bluuebunny/crossref_metadata_2025 huggingface dataset:
Phosphorylation of the adaptor protein SH2B1βregulates its ability to enhance growth hormone (GH)-dependent macrophage motility
Authors: Su Hsiao-Wen , Lanning Nathan J. , Morris David L. , Argetsinger Lawrence S. , Lumeng Carey N. , Carter-Su Christin
Published: February 2013

Previous studies have shown that growth hormone (GH) recruits the adapter protein SH2B1β to the GH-activated, GH receptor-associated tyrosine kinase JAK2, implicate SH2B1β in GH-dependent actin cytoskeleton remodeling, and suggest that phosphorylation at serine 161 and 165 in SH2B1β releases SH2B1β from the plasma membrane. Here, we examined the role of SH2B1β in GH regulation of macrophage migration. We show that GH stimulates migration of cultured RAW264.7 macrophages, and primary cultures of peritoneal and bone marrow-derived macrophages. SH2B1β overexpression enhances, while SH2B1 knockdown inhibits, GH-dependent motility of RAW macrophages. At least two independent mechanisms regulate the SH2B1β-mediated changes in motility. In response to GH, tyrosines 439 and 494 in SH2B1β are phosphorylated. Mutating these tyrosines in SH2B1β decreases both basal and GH-stimulated macrophage migration. In addition, mutating the polybasic nuclear localization sequence (NLS) in SH2B1β or creating the phosphomimetics SH2B1β(S161E) or SH2B1β(S165E), all of which release SH2B1β from the plasma membrane, enhances macrophage motility. Conversely, SH2B1β(S161/165A) exhibits increased localization at the plasma membrane and decreased macrophage migration. Mutating the NLS or the nearby serines does not alter GH-dependent phosphorylation on tyrosines 439 and 494 in SH2B1β. Mutating tyrosines 439 and 494 does not affect localization of SH2B1β at the plasma membrane or movement of SH2B1β into focal adhesions. Taken together, these results suggest SH2B1β enhances GH-stimulated macrophage motility via mechanisms involving phosphorylation of SH2B1β on tyrosines 439 and 494 and movement of SH2B1β out of the plasma membrane (e.g. as a result of phosphorylation of serines 161 and 165).
Tumor suppressor p16INK4a inhibits cancer cell growth by down-regulating eEF1A2 through a direct interaction
Authors: Lee Mee-Hyun , Choi Bu Young , Cho Yong-Yeon , Lee Sung-Young , Huang Zunnan , Kundu Joydeb Kumar , Kim Myoung Ok , Kim Dong Joon , Bode Ann M. , Surh Young-Joon , Dong Zigang
Published: February 2013

The tumor suppressor p16INK4a protein is a member of the INK4 family of cyclin-dependent kinase (Cdk) inhibitors, which are involved in the regulation of the eukaryotic cell cycle. However, the mechanisms underlying the anti-proliferative effects of p16INK4a have not been fully elucidated. Using yeast two-hybrid screening, we identified the eukaryotic elongation factor (eEF)1A2 as a novel interacting partner of p16INK4a. eEF1A2 is known to function as a putative oncogene in cancers. The p16INK4a protein interacted with all but the D2 (250–327 aa) domain of eEF1A2. Ectopic expression of p16INK4a decreased the expression of eEF1A2 and inhibited cancer cell growth. Furthermore, suppression of protein synthesis by expression of p16INK4a ex vivo was verified by luciferase reporter activity. Microinjection of p16INK4a mRNA into the cytoplasm of Xenopus embryos suppressed the luciferase mRNA translation, whereas the combination of p16INK4a and morpholino-eEF1A2 showed a further reduction in translational activity. We conclude that the interaction of p16INK4a with eEF1A2 and subsequent down-regulation of the expression and function of eEF1A2 is a novel mechanism explaining the anti-proliferative effects of p16INK4a.
mTOR-dependent proliferation defect in human ES-derived neural stem cells affected by Myotonic Dystrophy Type1
Authors: Denis Jérôme Alexandre , Gauthier Morgane , Rachdi Latif , Aubert Sophie , Giraud-Triboult Karine , Poydenot Pauline , Benchoua Alexandra , Champon Benoite , Maury Yves , Baldeschi Christine , Scharfmann Raphael , Piétu Geneviève , Peschanski Marc , Martinat Cécile
Published: February 2013

Patients with Myotonic Dystrophy type 1 exhibit a diversity of symptoms that affect many different organs. Among those are cognitive dysfunctions, the origin of which has remained elusive due in part to the difficulty in accessing neural cells. Here, we have taken advantage of pluripotent stem cell lines derived from embryos identified during a pre-implantation genetic diagnosis as mutant gene-carriers, in order to differentiate cells along the neural lineage. Functional characterization of these cells revealed reduced proliferative capacity and increased autophagy linked to mTOR signaling pathway alterations. Interestingly, loss of function of MBNL1, a RNA-binding protein whose function is defective in DM1 patients, resulted in the mTOR signaling alteration whereas gain-of-function experiments rescued the phenotype. Collectively, these results provide a mechanism by which DM1 mutation might affect a major signaling pathway and highlight the pertinence of using pluripotent stem cells to study neuronal defects.
Transgenic GATA-4 expression induces adrenocortical tumorigenesis in C57Bl/6 mice
Authors: Chrusciel Marcin , Vuorenoja Susanna , Mohanty Bidut , Rivero-Müller Adolfo , Li Xiangdong , Toppari Jorma , Huhtaniemi Ilpo , Rahman Nafis A.
Published: February 2013

A link between elevated LH levels, GATA-4 and luteinizing hormone receptor (LHCGR) expression and gonadotropin-dependent adrenocortical tumorigenesis in humans and mice has been shown. To assess the mechanistic tumorigenic interrelationships between these factors, we transgenically expressed Gata4 under the 21-hydroxylase promoter (Cyp21a1, 21-OH) in C57Bl/6N mice. There was a gradual age-dependent increase of GATA-4 expression only in 21-OH-GATA-4 (TG) female adrenals, in association with slowly progressing neoplasia of non-steroidogenic spindle-shaped A cells in the subcapsular cortex. Gonadectomy (GDX), apparently through direct action of elevated serum LH, markedly enhanced the adrenocortical neoplasia, which now also appeared in GDX TG males. The neoplastic areas of the post-GDX TG adrenals contained, besides A cells, larger lipid-laden, steroidogenically active and LHCGR positive B cells. Prolonged (>10 months, mo) exposure to elevated post-GDX LH levels resulted in formation of adrenocortical adenomas in the TG mice. Intact and GDX TG mouse adrenals displayed elevated FOG-2 and decreased GATA-6 expression. Additionally, increased expression/activation of components of the Inhbb-Acvr2a-Acvr1c-Smad2/3 signaling system was observed in 12-mo-old GDX TG adrenals. Our findings showed the formation of two distinct GATA-4-dependent populations of neoplastic adrenocortical cells: non-steroidogenic, LH-independent A cells and steroidogenic, LH-dependent B cells.
Downregulation of Dickkopf-3 disrupts prostate acinar morphogenesis through TGF-β/Smad signaling
Authors: Romero Diana , Kawano Yoshiaki , Bengoa Nora , Walker Marjorie M. , Maltry Nicole , Niehrs Christof , Waxman Jonathan , Kypta Robert
Published: February 2013

Loss of tissue organization is a hallmark of the early stages of cancer, and there is considerable interest in proteins that maintain normal tissue architecture. Prostate epithelial cells cultured in Matrigel form three-dimensional acini that mimic aspects of prostate gland development. The organization of these structures requires the tumor suppressor Dickkopf-3 (Dkk-3), a divergent member of the Dkk family of secreted Wnt signaling antagonists that is frequently downregulated in prostate cancer. To gain further insight into the function of Dkk-3 in the prostate, we compared the prostates of Dkk3 null mice with those of control littermates. We found increased proliferation of prostate epithelial cells in the mutant mice and changes in prostate tissue organization. Consistent with these observations, cell proliferation was elevated in acini formed by human prostate epithelial cells stably silenced for Dkk-3. Silencing of Dkk-3 increased TGF-β/Smad signaling and inhibitors of TGF-β/Smad signaling rescued the defective acinar phenotype caused by loss of Dkk-3. These findings suggest that Dkk-3 maintains the structural integrity of the prostate gland by limiting TGF-β/Smad signaling.
Nck enables directional cell migration through the coordination of polarized membrane protrusion with adhesion dynamics
Authors: Chaki Sankar P. , Barhoumi Rola , Berginski Matthew E. , Sreenivasappa Harini , Trache Andreea , Gomez Shawn M. , Rivera Gonzalo M.
Published: February 2013

Directional migration requires the coordination of cytoskeletal changes essential for cell polarization and adhesion turnover. Extracellular signals that alter tyrosine phosphorylation drive directional migration by inducing reorganization of the actin cytoskeleton. It is recognized that Nck is an important link between tyrosine phosphorylation and actin dynamics, however, the role of Nck in cytoskeletal remodeling during directional migration and the underlying molecular mechanisms remain largely undetermined. In this study, a combination of molecular genetics and quantitative live cell microscopy was used to show that Nck is essential in the establishment of front-back polarity and directional migration of endothelial cells. Time-lapse differential interference contrast and total internal reflection fluorescence microscopy showed that Nck couples the formation of polarized membrane protrusions with their stabilization through the assembly and maturation of cell-substratum adhesions. Measurements by atomic force microscopy showed that Nck also modulates integrin α5β1-fibronectin adhesion force and cell stiffness. Fluorescence resonance energy transfer imaging revealed that Nck depletion results in delocalized and increased activity of Cdc42 and Rac. In contrast, the activity of RhoA and myosin II phosphorylation were reduced by Nck knockdown. Thus, this study identifies Nck as a key coordinator of cytoskeletal changes that enable cell polarization and directional migration which are critical processes in development and disease.
The cell polarity scaffold lethal giant larvae regulates synapse morphology and function
Authors: Staples Jon , Broadie Kendal
Published: February 2013

Lethal Giant Larvae (LGL) is a cytosolic cell polarity scaffold whose loss dominantly enhances neuromuscular junction (NMJ) synaptic overgrowth caused by loss of the Fragile X Mental Retardation Protein (FMRP). However, direct roles for LGL in NMJ morphological and functional development have not before been tested. Here, we use confocal imaging and two-electrode voltage-clamp electrophysiology at the Drosophila larval NMJ to define the synaptic requirements of LGL. We find that LGL is expressed both pre- and postsynaptically, where the scaffold localizes at the membrane on both sides of the synaptic interface. We show that LGL has a cell autonomous presynaptic role facilitating NMJ terminal branching and synaptic bouton formation. Moreover, loss of both pre- and postsynaptic LGL strongly decreases evoked neurotransmission strength, while the frequency and amplitude of spontaneous synaptic vesicle fusion events is increased. Cell-targeted RNAi/rescue reveals separable pre- and postsynaptic LGL roles mediating neurotransmission. We show that presynaptic LGL facilitates the assembly of active zone vesicle fusion sites, and that neuronally-targeted rescue of LGL is sufficient to ameliorate increased synaptic vesicle cycling imaged with FM1-43 dye labeling. Postsynaptically, we show that loss of LGL results in a net increase in total glutamate receptor (GluR) expression, associated with the selective elevation of GluRIIB subunit-containing receptors. Taken together, these data indicate that the presynaptic LGL scaffold facilitates the assembly of active zone fusion sites to regulate synaptic vesicle cycling, and that the postsynaptic LGL scaffold modulates glutamate receptor composition and function.
Doa4 function in ILV budding is restricted through its interaction with the Vps20 subunit of ESCRT-III
Authors: Richter Caleb M. , West Matthew , Odorizzi Greg
Published: February 2013

Assembly of the endosomal sorting complex required for transport (ESCRT)-III executes the formation of intralumenal vesicles (ILVs) at endosomes. Repeated cycles of ESCRT-III function requires disassembly of the complex by Vps4, an ATPase with a microtubule interaction and trafficking (MIT) domain that binds MIT-interacting motifs (MIM1 or MIM2) in ESCRT-III subunits. We identified a putative MIT domain at the N terminus of Doa4, which is the Ub hydrolase in Saccharomyces cerevisiae that deubiquitinates ILV cargo proteins. The Doa4 N terminus is predicted to have the α-helical structure common to MIT domains, and it binds directly to a MIM1-like sequence in the Vps20 subunit of ESCRT-III. Disrupting this interaction does not prevent endosomal localization of Doa4 but enhances the defect in ILV cargo protein deubiquitination observed in cells lacking Bro1, which is an ESCRT-III effector protein that stimulates Doa4 catalytic activity. Deletion of the BRO1 gene (bro1Δ) blocks ILV budding, but ILV budding was rescued upon disrupting the interaction between Vps20 and Doa4. This rescue in ILV biogenesis requires Doa4 expression but is independent of its Ub hydrolase activity. Thus, binding of Vps20 to the Doa4 N terminus inhibits a non-catalytic function of Doa4 that promotes ILV formation.
Nitrogen-bridged bidentate phosphaalkene ligands
Authors: du Mont Wolf-Walther , Gimeno Rafael Guerrero , Lungu Daniela , Bîrzoi Roxana M. , Daniliuc Constantin G. , Goers Christine , Riecke Antje , Bartsch Rainer
Published: February 2013

Nitrogen-bridged bidentate phosphaalkenes reveal several exceptional properties as a new class of P=C-unsaturated diphosphinoamine (PNP) ligands: N–Si bond cleavage of the first N-silylimino-bridged bis-phosphaalkene (R2C=P)2NSiMe3 (R = iPrMe2Si) with chlorides of AgI, AuI, and RhI leads to complexes of the 5c-6π-heteropentadienide imidobisphosphaalkene anion; double Cl– transfer from PtCl2 and PdCl2 to coordinated phosphaalkene phosphorus atoms of P-diphenylphosphanylamino phosphaalkenes R2C=PN(R')PPh2 (R' = Me3Si or iPrMe2Si; R = tBu, 1-Ada) furnishes unprecedented bis-chelate P-chloroylid complexes M[R2CP(Cl)N(R')PPh2]2 (M = Pd, Pt); CO- and RhI-induced coupling of two P-diphenylphosphanylamino phosphaalkenes under disilylketene elimination provides trigonal–bipyramidal RhIII complexes with novel tetradentate dianionic “PNP–C–PNP” ligands R2C[P(–)N(R')PPh2]2.
Retailer Private-Label Margins: The Role of Supplier and Quality-Tier Differentiation
Authors: ter Braak Anne , Dekimpe Marnik G. , Geyskens Inge
Published: February 2013

The authors show how new realities in the private-label (PL) landscape, including differential PL-sourcing relationships and differentiated, three-tiered PL portfolios, affect the gross margins that retailers realize on their PLs. In addition, they examine the moderating role of the identity of the PL supplier (dual brander vs. dedicated supplier). Retailer PL margins are lower for stockkeeping units from PL suppliers with whom the retailer shares a more intense relationship, as reflected in their relationship breadth and depth, but this negative effect can be countered through multisourcing. Building prolonged relationships with PL suppliers also results in lower retailer PL margins, but only for more national brand–oriented suppliers. Dedicated PL suppliers have little to gain by building long-term retailer relationships, but they are less vulnerable to the retailer's practice of multisourcing than dual branders. Although economy PLs may appeal to conventional supermarkets to keep (hard) discounters at bay, they result in lower margins (percentage-wise and absolute) than the standard PLs they cannibalize. Premium PLs, in turn, offer the retailer a higher margin, but only when produced by suppliers with a sufficient extent of national brand focus. However, the higher promotional support often given to premium PLs tends to mitigate the actual margin advantage.
Nutritional significance of coprophagy in the rat-like hamster Tscherskia triton
Authors: Shichijo Hiroki , Takahashi Toshihiro , Kondo Yuji , Sakamoto Shinsuke H. , Morita Tetsuo
Published: February 2013

Coprophagy is widespread among rodent species and has nutritional significance in providing microbial protein to animals via feces. However, studies of coprophagy in rodents have focused mainly on species that are cecal fermenters. In this study using rat-like hamsters (Tscherskia triton), which have a large forestomach and cecum, we investigated the contribution of coprophagy to protein nutrition in pregastric and cecal fermenters and also examined whether or not the cecum is involved in protein nutrition enhanced by coprophagy. With or without a forestomach, coprophagy may affect protein digestion in T. triton, and coprophagy cannot provide beneficial effects without a cecal contribution. Prevention of coprophagy increased the fecal concentration of crude protein in animals with an intact cecum. Therefore, we conclude that coprophagy is closely related to the cecum in terms of protein nutrition, even in the pregastric and cecal fermenter T. triton.
The Thalamus and Brainstem Act As Key Hubs in Alterations of Human Brain Network Connectivity Induced by Mild Propofol Sedation
Authors: Gili Tommaso , Saxena Neeraj , Diukova Ana , Murphy Kevin , Hall Judith E. , Wise Richard G.
Published: February 2013

Despite their routine use during surgical procedures, no consensus has yet been reached on the precise mechanisms by which hypnotic anesthetic agents produce their effects. Molecular, animal and human studies have suggested disruption of thalamocortical communication as a key component of anesthetic action at the brain systems level. Here, we used the anesthetic agent, propofol, to modulate consciousness and to evaluate differences in the interactions of remote neural networks during altered consciousness. We investigated the effects of propofol, at a dose that produced mild sedation without loss of consciousness, on spontaneous cerebral activity of 15 healthy volunteers using functional magnetic resonance imaging (fMRI), exploiting oscillations (<0.1 Hz) in blood oxygenation level-dependent signal across functionally connected brain regions. We considered the data as a graph, or complex network of nodes and links, and used eigenvector centrality (EC) to characterize brain network properties. The EC mapping of fMRI data in healthy humans under propofol mild sedation demonstrated a decrease of centrality of the thalamus versus an increase of centrality within the pons of the brainstem, highlighting the important role of these two structures in regulating consciousness. Specifically, the decrease of thalamus centrality results from its disconnection from a widespread set of cortical and subcortical regions, while the increase of brainstem centrality may be a consequence of its increased influence, in the mildly sedated state, over a few highly central cortical regions key to the default mode network such as the posterior and anterior cingulate cortices.
Rhes Deletion Is Neuroprotective in the 3-Nitropropionic Acid Model of Huntington's Disease
Authors: Mealer Robert G. , Subramaniam Srinivasa , Snyder Solomon H.
Published: February 2013

Although the mutated protein causing Huntington's disease (HD) is expressed throughout the body, the major pathology of HD is localized to the striatum of the brain. We previously reported that the striatal-enriched protein Rhes binds the mutated huntingtin protein and enhances its cytotoxicity. We now demonstrate that Rhes-deleted mice are dramatically protected from neurotoxicity and motor dysfunction in a striatal-specific model of HD elicited by 3-nitropropionic acid. This finding suggests that Rhes may, in part, determine the striatal selectivity of HD.
Progression of Neurogenesis in the Inner Ear Requires Inhibition ofSox2Transcription by Neurogenin1 and Neurod1
Authors: Evsen Lale , Sugahara Satoko , Uchikawa Masanori , Kondoh Hisato , Wu Doris K.
Published: February 2013

Sox2is required for proper neuronal formation in the CNS, but the molecular mechanisms involved are not well characterized. Here, we addressed the role of Sox2 in neurogenesis of the developing chicken inner ear. OverexpressingSox2from a constitutive (β-actin) promoter induces the expression of the proneural gene,Neurogenin1(Ngn1); however, the expression of a downstream target of Ngn1,Neurod1, is unchanged. As a result, there is a reduction of neural precursors to delaminate and populate the developing cochleo-vestibular ganglion. In contrast, overexpression of eitherNgn1orNeurod1is sufficient to promote the neural fate in this system. These results suggest that high levels of Sox2 inhibit progression of neurogenesis in the developing inner ear. Furthermore, we provide evidence that Ngn1 and Neurod1 inhibitSox2transcription through a phylogenetically conservedSox2enhancer to mediate neurogenesis. We propose that Sox2 confers neural competency by promotingNgn1expression, and that negative feedback inhibition ofSox2by Ngn1 is an essential step in the progression from neural precursor to nascent neuron.
GABA-Independent GABAAReceptor Openings Maintain Tonic Currents
Authors: Wlodarczyk Agnieszka I. , Sylantyev Sergiy , Herd Murray B. , Kersanté Flavie , Lambert Jeremy J. , Rusakov Dmitri A. , Linthorst Astrid C. E. , Semyanov Alexey , Belelli Delia , Pavlov Ivan , Walker Matthew C.
Published: February 2013

Activation of GABAAreceptors (GABAARs) produces two forms of inhibition: phasic inhibition generated by the rapid, transient activation of synaptic GABAARs by presynaptic GABA release, and tonic inhibition generated by the persistent activation of perisynaptic or extrasynaptic GABAARs, which can detect extracellular GABA. Such tonic GABAAR-mediated currents are particularly evident in dentate granule cells in which they play a major role in regulating cell excitability. Here we show that in rat dentate granule cells inex vivohippocampal slices, tonic currents are predominantly generated by GABA-independent GABAAreceptor openings. This tonic GABAAR conductance is resistant to the competitive GABAAR antagonist SR95531 (gabazine), which at high concentrations acts as a partial agonist, but can be blocked by an open channel blocker, picrotoxin. When slices are perfused with 200 nmGABA, a concentration that is comparable to CSF concentrations but is twice that measured by us in the hippocampusin vivousing zero-net-flux microdialysis, negligible GABA is detected by dentate granule cells. Spontaneously opening GABAARs, therefore, maintain dentate granule cell tonic currents in the face of low extracellular GABA concentrations.
Layer-Specific Experience-Dependent Rewiring of Thalamocortical Circuits
Authors: Wang Lang , Kloc Michelle , Gu Yan , Ge Shaoyu , Maffei Arianna
Published: February 2013

Thalamocortical circuits are central to sensory and cognitive processing. Recent work suggests that the thalamocortical inputs onto L4 and L6, the main input layers of neocortex, are activated differently by visual stimulation. Whether these differences depend on layer-specific organization of thalamocortical circuits; or on specific properties of synapses onto receiving neurons is unknown. Here we combined optogenetic stimulation of afferents from the visual thalamus and paired recording electrophysiology in L4 and L6 of rat primary visual cortex to determine the organization and plasticity of thalamocortical synapses. We show that thalamocortical inputs onto L4 and L6 differ in synaptic dynamics and sensitivity to visual drive. We also demonstrate that the two layers differ in the organization of thalamocortical and recurrent intracortical connectivity. In L4, a significantly larger proportion of excitatory neurons responded to light activation of thalamocortical terminal fields than in L6. The local microcircuit in L4 showed a higher degree of recurrent connectivity between excitatory neurons than the microcircuit in L6. In addition, L4 recurrently connected neurons were driven by thalamocortical inputs of similar magnitude indicating the presence of local subnetworks that may be activated by the same axonal projection. Finally, brief manipulation of visual drive reduced the amplitude of light-evoked thalamocortical synaptic currents selectively onto L4. These data are the first direct indication that thalamocortical circuits onto L4 and L6 support different aspects of cortical function through layer-specific synaptic organization and plasticity.
Paired Related Homeobox Protein 1 is a Regulator of Stemness in Adult Neural Stem/Progenitor Cells
Authors: Shimozaki Koji , Clemenson Gregory D. , Gage Fred H.
Published: February 2013

Newborn neurons are generated from neural stem cells (NSCs) in two major niches of the adult brain. Maintenance of self-renewal and multipotency of adult NSCs is controlled by multiple transcription factor networks. We show here that paired related homeobox protein Prx1 (MHox1/Prrx1) plays an important role in the maintenance of adult NSCs. Prx1 works with the transcription factor Sox2 as a coactivator, and depletion of Prx1 in cultured adult mouse NSCs reduces their self-renewal. In addition, we find that Prx1 protein is expressed in Sox2+/GFAP+/Nestin+astrocytes in the germinal regions of the adult mouse forebrain. The continuous expression of Prx1 in proliferating adult mouse hippocampal stem/progenitor cellsin vivoleads to the generation of radial/horizontal-shaped astrocyte progenitor- and oligodendrocyte progenitor-like cells with no newborn neurons in the neurogenic niche. These data suggest that Prx1 plays an important role as a key switch for neural cell lineage determination and the maintenance of the self-renewal of adult NSCs at several stages in the adult brain.
Temporal Expectation Enhances Contrast Sensitivity by Phase Entrainment of Low-Frequency Oscillations in Visual Cortex
Authors: Cravo André M. , Rohenkohl Gustavo , Wyart Valentin , Nobre Anna C.
Published: February 2013

Although it is increasingly accepted that temporal expectation can modulate early perceptual processing, the underlying neural computations remain unknown. In the present study, we combined a psychophysical paradigm with electrophysiological recordings to investigate the putative contribution of low-frequency oscillatory activity in mediating the modulation of visual perception by temporal expectation. Human participants judged the orientation of brief targets (visual Gabor patterns tilted clockwise or counterclockwise) embedded within temporally regular or irregular streams of noise-patches used as temporal cues. Psychophysical results indicated that temporal expectation enhanced the contrast sensitivity of visual targets. A diffusion model indicated that rhythmic temporal expectation modulated the signal-to-noise gain of visual processing. The concurrent electrophysiological data revealed that the phase of delta oscillations overlying human visual cortex (1–4 Hz) was predictive of the quality of target processing only in regular streams of events. Moreover, in the regular condition, the optimum phase of these perception-predictive oscillations occurred in anticipation of the expected events. Together, these results show a strong correspondence between psychophysical and neurophysiological data, suggesting that the phase entrainment of low-frequency oscillations to external sensory cues can serve as an important and flexible mechanism for enhancing sensory processing.
Latent Modulation: A Basis for Non-Disruptive Promotion of Two Incompatible Behaviors by a Single Network State
Authors: Dacks Andrew M. , Weiss Klaudiusz R.
Published: February 2013

Behavioral states often preferentially enhance specific classes of behavior and suppress incompatible behaviors. In the nervous system, this may involve upregulation of the efficacy of neural modules that mediate responses to one stimulus and suppression of modules that generate antagonistic or incompatible responses to another stimulus. InAplysia, prestimulation of egestive inputs [esophageal nerve (EN)] facilitates subsequent EN-elicited egestive responses and weakens ingestive responses to ingestive inputs [Cerebral-Buccal Interneuron (CBI-2)]. However, a single state can also promote incompatible behaviors in response to different stimuli. This is the case inAplysia, where prestimulation of CBI-2 inputs not only enhances subsequent CBI-2-elicited ingestive responses, but also strengthens EN-elicited egestive responses. We used the modularly organized feeding network ofAplysiato characterize the organizational principles that allow a single network state to promote two opposing behaviors, ingestion and egestion, without the two interfering with each other. We found that the CBI-2 prestimulation-induced state upregulates the excitability of neuron B65 which, as a member of the egestive module, increases the strength of egestive responses. Furthermore, we found that this upregulation is likely mediated by the actions of the neuropeptides FCAP (Feeding Circuit Activating Peptide) and CP2 (Cerebral Peptide 2). This increased excitability is mediated by a form of modulation that we refer to as “latent modulation” because it is established during stimulation of CBI-2, which does not activate B65. However, when B65 is recruited into EN-elicited egestive responses, the effects of the latent modulation are expressed as a higher B65 firing rate and a resultant strengthening of the egestive response.
Adventures at Sea
Authors: Apostol Jane
Published: February 2013

The shipboard account kept by nineteen-year-old forty-niner Arthur M. Ebbets brings to life the hardships and diversions of the journey around Cape Horn. His adventures on the voyage presaged a later career marked by risks, setbacks, and successes in California.
Thyroglobulin in smoking mothers and their newborns at delivery suggests autoregulation of placental iodide transport overcoming thiocyanate inhibition
Authors: Andersen Stine L , Nøhr Susanne B , Wu Chun S , Olsen Jørn , Pedersen Klaus M , Laurberg Peter
Published: February 2013

Background

Placental transport of iodide is required for fetal thyroid hormone production. The sodium iodide symporter (NIS) mediates active iodide transport into the thyroid and the lactating mammary gland and is also present in placenta. NIS is competitively inhibited by thiocyanate from maternal smoking, but compensatory autoregulation of iodide transport differs between organs. The extent of autoregulation of placental iodide transport remains to be clarified.

Objective

To compare the impact of maternal smoking on thyroglobulin (Tg) levels in maternal serum at delivery and in cord serum as markers of maternal and fetal iodine deficiency.

Methods

One hundred and forty healthy, pregnant women admitted for delivery and their newborns were studied before the iodine fortification of salt in Denmark. Cotinine in urine and serum classified mothers as smokers (n=50) or nonsmokers (n=90). The pregnant women reported on intake of iodine-containing supplements during pregnancy and Tg in maternal serum at delivery and in cord serum were analyzed.

Results

In a context of mild-to-moderate iodine deficiency, smoking mothers had significantly higher serum Tg than nonsmoking mothers (mean Tg smokers 40.2 vs nonsmokers 24.4 μg/l, P=0.004) and so had their respective newborns (cord Tg 80.2 vs 52.4 μg/l, P=0.006), but the ratio between Tg in cord serum and maternal serum was not significantly different in smokers compared with nonsmokers (smoking 2.06 vs nonsmoking 2.22, P=0.69).

Conclusion

Maternal smoking increased the degree of iodine deficiency in parallel in the mother and the fetus, as reflected by increased Tg levels. However, placental iodide transport seemed unaffected despite high thiocyanate levels, suggesting that thiocyanate-insensitive iodide transporters alternative to NIS are active or that NIS in the placenta is autoregulated to keep iodide transport unaltered.
Increased glucagon-like peptide-1 secretion may be involved in antidiabetic effects of ginsenosides
Authors: Liu Can , Zhang Mian , Hu Meng-yue , Guo Hai-fang , Li Jia , Yu Yun-li , Jin Shi , Wang Xin-ting , Liu Li , Liu Xiao-dong
Published: February 2013

Panax ginseng is one of the most popular herbal remedies. Ginsenosides, major bioactive constituents in P. ginseng, have shown good antidiabetic action, but the precise mechanism was not fully understood. Glucagon-like peptide-1 (GLP1) is considered to be an important incretin that can regulate glucose homeostasis in the gastrointestinal tract after meals. The aim of this study was to investigate whether ginseng total saponins (GTS) exerts its antidiabetic effects via modulating GLP1 release. Ginsenoside Rb1 (Rb1), the most abundant constituent in GTS, was selected to further explore the underlying mechanisms in cultured NCI-H716 cells. Diabetic rats were developed by a combination of high-fat diet and low-dose streptozotocin injection. The diabetic rats orally received GTS (150 or 300 mg/kg) daily for 4 weeks. It was found that GTS treatment significantly ameliorated hyperglycemia and dyslipidemia, accompanied by a significant increase in glucose-induced GLP1 secretion and upregulation of proglucagon gene expression. Data from NCI-H716 cells showed that both GTS and Rb1 promoted GLP1 secretion. It was observed that Rb1 increased the ratio of intracellular ATP to ADP concentration and intracellular Ca2+ concentration. The metabolic inhibitor azide (3 mM), the KATP channel opener diazoxide (340 μM), and the Ca2+ channel blocker nifedipine (20 μM) significantly reversed Rb1-mediated GLP1 secretion. All these results drew a conclusion that ginsenosides stimulated GLP1 secretion both in vivo and in vitro. The antidiabetic effects of ginsenosides may be a result of enhanced GLP1 secretion.
Repair of Aortic Regurgitation due to Takayasu Arteritis
Authors: Li ChengNan , Liu YongMin , Qi RuiDong , Zheng Jun , Zhu JunMing , Chang Qian , Sun LiZhong
Published: February 2013

Background: Prosthetic valve detachment after aortic valve replacement and pseudoaneurysm formation are the most important postoperative complications in patients with Takayasu arteritis with aortic regurgitation. We reviewed our experience of surgical treatment of aortic regurgitation in patients with Takayasu disease.

Methods: Between November 1997 and September 2011, 11 patients (4 women and 7 men) with Takayasu arteritis with aortic regurgitation underwent surgical treatment. The age of the patients ranged from 26 to 56 years (mean, 40 � 9 years). Primary isolated aortic valve replacement was performed in 1 patient, David procedure in 1 patient, Wheat procedure in 1 patient, Bentall procedure in 2 patients, and Cabrol procedure in 6 patients (including 2 patients who underwent primary aortic valve replacement in other hospitals before being admitted to our surgical team).

Results: There was no in-hospital death. All patients had an uneventful recovery during the postoperative course and were discharged. Prosthetic valve detachment, pseudoaneurysm formation at the suture line, and dilatation of the ascending aorta were not found in patients with composite aortic root replacement during a mean follow-up of 98 � 45 months. One patient died during follow-up.

Conclusion: Valve detachment after composite aortic root replacement was not observed in patients with Takayasu disease with aortic regurgitation. Satisfactory surgical outcomes were obtained using composite aortic root replacement. However, close follow-up was needed to assess the effectiveness of the Cabrol procedure in patients with Takayasu disease with aortic regurgitation.
An Intramural Left Main Coronary Artery with a Left Sinus of Valsalva Aneurysm: A Unique Combination of Congenital Anomalies
Authors: Altarabsheh Salah Eldien , Deo Salil V. , Spitell Peter , Araoz Philip , Park Soon J.
Published: February 2013

The congenital anomaly of an intramural left main coronary artery arising in the anatomically correct aortic sinus is very infrequent. Aneurysms involving the sinus of Valsalva rarely arise from the left aortic sinus. We present the clinical features and surgical correction of this rare anomaly along with a short discussion of these congenital malformations.
Computer-Generated Reminders and Quality of Pediatric HIV Care in a Resource-Limited Setting
Authors: Were Martin C. , Nyandiko Winstone M. , Huang Kristin T.L. , Slaven James E. , Shen Changyu , Tierney William M. , Vreeman Rachel C.
Published: February 2013

OBJECTIVES:

To evaluate the impact of clinician-targeted computer-generated reminders on compliance with HIV care guidelines in a resource-limited setting.

METHODS:

We conducted this randomized, controlled trial in an HIV referral clinic in Kenya caring for HIV-infected and HIV-exposed children (<14 years of age). For children randomly assigned to the intervention group, printed patient summaries containing computer-generated patient-specific reminders for overdue care recommendations were provided to the clinician at the time of the child’s clinic visit. For children in the control group, clinicians received the summaries, but no computer-generated reminders. We compared differences between the intervention and control groups in completion of overdue tasks, including HIV testing, laboratory monitoring, initiating antiretroviral therapy, and making referrals.

RESULTS:

During the 5-month study period, 1611 patients (49% female, 70% HIV-infected) were eligible to receive at least 1 computer-generated reminder (ie, had an overdue clinical task). We observed a fourfold increase in the completion of overdue clinical tasks when reminders were availed to providers over the course of the study (68% intervention vs 18% control, P < .001). Orders also occurred earlier for the intervention group (77 days, SD 2.4 days) compared with the control group (104 days, SD 1.2 days) (P < .001). Response rates to reminders varied significantly by type of reminder and between clinicians.

CONCLUSIONS:

Clinician-targeted, computer-generated clinical reminders are associated with a significant increase in completion of overdue clinical tasks for HIV-infected and exposed children in a resource-limited setting.
Impacts of Back Surface Conditions on the Behavior of Oxygen in Heavily Arsenic Doped Czochralski Silicon Wafers
Authors: Wang Q. , Daggubati Manmohan , Paravi Hossein , Yu Rong , Zhang Xiao Feng
Published: February 2013

The precipitation of interstitial oxygen (Oi) in heavily arsenic doped Czochralski (CZ) silicon wafers (As-wafer) has been studied for both polysilicon and damaged back surfaces. After annealed at 1200°C for 45 minutes and 950°C for 15hrs sequentially, the As-wafers with polysilicon show no Oi precipitation in the bulk while polyhedral Oi precipitates are observed at the interface between polysilicon and the silicon substrate. They exhibit a habit plane of {100}. The lack of the Oi precipitation in the bulk may reduce the total gettering efficiency of the polysilicon layer on the As-wafer. The same annealing led to rod-like SiOx precipitates in the wafers with damaged back surface. These precipitates extended about 1um into the bulk and had a habit plane of {111}. This morphology has high interfacial energy and is only possible when strain relief is dominant. The Oi outdiffusion has been observed to be same for both backside surface conditions and is only determined by annealing process.
Mercado de trabalho e vulnerabilidade em regiões metropolitanas brasileiras
Authors: Carvalho Inaiá Maria Moreira de
Published: February 2013

Este artigo analisa as transformações do mercado de trabalho ocorridas nas últimas décadas nas regiões metropolitanas brasileiras, com base em dados da Pesquisa de Emprego e Desemprego - PED. Discutindo a evolução da População em Idade Ativa, da População Economicamente Ativa e da População Ocupada, as condições de ocupação, o desemprego e o rendimento médio dos trabalhadores, ele procura demonstrar como ocorreu uma verdadeira desestruturação do mercado de trabalho na década de 1990, interrompida nos últimos anos, mas sem que chegassem a ser superadas a precariedade ocupacional e a vulnerabilidade de uma significativa parcela da população dessas cidades.
A Review of Breast Cancer Care and Outcomes in Latin America
Authors: Justo Nahila , Wilking Nils , Jönsson Bengt , Luciani Silvana , Cazap Eduardo
Published: February 2013

Learning Objectives

Describe associations between epidemiologic factors and breast cancer risk in the countries included in this review. Compare presentation profiles among the countries studied and discuss implications for outcomes.

This review presents an overview of breast cancer care, burden, and outcomes in Latin America, as well as the challenges and opportunities for improvement. Information was gleaned through a review of the literature, public databases, and conference presentations, in addition to a survey of clinical experts and patient organizations from the region. Breast cancer annual incidence (114,900 cases) and mortality (37,000 deaths) are the highest of all women's cancers in Latin America, and they are increasing. Twice as many breast cancer deaths are expected by 2030. In Peru, Mexico, Colombia, and Brazil, diagnosis and death at younger ages deprives society of numerous productive years, as does high disease occurrence in Argentina and Uruguay. Approximately 30%–40% of diagnoses are metastatic disease. High mortality-to-incidence ratios (MIRs) in Latin America indicate poor survival, partly because of the late stage at diagnosis and poorer access to treatment. Between 2002 and 2008, MIRs decreased in all countries, albeit unevenly. Costa Rica's change in MIR outpaced incidence growth, indicating impressive progress in breast cancer survival. The situation is similar, although to a lesser extent, in Colombia and Ecuador. The marginal drops of MIRs in Brazil and Mexico mainly reflect incidence growth rather than progress in outcomes. Panama's MIR is still high. Epidemiological data are scattered and of varying quality in Latin America. However, one could ascertain that the burden of breast cancer in the region is considerable and growing due to demographic changes, particularly the aging population, and socioeconomic development. Early diagnosis and population-wide access to evidence-based treatment remain unresolved problems, despite progress achieved by some countries.
Expert perspectives on the role of the bus in school travel
Authors: Van Ristell Jessica , Enoch Marcus , Quddus Mohammed , Hardy Peter
Published: February 2013

Millions of children travel to and from school each day as part of their daily routine, contributing to increased congestion and traffic on the roads. This paper examines the role of the bus within school travel and reports the views of current professionals in the school travel industry gained from interviews with school travel experts in the UK. The findings suggest that parents, schools, local authorities and bus operators are the key stakeholders, while the children are relatively minor players despite being the main users of the system. The key issues facing the sector concern costs to government and users, institutional and political factors, and social issues around the behaviour of children on buses. The interviewees all see a prominent place for buses in school travel, both now and in the future.
Reconstruction and Optimization of Tritium Time Series in Precipitation of Beijing, China
Authors: Zhai Yuanzheng , Wang Jinsheng , Guo Hui , Cao Yang , Teng Yanguo
Published: February 2013

Tritium time series for precipitation in Beijing have been reconstructed for the period 1953–2002 using various methods: Guanbingjun method; trend surface analysis method; double reference curve method; triangulation method; and correlation method. By comparing the reconstructed results with the measured data of Beijing as well as data of other regions available in the IAEA GNIP database, the corresponding tritium time series have been developed for Beijing for the period 1953–2002, and the optimal time series was selected. The reconstructed result can be used for groundwater dating and related studies in Beijing as well as the surrounding areas.
Using In-Slag Charcoal as an Indicator of “Terminal” Iron Production within the Angkorian Period (10th–13th Centuries AD) Center of Preah Khan of Kompong Svay, Cambodia
Authors: Hendrickson Mitch , Hua Quan , Pryce Thomas Oliver
Published: February 2013

Recent fieldwork by the Industries of Angkor Project (INDAP) has identified the first extensive evidence of iron production within an Angkorian Khmer (9th to 15th centuries AD) center at Preah Khan of Kompong Svay (Preah Khan) in Preah Vihear province, Cambodia. This immense 22-km2temple complex appears to be an outpost of Khmer settlement situated in close proximity to Phnom Dek (“Iron Mountain”), the richest known source of iron oxide in Cambodia. Combined with the fact that Preah Khan's temple architecture dates between the late 10th to early 13th centuries, the period that the Khmer greatly expanded their territorial influence, our primary hypothesis is that this complex was established to gain access to and monitor production of iron for the capital of Angkor. The vast number and size of these iron slag concentrations, some up to 5 m in height by 35 m in length, precludes the use of traditional excavation and dating methods. Instead, this paper employs14C dating of “in-slag” charcoal from surface slag cakes to produce a spatial chronology of late or “terminal” industrial activities. The results indicate that metallurgy was “last” practiced at various locations within Preah Khan in the mid-13th to late 17th centuries, with 3 distinct clusters between the late 13th and late 15th centuries. Based on this initial survey of surface collections, it appears that iron production at Preah Khan occurred after the final phase of masonry construction. More significantly, this work provides the first robust set of dates for late Angkorian and Middle period industrial activities in Cambodia.