bluuebunny/crossref_metadata_2025 huggingface dataset:
Contrast Gain Control in the Visual Cortex: Monocular Versus Binocular Mechanisms
Authors: Truchard Anthony M. , Ohzawa Izumi , Freeman Ralph D.
Published: April 2018

In this study, we compare binocular and monocular mechanisms underlying contrast encoding by binocular simple cells in primary visual cortex. At mid to high levels of stimulus contrast, contrast gain of cortical neurons typically decreases as stimulus contrast is increased (Albrecht and Hamilton, 1982). We have devised a technique by which it is possible to determine the relative contributions of monocular and binocular processes to such reductions in contrast gain. First, we model the simple cell as an adjustable linear mechanism with a static output nonlinearity. For binocular cells, the linear mechanism is sensitive to inputs from both eyes. To constrain the parameters of the model, we record from binocular simple cells in striate cortex. To activate each cell, drifting sinusoidal gratings are presented dichoptically at various relative interocular phases. Stimulus contrast for one eye is varied over a large range whereas that for the other eye is fixed. We then determine the best-fitting parameters of the model for each cell for all of the interocular contrast ratios. This allows us to determine the effect of contrast on the contrast gain of the system. Finally, we decompose the contrast gain into monocular and binocular components. Using the data to constrain the model for a fixed contrast in one eye and increased contrasts in the other eye, we find steep reductions in monocular gain, whereas binocular gain exhibits modest and variable changes. These findings demonstrate that contrast gain reductions occur primarily at a monocular site, before convergence of information from the two eyes.
Phosphorylation of the Postsynaptic Density-95 (PSD-95)/Discs Large/Zona Occludens-1 Binding Site of Stargazin Regulates Binding to PSD-95 and Synaptic Targeting of AMPA Receptors
Authors: Chetkovich Dane M. , Chen Lu , Stocker Timothy J. , Nicoll Roger A. , Bredt David S.
Published: April 2018

Dynamic regulation of AMPA-type receptors at the synapse is proposed to play a critical role in alterations of the synaptic strength seen in cellular models of learning and memory such as long-term potentiation in the hippocampus. Stargazin, previously identified as an AMPA receptor (AMPAR)-interacting protein, is critical for surface expression and synaptic targeting of AMPARs. Stargazin interacts with postsynaptic density-95/discs large/zona occludens-1 (PDZ) proteins via a C-terminal PDZ binding motif. Interestingly, the C terminal of stargazin also predicts phosphorylation at a threonine residue critical for PDZ protein binding. Because protein phosphorylation regulates synaptic plasticity, we characterized this site and the effects of stargazin phosphorylation on AMPAR function.In vitropeptide phosphorylation assays and Western blot analysis with phospho-stargazin-specific antibodies indicate that the critical threonine within the stargazin PDZ binding site is phosphorylated by protein kinase A. This phosphorylation disrupts stargazin interaction and clustering with postsynaptic density-95 (PSD-95) in transfected COS-7 cells. Furthermore, a stargazin construct with a Thr-to-Glu mutation that mimics phosphorylation fails to cluster at synaptic spines and downregulates synaptic AMPAR function in cultured hippocampal neurons. These data suggest that phosphorylation of the stargazin PDZ ligand can disrupt stargazin interaction with PSD-95 and thereby regulate synaptic AMPAR function.
Sympathoexcitation by Bradykinin Involves Ca2+-Independent Protein Kinase C
Authors: Scholze Thomas , Moskvina Eugenia , Mayer Martina , Just Herwig , Kubista Helmut , Boehm Stefan
Published: April 2018

Bradykinin has long been known to excite sympathetic neurons via B2receptors, and this action is believed to be mediated by an inhibition of M-currents via phospholipase C and inositol trisphosphate-dependent increases in intracellular Ca2+. In primary cultures of rat superior cervical ganglion neurons, bradykinin caused an accumulation of inositol trisphosphate, an inhibition of M-currents, and a stimulation of action potential-mediated transmitter release. Blockade of inositol trisphosphate-dependent signaling cascades failed to affect the bradykinin-induced release of noradrenaline, but prevented the peptide-induced inhibition of M-currents. In contrast, inhibition or downregulation of protein kinase C reduced the stimulation of transmitter release, but not the inhibition of M-currents, by bradykinin. In cultures of superior cervical ganglia, classical (α, βI, βII), novel (δ, ε), and atypical (ζ) protein kinase C isozymes were detected by immunoblotting. Bradykinin induced a translocation of Ca2+-independent protein kinase C isoforms (δ and ε) from the cytosol to the membrane of the neurons, but left the cellular distribution of other isoforms unchanged. This activation of Ca2+-independent protein kinase C enzymes was prevented by a phospholipase C inhibitor. The bradykinin-dependent stimulation of noradrenaline release was reduced by inhibitors of classical and novel protein kinase C isozymes, but not by an inhibitor selective for Ca2+-dependent isoforms. These results demonstrate that bradykinin B2receptors are linked to phospholipase C to simultaneously activate two signaling pathways: one mediates an inositol trisphosphate- and Ca2+-dependent inhibition of M-currents, the other one leads to an excitation of sympathetic neurons independently of changes in M-currents through an activation of Ca2+-insensitive protein kinase C.
Serial Analysis of Gene Expression Identifies Metallothionein-II as Major Neuroprotective Gene in Mouse Focal Cerebral Ischemia
Authors: Trendelenburg George , Prass Konstantin , Priller Josef , Kapinya Krisztian , Polley Andreas , Muselmann Claudia , Ruscher Karsten , Kannbley Ute , Schmitt Armin O. , Castell Stefanie , Wiegand Frank , Meisel Andreas , Rosenthal André , Dirnagl Ulrich
Published: April 2018

We applied serial analysis of gene expression (SAGE) to study differentially expressed genes in mouse brain 14 hr after the induction of focal cerebral ischemia. Analysis of >60,000 transcripts revealed 83 upregulated and 94 downregulated transcripts (more than or equal to eightfold). Reproducibility was demonstrated by performing SAGE in duplicate on the same starting material. Metallothionein-II (MT-II) was the most significantly upregulated transcript in the ischemic hemisphere. MT-I and MT-II are assumed to be induced by metals, glucocorticoids, and inflammatory signals in a coordinated manner, yet their function remains elusive. Upregulation of both MT-I and MT-II was confirmed by Northern blotting. MT-I and MT-II mRNA expression increased as early as 2 hr after 2 hr of transient ischemia, with a maximum after 16 hr. Western blotting and immunohistochemistry revealed MT-I/-II upregulation in the ischemic hemisphere, whereas double labeling demonstrated the colocalization of MT with markers for astrocytes as well as for monocytes/macrophages. MT-I- and MT-II-deficient mice developed approximately threefold larger infarcts than wild-type mice and a significantly worse neurological outcome.

For the first time we make available a comprehensive data set on brain ischemic gene expression and underscore the important protective role of metallothioneins in ischemic damage of the brain. Our results demonstrate the usefulness of SAGE to screen functionally relevant genes and the power of knock-out models in linking function to expression data generated by high throughput techniques.
Ischemia Induces a Translocation of the Splicing Factor tra2-β1 and Changes Alternative Splicing Patterns in the Brain
Authors: Daoud Rosette , Mies Günter , Smialowska Agata , Oláh Laszlo , Hossmann Konstantin-Alexander , Stamm Stefan
Published: April 2018

Alternative splice-site selection is regulated by the relative concentration of individual members of the serine-arginine family of proteins and heterogeneous nuclear ribonucleoproteins. Most of these proteins accumulate predominantly in the nucleus, and a subset of them shuttles continuously between nucleus and cytosol. We demonstrate that in primary neuronal cultures, a rise in intracellular calcium concentration induced by thapsigargin leads to a translocation of the splicing regulatory protein tra2-β1 and a consequent change in splice-site selection. To investigate this phenomenon under physiological conditions, we used an ischemia model. Ischemia induced in the brain causes a cytoplasmic accumulation and hyperphosphorylation of tra2-β1. In addition, several of the proteins binding to tra2-β1, such as src associated in mitosis 68 and serine/arginine-rich proteins, accumulate in the cytosol. Concomitant with this subcellular relocalization, we observed a change in alternative splice-site usage of theICH-1gene. The increased usage of its alternative exons is in agreement with previous studies demonstrating its repression by a high concentration of proteins with serine/arginine-rich domains. Our findings suggest that a change in the calcium concentration associated with ischemia is part of a signaling event, which changes pre-mRNA splicing pathways by causing relocalization of proteins that regulate splice-site selection.
Stomatin-Related Olfactory Protein, SRO, Specifically Expressed in the Murine Olfactory Sensory Neurons
Authors: Kobayakawa Ko , Hayashi Reiko , Morita Kenji , Miyamichi Kazunari , Oka Yuichiro , Tsuboi Akio , Sakano Hitoshi
Published: April 2018

We identified a stomatin-related olfactory protein (SRO) that is specifically expressed in olfactory sensory neurons (OSNs). The mousesrogene encodes a polypeptide of 287 amino acids with a calculated molecular weight of 32 kDa. SRO shares 82% sequence similarity with the murine stomatin, 78% withCaenorhabditis elegansMEC-2, and 77% withC. elegansUNC-1. Unlike other stomatin-family genes, thesrotranscript was present only in OSNs of the main olfactory epithelium. Nosroexpression was seen in vomeronasal neurons. SRO was abundant in most apical dendrites of OSNs, including olfactory cilia. Immunoprecipitation revealed that SRO associates with adenylyl cyclase type III and caveolin-1 in the low-density membrane fraction of olfactory cilia. Furthermore, anti-SRO antibodies stimulated cAMP production in fractionated cilia membrane. SRO may play a crucial role in modulating odorant signals in the lipid rafts of olfactory cilia.
Microtubule Reconfiguration during Axonal Retraction Induced by Nitric Oxide
Authors: He Yan , Yu Wenqian , Baas Peter W.
Published: April 2018

Axonal retraction is induced by different types of physiological cues and is responsible for the elimination of mistargeted axons. There is broad agreement that alterations in the cytoskeleton underlie axonal retraction. The prevailing view is that axonal retraction involves a wholesale depolymerization of microtubules and microfilaments. However, axons retracting physiologically display a very different morphology than axons induced to retract by experimental depolymerization of microtubules. Experimental depolymerization of microfilaments actually prevents retraction rather than causing it. We have proposed an alternative hypothesis, namely that axonal retraction involves a backward retreat of cytoskeletal elements rather than their wholesale depolymerization. In the present study, we sought to test this hypothesis with regard to microtubules. When a donor of nitric oxide was applied to cultured chick sensory neurons, the majority of axons retracted dramatically within 30–60 min. Retracting axons were characterized by an enlarged distal region, a thin trailing remnant, and sinusoidal bends along the shaft. Quantitative immunofluorescence analyses showed no detectable loss of microtubule mass during retraction, even with regard to the most labile microtubules. Instead, microtubules were reconfigured into coiling and sinusoidal bundles to accommodate the shortening of the axon. Stabilization of microtubules by taxol did not prevent the retraction, even at concentrations of the drug that actually caused microtubule levels to increase. The retractions induced by nitric oxide were remarkably similar to those observed when motor proteins are manipulated, suggesting that these retractions may result from alterations in the activities of the motors that configure microtubules.
Relations between Brain Pathology and Temporal Lobe Epilepsy
Authors: Zhang Xia , Cui Shu-Sen , Wallace Amy E. , Hannesson Darren K. , Schmued Larry C. , Saucier Deborah M. , Honer William G. , Corcoran Michael E.
Published: April 2018

Temporal lobe epilepsy, the most common type of epilepsy in adult humans, is characterized clinically by the progressive development of spontaneous recurrent seizures of temporal lobe origin and pathologically by hippocampal neuronal loss and mossy fiber sprouting. In this study, we sought to test the prominent hypothesis that neuronal loss and mossy fiber sprouting play a critical role in the genesis and progression of temporal lobe epilepsy.

Rats receiving a single kainic acid injection experienced a single sustained episode of epileptic status with massive neuronal loss and mossy fiber sprouting, whereas rats receiving triple kainic acid injections experienced two priming episodes and one sustained episode of epileptic status with no detectable neuronal loss and mossy fiber sprouting. Early in the process of chronic seizure development, primed rats that failed to show detectable neuronal loss and mossy fiber sprouting exhibited a starting date and a frequency of spontaneous recurrent seizures similar to those of nonprimed rats that showed massive neuronal loss and mossy fiber sprouting. However, nonprimed rats displayed significantly prolonged episodes of spontaneous recurrent seizures over the whole process of chronic seizure development and more frequent severe seizures later in the process. Similar results were observed in both Fischer-344 and Wistar rats as well as in the rat pilocarpine preparation of temporal lobe epilepsy.

These results fail to reveal a relation between neuronal loss–mossy fiber sprouting and the genesis of temporal lobe epilepsy but suggest that neuronal loss, mossy fiber sprouting, or both contribute to the intensification of chronic seizures.
Maturation and Death of Adult-Born Olfactory Bulb Granule Neurons: Role of Olfaction
Authors: Petreanu Leopoldo , Alvarez-Buylla Arturo
Published: April 2018

Young neurons born in the subventricular zone (SVZ) of adult mice migrate to the olfactory bulb (OB) where they differentiate into granule cells (GCs) and periglomerular interneurons. Using retroviral labeling of precursors in the SVZ, we describe five stages and the timing for the maturation of newly formed GCs: (1) tangentially migrating neuroblasts (days 2–7); (2) radially migrating young neurons (days 5–7); (3) GCs with a simple unbranched dendrite that does not extend beyond the mitral cell layer (days 9–13); (4) GCs with a nonspiny branched dendrite in the external plexiform layer (days 11–22); and (5) mature GCs (days 15–30). Using [3H]thymidine, we show that the maximum number of labeled GCs is observed around day 15 after injection. Interestingly, between days 15 and 45 after birth, soon after the cells developed spines, the number of [3H]thymidine-labeled GCs declined by 50%. Using anosmic mice, we found that sensory input was critical for the survival of GCs from day 15 to 45 after labeling. However, the number and morphology of 15-d-old cells in the granule cell layer was similar in anosmic and wild-type mice. We infer that the lack of activity did not have an effect on the generation, migration, and early differentiation of granule cells. Soon after young GCs matured, and presumably became synaptically connected, their survival depended on the level of activity that they received. This selection mechanism might allow the construction of specific OB circuits based on olfactory experience and suggests possible functions of OB cell replacement.
Concurrent Activation of Dopamine D1and D2Receptors Is Required to Evoke Neural and Behavioral Phenotypes of Cocaine Sensitization
Authors: Capper-Loup Christine , Canales Juan J. , Kadaba Neena , Graybiel Ann M.
Published: April 2018

Repeated exposure to psychomotor stimulants produces a striking behavioral syndrome involving repetitive, stereotypic behaviors that occur if an additional exposure to the stimulant is experienced. The same stimulant exposure produces specific alterations in gene expression patterns in the striatum. To identify the dopamine receptor subtypes required for the parallel expression of these acquired neural and behavioral responses, we treated rats with different D1-class and D2-class dopamine receptor agonists and compared the responses of drug-naive rats with those of rats given previous intermittent treatment with cocaine. In rats exposed to repeated cocaine treatment, the effects of a subsequent challenge treatment with either a D1-class agonist (SKF 81297) or a D2-class agonist (quinpirole) were not significantly different from those observed in drug-naive animals: the drugs administered singly did not induce robust stereotyped motor behaviors nor produce significantly striosome-predominant expression of early genes in the striatum. In contrast, challenge treatment with the D1-class and D2-class agonists in combination led to marked and correlated increases in stereotypy and striosome-predominant gene expression in the striatum. Thus, immediately after repeated psychomotor stimulant exposure, only the concurrent activation of D1and D2receptor subclasses evoked expression of the neural and behavioral phenotypes acquired through repeated cocaine exposure. These findings suggest that D1–D2dopamine receptor synergisms underlie the coordinate expression of both network-level changes in basal ganglia activation patterns and the repetitive and stereotypic motor response patterns characteristic of psychomotor stimulant sensitization.
Leptin Regulates Growth Hormone-Releasing Factor, Somatostatin, and α-Melanocyte-Stimulating Hormone But Not Neuropeptide Y Release in Rat HypothalamusIn Vivo: Relation with Growth Hormone Secretion
Authors: Watanobe Hajime , Habu Satoshi
Published: April 2018

It is known that leptin, an adipocyte-derived hormone, exerts a stimulatory effect on growth hormone (GH) secretion in various animal species. However, no previous study examinedin vivowhether leptin affects the secretion of GH-releasing factor (GRF), somatostatin (SRIH), and some other closely relevant neurohormones in the hypothalamus. Therefore, in this study we investigated the effects of direct leptin infusion into the hypothalamus on thein vivorelease of GRF, SRIH, α-melanocyte-stimulating hormone (α-MSH), and neuropeptide Y (NPY) in freely moving adult male rats using the push–pull perfusion. Leptin was infused into the median eminence–arcuate nucleus complex at three different concentrations, i.e., 1.0 (normal feeding level), 3.0, and 10 ng/ml (mild obesity level). In normally fed rats, only 10 ng/ml leptin was able to stimulate GH secretion, whereas in 3 d fasted rats, GH release was dose-dependently stimulated by 1.0 and 3.0 ng/ml leptin, although its 10 ng/ml dose did not produce additional effects. The facilitation of GH secretion occurred as increased pulse amplitudes without significant changes in the pulse frequency. During the leptin infusion, the hypothalamic GRF increased and SRIH decreased in magnitudes that approximately paralleled those of GH changes. Leptin stimulated the release of α-MSH in the fasted but not fed rats. It is likely that the fasting-induced increase in the hypothalamic α-MSH sensitivity to leptin is relevant to ingestive behavior involving leptin. Leptin was without effect on NPY release in either the fed or fasted group. Although it is certain that NPY mediates at least part of the metabolic actions of leptin, NPY is unlikely to be involved in the acute effects of leptin on GH, GRF, and SRIH secretion. These results demonstrate for the first time that leptin can alter thein vivorelease of both GRF and SRIH in rat hypothalamus concurrently with the stimulation of GH secretion.
Temporal Encoding for Auditory Computation: Physiology of Primary Afferent Neurons in Sound-Producing Fish
Authors: Suzuki Aae , Kozloski James , Crawford John D.
Published: April 2018

Many fish rely on sounds for communication, yet the peripheral structures containing the hair cells are simple, without the morphological specializations that facilitate frequency analysis in the mammalian cochlea. Despite this, neurons in the midbrain of sound-producing fish (Pollimyrus) have complex receptive fields, extracting features from courtship sounds. Here we present an analysis of the initial encoding of sounds by the primary afferents and demonstrate that the representation of sound undergoes a substantial transformation as it ascends to the midbrain. Afferents were isolated as they coursed from the sacculus through the medulla. Tones (100 Hz-1.2 kHz) elicited synchronized spikes [vector strength (VS) >0.9] on each stimulus cycle [coefficient of variation (CV) <1.1], with little spike rate adaptation. Most afferents (67%) were spontaneously active and began synchronizing 10 dB below rate threshold. Rate thresholds for the most sensitive afferents (65 dB) were close to behavioral thresholds. The distribution of characteristic frequencies and best sensitivities was matched to the spectrum of sounds of this species and to its audiogram. Three clusters of afferents were identified, one including afferents that generated spike bursts and had v-shaped response areas (bursters), and two others that included entrained afferents with broad response areas (entrained types I and II). All afferents encoded the timing of clicks within click trains with time-locked spikes, and none showed selectivity for interclick intervals. Understanding the computations that yield complex receptive fields is an essential goal for auditory neuroscience, and these data on primary encoding advance this goal, allowing a comparison of inputs with feature-extracting midbrain neurons.
Axonal Regeneration through Regions of Chondroitin Sulfate Proteoglycan Deposition after Spinal Cord Injury: A Balance of Permissiveness and Inhibition
Authors: Jones Leonard L. , Sajed Dana , Tuszynski Mark H.
Published: April 2018

Increased expression of certain extracellular matrix (ECM) molecules after CNS injury is believed to restrict axonal regeneration. The chondroitin sulfate proteoglycans (CSPGs) are one such class of ECM molecules that inhibit neurite outgrowthin vitroand are upregulated after CNS injury. We examined growth responses of several classes of axons to this inhibitory environment in the presence of a cellular fibroblast bridge in a spinal cord lesion site and after a growth factor stimulus at the lesion site (fibroblasts genetically modified to secrete NGF). Immunohistochemical analysis showed dense labeling of the CSPGs NG2, brevican, neurocan, versican, and phosphacan at the host-lesion interface after spinal cord injury (SCI). Furthermore, robust expression of NG2, and to a lesser extent versican, was also observed throughout grafts of control and NGF-secreting fibroblasts. Despite this inhibitory milieu, several axonal classes penetrated control fibroblast grafts, including dorsal column sensory, rubrospinal, and nociceptive axons. Axon growth was amplified more in the presence of NGF-secreting grafts. Confocal microscopy demonstrated that axon growth was, paradoxically, preferentially associated with NG2-rich substrates in both graft types. NG2 expression also increased after sciatic nerve injury, wherein axons successfully regenerate. Cellular sources of NG2 in SCI and peripheral nerve lesion sites included Schwann cells and endothelial cells. Notably, these same cellular sources in lesion sites produced the cell adhesion molecules L1 and laminin, and these molecules all colocalized. Thus, axons grow along substrates coexpressing both inhibitory and permissive molecules, suggesting that regeneration is successful when local permissive signals balance and exceed inhibitory signals.
Cholinergic Activity Enhances Hippocampal Long-Term Potentiation in CA1 during Walking in Rats
Authors: Leung L. Stan , Shen Bixia , Rajakumar Nagalingam , Ma Jingyi
Published: April 2018

Long-term potentiation (LTP) at the basal-dendritic synapses of CA1 pyramidal cells was induced by a single 200 Hz stimulation train (0.5-1 sec duration) in freely behaving rats during one of four behavioral states: awake-immobility (IMM), walking, slow-wave sleep (SWS), and rapid eye movement sleep (REM). Field EPSPs generated by basal-dendritic excitation of CA1 were recorded before and up to 1 d after the tetanus. After a tetanus during any behavioral state, basal-dendritic LTP was >170% of the baseline for the first hour after the tetanus and decayed to ∼120% 1 d after. LTP induced during walking was significantly larger than that induced during IMM, SWS, or REM, which had similar LTP magnitudes. To test the hypothesis that septohippocampal cholinergic activity enhanced LTP during walking as compared with IMM, rats were either pretreated with muscarinic cholinergic antagonist scopolamine or injected with IgG192-saporin in the medial septum to selectively lesion cholinergic septohippocampal neurons. Pretreatment with scopolamine decreased the LTP induced during walking but did not affect that induced during IMM, such that the difference between the LTP induced during walking and IMM was abolished after scopolamine. Rats injected with IgG192-saporin showed no difference in the LTP induced during walking and IMM, and scopolamine did not reduce the LTP during walking. In contrast, sham-lesion rats showed larger LTP induced during walking than IMM, and the LTP induced during walking was attenuated by scopolamine. This is the first demonstration of an enhancement of hippocampal LTP by physiologically activated cholinergic inputs.
Selective Adaptation in Networks of Cortical Neurons
Authors: Eytan Danny , Brenner Naama , Marom Shimon
Published: April 2018

A key property of neural systems is their ability to adapt selectively to stimuli with different features. Using multisite electrical recordings from networks of cortical neurons developingex vivo, we show that neurons adapt selectively to different stimuli invading the network. We focus on selective adaptation to frequent and rare stimuli; networks were stimulated at two sites with two different stimulus frequencies. When both stimuli were presented within the same period, neurons in the network attenuated their responsiveness to the more frequent input, whereas their responsiveness to the rarely delivered stimuli showed a marked average increase. The amplification of the response to rare stimuli required the presence of the other, more frequent stimulation source. By contrast, the decreased response to the frequent stimuli occurred regardless of the presence of the rare stimuli. Analysis of the response of single units suggests that both of these effects are caused by changes in synaptic transmission. By using synaptic blockers, we find that the increased responsiveness to the rarely stimulated site depends specifically on fast GABAergic transmission. Thus, excitatory synaptic depression, the inhibitory sub-network, and their balance play an active role in generating selective gain control. The observation that selective adaptation arises naturally in a network of cortical neurons developingex vivoindicates that this is an inherent feature of spontaneously organizing cortical networks.
Clinical significance of RET and RAS mutations in sporadic medullary thyroid carcinoma: a meta-analysis
Authors: Vuong Huy Gia , Odate Toru , Ngo Hanh T T , Pham Thong Quang , Tran Thao T K , Mochizuki Kunio , Nakazawa Tadao , Katoh Ryohei , Kondo Tetsuo
Published: April 2018

There are ongoing debates with respect to the prognostic roles of molecular biomarkers in sporadic medullary thyroid carcinoma (MTC). In this study, we aimed at investigating the prognostic value of RET and RAS mutations – the two most common mutations in sporadic MTCs. A search was conducted in four electronic databases. Relevant data were extracted and pooled into odds ratios (OR), mean differences (MD) and corresponding 95% confidence intervals (CI) using the random-effect model. We used Egger’s regression test and visual of funnel plots to assess the publication bias. From 2581 studies, we included 23 studies with 964 MTCs for meta-analysis. Overall, the presence of RET mutation was associated with an elevated risk for lymph node metastasis (OR = 3.61; 95% CI = 2.33–5.60), distant metastasis (OR = 2.85; 95% CI = 1.64–4.94), advanced tumor stage (OR = 3.25; 95% CI = 2.02–5.25), tumor recurrence (OR = 3.01; 95% CI = 1.65–5.48) and patient mortality (OR = 2.43; 95% CI = 1.06–5.57). RAS mutation had no significant prognostic value in predicting tumor aggressiveness. To summarize, our results affirmed that RET mutation is a reliable molecular biomarker to identify a group of highly aggressive sporadic MTCs. It can help clinicians better assess patient prognosis and select appropriate treatment decisions.
MicroRNAs: crucial regulators of placental development
Authors: Hayder Heyam , O’Brien Jacob , Nadeem Uzma , Peng Chun
Published: April 2018

MicroRNAs (miRNAs) are small non-coding single-stranded RNAs that are integral to a wide range of cellular processes mainly through the regulation of translation and mRNA stability of their target genes. The placenta is a transient organ that exists throughout gestation in mammals, facilitating nutrient and gas exchange and waste removal between the mother and the fetus. miRNAs are expressed in the placenta, and many studies have shown that miRNAs play an important role in regulating trophoblast differentiation, migration, invasion, proliferation, apoptosis, vasculogenesis/angiogenesis and cellular metabolism. In this review, we provide a brief overview of canonical and non-canonical pathways of miRNA biogenesis and mechanisms of miRNA actions. We highlight the current knowledge of the role of miRNAs in placental development. Finally, we point out several limitations of the current research and suggest future directions.
So much more than a necessary evil? Lessons from a study following the implementation of recognition of trainers
Authors: Crichton Fiona J. B. , Jones Linda
Published: April 2018

This article was migrated. The article was not marked as recommended. Background: The UK General Medical Council (GMC) now requires that trainers in specified roles be "recognised" by evidencing training (General Medical Council, 2012), with wide variation across the UK in implementation. This study aimed to understand the impact on established local educators of this mandatory requirement but also to investigate how our faculty development programme (the Clinical Educator Programme - CEP) can optimise this process for future trainers. Literature review found little published work on the Framework Standards used for this process. Methods: From a pragmatic stance, case study methodology was used allowing for mixed methods of data collection (online survey and focus groups) and "insider research" (Unluer, 2012). Consultants holding a named role (n=875) as defined by the GMC (2012, p.15) were sampled. Results: Of the28% who responded, the majority (83.3%) were clinical supervisors (n=204). 77.6% were registered on the Faculty Development Programme (CEP, n=190), most stating they registered because of Recognition of Trainers (RoT) (n=107). Demonstrable differences were found between CEP participants and others and between those registered for personal developmental reasons when compared to those who gave RoT as their only reason. This included potential benefits and risks of the process. Ten themes emerged including "a necessary evil". Support for CEP contributing to a community of practice (Lave & Wenger, 1991) was found. Mandatory requirements should not detract from professionalization of medical education, yet this study found just over half of respondents were supportive of the implemented process (51.8%). Conclusion: Further support is needed to help clinical educators understand the potential benefits of on-going educational CPD.
INVESTIGATION ON UTILITY OF PLASTIC WASTE AS AN ADDITIVE FOR BITUMINOUS CONCRETE USING WET PROCESS OF MIXING
Authors: Tiwari Anurag Virendra , Rao Y.R.M.
Published: April 2018

Purpose. Plastic waste has become a major environmental issue of concern due to its exponential growth due to rapid urbanization. The paper investigates utility of plastic waste as an additive for bituminous concrete using wet process of mixing. Methodology. The methodology for the present paper has been designed with complex research consisting of Marshall mix design of the bituminous mix added with plastic waste for modifying bitumen using wet process of mixing, performing the tests on the samples and analyzing the results in the form of table and figures. In the present paper LDPE and HDPE type of plastic waste are used to modify the bitumen. Finding. The results show that addition of 6 percent of bitumen improves the Marshall properties of the mix. Use of plastic to modify the bitumen not only makes the road surface more durable but also it is an eco-friendly way of proper disposal of plastic waste. Originality. The processes used for mixing the plastic waste to the bitumen are dry process and wet process. Dry process of mixing the plastic waste to the bituminous mix is most common and lot of study is carried out on its application. In the present paper wet process of mixing has not yet been studied much. Practical Value. The practical application of utilizing the plastic waste to modify bitumen in the bituminous mix improves the stability values resulting in the more durable road surface. Also the method ensures the proper disposal of plastic waste in eco-friendly way.
PROSPECTS OF THE PRIVATE LOCOMOTIVES USAGE FOR GOODS TRAFFIC IN THE DIRECTION OF SEA PORTS
Authors: D. M. Kozachenko  , O. B. Ochkasov  , A. P. Shepotenko  , N. M. Sannytsky
Published: April 2018

Purpose. At the present time, Ukraine's mainline railway transport is entirely in state ownership. Ukraine has undertaken to implement the European Union Directives providing of non-discriminatory access to the railway infrastructure of independent carriers. A considerable quantity of options significantly affects the working conditions of carriers that do not depend on Ukrzaliznytsia. One of the tasks that arises when performing transportation by independent carriers is the organization of private locomotives operation and their servicing by engine crews. The purpose of the article is to evaluate the technical characteristic of the private locomotives usage in order to perform goods traffic in the direction of sea ports. Methodology. The researches were carried out on the basis of methods for organizing the operational work of railways and methods of traction calculations. Findings. The paper highlights the problem of goods traffic organization to seaports by independent carriers. It determines the requirements for equipment for diesel locomotives and electric locomotives depending on the distance of transportation. Permissible distances that can be served by engine crews in performing the requirements for the duration of their continuous operation were also determined. Schemes of infrastructure objects location for the locomotives and engine crews operation have been developed. It was established that diesel locomotives of independent carriers will be able to serve transportation between loading and unloading stations up to 822 km, and electric locomotives up to 1000 km with the construction of the main part of the locomotive infrastructure at the port station. The performed calculations show the potential coverage of rail transportation to sea ports by independent carriers with the use of its own locomotive infrastructure. To define more exactly the haul length of train servicing by locomotives and locomotives by engine crews, it is necessary to perform additional calculations based on detailed service section profiles. Originality. Access circuitry of locomotives and engine crews of independent carriers when servicing sea ports by them were obtained. Practical value. The results of the research allow evaluating the needs in the locomotive infrastructure that arise at opening of the rail market for independent carriers.
FROM EXPERIENCE OF CONDUCTING COMPARATIVE TESTS OF LOESS SOILS BY MANUAL DYNAMIC PROBES OF DIFFERENT CONSTRUCTIONS
Authors: Y. V. Ulyanov
Published: April 2018

Purpose. To determine the parameters of soils of loess formation, which are considered difficult in the construction or operation of housing and industrial facilities it is provided an analysis of the obtained field test data in order to use them in calculations to predict the situation, which can be complicated during operation of the facilities. The main purpose is: 1) improvement of our ideas about soils of loess formation using the example of determining possible changes in parameters of the loess mass, which is under load from the total weight of the structure; 2) testing the methodology of sounding by introducing improved manual probes: comparing the data of these studies with those obtained by other methods; 3) determination of the ways of further research using manual probes. Methodology. The directions of engineering-geological research were updated with the help of analysis and synthesis methods. Dynamic sounding was performed as a tool. Findings. The authors analyzed the data of dynamic sounding of soils by probes of the type DIIT-5 made by the Dnipropetrovsk National University of Railway Transport named after Academician V. Lazaryan (DNURT). Also, it was sounded the research object in difficult engineering-geological conditions: in a built-up area, the soil of which is represented by forests. The sounding was carried out using the small-sized LIATE probe. Further, the dynamic soil resistance to sounding was determined and the dependency formula between the obtained indices was derived. Originality. The sounding of the unwatered loess soils was carried out by light non-standard probe developed by the DNURT and, for comparison, by a self-developed probe of a group of authors, including the author of the article. The probe was used at the first time. Practical value. Dynamic sounding, which had spread significantly during engineering research in the construction of 60-70 years of the last century, is currently used rare. As for research of loess soils in their various states (watered, unwatered, disturbed and undisturbed, etc.) it is practically not developed. Therefore, the derivation of correlation formulas that confirm the rights to use existing formulas and design coefficients precisely for the loess mass (and this is about 90% of modern Quaternary soils of Ukraine) seems to be a topical subject.
RAILWAY TRACK REPRESENTATION IN MATHEMATICAL MODEL OF VEHICLES MOVEMENT
Authors: Kurhan M. B. , Kurhan D. M.
Published: April 2018

Purpose. The tasks of modeling the interaction of track and rolling stock are basic ones for most areas of mo-dern scientific research of railway transport. The compilation of the model by the principle of Lagrange d'Alembert has found a very wide application for solving the problems of rolling stock dynamics. Representation of the railway track in the model of crew movement can be implemented in several ways, which, among other things, will differ in detail. The purpose of this work is to create a methodology for representing the railway track in mathematical mo-dels of interaction with rolling stock and obtaining practical results for different characteristics and design of the track and the level of maximum speed. Methodology. The problem consists of determining such characteristics of the path as the reduced mass, the stiffness coefficient, and the dissipation coefficient. As a tool for solving this problem it was used the model of the stress-strain behavior of the railway track based on the joint use of the elastic wave propagation equations to describe the geometry of the outline of the part of the system space that is involved in the interaction at a given time and the equations of dynamic equilibrium of its deformation. This makes it possible to take into account the dynamics of the deflection of the under-rail base, which is especially important for the conditions of passenger traffic, which can be carried out at high speed. Findings. Theoretically justified stiffness and dissipation coefficients of the railway track for calculating the dynamics of rolling stock in modern models based on systems of equations in accordance with the Lagrange d'Alembert principle are obtained. The established va-lues, in contrast to those given in other sources, have a reasonable dependence on the design of the path and the speed of movement. Originality. The approaches of railroad track representation in models of rolling stock described by systems of equations by the Lagrange-d'Alembert principle are expanded. A method for determining the characteristics of the railway track for such models is developed based on the results of variant calculations of the dynamic deflection of the rail from the passage of the wheel. Practical value. The values of the stiffness and dissipation coefficients of the railway track are obtained depending on the design and speed of motion for practical use in appropriate models of interaction between track and rolling stock.
Electrical conductivity and dielectric constant of geopolymer cement mortar
Authors: Saxena Sunil K , Kumar Mukesh , Singh Nakshatra B
Published: April 2018

In the last few decades, increasing efforts have been made towards the utilization of fly ash, especially in an efficient and green fashion. The geopolymer technology provides a green solution to the utilization of fly ash, avoiding its negative impact on environment and ecology. Geopolymer cement was made by activating pond fly ash with 14 M sodium hydroxide (NaOH) and sodium silicate solutions. Natural sand was used to make the mortar. Alccofine powder, a substitute of silica fume, was also added during the geopolymerization process. Curing was done at 80°C for 12 h. It is reported that geopolymer possess high electrical conductivity at room temperature which can play an important role in fast ionic conduction used for solid-state batteries and other solid-state electrochemical devices. In this paper, electrical conductivity and dielectric constant, compressive strength and scanning electron microscopy studies were done to characterize the geopolymer. The energy of the activation for conduction was found to increase with frequency. The results are discussed.
Assessment method for leaning instability of jackups during preloading in deep soft clay
Authors: Dean E. T. Richard
Published: April 2018

The main codes of practice governing jackup preloading presently mention leaning instability as a potential hazard for jackups, but give little guidance on how to assess it. This paper proposes an explicit calculation, based on concepts that are already used in the literature and codes. Practical application is illustrated by reference to a documented field event.
Experimental study of ice accumulation in unsaturated clean sand
Authors: Teng J. , Shan F. , He Z. , Zhang S. , Zhao G. , Sheng D.
Published: April 2018

A series of laboratory experiments is carried out to replicate moisture accumulation in an unsaturated coarse-grained soil underneath an impervious cover. The results show that significant moisture accumulation occurs in relatively dry specimens when the temperature at the cover drops below the freezing point. The tested soil is a coarse-grained sand and is not expected to generate much moisture accumulation according to existing frost susceptibility criteria in the literature. The primary mechanism of moisture migration in the soil is observed to be vapour diffusion, and the primary mechanism of moisture accumulation is ice formation by way of vapour–ice desublimation. It is also observed that two peak values exist along the total water content profile of the 13·5 cm long specimen. For a non-freezing condition, water content gradually decreases from the warmer end to the colder end without any peak value, and the amount of moisture accumulation is less than occurs under freezing conditions. The test results are considered to be useful for understanding vapour diffusion in unsaturated freezing soils, and for validating theoretical and numerical models.
PHOENEXS: System for Angle- and Spin-Resolved Photoemission at BESSY II
Authors: Rader Oliver , Varykhalov Andrei
Published: April 2018

Article addresses overall performance, technical features and sample preparation facilities of movable endstation PHOENEXS at BESSY II which is used for spin- and angle-resolved photoemission.
THE DEVELOPMENT OF SOCIAL ENTREPRENEURSHIP IN THE KHANTY-MANSI AUTONOMOUS DISTRICT - YUGRA
Authors: Bogomolova Lioubov Leonidovna
Published: April 2018

In the article the tendencies of development of social entrepreneurship at the present stage are considered, and the state support of this sphere of entrepreneurship is estimated. The main directions of state support of social entrepreneurship of Ugra are marked and priorities and key tasks are outlined. The urgency of the work lies in the increasing role of the development of social initiatives in entrepreneurship and state support for social entrepreneurship as a phenomenon in public life. The aim of the research, the results of which are given in this article, is to assess the role of state support in the development of social entrepreneurship in Yugra. The scientific significance of the research is a comprehensive study of the impact of state support on the current state of social entrepreneurship and the development of social initiatives. The practical importance of the work lies in applying the results of research in decision-making in the field of social project management and their effectiveness in implementation. The objectives of the study are: determination of directions of state support affecting the development of social entrepreneurship; determining the degree of influence of state support on the development of social entrepreneurship in the Autonomous Okrug; forecasting the further development of social entrepreneurship. In the process of scientific research, logical and formal methods of analysis and statistics were used: comparisons, computational and constructive, graphical, expert assessments, and others. The result of this work is the identification of the factors influencing state support for the development of social entrepreneurship in Ugra.
Automatic classification of welding defects from ultrasonic signals using an SVM-based RBF neural network approach
Authors: Chen Yuan , Ma Hong-Wei , Dong Ming
Published: April 2018

To improve the accuracy of classifying welding defects in ultrasonic non-destructive testing (NDT), a support vector machine-based radial basis function neural network (SVM-RBFNN) approach is presented in this paper. Based on the equivalence of a radial basis function neural network
(RBFNN) and a support vector machine (SVM) in terms of structure, a modified RBF neural network model is established. An artificial bee colony (ABC) algorithm is employed to optimise the parameters of the SVM-RBFNN model. The optimised SVM-RBFNN model is applied to classify welding defects
from ultrasonic signals. The experimental results demonstrate that the proposed approach is effective and feasible for the classification of welding defects in ultrasonic testing (UT). Moreover, the results show that the proposed approach is superior to RBFNNs and SVMs in terms of the classification
accuracy, computation speed and generalisation achieved.