bluuebunny/crossref_metadata_2025 huggingface dataset:
The protective effect of daidzein on high glucose-induced oxidative stress in human umbilical vein endothelial cells
Authors: Park Mi Hwa , Ju Jae-Won , Kim Mihyang , Han Ji-Sook
Published: January 2016

Endothelial cell dysfunction is considered a major cause of vascular complications in diabetes. In the present study, we investigated the protective effect of daidzein, a natural isoflavonoid, against high-glucose–induced oxidative damage in human umbilical vein endothelial cells (HUVECs). Treatment with a high concentration of glucose (30 mM) induced oxidative stress in the endothelial cells, against which daidzein protected the cells as demonstrated by significantly increased cell viability. In addition, lipid peroxidation, intracellular reactive oxygen species (ROS) generation, and indirect nitric oxide levels induced by the high glucose treatment were significantly reduced in the presence of daidzein (0.02–0.1 mM) in a dose-dependent manner. High glucose levels induced the overexpression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and NF-κB proteins in HUVECs, which was suppressed by treatment with 0.04 mM daidzein. These findings indicate the potential of daidzein to reduce high glucose-induced oxidative stress.
Understanding the Electronic Structure of Graphene Quantum Dot-Fullerene Nanohybrids for Photovoltaic Applications
Authors: Chakravarty Chandrima , Ghosh Poulami , Mandal Bikash , Sarkar Pranab
Published: January 2016

By using density-functional tight-binding method we have calculated the electronic structure
of graphene quantum dot (GQD)-fullerene hybrid systems and explored the efficacy of their
use in designing solar cells. We have shown that the electronic energy levels of the
nanohybrids can be tuned either by varying the size of the quantum dots or by proper
functionalization of the quantum dot (QD). The GQD-fullerene nanohybrids form type-I or
type-II band energy alignment depending upon the size of the GQD. Thus, hybrid systems with
smaller sized QDs form type-II band energy alignment while those of larger GQDs form type-I
alignment. The type-II band alignment confirms the spatial charge separation for the systems
and thus the rate of recombination of charge carriers will be low. The value of ΔG i.e. the difference in energy between the LUMO of the donor (GQD) and LUMO of the
acceptor (fullerene) which measures the rate of electron injection from the donor to the
acceptor is also large for the nanohybrids with smaller GQDs. So, we suggest that
GQD-fullerene nanocomposites with smaller GQD will be a suitable system for photovoltaic
devices. We also show that the type-II band energy alignment for the nanohybrids with larger
QDs can be achieved through the functionalization of the GQD with electron donating group
such as -NH2.
Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Regulate Feeding and Reward
Authors: Stamatakis Alice M. , Van Swieten Maaike , Basiri Marcus L. , Blair Grace A. , Kantak Pranish , Stuber Garret D.
Published: January 2016

The overconsumption of calorically dense, highly palatable foods is thought to be a major contributor to the worldwide obesity epidemic; however, the precise neural circuits that directly regulate hedonic feeding remain elusive. Here, we show that lateral hypothalamic area (LHA) glutamatergic neurons, and their projections to the lateral habenula (LHb), negatively regulate the consumption of palatable food. Genetic ablation of LHA glutamatergic neurons increased daily caloric intake and produced weight gain in mice that had access to a high-fat diet, while not altering general locomotor activity. Anterior LHA glutamatergic neurons send a functional glutamatergic projection to the LHb, a brain region involved in processing aversive stimuli and negative reward prediction outcomes. Pathway-specific, optogenetic stimulation of glutamatergic LHA-LHb circuit resulted in detectable glutamate-mediated EPSCs as well as GABA-mediated IPSCs, although the net effect of neurotransmitter release was to increase the firing of most LHb neurons.In vivooptogenetic inhibition of LHA-LHb glutamatergic fibers produced a real-time place preference, whereas optogenetic stimulation of LHA-LHb glutamatergic fibers had the opposite effect. Furthermore, optogenetic inhibition of LHA-LHb glutamatergic fibers acutely increased the consumption of a palatable liquid caloric reward. Collectively, these results demonstrate that LHA glutamatergic neurons are well situated to bidirectionally regulate feeding and potentially other behavioral states via their functional circuit connectivity with the LHb and potentially other brain regions.

SIGNIFICANCE STATEMENTIn this study, we show that the genetic ablation of LHA glutamatergic neurons enhances caloric intake. Some of these LHA glutamatergic neurons project to the lateral habenula, a brain area important for generating behavioral avoidance. Optogenetic stimulation of this circuit has net excitatory effects on postsynaptic LHb neurons. This is the first study to characterize the functional connectivity and behavioral relevance of this circuit within the context of feeding and reward-related behavior.
Post-Traumatic Stress Constrains the Dynamic Repertoire of Neural Activity
Authors: Mišić Bratislav , Dunkley Benjamin T. , Sedge Paul A. , Da Costa Leodante , Fatima Zainab , Berman Marc G. , Doesburg Sam M. , McIntosh Anthony R. , Grodecki Richard , Jetly Rakesh , Pang Elizabeth W. , Taylor Margot J.
Published: January 2016

Post-traumatic stress disorder (PTSD) is an anxiety disorder arising from exposure to a traumatic event. Although primarily defined in terms of behavioral symptoms, the global neurophysiological effects of traumatic stress are increasingly recognized as a critical facet of the human PTSD phenotype. Here we use magnetoencephalographic recordings to investigate two aspects of information processing: inter-regional communication (measured by functional connectivity) and the dynamic range of neural activity (measured in terms of local signal variability). We find that both measures differentiate soldiers diagnosed with PTSD from soldiers without PTSD, from healthy civilians, and from civilians with mild traumatic brain injury, which is commonly comorbid with PTSD. Specifically, soldiers with PTSD display inter-regional hypersynchrony at high frequencies (80–150 Hz), as well as a concomitant decrease in signal variability. The two patterns are spatially correlated and most pronounced in a left temporal subnetwork, including the hippocampus and amygdala. We hypothesize that the observed hypersynchrony may effectively constrain the expression of local dynamics, resulting in less variable activity and a reduced dynamic repertoire. Thus, the re-experiencing phenomena and affective sequelae in combat-related PTSD may result from functional networks becoming “stuck” in configurations reflecting memories, emotions, and thoughts originating from the traumatizing experience.

SIGNIFICANCE STATEMENTThe present study investigates the effects of post-traumatic stress disorder (PTSD) in combat-exposed soldiers. We find that soldiers with PTSD exhibit hypersynchrony in a circuit of temporal lobe areas associated with learning and memory function. This rigid functional architecture is associated with a decrease in signal variability in the same areas, suggesting that the observed hypersynchrony may constrain the expression of local dynamics, resulting in a reduced dynamic range. Our findings suggest that the re-experiencing of traumatic events in PTSD may result from functional networks becoming locked in configurations that reflect memories, emotions, and thoughts associated with the traumatic experience.
Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease
Authors: Lian Hong , Litvinchuk Alexandra , Chiang Angie C.-A. , Aithmitti Nadia , Jankowsky Joanna L. , Zheng Hui
Published: January 2016

Increasing evidence supports a role of neuroinflammation in the pathogenesis of Alzheimer's disease (AD). Previously, we identified a neuron–glia signaling pathway whereby Aβ acts as an upstream activator of astroglial nuclear factor kappa B (NF-κB), leading to the release of complement C3, which acts on the neuronal C3a receptor (C3aR) to influence dendritic morphology and cognitive function. Here we report that astrocytic complement activation also regulates Aβ dynamicsin vitroand amyloid pathology in AD mouse models through microglial C3aR. We show that in primary microglial cultures, acute C3 or C3a activation promotes, whereas chronic C3/C3a treatment attenuates, microglial phagocytosis and that the effect of chronic C3 exposure can be blocked by cotreatment with a C3aR antagonist and by genetic deletion ofC3aR. We further demonstrate that Aβ pathology and neuroinflammation in amyloid precursor protein (APP) transgenic mice are worsened by astroglial NF-κB hyperactivation and resulting C3 elevation, whereas treatment with the C3aR antagonist (C3aRA) ameliorates plaque load and microgliosis. Our studies define a complement-dependent intercellular cross talk in which neuronal overproduction of Aβ activates astroglial NF-κB to elicit extracellular release of C3. This promotes a pathogenic cycle by which C3 in turn interacts with neuronal and microglial C3aR to alter cognitive function and impair Aβ phagocytosis. This feedforward loop can be effectively blocked by C3aR inhibition, supporting the therapeutic potential of C3aR antagonists under chronic neuroinflammation conditions.

SIGNIFICANCE STATEMENTThe complement pathway is activated in Alzheimer's disease. Here we show that the central complement factor C3 secreted from astrocytes interacts with microglial C3a receptor (C3aR) to mediate β-amyloid pathology and neuroinflammation in AD mouse models. Our study provides support for targeting C3aR as a potential therapy for Alzheimer's disease.
Altered Intrinsic Pyramidal Neuron Properties and Pathway-Specific Synaptic Dysfunction Underlie Aberrant Hippocampal Network Function in a Mouse Model of Tauopathy
Authors: Booth Clair A. , Witton Jonathan , Nowacki Jakub , Tsaneva-Atanasova Krasimira , Jones Matthew W. , Randall Andrew D. , Brown Jonathan T.
Published: January 2016

The formation and deposition of tau protein aggregates is proposed to contribute to cognitive impairments in dementia by disrupting neuronal function in brain regions, including the hippocampus. We used a battery ofin vivoandin vitroelectrophysiological recordings in the rTg4510 transgenic mouse model, which overexpresses a mutant form of human tau protein, to investigate the effects of tau pathology on hippocampal neuronal function in area CA1 of 7- to 8-month-old mice, an age point at which rTg4510 animals exhibit advanced tau pathology and progressive neurodegeneration.In vitrorecordings revealed shifted theta-frequency resonance properties of CA1 pyramidal neurons, deficits in synaptic transmission at Schaffer collateral synapses, and blunted plasticity and imbalanced inhibition at temporoammonic synapses. These changes were associated with aberrant CA1 network oscillations, pyramidal neuron bursting, and spatial information codingin vivo. Our findings relate tauopathy-associated changes in cellular neurophysiology to altered behavior-dependent network function.

SIGNIFICANCE STATEMENTDementia is characterized by the loss of learning and memory ability. The deposition of tau protein aggregates in the brain is a pathological hallmark of dementia; and the hippocampus, a brain structure known to be critical in processing learning and memory, is one of the first and most heavily affected regions. Our results show that, in area CA1 of hippocampus, a region involved in spatial learning and memory, tau pathology is associated with specific disturbances in synaptic, cellular, and network-level function, culminating in the aberrant encoding of spatial information and spatial memory impairment. These studies identify several novel ways in which hippocampal information processing may be disrupted in dementia, which may provide targets for future therapeutic intervention.
Causal Link between the Cortico-Rubral Pathway and Functional Recovery through Forced Impaired Limb Use in Rats with Stroke
Authors: Ishida Akimasa , Isa Kaoru , Umeda Tatsuya , Kobayashi Kazuto , Kobayashi Kenta , Hida Hideki , Isa Tadashi
Published: January 2016

Intensive rehabilitation is believed to induce use-dependent plasticity in the injured nervous system; however, its causal relationship to functional recovery is unclear. Here, we performed systematic analysis of the effects of forced use of an impaired forelimb on the recovery of rats after lesioning the internal capsule with intracerebral hemorrhage (ICH). Forced limb use (FLU) group rats exhibited better recovery of skilled forelimb functions and their cortical motor area with forelimb representation was restored and enlarged on the ipsilesional side. In addition, abundant axonal sprouting from the reemerged forelimb area was found in the ipsilateral red nucleus after FLU. To test the causal relationship between the plasticity in the cortico-rubral pathway and recovery, loss-of-function experiments were conducted using a double-viral vector technique, which induces selective blockade of the target pathway. Blockade of the cortico-rubral tract resulted in deficits of the recovered forelimb function in FLU group rats. These findings suggest that the cortico-rubral pathway is a substrate for recovery induced by intensive rehabilitation after ICH.

SIGNIFICANCE STATEMENTThe research aimed at determining the causal linkage between reorganization of the motor pathway induced by intensive rehabilitative training and recovery after stroke. We clarified the expansion of the forelimb representation area of the ipsilesional motor cortex by forced impaired forelimb use (FLU) after lesioning the internal capsule with intracerebral hemorrhaging (ICH) in rats. Anterograde tracing showed robust axonal sprouting from the forelimb area to the red nucleus in response to FLU. Selective blockade of the cortico-rubral pathway by the novel double-viral vector technique clearly revealed that the increased cortico-rubral axonal projections had causal linkage to the recovery of reaching movements induced by FLU. Our data demonstrate that the cortico-rubral pathway is responsible for the effect of intensive limb use.
Tmc1Point Mutation Affects Ca2+Sensitivity and Block by Dihydrostreptomycin of the Mechanoelectrical Transducer Current of Mouse Outer Hair Cells
Authors: Corns Laura F. , Johnson Stuart L. , Kros Corné J. , Marcotti Walter
Published: January 2016

The transduction of sound into electrical signals depends on mechanically sensitive ion channels in the stereociliary bundle. The molecular composition of this mechanoelectrical transducer (MET) channel is not yet known. Transmembrane channel-like protein isoforms 1 (TMC1) and 2 (TMC2) have been proposed to form part of the MET channel, although their exact roles are still unclear. UsingBeethoven(Tmc1Bth/Bth) mice, which have an M412K point mutation in TMC1 that adds a positive charge, we found that Ca2+permeability and conductance of the MET channel of outer hair cells (OHCs) were reduced.Tmc1Bth/BthOHCs were also less sensitive to block by the permeant MET channel blocker dihydrostreptomycin, whether applied extracellularly or intracellularly. These findings suggest that the amino acid that is mutated inBthis situated at or near the negatively charged binding site for dihydrostreptomycin within the permeation pore of the channel. We also found that the Ca2+dependence of the operating range of the MET channel was altered by the M412K mutation. Depolarization did not increase the resting open probability of the MET current ofTmc1Bth/BthOHCs, whereas raising the intracellular concentration of the Ca2+chelator BAPTA caused smaller increases in resting open probability inBthmutant OHCs than in wild-type control cells. We propose that these observations can be explained by the reduced Ca2+permeability of the mutated MET channel indirectly causing the Ca2+sensor for adaptation, at or near the intracellular face of the MET channel, to become more sensitive to Ca2+influx as a compensatory mechanism.

SIGNIFICANCE STATEMENTIn the auditory system, the hair cells convert sound-induced mechanical movement of the hair bundles atop these cells into electrical signals through the opening of mechanically gated ion channels at the tips of the bundles. Although the nature of these mechanoelectrical transducer (MET) channels is still unclear, recent studies implicate transmembrane channel-like protein isoform 1 (TMC1) channels in the mammalian cochlea. Using a mutant mouse model (Beethoven) for progressive hearing loss in humans (DFNA36), which harbors a point mutation in theTmc1gene, we show that this mutation affects the MET channel pore, reducing its Ca2+permeability and its affinity for the permeant blocker dihydrostreptomycin. A number of phenomena that we ascribe to Ca2+-dependent adaptation appear stronger, in compensation for the reduced Ca2+entry.
Cortical Plasticity Induction by Pairing Subthalamic Nucleus Deep-Brain Stimulation and Primary Motor Cortical Transcranial Magnetic Stimulation in Parkinson's Disease
Authors: Udupa Kaviraja , Bahl Nina , Ni Zhen , Gunraj Carolyn , Mazzella Filomena , Moro Elena , Hodaie Mojgan , Lozano Andres M. , Lang Anthony E. , Chen Robert
Published: January 2016

Noninvasive brain stimulation studies have shown abnormal motor cortical plasticity in Parkinson's disease (PD). These studies used peripheral nerve stimulation paired with transcranial magnetic stimulation (TMS) to primary motor cortex (M1) at specific intervals to induce plasticity. Induction of cortical plasticity through stimulation of the basal ganglia (BG)–M1 connections has not been studied. In the present study, we used a novel technique of plasticity induction by repeated pairing of deep-brain stimulation (DBS) of the BG with M1 stimulation using TMS. We hypothesize that repeated pairing of subthalamic nucleus (STN)-DBS and M1-TMS at specific time intervals will lead to plasticity in the M1. Ten PD human patients with STN-DBS were studied in the on-medication state with DBS set to 3 Hz. The interstimulus intervals (ISIs) between STN-DBS and TMS that produced cortical facilitation were determined individually for each patient. Three plasticity induction conditions with repeated pairings (180 times) at specific ISIs (∼3 and ∼23 ms) that produced cortical facilitation and a control ISI of 167 ms were tested in random order. Repeated pairing of STN-DBS and M1-TMS at short (∼3 ms) and medium (∼23 ms) latencies increased M1 excitability that lasted for at least 45 min, whereas the control condition (fixed ISI of 167 ms) had no effect. There were no specific changes in motor thresholds, intracortical circuits, or recruitment curves. Our results indicate that paired-associative cortical plasticity can be induced by repeated STN and M1 stimulation at specific intervals. These results show that STN-DBS can modulate cortical plasticity.

SIGNIFICANCE STATEMENTWe introduced a new experimental paradigm to test the hypothesis that pairing subthalamic nucleus deep-brain stimulation (STN-DBS) with motor cortical transcranial magnetic stimulation (M1-TMS) at specific times can induce cortical plasticity in patients with Parkinson's disease (PD). We found that repeated pairing of STN-DBS with TMS at short (∼3 ms) and medium (∼23 ms) intervals increased cortical excitability that lasted for up to 45 min, whereas the control condition (fixed latency of 167 ms) had no effects on cortical excitability. This is the first demonstration of associative plasticity in the STN-M1 circuits in PD patients using this novel technique. The potential therapeutic effects of combining DBS and noninvasive cortical stimulation should be investigated further.
Isolated P/Q Calcium Channel Deletion in Layer VI Corticothalamic Neurons Generates Absence Epilepsy
Authors: Bomben Valerie C. , Aiba Isamu , Qian Jing , Mark Melanie D. , Herlitze Stefan , Noebels Jeffrey L.
Published: January 2016

Generalized spike-wave seizures involving abnormal synchronization of cortical and underlying thalamic circuitry represent a major category of childhood epilepsy. Inborn errors ofCacna1a, the P/Q-type voltage-gated calcium channel α subunit gene, expressed throughout the brain destabilize corticothalamic rhythmicity and produce this phenotype. To determine the minimal cellular lesion required for this network disturbance, we used neurotensin receptor 1 (Ntsr1) cre-driver mice to ablate floxedCacna1ain layer VI pyramidal neurons, which supply the sole descending cortical synaptic input to thalamocortical relay cells and reticular interneurons and activate intrathalamic circuits. TargetedCacna1aablation in layer VI cells resulted in mice that display a robust spontaneous spike-wave absence seizure phenotype accompanied by behavioral arrest and inhibited by ethosuximide. To verify the selectivity of the molecular lesion, we determined that P/Q subunit proteins were reduced in corticothalamic relay neuron terminal zones, and confirmed that P/Q-mediated glutamate release was reduced at these synapses. Spike-triggered exocytosis was preserved by N-type calcium channel rescue, demonstrating that evoked release at layer VI terminals relies on both P/Q and N-type channels. Whereas intrinsic excitability of the P/Q channel depleted layer VI neurons was unaltered, T-type calcium currents in the postsynaptic thalamic relay and reticular cells were dramatically elevated, favoring rebound bursting and seizure generation. We find that an early P/Q-type release defect, limited to synapses of a single cell-type within the thalamocortical circuit, is sufficient to remodel synchronized firing behavior and produce a stable generalized epilepsy phenotype.

SIGNIFICANCE STATEMENTThis study dissects a critical component of the corticothalamic circuit in spike-wave epilepsy and identifies the developmental importance of P/Q-type calcium channel-mediated presynaptic glutamate release at layer VI pyramidal neuron terminals. Genetic ablation ofCacna1ain layer VI neurons produced synchronous spike-wave discharges in the cortex and thalamus that were inhibited by ethosuximide. These mice also displayed N-type calcium channel compensation at descending thalamic synapses, and consistent with other spike-wave models increased low-threshold T-type calcium currents within postsynaptic thalamic relay and reticular neurons. These results demonstrate, for the first time, that preventing the developmental homeostatic switch from loose to tightly coupled synaptic release at a single class of deep layer cortical excitatory output neurons results in generalized spike-wave epilepsy.
Electrical and Network Neuronal Properties Are Preferentially Disrupted in Dorsal, But Not Ventral, Medial Entorhinal Cortex in a Mouse Model of Tauopathy
Authors: Booth Clair A. , Ridler Thomas , Murray Tracey K. , Ward Mark A. , de Groot Emily , Goodfellow Marc , Phillips Keith G. , Randall Andrew D. , Brown Jonathan T.
Published: January 2016

The entorhinal cortex (EC) is one of the first areas to be disrupted in neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia. The responsiveness of individual neurons to electrical and environmental stimuli varies along the dorsal–ventral axis of the medial EC (mEC) in a manner that suggests this topographical organization plays a key role in neural encoding of geometric space. We examined the cellular properties of layer II mEC stellate neurons (mEC-SCs) in rTg4510 mice, a rodent model of neurodegeneration. Dorsoventral gradients in certain intrinsic membrane properties, such as membrane capacitance and afterhyperpolarizations, were flattened in rTg4510 mEC-SCs, while other cellular gradients [e.g., input resistance (Ri), action potential properties] remained intact. Specifically, the intrinsic properties of rTg4510 mEC-SCs in dorsal aspects of the mEC were preferentially affected, such that action potential firing patterns in dorsal mEC-SCs were altered, while those in ventral mEC-SCs were unaffected. We also found that neuronal oscillations in the gamma frequency band (30–80 Hz) were preferentially disrupted in the dorsal mEC of rTg4510 slices, while those in ventral regions were comparatively preserved. These alterations corresponded to a flattened dorsoventral gradient in theta-gamma cross-frequency coupling of local field potentials recorded from the mEC of freely moving rTg4510 mice. These differences were not paralleled by changes to the dorsoventral gradient in parvalbumin staining or neurodegeneration. We propose that the selective disruption to dorsal mECs, and the resultant flattening of certain dorsoventral gradients, may contribute to disturbances in spatial information processing observed in this model of dementia.

SIGNIFICANCE STATEMENTThe medial entorhinal cortex (mEC) plays a key role in spatial memory and is one of the first areas to express the pathological features of dementia. Neurons of the mEC are anatomically arranged to express functional dorsoventral gradients in a variety of neuronal properties, including grid cell firing field spacing, which is thought to encode geometric scale. We have investigated the effects of tau pathology on functional dorsoventral gradients in the mEC. Using electrophysiological approaches, we have shown that, in a transgenic mouse model of dementia, the functional properties of the dorsal mEC are preferentially disrupted, resulting in a flattening of some dorsoventral gradients. Our data suggest that neural signals arising in the mEC will have a reduced spatial content in dementia.
The Neural Representation of Goal-Directed Actions and Outcomes in the Ventral Striatum's Olfactory Tubercle
Authors: Gadziola Marie A. , Wesson Daniel W.
Published: January 2016

The ventral striatum is critical for evaluating reward information and the initiation of goal-directed behaviors. The many cellular, afferent, and efferent similarities between the ventral striatum's nucleus accumbens and olfactory tubercle (OT) suggests the distributed involvement of neurons within the ventral striatopallidal complex in motivated behaviors. Although the nucleus accumbens has an established role in representing goal-directed actions and their outcomes, it is not known whether this function is localized within the nucleus accumbens or distributed also within the OT. Answering such a fundamental question will expand our understanding of the neural mechanisms underlying motivated behaviors. Here we address whether the OT encodes natural reinforcers and serves as a substrate for motivational information processing. In recordings from mice engaged in a novel water-motivated instrumental task, we report that OT neurons modulate their firing rate during initiation and progression of the instrumental licking behavior, with some activity being internally generated and preceding the first lick. We further found that as motivational drive decreases throughout a session, the activity of OT neurons is enhanced earlier relative to the behavioral action. Additionally, OT neurons discriminate the types and magnitudes of fluid reinforcers. Together, these data suggest that the processing of reward information and the orchestration of goal-directed behaviors is a global principle of the ventral striatum and have important implications for understanding the neural systems subserving addiction and mood disorders.

SIGNIFICANCE STATEMENTGoal-directed behaviors are widespread among animals and underlie complex behaviors ranging from food intake, social behavior, and even pathological conditions, such as gambling and drug addiction. The ventral striatum is a neural system critical for evaluating reward information and the initiation of goal-directed behaviors. Here we show that neurons in the olfactory tubercle subregion of the ventral striatum robustly encode the onset and progression of motivated behaviors, and discriminate the type and magnitude of a reward. Our findings are novel in showing that olfactory tubercle neurons participate in such coding schemes and are in accordance with the principle that ventral striatum substructures may cooperate to guide motivated behaviors.
MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency
Authors: Castinetti Frederic , Reynaud Rachel , Saveanu Alexandru , Jullien Nicolas , Quentien Marie Helene , Rochette Claire , Barlier Anne , Enjalbert Alain , Brue Thierry
Published: January 2016

Over the last 5 years, new actors involved in the pathogenesis of combined pituitary hormone deficiency in humans have been reported: they included a member of the immunoglobulin superfamily glycoprotein and ciliary G protein-coupled receptors, as well as new transcription factors and signalling molecules. New modes of inheritance for alterations of genes encoding transcription factors have also been described. Finally, actors known to be involved in a very specific phenotype (hypogonadotroph hypogonadism for instance) have been identified in a wider range of phenotypes. These data thus suggest that new mechanisms could explain the low rate of aetiological identification in this heterogeneous group of diseases. Taking into account the fact that several reviews have been published in recent years on classical aetiologies of CPHD such as mutations ofPOU1F1orPROP1, we focused the present overview on the data published in the last 5 years, to provide the reader with an updated review on this rapidly evolving field of knowledge.
ENDOCRINE TUMOURS: The genomics of adrenocortical tumors
Authors: Faillot Simon , Assie Guillaume
Published: January 2016

The last decade witnessed the emergence of genomics, a set of high-throughput molecular measurements in biological samples. These pan-genomic and agnostic approaches have revolutionized the molecular biology and genetics of malignant and benign tumors. These techniques have been applied successfully to adrenocortical tumors. Exome sequencing identified new major drivers in all tumor types, includingKCNJ5,ATP1A1,ATP2B3andCACNA1Dmutations in aldosterone-producing adenomas (APA),PRKACAmutations in cortisol-producing adenomas (CPA),ARMC5mutations in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) andZNRF3mutations in adrenocortical carcinomas (ACC). Moreover, the various genomic approaches – including exome sequencing, transcriptome, miRNome, genome and methylome – converge into a single molecular classification of adrenocortical tumors. Especially for ACC, two main molecular groups have emerged, showing major differences in outcomes. These ACC groups differ by their gene expression profiles, but also by recurrent mutations and specific DNA hypermethylation patterns in the subgroup of poor outcome. The clinical impact of these findings is just starting. The main altered signaling pathways now become therapeutic targets. The molecular groups of diseases individualize robust subtypes within diseases such as APA, CPA, PBMAH and ACC. A revised nosology of adrenocortical tumors should impact the clinical research. Obvious consequences also include genetic counseling for the new genetic diseases such asARMC5mutations in PBMAH, and a better prognostication of ACC based on targeted measurements of a few discriminant molecular alterations. Identifying the main molecular groups of adrenocortical tumors by extensively gathering the molecular variations is a significant step forward towards precision medicine.
Effectiveness of chemotherapy in advanced differentiated thyroid cancer: a systematic review
Authors: Albero Ana , Lopéz Juliana Ester , Torres Alberto , de la Cruz Luis , Martín Tomas
Published: January 2016

In differentiated thyroid carcinoma refractory to radioactive iodine (CDT-RTI), chemotherapy has been considered for decades to be the only systemic therapy with palliative purpose. Phase II studies assessing the efficacy of different chemotherapy outlines have been published. Nevertheless, phase III studies in these tumours have not been performed. Our objective is to evaluate the effectiveness of chemotherapy in patients with CDT-RTI by a systematic review of published studies. Systematic research of the literature in Medline and Embase databases (among others) was carried out. The full texts of selected references were analysed by two independent reviewers and then assessed for risk of bias in each study. We also extracted data using specifically designed questionnaires. Later, a qualitative synthesis of results was performed and pooled data were calculated. We found that 16 studies with 473 patients published in the last 40 years were included out of 509 identified references in databases. Thirteen studies (176 patients) included data on response to treatment and histology. Four studies included 70 patients only with well-differentiated non-medullary tumours. Response rate (RR) was 22.1% (0–57%) for 13 studies, 25% for the 176 patients and 27.1% for the 70 patients, with 2.5, 3.4 and 2.8% complete responses respectively. Survival times could not be assessed or pooled due to the lack of data and heterogeneity of the studies, and was determined to have a high risk of bias. Although it has not been possible to find solid evidence about the efficacy of chemotherapy, the results shown indicate that it may have some effectiveness, although this should be proven with well-designed studies using modern drugs.
Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours
Authors: Vitali Eleonora , Cambiaghi Valeria , Zerbi Alessandro , Carnaghi Carlo , Colombo Piergiuseppe , Peverelli Erika , Spada Anna , Mantovani Giovanna , Lania Andrea G
Published: January 2016

Somatostatin receptor type 2 (SST2) is the main pharmacological target of somatostatin (SS) analogues widely used in patients with pancreatic neuroendocrine tumours (P-NETs), this treatment being ineffective in a subset of patients. Since it has been demonstrated that Filamin A (FLNA) is involved in mediating GPCR expression, membrane anchoring and signalling, we investigated the role of this cytoskeleton protein in SST2 expression and signalling, angiogenesis, cell adhesion and cell migration in human P-NETs and in QGP1 cell line. We demonstrated that FLNA silencing was not able to affect SST2 expression in P-NET cells in basal conditions. Conversely, a significant reduction in SST2 expression (−43±21%, P<0.05 vs untreated cells) was observed in FLNA silenced QGP1 cells after long term SST2 activation with BIM23120. Moreover, the inhibitory effect of BIM23120 on cyclin D1 expression (−46±18%, P<0.05 vs untreated cells), P-ERK1/2 levels (−42±14%; P<0.05 vs untreated cells), cAMP accumulation (−24±3%, P<0.05 vs untreated cells), VEGF expression (−31±5%, P<0.01 vs untreated cells) and in vitro release (−40±24%, P<0.05 vs untreated cells) was completely lost after FLNA silencing. Interestingly, BIM23120 promoted cell adhesion (+86±45%, P<0.05 vs untreated cells) and inhibited cell migration (−24±2%, P<0.00001 vs untreated cells) in P-NETs cells and these effects were abolished in FLNA silenced cells. In conclusion, we demonstrated that FLNA plays a crucial role in SST2 expression and signalling, angiogenesis, cell adhesion and cell migration in P-NETs and in QGP1 cell line, suggesting a possible role of FLNA in determining the different responsiveness to SS analogues observed in P-NET patients.
Bilateral adrenalectomy in the 21st century: when to use it for hypercortisolism?
Authors: Guerin Carole , Taieb David , Treglia Giorgio , Brue Thierry , Lacroix André , Sebag Frederic , Castinetti Frederic
Published: January 2016

Therapeutic options available for the treatment of Cushing's syndrome (CS) have expanded over the last 5 years. For instance, the efficient management of severe hypercortisolism using a combination of fast-acting steroidogenesis inhibitors has been reported. Recent publications on the long-term efficacy of drugs or radiation techniques have also demonstrated low toxicity. These data should encourage endocrinologists to reconsider the place of bilateral adrenalectomy in patients with ACTH-dependent aetiologies of CS; similarly, the indication of bilateral adrenalectomy is reassessed in primary bilateral macronodular adrenal hyperplasia. The objective of this review is to compare the efficacy and side effects of the various therapeutic options of hypercortisolism with those of bilateral adrenalectomy, in order to better define its indications in the 21st century.
Current understanding of metformin effect on the control of hyperglycemia in diabetes
Authors: An Hongying , He Ling
Published: January 2016

Metformin is a first-line oral anti-diabetic agent that has been used clinically to treat patients with type 2 diabetes for over 60 years. Due to its efficacy in therapy and affordable price, metformin is taken by more than 150 million people each year. Metformin improves hyperglycemia mainly through the suppression of hepatic gluconeogenesis along with the improvement of insulin signaling. However, its mechanism of action remains partially understood and controversial, especially in regard to the role of AMPK in metformin's action and the mechanism of AMPK activation. In this review, we discuss recent advances in the understanding of metformin's suppression of hepatic glucose production and the mechanism related to the improvement of insulin signaling.
Előbb az összetett, később az egyszerű: Csecsemők magasabb szintű hangfeldolgozási képességei a beszédértés előtti időszakban
Authors: Winkler István
Published: January 2016

Bár a legalapvetőbb hangjellemzők észlelt felbontása fiatal csecsemőknél messze elmarad a felnőttek hasonló képességeitől, a fejlettebb hangfeldolgozási funkciókat tekintve minőségileg nem különböznek tőlük. A csecsemők kompetens észlelők a hangok világában, hallási tárgyreprezentációkat alkotnak, és képesek kiemelni a beérkező hangok bonyolult belső összefüggéseit. Áttekintve a hangfeldolgozási képességek mintázatát fiatal csecsemőknél, a cikk amellett érvel, hogy e képességek jelentős része a hangokkal történő kommunikáció, azon belül is a dialógusok felépítésének és fenntartásának szolgálatában áll. Az emberi fejlődésben a szociális kommunikációnak kiemelt jelentősége van, mivel lehetővé teszi, hogy az élet kezdetén rövid idő alatt igen nagy mennyiségű kész tudást vehessünk át. Ez indokolja, hogy a fiatal csecsemők hallórendszere az első pillanattól kezdve készen áll az emberi tanulás e leghatékonyabb formájának támogatására.
A Sarkvidéktől a világűrig: A pszichológiai tartalomelemzés alkalmazása izolált kiscsoportok vizsgálatára
Authors: Ehmann Bea , Balázs László
Published: January 2016

Jelen tanulmány alapja a Magyar Pszichológiai Társaság XXIV. Országos Tudományos Nagygyűlésén, Egerben elhangzott Mérei Ferenc-emlékelőadás. Konkrét célja, hogy áttekintést adjon az izolált kiscsoportok pszichológiai kutatásáról, ezen belül a földi űranalóg környezetekkel és valóságos űrutazókkal kapcsolatosan végzett pszichológiai tartalomelemzéses vizsgálatokról. Ennek során ismerteti a pszichológiai tartalomelemzés fő típusait – a tematikus, a pszichológiai konstruktum alapú, a narratív pszichológiai és – az esetenként többnyelvű – korpusznyelvészeti tartalomelemzést. Bemutatja ezek szemléletmódját és nyelvtechnológiai feltételeit, valamint a szerzők által végzett hazai és nemzetközi együttműködésben végzett kutatások néhány eredményét. Tágabb célja, hogy rávilágítson a pszichológiai tartalomelemzés számos területen történő alkalmazhatóságára.
Valóság és fikció: Téri tájékozódás fizikailag valós és computer által létrehozott virtuális környezetben
Authors: Kállai János
Published: January 2016

Az összefoglaló rövid áttekintést ad a téri tájékozódás kognitív idegtudományi kutatásának előzményeiről, bemutatja meghatározó egyéniségeit. A neuropszichológiai szemelvények és a helytanulás tudománytörténeti ismertetése után kitér a helyhez kötött emlékezés többdimenziós természetére. A teret különböző modalitású ingerek alkotják, amelyek mind alkotórészei egy történetnek, amit magunk szövünk mások inspirációi alapján. Megvizsgáljuk az egocentrikus-allocentrikus reprezentációk dinamikai változásait, valamint a figyelmi előtér és háttér klinikai vonzatait, a szorongás és a téri navigáció kölcsönhatásait. A felsorakoztatott adatok felhívják a figyelmet a jövő évtizedeket érintő néhány aktuális kérdésre. Hogyan alkalmazkodjunk a tömegesen megjelenő computer által létrehozott valóságokhoz? A tér általános szemlélete mennyiben segíti az én elhatárolódásra vagy fúzióra törekvő automatizmusait? Mit kínál nekünk, szakembereknek a taktilis, auditív, proprioceptív ingereket is alkalmazó fejlettebb virtuális realitás?
Az elvárások és a hanginger szerepe a binaurális ütemek hallgatása során átélt szubjektív élményekre
Authors: Szabó Gergely , Drótos Gergely , Szabó Csaba
Published: January 2016

Háttér és célok

A binaurális ütemek a két fül közötti frekvenciakülönbség hatására létrejövő pulzáló hangok. A „binaurális ütem” angol megfelelőinek szavaira az internetes keresési találatok az elmúlt három évben megduplázódtak, ami jól példázza az utóbbi időben egyre inkább növekvő érdeklődést. Ezeket a hangokat feltételezett pszichológiai hatásaik miatt keresik, noha a tudományos adatok ellentmondásosak a témában. Tanulmányunkban arra kerestük a választ, hogy a binaurális ütemek hallgatása milyen szubjektív élményeket vált ki a hallgatóból, és ezeket milyen tényezők befolyásolják, tehát hogy mi a szerepe az elvárásoknak, a hang speciális akusztikai tulajdonságainak, illetve a binaurális ütemek frekvenciatartományának.

Módszer

Jelen tanulmányban két vizsgálatot mutatunk be. Az élményeket a (Phenomenology of Consciousness; PCI) élményfeltáró kérdőívvel és a személyekkel készült interjúk tartalomelemzésével mértük. Az első vizsgálatban 109, a másodikban 159 egyetemi hallgató vett részt. Az első kísérletben az instrukció, a másodikban az ingerek fizikai jellemzőinek hatását vizsgáltuk.

Eredmények

A binaurális ingerlés hatására a személyek élményei szignifikánsan megváltoztak, és az élményeket befolyásolta az instrukció. A különböző akusztikai tulajdonságokkal rendelkező hangok hatásában nem volt különbség.

Következtetések

A binaurális ütemek alkalmasak transzszerű élmények kiváltására. Az átélt élményeket jelentősen befolyásolják az előzetes instrukciók. Az átélt élményeket nem befolyásolja a hangok binaurális tulajdonsága, feltehetőleg az ingerek monotonitása okozza az élményváltozásokat.
A feltételes önbecsülés skála (CSES-H) Magyar változatának validálása és pszichometriai jellemzői
Authors: Sági Andrea
Published: January 2016

Elméleti háttér

Az önbecsülés alapvető pszichológiai szükséglet, de egyes típusainak a mentális egészség szempontjából nemcsak jó, hanem káros következményei is lehetnek. A feltételes önbecsülés az alacsony alapönbecsülésből és különböző énmegerősítő szükségletekből (kompetencia és kapcsolatok) származik, negatívan korrelál a mentális egészség indikátoraival és számos negatív pszichológiai jellemzővel jár együtt.

Cél

A Feltételes Önbecsülés Skála magyar változata (CSES-H) pszichometriai jellemzőinek vizsgálata több független mintán.

Módszer

1. minta: 272 fő egyetemi hallgató, 75 férfi és 197 nő (átlag életkor 23,48±2,14), egy hónappal később 153 fő töltötte ki a következő kérdőíveket: Feltételes Önbecsülés Kérdőív (CSES-H), Rosenberg-féle Önbecsülés Skála (RSES), Önegyüttérzés Skála (SCS-H), Spielberger-féle Vonásszorongás Skála (STAI-T), Beck Depresszió Kérdőív (BDI), Diszpozicionális Optimizmus Kérdőív (LOT-R).

A 2. mintában rendszeresen táncoló 162 fő, 52 férfi és 110 nő (átlag életkor 28,5±8,59) és 208 aerobikozó nő (átlag életkor 28,4 ±8,46) töltötte ki a következő kérdőíveket: CSES-H, RSES, WHO Jóllét Kérdőív rövidített változat (WHO-5), Rövidített Pozitív és Negatív Affektivitás Skála (PANAS).

Eredmények

A Feltételes Önbecsülés Skála és két skálája jó reliabilitás értékeket (0,72 és 0,91 között) és teszt-reteszt reliabilitást (0,74–0,79), a megerősítő faktorelemzés pedig elfogadható mértékű illeszkedést mutatott. A feltételes önbecsülés a globális önbecsüléssel, az önegyüttérzéssel, a diszpozicionális optimizmussal, a jólléttel és a pozitív affektivitással negatívan, míg a vonásszorongással, a depresszióval és a negatív affektivitással pozitívan korrelált.

Következtetések

A Feltételes Önbecsülés Skála magyar változatának pszichometriai jellemzői megfelelőek.
A fonológiai tudatosság fejlődése és szövegértéssel való kapcsolata az általános iskola első négy évfolyamán a szocioökonómiai státusz tükrében
Authors: Török Tímea , Hódi Ágnes
Published: January 2016

Az elmúlt évtizedekben számos külföldi kutatás mutatott rá a fonológiai tudatosság olvasásban betöltött kiemelt szerepére. A vizsgálatok többsége az olvasási teljesítményt a szóolvasással, dekódolással jellemezte, kevesebb figyelem irányult e metanyelvi készség szövegértésben betöltött szerepére. Azon kevés angol nyelvterületen végzett empirikus vizsgálat, amely a fonológiai tudatosság szövegértésben betöltött szerepét tárta fel, hosszabb időn keresztül fennálló együttjárást mutatott a két változó között. Jól ismert tény, hogy a magyar diákok szövegértési teljesítményének egyik befolyásoló tényezője a család szocioökonómiai státusza (SES). A legtöbb nemzetközi vizsgálati eredmény szerint a SES meghatározó szerepet tölt be a fonológiai tudatosság alakulásában is, de hazai kontextusban még nem vizsgálták e kapcsolatrendszert. Jelen tanulmány célja a fonológiai tudatosság fejlődésének és szövegértéssel való kapcsolatának vizsgálata a SES tükrében az általános iskola első négy évfolyamán.

A vizsgálatban egy általános iskola alsó tagozatos tanulói vettek részt (N=205). A tanulók egy online fonológiai tudatosságot, egy szövegértést mérő tesztet és egy papír-ceruza alapú háttérkérdőívet töltöttek ki.

A fonológiai tudatosság fejlettségi szintjében szignifikáns változás második és harmadik évfolyam között történt. A teljesítmény a negyedik évfolyamon sem érte el a maximumot. Adataink szerint a SES mind a fonológiai tudatossággal, mind a szövegértéssel szignifikáns kapcsolatot mutatott. A három változó közötti kapcsolatrendszert feltáró modell szerint a SES meghatározza a fonológiai tudatosság és a szövegértés alakulását egyaránt, és e két kognitív változó között kölcsönös kapcsolat áll fenn.

Tanulmányunk felhívja a figyelmet a fonológiai tudatosság fejlesztésének fontosságára az olvasástanulás időszakában, valamint az otthoni környezetből fakadó hátrányok időben történő kompenzálására, megteremtve ezzel a tanulók szövegértési teljesítménye javulásának és sikeresebb iskolai pályafutásának lehetőségét.
A képességalapú érzelmi intelligencia: új paradigmák a tesztfejlesztésben és pontozásban. Hazai tapasztalatok az érzelemmegértés és érzelemszabályozás szituációs tesztekkel
Authors: Nagy Henriett , Magyaródi Tímea , Séllei Beatrix
Published: January 2016

Jelen tanulmány két, a MSCEIT (Mayer–Salovey–Caruso Érzelmi Intelligencia Teszt) alternatívájaként megjelenő érzelmi intelligencia (EI) tesztre: az Érzelemmegértés (STEU) és az Érzelemszabályozás (STEM) szituációs tesztekre fókuszál. A STEU azért újszerű megközelítés az EI-mérés területén, mert bevezeti a sztenderdekre épülő pontozás lehetőségét, a STEM pedig azért, mert az SJT (situational judgement test method) megközelítést alkalmazza. Jelen kutatás célja a STEU- és STEM-tesztek magyar változatainak elkészítése, valamint a tesztek megbízhatóságával és validitásával kapcsolatos bizonyítékok bővítése. A tesztek érvényességének vizsgálata során a STEU- és STEM-pontszámok fluid intelligenciával, vonás EI-vel, érzelemfelismerő képességgel, személyiséggel, valamint az alexithymiával és az élettel való elégedettséggel mutatott együttjárásait elemeztük. Konklúzióként megállapíthatjuk, hogy ezek az új tesztfejlesztési, illetve pontozási megközelítések hasznosak és ígéretesek a képességalapú EI-mérés területén, ugyanakkor további vizsgálatok szükségesek, ha igazolni szeretnénk, hogy a STEUés a STEM-tesztek inkább mérnek érzelmi intelligenciát, mint más kognitív képességet, illetve, hogy az EI-feladatok együttesen különálló faktort alkotnak, amely megkülönböztethető más kognitív képességektől.