bluuebunny/crossref_metadata_2025 huggingface dataset:
Aromatase Cytochrome P450 and Extragonadal Estrogen Play a Role in Ischemic Neuroprotection
Authors: McCullough Louise D. , Blizzard Kathleen , Simpson Evan R. , Öz Orhan K. , Hurn Patricia D.
Published: April 2018

Female animals are protected from many forms of neurological injury and degeneration relative to their male counterparts, in part attributable to their native estrogens. We hypothesized that estradiol aromatized from precursor androgens via the cytochrome P450 aromatase contributes to ischemic neuroprotection in the female. Female homozygous aromatase knock-out (ArKO) mice and randomly cycling, wild-type (WT) female littermates were treated with reversible middle cerebral artery occlusion (90 min; 22 hr reperfusion). Total and regional ischemic damage was greater in female ArKOs (total, 33.5 ± 4.8%; cortical, 47.4 ± 5.7%; striatal, 44.8 ± 7.8%) compared with WT (total, 14.2 ± 5%; cortical, 14.2 ± 4.5%; striatal, 17.5 ± 8%). Baseline blood pressure and intra-ischemic cortical perfusion were comparable in knock-outs and WT, suggesting that vascular factors do not explain ArKO ischemic sensitivity. Injury was smaller in ovariectomized WT than in ArKO, emphasizing that extragonadal local estradiol plays a critical role in females. Similar increases in cortical and striatal damage were observed in female WT mice chronically treated with the aromatase inhibitor fadrozole compared with vehicle-treated control mice. Restoration of plasma 17β-estradiol to physiological levels completely reversed the ArKO female's susceptibility to injury. These findings indicate that the biosynthetic enzyme P450 aromatase is key to endogenous neuroprotection in females and suggest that enhancing local, nongonadal estrogen formation could have therapeutic implications is ischemic neuropathology.
A Specific Inhibitory Pathway between Substantia Gelatinosa Neurons Receiving Direct C-Fiber Input
Authors: Lu Yan , Perl Edward R.
Published: April 2018

The spinal substantia gelatinosa (SG) is a major termination region for unmyelinated (C) primary afferent fibers; however, how the input it receives from these sensory fibers is processed by SG neurons remains primarily a matter of conjecture. To gain insight on connections and functional interactions between intrinsic SG neurons, simultaneous tight-seal, whole-cell recordings were made from pairs of neurons in rat spinal cord slices to examine whether impulses in one cell generated synaptic activity in the other. Most SG neuron pairs sampled lacked synaptic interaction. Those showing a linkage included a recurring pattern consisting of a monosynaptic, bicuculline-sensitive inhibitory connection from an islet cell to a transient central neuron, each of which received direct excitatory input from different afferent C-fibers. This newly defined inhibitory circuit is postulated to represent a SG neural module by which a nociceptive C-fiber input to transient central cells is modified by other C-fiber messages.
Dissociable Contributions of the Orbitofrontal and Infralimbic Cortex to Pavlovian Autoshaping and Discrimination Reversal Learning: Further Evidence for the Functional Heterogeneity of the Rodent Frontal Cortex
Authors: Chudasama Y. , Robbins Trevor W.
Published: April 2018

To examine possible heterogeneity of function within the ventral regions of the rodent frontal cortex, the present study compared the effects of excitotoxic lesions of the orbitofrontal cortex (OFC) and the infralimbic cortex (ILC) on pavlovian autoshaping and discrimination reversal learning. During the pavlovian autoshaping task, in which rats learn to approach a stimulus predictive of reward [conditional stimulus (CS+)], only the OFC group failed to acquire discriminated approach but was unimpaired when preoperatively trained. In the visual discrimination learning and reversal task, rats were initially required to discriminate a stimulus positively associated with reward. There was no effect of either OFC or ILC lesions on discrimination learning. When the stimulus-reward contingencies were reversed, both groups of animals committed more errors, but only the OFC-lesioned animals were unable to suppress the previously rewarded stimulus-reward association, committing more “stimulus perseverative” errors. In contrast, the ILC group showed a pattern of errors that was more attributable to “learning” than perseveration. These findings suggest two types of dissociation between the effects of OFC and ILC lesions: (1) OFC lesions impaired the learning processes implicated in pavlovian autoshaping but not instrumental simultaneous discrimination learning, whereas ILC lesions were unimpaired at autoshaping and their reversal learning deficit did not reflect perseveration, and (2) OFC lesions induced perseverative responding in reversal learning but did not disinhibit responses to pavlovian CS-. In contrast, the ILC lesion had no effect on response inhibitory control in either of these settings. The findings are discussed in the context of dissociable executive functions in ventral sectors of the rat prefrontal cortex.
Orientation-Specific Adaptation in Human Visual Cortex
Authors: Boynton Geoffrey M. , Finney Eva M.
Published: April 2018

Nearly all methods for analyzing and interpreting functional magnetic resonance imaging (fMRI) data assume that the fMRI signal behaves in an approximately linear manner. However, it has been shown that the mean fMRI response to a pair of briefly presented visual stimuli is significantly smaller than would be expected from the response to a single stimulus. This smaller response could be the result of either a nonlinearity in the fMRI signal or neuronal adaptation. We tested the neuronal adaptation hypothesis by measuring the fMRI response to sequential pairs of sinusoidal gratings that had either the same or orthogonal orientation. The adaptation hypothesis predicts that brain areas with orientation-selective neurons should show a more linear response when the stimulus pair is orthogonal than when the pair is identical. Our results show no orientation-specific adaptation effects in primary visual cortex (V1) but increasing effects along the hierarchy of visual areas (V2, V3, and V4V). A psychophysical contrast detection experiment, using similar oriented gratings as adapters, shows evidence of orientation-specific adaptation in the visual system. These results have implications for the interpretation of rapid event-related fMRI experiments, as well as for recently developed methods that use adaptation as a tool to measure the response properties of underlying neuronal subpopulations.
Impaired Repression at a 5-Hydroxytryptamine 1A Receptor Gene Polymorphism Associated with Major Depression and Suicide
Authors: Lemonde Sylvie , Turecki Gustavo , Bakish David , Du Lisheng , Hrdina Pavel D. , Bown Christopher D. , Sequeira Adolfo , Kushwaha Neena , Morris Stephen J. , Basak Ajoy , Ou Xiao-Ming , Albert Paul R.
Published: April 2018

Inhibition of serotonergic raphe neurons is mediated by somatodendritic 5-HT1A autoreceptors, which may be increased in depressed patients. We report an association of the C(-1019)G 5-HT1A promoter polymorphism with major depression and suicide in separate cohorts. In depressed patients, the homozygous G(-1019) allele was enriched twofold versus controls (p= 0.0017 and 0.0006 for G/G genotype and G allele distribution, respectively), and in completed suicide cases the G(-1019) allele was enriched fourfold (p= 0.002 and 0.00008 for G/G genotype and G allele distribution, respectively). The C(-1019) allele was part of a 26 bp imperfect palindrome that bound transcription factors nuclear NUDR [nuclear deformed epidermal autoregulatory factor (DEAF-1)]/suppressin and Hairy/Enhancer-of-split-5 (Drosophila) (Hes5) to repress 5-HT1A or heterologous promoters, whereas the G(-1019) allele abolished repression by NUDR, but only partially impaired Hes5-mediated repression. Recombinant NUDR bound specifically to the 26 bp palindrome, and endogenous NUDR was present in the major protein-DNA complex from raphe nuclear extracts. Stable expression of NUDR in raphe cells reduced levels of endogenous 5-HT1A protein and binding. NUDR protein was colocalized with 5-HT1A receptors in serotonergic raphe cells, hippocampal and cortical neurons, and adult brain regions including raphe nuclei, indicating a role in regulating 5-HT1A autoreceptor expression. Our data indicate that NUDR is a repressor of the 5-HT1A receptor in raphe cells the function of which is abrogated by a promoter polymorphism. We suggest a novel transcriptional model in which the G(-1019) allele derepresses 5-HT1A autoreceptor expression to reduce serotonergic neurotransmission, predisposing to depression and suicide.
Stimulation of Medial Prefrontal Cortex Decreases the Responsiveness of Central Amygdala Output Neurons
Authors: Quirk Gregory J. , Likhtik Ekaterina , Pelletier Joe Guillaume , Paré Denis
Published: April 2018

In extinction of auditory fear conditioning, rats learn that a tone no longer predicts the occurrence of a footshock. Recent lesion and unit recording studies suggest that the medial prefrontal cortex (mPFC) plays an essential role in the inhibition of conditioned fear following extinction. mPFC has robust projections to the amygdala, a structure that is known to mediate the acquisition and expression of conditioned fear. Fear conditioning potentiates the tone responses of neurons in the basolateral amygdala (BLA), which excite neurons in the central nucleus (Ce) of the amygdala. In turn, the Ce projects to the brainstem and hypothalamic areas that mediate fear responses. The present study was undertaken to test the hypothesis that the mPFC inhibits conditioned fear via feedforward inhibition of Ce output neurons. Recording extracellularly from physiologically identified brainstem-projecting Ce neurons, we tested the effect of mPFC prestimulation on Ce responsiveness to synaptic input. In support of our hypothesis, mPFC prestimulation dramatically reduced the responsiveness of Ce output neurons to inputs from the insular cortex and BLA. Thus, our findings support the idea that mPFC gates impulse transmission from the BLA to Ce, perhaps through GABAergic intercalated cells, thereby gating the expression of conditioned fear.
In VivoAssessment of Brain Interstitial Fluid with Microdialysis Reveals Plaque-Associated Changes in Amyloid-β Metabolism and Half-Life
Authors: Cirrito John R. , May Patrick C. , O'Dell Mark A. , Taylor Jennie W. , Parsadanian Maia , Cramer Jeffrey W. , Audia James E. , Nissen Jeffrey S. , Bales Kelly R. , Paul Steven M. , DeMattos Ronald B. , Holtzman David M.
Published: April 2018

Soluble amyloid-β (Aβ) peptide converts to structures with high β-sheet content in Alzheimer's disease (AD). Soluble Aβ is released by neurons into the brain interstitial fluid (ISF), in which it can convert into toxic aggregates. Because assessment of ISF Aβ levels may provide unique insights into Aβ metabolism and AD, anin vivomicrodialysis technique was developed to measure it. Our Aβ microdialysis technique was validatedex vivowith human CSF and thenin vivoin awake, freely moving mice. Using human amyloid precursor protein (APP) transgenic mice, we found that, before the onset of AD-like pathology, ISF Aβ in hippocampus and cortex correlated with levels of APP in those tissues. After the onset of Aβ deposition, significant changes in the ISF Aβ40/Aβ42ratio developed without changes in Aβ1-x. These changes differed from changes seen in tissue lysates from the same animals. By rapidly inhibiting Aβ production, we found that ISF Aβ half-life was short (∼2 hr) in young mice but was twofold longer in mice with Aβ deposits. This increase in half-life, without an increase in steady-state levels, suggests that inhibition of Aβ synthesis reveals a portion of the insoluble Aβ pool that is in dynamic equilibrium with ISF Aβ. This now measurablein vivopool is a likely target for new diagnostic and therapeutic strategies.
Dynamic Coding of Taste Stimuli in the Brainstem: Effects of Brief Pulses of Taste Stimuli on Subsequent Taste Responses
Authors: Di Lorenzo Patricia M. , Lemon Christian H. , Reich Christian G.
Published: April 2018

Recent studies have suggested that the response profiles of taste-responsive cells in the brainstem may be modulated by inhibitory interactions, potentially originating from activity in peripheral taste nerves. This idea was explored by testing the hypothesis that brief (100 msec) pulses of taste stimuli would alter the responses to subsequently presented tastants in the nucleus of the solitary tract (NTS) of urethane-anesthetized rats. Pulses of taste stimuli, called prepulses, were followed by a 3 sec presentation of the same or different taste stimulus. The prepulse-stimulus interval was either 1 or 5 sec, during which the tongue was rinsed with distilled water. Taste stimuli consisted of 0.1mNaCl, 0.5msucrose, 0.01mquinine HCl, and 0.01mHCl. Taste prepulses suppressed (or enhanced) subsequent taste responses in 30 of 49 (61%) units when the prepulse-stimulus interval was 1 sec but were ineffective when this interval was 5 sec. Most commonly, NaCl or HCl prepulses attenuated the response to quinine. Control experiments showed that these effects were not attributable to adaptation, mixture effects, or response variability. In 19 (39%) of the units tested, effects of prepulses were large enough to change the order of effectiveness of the taste stimuli. Taste responses in these cells were “dynamically tuned” in that the magnitude of response was a function of the taste stimulus that immediately preceded it. Dynamic tuning may be the result of inhibitory interactions within the NTS; cells that show dynamic tuning may have a unique function in taste coding.
Dopaminergic Modulation of Axon Collaterals Interconnecting Spiny Neurons of the Rat Striatum
Authors: Guzmán Jaime N. , Hernández Adán , Galarraga Elvira , Tapia Dagoberto , Laville Antonio , Vergara Ramiro , Aceves Jorge , Bargas José
Published: April 2018

Dopamine is a critical modulator of striatal function; its absence produces Parkinson's disease. Most cellular actions of dopamine are still unknown. This work describes the presynaptic actions of dopaminergic receptor agonists on GABAergic transmission between neostriatal projection neurons. Axon collaterals interconnect projection neurons, the main axons of which project to other basal ganglia nuclei. Most if not all of these projecting axons pass through the globus pallidus. Thus, we lesioned the intrinsic neurons of the globus pallidus and stimulated neostriatal efferent axons antidromically with a bipolar electrode located in this nucleus. This maneuver revealed a bicuculline-sensitive synaptic current while recording in spiny cells. D1receptor agonists facilitated whereas D2receptor agonists depressed this synaptic current. In contrast, a bicuculline-sensitive synaptic current evoked by field stimulation inside the neostriatum was not consistently modulated, in agreement with previous studies. The data are discussed in light of the most recent experimental and modeling results. The conclusion was that inhibition of spiny cells by axon collaterals of other spiny cells is quantitatively important; however, to be functionally important, this inhibition might be conditioned to the synchronized firing of spiny neurons. Finally, dopamine exerts a potentially important role regulating the extent of lateral inhibition.
Glycine Is Used as a Transmitter by Decrementing Expiratory Neurons of the Ventrolateral Medulla in the Rat
Authors: Ezure Kazuhisa , Tanaka Ikuko , Kondo Masahiro
Published: April 2018

The medullary respiratory network involves various types of respiratory neurons. The present study focused on possible inhibitory neurons called decrementing expiratory (E-DEC) neurons and aimed to determine whether their transmitter is glycine or GABA. In Nembutal-anesthetized, neuromuscularly blocked, and artificially ventilated rats we labeled E-DEC neurons with Neurobiotin and processed the tissues for detection of mRNA encoding either glycine transporter 2 (GLYT2) as a marker for glycinergic neurons or glutamic acid decarboxylase isoform 67 (GAD67) as a marker for GABAergic neurons, usingin situhybridization. Of 38 E-DEC neurons that were labeled, cranial motoneurons (n= 14), which were labeled as control, were negative for either GLYT2 mRNA (n= 10) or GAD67 mRNA (n= 4). The other E-DEC neurons (n= 24) were non-motoneurons. Sixteen of them were examined for GLYT2 mRNA, and the majority (11 of 16) was GLYT2 mRNA-positive. The remaining E-DEC neurons (n= 8) were examined for GAD67 mRNA, and all of them were GAD67 mRNA-negative. The GLYT2 mRNA-positive E-DEC neurons were located in the ventrolateral medulla spanning the Bötzinger complex (BOT), the rostral ventral respiratory group (VRG), and the caudal VRG. We conclude that not only E-DEC neurons of the BOT but also many E-DEC neurons of the VRG are inhibitory and use glycine as a transmitter. Although the present negative data cannot rule out completely the release of GABA or co-release of glycine and GABA from E-DEC neurons, several lines of evidence suggest that the glycinergic process is primarily responsible for the phasic inhibition of the respiratory network during the expiratory phase.
Mechanisms of Caspase-Independent Neuronal Death: Energy Depletion and Free Radical Generation
Authors: Lang-Rollin Isabelle C. J. , Rideout Hardy J. , Noticewala Manish , Stefanis Leonidas
Published: April 2018

Cultured rat embryonic cortical neurons undergo apoptosis when treated with the topoisomerase-I inhibitor camptothecin. Pharmacological or molecular caspase inhibition prevents apoptosis, but the neurons still die in a delayed nonapoptotic manner. Here we examine the mechanisms leading to such caspase-independent death, focusing on events related to mitochondrial malfunction, which accompanies this delayed death. Given that mitochondria are the major source of ATP in primary neurons, we examined the cellular energy state. Mitochondrially generated ATP was specifically reduced in neurons treated with camptothecin and Boc-aspartyl-fluoromethylketone. Augmentation of cellular ATP by manipulation of the glucose content in the cultures led to an increase in survival specifically in delayed caspase-independent but not early caspase-dependent death. As another possible consequence of mitochondrial malfunction, we found an induction of reactive oxygen species in delayed death. The free radical scavenger Tempol, but not other classes of antioxidants, reduced oxidative stress and promoted survival. Other potential events known to be a direct or indirect consequence of mitochondrial dysfunction, such as the induction of autophagy, release of apoptosis-inducing factor, or opening of the mitochondrial permeability transition pore, were not found to play a significant role in caspase-independent neuronal death. Combining the strategies of increasing intracellular ATP and reducing free radicals led to an additive increase in neuronal survival. We conclude that energy failure and free radical generation contribute to caspase-independent neuronal death. Both could represent potential targets for therapeutic interventions complementary to caspase inhibition.
Neurotrophic Effects of Vascular Endothelial Growth Factor on Organotypic Cortical Explants and Primary Cortical Neurons
Authors: Rosenstein Jeffrey M. , Mani Nina , Khaibullina Alfia , Krum Janette M.
Published: April 2018

Vascular endothelial growth factor (VEGF) is well known to play an important regulatory role in vascular growth and development. Because gene knock-outs of VEGF and its receptorsflk-1andflt-1result in early embryonic lethality, determining roles for VEGF in CNS development has been particularly difficult. Recent studies have shown that VEGF is upregulated after various injuries to the adult brain and that the cytokine affords protection to cultured neurons affected by oxidative or excitotoxic stress. The present study demonstrates, for the first time, that VEGF is directly neurotrophic to CNS neurons in culture. We applied VEGF to normoxic fetal organotypic cortical explants as a model of CNS neuropil, in addition to primary cortical neurons, to assess direct growth effects absent vascular or astroglial activity. We found that VEGF provided a significant dose-responsive increase in the neuronal microtubule markers TUJ1 and MAP-2, as well as mRNA for MAP-2 andflk-1. Antisense oligodeoxynucleotides toflk-1, but notflt-1, inhibited neuritic outgrowth, whereas inhibitors of the signaling pathways MEK1 and P13-AKT both abrogated VEGF-induced growth. VEGF applied to primary cortical neurons produced significant increases in neuronal cell body diameter and the number of emerging neurites mediated byflk-1. Possibly, VEGF achieves its effects by acting on the neuronal microtubular content, which is involved with growth, stability and maturation. Several studies have now shown that VEGF is neurotrophic and neuroprotective independent of a vascular component; we suggest that VEGF plays seminal pleiotrophic roles in CNS development and repair.
Maturation of Long-Term Potentiation Induction Rules in Rodent Hippocampus: Role of GABAergic Inhibition
Authors: Meredith Rhiannon M. , Floyer-Lea Anna M. , Paulsen Ole
Published: April 2018

The induction rules of synaptic plasticity are important for the functional operation of a neural network. We asked whether such synaptic plasticity rules change during development from juvenile to adult animals. Using perforated patch and whole-cell recordings from CA1 pyramidal cells in hippocampal slices, we demonstrate here that the postsynaptic requirements for induction of associative long-term potentiation (LTP) shift gradually. Presynaptic stimulation paired with single postsynaptic action potentials became progressively less effective at inducing LTP with advancing developmental age until, in adult hippocampus, postsynaptic bursts of action potentials were necessary to induce synaptic potentiation. This developmental change might be accounted for by changes in GABAAreceptor-mediated inhibition known to occur in the hippocampus during this postnatal period, because blocking GABAAreceptor-mediated inhibition re-established the effectiveness of single postsynaptic action potentials at inducing LTP in adult hippocampus. These data reveal a gradual shift in the induction rules for LTP, explained by a maturational change in GABAergic inhibition, and could have implications for our understanding of the role of inhibition in information processing in the brain.
Individual Properties of the Two Functional Agonist Sites in GABAAReceptors
Authors: Baumann Sabine W. , Baur Roland , Sigel Erwin
Published: April 2018

The members of the pentameric ligand-gated receptor channel family are involved in information transfer in synapses and the neuromuscular junction. They often contain several copies of the same subunit isoform. Here, we present a method to functionally dissect the role of individual subunits that occur in multiple copies in these receptors.

Opening of the inherent chloride channel in the GABAAreceptor is achieved through the binding of two agonist molecules; however, it has been difficult to obtain information on the contribution of the two individual binding sites. The sites are both located at β(+)/α(-) subunit interfaces, suggesting similar properties. One pair of subunits is flanked by γ and β (site 1) and the other by α and γ (site 2), the different environment possibly affecting the binding sites. Here, we used concatenated subunits and two point mutations of amino acid residues, each in α and β subunits, both located in the agonist binding pocket, to investigate the properties of these two sites. The sites were individually mutated, and consequences of these mutations on GABA and muscimol-induced channel opening and its competitive inhibition by bicuculline were studied. A model predicts that opening also occurs for receptors occupied with a single agonist molecule but is promoted approximately 60-fold in those occupied by two agonists and that site 2 has an approximately threefold higher affinity for GABA than site 1, whereas muscimol and bicuculline show some preference for site 1.
Developmental Decrease in NMDA Receptor Desensitization Associated with Shift to Synapse and Interaction with Postsynaptic Density-95
Authors: Li Bo , Otsu Yo , Murphy Timothy H. , Raymond Lynn A.
Published: April 2018

NMDA receptors (NMDARs) play a crucial role in neuronal development, synaptic plasticity, and excitotoxicity; therefore, regulation of NMDAR function is important in both physiological and pathological conditions. Previous studies indicate that the NMDAR-mediated synaptic current decay rate increases during development because of a switch in receptor subunit composition, contributing to developmental changes in plasticity. To test whether NMDAR desensitization also changes during development, we recorded whole-cell NMDA-evoked currents in cultured rat hippocampal neurons. We found that glycine-independent desensitization of NMDARs decreases during development. This decrease was not dependent on a switch in subunit composition or differential receptor sensitivity to agonist-, Ca2+-, or Zn2+-induced increase in desensitization. Instead, several lines of evidence indicated that the developmental decrease in desensitization was tightly correlated with synaptic localization of the receptor, suggesting that association of NMDARs with proteins selectively expressed at synapses in mature neurons might account for developmental alterations in desensitization. Accordingly, we tested the role of interactions between PSD-95 (postsynaptic density-95) and NMDARs in regulating receptor desensitization. Overexpression of PSD-95 reduced NMDAR desensitization in immature neurons, whereas agents that interfere with synaptic targeting of PSD-95, or induce movement of NMDARs away from synapses and uncouple the receptor from PSD-95, increased NMDAR desensitization in mature neurons. We conclude that synaptic localization and association with PSD-95 increases stability of hippocampal neuronal NMDAR responses to sustained agonist exposure. Our results elucidate an additional mechanism for differentially regulating NMDAR function in neurons of different developmental stages or the response of subpopulations of NMDARs in a single neuron.
Credit Assignment in a Motor Decision Making Task Is Influenced by Agency and Not Sensory Prediction Errors
Authors: Parvin Darius E. , McDougle Samuel D. , Taylor Jordan A. , Ivry Richard B.
Published: April 2018

Failures to obtain reward can occur from errors in action selection or action execution. Recently, we observed marked differences in choice behavior when the failure to obtain a reward was attributed to errors in action execution compared with errors in action selection (McDougle et al., 2016). Specifically, participants appeared to solve this credit assignment problem by discounting outcomes in which the absence of reward was attributed to errors in action execution. Building on recent evidence indicating relatively direct communication between the cerebellum and basal ganglia, we hypothesized that cerebellar-dependent sensory prediction errors (SPEs), a signal indicating execution failure, could attenuate value updating within a basal ganglia-dependent reinforcement learning system. Here we compared the SPE hypothesis to an alternative, “top-down” hypothesis in which changes in choice behavior reflect participants' sense of agency. In two experiments with male and female human participants, we manipulated the strength of SPEs, along with the participants' sense of agency in the second experiment. The results showed that, whereas the strength of SPE had no effect on choice behavior, participants were much more likely to discount the absence of rewards under conditions in which they believed the reward outcome depended on their ability to produce accurate movements. These results provide strong evidence that SPEs do not directly influence reinforcement learning. Instead, a participant's sense of agency appears to play a significant role in modulating choice behavior when unexpected outcomes can arise from errors in action execution.

SIGNIFICANCE STATEMENTWhen learning from the outcome of actions, the brain faces a credit assignment problem: Failures of reward can be attributed to poor choice selection or poor action execution. Here, we test a specific hypothesis that execution errors are implicitly signaled by cerebellar-based sensory prediction errors. We evaluate this hypothesis and compare it with a more “top-down” hypothesis in which the modulation of choice behavior from execution errors reflects participants' sense of agency. We find that sensory prediction errors have no significant effect on reinforcement learning. Instead, instructions influencing participants' belief of causal outcomes appear to be the main factor influencing their choice behavior.
Livedo reticularis: a cutaneous clue to an underlying endocrine crisis
Authors: Shrikrishnapalasuriyar Natasha , Noyvirt Mirena , Evans Philip , Gibson Bethan , Foden Elin , Kalhan Atul
Published: April 2018

A 54-year-old woman was admitted to hospital with a presumed allergic reaction to a single dose of amoxicillin given for a suspected upper respiratory tract infection. She complained of chest tightness although there was no wheeze or stridor. On examination, she was pyrexial, tachycardic, hypertensive and had a diffuse mottled rash on her lower limbs. Her initial investigations showed raised inflammatory markers. She was treated in the intensive care for a presumed anaphylactic reaction with an underlying sepsis. Further investigations including CT head and CSF examination were unremarkable; however, a CT abdomen showed a 10 cm heterogeneous right adrenal mass. Based on review by the endocrine team, a diagnosis of pheochromocytoma crisis was made, which was subsequently confirmed on 24-h urinary metanephrine measurement. An emergency adrenalectomy was considered although she was deemed unfit for surgery. Despite intensive medical management, her conditioned deteriorated and she died secondary to multi-organ failure induced by pheochromocytoma crisis.

Learning points:

Pheochromocytoma have relatively higher prevalence in autopsy series (0.05–1%) suggestive of a diagnosis, which is often missed.

Pheochromocytoma crisis is an endocrine emergency characterized by hemodynamic instability induced by surge of catecholamines often precipitated by trauma and medications (β blockers, general anesthetic agents, ephedrine and steroids).

Pheochromocytoma crisis can mimic acute coronary syndrome, cardiogenic or septic shock.

Livedo reticularis can be a rare although significant cutaneous marker of underlying pheochromocytoma crisis.
Factores que inciden en la intención emprendedora del estudiantado universitario: Un análisis cualitativo
Authors: Echeverri-Sanchez Laura , Valencia-Arias Alejandro , Benjumea-Arias Martha , Barrera-Del Toro Andry
Published: April 2018

This research aims to explore the factors encouraging entrepreneurial intentions at the Instituto Tecnológico Metropolitano (ITM - Metropolitan Technological Institute), located in Medellín. The methodological design set out is a qualitative type through the application of 29 semi-structured interviews to undergraduate students from Instituto Tecnológico Metropolitano (ITM). They were interrogated about identified opportunities for new products, family social influence to create a business, balance between work and private life, as well as the motivating situation for business creation. Among the results, it was observed that students searched for creating a business by the expectation of labor independence. Among the suggestions, is set out that universities adopt teaching models oriented to entrepreneurship in order to have an overview over structure of the business sector when students finish their studies.
Alfabetización mediática y aprendizaje. Aporte conceptual en el campo de la comunicación-educación
Authors: Valdivia-Barrios Andrea , Pinto-Torres Daniel , Herrera-Barraza Minka
Published: April 2018

The social transformations related to digital technologies and new media offer important challenges to education. The school ceases to be the main space; ways of knowing and producing knowledge expand and diversify; and communicative practices become more complex. This makes it necessary to examine skills and learnings that should be promoted to act and participate in digital and media settings. This article presents a critical conceptual review on media literacy and learning from Latin American, American and European traditions. A reading integrating theoretical contribution from communication and education is proposed. Literacy is understood as a social practice that implies construction and social consensus for the generation and negotiation of meanings through language and learning. It offers pertinent guidelines for an educational curriculum in tune with the challenges of digitization and mediatization of society.
Zu kompliziert, um zu funktionieren – Eine kritische Bewertung des Bail-in-Instruments im europäischen Recht der Bankenabwicklung
Authors: Tröger Tobias H.
Published: April 2018

Dieser Beitrag hinterfragt die Umsetzung einer auf Bail-in ausgerichteten Regelungsstrategie im europäischen Recht der Bankenabwicklung kritisch. Er bezieht jenseits nationaler Umsetzungs- und Anwendungsfragen eine Position im Rahmen der paneuropäischen Debatte. Diese darf nicht auf technische Verfeinerungen innerhalb eines nicht mehr in Frage gestellten Regelungskonzepts beschränkt sein, sondern muss auch Pfadabhängigkeiten überwindende Neuansätze berücksichtigen. Der Beitrag kommt zu dem Schluss, dass das Bail-in-Instrument in seiner gegenwärtigen Gestalt ein zentrales Regelungsziel verfehlen wird, das hinter der zwingenden Beteiligung des Privatsektors (private sector involvement – PSI) an den Kosten der Bankenabwicklung steht. Eine risikoadäquate Bepreisung von Bankkapital, d. h. Marktdisziplin, wird sich unter der Sanierungs- und Abwicklungsrichtlinie (Bank Recovery and Resolution Directive – BRRD) und der Verordnung über den Einheitlichen Abwicklungsmechanismus (Single Resolution Mechanism Regulation – SRM-VO) nicht einstellen. Deshalb sollte ein alternativer Regelungsansatz verfolgt werden, der die anreizbegründende Verlustbeteiligung des Privatsektors möglichst weitgehend von der umfassenderen Abwicklung trennt und in prädesignierten Finanzinstrumenten konzentriert.
Ist Deutschlands Mittelstand bereit für FinTech und Online-Kredite?
Authors: Alscher Alexander , Kolbecher Marcel
Published: April 2018

Der technische Fortschritt und die Digitalisierung in der Finanzindustrie (u. a. durch FinTechs) haben angefangen den weltweiten Banken- und Kreditmarkt stark zu verändern. In einer empirischen Analyse über die Akzeptanz von kleinen und mittleren Unternehmen (KMU) in Deutschland untersucht der Artikel die Möglichkeiten und Chancen von FinTechs im Bereich von innovativen Peer-to-Business-(P2B)-Lending-Plattformen als Finanzierungsalternative zu Bankkrediten. In der Arbeit werden die in der Theorie vorhandenen Akzeptanzkriterien identifiziert, empirisch mit Experten validiert und gewichtet sowie in einer empirischen Umfrage bei 53 mittelständischen Unternehmen getestet. Die Studie zeigt, dass ein transparenter Antragsprozess, ein persönlicher and qualifizierter Ansprechpartner, eine positive Reputation des Anbieters und die Transparenz der Gebühren maßgeblich für eine erfolgreiche Geschäftsmodellentwicklung von Peer-to-Business-Lending-Möglichkeiten bei deutschen KMU sind. Die Arbeit leistet sowohl einen wissenschaftlichen Verständnisbeitrag über die aktuelle Wahrnehmung und Akzeptanz von FinTech-Angeboten in Deutschland als auch einen praxisorientierten Bezugsrahmen, um kundenorientierte Geschäftsmodelle im P2B-Lending-Segment zu entwickeln und zu optimieren.
Ertragsteuerlicher Vorteilhaftigkeitsvergleich zwischen Aktienfonds- und Aktiendirektanlage im Privatvermögen nach dem Investmentsteuerreformgesetz
Authors: Kalies Kristin , Müller Heiko , Taqi Syeda Fariha
Published: April 2018

Mit Inkrafttreten der Investmentsteuerreform am 1. 1. 2018 wird die bisher semi-transparente Besteuerung für Publikums-Investmentfonds durch ein neues Besteuerungsverfahren ersetzt, das grundsätzlich auf der getrennten Besteuerung des Investmentfonds und des Anteilseigners basiert. Da nunmehr Investmentfonds körperschaftsteuerpflichtig sind und auf Ebene des Aktienfonds Gewinnausschüttungen und Veräußerungsgewinne unterschiedlich besteuert werden, ergeben sich maßgebliche steuerliche Unterschiede im Vergleich zur Aktiendirektanlage im Privatvermögen. Die steuerliche Vorteilhaftigkeit der Anlagealternative wird insbesondere durch die Höhe der Vorsteuer-Rendite, den Dividenden- und Kursgewinnanteil, die Kursgewinn-Realisationsquote, den Umfang der Fondsausschüttung und den Betrachtungszeitraum bestimmt.
Förderung einer Risikokultur durch den Aufbau transformationaler Führungskompetenz
Authors: Wolf Juliane , Öhlschlegel-Haubrock Sonja , Rach Jutta
Published: April 2018

Banken sind mit der 5. MaRisk-Novelle 2017 zur Schaffung einer angemessenen Risikokultur verpflichtet. Sowohl in der Literatur als auch durch die BaFin wird dabei auf die Rolle von Führung aufmerksam gemacht. Allerdings wurde bislang kaum betrachtet, wie eine entsprechende Führung aussehen muss. Hier wird aufgezeigt, dass gerade transformationale Führung einen Beitrag zur Förderung einer Risikokultur leistet. Diese Form der Mitarbeiterführung fördert die Verantwortlichkeit der Mitarbeiter für die Identifikation, Bewertung und Steuerung von Risiken aus Gesamtinstitutssicht und schafft es, dieses Wissen für das Unternehmen zugänglich und nutzbar zu machen.
Zur Zulässigkeit pauschaler Plattformverbote im Internetvertrieb von Luxuswaren
Authors: Kumkar Lea Katharina
Published: April 2018

Am 6. Dezember des vergangenen Jahres hat der EuGH seine mit Spannung erwartete Entscheidung in dem Vorabentscheidungsverfahren Coty Germany GmbH gegen Parfümerie Akzente GmbH (Rs C-230/16) verkündet und dabei die rechtliche Zulässigkeit von pauschalen Plattformverboten im Selektivvertrieb zum Schutz des Prestigeimages von Luxusprodukten im Wesentlichen bestätigt. Obwohl der EuGH in seiner Entscheidung zu allen vier vom zuständigen Senat des OLG Frankfurt/M. formulierten Vorlagefragen Stellung bezieht, schafft das Urteil nur vermeintlich die in der Praxis lang ersehnte Klarheit: So bleibt nach wie vor offen, nach welchen Grundsätzen die Rechtmäßigkeit von Plattformverboten für den bedeutsamen Bereich hochwertiger Markenartikel zu beurteilen ist.
Hebrew stress: Back to the future
Authors: Bat-El Outi
Published: April 2018

The paper addresses historical changes in the stress system of Hebrew, attending to the difference between Biblical Hebrew (script-based) and contemporary Hebrew (attested), and predicting the system of post-Hebrew; on the basis of experimental evidence and words from the periphery of the lexicon, it is predicted that the stress system of post-Hebrew will be similar to that of Biblical Hebrew. The predicted change from contemporary Hebrew to post-Hebrew is attributed to a combination of two factors: the inconsistency of the present system, and its incompliance with universal principles. The changes are addressed in terms of constraint reranking within the framework of Optimality Theory.
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Central Nervous System Metastases from Non-Small Cell Lung Cancer
Authors: Ahluwalia Manmeet S. , Becker Kevin , Levy Benjamin P.
Published: April 2018

Central nervous system (CNS) metastases are a common complication in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), resulting in a poor prognosis and limited treatment options. Treatment of CNS metastases requires a multidisciplinary approach, and the optimal treatment options and sequence of therapies are yet to be established. Many systemic therapies have poor efficacy in the CNS due to the challenges of crossing the blood-brain barrier (BBB), creating a major unmet need for the development of agents with good BBB-penetrating biopharmaceutical properties. Although the CNS penetration of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) is generally low, EGFR-TKI treatment has been shown to delay time to CNS progression in patients with CNS metastases from EGFR-mutated disease. However, a major challenge with EGFR-TKI treatment for patients with NSCLC is the development of acquired resistance, which occurs in most patients treated with a first-line EGFR-TKI. Novel EGFR-TKIs, such as osimertinib, have been specifically designed to address the challenges of acquired resistance and poor BBB permeability and have demonstrated efficacy in the CNS. A rational, iterative drug development process to design agents that could penetrate the BBB could prevent morbidity and mortality associated with CNS disease progression. To ensure a consistent approach to evaluating CNS efficacy, special consideration also needs to be given to clinical trial endpoints.

Implications for Practice

Historically, treatment options for patients who develop central nervous system (CNS) metastases have been limited and associated with poor outcomes. The development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has improved outcomes for patients with EGFR-mutated disease, and emerging data have demonstrated the ability of these drugs to cross the blood-brain barrier and elicit significant intracranial responses. Recent studies have indicated a role for next-generation EGFR-TKIs, such as osimertinib, in the treatment of CNS metastases. In the context of an evolving treatment paradigm, treatment should be individualized to the patient and requires a multidisciplinary approach.
Osimertinib: A Novel Dermatologic Adverse Event Profile in Patients with Lung Cancer
Authors: Chu Chia-Yu , Choi Jennifer , Eaby-Sandy Beth , Langer Corey J. , Lacouture Mario E.
Published: April 2018

Dermatologic adverse events (dAEs) are common with the use of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. First- and second-generation agents (erlotinib, gefitinib, and afatinib) are frequently associated with acneiform rash, pruritus, xerosis, and paronychia; the incidence and characterization of these dAEs have been well described. However, there is evidence that the dAE profile is different with third-generation EGFR-TKIs. Herein, we describe the dAEs associated with third-generation EGFR-TKIs and our clinical experience with osimertinib, a third-generation EGFR-TKI approved by the U.S. Food and Drug Administration for the treatment of metastatic, EGFR T790M mutation-positive non-small cell lung cancer in patients whose disease has progressed on or after EGFR-TKI therapy. Case summaries of patients from two of our institutions who received osimertinib and were referred to a dermatologist for dAEs are also presented. Overall, the evidence suggests that osimertinib is associated with less severe and less frequent dAEs than first- and second-generation EGFR-TKIs and that therefore a different approach is warranted. Finally, we outline dAE management approaches for osimertinib in the context of those typically employed with first- and second-generation EGFR-TKIs.

Implications for Practice

Appropriate prevention and management of dermatologic adverse events (dAEs) associated with the use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) may help patients to continue therapy and lessen any negative impact on their quality of life. EGFR-TKIs are frequently associated with acneiform rash, pruritus, xerosis, and paronychia; however, dAEs associated with third-generation EGFR-TKIs are lower in frequency and severity. Before therapy, health care providers should discuss the potential osimertinib-associated dAEs and encourage patients to report their dAEs. Patients should also be educated on prophylactic measures to minimize the severity of dAEs and the importance of adherence to the treatment regimen.
Diamond-like carbon-deposited films: a new class of biocorrosion protective coatings
Authors: Derakhshandeh Mohammad Reza , Eshraghi Mohammad Javad , Javaheri Masoumeh , Khamseh Sara , Sari Morteza Ganjaee , Zarrintaj Payam , Saeb Mohammad Reza , Mozafari Masoud
Published: April 2018

A series of diamond-like carbon thin films was applied on AISI 316L stainless steel substrates through a pulsed-direct current plasma-enhanced chemical vapor deposition technique to study the effects of working parameters (bias voltage and deposition pressure) on the microstructure and biocorrosion resistance of films. Raman spectra indicated that under low bias voltage and higher deposition pressure, the films possess a higher amount of sp2structure, lower internal stress and an improved biocorrosion resistance due to a smooth and defect-free morphology. The lamellar sp2structure blocked a penetration of corrosive entities. The oxygen content of locally corroded areas (∼11·9 wt.%) was much higher than that of non-corroded areas (2·6 wt.%) corroborating galvanic corrosion between carbide and nitride phases. Moreover, by increasing the deposition pressure from 20 to 40 Pa, the internal stress decreased from 1·03 to 0·82 GPa. The results confirmed that it is possible to tailor the properties of the coatings such as structural composition and particularly biocorrosion resistance by the control over the working parameters. Such anticorrosive diamond-like coatings could benefit biomedical implants used for tissue regeneration.
Importance of adding waste plastics to high-performance concrete
Authors: Al-Hadithi Abdulkader I. , Alani Mahmood Fawzi
Published: April 2018

The main aim of this research is to study the effects of adding polyethylene terephthalate or ‘PET’ waste to high-performance concrete (HPC) and the resulting properties and behaviour under freezing–thawing conditions. Natural sand is substituted with the PET aggregates at varying dosages (0–7·5% by volume of the sand) to produce HPC mixes. Mechanical properties of HPC were evaluated. The freezing–thawing resistance was measured to determine the durability factor (DF) of HPC with and without PET aggregates. The results indicated that the frost resistance of concrete mixes containing various amounts of PET aggregate was better than that of the reference mix, and the higher DF was that of the mix containing 5% replacement ratio, during 300 cycles of rapid freezing and thawing tests. The use of PET waste aggregates presented various advantages like increased flexural strength, improved frost resistance and a change in failure mode. This research study ensured that recycled waste plastic as a substitution of sand in HPC can help with decreasing the consumption of natural sand and with solving some of the environmental problems posed by plastic wastes.
Pertencimento e tradição: a identidade germânica de Rio da Ilha frente a multiculturalidade
Authors: Gevehr Daniel Luciano , Fetter Shirlei Alexandra
Published: April 2018

O objetivo do estudo é discutir as características identitárias da cultura germânica na localidade de Rio da Ilha, pertencente ao município de Taquara/RS. Destaca-se a identidade cultural expressa às características marcantes do indivíduo, na medida em que o mesmo é influenciado ou não pela cultura do grupo a que pertença. Como metodologia, abordaram-se moradores que mantiveram vínculos com imigrantes alemães chegados a comunidade, também se fez registro por imagens sobre patrimônios matérias de característica germânica. Os resultados demonstraram que a ressignificação da cultura germânica é repassada - de diferentes maneiras - por meio das gerações, como forma de preservar a identidade étnica. Atualmente a localidade está marcada por multiculturalidade, as quais se encontram associadas aos processos híbridos estabelecendo interações entre as diferentes culturas. Evidenciam-se características que naturalizam e cristalizam as identidades dos habitantes de uma região, composta pela etnicidade, que se articula com o passado em comum dos habitantes de um território, os quais vão articulando estratégias que visam fortalecer e preservar a cultura por intermédio dos vínculos locais. Contudo, conclui-se que os imigrantes alemães de Rio da Ilha tinham como propósito a busca pela sustentabilidade através de seu trabalho.