate process because of the complex relationship between slag chemistry and temperature, limitations of feedstock materials, and operational preference. High gasification temperatures increase refractory degradation, while low gasification temperatures can lead to slag buildup on the gasifier sidewall or exit, either of which are problematic during operation. Maximizing refractory service life and gasifier performance require finding an optimized operating temperature range which is a function of the coal slag chemistry and viscosity. Gasifier operators typically use a slag’s viscosity-temperature relationship and/or ash-fusion fluid temperature to determine the gasification temperature range. NETL has built a slag management toolset to determine the optimal temperature range for gasification of a carbon feedstock. This toolset is based on a viscosity database containing experimental data, and a number of models used to predict slag viscosity as a function of composition and temperature. Gasifier users typically have no scientific basis for selecting an operational temperature range for gasification, instead using experience to select operational conditions. The use of the toolset presented in this paper provides a basis for estimating or modifying carbon feedstock slags generated from ash impurities in carbon feedstock.
Multi-Objective Optimization of HAZ Characteristics for Submerged Arc Welding of Micro-Alloyed High Strength Pipeline Steel using GRA-PCA Approach
Authors: Sharma Satish Kumar , Maheshwari Sachin
Published: December 2016

In any type of welding, its heat affected zone (HAZ) is the most critical section where the probability of hydrogen or solidification cracking is prominent. Continuous efforts are being applied by researchers and welders to minimize HAZ and its alterations. For the same purpose, by varying the factors of submerged arc welding (SAW) process which directly influences the heat input and cooling rate of the weld, experiments are carried out on the plates of micro-alloyed high strength pipeline steel. Voltage, welding speed, contact tube to work distance, wire feed rate and preheating temperature are taken as process variables. The experiments are designed according to the central composite rotatable design approach of response surface methodology (RSM). Multi-objective optimization of HAZ characteristics (HAZ area and its hardness) is carried out using grey relational analysis (GRA). To un-correlate the correlated characteristics of HAZ, principal component analysis (PCA) approach is coupled with GRA. The results of the confirmatory test have shown an improvement of 28.51 % and 5.94 % in area and hardness value of HAZ respectively at optimal setting combination of SAW process parameters.
Slag Formation – Thermodynamic Aspects and Experimental Observations
Authors: Holappa Lauri , Kacar Yilmaz
Published: December 2016

Slags have a central role in pyro-metallurgical processes. They bind impurity compounds and absorb reaction products like oxides and sulfides. Functional slags are made by adding lime, magnesia, fluorspar, bauxite, calcium aluminate or other compounds into the reactor vessel where they form the slag together with the targeted reaction products. Additionally, refractory materials of the vessel tend to dissolve into the slag and thus influence its properties. Converter process for steelmaking is a rapid process and slag formation is extremely essential to ensure slag’s metallurgical functions and to avoid harmful reactions with the refractory materials. In this contribution, the progress of understanding the phenomena controlling slag formation and means to promote it were shortly reviewed. Thermodynamic constraints in slag formation were examined and the influence of fluxing additions was experimentally stated. Prefabricated “self-fluxing” lime was tested in industrial scale and proved to be a potential slag forming agent. Slag formation in secondary metallurgy and reduction of slag with aluminum dross or granules were experienced, and the effect on desulfurization and steel cleanliness was discussed.
Investigation on Effect of Machining Parameters of End Milling on Surface Finish and Temperature Using Taguchi Technique
Authors: N Tamiloli , J Venkatesan
Published: December 2016

Machining of alloy materials at high cutting speeds produces high temperatures in the cutting zone, which affects the surface quality. Thus, developing a model for estimating the cutting parameters and optimizing this model to minimize the surface roughness and cutting temperatures becomes utmost important to avoid any damage to the quality surface. This paper presents the development of new models and optimizing these models of machining parameters to minimize the surface roughness and cutting temperature in end milling process by Taguchi method with the statistical approach. Two objectives have been considered, minimum arithmetic mean roughness (Ra) and cutting temperature. Due to the complexity of this machining optimization problem, a single objective Taguchi method has been applied to resolve the problem, and the results have been analyzed.
Toucan predation attempt on a Neotropical pygmy squirrel
Authors: Amasifuén Camilo Flores , Heymann Eckhard W.
Published: December 2016

Predation on arboreal squirrels is rarely observed directly. Here we report the observation of a predatory attack on a Neotropical pygmy squirrel,
Synthesis and study of structural properties of Sn doped ZnO nanoparticles
Authors: Javid M. Arshad , Rafi M. , Ali Ihsan , Hussain Fayyaz , Imran M. , Nasir Ali
Published: December 2016

Pure and Sn-doped ZnO nanostructures were synthesized by simple chemical solution method. In this method we used zinc nitrate and NaOH as precursors. Sn doping content in ZnO was taken with the ratio 0, 5, 10, 15 and 20 percent by weight. Physical properties of Sn-doped ZnO powder were studied by XRD analysis which revealed that Sn doping had a significant effect on crystalline quality, grain size, intensity, dislocation density and strain. The calculated average grain size of pure ZnO was 21 nm. The best crystalline structure was found for 0 wt.%, 5 wt.% and 10 wt.% Sn doping as observed by FESEM and XRD. However, higher Sn-doping (> 10 wt.%) degraded the crystallinity and the grain size of 27.67 nm to 17.76 nm. The structures observed in FESEM images of the samples surfaces were irregular and non-homogeneous. EDX depicted no extra peak of impurity and confirmed good quality of the samples.
Crystal structure (7,8-bis(diisopropylphosphino)-7,8-dicarba-nido-undecaborane-κ2
P,P′)-(benzoato-κ2
O,O′)nickel(II), C21H42B9NiO2P2
Authors: Liguo Yang , xin Wang , Qianqian Gao , Yuqiang Dai
Published: December 2016

C21H42B9NiO2P2, monoclinic, P21/c, a = 9.3840(9)Å, b = 17.0119(18) Å, c = 19.9631(19) Å, β = 112.250(2)°, V = 2949.6(5)Å3, Z = 4, R
gt(F) = 0.0585, wR
ref(F
2) = 0.1489, T = 298 K.
Group adjectives, possessives and single-participant derived nominals in Polish
Authors: Cetnarowska Bożena
Published: December 2016

The article compares the occurrence of pronominal possessive adjectives and denominal group adjectives in Polish event nominals. It is demonstrated that while in other Slavonic languages (e.g., in Russian) relational adjectives clearly contrast with possessive adjectives (both pronominal and lexical ones), in Polish denominal group adjectives, such as prezydencki ‘presidential’, ministerialny ‘ministerial’, or urzędniczy ‘clerk.ADJ’, resemble possessive pronouns in functioning as elements which can satisfy the argument structure of event nominals. The focus is laid on intransitive nominals, in view of the Possessor Principle proposed for Polish by Rozwadowska (1997). While some Polish intransitive nominals accompanied by possessives or by group adjectives are recognized as referential nominals (as is predicted by the analysis of Greek and Romanian group adjectives presented by Alexiadou and Stavrou, 2011, and Moreno, 2015), other intransitive nominals with such adjectival satellites are argued to be argument-supporting nominals. The association with the agentive reading (i.e., external argument interpretation) is shown to be characteristic, but not obligatory, with thematic group adjectives.
A brief note on undermerge and case overwriting
Authors: Witkoś Jacek
Published: December 2016

This brief contribution constitutes a critical reference to David Pesetsky’s Russian case morphology and the syntactic categories (2013), a new monograph proposing an entirely new program of research into the grammar of case. After an introduction of the new theory the paper focuses on two areas for a more critical analysis: the derivation of the Genitive of Quantification and overt evidence for case overwriting in Russian (and Polish). In the former case the procedure of undermerge is put under scrutiny and in the latter a crucial morphological formative is argued to be of a derivational rather than inflectional nature.
Conservation and Restoration of the Don José I Monument in Lisbon, Portugal. Part II: Metal Components
Authors: Matteini Mauro , Delgado Rodrigues José , Fontinha Rute , Charola A. Elena
Published: December 2016

The equestrian statue of D. José I, in Lisbon, is a masterpiece of the sculptor Joaquim Machado de Castro. It weights over thirty eight tons and was made in a single casting by Bartolomeu da Costa in a copper alloy (brass). After over two centuries exposure, the statue presented an unappealing heterogeneous appearance and showed some deterioration features that required attention. Preliminary studies showed that the deterioration phenomena were typical of copper alloys exposed to outdoor urban environments. The proximity of the seacoast also contributed to some specific decay mechanisms. The highly contrasting patterns of the superficial patinas consisted of black dense deposits covering an original cuprite layer side by side with the common green deposits of basic copper sulfates, hydroxides and chlorides. The highly corrosive nantokite was present in sheltered areas, where chlorides are able to accumulate. The conservation intervention included cleaning, mostly carried out with low pressure jets of round glass beads. Onsite tests were made to select the cleaning levels required to match the areas of black and green patinas. A reddish brown cuprite layer was found underneath most of the areas with black dense deposits, while it could only be perceived by transparency on the green covered areas. When a high contrast remained between the two areas, these were mitigated with the application of water colors during the final protection phase. Nantokite active areas were passivated with sodium oxalate after the entire statue was first washed with clean water and treated with lime water to leave an alkaline reserve to slow down the eventual corrosion process, and the sculpture rinsed with ethanol to accelerate its drying. The final protection was made with Paraloid B44 and microcrystalline waxes.
Einfluss der Wertestruktur von Genossenschaftsbanken auf Organisationsaufbau und Positionierung
Authors: Reifschneider Annika , Doluschitz Reiner
Published: December 2016

Cooperative banks are distinguished by their special principles and values and their unique management structure, which differences them from other competitors in the financial sector. But are these characteristics still important in modern bank life? And, should this be the case, can these features contribute to the competitiveness of cooperative banks? Viewed in the context of the new Basel III regulations, these questions are of special interest.
Reformation inszenieren.Religionspädagogische Vergegenwärtigungen lutherischer Freiheitsimpulse
Authors: Klie Thomas
Published: December 2016

Die Reformation war nicht nur ideengeschichtlich von Bedeutung. Die Zeitgenossen und die folgenden Generationen haben die weit reichenden theologischen Umcodierungen Luthers vor allem als eine veränderte Praxis wahrgenommen. Es änderten sich die religiösen Vollzüge, der lutherische Protestantismus zeigte sich als Kultur. An Reformationsgeschichte zu erinnern, heißt darum immer auch, diese religionskulturelle Wirkungsgeschichte performativ ins Gedächtnis zu rufen. Dies soll hier anhand von fünf exemplarischen Szenen eingelöst werden: der Kanzelauftritt, das evangelische Singen, die Katechismen, der Bildersturm und die regional wirksamen Reformatoren.
Muslimische Ansätze zur Erziehung und Erlösung in einer pluralen Gesellschaft
Authors: Khalfaoui Mouez
Published: December 2016

In der christlichen Religionspädagogik hat sich die durch Martin Luther erzielte Unterscheidung zwischen Erziehung und Erlösung im Rahmen der Zwei-Reiche-Lehre als geeignetes Konzept für moderne Gesellschaften bewährt. Dieser Beitrag geht der Frage nach wie die o. g. Thematik bei muslimischen Denkern diskutiert wurde bzw. wird. Der Autor bestätigt die Annahme, dass der Unterschied zwischen den beiden Welten Diesseits und Jenseits in der muslimischen Kultur tief verankert ist und für moderne Plurale Gesellschaften nützlich sein kann.
Practical Active and Passive Recovery Strategies for Soccer Players
Authors: Rey Ezequiel , Padrón-Cabo Alexis , Barcala-Furelos Roberto , Casamichana David , Romo-Pérez Vicente
Published: December 2016

AS A RESULT OF TRAINING AND COMPETITION LOAD IN SOCCER, THE MAJORITY OF THE BODY'S PHYSIOLOGICAL SYSTEMS ARE STRESSED. TO ACCELERATE THE RECOVERY PROCESS AND ENHANCE PERFORMANCE IN SOCCER, DIFFERENT POSTEXERCISE RECOVERY MODES HAVE BEEN SUGGESTED AND ARE BROADLY CLASSIFIED INTO 2 CATEGORIES: ACTIVE RECOVERY OR PASSIVE RECOVERY. DESPITE THE POPULARITY, THERE IS A LACK OF SCIENTIFIC EVIDENCE FOR THE VALIDITY OF THESE RECOVERY INTERVENTIONS. THIS REVIEW SUMMARIZES THE EVIDENCE BASE FOR USING ACTIVE RECOVERY, COLD WATER IMMERSION, WHOLE-BODY VIBRATION, NEUROMUSCULAR ELECTRICAL STIMULATION, AND COMPRESSION GARMENTS, AS EXERCISE RECOVERY AIDS IN SOCCER, AND WHERE POSSIBLE, PROVIDES PRACTICAL RECOMMENDATIONS REGARDING USAGE.
Heat Acclimatization and Exertional Heat Illness Prevention in Youth Football Programs
Authors: Poole Jordan A. , Stearns Rebecca L. , Lopez Rebecca M.
Published: December 2016

ATHLETES ARE AT AN INCREASED RISK OF EXPERIENCING AN EXERTIONAL HEAT ILLNESS (EHI) DUE TO THE PHYSICAL EXERTION REQUIRED BY FOOTBALL, PARTICULARLY WHEN PERFORMED IN HOT AND HUMID CONDITIONS. VARIOUS MODIFICATIONS TOGETHER WITH EDUCATION AND PREPARATION BY THOSE WORKING WITH YOUTH FOOTBALL ATHLETES CAN HELP MITIGATE THE RISKS OF EXERCISING IN THE HEAT. THE OVERALL EHI RISK FOR YOUTH ATHLETES IS NOT WELL KNOWN. THE PURPOSE OF THIS ARTICLE IS TO REVIEW THE EXISTING LITERATURE REGARDING THERMOREGULATION OF YOUNGER ATHLETES AND TO PROVIDE GUIDELINES FOR COACHES AND CLINICIANS ON HOW TO PREVENT EHI FOR SAFER PARTICIPATION IN YOUTH FOOTBALL.
Circulating Estradiol Regulates Brain-Derived Estradiol via Actions at GnRH Receptors to Impact Memory in Ovariectomized Rats
Authors: Nelson Britta S. , Black Katelyn L. , Daniel Jill M.
Published: December 2016

Systemic estradiol treatment enhances hippocampus-dependent memory in ovariectomized rats. Although these enhancements are traditionally thought to be due to circulating estradiol, recent data suggest these changes are brought on by hippocampus-derived estradiol, the synthesis of which depends on gonadotropin-releasing hormone (GnRH) activity. The goal of the current work is to test the hypothesis that peripheral estradiol affects hippocampus-dependent memory through brain-derived estradiol regulated via hippocampal GnRH receptor activity. In the first experiment, intracerebroventricular infusion of letrozole, which prevents the synthesis of estradiol, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory in a radial-maze task. In the second experiment, hippocampal infusion of antide, a long-lasting GnRH receptor antagonist, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory. In the third experiment, hippocampal infusion of GnRH enhanced hippocampus-dependent memory, the effects of which were blocked by letrozole infusion. Results indicate that peripheral estradiol-induced enhancement of cognition is mediated by brain-derived estradiol via hippocampal GnRH receptor activity.
Action Categories in Lateral Occipitotemporal Cortex Are Organized Along Sociality and Transitivity
Authors: Wurm Moritz F. , Caramazza Alfonso , Lingnau Angelika
Published: December 2016

How neural specificity for distinct conceptual knowledge categories arises is central for understanding the organization of semantic memory in the human brain. Although there is a large body of research on the neural processing of distinct object categories, the organization of action categories remains largely unknown. In particular, it is unknown whether different action categories follow a specific topographical organization on the cortical surface analogously to the category-specific organization of object knowledge. Here, we tested whether the neural representation of action knowledge is organized in terms of nonsocial versus social and object-unrelated versus object-related actions (sociality and transitivity, respectively, hereafter). We hypothesized a major distinction of sociality and transitivity along dorsal and ventral lateral occipitotemporal cortex (LOTC), respectively. Using fMRI-based multivoxel pattern analysis, we identified neural representations of action information associated with sociality and transitivity in bilateral LOTC. Representational similarity analysis revealed a dissociation between dorsal and ventral LOTC. We found that action representations in dorsal LOTC are segregated along features of sociality, whereas action representations in ventral LOTC are segregated along features of transitivity. In addition, representations of sociality and transitivity features were found more anteriorly in LOTC than representations of specific subtypes of actions, suggesting a posterior–anterior gradient from concrete to abstract action features. These findings elucidate how the neural representations of perceptually and conceptually diverse actions are organized in distinct subsystems in the LOTC.

SIGNIFICANCE STATEMENTThe lateral occipitotemporal cortex (LOTC) is critically involved in the recognition of objects and actions, but our knowledge about the underlying organizing principles is limited. Here, we discovered a dorsal–ventral distinction of actions in LOTC: dorsal LOTC represents actions based on sociality (how much an action is directed to another person) in proximity to person knowledge. In contrast, ventral LOTC represents actions based on transitivity (how much an action involves the interaction with inanimate objects) in proximity to tools/artifacts in ventral LOTC, suggesting a mutually dependent organization of actions and objects. In addition, we found a posterior-to-anterior organization of the LOTC for concrete and abstract representations, respectively. Our findings provide important insights about the organization of actions in LOTC.
Complexin Mutants Reveal Partial Segregation between Recycling Pathways That Drive Evoked and Spontaneous Neurotransmission
Authors: Sabeva Nadezhda , Cho Richard W. , Vasin Alexander , Gonzalez Agustin , Littleton J. Troy , Bykhovskaia Maria
Published: December 2016

Synaptic vesicles fuse at morphological specializations in the presynaptic terminal termed active zones (AZs). Vesicle fusion can occur spontaneously or in response to an action potential. Following fusion, vesicles are retrieved and recycled within nerve terminals. It is still unclear whether vesicles that fuse spontaneously or following evoked release share similar recycling mechanisms. Genetic deletion of the SNARE-binding protein complexin dramatically increases spontaneous fusion, with the protein serving as the synaptic vesicle fusion clamp atDrosophilasynapses. We examined synaptic vesicle recycling pathways atcomplexin nullneuromuscular junctions, where spontaneous release is dramatically enhanced. We combined loading of the lipophilic dye FM1–43 with photoconversion, electron microscopy, and electrophysiology to monitor evoked and spontaneous recycling vesicle pools. We found that the total number of recycling vesicles was equal to those retrieved through spontaneous and evoked pools, suggesting that retrieval following fusion is partially segregated for spontaneous and evoked release. In addition, the kinetics of FM1–43 destaining and synaptic depression measured in the presence of the vesicle-refilling blocker bafilomycin indicated that spontaneous and evoked recycling pools partially intermix during the release process. Finally, FM1–43 photoconversion combined with electron microscopy analysis indicated that spontaneous recycling preferentially involves synaptic vesicles in the vicinity of AZs, whereas vesicles recycled following evoked release involve a larger intraterminal pool. Together, these results suggest that spontaneous and evoked vesicles use separable recycling pathways and then partially intermix during subsequent rounds of fusion.

SIGNIFICANCE STATEMENTNeurotransmitter release involves fusion of synaptic vesicles with the plasma membrane in response to an action potential, or spontaneously in the absence of stimulation. Upon fusion, vesicles are retrieved and recycled, and it is unclear whether recycling pathways for evoked and spontaneous vesicles are segregated after fusion. We addressed this question by taking advantage of preparations lacking the synaptic protein complexin, which have elevated spontaneous release that enables reliable tracking of the spontaneous recycling pool. Our results suggest that spontaneous and evoked recycling pathways are segregated during the retrieval process but can partially intermix during stimulation.
SuppressingN-Acetyl-l-Aspartate Synthesis Prevents Loss of Neurons in a Murine Model of Canavan Leukodystrophy
Authors: Sohn Jiho , Bannerman Peter , Guo Fuzheng , Burns Travis , Miers Laird , Croteau Christopher , Singhal Naveen K. , McDonough Jennifer A. , Pleasure David
Published: December 2016

Canavan disease is a leukodystrophy caused by aspartoacylase (ASPA) deficiency. The lack of functional ASPA, an enzyme enriched in oligodendroglia that cleavesN-acetyl-l-aspartate (NAA) to acetate andl-aspartic acid, elevates brain NAA and causes “spongiform” vacuolation of superficial brain white matter and neighboring gray matter. In children with Canavan disease, neuroimaging shows early-onset dysmyelination and progressive brain atrophy. Neuron loss has been documented at autopsy in some cases. Prior studies have shown that mice homozygous for theAspanonsense mutationNur7also develop brain vacuolation. We now report that numbers of cerebral cortical and cerebellar neurons are decreased and that cerebral cortex progressively thins inAspaNur7/Nur7mice. This neuronal pathology is prevented by constitutive disruption ofNat8l, which encodes the neuronal NAA-synthetic enzymeN-acetyltransferase-8-like.

SIGNIFICANCE STATEMENTThis is the first demonstration of cortical and cerebellar neuron depletion and progressive cerebral cortical thinning in an animal model of Canavan disease. Genetic suppression ofN-acetyl-l-aspartate (NAA) synthesis, previously shown to block brain vacuolation in aspartoacylase-deficient mice, also prevents neuron loss and cerebral cortical atrophy in these mice. These results suggest that lowering the concentration of NAA in the brains of children with Canavan disease would prevent or slow progression of neurological deficits.
Control of Spike Transfer at Hippocampal Mossy Fiber SynapsesIn Vivoby GABAAand GABABReceptor-Mediated Inhibition
Authors: Zucca Stefano , Griguoli Marilena , Malézieux Meryl , Grosjean Noëlle , Carta Mario , Mulle Christophe
Published: December 2016

Despite extensive studies in hippocampal slices and incentive from computational theories, the synaptic mechanisms underlying information transfer at mossy fiber (mf) connections between the dentate gyrus (DG) and CA3 neuronsin vivoare still elusive. Here we used an optogenetic approach in mice to selectively target and control the activity of DG granule cells (GCs) while performing whole-cell and juxtacellular recordings of CA3 neuronsin vivo. In CA3 pyramidal cells (PCs), mf–CA3 synaptic responses consisted predominantly of an IPSP at low stimulation frequency (0.05 Hz). Upon increasing the frequency of stimulation, a biphasic response was observed consisting of a brief mf EPSP followed by an inhibitory response lasting on the order of 100 ms. Spike transfer at DG–CA3 interneurons recorded in the juxtacellular mode was efficient at low presynaptic stimulation frequency and appeared insensitive to an increased frequency of GC activity. Overall, this resulted in a robust and slow feedforward inhibition of spike transfer at mf–CA3 pyramidal cell synapses. Short-term plasticity of EPSPs with increasing frequency of presynaptic activity allowed inhibition to be overcome to reach spike discharge in CA3 PCs. Whereas the activation of GABAAreceptors was responsible for the direct inhibition of light-evoked spike responses, the slow inhibition of spiking activity required the activation of GABABreceptors in CA3 PCs. The slow inhibitory response defined an optimum frequency of presynaptic activity for spike transfer at ∼10 Hz. Altogether these properties define the temporal rules for efficient information transfer at DG–CA3 synaptic connections in the intact circuit.

SIGNIFICANCE STATEMENTActivity-dependent changes in synaptic strength constitute a basic mechanism for memory. Synapses from the dentate gyrus (DG) to the CA3 area of the hippocampus are distinctive for their prominent short-term plasticity, as studied in slices. Plasticity of DG–CA3 connections may assist in the encoding of precise memory in the CA3 network. Here we characterize DG–CA3 synaptic transmissionin vivousing targeted optogenetic activation of DG granule cells while recording in whole-cell patch-clamp and juxtacellular configuration from CA3 pyramidal cells and interneurons. We show that,in vivo, short-term plasticity of excitatory inputs to CA3 pyramidal cells combines with robust feedforward inhibition mediated by both GABAAand GABABreceptors to control the efficacy and temporal rules for information transfer at DG–CA3 connections.
Integrin-Linked Kinase (ILK) Deletion Disrupts Oligodendrocyte Development by Altering Cell Cycle
Authors: Hussain Rashad , Macklin Wendy B.
Published: December 2016

During development, oligodendrocytes are initially specified, after which oligodendrocyte precursor cells (OPCs) migrate and proliferate before differentiating into myelinating cells. Lineage-specific programming of oligodendrocytes results from sensing environmental cues through membrane-bound receptors and related intracellular signaling molecules. Integrin-linked kinase (ILK) is an important protein that is expressed at the inner margins of the plasma membrane and can mediate some of these signals. The current studies demonstrate that ILK deletion reduces the proliferation and differentiation of OPCs in the developing CNS. There was a significant decrease in the number of OPCs and mature oligodendrocytes throughout postnatal development in Olig1Cre+/−× ILKfl/flmice. These changes were accompanied by reduced numbers of myelinated axons. Key proteins involved in cell cycle regulation were dysregulated. Cyclin D1/D3 and cyclin-dependent kinase 2/4 (cdc2/cdc4) were downregulated and the cell cycle inhibitor protein p27 Kip1 was upregulated. Therefore, ILK deletion impaired the developmental profile, proliferation, and differentiation of OPCs by altering the expression of regulatory cytoplasmic and nuclear factors.

SIGNIFICANCE STATEMENTIntegrin-linked kinase (ILK) is a scaffolding protein involved in integrating signals from the extracellular environment and communicating those signals to downstream effectors within cells. It has been proposed to regulate aspects of oligodendrocyte process extension and thereby myelination. However, the current studies demonstrate that it has an earlier impact on cells in this lineage. Knocking down ILK in Olig1-Cre-expressing cells reduces the pool of oligodendrocyte progenitor cells (OPCs). This smaller pool of OPCs results from altered cell cycle and reduced cell proliferation. These cells myelinate fewer axons than in wild-type mice and, in corpus callosum, the myelin is thinner than in controls. Interestingly, the smaller pool of spinal cord oligodendrocytes generates myelin that is of normal thickness.
Temporal Expectations Guide Dynamic Prioritization in Visual Working Memory through Attenuated α Oscillations
Authors: van Ede Freek , Niklaus Marcel , Nobre Anna C.
Published: December 2016

Although working memory is generally considered a highly dynamic mnemonic store, popular laboratory tasks used to understand its psychological and neural mechanisms (such as change detection and continuous reproduction) often remain relatively “static,” involving the retention of a set number of items throughout a shared delay interval. In the current study, we investigated visual working memory in a more dynamic setting, and assessed the following: (1) whether internally guided temporal expectations can dynamically and reversibly prioritize individual mnemonic items at specific times at which they are deemed most relevant; and (2) the neural substrates that support such dynamic prioritization. Participants encoded two differently colored oriented bars into visual working memory to retrieve the orientation of one bar with a precision judgment when subsequently probed. To test for the flexible temporal control to access and retrieve remembered items, we manipulated the probability for each of the two bars to be probed over time, and recorded EEG in healthy human volunteers. Temporal expectations had a profound influence on working memory performance, leading to faster access times as well as more accurate orientation reproductions for items that were probed at expected times. Furthermore, this dynamic prioritization was associated with the temporally specific attenuation of contralateral α (8–14 Hz) oscillations that, moreover, predicted working memory access times on a trial-by-trial basis. We conclude that attentional prioritization in working memory can be dynamically steered by internally guided temporal expectations, and is supported by the attenuation of α oscillations in task-relevant sensory brain areas.

SIGNIFICANCE STATEMENTIn dynamic, everyday-like, environments, flexible goal-directed behavior requires that mental representations that are kept in an active (working memory) store are dynamic, too. We investigated working memory in a more dynamic setting than is conventional, and demonstrate that expectations about when mnemonic items are most relevant can dynamically and reversibly prioritize these items in time. Moreover, we uncover a neural substrate of such dynamic prioritization in contralateral visual brain areas and show that this substrate predicts working memory retrieval times on a trial-by-trial basis. This places the experimental study of working memory, and its neuronal underpinnings, in a more dynamic and ecologically valid context, and provides new insights into the neural implementation of attentional prioritization within working memory.
Higher Heart-Rate Variability Is Associated with Ventromedial Prefrontal Cortex Activity and Increased Resistance to Temptation in Dietary Self-Control Challenges
Authors: Maier Silvia U. , Hare Todd A.
Published: December 2016

Higher levels of self-control in decision making have been linked to better psychosocial and physical health. A similar link to health outcomes has been reported for heart-rate variability (HRV), a marker of physiological flexibility. Here, we sought to link these two, largely separate, research domains by testing the hypothesis that greater HRV would be associated with better dietary self-control in humans. Specifically, we examined whether total HRV at sedentary rest (measured as the SD of normal-to-normal intervals) can serve as a biomarker for the neurophysiological adaptability that putatively underlies self-controlled behavior. We found that HRV explained a significant portion of the individual variability in dietary self-control, with individuals having higher HRV being better able to downregulate their cravings in the face of taste temptations. Furthermore, HRV was associated with activity patterns in the ventromedial prefrontal cortex (vmPFC), a key node in the brain's valuation and decision circuitry. Specifically, individuals with higher HRV showed both higher overall vmPFC blood-oxygen-level-dependent activity and attenuated taste representations when presented with a dietary self-control challenge. Last, the behavioral and neural associations with HRV were consistent across both our stress induction and control experimental conditions. The stability of this association across experimental conditions suggests that HRV may serve as both a readily obtainable and robust biomarker for self-control ability across environmental contexts.

SIGNIFICANCE STATEMENTSelf-control is associated with better health, but behavioral and psychometric self-control measures allow only indirect associations with health outcomes and may be distorted by reporting bias. We tested whether resting heart-rate variability (HRV), a physiological indicator of psychological and physical health, can predict individual differences in dietary self-control in humans. We found that higher HRV was associated with better self-control and improved predictions of choice behavior. Specifically, higher HRV was associated with more effective downregulation of taste temptations, and with a diminished neural representation of taste temptations during self-control challenges. Our results suggest that HRV may serve as an easily acquired, noninvasive, and low-cost biomarker for self-control ability.
Local Circuits of V1 Layer 4B Neurons Projecting to V2 Thick Stripes Define Distinct Cell Classes and Avoid Cytochrome Oxidase Blobs
Authors: Yarch Jeff , Federer Frederick , Angelucci Alessandra
Published: December 2016

Decades of anatomical studies on the primate primary visual cortex (V1) have led to a detailed diagram of V1 intrinsic circuitry, but this diagram lacks information about the output targets of V1 cells. Understanding how V1 local processing relates to downstream processing requires identification of neuronal populations defined by their output targets. In primates, V1 layers (L)2/3 and 4B send segregated projections to distinct cytochrome oxidase (CO) stripes in area V2: neurons in CO blob columns project to thin stripes while neurons outside blob columns project to thick and pale stripes, suggesting functional specialization of V1-to-V2 CO streams. However, the conventional diagram of V1 shows all L4B neurons, regardless of their soma location in blob or interblob columns, as projecting selectively to CO blobs in L2/3, suggesting convergence of blob/interblob information in L2/3 blobs and, possibly, some V2 stripes. However, it is unclear whether all L4B projection neurons show similar local circuitries. Using viral-mediated circuit tracing, we have identified the local circuits of L4B neurons projecting to V2 thick stripes in macaque. Consistent with previous studies, we found the somata of this L4B subpopulation to reside predominantly outside blob columns; however, unlike previous descriptions of local L4B circuits, these cells consistently projected outside CO blob columns in all layers. Thus, the local circuits of these L4B output neurons, just like their extrinsic projections to V2, preserve CO streams. Moreover, the intra-V1 laminar patterns of axonal projections identify two distinct neuron classes within this L4B subpopulation, including a rare novel neuron type, suggestive of two functionally specialized output channels.

SIGNIFICANCE STATEMENTConventional diagrams of primate primary visual cortex (V1) depict neuronal connections within and between different V1 layers, but lack information about the cells' downstream targets. This information is critical to understanding how local processing in V1 relates to downstream processing. We have identified the local circuits of a population of cells in V1 layer (L)4B that project to area V2. These cells' local circuits differ from classical descriptions of L4B circuits in both the laminar and functional compartments targeted by their axons, and identify two neuron classes. Our results demonstrate that both local intra-V1 and extrinsic V1-to-V2 connections of L4B neurons preserve CO-stream segregation, suggesting that across-stream integration occurs downstream of V1, and that output targets dictate local V1 circuitry.
MECHANISMS IN ENDOCRINOLOGY: Skeletal muscle lipotoxicity in insulin resistance and type 2 diabetes: a causal mechanism or an innocent bystander?
Authors: Brøns Charlotte , Grunnet Louise Groth
Published: December 2016

Dysfunctional adipose tissue is associated with an increased risk of developing type 2 diabetes (T2D). One characteristic of a dysfunctional adipose tissue is the reduced expandability of the subcutaneous adipose tissue leading to ectopic storage of fat in organs and/or tissues involved in the pathogenesis of T2D that can cause lipotoxicity. Accumulation of lipids in the skeletal muscle is associated with insulin resistance, but the majority of previous studies do not prove any causality. Most studies agree that it is not the intramuscular lipids per se that causes insulin resistance, but rather lipid intermediates such as diacylglycerols, fatty acyl-CoAs and ceramides and that it is the localization, composition and turnover of these intermediates that play an important role in the development of insulin resistance and T2D. Adipose tissue is a more active tissue than previously thought, and future research should thus aim at examining the exact role of lipid composition, cellular localization and the dynamics of lipid turnover on the development of insulin resistance. In addition, ectopic storage of fat has differential impact on various organs in different phenotypes at risk of developing T2D; thus, understanding how adipogenesis is regulated, the interference with metabolic outcomes and what determines the capacity of adipose tissue expandability in distinct population groups is necessary. This study is a review of the current literature on the adipose tissue expandability hypothesis and how the following ectopic lipid accumulation as a consequence of a limited adipose tissue expandability may be associated with insulin resistance in muscle and liver.
Non-alcoholic fatty liver disease is associated with early left ventricular dysfunction in childhood acute lymphoblastic leukaemia survivors
Authors: Delvecchio Maurizio , Muggeo Paola , Monteduro Mariantonietta , Lassandro Giuseppe , Novielli Chiara , Valente Federica , Salinaro Emanuela , Zito Annapaola , Ciccone Marco Matteo , Miniello Vito Leonardo , Santoro Nicola , Giordano Paola , Faienza Maria Felicia
Published: December 2016

Background

Childhood acute lymphoblastic leukaemia (ALL) survivors have an increased risk of metabolic and cardiovascular disease. We aimed to assess the presence of non-alcoholic fatty liver disease (NAFLD) in childhood ALL and if it is associated with early cardiovascular dysfunction.

Methods

In total, 53 childhood ALL survivors and 34 controls underwent auxological evaluation, biochemical assay, liver, heart and vascular ultrasound study.

Results

NAFLD was more frequent in ALL patients than in controls (39.6% vs 11.7%, P < 0.01). Patients with NAFLD were more obese and insulin resistant than patients without NAFLD. Flow-mediated dilatation and interventricular septum were lower in the ALL group than those in the control group (P < 0.001 for both). The patients with NAFLD showed lower left ventricular ejection fraction than those without NAFLD (P = 0.011). In ALL survivors, BMI-SDS and subcutaneous fat were the strongest predictors of NAFLD, whereas preperitoneal adipose tissue and C-reactive protein were the strongest predictors of left ventricular ejection fraction.

Conclusions

Childhood ALL survivors had higher prevalence of NAFLD than healthy controls, which is associated with early left ventricular impairment. In the case of fatty liver, a comprehensive heart evaluation is mandatory. We strongly recommend to prevent visceral adiposity in ALL survivors, to search for metabolic syndrome or its components and to reinforce the need of intervention on diet and lifestyle during the follow-up of these patients.
Very low-density lipoprotein (VLDL)-induced signals mediating aldosterone production
Authors: Tsai Ying-Ying , Rainey William E , Bollag Wendy B
Published: December 2016

Aldosterone, secreted by the adrenal zona glomerulosa, enhances sodium retention, thus increasing blood volume and pressure. Excessive production of aldosterone results in high blood pressure and contributes to cardiovascular and renal disease, stroke and visual loss. Hypertension is also associated with obesity, which is correlated with other serious health risks as well. Although weight gain is associated with increased blood pressure, the mechanism by which excess fat deposits increase blood pressure remains unclear. Several studies have suggested that aldosterone levels are elevated with obesity and may represent a link between obesity and hypertension. In addition to hypertension, obese patients typically have dyslipidemia, including elevated serum levels of very low-density lipoprotein (VLDL). VLDL, which functions to transport triglycerides from the liver to peripheral tissues, has been demonstrated to stimulate aldosterone production. Recent studies suggest that the signaling pathways activated by VLDL are similar to those utilized by AngII. Thus, VLDL increases cytosolic calcium levels and stimulates phospholipase D (PLD) activity to result in the induction of steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2) expression. These effects seem to be mediated by the ability of VLDL to increase the phosphorylation (activation) of their regulatory transcription factors, such as the cAMP response element-binding (CREB) protein family of transcription factors. Thus, research into the pathways by which VLDL stimulates aldosterone production may identify novel targets for the development of therapies for the treatment of hypertension, particularly those associated with obesity, and other aldosterone-modulated pathologies.