bluuebunny/crossref_metadata_2025 huggingface dataset:
Heat shock factor binding in Alu repeats expands its involvement in stress through an antisense mechanism
Authors: Pandey Rajesh , Mandal Amit K , Jha Vineet , Mukerji Mitali
Published: November 2011

Background

Alu RNAs are present at elevated levels in stress conditions and, consequently, Alu repeats are increasingly being associated with the physiological stress response. Alu repeats are known to harbor transcription factor binding sites that modulate RNA pol II transcription and Alu RNAs act as transcriptional co-repressors through pol II binding in the promoter regions of heat shock responsive genes. An observation of a putative heat shock factor (HSF) binding site in Alu led us to explore whether, through HSF binding, these elements could further contribute to the heat shock response repertoire.

Results

Alu density was significantly enriched in transcripts that are down-regulated following heat shock recovery in HeLa cells. ChIP analysis confirmed HSF binding to a consensus motif exhibiting positional conservation across various Alu subfamilies, and reporter constructs demonstrated a sequence-specific two-fold induction of these sites in response to heat shock. These motifs were over-represented in the genic regions of down-regulated transcripts in antisense oriented Alus. Affymetrix Exon arrays detected antisense signals in a significant fraction of the down-regulated transcripts, 50% of which harbored HSF sites within 5 kb. siRNA knockdown of the selected antisense transcripts led to the over-expression, following heat shock, of their corresponding down-regulated transcripts. The antisense transcripts were significantly enriched in processes related to RNA pol III transcription and the TFIIIC complex.

Conclusions

We demonstrate a non-random presence of Alu repeats harboring HSF sites in heat shock responsive transcripts. This presence underlies an antisense-mediated mechanism that represents a novel component of Alu and HSF involvement in the heat shock response.
Salt-Inducible Kinase Is Involved in the Regulation of Corticotropin-Releasing Hormone Transcription in Hypothalamic Neurons in Rats
Authors: Liu Ying , Poon Victoria , Sanchez-Watts Graciela , Watts Alan G. , Takemori Hiroshi , Aguilera Greti
Published: November 2011

Activation of CRH transcription requires phosphorylation of cAMP response element-binding protein (CREB) and translocation of the CREB coactivator, transducer of regulated CREB activity (TORC) from cytoplasm to nucleus. In basal conditions, transcription is low because TORC remains in the cytoplasm, inactivated by phosphorylation through Ser/Thr protein kinases of the AMP-dependent protein kinases (AMPK) family, including salt-inducible kinase (SIK). To determine which kinase is responsible for TORC phosphorylation in CRH neurons, we measured SIK1 and SIK2 mRNA in the hypothalamic paraventricular nucleus of rats by in situ hybridization. In basal conditions, low mRNA levels of the two kinases were found in the dorsomedial paraventricular nucleus, consistent with location in CRH neurons. One hour of restraint stress increased SIK1 mRNA levels, whereas SIK2 mRNA showed only minor increases. In 4B hypothalamic neurons, or primary cultures, SIK1 mRNA (but not SIK2 mRNA) was inducible by the cAMP stimulator, forskolin. Overexpression of either SIK1 or SIK2 in 4B cells reduced nuclear TORC2 levels (Western blot) and inhibited forskolin-stimulated CRH transcription (luciferase assay). Conversely, the nonselective SIK inhibitor, staurosporine, increased nuclear TORC2 content and stimulated CRH transcription in 4Bcells and primary neuronal cultures (heteronuclear RNA). Unexpectedly, in 4B cells specific short hairpin RNA knockdown of endogenous SIK2 but not SIK1 induced nuclear translocation of TORC2 and CRH transcription, suggesting that SIK2 mediates TORC inactivation in basal conditions, whereas induction of SIK1 limits transcriptional activation. The study provides evidence that SIK represses CRH transcription by inactivating TORC, providing a potential mechanism for rapid on/off control of CRH transcription.
Ubiquitin-Proteasomal Degradation of COX-2 in TGF-β Stimulated Human Endometrial Cells Is Mediated Through Endoplasmic Reticulum Mannosidase I
Authors: Singh Mohan , Chaudhry Parvesh , Parent Sophie , Asselin Eric
Published: November 2011

Cyclooxygenase (COX)-2 is a key regulatory enzyme in the production of prostaglandins (PG) during various physiological processes. Mechanisms of COX-2 regulation in human endometrial stromal cells (human endometrial stromal cells) are not fully understood. In this study, we investigate the role of TGF-β in the regulation of COX-2 in human uterine stromal cells. Each TGF-β isoform decreases COX-2 protein level in human uterine stromal cells in Smad2/3-dependent manner. The decrease in COX-2 is accompanied by a decrease in PG synthesis. Knockdown of Smad4 using specific small interfering RNA prevents the decrease in COX-2 protein, confirming that Smad pathway is implicated in the regulation of COX-2 expression in human endometrial stromal cells. Pretreatment with 26S proteasome inhibitor, MG132, significantly restores COX-2 protein and PG synthesis, indicating that COX-2 undergoes proteasomal degradation in the presence of TGF-β. In addition, each TGF-β isoform up-regulates endoplasmic reticulum (ER)-mannosidase I (ERManI) implying that COX-2 degradation is mediated through ER-associated degradation pathway in these cells. Furthermore, inhibition of ERManI activity using the mannosidase inhibitor (kifunensine), or small interfering RNA-mediated knockdown of ERManI, prevents TGF-β-induced COX-2 degradation. Taken together, these studies suggest that TGF-β promotes COX-2 degradation in a Smad-dependent manner by up-regulating the expression of ERManI and thereby enhancing ER-associated degradation and proteasomal degradation pathways.
PPARγ Agonist Improves Neuronal Insulin Receptor Function in Hippocampus and Brain Mitochondria Function in Rats with Insulin Resistance Induced by Long Term High-Fat Diets
Authors: Pipatpiboon Noppamas , Pratchayasakul Wasana , Chattipakorn Nipon , Chattipakorn Siriporn C.
Published: November 2011

We previously demonstrated that a high-fat diet (HFD) consumption can cause not only peripheral insulin resistance, but also neuronal insulin resistance. Moreover, the consumption of an HFD has been shown to cause mitochondrial dysfunction in both the skeletal muscle and liver. Rosiglitazone, a peroxizome proliferator-activated receptor-γ ligand, is a drug used to treat type 2 diabetes mellitus. Recent studies suggested that rosiglitazone can improve learning and memory in both human and animal models. However, the effects of rosiglitazone on neuronal insulin resistance and brain mitochondria after the HFD consumption have not yet been investigated. Therefore, we tested the hypothesis that rosiglitazone improves neuronal insulin resistance caused by a HFD via attenuating the dysfunction of neuronal insulin receptors and brain mitochondria. Rosiglitazone (5 mg/kg · d) was given for 14 d to rats that were fed with either a HFD or normal diet for 12 wk. After the 14th week, all animals were euthanized, and their brains were removed and examined for insulin-induced long-term depression, neuronal insulin signaling, and brain mitochondrial function. We found that rosiglitazone significantly improved peripheral insulin resistance and insulin-induced long-term depression and increased neuronal Akt/PKB-ser phosphorylation in response to insulin. Furthermore, rosiglitazone prevented brain mitochondrial conformational changes and attenuated brain mitochondrial swelling, brain mitochondrial membrane potential changes, and brain mitochondrial ROS production. Our data suggest that neuronal insulin resistance and the impairment of brain mitochondria caused by a 12-wk HFD consumption can be reversed by rosiglitazone.
Homologous and Heterologous in Vitro Regulation of Pituitary Receptors for Somatostatin, Growth Hormone (GH)-Releasing Hormone, and Ghrelin in a Nonhuman Primate (Papio anubis)
Authors: Córdoba-Chacón Jose , Gahete Manuel D. , Castaño Justo P. , Kineman Rhonda D. , Luque Raul M.
Published: November 2011

Secretion of GH by pituitary somatotrophs is primarily stimulated by GHRH and ghrelin and inhibited by somatostatin through the activation of specific receptors [GHRH receptor (GHRH-R), GH secretagogue receptor (GHS-R) and somatostatin receptors (sst1–5), respectively]. However, we have shown that somatostatin, at low doses, can also stimulate GH release, directly and specifically, in primary pituitary cultures from a nonhuman primate (baboons, Papio anubis) and pigs. To determine whether somatostatin, GHRH, and ghrelin can also regulate the expression of their receptors in primates, pituitary cultures from baboons were treated for 4 h with GHRH or ghrelin (10−8m) or with high (10−7m) and low (10−15m) doses of somatostatin, and GH release and expression levels of all receptors were measured. GHRH/ghrelin decreased the expression of their respective receptors (GHRH-R and GHS-R). Both peptides increased sst1, only GHRH decreased sst5 expression, whereas sst2 expression remained unchanged. The effects of GHRH/ghrelin were completely mimicked by forskolin (adenylate cyclase activator) and phorbol 12-myristate 13-acetate (protein kinase C activator), respectively, indicating the regulation of receptor subtype levels by GHRH and ghrelin involved distinct signaling pathways. In contrast, high-dose somatostatin did not alter GH release but increased sst1, sst2, and sst5 expression, whereas GHRH-R and GHS-R expression were unaffected. Interestingly, low-dose somatostatin increased GH release and sst1 mRNA but decreased sst5 and GHRH-R expression, similar to that observed for GHRH. Altogether, our data show for the first time in a primate model that the primary regulators of somatotroph function (GHRH/ghrelin/somatostatin) exert both homologous and heterologous regulation of receptor synthesis which is dose and subtype dependent and involves distinct signaling pathways.
Ablation of 3-Phosphoinositide-Dependent Protein Kinase 1 (PDK1) in Vascular Endothelial Cells Enhances Insulin Sensitivity by Reducing Visceral Fat and Suppressing Angiogenesis
Authors: Tawaramoto Kazuhito , Kotani Ko , Hashiramoto Mitsuru , Kanda Yukiko , Nagare Tomoki , Sakaue Hiroshi , Ogawa Wataru , Emoto Noriaki , Yanagisawa Masashi , Noda Tetsuo , Kasuga Masato , Kaku Kohei
Published: November 2011

The phosphatidylinositol 3-kinase signaling pathway in vascular endothelial cells is important for systemic angiogenesis and glucose metabolism. In this study, we addressed the precise role of the 3-phosphoinositide-dependent protein kinase 1 (PDK1)-regulated signaling network in endothelial cells in vivo, using vascular endothelial PDK1 knockout (VEPDK1KO) mice. Surprisingly, VEPDK1KO mice manifested enhanced glucose tolerance and whole-body insulin sensitivity due to suppression of their hepatic glucose production with no change in either peripheral glucose disposal or even impaired vascular endothelial function at 6 months of age. When mice were fed a standard diet at 6 months of age and a high-fat diet at 3 months of age, hypertrophy of epididymal adipose tissues was inhibited, adiponectin mRNA was significantly increased, and mRNA of MCP1, leptin, and TNFα was decreased in the white adipose tissue of VEPDK1KO mice in comparison with controls. Consequently, both the circulating adiponectin levels and the activity of hepatic AMP-activated protein kinase were significantly increased, subsequently enhancing whole-body insulin sensitivity and energy expenditure with increased hepatic fatty acid oxidation in VEPDK1KO mice. These results provide the first in vivo evidence that lowered angiogenesis through the deletion of PDK1 signaling not only interferes with the growth of adipose tissue but also induces increased energy expenditure due to amelioration of the adipocytokine profile. This demonstrates an unexpected role of PDK1 signaling in endothelial cells on the maintenance of proper glucose homeostasis through the regulation of adipocyte development.
Studying synthetic lethal interactions in the zebrafish system: insight into disease genes and mechanisms
Authors: Hajeri Vinita A. , Amatruda James F.
Published: November 2011

The post-genomic era is marked by a pressing need to functionally characterize genes through understanding gene-gene interactions, as well as interactions between biological pathways. Exploiting a phenomenon known as synthetic lethality, in which simultaneous loss of two interacting genes leads to loss of viability, aids in the investigation of these interactions. Although synthetic lethal screening is a powerful technique that has been used with great success in many model organisms, including Saccharomyces cerevisiae, Drosophila melanogaster and Caenorhabditis elegans, this approach has not yet been applied in the zebrafish, Danio rerio. Recently, the zebrafish has emerged as a valuable system to model many human disease conditions; thus, the ability to conduct synthetic lethal screening using zebrafish should help to uncover many unknown disease-gene interactions. In this article, we discuss the concept of synthetic lethality and provide examples of its use in other model systems. We further discuss experimental approaches by which the concept of synthetic lethality can be applied to the zebrafish to understand the functions of specific genes.
The role of vision in odor-plume tracking by walking and flying insects
Authors: Willis Mark A. , Avondet Jennifer L. , Zheng Elizabeth
Published: November 2011

The walking paths of male cockroaches, Periplaneta americana, tracking point-source plumes of female pheromone often appear similar in structure to those observed from flying male moths. Flying moths use visual-flow-field feedback of their movements to control steering and speed over the ground and to detect the wind speed and direction while tracking plumes of odors. Walking insects are also known to use flow field cues to steer their trajectories. Can the upwind steering we observe in plume-tracking walking male cockroaches be explained by visual-flow-field feedback, as in flying moths? To answer this question, we experimentally occluded the compound eyes and ocelli of virgin P. americana males, separately and in combination, and challenged them with different wind and odor environments in our laboratory wind tunnel. They were observed responding to: (1) still air and no odor, (2) wind and no odor, (3) a wind-borne point-source pheromone plume and (4) a wide pheromone plume in wind. If walking cockroaches require visual cues to control their steering with respect to their environment, we would expect their tracks to be less directed and more variable if they cannot see. Instead, we found few statistically significant differences among behaviors exhibited by intact control cockroaches or those with their eyes occluded, under any of our environmental conditions. Working towards our goal of a comprehensive understanding of chemo-orientation in insects, we then challenged flying and walking male moths to track pheromone plumes with and without visual feedback. Neither walking nor flying moths performed as well as walking cockroaches when there was no visual information available.
Damping in flapping flight and its implications for manoeuvring, scaling and evolution
Authors: Hedrick Tyson L.
Published: November 2011

Flying animals exhibit remarkable degrees of both stability and manoeuvrability. Our understanding of these capabilities has recently been improved by the identification of a source of passive damping specific to flapping flight. Examining how this damping effect scales among different species and how it affects active manoeuvres as well as recovery from perturbations provides general insights into the flight of insects, birds and bats. These new damping models offer a means to predict manoeuvrability and stability for a wide variety of flying animals using prior reports of the morphology and flapping motions of these species. Furthermore, the presence of passive damping is likely to have facilitated the evolution of powered flight in animals by providing a stability benefit associated with flapping.
Potentially adaptive effects of maternal nutrition during gestation on offspring phenotype of a viviparous reptile
Authors: Cadby Chloé D. , Jones Susan M. , Wapstra Erik
Published: November 2011

Viviparous reptiles have been used as model species for many studies that seek to explain the evolution of viviparity. The vast majority of such studies have focused on the advantage viviparity provides with regards to maternal control of embryonic developmental temperature. However, viviparity may also allow increased control of nutrient transfer, such that mothers adaptively manipulate offspring phenotype through varying maternal nutritional support. Because maternal nutritional transfer is temperature dependent, maternal nutritional strategies may vary between climatically distinct populations. In this study we used an orthogonal experimental design in which mothers and offspring from climatically distinct populations of a viviparous skink (Niveoscincus ocellatus) were allocated randomly to either a protein-rich or a protein-poor diet. Our results suggest that N. ocellatus mothers are able to compensate for sub-optimal nutritional conditions and can adaptively manipulate offspring phenotype to best fit the postnatal nutritional environment. Furthermore, maternal nutritional strategies appear to vary between climatically distinct populations. These results suggest that in viviparous reptiles, matrotrophy provides a means of producing an adaptive offspring phenotype, in addition to maternal control of developmental temperature.
Negative correlation between milk production and brown adipose tissue gene expression in lactating mice
Authors: Król Elzbieta , Martin Samuel A. M. , Huhtaniemi Ilpo T. , Douglas Alex , Speakman John R.
Published: November 2011

It has been proposed that the performance of lactating animals is limited by the capacity of the female to dissipate body heat – the heat dissipation limit (HDL) theory. This theory predicts that milk production might be constrained not by intrinsic properties of the mammary glands but rather by competitive heat production such as thermogenesis in brown adipose tissue (BAT). To test this prediction, we measured the expression of genes linked to thermogenesis in BAT of lactating laboratory mice. The applicability of BAT gene expression to reflect thermogenic activity of BAT was confirmed by a positive relationship between expression levels of several BAT genes (summarised by the first principal component following principal component analysis) and daily energy expenditure in virgin mice. Milk production at peak lactation was strongly and negatively associated with the expression of thermogenic genes in BAT. Downregulation of these genes during lactation was correlated with low levels of circulating leptin and high levels of circulating prolactin. Our results are consistent with the HDL theory. However, we cannot discount the converse interpretation that milk production may reduce BAT activity. If the reduction in BAT activity does facilitate increased milk production, then reducing the heat generated by competitive processes may be a more productive route to increase lactational performance than attempts to improve mammary gland performance in isolation from the other body systems.
Cyclization reaction of amines with dialkyl carbonates to yield 1,3-oxazinan-2-ones
Authors: McElroy C. Robert , Aricò Fabio , Benetollo Franco , Tundo Pietro
Published: November 2011

A number of six-membered cyclic carbamates (oxazinanones) were synthesized from the reaction of a primary amine or hydrazine with a dicarbonate derivative of 1,3-diols in a one-pot reaction, in good yield, short time span, and in the absence of a solvent. The reaction proceeds in two steps: an intermolecular reaction to give a linear intermediate and an intramolecular cyclization to yield the cyclic carbamate. This is the first example of a carbonate reacting selectively and sequentially, firstly at the carbonyl center to form a linear carbamate and then as a leaving group to yield a cyclic carbamate.
Reactive cysteine in the active-site motif of Bacteroides thetaiotaomicron dipeptidyl peptidase III is a regulatory residue for enzyme activity
Authors: Vukelić Bojana , Salopek-Sondi Branka , Špoljarić Jasminka , Sabljić Igor , Meštrović Nevenka , Agić Dejan , Abramić Marija
Published: November 2011

Dipeptidyl peptidase III (DPP III), a member of the metallopeptidase family M49, was considered as an exclusively eukaryotic enzyme involved in intracellular peptide cata­bolism and pain modulation. In 2003, new data on genome sequences revealed the first prokaryotic orthologs, which showed low sequence similarity to eukaryotic ones and a cysteine (Cys) residue in the zinc-binding motif HEXXGH. Here we report the cloning and heterologous expression of DPP III from the human gut symbiontBacteroides thetaiotaomicron. The catalytic efficiency of bacterial DPP III for preferred synthetic substrate hydrolysis was very similar to that of the human host enzyme. Substitution of Cys450from the active-site motif by serine did not substantially change the enzymatic activity. However, this residue was wholly responsible for the inactivation effect of sulfhydryl reagents. Molecular modeling indicated seven basic amino acid residues in the local environment of Cys450as a possible cause for its high reactivity. Sequence analysis of 81 bacterial M49 peptidases showed conservation of the HECLGH motif in 68 primary structures with the majority of proteins lacking an active-site Cys originated from aerobic bacteria. Data obtained suggest that Cys450ofB. thetaiotaomicronDPP III is a regulatory residue for the enzyme activity.
Proteome analysis of protein partners to nucleosomes containing canonical H2A or the variant histones H2A.Z or H2A.X
Authors: Fujimoto Satoru , Seebart Corrine , Guastafierro Tiziana , Prenni Jessica , Caiafa Paola , Zlatanova Jordanka
Published: November 2011

Although the existence of histone variants has been known for quite some time, only recently are we grasping the breadth and diversity of the cellular processes in which they are involved. Of particular interest are the two variants of histone H2A, H2A.Z and H2A.X because of their roles in regulation of gene expression and in DNA double-strand break repair, respectively. We hypothesize that nucleosomes containing these variants may perform their distinct functions by interacting with different sets of proteins. Here, we present our proteome analysis aimed at identifying protein partners that interact with nucleosomes containing H2A.Z, H2A.X or their canonical H2A counterpart. Our development of a nucleosome-pull down assay and analysis of the recovered nucleosome-interacting proteins by mass spectrometry allowed us to directly compare nuclear partners of these variant-containing nucleosomes to those containing canonical H2A. To our knowledge, our data represent the first systematic analysis of the H2A.Z and H2A.X interactome in the context of nucleosome structure.
Increased Functional Selectivity over Development in Rostrolateral Prefrontal Cortex
Authors: Wendelken Carter , O'Hare Elizabeth D. , Whitaker Kirstie J. , Ferrer Emilio , Bunge Silvia A.
Published: November 2011

Relational reasoning, or the ability to identify and consider relationships between multiple mental representations, is a fundamental component of high-level cognition (Robin and Holyoak, 1995). The capacity to reason with relations enables abstract thought and may be at the core of what makes human cognition unique (Penn et al., 2008). This capacity improves throughout childhood and adolescence (Ferrer et al., 2009). Here, we sought to better understand the neural mechanisms that support its emergence. We have hypothesized previously, based on fMRI research in adults, that (1) inferior parietal lobe (IPL) plays a central role in representing relationships between mental representations (first-order relations) and (2) rostrolateral prefrontal cortex (RLPFC) integrates inputs from IPL to build second-order relational structures (i.e., relations between relations). In the present study, we examined fMRI and cortical thickness data from 85 children and adolescents (ages 6–18 years). Participants performed a relational matching task in which they viewed arrays of four visual stimuli and determined whether two stimuli shared a particular feature (a first-order relational judgment) or whether two pairs of stimuli matched according to the same feature (a second-order relational judgment). fMRI results provide evidence for increased functional selectivity across ages 6–18 years in RLPFC and IPL. Specifically, young children engaged RLPFC and IPL indiscriminately for first-order and second-order relational judgments, and activation for first-order relations diminished with age whereas activation for second-order relations stayed elevated. Examination of cortical thickness revealed that increased functional selectivity in RLPFC could be partly accounted for by cortical thinning in IPL.
Effect of Auditory Cortex Deactivation on Stimulus-Specific Adaptation in the Medial Geniculate Body
Authors: Antunes Flora M. , Malmierca Manuel S.
Published: November 2011

An animal's survival may depend on detecting new events or objects in its environment, and it is likely that the brain has evolved specific mechanisms to detect such changes. In sensory systems, neurons often exhibit stimulus-specific adaptation (SSA) whereby they adapt to frequently occurring stimuli, but resume firing when “surprised” by rare or new ones. In the auditory system, SSA has been identified in the midbrain, thalamus, and auditory cortex (AC). It has been proposed that the SSA observed subcortically originates in the AC as a higher-order property that is transmitted to the subcortical nuclei via corticofugal pathways. Here we report that SSA in the auditory thalamus of the rat remains intact when the AC is deactivated by cooling, thus demonstrating that the AC is not necessary for the generation of SSA in the thalamus. The AC does, however, modulate the responses of thalamic neurons in a way that strongly indicates a gain modulation mechanism. The changes imposed by the AC in thalamic neurons depend on the level of SSA that they exhibit.
Iterative Bayesian Estimation as an Explanation for Range and Regression Effects: A Study on Human Path Integration
Authors: Petzschner Frederike H. , Glasauer Stefan
Published: November 2011

Systematic errors in human path integration were previously associated with processing deficits in the integration of space and time. In the present work, we hypothesized that these errors are de facto the result of a system that aims to optimize its performance by incorporating knowledge about prior experience into the current estimate of displacement. We tested human linear and angular displacement estimation behavior in a production–reproduction task under three different prior experience conditions where samples were drawn from different overlapping sample distributions. We found that (1) behavior was biased toward the center of the underlying sample distribution, (2) the amount of bias increased with increasing sample range, and (3) the standard deviation for all conditions was linearly dependent on the mean reproduced displacements. We propose a model of Bayesian estimation on logarithmic scales that explains the observed behavior by optimal fusion of an experience-dependent prior expectation with the current noisy displacement measurement. The iterative update of prior experience is modeled by the formulation of a discrete Kalman filter. The model provides a direct link between Weber–Fechner and Stevens' power law, providing a mechanistic explanation for universal psychophysical effects in human magnitude estimation such as the regression to the mean and the range effect.
Binocular Eye Movements Evoked by Self-Induced Motion Parallax
Authors: Frey Jared , Ringach Dario L.
Published: November 2011

Perception often triggers actions, but actions may sometimes be necessary to evoke percepts. This is most evident in the recovery of depth by self-induced motion parallax. Here we show that depth information derived from one's movement through a stationary environment evokes binocular eye movements consistent with the perception of three-dimensional shape. Human subjects stood in front of a display and viewed a simulated random-dot sphere presented monocularly or binocularly. Eye movements were recorded by a head-mounted eye tracker, while head movements were monitored by a motion capture system. The display was continuously updated to simulate the perspective projection of a stationary, transparent random dot sphere viewed from the subject's vantage point. Observers were asked to keep their gaze on a red target dot on the surface of the sphere as they moved relative to the display. The movement of the target dot simulated jumps in depth between the front and back surfaces of the sphere along the line of sight. We found the subjects' eyes converged and diverged concomitantly with changes in the perceived depth of the target. Surprisingly, even under binocular viewing conditions, when binocular disparity signals conflict with depth information from motion parallax, transient vergence responses were observed. These results provide the first demonstration that self-induced motion parallax is sufficient to drive vergence eye movements under both monocular and binocular viewing conditions.
β-Pix Modulates Actin-Mediated Recruitment of Synaptic Vesicles to Synapses
Authors: Sun Yu , Bamji Shernaz X.
Published: November 2011

Presynaptic compartments are formed through the recruitment of preassembled clusters of proteins to points of cell—cell contact, however, the molecular mechanism(s) underlying this process remains unclear. We demonstrate that clusters of polymerized actin can recruit and maintain synaptic vesicles to discrete sites along the axon, and that cadherin/β-catenin/scribble/β-pix complexes play an important role in this event. Previous work has demonstrated that β-catenin and scribble are important for the clustering of vesicles at synapses. We demonstrate that β-pix, a Rac/Cdc42 guanine nucleotide exchange factor (GEF), forms a complex with cadherin, β-catenin, and scribble at synapses and enhances localized actin polymerization in rat hippocampal neurons. In cells expressing β-pix siRNA or dominant-negative β-pix that lacks its GEF activity, actin polymerization at synapses is dramatically reduced, and synaptic vesicle localization is disrupted. This β-pix phenotype can be rescued by cortactin overexpression, suggesting that β-pix-mediated actin polymerization at synapses regulates vesicle localization.
Developmental Switching of Perisomatic Innervation from Climbing Fibers to Basket Cell Fibers in Cerebellar Purkinje Cells
Authors: Ichikawa Ryoichi , Yamasaki Miwako , Miyazaki Taisuke , Konno Kohtarou , Hashimoto Kouichi , Tatsumi Haruyuki , Inoue Yoshiro , Kano Masanobu , Watanabe Masahiko
Published: November 2011

In early postnatal development, perisomatic innervation of cerebellar Purkinje cells (PCs) switches from glutamatergic climbing fibers (CFs) to GABAergic basket cell fibers (BFs). Here we examined the switching process in C57BL/6 mice. At postnatal day 7 (P7), most perisomatic synapses were formed by CFs on to somatic spines. The density of CF–spine synapses peaked at P9, when pericellular nest around PCs by CFs was most developed, and CF–spine synapses constituted 88% of the total perisomatic synapses. Thereafter, CF–spine synapses dropped to 63% at P12, 6% at P15, and <1% at P20, whereas BF synapses increased reciprocally. During the switching period, a substantial number of BF synapses existed as BF–spine synapses (37% of the total perisomatic synapses at P15), and free spines surrounded by BFs or Bergmann glia also emerged. By P20, BF–spine synapses and free spines virtually disappeared, and BF–soma synapses became predominant (88%), thus attaining the adult pattern of perisomatic innervation. Parallel with the presynaptic switching, postsynaptic receptor phenotype also switched from glutamatergic to GABAergic. In the active switching period, particularly at P12, fragmental clusters of AMPA-type glutamate receptor were juxtaposed with those of GABAAreceptor. When examined with serial ultrathin sections, immunogold labeling for glutamate and GABAAreceptors was often clustered beneath single BF terminals. These results suggest that a considerable fraction of somatic spines is succeeded from CFs to BFs and Bergmann glia in the early postnatal period, and that the switching of postsynaptic receptor phenotypes mainly proceeds under the coverage of BF terminals.
Dynamic Processing in the Human Language System: Synergy between the Arcuate Fascicle and Extreme Capsule
Authors: Rolheiser Tyler , Stamatakis Emmanuel A. , Tyler Lorraine K.
Published: November 2011

The production and comprehension of human language is thought to involve a network of frontal, parietal, and temporal cortical loci interconnected by two dominant white matter pathways. These two white matter bundles, often referred to as the dorsal and ventral processing tracts, are hypothesized to have markedly different language functions. The dorsal tract is thought to process phonological processing, while the ventral tract is considered to abet semantics. This proposed functional differentiation of tracts is similar to the ventral and dorsal dichotomy proposed for the visual and auditory systems. The present study evaluated this characterization of the language system in the context of various components involved in its function. Twenty-four chronic stroke patients completed a battery of 10 language tests designed to measure performance on the comprehension and production of phonology, morphology, semantics, and syntax. The patients also completed diffusion MRI scanning. Lesions were confined to the left hemisphere, but the size and location of the insult varied so that patients had damage to a single tract, both tracts, or neither tract. Individual FA maps were generated, and focal areas of hypointensity served as markers of white matter damage. Whole-brain voxel-by-voxel correlations revealed that only phonological and semantic tasks fit into the dual-stream model, while syntax and morphology involved both pathways. ROI analyses of the arcuate fascicle and extreme capsule supported this finding. These data suggest that natural language function is more likely to reflect a synergistic system rather than a segregated dual-stream system.
Gain Field Encoding of the Kinematics of Both Arms in the Internal Model Enables Flexible Bimanual Action
Authors: Yokoi Atsushi , Hirashima Masaya , Nozaki Daichi
Published: November 2011

Bimanual action requires the neural controller (internal model) for each arm to predictively compensate for mechanical interactions resulting from movement of both that arm and its counterpart on the opposite side of the body. Here, we demonstrate that the brain may accomplish this by constructing the internal model with primitives multiplicatively encoding information from the kinematics of both arms. We had human participants adapt to a novel force field imposed on one arm while both arms were moving in particular directions and examined the generalization pattern of motor learning when changing the movement directions of both arms. The generalization pattern was consistent with the pattern predicted from the multiplicative encoding scheme. As proposed by previous theoretical studies, the strength of multiplicative encoding was manifested in the observation that participants could adapt reaching movements to complicated force fields depending nonlinearly on the movement directions of both arms. These results indicate that multiplicative neuronal influence of the kinematics of the opposing arm on the internal models enables the brain to control bimanual movement by providing great flexible ability to handle arbitrary dynamical environments resulting from the interactions of both arms.
Preventing the Stress-Induced Shift from Goal-Directed to Habit Action with a β-Adrenergic Antagonist
Authors: Schwabe Lars , Höffken Oliver , Tegenthoff Martin , Wolf Oliver T.
Published: November 2011

Stress modulates instrumental action in favor of habit processes that encode the association between a response and preceding stimuli and at the expense of goal-directed processes that learn the association between an action and the motivational value of the outcome. Here, we asked whether this stress-induced shift from goal-directed to habit action is dependent on noradrenergic activation and may therefore be blocked by a β-adrenoceptor antagonist. To this end, healthy men and women were administered a placebo or the β-adrenoceptor antagonist propranolol before they underwent a stress or a control procedure. Shortly after the stress or control procedure, participants were trained in two instrumental actions that led to two distinct food outcomes. After training, one of the food outcomes was selectively devalued by feeding participants to satiety with that food. A subsequent extinction test indicated whether instrumental behavior was goal-directed or habitual. As expected, stress after placebo rendered participants' behavior insensitive to the change in the value of the outcome and thus habitual. After propranolol intake, however, stressed participants behaved, same as controls, goal-directed, suggesting that propranolol blocked the stress-induced bias toward habit behavior. Our findings show that the shift from goal-directed to habitual control of instrumental action under stress necessitates noradrenergic activation and could have important clinical implications, particularly for addictive disorders.
Scene Identification and Emotional Response: Which Spatial Frequencies Are Critical?
Authors: De Cesarei Andrea , Codispoti Maurizio
Published: November 2011

Emotional responses are regulated by basic motivational systems (appetitive and defensive), which allow for adaptive behavior when opportunities and threats are detected. It has been suggested that specific ranges of spatial frequencies of the visual input may contain information that is diagnostic for discriminating emotionally relevant from less relevant contents, and that specialized neural modules may analyze these spatial frequencies to allow efficient detection and response to life-threatening or life-sustaining stimuli. However, there is no evidence supporting this possibility regarding natural scenes, which are highly varied in terms of pictorial composition. The present study examines how low and high spatial frequency filtering affects the understanding of natural scene contents and modulates the amplitude of the late positive potential (LPP), a well-known component of the event-related potentials that reflects motivational significance. The content of an initially degraded (low- or high-passed) picture was progressively revealed in a sequence of steps by adding high or low spatial frequencies. At each step, human participants reported whether they identified the gist of the image. The results showed that the affective modulation of the LPP varied with picture identification similarly for low-passed and high-passed pictures. The engagement of corticolimbic appetitive and defensive systems, reflected in the LPP affective modulation, varied with picture identification, and did not critically or preferentially depend on either low or high spatial frequencies.
Selective Neural Pathway Targeting Reveals Key Roles of Thalamostriatal Projection in the Control of Visual Discrimination
Authors: Kato Shigeki , Kuramochi Masahito , Kobayashi Kenta , Fukabori Ryoji , Okada Kana , Uchigashima Motokazu , Watanabe Masahiko , Tsutsui Yuji , Kobayashi Kazuto
Published: November 2011

The dorsal striatum receives converging excitatory inputs from diverse brain regions, including the cerebral cortex and the intralaminar/midline thalamic nuclei, and mediates learning processes contributing to instrumental motor actions. However, the roles of each striatal input pathway in these learning processes remain uncertain. We developed a novel strategy to target specific neural pathways and applied this strategy for studying behavioral roles of the pathway originating from the parafascicular nucleus (PF) and projecting to the dorsolateral striatum. A highly efficient retrograde gene transfer vector encoding the recombinant immunotoxin (IT) receptor was injected into the dorsolateral striatum in mice to express the receptor in neurons innervating the striatum. IT treatment into the PF of the vector-injected animals caused a selective elimination of neurons of the PF-derived thalamostriatal pathway. The elimination of this pathway impaired the response selection accuracy and delayed the motor response in the acquisition of a visual cue-dependent discrimination task. When the pathway elimination was induced after learning acquisition, it disturbed the response accuracy in the task performance with no apparent change in the response time. The elimination did not influence spontaneous locomotion, methamphetamine-induced hyperactivity, and motor skill learning that demand the function of the dorsal striatum. These results demonstrate that thalamostriatal projection derived from the PF plays essential roles in the acquisition and execution of discrimination learning in response to sensory stimulus. The temporal difference in the pathway requirement for visual discrimination suggests a stage-specific role of thalamostriatal pathway in the modulation of response time of learned motor actions.
AgroShopping in Urban Paraguay
Authors: Finnis Elizabeth , Candia Fatima
Published: November 2011

This article discusses the popular weekly AgroShopping market in Asuncion, Paraguay, which merges the atmosphere of a farmer's market with markers of gastronomic and cultural diversity and national identity. Located in the parking lot of a modern shopping mall, AgroShopping provides urban dwellers with the opportunity to buy fresh fruits, vegetables, meats, cheeses, and other agricultural or artisanal products, as well as a range of prepared foods from various culinary traditions. At least some of the agricultural products can be purchased directly from producers. Thus, while shoppers at supermarkets or street stalls may not be able to ascertain the origins of some fresh foods, at AgroShopping, consumers can speak directly with producers in order to learn more about when something was picked, produced, or packaged. AgroShopping vendors may also choose to highlight the Paraguayan origin of their products by drawing on traditional markers of national identity. The AgroShopping slogan, Una costumbre natural, highlights the market's attempt to position itself as drawing on the agricultural history of Paraguay, and as helping to maintain contemporary field-to-table relationships with food producers.
Food Pairing Theory: A European Fad
Authors: de Klepper Maurits
Published: November 2011

In Europe's culinary scene, a new Food Pairing Theory is all the rage among top chefs, particularly those with an experimental inclination. The main hypothesis of this theory is quite straightforward: the more characteristic aroma compounds that two foods have in common, the better they taste together. The hypothesis is based on the fact that 80 percent of food's flavor is determined by how our nose picks up volatile aromatic compounds. Although the elegance and simplicity of Food Pairing Theory makes it convincing, in this article it is shown that it is as scientifically unsound as it is popular with the practitioners of European haute cuisine. Moreover, it is argued that because of the impracticality of the Food Pairing Theory and the availability of easier food pairing alternatives, it is likely that this theory will not stand the test of time to become a part of cooks’ repertoires. It is a food fad that will likely disappear and soon make place for a new one.
Whatever Happened to the Farm Problem?
Authors: Hillman Jimmye S.
Published: November 2011

The “farm problem” was a phrase that appeared on the scene in the 1930s after a continued inability of the market to absorb what farmers were producing. Actually, there had always been a farm problem, mostly one of overproduction, and lack of rural employment. Short-term crises were treated with short-term remedies. Banking “panics” came and went; tariff policy was a principal worry for farmers, and land policy (the public domain) had affected farmers since the time of Thomas Jefferson.

It was not until the Great Depression that the federal government intervened directly in the market place to affect prices and incomes. The government also intervened in labor markets and foreign trade to benefit the farm sector. Government has never been able to extract itself. The farm problem is that too many resources being committed to agriculture, and farmers and the rural sector are unable to adjust. Ultimately, the issue became political: how much (or how little) money should be spent on agriculture, and in what way should it be spent? So long as the agricultural budget dominated the federal budget there was “war.”

Today, agriculture has a smaller share of the budget but the farm problem remains. Henry Wallace, US Secretary of Agriculture under FDR, would be astounded!
Side-effects of pegylated interferon plus ribavirin therapy with or without protease inhibitor direct acting antiviral agents during treatment of chronic hepatitis C virus infection
Authors: Hunyady Béla , Kovács Balázs , Battyáni Zita
Published: November 2011

Hepatitis C virus (HCV) infection affects 2–3% of the population, approximately 170 million people worldwide, causing chronic HCV-related hepatitis with subsequent liver cirrhosis, hepatic failure, hepatocellular cancer, and liver-related mortality in a large number of patients. The gold standard therapy, pegylated interferon alpha in combination with ribavirin can eradicate hepatitis C virus infection in approx. 40% of treatment-naïve patients infected with HCV genotype G1, and only 15–20% of patients with previous treatment. Success rate is substantially improved with the development and registration of two direct acting anti-hepatitis C virus protease inhibitors (boceprevir and telaprevir) in the second decade of 21st century: combined with the standard therapy, almost three quarter of previously untreated, and more than half of previously unsuccessfully treated patients can achieve sustained viral response with protease inhibitor based triple therapies. A major barrier to successful treatment is the association of peginterferon/ribavirin therapy with frequent and sometimes serious adverse effects. In clinical trials, approximately 10–15% of treated patients discontinue peginterferon and ribavirin due to adverse events; however, in routine clinical practice, the rate of treatment discontinuation has been reported to be substantially higher. The side effects of peginterferon/ribavirin therapy affect virtually all organ systems, and addition of protease inhibitor can amplify these side effects (particularly anemia), and/or may lead to new ones (i.e., dysgeusia with boceprevir or skin rush with telaprevir). There is considerable regional and global variability in the nature and prevalence of these adverse effects as well as in the best strategies to ameliorate their impact on hepatitis C virus treatment. This article summarizes the side effects of dual and triple therapies and their management based on the labels of the drugs, on a comprehensive literature review, as well as on the recently published opinion of an international panel of experts – with the provision of providing help for the physicians treating hepatitis C virus infection to achieve the best possible success with the highest possible safety for the patients. Orv. Hetil., 2011, 152, 1997–2009.