Spatial information outflow from the hippocampal circuit: distributed spatial coding and phase precession in the subiculum.

PubMed

Kim, Steve M; Ganguli, Surya; Frank, Loren M

2012-08-22

Hippocampal place cells convey spatial information through a combination of spatially selective firing and theta phase precession. The way in which this information influences regions like the subiculum that receive input from the hippocampus remains unclear. The subiculum receives direct inputs from area CA1 of the hippocampus and sends divergent output projections to many other parts of the brain, so we examined the firing patterns of rat subicular neurons. We found a substantial transformation in the subicular code for space from sparse to dense firing rate representations along a proximal-distal anatomical gradient: neurons in the proximal subiculum are more similar to canonical, sparsely firing hippocampal place cells, whereas neurons in the distal subiculum have higher firing rates and more distributed spatial firing patterns. Using information theory, we found that the more distributed spatial representation in the subiculum carries, on average, more information about spatial location and context than the sparse spatial representation in CA1. Remarkably, despite the disparate firing rate properties of subicular neurons, we found that neurons at all proximal-distal locations exhibit robust theta phase precession, with similar spiking oscillation frequencies as neurons in area CA1. Our findings suggest that the subiculum is specialized to compress sparse hippocampal spatial codes into highly informative distributed codes suitable for efficient communication to other brain regions. Moreover, despite this substantial compression, the subiculum maintains finer scale temporal properties that may allow it to participate in oscillatory phase coding and spike timing-dependent plasticity in coordination with other regions of the hippocampal circuit.

Encoding, consolidation, and retrieval of contextual memory: differential involvement of dorsal CA3 and CA1 hippocampal subregions.

PubMed

Daumas, Stéphanie; Halley, Hélène; Francés, Bernard; Lassalle, Jean-Michel

2005-01-01

Studies on human and animals shed light on the unique hippocampus contributions to relational memory. However, the particular role of each hippocampal subregion in memory processing is still not clear. Hippocampal computational models and theories have emphasized a unique function in memory for each hippocampal subregion, with the CA3 area acting as an autoassociative memory network and the CA1 area as a critical output structure. In order to understand the respective roles of the CA3- and CA1-hippocampal areas in the formation of contextual memory, we studied the effects of the reversible inactivation by lidocaine of the CA3 or CA1 areas of the dorsal hippocampus on acquisition, consolidation, and retrieval of a contextual fear conditioning. Whereas infusions of lidocaine never impaired elementary tone conditioning, their effects on contextual conditioning provided interesting clues about the role of these two hippocampal regions. They demonstrated first that the CA3 area is necessary for the rapid elaboration of a unified representation of the context. Secondly, they suggested that the CA1 area is rather involved in the consolidation process of contextual memory. Third, they showed that CA1 or CA3 inactivation during retention test has no effect on contextual fear retrieval when a recognition memory procedure is used. In conclusion, our findings point as evidence that CA1 and CA3 subregions of the dorsal hippocampus play important and different roles in the acquisition and consolidation of contextual fear memory, whereas they are not required for context recognition.

Cannabinoids disrupt memory encoding by functionally isolating hippocampal CA1 from CA3.

PubMed

Sandler, Roman A; Fetterhoff, Dustin; Hampson, Robert E; Deadwyler, Sam A; Marmarelis, Vasilis Z

2017-07-01

Much of the research on cannabinoids (CBs) has focused on their effects at the molecular and synaptic level. However, the effects of CBs on the dynamics of neural circuits remains poorly understood. This study aims to disentangle the effects of CBs on the functional dynamics of the hippocampal Schaffer collateral synapse by using data-driven nonparametric modeling. Multi-unit activity was recorded from rats doing an working memory task in control sessions and under the influence of exogenously administered tetrahydrocannabinol (THC), the primary CB found in marijuana. It was found that THC left firing rate unaltered and only slightly reduced theta oscillations. Multivariate autoregressive models, estimated from spontaneous spiking activity, were then used to describe the dynamical transformation from CA3 to CA1. They revealed that THC served to functionally isolate CA1 from CA3 by reducing feedforward excitation and theta information flow. The functional isolation was compensated by increased feedback excitation within CA1, thus leading to unaltered firing rates. Finally, both of these effects were shown to be correlated with memory impairments in the working memory task. By elucidating the circuit mechanisms of CBs, these results help close the gap in knowledge between the cellular and behavioral effects of CBs.

Cannabinoids disrupt memory encoding by functionally isolating hippocampal CA1 from CA3

PubMed Central

Fetterhoff, Dustin; Hampson, Robert E.; Deadwyler, Sam A.; Marmarelis, Vasilis Z.

2017-01-01

Much of the research on cannabinoids (CBs) has focused on their effects at the molecular and synaptic level. However, the effects of CBs on the dynamics of neural circuits remains poorly understood. This study aims to disentangle the effects of CBs on the functional dynamics of the hippocampal Schaffer collateral synapse by using data-driven nonparametric modeling. Multi-unit activity was recorded from rats doing an working memory task in control sessions and under the influence of exogenously administered tetrahydrocannabinol (THC), the primary CB found in marijuana. It was found that THC left firing rate unaltered and only slightly reduced theta oscillations. Multivariate autoregressive models, estimated from spontaneous spiking activity, were then used to describe the dynamical transformation from CA3 to CA1. They revealed that THC served to functionally isolate CA1 from CA3 by reducing feedforward excitation and theta information flow. The functional isolation was compensated by increased feedback excitation within CA1, thus leading to unaltered firing rates. Finally, both of these effects were shown to be correlated with memory impairments in the working memory task. By elucidating the circuit mechanisms of CBs, these results help close the gap in knowledge between the cellular and behavioral effects of CBs. PMID:28686594

CaV1.3 L-type Ca2+ channels modulate depression-like behaviour in mice independent of deaf phenotype.

PubMed

Busquet, Perrine; Nguyen, Ngoc Khoi; Schmid, Eduard; Tanimoto, Naoyuki; Seeliger, Mathias W; Ben-Yosef, Tamar; Mizuno, Fengxia; Akopian, Abram; Striessnig, Jörg; Singewald, Nicolas

2010-05-01

Mounting evidence suggests that voltage-gated L-type Ca2+ channels can modulate affective behaviour. We therefore explored the role of CaV1.3 L-type Ca2+ channels in depression- and anxiety-like behaviours using CaV1.3-deficient mice (CaV1.3-/-). We showed that CaV1.3-/- mice displayed less immobility in the forced swim test as well as in the tail suspension test, indicating an antidepressant-like phenotype. Locomotor activity in the home cage or a novel open-field test was not influenced. In the elevated plus maze (EPM), CaV1.3-/- mice entered the open arms more frequently and spent more time there indicating an anxiolytic-like phenotype which was, however, not supported in the stress-induced hyperthermia test. By performing parallel experiments in Claudin 14 knockout mice (Cldn14-/-), which like CaV1.3-/- mice are congenitally deaf, an influence of deafness on the antidepressant-like phenotype could be ruled out. On the other hand, a similar EPM behaviour indicative of an anxiolytic phenotype was also found in the Cldn14-/- animals. Using electroretinography and visual behavioural tasks we demonstrated that at least in mice, CaV1.3 channels do not significantly contribute to visual function. However, marked morphological changes were revealed in synaptic ribbons in the outer plexiform layer of CaV1.3-/- retinas by immunohistochemistry suggesting a possible role of this channel type in structural plasticity at the ribbon synapse. Taken together, our findings indicate that CaV1.3 L-type Ca2+ channels modulate depression-like behaviour but are not essential for visual function. The findings raise the possibility that selective modulation of CaV1.3 channels could be a promising new therapeutic concept for the treatment of mood disorders.

Functional Differences in the Backward Shifts of CA1 and CA3 Place Fields in Novel and Familiar Environments

PubMed Central

Roth, Eric D.; Yu, Xintian; Rao, Geeta; Knierim, James J.

2012-01-01

Insight into the processing dynamics and other neurophysiological properties of different hippocampal subfields is critically important for understanding hippocampal function. In this study, we compared shifts in the center of mass (COM) of CA3 and CA1 place fields in a familiar and completely novel environment. Place fields in CA1 and CA3 were simultaneously recorded as rats ran along a closed loop track in a familiar room followed by a session in a completely novel room. This process was repeated each day over a 4-day period. CA3 place fields shifted backward (opposite to the direction of motion of the rat) only in novel environments. This backward shift gradually diminished across days, as the novel environment became more familiar with repeated exposures. Conversely, CA1 place fields shifted backward across all days in both familiar and novel environments. Prior studies demonstrated that CA1 place fields on average do not exhibit a backward shift during the first exposure to an environment in which the familiar cues are rearranged into a novel configuration, although CA3 place fields showed a strong backward shift. Under the completely novel conditions of the present study, no dissociation was observed between CA3 and CA1 during the first novel session (although a strong dissociation was observed in the familiar sessions and the later novel sessions). In summary, this is the first study to use simultaneous recordings in CA1 and CA3 to compare place field COM shift and other associated properties in truly novel and familiar environments. This study further demonstrates functional differentiation between CA1 and CA3 as the plasticity of CA1 place fields is affected differently by exposure to a completely novel environment in comparison to an altered, familiar environment, whereas the plasticity of CA3 place fields is affected similarly during both types of environmental novelty. PMID:22558316

Altered thalamocortical rhythmicity and connectivity in mice lacking CaV3.1 T-type Ca2+ channels in unconsciousness

PubMed Central

Choi, Soonwook; Yu, Eunah; Lee, Seongwon; Llinás, Rodolfo R.

2015-01-01

In unconscious status (e.g., deep sleep and anesthetic unconsciousness) where cognitive functions are not generated there is still a significant level of brain activity present. Indeed, the electrophysiology of the unconscious brain is characterized by well-defined thalamocortical rhythmicity. Here we address the ionic basis for such thalamocortical rhythms during unconsciousness. In particular, we address the role of CaV3.1 T-type Ca2+ channels, which are richly expressed in thalamic neurons. Toward this aim, we examined the electrophysiological and behavioral phenotypes of mice lacking CaV3.1 channels (CaV3.1 knockout) during unconsciousness induced by ketamine or ethanol administration. Our findings indicate that CaV3.1 KO mice displayed attenuated low-frequency oscillations in thalamocortical loops, especially in the 1- to 4-Hz delta band, compared with control mice (CaV3.1 WT). Intriguingly, we also found that CaV3.1 KO mice exhibited augmented high-frequency oscillations during unconsciousness. In a behavioral measure of unconsciousness dynamics, CaV3.1 KO mice took longer to fall into the unconscious state than controls. In addition, such unconscious events had a shorter duration than those of control mice. The thalamocortical interaction level between mediodorsal thalamus and frontal cortex in CaV3.1 KO mice was significantly lower, especially for delta band oscillations, compared with that of CaV3.1 WT mice, during unconsciousness. These results suggest that the CaV3.1 channel is required for the generation of a given set of thalamocortical rhythms during unconsciousness. Further, that thalamocortical resonant neuronal activity supported by this channel is important for the control of vigilance states. PMID:26056284

Altered thalamocortical rhythmicity and connectivity in mice lacking CaV3.1 T-type Ca2+ channels in unconsciousness.

PubMed

Choi, Soonwook; Yu, Eunah; Lee, Seongwon; Llinás, Rodolfo R

2015-06-23

In unconscious status (e.g., deep sleep and anesthetic unconsciousness) where cognitive functions are not generated there is still a significant level of brain activity present. Indeed, the electrophysiology of the unconscious brain is characterized by well-defined thalamocortical rhythmicity. Here we address the ionic basis for such thalamocortical rhythms during unconsciousness. In particular, we address the role of CaV3.1 T-type Ca(2+) channels, which are richly expressed in thalamic neurons. Toward this aim, we examined the electrophysiological and behavioral phenotypes of mice lacking CaV3.1 channels (CaV3.1 knockout) during unconsciousness induced by ketamine or ethanol administration. Our findings indicate that CaV3.1 KO mice displayed attenuated low-frequency oscillations in thalamocortical loops, especially in the 1- to 4-Hz delta band, compared with control mice (CaV3.1 WT). Intriguingly, we also found that CaV3.1 KO mice exhibited augmented high-frequency oscillations during unconsciousness. In a behavioral measure of unconsciousness dynamics, CaV3.1 KO mice took longer to fall into the unconscious state than controls. In addition, such unconscious events had a shorter duration than those of control mice. The thalamocortical interaction level between mediodorsal thalamus and frontal cortex in CaV3.1 KO mice was significantly lower, especially for delta band oscillations, compared with that of CaV3.1 WT mice, during unconsciousness. These results suggest that the CaV3.1 channel is required for the generation of a given set of thalamocortical rhythms during unconsciousness. Further, that thalamocortical resonant neuronal activity supported by this channel is important for the control of vigilance states.

Suppression of Sleep Spindle Rhythmogenesis in Mice with Deletion of CaV3.2 and CaV3.3 T-type Ca(2+) Channels.

PubMed

Pellegrini, Chiara; Lecci, Sandro; Lüthi, Anita; Astori, Simone

2016-04-01

Low-threshold voltage-gated T-type Ca(2+) channels (T-channels or CaV3 channels) sustain oscillatory discharges of thalamocortical (TC) and nucleus Reticularis thalami (nRt) cells. The CaV3.3 subtype dominates nRt rhythmic bursting and mediates a substantial fraction of spindle power in the NREM sleep EEG. CaV3.2 channels are also found in nRt, but whether these contribute to nRt-dependent spindle generation is unexplored. We investigated thalamic rhythmogenesis in mice lacking this subtype in isolation (CaV3.2KO mice) or in concomitance with CaV3.3 deletion (CaV3.double-knockout (DKO) mice). We examined discharge characteristics of thalamic cells and intrathalamic evoked synaptic transmission in brain slices from wild-type, CaV3.2KO and CaV3.DKO mice through patch-clamp recordings. The sleep profile of freely behaving CaV3.2KO and CaV3.DKO mice was assessed by polysomnographic recordings. CaV3.2 channel deficiency left nRt discharge properties largely unaltered, but additional deletion of CaV3.3 channels fully abolished low-threshold whole-cell Ca(2+) currents and bursting, and suppressed burst-mediated inhibitory responses in TC cells. CaV3.DKO mice had more fragmented sleep, with shorter NREM sleep episodes and more frequent microarousals. The NREM sleep EEG power spectrum displayed a relative suppression of the σ frequency band (10-15 Hz), which was accompanied by an increase in the δ band (1-4 Hz). Consistent with previous findings, CaV3.3 channels dominate nRt rhythmogenesis, but the lack of CaV3.2 channels further aggravates neuronal, synaptic, and EEG deficits. Therefore, CaV3.2 channels can boost intrathalamic synaptic transmission, and might play a modulatory role adjusting the relative presence of NREM sleep EEG rhythms. © 2016 Associated Professional Sleep Societies, LLC.

Suppression of Sleep Spindle Rhythmogenesis in Mice with Deletion of CaV3.2 and CaV3.3 T-type Ca2+ Channels

PubMed Central

Pellegrini, Chiara; Lecci, Sandro; Lüthi, Anita; Astori, Simone

2016-01-01

Study Objectives: Low-threshold voltage-gated T-type Ca2+ channels (T-channels or CaV3 channels) sustain oscillatory discharges of thalamocortical (TC) and nucleus Reticularis thalami (nRt) cells. The CaV3.3 subtype dominates nRt rhythmic bursting and mediates a substantial fraction of spindle power in the NREM sleep EEG. CaV3.2 channels are also found in nRt, but whether these contribute to nRt-dependent spindle generation is unexplored. We investigated thalamic rhythmogenesis in mice lacking this subtype in isolation (CaV3.2KO mice) or in concomitance with CaV3.3 deletion (CaV3.double-knockout (DKO) mice). Methods: We examined discharge characteristics of thalamic cells and intrathalamic evoked synaptic transmission in brain slices from wild-type, CaV3.2KO and CaV3.DKO mice through patch-clamp recordings. The sleep profile of freely behaving CaV3.2KO and CaV3.DKO mice was assessed by polysomnographic recordings. Results: CaV3.2 channel deficiency left nRt discharge properties largely unaltered, but additional deletion of CaV3.3 channels fully abolished low-threshold whole-cell Ca2+ currents and bursting, and suppressed burst-mediated inhibitory responses in TC cells. CaV3.DKO mice had more fragmented sleep, with shorter NREM sleep episodes and more frequent microarousals. The NREM sleep EEG power spectrum displayed a relative suppression of the σ frequency band (10–15 Hz), which was accompanied by an increase in the δ band (1–4 Hz). Conclusions: Consistent with previous findings, CaV3.3 channels dominate nRt rhythmogenesis, but the lack of CaV3.2 channels further aggravates neuronal, synaptic, and EEG deficits. Therefore, CaV3.2 channels can boost intrathalamic synaptic transmission, and might play a modulatory role adjusting the relative presence of NREM sleep EEG rhythms. Citation: Pellegrini C, Lecci S, Lüthi A, Astori S. Suppression of sleep spindle rhythmogenesis in mice with deletion of Cav3.2 and Cav3.3 T-type Ca2+ channels. SLEEP 2016;39(4):875�

Hippocampal CA3-dentate gyrus volume uniquely linked to improvement in associative memory from childhood to adulthood.

PubMed

Daugherty, Ana M; Flinn, Robert; Ofen, Noa

2017-06-01

Associative memory develops into adulthood and critically depends on the hippocampus. The hippocampus is a complex structure composed of subfields that are functionally-distinct, and anterior-posterior divisions along the length of the hippocampal horizontal axis that may also differ by cognitive correlates. Although each of these aspects has been considered independently, here we evaluate their relative contributions as correlates of age-related improvement in memory. Volumes of hippocampal subfields (subiculum, CA1-2, CA3-dentate gyrus) and anterior-posterior divisions (hippocampal head, body, tail) were manually segmented from high-resolution images in a sample of healthy participants (age 8-25 years). Adults had smaller CA3-dentate gyrus volume as compared to children, which accounted for 67% of the indirect effect of age predicting better associative memory via hippocampal volumes. Whereas hippocampal body volume demonstrated non-linear age differences, larger hippocampal body volume was weakly related to better associative memory only when accounting for the mutual correlation with subfields measured within that region. Thus, typical development of associative memory was largely explained by age-related differences in CA3-dentate gyrus. Copyright © 2017 Elsevier Inc. All rights reserved.

Hippocampal CA3-dentate gyrus volume uniquely linked to improvement in associative memory from childhood to adulthood

PubMed Central

Daugherty, Ana M.; Flinn, Robert; Ofen, Noa

2017-01-01

Associative memory develops into adulthood and critically depends on the hippocampus. The hippocampus is a complex structure composed of subfields that are functionally-distinct, and anterior-posterior divisions along the length of the hippocampal horizontal axis that may also differ by cognitive correlates. Although each of these aspects has been considered independently, here we evaluate their relative contributions as correlates of age-related improvement in memory. Volumes of hippocampal subfields (subiculum, CA1-2, CA3-dentate gyrus) and anterior-posterior divisions (hippocampal head, body, tail) were manually segmented from high-resolution proton density-weighted images in a sample of healthy participants (age 8–25 years). Adults had smaller CA3-dentate gyrus volume as compared to children, which accounted for 67% of the indirect effect of age predicting better associative memory via hippocampal volumes. Whereas hippocampal body volume demonstrated non-linear age differences, larger hippocampal body volume was weakly related to better associative memory only when accounting for the mutual correlation with subfields measured within that region. Thus, typical development of associative memory was largely explained by age-related differences in CA3-dentate gyrus. PMID:28342999

The Pepper RING-Type E3 Ligase CaAIRF1 Regulates ABA and Drought Signaling via CaADIP1 Protein Phosphatase Degradation.

PubMed

Lim, Chae Woo; Baek, Woonhee; Lee, Sung Chul

2017-04-01

Ubiquitin-mediated protein modification occurs at multiple steps of abscisic acid (ABA) signaling. Here, we sought proteins responsible for degradation of the pepper ( Capsicum annuum ) type 2C protein phosphatase CaADIP1 via the 26S proteasome system. We showed that the RING-type E3 ligase CaAIRF1 ( Capsicum annuum ADIP1 Interacting RING Finger Protein 1) interacts with and ubiquitinates CaADIP1. CaADIP1 degradation was slower in crude proteins from CaAIRF1 -silenced peppers than in those from control plants. CaAIRF1 -silenced pepper plants displayed reduced ABA sensitivity and decreased drought tolerance characterized by delayed stomatal closure and suppressed induction of ABA- and drought-responsive marker genes. In contrast, CaAIRF1 -overexpressing Arabidopsis ( Arabidopsis thaliana ) plants exhibited ABA-hypersensitive and drought-tolerant phenotypes. Moreover, in these plants, CaADIP1-induced ABA hyposensitivity was strongly suppressed by CaAIRF1 overexpression. Our findings highlight a potential new route for fine-tune regulation of ABA signaling in pepper via CaAIRF1 and CaADIP1. © 2017 American Society of Plant Biologists. All Rights Reserved.

Roles for the subiculum in spatial information processing, memory, motivation and the temporal control of behaviour.

PubMed

O'Mara, Shane M; Sanchez-Vives, Maria V; Brotons-Mas, Jorge R; O'Hare, Eugene

2009-08-01

The subiculum is in a pivotal position governing the output of the hippocampal formation. Despite this, it is a rather under-explored and sometimes ignored structure. Here, we discuss recent data indicating that the subiculum participates in a wide range of neurocognitive functions and processes. Some of the functions of subiculum are relatively well-known-these include providing a relatively coarse representation of space and participating in, and supporting certain aspects of, memory (particularly in the dynamic bridging of temporal intervals). The subiculum also participates in a wide variety of other neurocognitive functions too, however. Much less well-known are roles for the subiculum, and particularly the ventral subiculum, in the response to fear, stress and anxiety, and in the generation of motivated behaviour (particularly the behaviour that underlies drug addiction and the response to reward). There is an emerging suggestion that the subiculum participates in the temporal control of behaviour. It is notable that these latter findings have emerged from a consideration of instrumental behaviour using operant techniques; it may well be the case that the use of the watermaze or similar spatial tasks to assess subicular function (on the presumption that its functions are very similar to the hippocampus proper) has obscured rather than revealed neurocognitive functions of subiculum. The anatomy of subiculum suggests it participates in a rather subtle fashion in a very broad range of functions, rather than in a relatively more isolated fashion in a narrower range of functions, as might be the case for "earlier" components of hippocampal circuitry, such as the CA1 and CA3 subfields. Overall, there appears to a strong dorso-ventral segregation of function within subiculum, with the dorsal subiculum relatively more concerned with space and memory, and the ventral hippocampus concerned with stress, anxiety and reward. Finally, it may be the case that the whole

Lysosomes shape Ins(1,4,5)P3-evoked Ca2+ signals by selectively sequestering Ca2+ released from the endoplasmic reticulum

PubMed Central

López-Sanjurjo, Cristina I.; Tovey, Stephen C.; Prole, David L.; Taylor, Colin W.

2013-01-01

Summary Most intracellular Ca2+ signals result from opening of Ca2+ channels in the plasma membrane or endoplasmic reticulum (ER), and they are reversed by active transport across these membranes or by shuttling Ca2+ into mitochondria. Ca2+ channels in lysosomes contribute to endo-lysosomal trafficking and Ca2+ signalling, but the role of lysosomal Ca2+ uptake in Ca2+ signalling is unexplored. Inhibition of lysosomal Ca2+ uptake by dissipating the H+ gradient (using bafilomycin A1), perforating lysosomal membranes (using glycyl-L-phenylalanine 2-naphthylamide) or lysosome fusion (using vacuolin) increased the Ca2+ signals evoked by receptors that stimulate inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] formation. Bafilomycin A1 amplified the Ca2+ signals evoked by photolysis of caged Ins(1,4,5)P3 or by inhibition of ER Ca2+ pumps, and it slowed recovery from them. Ca2+ signals evoked by store-operated Ca2+ entry were unaffected by bafilomycin A1. Video-imaging with total internal reflection fluorescence microscopy revealed that lysosomes were motile and remained intimately associated with the ER. Close association of lysosomes with the ER allows them selectively to accumulate Ca2+ released by Ins(1,4,5)P3 receptors. PMID:23097044

Interfacial Ferromagnetism and Exchange Bias in CaRuO3/CaMnO3 Superlattices

NASA Astrophysics Data System (ADS)

He, C.; Grutter, A. J.; Gu, M.; Browning, N. D.; Takamura, Y.; Kirby, B. J.; Borchers, J. A.; Kim, J. W.; Fitzsimmons, M. R.; Zhai, X.; Mehta, V. V.; Wong, F. J.; Suzuki, Y.

2012-11-01

We have found ferromagnetism in epitaxially grown superlattices of CaRuO3/CaMnO3 that arises in one unit cell at the interface. Scanning transmission electron microscopy and electron energy loss spectroscopy indicate that the difference in magnitude of the Mn valence states between the center of the CaMnO3 layer and the interface region is consistent with double exchange interaction among the Mn ions at the interface. Polarized neutron reflectivity and the CaMnO3 thickness dependence of the exchange bias field together indicate that the interfacial ferromagnetism is only limited to one unit cell of CaMnO3 at each interface. The interfacial moment alternates between the 1μB/interface Mn ion for even CaMnO3 layers and the 0.5μB/interface Mn ion for odd CaMnO3 layers. This modulation, combined with the exchange bias, suggests the presence of a modulating interlayer coupling between neighboring ferromagnetic interfaces via the antiferromagnetic CaMnO3 layers.

Involvement of dominant-negative spliced variants of the intermediate conductance Ca2+-activated K+ channel, K(Ca)3.1, in immune function of lymphoid cells.

PubMed

Ohya, Susumu; Niwa, Satomi; Yanagi, Ayano; Fukuyo, Yuka; Yamamura, Hisao; Imaizumi, Yuji

2011-05-13

The intermediate conductance Ca(2+)-activated K(+) channel (IK(Ca) channel) encoded by K(Ca)3.1 is responsible for the control of proliferation and differentiation in various types of cells. We identified novel spliced variants of K(Ca)3.1 (human (h) K(Ca)3.1b) from the human thymus, which were lacking the N-terminal domains of the original hK(Ca)3.1a as a result of alternative splicing events. hK(Ca)3.1b was significantly expressed in human lymphoid tissues. Western blot analysis showed that hK(Ca)3.1a proteins were mainly expressed in the plasma membrane fraction, whereas hK(Ca)3.1b was in the cytoplasmic fraction. We also identified a similar N terminus lacking K(Ca)3.1 variants from mice and rat lymphoid tissues (mK(Ca)3.1b and rK(Ca)3.1b). In the HEK293 heterologous expression system, the cellular distribution of cyan fluorescent protein-tagged hK(Ca)3.1a and/or YFP-tagged hK(Ca)3.1b isoforms showed that hK(Ca)3.1b suppressed the localization of hK(Ca)3.1a to the plasma membrane. In the Xenopus oocyte translation system, co-expression of hK(Ca)3.1b with hK(Ca)3.1a suppressed IK(Ca) channel activity of hK(Ca)3.1a in a dominant-negative manner. In addition, this study indicated that up-regulation of mK(Ca)3.1b in mouse thymocytes differentiated CD4(+)CD8(+) phenotype thymocytes into CD4(-)CD8(-) ones and suppressed concanavalin-A-stimulated thymocyte growth by down-regulation of mIL-2 transcripts. Anti-proliferative effects and down-regulation of mIL-2 transcripts were also observed in mK(Ca)3.1b-overexpressing mouse thymocytes. These suggest that the N-terminal domain of K(Ca)3.1 is critical for channel trafficking to the plasma membrane and that the fine-tuning of IK(Ca) channel activity modulated through alternative splicing events may be related to the control in physiological and pathophysiological conditions in T-lymphocytes.

Interfacial Ferromagnetism and Exchange Bias in CaRuO3/CaMnO3 Superlattices

DTIC Science & Technology

2012-11-07

microscopy and electron energy loss spectroscopy indicate that the difference in magnitude of the Mn valence states between the center of the CaMnO3 layer...CaMnO3 thickness dependence of the exchange bias field together indicate that the interfacial 1. REPORT DATE (DD-MM-YYYY) 4. TITLE AND SUBTITLE 13...superlattices of CaRuO3/CaMnO3 that arises in one unit cell at the interface. Scanning transmission electron microscopy and electron energy loss

Stimulation-evoked Ca2+ signals in astrocytic processes at hippocampal CA3-CA1 synapses of adult mice are modulated by glutamate and ATP.

PubMed

Tang, Wannan; Szokol, Karolina; Jensen, Vidar; Enger, Rune; Trivedi, Chintan A; Hvalby, Øivind; Helm, P Johannes; Looger, Loren L; Sprengel, Rolf; Nagelhus, Erlend A

2015-02-18

To date, it has been difficult to reveal physiological Ca(2+) events occurring within the fine astrocytic processes of mature animals. The objective of the study was to explore whether neuronal activity evokes astrocytic Ca(2+) signals at glutamatergic synapses of adult mice. We stimulated the Schaffer collateral/commissural fibers in acute hippocampal slices from adult mice transduced with the genetically encoded Ca(2+) indicator GCaMP5E driven by the glial fibrillary acidic protein promoter. Two-photon imaging revealed global stimulation-evoked astrocytic Ca(2+) signals with distinct latencies, rise rates, and amplitudes in fine processes and somata. Specifically, the Ca(2+) signals in the processes were faster and of higher amplitude than those in the somata. A combination of P2 purinergic and group I/II metabotropic glutamate receptor (mGluR) antagonists reduced the amplitude of the Ca(2+) transients by 30-40% in both astrocytic compartments. Blockage of the mGluRs alone only modestly reduced the magnitude of the stimulation-evoked Ca(2+) signals in processes and failed to affect the somatic Ca(2+) response. Local application of group I or I/II mGluR agonists or adenosine triphosphate (ATP) elicited global astrocytic Ca(2+) signals that mimicked the stimulation-evoked astrocytic Ca(2+) responses. We conclude that stimulation-evoked Ca(2+) signals in astrocytic processes at CA3-CA1 synapses of adult mice (1) differ from those in astrocytic somata and (2) are modulated by glutamate and ATP. Copyright © 2015 the authors 0270-6474/15/353016-06$15.00/0.

Thermoelectric properties of antiperovskite calcium oxides Ca{sub 3}PbO and Ca{sub 3}SnO

DOE Office of Scientific and Technical Information (OSTI.GOV)

Okamoto, Y., E-mail: yokamoto@nuap.nagoya-u.ac.jp; Institute for Advanced Research, Nagoya University, Nagoya 464-8601; Sakamaki, A.

We report the thermoelectric properties of polycrystalline samples of Ca{sub 3}Pb{sub 1−x}Bi{sub x}O (x = 0, 0.1, 0.2) and Ca{sub 3}SnO, both crystallizing in a cubic antiperovskite-type structure. The Ca{sub 3}SnO sample shows metallic resistivity and its thermoelectric power approaches 100 μV K{sup −1} at room temperature, resulting in the thermoelectric power factor of Ca{sub 3}SnO being larger than that of Ca{sub 3}Pb{sub 1−x}Bi{sub x}O. On the basis of Hall and Sommerfeld coefficients, the Ca{sub 3}SnO sample is found to be a p-type metal with a carrier density of ∼10{sup 19 }cm{sup −3}, a mobility of ∼80 cm{sup 2} V{sup −1} s{sup −1}, both comparablemore » to those in degenerated semiconductors, and a moderately large hole carrier effective mass. The coexistence of moderately high mobility and large effective mass observed in Ca{sub 3}SnO, as well as possible emergence of a multivalley electronic structure with a small band gap at low-symmetry points in k-space, suggests that the antiperovskite Ca oxides have strong potential as a thermoelectric material.« less

Far-infrared and dc magnetotransport of CaMnO3-CaRuO3 superlattices

NASA Astrophysics Data System (ADS)

Yordanov, P.; Boris, A. V.; Freeland, J. W.; Kavich, J. J.; Chakhalian, J.; Lee, H. N.; Keimer, B.

2011-07-01

We report temperature- and magnetic-field-dependent measurements of the dc resistivity and the far-infrared reflectivity (FIR) (photon energies ℏω=50-700 cm-1) of superlattices comprising ten consecutive unit cells of the antiferromagnetic insulator CaMnO3, and four to ten unit cells of the correlated paramagnetic metal CaRuO3. Below the Néel temperature of CaMnO3, the dc resistivity exhibits a logarithmic divergence upon cooling, which is associated with a large negative, isotropic magnetoresistance. The ω→0 extrapolation of the resistivity extracted from the FIR reflectivity, on the other hand, shows a much weaker temperature and field dependence. We attribute this behavior to scattering of itinerant charge carriers in CaRuO3 from sparse, spatially isolated magnetic defects at the CaMnO3-CaRuO3 interfaces. This field-tunable “transport bottleneck” effect may prove useful for functional metal-oxide devices.

Photocatalyst of Perovskite CaTiO3 Nanopowder Synthesized from CaO derived from Snail Shell in Comparison with The Use of CaO and CaCO3

NASA Astrophysics Data System (ADS)

Fatimah, I.; Rahmadianti, Y.; Pudiasari, R. A.

2018-04-01

Calcium titanate belongs to the important group of compounds with a perovskite structure having high dielectric loss for various applications including photocatalysis mechanism. Refer to the principles of green chemistry, in this work preparation of CaTiO3 was conducted by using CaO derived from snail shell. Aim of this research are to study the physicochemical character of perovskite derived from snail shell and its comparison with CaO and CaCO3 as Ca sources. Material preparation was performed by solid reaction of Ca sources with TiO2 under comparison with CaO and CaCO3 precursors. Mixture of Ca sources with TiO2 in certain proportion were ground and calcined at the temperature of 200 °C for 2 hs. Materials were characterized by using X-ray diffractometer (XRD), Fourier Transform-Infra Red (FTIR) and the photocatalytic activity was tested by using methylene blue photooxidation. Perovskite synthesized using CaO derived from snail shell exhibits the similar XRD pattern with that were prepared by using CaO and CaCO3. From the photooxidation activity test, it is proven that CaTiO3 shows similar photocatalytic activity correspond to that were prepared by CaO and CaCO3. Utilazation of shell as agricultural waste of the synthesis of CaTiO3 perovskite is the novelty of this work. Furthermore, the study on material structure and photoactivity is the main focuses for the application in industry and environment.

The Influence of Layer Thickness-Ratio on Magnetoresistance in La2/3Ca1/3MnO3/La1/3Ca2/3MnO3 Exchange Biased System

NASA Astrophysics Data System (ADS)

Gomez, Maria Elena; Milena Diez, Sandra; Cuartas, Lina Maria; Marin, Lorena; Prieto, Pedro

2012-02-01

Isothermal magnetic field dependence of the resistance in La2/3Ca1/3MnO3 (F-LCMO)/ La1/3Ca2/3MnO3(AF-LCMO) bilayer and AF-LCMO/F-LCMO/AF-LCMO trilayer at temperatures below N'eel temperature of the antiferromagnetic layer were carried out to study the thickness layers influence on magneto transport properties. We grew multilayers using a high oxygen pressure sputtering technique. We systematically varied the thickness of the F-LCMO layer, tF, maintaining constant the thickness of the AF-LCMO layer, tAF. We studied the influence of the thickness ratio tF/tAF on the ZFC and FC magnetoresistance (MR) loops. HFC was varied from 100 Oe to 400 Oe. We found that MR has hysteretic behavior as observed in [La2/3Ca1/3MnO3/La1/3Ca2/3MnO3]N superlattices, where MR increases with the increasing field from H=0 to a maximum and then it decreases continuously. The position and magnitude of the maximum is not symmetric with respect to the axis H=0 for both FC and ZFC loops. We found that magnetoresistance behavior of the bilayer and trilayer is thickness-ratio dependent for both ZFC and FC loops.

Evaluation of serum CA27.29, CA15-3 and CEA in patients with breast cancer.

PubMed

Hou, M F; Chen, Y L; Tseng, T F; Lin, C M; Chen, M S; Huang, C J; Huang, Y S; Hsieh, J S; Huang, T J; Jong, S B; Huang, Y F

1999-09-01

The Truquant BR radioimmunoassay (RIA) using monoclonal antibody BR 27.29 to recognize a peptide sequence on the MUC-1 gene product for quantification of the CA 27.29 antigen in serum was used in this report to evaluate in 145 patients with breast cancer and compared the other conventional serum markers such as CA15-3 and CEA. The upper limit of normal (25 u/ml) was determined from CA27.29 values 12.4 +/- 4.1 u/ml (mean +/- 3 S.D.) for 112 female subjects apparently free of disease. The CA15-3 levels above 25 u/ml and CEA levels above 5 ng/ml were considered positive values. Thirty-seven cases of 145 patients studied had elevated CA 27.29 levels (sensitivity: 25.5%), 35 of 145 had positive CA15-3 levels (sensitivity 24.1%) and 27 of 145 patients had positive CEA levels (sensitivity: 18.6%) (p < 0.05). One hundred and ten cases of the breast cancer patients (75.8%) did not have metastatic disease. In this group CA 27.29 sensitivity was 6.4%, while CA15-3 sensitivity was 5.5% and CEA sensitivity was 4.5% (p > 0.05). Mean values were 10.2 +/- 9.2 u/ml for CA 27.29, 14.1 +/- 5.6 u/ml for CA 15-3 and 1.7 +/- 1.5 ng/ml for CEA. Thirty-five patients (24.2%) had metastatic disease. In this group CA 27.29 sensitivity was 85.7%, CA15-3 sensitivity was 82.8% and CEA sensitivity was 62.8% (p < 0.05). Mean values for CA27.29 was 152.6 +/- 131.6 u/ml, CA15-3 was 123.1 +/- 107.6 u/ml and 21.8 +/- 36.9 ng/ml of CEA. With regard to the correlation of three tumor markers with clinical stages, patients had significantly higher levels of CA27.29 than CEA, but they were similar to CA 15-3 in metastatic breast cancer. These results suggest CA27.29 to be more sensitive and specific than CEA, but that it is similar to CA15-3 for metastatic breast cancer detection and monitoring.

Modulation of K(Ca)3.1 channels by eicosanoids, omega-3 fatty acids, and molecular determinants.

PubMed

Kacik, Michael; Oliván-Viguera, Aida; Köhler, Ralf

2014-01-01

Cytochrome P450- and ω-hydrolase products (epoxyeicosatrienoic acids (EETs), hydroxyeicosatetraeonic acid (20-HETE)), natural omega-3 fatty acids (ω3), and pentacyclic triterpenes have been proposed to contribute to a wide range of vaso-protective and anti-fibrotic/anti-cancer signaling pathways including the modulation of membrane ion channels. Here we studied the modulation of intermediate-conductance Ca(2+)/calmodulin-regulated K(+) channels (K(Ca)3.1) by EETs, 20-HETE, ω3, and pentacyclic triterpenes and the structural requirements of these fatty acids to exert channel blockade. We studied modulation of cloned human hK(Ca)3.1 and the mutant hK(Ca)3.1(V275A) in HEK-293 cells, of rK(Ca)3.1 in aortic endothelial cells, and of mK(Ca)3.1 in 3T3-fibroblasts by inside-out and whole-cell patch-clamp experiments, respectively. In inside-out patches, Ca(2+)-activated hK(Ca)3.1 were inhibited by the ω3, DHA and α-LA, and the ω6, AA, in the lower µmolar range and with similar potencies. 5,6-EET, 8,9-EET, 5,6-DiHETE, and saturated arachidic acid, had no appreciable effects. In contrast, 14,15-EET, its stable derivative, 14,15-EEZE, and 20-HETE produced channel inhibition. 11,12-EET displayed less inhibitory activity. The K(Ca)3.1(V275A) mutant channel was insensitive to any of the blocking EETs. Non-blocking 5,6-EET antagonized the inhibition caused by AA and augmented cloned hK(Ca)3.1 and rK(Ca)3.1 whole-cell currents. Pentacyclic triterpenes did not modulate K(Ca)3.1 currents. Inhibition of K(Ca)3.1 by EETs (14,15-EET), 20-HETE, and ω3 critically depended on the presence of electron double bonds and hydrophobicity within the 10 carbons preceding the carboxyl-head of the molecules. From the physiological perspective, metabolism of AA to non-blocking 5,6,- and 8,9-EET may cause AA-de-blockade and contribute to cellular signal transduction processes influenced by these fatty acids.

Modulation of voltage- and Ca2+-dependent gating of CaV1.3 L-type calcium channels by alternative splicing of a C-terminal regulatory domain.

PubMed

Singh, Anamika; Gebhart, Mathias; Fritsch, Reinhard; Sinnegger-Brauns, Martina J; Poggiani, Chiara; Hoda, Jean-Charles; Engel, Jutta; Romanin, Christoph; Striessnig, Jörg; Koschak, Alexandra

2008-07-25

Low voltage activation of Ca(V)1.3 L-type Ca(2+) channels controls excitability in sensory cells and central neurons as well as sinoatrial node pacemaking. Ca(V)1.3-mediated pacemaking determines neuronal vulnerability of dopaminergic striatal neurons affected in Parkinson disease. We have previously found that in Ca(V)1.4 L-type Ca(2+) channels, activation, voltage, and calcium-dependent inactivation are controlled by an intrinsic distal C-terminal modulator. Because alternative splicing in the Ca(V)1.3 alpha1 subunit C terminus gives rise to a long (Ca(V)1.3(42)) and a short form (Ca(V)1.3(42A)), we investigated if a C-terminal modulatory mechanism also controls Ca(V)1.3 gating. The biophysical properties of both splice variants were compared after heterologous expression together with beta3 and alpha2delta1 subunits in HEK-293 cells. Activation of calcium current through Ca(V)1.3(42A) channels was more pronounced at negative voltages, and inactivation was faster because of enhanced calcium-dependent inactivation. By investigating several Ca(V)1.3 channel truncations, we restricted the modulator activity to the last 116 amino acids of the C terminus. The resulting Ca(V)1.3(DeltaC116) channels showed gating properties similar to Ca(V)1.3(42A) that were reverted by co-expression of the corresponding C-terminal peptide C(116). Fluorescence resonance energy transfer experiments confirmed an intramolecular protein interaction in the C terminus of Ca(V)1.3 channels that also modulates calmodulin binding. These experiments revealed a novel mechanism of channel modulation enabling cells to tightly control Ca(V)1.3 channel activity by alternative splicing. The absence of the C-terminal modulator in short splice forms facilitates Ca(V)1.3 channel activation at lower voltages expected to favor Ca(V)1.3 activity at threshold voltages as required for modulation of neuronal firing behavior and sinoatrial node pacemaking.

Dual CCNE1/PIK3CA targeting is synergistic in CCNE1-amplified/PIK3CA-mutated uterine serous carcinomas in vitro and in vivo

PubMed Central

Cocco, Emiliano; Lopez, Salvatore; Black, Jonathan; Bellone, Stefania; Bonazzoli, Elena; Predolini, Federica; Ferrari, Francesca; Schwab, Carlton L; Menderes, Gulden; Zammataro, Luca; Buza, Natalia; Hui, Pei; Wong, Serena; Zhao, Siming; Bai, Yalai; Rimm, David L; Ratner, Elena; Litkouhi, Babak; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E; Santin, Alessandro D

2016-01-01

Background: Clinical options for patients harbouring advanced/recurrent uterine serous carcinoma (USC), an aggressive variant of endometrial tumour, are very limited. Next-generation sequencing (NGS) data recently demonstrated that cyclin E1 (CCNE1) gene amplification and pik3ca driver mutations are common in USC and may therefore represent ideal therapeutic targets. Methods: Cyclin E1 expression was evaluated by immunohistochemistry (IHC) on 95 USCs. The efficacy of the cyclin-dependent kinase 2/9 inhibitor CYC065 was assessed on multiple primary USC cell lines with or without CCNE1 amplification. Cell-cycle analyses and knockdown experiments were performed to assess CYC065 targeting specificity. Finally, the in vitro and in vivo activity of CYC065, Taselisib (a PIK3CA inhibitor) and their combinations was tested on USC xenografts derived from CCNE1-amplified/pik3ca-mutated USCs. Results: We found that 89.5% of the USCs expressed CCNE1. CYC065 blocked cells in the G1 phase of the cell cycle and inhibited cell growth specifically in CCNE1-overexpressing USCs. Cyclin E1 knockdown conferred increased resistance to CYC065, whereas CYC065 treatment of xenografts derived from CCNE1-amplified USCs significantly reduced tumour growth. The combination of CYC065 and Taselisib demonstrated synergistic effect in vitro and was significantly more effective than single-agent treatment in decreasing tumour growth in xenografts of CCNE1-amplified/pik3ca-mutated USCs. Conclusions: Dual CCNE1/PIK3CA blockade may represent a novel therapeutic option for USC patients harbouring recurrent CCNE1-amplified/pi3kca-mutated tumours. PMID:27351214

Myogenic tone is impaired at low arterial pressure in mice deficient in the low-voltage-activated CaV 3.1 T-type Ca(2+) channel.

PubMed

Björling, K; Morita, H; Olsen, M F; Prodan, A; Hansen, P B; Lory, P; Holstein-Rathlou, N-H; Jensen, L J

2013-04-01

Using mice deficient in the CaV 3.1 T-type Ca(2+) channel, the aim of the present study was to elucidate the molecular identity of non-L-type channels involved in vascular tone regulation in mesenteric arteries and arterioles. We used immunofluorescence microscopy to localize CaV 3.1 channels, patch clamp electrophysiology to test the effects of a putative T-type channel blocker NNC 55-0396 on whole-cell Ca(2+) currents, pressure myography and Ca(2+) imaging to test diameter and Ca(2+) responses of the applied vasoconstrictors, and Q-PCR to check mRNA expression levels of several Ca(2+) handling proteins in wild-type and CaV 3.1(-/-) mice. Our data indicated that CaV 3.1 channels are important for the maintenance of myogenic tone at low pressures (40-80 mm Hg), whereas they are not involved in high-voltage-activated Ca(2+) currents, Ca(2+) entry or vasoconstriction to high KCl in mesenteric arteries and arterioles. Furthermore, we show that NNC 55-0396 is not a specific T-type channel inhibitor, as it potently blocks L-type and non-L-type high-voltage-activated Ca(2+) currents in mouse mesenteric vascular smooth muscle cell. Our data using mice deficient in the CaV 3.1 T-type channel represent new evidence for the involvement of non-L-type channels in arteriolar tone regulation. We showed that CaV 3.1 channels are important for the myogenic tone at low arterial pressure, which is potentially relevant under resting conditions in vivo. Moreover, CaV 3.1 channels are not involved in Ca(2+) entry and vasoconstriction to large depolarization with, for example, high KCl. Finally, we caution against using NNC 55-0396 as a specific T-type channel blocker in native cells expressing high-voltage-activated Ca(2+) channels. Acta Physiologica © 2013 Scandinavian Physiological Society.

Interface ferromagnetism in oxide superlattices of CaMnO3/CaRuO3

NASA Astrophysics Data System (ADS)

Takahashi, K. S.; Kawasaki, M.; Tokura, Y.

2001-08-01

Oxide superlattices composed of antiferromagnetic insulator layers of CaMnO3 (10 unit cells) and paramagnetic metal layers of CaRuO3 (N unit cells) were fabricated on LaAlO3 substrates by pulsed-laser deposition. All the superlattices show ferromagnetic transitions at an almost identical temperature (TC˜95 K) and negative magnetoresistance below TC. Each magnetization and magnetoconductance of the whole superlattice at 5 K is constant and independent of CaRuO3 layer thickness when normalized by the number of the interfaces between CaMnO3 and CaRuO3. These results indicate that the ferromagnetism shows up only at the interface and is responsible for the magnetoresistance.

The CaV2.3 R-type voltage-gated Ca2+ channel in mouse sleep architecture.

PubMed

Siwek, Magdalena Elisabeth; Müller, Ralf; Henseler, Christina; Broich, Karl; Papazoglou, Anna; Weiergräber, Marco

2014-05-01

Voltage-gated Ca(2+) channels (VGCCs) are key elements in mediating thalamocortical rhythmicity. Low-voltage activated (LVA) CaV 3 T-type Ca(2+) channels have been related to thalamic rebound burst firing and to generation of non-rapid eye movement (NREM) sleep. High-voltage activated (HVA) CaV 1 L-type Ca(2+) channels, on the opposite, favor the tonic mode of action associated with higher levels of vigilance. However, the role of the HVA Non-L-type CaV2.3 Ca(2+) channels, which are predominantly expressed in the reticular thalamic nucleus (RTN), still remains unclear. Recently, CaV2.3(-/-) mice were reported to exhibit altered spike-wave discharge (SWD)/absence seizure susceptibility supported by the observation that CaV2.3 mediated Ca(2+) influx into RTN neurons can trigger small-conductance Ca(2+)-activated K(+)-channel type 2 (SK2) currents capable of maintaining thalamic burst activity. Based on these studies we investigated the role of CaV2.3 R-type Ca(2+) channels in rodent sleep. The role of CaV2.3 Ca(2+) channels was analyzed in CaV2.3(-/-) mice and controls in both spontaneous and artificial urethane-induced sleep, using implantable video-EEG radiotelemetry. Data were analyzed for alterations in sleep architecture using sleep staging software and time-frequency analysis. CaV2.3 deficient mice exhibited reduced wake duration and increased slow-wave sleep (SWS). Whereas mean sleep stage durations remained unchanged, the total number of SWS epochs was increased in CaV2.3(-/-) mice. Additional changes were observed for sleep stage transitions and EEG amplitudes. Furthermore, urethane-induced SWS mimicked spontaneous sleep results obtained from CaV2.3 deficient mice. Quantitative Real-time PCR did not reveal changes in thalamic CaV3 T-type Ca(2+) channel expression. The detailed mechanisms of SWS increase in CaV2.3(-/-) mice remain to be determined. Low-voltage activated CaV2.3 R-type Ca(2+) channels in the thalamocortical loop and extra

Control of IP3-mediated Ca2+ puffs in Xenopus laevis oocytes by the Ca2+-binding protein parvalbumin

PubMed Central

John, Linu M; Mosquera-Caro, Monica; Camacho, Patricia; Lechleiter, James D

2001-01-01

Elementary events of Ca2+ release (Ca2+ puffs) can be elicited from discrete clusters of inositol 1,4,5 trisphosphate receptors (IP3Rs) at low concentrations of IP3. Ca2+ puffs have rarely been observed unless elicited by either hormone treatment or introduction of IP3 into the cell. However, cells appear to have sufficient concentrations of IP3 (0.1-3.0 μM) to induce Ca2+ release under resting conditions. Here, we investigated Ca2+ puff activity in non-stimulated Xenopus oocytes using confocal microscopy. The fluorescent Ca2+ dye indicators Calcium Green 1 and Oregon Green 488 BAPTA-2 were injected into oocytes to monitor basal Ca2+ activity. In this preparation, injection or overexpression of parvalbumin, an EF-hand Ca2+-binding protein (CaBP), induced Ca2+ puffs in resting Xenopus oocytes. This activity was inhibited by heparin, an IP3R channel blocker, and by mutation of the Ca2+-binding sites in parvalbumin. Ca2+ puff activity was also evoked by injection of low concentrations of the Ca2+ chelator EGTA, but not by calbindin D28k, another member of the EF-hand CaBP superfamily. BAPTA and the Ca2+ indicator dye Oregon Green 488 BAPTA-1 evoked Ca2+ puff activity, while the dextran conjugate of Oregon Green 488 BAPTA-1 did not. These data indicate that a Ca2+ buffer must be mobile in order to increase Ca2+ puff activity. Together, the data indicate that some IP3Rs spontaneously release Ca2+ under resting concentrations of IP3. These elementary Ca2+ events appear to be below the level of detection of current imaging techniques. We suggest that parvalbumin evokes Ca2+ puffs by coordinating the activity of elementary IP3R channel openings. We conclude that Ca2+ release can be evoked not only by hormone-induced increases in IP3, but also by expression of mobile cytosolic CaBPs under resting concentrations of IP3. PMID:11507154

The intermediate-conductance Ca2+ -activated K+ channel (KCa3.1) in vascular disease.

PubMed

Tharp, D L; Bowles, D K

2009-01-01

The intermediate-conductance Ca(2+)-activated K(+) channel (K(Ca)3.1) was first described by Gardos in erythrocytes and later confirmed to play a significant role in T-cell activation and the immune response. More recently, K(Ca)3.1 has been characterized in numerous cell types which contribute to the development of vascular disease, such as T-cells, B-cells, endothelial cells, fibroblasts, macrophages, and dedifferentiated smooth muscle cells (SMCs). Physiologically, K(Ca)3.1 has been demonstrated to play a role in acetylcholine and endothelium-derived hyperpolarizing factor (EDHF) induced hyperpolarization, and thus control of blood pressure. Pathophysiologically, K(Ca)3.1 contributes to proliferation of T-cells, B-cells, fibroblasts, and vascular SMCs, as well as the migration of SMCs and macrophages and platelet coagulation. Recent studies have indicated that blockade of K(Ca)3.1, by specific blockers such as TRAM-34, could prove to be an effective treatment for vascular disease by inhibiting T-cell activation as well as preventing proliferation and migration of macrophages, endothelial cells, and SMCs. This vasculoprotective potential of K(Ca)3.1 inhibition has been confirmed in both rodent and swine models of restenosis. In this review, we will discuss the physiological and pathophysiological role of K(Ca)3.1 in cells closely associated with vascular biology, and the effect of K(Ca)3.1 blockers on the initiation and progression of vascular disease.

Site overview. Part 1 of 3part panorama with nos. CA27022 ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Site overview. Part 1 of 3-part panorama with nos. CA-2702-2 and CA-2707-3. Southern LTA ship hangar (building 28; hangar no. 2 in distant center of photograph. Seen from roadway leading to northern LTA ship hangar (building 29; hangar no. 1) landing pad. Looking 208 SSW. - Marine Corps Air Station Tustin, East of Red Hill Avenue between Edinger Avenue & Barranca Parkway, Tustin, Orange County, CA

Site overview. Part 1 of 3part panorama with nos. CA27022 ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Site overview. Part 1 of 3-part panorama with nos. CA-2702-2 and CA-2707-3. Southern LTA ship hangar (building 28; hangar no. 2 in distant center of photograph. Seen from roadway leading to northern LTA ship hangar (building 29; hangar no. 1) landing pad. Looking 208 SSW. - Marine Corps Air Station Tustin, Northern Lighter Than Air Ship Hangar, Meffett Avenue & Maxfield Street, Tustin, Orange County, CA

High-pressure transitions of diopside and wollastonite: phase equilibria and thermochemistry of CaMgSi 2O 6, CaSiO 3 and CaSi 2O 5-CaTiSiO 5 system

NASA Astrophysics Data System (ADS)

Akaogi, M.; Yano, M.; Tejima, Y.; Iijima, M.; Kojitani, H.

2004-06-01

Phase transitions of CaMgSi 2O 6 diopside and CaSiO 3 wollastonite were examined at pressures to 23 GPa and temperatures to 2000 °C, using a Kawai-type multiavil apparatus. Enthalpies of high-pressure phases in CaSiO 3 and in the CaSi 2O 5-CaTiSiO 5 system were also measured by high-temperature calorimetry. At 17-18 GPa, diopside dissociates to CaSiO 3-rich perovskite + Mg-rich (Mg,Ca)SiO 3 tetragonal garnet (Gt) above about 1400 °C. The solubilities of CaSiO 3 in garnet and MgSiO 3 in perovskite increase with temperature. At 17-18 GPa below about 1400 °C, diopside dissociates to Ca-perovskite + β-Mg 2SiO 4 + stishovite. The Mg, Si-phases coexisting with Ca-perovskite change to γ-Mg 2SiO 4 + stishovite, to ilmenite, and finally to Mg-perovskite with increasing pressure. CaSiO 3 wollastonite transforms to the walstromite structure, and further dissociates to Ca 2SiO 4 larnite + CaSi 2O 5 titanite. The latter transition occurs at 9-11 GPa with a positive Clapeyron slope. At 1600 °C, larnite + titanite transform to CaSiO 3 perovskite at 14.6±0.6 GPa, calibrated against the α-β transition pressure of Mg 2SiO 4. The enthalpies of formation of CaSiO 3 walstromite and CaSi 2O 5 titanite from the mixture of CaO and SiO 2 quartz at 298 K have been determined as -76.1±2.8, and -27.8±2.1 kJ/mol, respectively. The latter was estimated from enthalpy measurements of titanite solid solutions in the system CaSi 2O 5-CaTiSiO 5, because CaSi 2O 5 titanite transforms to a triclinic phase upon decompression. The enthalpy difference between titanite and the triclinic phase is only 1.5±4.8 kJ/mol. Using these enthalpies of formation and those of larnite and CaSiO 3 perovskite, the transition boundaries in CaSiO 3 have been calculated. The calculated boundaries for the wollastonite-walstromite-larnite + titanite transitions are consistent with the experimental determinations within the errors. The calculated boundary between larnite + titanite and Ca-perovskite has a slope of

The CaV2.3 R-Type Voltage-Gated Ca2+ Channel in Mouse Sleep Architecture

PubMed Central

Siwek, Magdalena Elisabeth; Müller, Ralf; Henseler, Christina; Broich, Karl; Papazoglou, Anna; Weiergräber, Marco

2014-01-01

Study Objectives: Voltage-gated Ca2+ channels (VGCCs) are key elements in mediating thalamocortical rhythmicity. Low-voltage activated (LVA) CaV 3 T-type Ca2+ channels have been related to thalamic rebound burst firing and to generation of non-rapid eye movement (NREM) sleep. High-voltage activated (HVA) CaV 1 L-type Ca2+ channels, on the opposite, favor the tonic mode of action associated with higher levels of vigilance. However, the role of the HVA Non-L-type CaV2.3 Ca2+ channels, which are predominantly expressed in the reticular thalamic nucleus (RTN), still remains unclear. Recently, CaV2.3−/− mice were reported to exhibit altered spike-wave discharge (SWD)/absence seizure susceptibility supported by the observation that CaV2.3 mediated Ca2+ influx into RTN neurons can trigger small-conductance Ca2+-activated K+-channel type 2 (SK2) currents capable of maintaining thalamic burst activity. Based on these studies we investigated the role of CaV2.3 R-type Ca2+ channels in rodent sleep. Methods: The role of CaV2.3 Ca2+ channels was analyzed in CaV2.3−/− mice and controls in both spontaneous and artificial urethane-induced sleep, using implantable video-EEG radiotelemetry. Data were analyzed for alterations in sleep architecture using sleep staging software and time-frequency analysis. Results: CaV2.3 deficient mice exhibited reduced wake duration and increased slow-wave sleep (SWS). Whereas mean sleep stage durations remained unchanged, the total number of SWS epochs was increased in CaV2.3−/− mice. Additional changes were observed for sleep stage transitions and EEG amplitudes. Furthermore, urethane-induced SWS mimicked spontaneous sleep results obtained from CaV2.3 deficient mice. Quantitative Real-time PCR did not reveal changes in thalamic CaV3 T-type Ca2+ channel expression. The detailed mechanisms of SWS increase in CaV2.3−/− mice remain to be determined. Conclusions: Low-voltage activated CaV2.3 R-type Ca2+ channels in the thalamocortical

Multiple C-terminal tail Ca2+/CaMs regulate CaV1.2 function but do not mediate channel dimerization

PubMed Central

Kim, Eun Young; Rumpf, Christine H; Van Petegem, Filip; Arant, Ryan J; Findeisen, Felix; Cooley, Elizabeth S; Isacoff, Ehud Y; Minor, Daniel L

2010-01-01

Interactions between voltage-gated calcium channels (CaVs) and calmodulin (CaM) modulate CaV function. In this study, we report the structure of a Ca2+/CaM CaV1.2 C-terminal tail complex that contains two PreIQ helices bridged by two Ca2+/CaMs and two Ca2+/CaM–IQ domain complexes. Sedimentation equilibrium experiments establish that the complex has a 2:1 Ca2+/CaM:C-terminal tail stoichiometry and does not form higher order assemblies. Moreover, subunit-counting experiments demonstrate that in live cell membranes CaV1.2s are monomers. Thus, contrary to previous proposals, the crystallographic dimer lacks physiological relevance. Isothermal titration calorimetry and biochemical experiments show that the two Ca2+/CaMs in the complex have different properties. Ca2+/CaM bound to the PreIQ C-region is labile, whereas Ca2+/CaM bound to the IQ domain is not. Furthermore, neither of lobes of apo-CaM interacts strongly with the PreIQ domain. Electrophysiological studies indicate that the PreIQ C-region has a role in calcium-dependent facilitation. Together, the data show that two Ca2+/CaMs can bind the CaV1.2 tail simultaneously and indicate a functional role for Ca2+/CaM at the C-region site. PMID:20953164

Multiple C-terminal tail Ca(2+)/CaMs regulate Ca(V)1.2 function but do not mediate channel dimerization.

PubMed

Kim, Eun Young; Rumpf, Christine H; Van Petegem, Filip; Arant, Ryan J; Findeisen, Felix; Cooley, Elizabeth S; Isacoff, Ehud Y; Minor, Daniel L

2010-12-01

Interactions between voltage-gated calcium channels (Ca(V)s) and calmodulin (CaM) modulate Ca(V) function. In this study, we report the structure of a Ca(2+)/CaM Ca(V)1.2 C-terminal tail complex that contains two PreIQ helices bridged by two Ca(2+)/CaMs and two Ca(2+)/CaM-IQ domain complexes. Sedimentation equilibrium experiments establish that the complex has a 2:1 Ca(2+)/CaM:C-terminal tail stoichiometry and does not form higher order assemblies. Moreover, subunit-counting experiments demonstrate that in live cell membranes Ca(V)1.2s are monomers. Thus, contrary to previous proposals, the crystallographic dimer lacks physiological relevance. Isothermal titration calorimetry and biochemical experiments show that the two Ca(2+)/CaMs in the complex have different properties. Ca(2+)/CaM bound to the PreIQ C-region is labile, whereas Ca(2+)/CaM bound to the IQ domain is not. Furthermore, neither of lobes of apo-CaM interacts strongly with the PreIQ domain. Electrophysiological studies indicate that the PreIQ C-region has a role in calcium-dependent facilitation. Together, the data show that two Ca(2+)/CaMs can bind the Ca(V)1.2 tail simultaneously and indicate a functional role for Ca(2+)/CaM at the C-region site.

Dependence of electrical transport properties of CaO(CaMnO3)m (m = 1, 2, 3, ∞) thermoelectric oxides on lattice periodicity

NASA Astrophysics Data System (ADS)

Baranovskiy, Andrei; Amouyal, Yaron

2017-02-01

The electrical transport properties of CaO(CaMnO3)m (m = 1, 2, 3, ∞) compounds are studied applying the density functional theory (DFT) in terms of band structure at the vicinity of the Fermi level (EF). It is shown that the total density of states (DOS) values at EF increase with increase in the m-values, which implies an increase in the electrical conductivity, σ, with increasing m-values, in full accordance with experimental results. Additionally, the calculated values of the relative slopes of the DOS at EF correlate with the experimentally measured Seebeck coefficients. The electrical conductivity and Seebeck coefficients were calculated in the framework of the Boltzmann transport theory applying the constant relaxation time approximation. By the analysis of experimental and calculated σ(Τ) dependences, the electronic relaxation time and mean free path values were estimated. It is shown that the electrical transport is dominated by electron scattering on the boundaries between perovskite (CaMnO3) and Ca oxide (CaO) layers inside the crystal lattice.

Optical magnetoelectric effect at CaRuO3-CaMnO3 interfaces as a polar ferromagnet

NASA Astrophysics Data System (ADS)

Yamada, Hiroyuki; Sato, H.; Akoh, H.; Kida, N.; Arima, T.; Kawasaki, M.; Tokura, Y.

2008-02-01

A correlated electron interface between paramagnetic CaRuO3 and antiferromagnetic CaMnO3 has been characterized with optical magnetoelectric (OME) effect as an interface-selective probe for spin and charge states. To detect the OME effect, i.e., nonreciprocal directional dichroism for visible or near-infrared light, we have constructed a "tricolor" superlattice with artificially broken inversion symmetry by stacking CaRuO3, CaMnO3, and CaTiO3, and patterned a grating structure with 4μm period on the superlattice. The observed intensity modulation (0.3% at 50K) in the Bragg diffraction verifies a charge transfer and concomitant ferromagnetism at the CaRuO3-CaMnO3 interface.

Carbachol-induced long-term synaptic depression is enhanced during senescence at hippocampal CA3-CA1 synapses.

PubMed

Kumar, Ashok

2010-08-01

Dysregulation of the cholinergic transmitter system is a hallmark of Alzheimer's disease and contributes to an age-associated decline in memory performance. The current study examined the influence of carbachol, a cholinergic receptor agonist, on synaptic transmission over the course of aging. Extracellular excitatory postsynaptic field potentials were recorded from CA3-CA1 synapses in acute hippocampal slices obtained from young adult (5-8 mo) and aged (22-24 mo) male Fischer 344 rats. Bath application of carbachol elicited a transient depression of synaptic transmission, which was followed by a long-lasting depression (CCh-LTD) observed 90 min after carbachol cessation in both age groups. However, the magnitude of CCh-LTD was significantly larger in senescent animals and was attenuated by N-methyl-D-aspartate receptor blockade in aged animals. Blockade of L-type Ca(2+) channels inhibited CCh-LTD to a greater extent in aged animals compared to young adults. Finally, the expression of CCh-LTD was dependent on protein synthesis. The results indicate that altered Ca(2+) homeostasis or muscarinic activation of Ca(2+) signaling contribute to the enhanced CCh-LTD during senescence.

Distinct pattern separation related transfer functions in human CA3/dentate and CA1 revealed using high-resolution fMRI and variable mnemonic similarity

PubMed Central

Lacy, Joyce W.; Yassa, Michael A.; Stark, Shauna M.; Muftuler, L. Tugan; Stark, Craig E.L.

2011-01-01

Producing and maintaining distinct (orthogonal) neural representations for similar events is critical to avoiding interference in long-term memory. Recently, our laboratory provided the first evidence for separation-like signals in the human CA3/dentate. Here, we extended this by parametrically varying the change in input (similarity) while monitoring CA1 and CA3/dentate for separation and completion-like signals using high-resolution fMRI. In the CA1, activity varied in a graded fashion in response to increases in the change in input. In contrast, the CA3/dentate showed a stepwise transfer function that was highly sensitive to small changes in input. PMID:21164173

Ferromagnetic CaRuO3

PubMed Central

Tripathi, Shivendra; Rana, Rakesh; Kumar, Sanjay; Pandey, Parul; Singh, R. S.; Rana, D. S.

2014-01-01

The non-magnetic and non-Fermi-liquid CaRuO3 is the iso-structural analog of the ferromagnetic (FM) and Fermi-liquid SrRuO3. We show that an FM order in the orthorhombic CaRuO3 can be established by the means of tensile epitaxial strain. The structural and magnetic property correlations in the CaRuO3 films formed on SrTiO3 (100) substrate establish a scaling relation between the FM moment and the tensile strain. The strain dependent crossover from non-magnetic to FM CaRuO3 was observed to be associated with switching of non-Fermi liquid to Fermi-liquid behavior. The intrinsic nature of this strain-induced FM order manifests in the Hall resistivity too; the anomalous Hall component realizes in FM tensile-strained CaRuO3 films on SrTiO3 (100) whereas the non-magnetic compressive-strained films on LaAlO3 (100) exhibit only the ordinary Hall effect. These observations of an elusive FM order are consistent with the theoretical predictions of scaling of the tensile epitaxial strain and the magnetic order in tensile CaRuO3. We further establish that the tensile strain is more efficient than the chemical route to induce FM order in CaRuO3. PMID:24464302

Identification of expressed genes in cDNA library of hemocytes from the RLO-challenged oyster, Crassostrea ariakensis Gould with special functional implication of three complement-related fragments (CaC1q1, CaC1q2 and CaC3).

PubMed

Xu, Ting; Xie, Jiasong; Li, Jianming; Luo, Ming; Ye, Shigen; Wu, Xinzhong

2012-06-01

A SMARTer™ cDNA library of hemocyte from Rickettsia-like organism (RLO) challenged oyster, Crassostrea ariakensis Gould was constructed. Random clones (400) were selected and single-pass sequenced, resulted in 200 unique sequences containing 96 known genes and 104 unknown genes. The 96 known genes were categorized into 11 groups based on their biological process. Furthermore, we identified and characterized three complement-related fragments (CaC1q1, CaC1q2 and CaC3). Tissue distribution analysis revealed that all of three fragments were ubiquitously expressed in all tissues studied including hemocyte, gills, mantle, digestive glands, gonads and adductor muscle, while the highest level was seen in the hemocyte. Temporal expression profile in the hemocyte monolayers reveled that the mRNA expression levels of three fragments presented huge increase after the RLO incubation at 3 h and 6 h in post-challenge, respectively. And the maximal expression levels at 3 h in post-challenge are about 256, 104 and 64 times higher than the values detected in the control of CaC1q1, CaC1q2 and CaC3, respectively. Copyright © 2012 Elsevier Ltd. All rights reserved.

CaV3.1 is a tremor rhythm pacemaker in the inferior olive

PubMed Central

Park, Young-Gyun; Park, Hye-Yeon; Lee, C. Justin; Choi, Soonwook; Jo, Seonmi; Choi, Hansol; Kim, Yang-Hann; Shin, Hee-Sup; Llinas, Rodolfo R.; Kim, Daesoo

2010-01-01

The rhythmic motor pathway activation by pacemaker neurons or circuits in the brain has been proposed as the mechanism for the timing of motor coordination, and the abnormal potentiation of this mechanism may lead to a pathological tremor. Here, we show that the potentiation of CaV3.1 T-type Ca2+ channels in the inferior olive contributes to the onset of the tremor in a pharmacological model of essential tremor. After administration of harmaline, 4- to 10-Hz synchronous neuronal activities arose from the IO and then propagated to cerebellar motor circuits in wild-type mice, but those rhythmic activities were absent in mice lacking CaV3.1 gene. Intracellular recordings in brain-stem slices revealed that the CaV3.1-deficient inferior olive neurons lacked the subthreshold oscillation of membrane potentials and failed to trigger 4- to 10-Hz rhythmic burst discharges in the presence of harmaline. In addition, the selective knockdown of CaV3.1 gene in the inferior olive by shRNA efficiently suppressed the harmaline-induced tremor in wild-type mice. A mathematical model constructed based on data obtained from patch-clamping experiments indicated that harmaline could efficiently potentiate CaV3.1 channels by changing voltage-dependent responsiveness in the hyperpolarizing direction. Thus, CaV3.1 is a molecular pacemaker substrate for intrinsic neuronal oscillations of inferior olive neurons, and the potentiation of this mechanism can be considered as a pathological cause of essential tremor. PMID:20498062

Radioisotope tracer studies of inorganic carbon and Ca in microbially derived CaCO3

USGS Publications Warehouse

Yates, Kimberly K.; Robbins, Lisa L.

1999-01-01

Microbial calcification significantly impacts the cycling and deposition of inorganic carbon. This research employs 45Ca and 14C techniques as radioisotopic tracers to examine the role of cellular cycling of Ca2+ and inorganic carbon in CaCO3 precipitation by the unicellular green alga Nannochloris atomus. Implications of the effects of these physiological aspects on CaCO3 precipitation and the effects of microbial calcification on CaCO3 δ13C ratios are discussed. Results from pulse/chase experiments indicate that intracellular Ca2+ is incorporated into extracellular CaCO3. Intracellular inorganic carbon leaks from cells within 10 to 12 s after injection of unlabelled NaHCO3, providing a source of inorganic carbon for extracellular CaCO3. Cellular expulsion of calcium plays a key role in increasing the CaCO3 saturation state at the site of calcification. The δ13C ratios of microbial carbonates may vary depending on the amount of photorespiratory CO2 incorporated.

Possibility of adjusting the photoluminescence spectrum of Ca scheelites to the emission spectrum of incandescent lamps: [ nCaWO4-(1- n)CaMoO4]: Eu3+ solid solutions

NASA Astrophysics Data System (ADS)

Bakovets, V. V.; Zolotova, E. S.; Antonova, O. V.; Korol'kov, I. V.; Yushina, I. V.

2016-12-01

The specific features of the photoluminescence of [ nCaWO4-(1- n)CaMoO4]:Eu3+ solid solutions with the scheelite structure are examined using X-ray phase analysis and photoluminescence, Raman scattering, and diffuse reflectance spectroscopy. The studied features are associated with a change in the long- and short-range orders of the crystal lattice upon variations in the composition of solutions in the range n = 0-1.0 (with a pitch of 0.2) at a concentration of red photoluminescence activator Eu3+ of 2 mol %. The mechanism of the modification of photoluminescence of solid solutions upon variations in their composition has been discussed. Anomalies in the variations in parameters of the crystal lattice, its short-range order, and luminescence spectra have been observed in the transition from pure compounds CaMoO4:Eu3+ and CaWO4:Eu3+ to solutions; the concentration of Eu3+ ions in the centrosymmetric localization increases (decreases) in the transition from the molybdate (tungstate). It has been demonstrated that the spectral radiant emittance of solid solution [0.4CaWO4-0.6CaMoO4]:Eu3+ (2 mol %) is the closest to that of an incandescent lamp.

Ca2+ spike initiation from sensitized inositol 1,4,5-trisphosphate-sensitive Ca2+ stores in megakaryocytes.

PubMed

Ikeda, M; Kurokawa, K; Maruyama, Y

1994-06-01

Ca(2+)-mediated Ca2+ spikes were analysed in fura-2-loaded megakaryocytes. Direct Ca2+ loading using whole-cell dialysis induced an all-or-none Ca2+ spike on top of a tonic increase in cellular Ca2+ concentration ([Ca2+]i) with a latency of 3-7 s. The latency decreased with increasingly higher concentrations of Ca2+ in the dialysing solution. Spike size and its initiation did not correlate with the tonic level of [Ca2+]i. Thapsigargin completely abolished the Ca(2+)-induced spike initiation, suggesting that Ca2+ spikes originate from thapsigargin-sensitive Ca2+ pools. An inhibitor of phosphatidylinositide-specific phospholipase C (PLC), 2-nitro-4-carboxyphenyl-N,N-diphenyl-carbamate prolonged the latency without changes of spike size in most cases (6/9 cells), but abolished the spike initiation in the other cells (3/9). The results suggest that an increase in [Ca2+]i charges up the inositol-1,4,5-trisphosphate-(InsP3)- and thapsigargin-sensitive Ca2+ pools which progressively sensitize to low or slightly elevated levels of InsP3 by the action of Ca(2+)-dependent PLC until a critical Ca2+ content is reached, and then the Ca2+ spike is triggered. Thus, the limiting step of Ca2+ spike triggering is the initial filling process and the level of InsP3 in megakaryocytes.

Dynamic redistribution of calcium sensitive potassium channels (hK(Ca)3.1) in migrating cells.

PubMed

Schwab, Albrecht; Nechyporuk-Zloy, Volodymyr; Gassner, Birgit; Schulz, Christoph; Kessler, Wolfram; Mally, Sabine; Römer, Michael; Stock, Christian

2012-02-01

Calcium-sensitive potassium channels (K(Ca)3.1) are expressed in virtually all migrating cells. Their activity is required for optimal cell migration so that their blockade leads to slowing down. K(Ca)3.1 channels must be inserted into the plasma membrane in order to elicit their physiological function. However, the plasma membrane of migrating cells is subject to rapid recycling by means of endo- and exocytosis. Here, we focussed on the endocytic internalization and the intracellular transport of the human isoform hK(Ca)3.1. A hK(Ca)3.1 channel construct with an HA-tag in the extracellularly located S3-S4 linker was transfected into migrating transformed renal epithelial MDCK-F cells. Channel internalization was visualized and quantified with immunofluorescence and a cell-based ELISA. Movement of hK(Ca)3.1 channel containing vesicles as well as migration of MDCK-F cells were monitored by means of time lapse video microscopy. hK(Ca)3.1 channels are endocytosed during migration. Most of the hK(Ca)3.1 channel containing vesicles are moving at a speed of up to 2 µm/sec in a microtubule-dependent manner towards the front of MDCK-F cells. Our experiments indicate that endocytosis of hK(Ca)3.1 channels is clathrin-dependent since they colocalize with clathrin adaptor proteins and since it is impaired when a C-terminal dileucine motif is mutated. The C-terminal dileucine motif is also important for the subcellular localization of hK(Ca)3.1 channels in migrating cells. Mutated channels are no longer concentrated at the leading edge. We therefore propose that recycling of hK(Ca)3.1 channels contributes to their characteristic subcellular distribution in migrating cells. Copyright © 2011 Wiley Periodicals, Inc.

Extracellular calcium-sensing-receptor (CaR)-mediated opening of an outward K(+) channel in murine MC3T3-E1 osteoblastic cells: evidence for expression of a functional CaR

NASA Technical Reports Server (NTRS)

Ye, C. P.; Yamaguchi, T.; Chattopadhyay, N.; Sanders, J. L.; Vassilev, P. M.; Brown, E. M.; O'Malley, B. W. (Principal Investigator)

2000-01-01

The existence in osteoblasts of the G-protein-coupled extracellular calcium (Ca(o)(2+))-sensing receptor (CaR) that was originally cloned from parathyroid and kidney remains controversial. In our recent studies, we utilized multiple detection methods to demonstrate the expression of CaR transcripts and protein in several osteoblastic cell lines, including murine MC3T3-E1 cells. Although we and others have shown that high Ca(o)(2+) and other polycationic CaR agonists modulate the function of MC3T3-E1 cells, none of these actions has been unequivocally shown to be mediated by the CaR. Previous investigations using neurons and lens epithelial cells have shown that activation of the CaR stimulates Ca(2+)-activated K(+) channels. Because osteoblastic cells express a similar type of channel, we have examined the effects of specific "calcimimetic" CaR activators on the activity of a Ca(2+)-activated K(+) channel in MC3T3-E1 cells as a way of showing that the CaR is not only expressed in those cells but is functionally active. Patch-clamp analysis in the cell-attached mode showed that raising Ca(o)(2+) from 0.75 to 2.75 mmol/L elicited about a fourfold increase in the open state probability (P(o)) of an outward K(+) channel with a conductance of approximately 92 pS. The selective calcimimetic CaR activator, NPS R-467 (0.5 micromol/L), evoked a similar activation of the channel, while its less active stereoisomer, NPSS-467 (0.5 micromol/L), did not. Thus, the CaR is not only expressed in MC3T3-E1 cells, but is also functionally coupled to the activity of a Ca(2+)-activated K(+) channel. This receptor, therefore, could transduce local or systemic changes in Ca(o)(2+) into changes in the activity of this ion channel and related physiological processes in these and perhaps other osteoblastic cells.

The diagnostic value of serum tumor markers CEA, CA19-9, CA125, CA15-3, and TPS in metastatic breast cancer.

PubMed

Wang, Weigang; Xu, Xiaoqin; Tian, Baoguo; Wang, Yan; Du, Lili; Sun, Ting; Shi, Yanchun; Zhao, Xianwen; Jing, Jiexian

2017-07-01

This study aims to understand the diagnostic value of serum tumor markers carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), cancer antigen 125 (CA125), cancer antigen 15-3 (CA15-3), and tissue polypeptide-specific antigen (TPS) in metastatic breast cancer (MBC). A total of 164 metastatic breast cancer patients in Shanxi Cancer Hospital were recruited between February 2016 and July 2016. 200 breast cancer patients without metastasis in the same period were randomly selected as the control group. The general characteristics, immunohistochemical, and pathological results were investigated between the two groups, and tumor markers were determined. There were statistical differences in the concentration and the positive rates of CEA, CA19-9, CA125, CA15-3, and TPS between the MBC and control group (P<0.05). The highest sensitivity was in CEA and the highest specificity was in CA125 for the diagnosis of MBC when using a single tumor marker at 56.7% and 97.0%, respectively. In addition, two tumor markers were used for the diagnosis of MBC and the CEA and TPS combination had the highest diagnostic sensitivity with 78.7%, while the CA15-3 and CA125 combination had the highest specificity of 91.5%. Analysis of tumor markers of 164 MBC found that there were statistical differences in the positive rates of CEA and CA15-3 between bone metastases and other metastases (χ 2 =6.00, P=0.014; χ 2 =7.32, P=0.007, respectively). The sensitivity and specificity values of the CEA and CA15-3 combination in the diagnosis of bone metastases were 77.1% and 45.8%, respectively. The positive rate of TPS in the lung metastases group was lower than in other metastases (χ 2 =8.06, P=0.005).There were significant differences in the positive rates of CA15-3 and TPS between liver metastases and other metastases (χ 2 =15.42, P<0.001; χ 2 =9.72, P=0.002, respectively). The sensitivity and specificity of the CA15-3 and TPS combination in the diagnosis of liver metastases were 92.3% and

4. PART 1 OF 3 PART PANORAMA WITH NOS. CA265J5 ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

4. PART 1 OF 3 PART PANORAMA WITH NOS. CA-265-J-5 AND CA-265-J-6 OF FIGUEROA STREET AND LOS ANGELES RIVER VIADUCTS. NOTE TUNNEL NO.1 NORTH PORTAL AT LEFT REAR. LOOKING 268°W. - Arroyo Seco Parkway, Figueroa Street Viaduct, Spanning Los Angeles River, Los Angeles, Los Angeles County, CA

Regional Specific Evidence for Memory-Load Dependent Activity in the Dorsal Subiculum and the Lateral Entorhinal Cortex

PubMed Central

Ku, Shih-pi; Nakamura, Nozomu H.; Maingret, Nicolas; Mahnke, Liv; Yoshida, Motoharu; Sauvage, Magdalena M.

2017-01-01

The subiculum and the lateral entorhinal cortex (LEC) are the main output areas of the hippocampus which contribute to spatial and non-spatial memory. The proximal part of the subiculum (bordering CA1) receives heavy projections from the perirhinal cortex and the distal part of CA1 (bordering the subiculum), both known for their ties to object recognition memory. However, the extent to which the proximal subiculum contributes to non-spatial memory is still unclear. Comparatively, the involvement of the LEC in non-spatial information processing is quite well known. However, very few studies have investigated its role within the frame of memory function. Thus, it is not known whether its contribution depends on memory load. In addition, the deep layers of the EC have been shown to be predictive of subsequent memory performance, but not its superficial layers. Hence, here we tested the extent to which the proximal part of the subiculum and the superficial and deep layers of the LEC contribute to non-spatial memory, and whether this contribution depends on the memory load of the task. To do so, we imaged brain activity at cellular resolution in these areas in rats performing a delayed nonmatch to sample task based on odors with two different memory loads (5 or 10 odors). This imaging technique is based on the detection of the RNA of the immediate-early gene Arc, which is especially tied to synaptic plasticity and behavioral demands, and is commonly used to map activity in the medial temporal lobe. We report for the first time that the proximal part of the subiculum is recruited in a memory-load dependent manner and the deep layers of the LEC engaged under high memory load conditions during the retrieval of non-spatial memory, thus shedding light on the specific networks contributing to non-spatial memory retrieval. PMID:28790897

Regional Specific Evidence for Memory-Load Dependent Activity in the Dorsal Subiculum and the Lateral Entorhinal Cortex.

PubMed

Ku, Shih-Pi; Nakamura, Nozomu H; Maingret, Nicolas; Mahnke, Liv; Yoshida, Motoharu; Sauvage, Magdalena M

2017-01-01

The subiculum and the lateral entorhinal cortex (LEC) are the main output areas of the hippocampus which contribute to spatial and non-spatial memory. The proximal part of the subiculum (bordering CA1) receives heavy projections from the perirhinal cortex and the distal part of CA1 (bordering the subiculum), both known for their ties to object recognition memory. However, the extent to which the proximal subiculum contributes to non-spatial memory is still unclear. Comparatively, the involvement of the LEC in non-spatial information processing is quite well known. However, very few studies have investigated its role within the frame of memory function. Thus, it is not known whether its contribution depends on memory load. In addition, the deep layers of the EC have been shown to be predictive of subsequent memory performance, but not its superficial layers. Hence, here we tested the extent to which the proximal part of the subiculum and the superficial and deep layers of the LEC contribute to non-spatial memory, and whether this contribution depends on the memory load of the task. To do so, we imaged brain activity at cellular resolution in these areas in rats performing a delayed nonmatch to sample task based on odors with two different memory loads (5 or 10 odors). This imaging technique is based on the detection of the RNA of the immediate-early gene Arc , which is especially tied to synaptic plasticity and behavioral demands, and is commonly used to map activity in the medial temporal lobe. We report for the first time that the proximal part of the subiculum is recruited in a memory-load dependent manner and the deep layers of the LEC engaged under high memory load conditions during the retrieval of non-spatial memory, thus shedding light on the specific networks contributing to non-spatial memory retrieval.

Down-regulation of CaV1.2 channels during hypertension: how fewer CaV1.2 channels allow more Ca2+ into hypertensive arterial smooth muscle

PubMed Central

Tajada, Sendoa; Cidad, Pilar; Colinas, Olaia; Santana, L Fernando; López-López, José R; Pérez-García, M Teresa

2013-01-01

Hypertension is a clinical syndrome characterized by increased arterial tone. Although the mechanisms are varied, the generally accepted view is that increased CaV1.2 channel function is a common feature of this pathological condition. Here, we investigated the mechanisms underlying vascular dysfunction in a mouse model of genetic hypertension. Contrary to expectation, we found that whole-cell CaV1.2 currents (ICa) were lower in hypertensive (BPH line) than normotensive (BPN line) myocytes. However, local CaV1.2 sparklet activity was higher in BPH cells, suggesting that the relatively low ICa in these cells was produced by a few hyperactive CaV1.2 channels. Furthermore, our data suggest that while the lower expression of the pore-forming α1c subunit of CaV1.2 currents underlies the lower ICa in BPH myocytes, the increased sparklet activity was due to a different composition in the auxiliary subunits of the CaV1.2 complexes. ICa currents in BPN cells were produced by channels composed of α1c/α2δ/β3 subunits, while in BPH myocytes currents were probably generated by the opening of channels formed by α1c/α2δ/β2 subunits. In addition, Ca2+ sparks evoked large conductance, Ca2+-activated K+ (BK) currents of lower magnitude in BPH than in BPN myocytes, because BK channels were less sensitive to Ca2+. Our data are consistent with a model in which a decrease in the global number of CaV1.2 currents coexist with the existence of a subpopulation of highly active channels that dominate the resting Ca2+ influx. The decrease in BK channel activity makes the hyperpolarizing brake ineffective and leads BPH myocytes to a more contracted resting state. PMID:24167226

Insight into Ca-Substitution Effects on O3-Type NaNi1/3 Fe1/3 Mn1/3 O2 Cathode Materials for Sodium-Ion Batteries Application.

PubMed

Sun, Liqi; Xie, Yingying; Liao, Xiao-Zhen; Wang, Hong; Tan, Guoqiang; Chen, Zonghai; Ren, Yang; Gim, Jihyeon; Tang, Wan; He, Yu-Shi; Amine, Khalil; Ma, Zi-Feng

2018-04-18

O3-type NaNi 1/3 Fe 1/3 Mn 1/3 O 2 (NaNFM) is well investigated as a promising cathode material for sodium-ion batteries (SIBs), but the cycling stability of NaNFM still needs to be improved by using novel electrolytes or optimizing their structure with the substitution of different elements sites. To enlarge the alkali-layer distance inside the layer structure of NaNFM may benefit Na + diffusion. Herein, the effect of Ca-substitution is reported in Na sites on the structural and electrochemical properties of Na 1- x Ca x /2 NFM (x = 0, 0.05, 0.1). X-ray diffraction (XRD) patterns of the prepared Na 1- x Ca x /2 NFM samples show single α-NaFeO 2 type phase with slightly increased alkali-layer distance as Ca content increases. The cycling stabilities of Ca-substituted samples are remarkably improved. The Na 0.9 Ca 0.05 Ni 1/3 Fe 1/3 Mn 1/3 O 2 (Na 0.9 Ca 0.05 NFM) cathode delivers a capacity of 116.3 mAh g -1 with capacity retention of 92% after 200 cycles at 1C rate. In operando XRD indicates a reversible structural evolution through an O3-P3-P3-O3 sequence of Na 0.9 Ca 0.05 NFM cathode during cycling. Compared to NaNMF, the Na 0.9 Ca 0.05 NFM cathode shows a wider voltage range in pure P3 phase state during the charge/discharge process and exhibits better structure recoverability after cycling. The superior cycling stability of Na 0.9 Ca 0.05 NFM makes it a promising material for practical applications in sodium-ion batteries. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Control theory-based regulation of hippocampal CA1 nonlinear dynamics.

PubMed

Hsiao, Min-Chi; Song, Dong; Berger, Theodore W

2008-01-01

We are developing a biomimetic electronic neural prosthesis to replace regions of the hippocampal brain area that have been damaged by disease or insult. Our previous study has shown that the VLSI implementation of a CA3 nonlinear dynamic model can functionally replace the CA3 subregion of the hippocampal slice. As a result, the propagation of temporal patterns of activity from DG-->VLSI-->CA1 reproduces the activity observed experimentally in the biological DG-->CA3-->CA1 circuit. In this project, we incorporate an open-loop controller to optimize the output (CA1) response. Specifically, we seek to optimize the stimulation signal to CA1 using a predictive dentate gyrus (DG)-CA1 nonlinear model (i.e., DG-CA1 trajectory model) and a CA1 input-output model (i.e., CA1 plant model), such that the ultimate CA1 response (i.e., desired output) can be first predicted by the DG-CA1 trajectory model and then transformed to the desired stimulation through the inversed CA1 plant model. Lastly, the desired CA1 output is evoked by the estimated optimal stimulation. This study will be the first stage of formulating an integrated modeling-control strategy for the hippocampal neural prosthetic system.

Thermal, spectroscopic properties and laser performance at 1.06 and 1.33 μm of Nd : Ca 4YO(BO 3) 3 and Nd : Ca 4GdO(BO 3) 3 crystals

NASA Astrophysics Data System (ADS)

Wang, Changqing; Zhang, Huaijin; Meng, Xianlin; Zhu, Li; Chow, Y. T.; Liu, Xuesong; Cheng, Ruiping; Yang, Zhaohe; Zhang, Shaojun; Sun, Lianke

2000-11-01

Nd : Ca 4YO(BO 3) 3 (Nd : YCOB) and Nd : Ca 4GdO(BO 3) 3 (Nd : GdCOB) crystals were grown by Czochralski method. Thermal expansion and specific heat of these two crystals were experimentally determined. Their fluorescence spectra were measured within the range from 1000 to 1500 nm. Laser output experiments at 1.06 and 1.33 μm of Nd : YCOB and Nd : GdCOB crystals were performed with a cw Ti : sapphire laser as the pump source.

Formation process of micro arc oxidation coatings obtained in a sodium phytate containing solution with and without CaCO3 on binary Mg-1.0Ca alloy

NASA Astrophysics Data System (ADS)

Zhang, R. F.; Zhang, Y. Q.; Zhang, S. F.; B. Qu; Guo, S. B.; Xiang, J. H.

2015-01-01

Micro arc oxidation (MAO) is an effective method to improve the corrosion resistance of magnesium alloys. In order to reveal the influence of alloying element Ca and CaCO3 electrolyte on the formation process and chemical compositions of MAO coatings on binary Mg-1.0Ca alloy, anodic coatings after different anodizing times were prepared on binary Mg-1.0Ca alloy in a base solution containing 3 g/L sodium hydroxide and 15 g/L sodium phytate with and without addition of CaCO3. The coating formation was studied by using scanning electron microscope (SEM), energy dispersive X-ray spectroscopy (EDS) and X-ray diffraction (XRD). The results show that Mg-1.0Ca alloy is composed of two phases, the Mg phase and Mg2Ca phase. After treating for 5 s, the coating began to develop and was preferentially formed on the area nearby Mg2Ca phase, which may be resulted from the intrinsic electronegative potential of the Mg phase than that of Mg2Ca phase. Anodic coatings unevenly covered the total surface after 20 s. After 80 s, the coatings were uniformly developed on Mg-1.0Ca alloy with micro pores. During MAO process, some sodium phytate molecules are hydrolyzed into inorganic phosphate. CaCO3 has minor influence on the calcium content of the obtained MAO coatings.

The system Na2CO3-CaCO3 at 3 GPa

NASA Astrophysics Data System (ADS)

Podborodnikov, Ivan V.; Shatskiy, Anton; Arefiev, Anton V.; Rashchenko, Sergey V.; Chanyshev, Artem D.; Litasov, Konstantin D.

2018-04-01

It was suggested that alkali-alkaline earth carbonates may have a substantial role in petrological processes relevant to metasomatism and melting of the Earth's mantle. Because natrite, Na2CO3, Na-Ca carbonate (shortite and/or nyerereite), and calcite, CaCO3, have been recently reported from xenoliths of shallow mantle (110-115 km) origin, we performed experiments on phase relations in the system Na2CO3-CaCO3 at 3 GPa and 800-1300 °C. We found that the system has one intermediate compound, Na2Ca3(CO3)4, at 800 °C, and two intermediate compounds, Na2Ca(CO3)2 and Na2Ca3(CO3)4, at 850 °C. CaCO3 crystals recovered from experiments at 950 and 1000 °C are aragonite and calcite, respectively. Maximum solid solution of CaCO3 in Na2CO3 is 20 mol% at 850 °C. The Na-carbonate-Na2Ca(CO3)2 eutectic locates near 860 °C and 56 mol% Na2CO3. Na2Ca(CO3)2 melts incongruently near 880 °C to produce Na2Ca3(CO3)4 and a liquid containing about 51 mol% Na2CO3. Na2Ca3(CO3)4 disappears above 1000 °C via incongruent melting to calcite and a liquid containing about 43 mol% Na2CO3. At 1050 °C, the liquid, coexisting with Na-carbonate, contains 87 mol% Na2CO3. Na-carbonate remains solid up to 1150 °C and melts at 1200 °C. The Na2CO3 content in the liquid coexisting with calcite decreases to 15 mol% as temperature increases to 1300 °C. Considering the present and previous data, a range of the intermediate compounds on the liquidus of the Na2CO3-CaCO3 join changes as pressure increases in the following sequence: Na2Ca(CO3)2 (0.1 GPa) → Na2Ca(CO3)2, Na2Ca3(CO3)4 (3 GPa) → Na4Ca(CO3)3, Na2Ca3(CO3)4 (6 GPa). Thus, the Na2Ca(CO3)2 nyerereite stability field extends to the shallow mantle pressures. Consequently, findings of nyerereite among daughter phases in the melt inclusions in olivine from the sheared garnet peridotites are consistent with their mantle origin.

Morphometric Parameters of Pyramidal Cells in CA1-CA4 Fields in the Hippocampus of Arctic Fox (Vulpes lagopus).

PubMed

Łuszczewska-Sierakowska, Iwona; Wawrzyniak-Gacek, Agata; Guz, Tomasz; Tatara, Marcin R; Charuta, Anna

2015-01-01

The aim of the study was a quantitative examination of neurons of hippocampal subfields (CA1-CA4) in mature male Arctic fox (Vulpes lagopus; syn. Alopex lagopus). The preparations were dyed using cresyl violet. Histological preparations were used to morphometricaly analyze the neurons of hippocampus. This analysis included the following parameters: average size of cells in μm, periphery of cells in μm, average cell area in μm2, percentage of cells in area and size of the largest and smallest cells in μm in CA1-CA4 fields. Morphometric observations show that the cells involved in hippocampal formation in polar fox in all layers CA1 -CA4 differ in size, shape, cell area and nucleus area. The size of the cell area in CA3 is the largest and fluctuates around 249.4 μm2, whereas in CA2 the cell area is 184.1 μm2. The cells of the CA2 field are densely arranged, pyramidal and contain a small amount of cytoplasm; their size fluctuates. Cells of CA2 and CA4 had the largest diameter of about 23.6 μm, whereas cells of the CA3 field had the smallest diameter of about 8.3 μm.

Memory retrieval along the proximodistal axis of CA1.

PubMed

Nakazawa, Yuki; Pevzner, Aleksandr; Tanaka, Kazumasa Z; Wiltgen, Brian J

2016-09-01

The proximal and distal segments of CA1 are thought to perform distinct computations. Neurons in proximal CA1 are reciprocally connected with the medial entorhinal cortex (MEC) and exhibit precise spatial firing. In contrast, cells in distal CA1 communicate with the lateral entorhinal cortex (LEC), exhibit more diffuse spatial firing and are affected by the presence of objects in the environment. To determine if these segments make unique contributions to memory retrieval, we examined cellular activity along the proximodistal axis of CA1 using transgenic reporter mice. Neurons tagged during context learning in proximal CA1 were more likely to be reactivated during testing than those in distal CA1. This was true following context fear conditioning and after exposure to a novel environment. Reactivation was also higher in brain regions connected to proximal CA1 (MEC, distal CA3) than those connected to the distal segment (LEC, proximal CA3). To examine contributions to memory retrieval, we performed neurotoxic lesions of proximal or distal CA1 after training. Lesions of the proximal segment significantly impaired memory retrieval while damage to distal CA1 had no effect. These data suggest that context memories are retrieved by a hippocampal microcircuit that involves the proximal but not distal segment of CA1. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Modafinil inhibits K(Ca)3.1 currents and muscle contraction via a cAMP-dependent mechanism.

PubMed

Choi, Shinkyu; Kim, Moon Young; Joo, Ka Young; Park, Seonghee; Kim, Ji Aee; Jung, Jae-Chul; Oh, Seikwan; Suh, Suk Hyo

2012-07-01

Modafinil has been used as a psychostimulant for the treatment of narcolepsy. However, its primary mechanism of action remains elusive. Therefore, we examined the effects of modafinil on K(Ca)3.1 channels and vascular smooth muscle contraction. K(Ca)3.1 currents and channel activity were measured using a voltage-clamp technique and inside-out patches in mouse embryonic fibroblast cell line, NIH-3T3 fibroblasts. Intracellular adenosine 3',5'-cyclic monophosphate (cAMP) concentration was measured, and the phosphorylation of K(Ca)3.1 channel protein was examined using western blotting in NIH-3T3 fibroblasts and/or primary cultured mouse aortic smooth muscle cells (SMCs). Muscle contractions were recorded from mouse aorta and rat pulmonary artery by using a myograph developed in-house. Modafinil was found to inhibit K(Ca)3.1 currents in a concentration-dependent manner, and the half-maximal inhibition (IC(50)) of modafinil for the current inhibition was 6.8 ± 0.7 nM. The protein kinase A (PKA) activator forskolin also inhibited K(Ca)3.1 currents. The inhibitory effects of modafinil and forskolin on K(Ca)3.1 currents were blocked by the PKA inhibitors PKI(14-22) or H-89. In addition, modafinil relaxed blood vessels (mouse aorta and rat pulmonary artery) in a concentration-dependent manner. Modafinil increased cAMP concentrations in NIH-3T3 fibroblasts or primary cultured mouse aortic SMCs and phosphorylated K(Ca)3.1 channel protein in NIH-3T3 fibroblasts. However, open probability and single-channel current amplitudes of K(Ca)3.1 channels were not changed by modafinil. From these results, we conclude that modafinil inhibits K(Ca)3.1 channels and vascular smooth muscle contraction by cAMP-dependent phosphorylation, suggesting that modafinil can be used as a cAMP-dependent K(Ca)3.1 channel blocker and vasodilator. Copyright © 2012 Elsevier Ltd. All rights reserved.

Inhibition of recombinant Ca(v)3.1 (alpha(1G)) T-type calcium channels by the antipsychotic drug clozapine.

PubMed

Choi, Kee-Hyun; Rhim, Hyewhon

2010-01-25

Low voltage-activated T-type calcium channels are involved in the regulation of the neuronal excitability, and could be subject to many antipsychotic drugs. The effects of clozapine, an atypical antipsychotic drug, on recombinant Ca(v)3.1 T-type calcium channels heterologously expressed in human embryonic kidney 293 cells were examined using whole-cell patch-clamp recordings. At a standard holding potential of -100 mV, clozapine inhibited Ca(v)3.1 currents with an IC(50) value of 23.7+/-1.3 microM in a use-dependent manner. However, 10 microM clozapine inhibited more than 50% of the Ca(v)3.1 currents in recordings at a more physiologically relevant holding potential of -75 mV. Clozapine caused a significant hyperpolarizing shift in the steady-state inactivation curve of the Ca(v)3.1 channels, which is presumably the main mechanism accounting for the inhibition of the Ca(v)3.1 currents. In addition, clozapine slowed Ca(v)3.1 deactivation and inactivation kinetics but not activation kinetics. Clozapine-induced changes in deactivation and inactivation rates of the Ca(v)3.1 channel gating would likely facilitate calcium influx via Ca(v)3.1 T-type calcium channels. Thus, clozapine may exert its therapeutic and/or side effects by altering cell's excitability and firing properties through actions on T-type calcium channels.

Interfacial magnetism in CaRuO3/CaMnO3 superlattices grown on (001) SrTiO3

NASA Astrophysics Data System (ADS)

He, C.; Zhai, X.; Mehta, V. V.; Wong, F. J.; Suzuki, Y.

2011-04-01

We have studied epitaxially grown superlattices of CaRuO3/CaMnO3 as well as an alloy film of CaMn0.5Ru0.5O3 on (001) SrTiO3 substrates. In contrast to previous experiments, we have studied CRO/CMO superlattices with a constant CRO thickness and variable CMO thickness. All superlattices exhibit Curie temperatures (TC) of 110 K. The saturated magnetization per interfacial Mn cation has been found to be 1.1 μB/Mn ion. The TC's of the superlattices are much lower than the TC of the alloy film while the saturated magnetization values are larger than that of the alloy film. These observations suggest that interdiffusion alone cannot account for ferromagnetism in the superlattices and that double exchange induced FM must play a role at the interfaces.

Ab-initio calculations of the Ruddlesden Popper phases CaMnO3, CaO(CaMnO3) and CaO(CaMnO3)2

NASA Astrophysics Data System (ADS)

Cardoso, C.; Borges, R. P.; Gasche, T.; Godinho, M.

2008-01-01

The present work reports ab-initio density functional theory calculations for the Ruddlesden-Popper phase CaO(CaMnO3)n compounds. In order to study the evolution of the properties with the number of perovskite layers, a detailed analysis of the densities of states calculated for each compound and for several magnetic configurations was performed. The effect of distortions of the crystal structure on the magnetic ground state is also analysed and the exchange constants and transition temperatures are calculated for the three compounds using a mean field model. The calculated magnetic ground state structures and magnetic moments are in good agreement with experimental results and previous calculations.

Functional properties of a newly identified C-terminal splice variant of Cav1.3 L-type Ca2+ channels.

PubMed

Bock, Gabriella; Gebhart, Mathias; Scharinger, Anja; Jangsangthong, Wanchana; Busquet, Perrine; Poggiani, Chiara; Sartori, Simone; Mangoni, Matteo E; Sinnegger-Brauns, Martina J; Herzig, Stefan; Striessnig, Jörg; Koschak, Alexandra

2011-12-09

An intramolecular interaction between a distal (DCRD) and a proximal regulatory domain (PCRD) within the C terminus of long Ca(v)1.3 L-type Ca(2+) channels (Ca(v)1.3(L)) is a major determinant of their voltage- and Ca(2+)-dependent gating kinetics. Removal of these regulatory domains by alternative splicing generates Ca(v)1.3(42A) channels that activate at a more negative voltage range and exhibit more pronounced Ca(2+)-dependent inactivation. Here we describe the discovery of a novel short splice variant (Ca(v)1.3(43S)) that is expressed at high levels in the brain but not in the heart. It lacks the DCRD but, in contrast to Ca(v)1.3(42A), still contains PCRD. When expressed together with α2δ1 and β3 subunits in tsA-201 cells, Ca(v)1.3(43S) also activated at more negative voltages like Ca(v)1.3(42A) but Ca(2+)-dependent inactivation was less pronounced. Single channel recordings revealed much higher channel open probabilities for both short splice variants as compared with Ca(v)1.3(L). The presence of the proximal C terminus in Ca(v)1.3(43S) channels preserved their modulation by distal C terminus-containing Ca(v)1.3- and Ca(v)1.2-derived C-terminal peptides. Removal of the C-terminal modulation by alternative splicing also induced a faster decay of Ca(2+) influx during electrical activities mimicking trains of neuronal action potentials. Our findings extend the spectrum of functionally diverse Ca(v)1.3 L-type channels produced by tissue-specific alternative splicing. This diversity may help to fine tune Ca(2+) channel signaling and, in the case of short variants lacking a functional C-terminal modulation, prevent excessive Ca(2+) accumulation during burst firing in neurons. This may be especially important in neurons that are affected by Ca(2+)-induced neurodegenerative processes.

Vibrational spectroscopic study of poldervaartite CaCa[SiO3(OH)(OH)].

PubMed

Frost, Ray L; López, Andrés; Scholz, Ricardo; Lima, Rosa Malena Fernandes

2015-02-25

We have studied the mineral poldervaartite CaCa[SiO3(OH)(OH)] which forms a series with its manganese analogue olmiite CaMn[SiO3(OH)](OH) using a range of techniques including scanning electron microscopy, thermogravimetric analysis, Raman and infrared spectroscopy. Chemical analysis shows the mineral is reasonably pure and contains only calcium and manganese with low amounts of Al and F. Thermogravimetric analysis proves the mineral decomposes at 485°C with a mass loss of 7.6% compared with the theoretical mass loss of 7.7%. A strong Raman band at 852 cm(-1) is assigned to the SiO stretching vibration of the SiO3(OH) units. Two Raman bands at 914 and 953 cm(-1) are attributed to the antisymmetric vibrations. Intense prominent peaks observed at 3487, 3502, 3509, 3521 and 3547 cm(-1) are assigned to the OH stretching vibration of the SiO3(OH) units. The observation of multiple OH bands supports the concept of the non-equivalence of the OH units. Vibrational spectroscopy enables a detailed assessment of the molecular structure of poldervaartite. Copyright © 2014 Elsevier B.V. All rights reserved.

Vibrational spectroscopic study of poldervaartite CaCa[SiO3(OH)(OH)

NASA Astrophysics Data System (ADS)

Frost, Ray L.; López, Andrés; Scholz, Ricardo; Lima, Rosa Malena Fernandes

2015-02-01

We have studied the mineral poldervaartite CaCa[SiO3(OH)(OH)] which forms a series with its manganese analogue olmiite CaMn[SiO3(OH)](OH) using a range of techniques including scanning electron microscopy, thermogravimetric analysis, Raman and infrared spectroscopy. Chemical analysis shows the mineral is reasonably pure and contains only calcium and manganese with low amounts of Al and F. Thermogravimetric analysis proves the mineral decomposes at 485 °C with a mass loss of 7.6% compared with the theoretical mass loss of 7.7%. A strong Raman band at 852 cm-1 is assigned to the SiO stretching vibration of the SiO3(OH) units. Two Raman bands at 914 and 953 cm-1 are attributed to the antisymmetric vibrations. Intense prominent peaks observed at 3487, 3502, 3509, 3521 and 3547 cm-1 are assigned to the OH stretching vibration of the SiO3(OH) units. The observation of multiple OH bands supports the concept of the non-equivalence of the OH units. Vibrational spectroscopy enables a detailed assessment of the molecular structure of poldervaartite.

Functional significance of co-occurring mutations in PIK3CA and MAP3K1 in breast cancer.

PubMed

Avivar-Valderas, Alvaro; McEwen, Robert; Taheri-Ghahfarokhi, Amir; Carnevalli, Larissa S; Hardaker, Elizabeth L; Maresca, Marcello; Hudson, Kevin; Harrington, Elizabeth A; Cruzalegui, Francisco

2018-04-20

The PI3Kα signaling pathway is frequently hyper-activated in breast cancer (BrCa), as a result of mutations/amplifications in oncogenes (e.g. HER2 ), decreased function in tumor suppressors (e.g. PTEN ) or activating mutations in key components of the pathway. In particular, activating mutations of PIK3CA (~45%) are frequently found in luminal A BrCa samples. Genomic studies have uncovered inactivating mutations in MAP3K1 (13-20%) and MAP2K4 (~8%), two upstream kinases of the JNK apoptotic pathway in luminal A BrCa samples. Further, simultaneous mutation of PIK3CA and MAP3K1 are found in ~11% of mutant PIK3CA tumors. How these two alterations may cooperate to elicit tumorigenesis and impact the sensitivity to PI3K and AKT inhibitors is currently unknown. Using CRISPR gene editing we have genetically disrupted MAP3K1 expression in mutant PIK3CA cell lines to specifically create in vitro models reflecting the mutational status of PIK3CA and MAP3K1 in BrCa patients. MAP3K1 deficient cell lines exhibited ~2.4-fold increased proliferation rate and decreased sensitivity to PI3Kα/δ(AZD8835) and AKT (AZD5363) inhibitors (~2.61 and ~5.23-fold IC 50 increases, respectively) compared with parental control cell lines. In addition, mechanistic analysis revealed that MAP3K1 disruption enhances AKT phosphorylation and downstream signaling and reduces sensitivity to AZD5363-mediated pathway inhibition. This appears to be a consequence of deficient MAP3K1-JNK signaling increasing IRS1 stability and therefore promoting IRS1 binding to p85, resulting in enhanced PI3Kα activity. Using 3D-MCF10A-PI3Kα H1047R models, we found that MAP3K1 depletion increased overall acinar volume and counteracted AZD5363-mediated reduction of acinar growth due to enhanced proliferation and reduced apoptosis. Furthermore, in vivo efficacy studies revealed that MAP3K1-deficient MCF7 tumors were less sensitive to AKT inhibitor treatment, compared with parental MCF7 tumors. Our study provides

Structural basis for the differential effects of CaBP1 and calmodulin on Ca(V)1.2 calcium-dependent inactivation.

PubMed

Findeisen, Felix; Minor, Daniel L

2010-12-08

Calcium-binding protein 1 (CaBP1), a calmodulin (CaM) homolog, endows certain voltage-gated calcium channels (Ca(V)s) with unusual properties. CaBP1 inhibits Ca(V)1.2 calcium-dependent inactivation (CDI) and introduces calcium-dependent facilitation (CDF). Here, we show that the ability of CaBP1 to inhibit Ca(V)1.2 CDI and induce CDF arises from interaction between the CaBP1 N-lobe and interlobe linker residue Glu94. Unlike CaM, where functional EF hands are essential for channel modulation, CDI inhibition does not require functional CaBP1 EF hands. Furthermore, CaBP1-mediated CDF has different molecular requirements than CaM-mediated CDF. Overall, the data show that CaBP1 comprises two structural modules having separate functions: similar to CaM, the CaBP1 C-lobe serves as a high-affinity anchor that binds the Ca(V)1.2 IQ domain at a site that overlaps with the Ca²+/CaM C-lobe site, whereas the N-lobe/linker module houses the elements required for channel modulation. Discovery of this division provides the framework for understanding how CaBP1 regulates Ca(V)s. Copyright © 2010 Elsevier Ltd. All rights reserved.

Structural basis for the differential effects of CaBP1 and calmodulin on CaV1.2 calcium-dependent inactivation

PubMed Central

Findeisen, Felix; Minor, Daniel L.

2010-01-01

Calcium-binding protein 1 (CaBP1), a calmodulin (CaM) homolog, endows certain voltage-gated calcium channels (CaVs) with unusual properties. CaBP1 inhibits CaV1.2 calcium-dependent inactivation (CDI) and introduces calcium-dependent facilitation (CDF). Here, we show that the ability of CaBP1 to inhibit CaV1.2 CDI and induce CDF arises from interaction between the CaBP1 N-lobe and interlobe linker residue Glu94. Unlike CaM, where functional EF hands are essential for channel modulation, CDI inhibition does not require functional CaBP1 EF-hands. Furthermore, CaBP1-mediated CDF has different molecular requirements than CaM-mediated CDF. Overall, the data show that CaBP1 comprises two structural modules having separate functions: similar to CaM, the CaBP1 C-lobe serves as a high-affinity anchor that binds the CaV1.2 IQ domain at a site that overlaps with the Ca2+/CaM C-lobe site, whereas the N-lobe/linker module houses the elements required for channel modulation. Discovery of this division provides the framework for understanding how CaBP1 regulates CaVs. PMID:21134641

Nicergoline inhibits T-type Ca2+ channels in rat isolated hippocampal CA1 pyramidal neurones.

PubMed Central

Takahashi, K.; Akaike, N.

1990-01-01

1. The effects of nicergoline on the T- and L-type Ca2+ currents in pyramidal cells freshly isolated from rat hippocampal CA1 region were investigated by use of a 'concentration-clamp' technique. The technique combines a suction-pipette technique, which allows intracellular perfusion under a single-electrode voltage-clamp, and rapid exchange of extracellular solution within 2 ms. 2. T-type Ca2+ currents were evoked by step depolarizations from a holding potential of -100 mV to potentials more positive than -70 to -60 mV, and reached a peak at about -30 mV in the current-voltage relationship. Activation and inactivation of T-type Ca2+ currents were highly potential-dependent. 3. Nicergoline and other Ca2+ antagonists dose-dependently blocked the T-type Ca2+ channel with an order of potency nicardipine greater than nicergoline greater than diltiazem. 4. The L-type Ca2+ channel was also blocked in the order nicardipine greater than nicergoline greater than diltiazem, although the T-type Ca2+ channel was more sensitive to nicergoline. 5. The inhibitory effects of nicergoline and nicardipine on the T-type Ca2+ current were voltage-, time-, and use-dependent, and the inhibition increased with a decrease in the external Ca2+ concentration. Diltiazem showed only a use-dependent block. PMID:2169937

Nicergoline inhibits T-type Ca2+ channels in rat isolated hippocampal CA1 pyramidal neurones.

PubMed

Takahashi, K; Akaike, N

1990-08-01

1. The effects of nicergoline on the T- and L-type Ca2+ currents in pyramidal cells freshly isolated from rat hippocampal CA1 region were investigated by use of a 'concentration-clamp' technique. The technique combines a suction-pipette technique, which allows intracellular perfusion under a single-electrode voltage-clamp, and rapid exchange of extracellular solution within 2 ms. 2. T-type Ca2+ currents were evoked by step depolarizations from a holding potential of -100 mV to potentials more positive than -70 to -60 mV, and reached a peak at about -30 mV in the current-voltage relationship. Activation and inactivation of T-type Ca2+ currents were highly potential-dependent. 3. Nicergoline and other Ca2+ antagonists dose-dependently blocked the T-type Ca2+ channel with an order of potency nicardipine greater than nicergoline greater than diltiazem. 4. The L-type Ca2+ channel was also blocked in the order nicardipine greater than nicergoline greater than diltiazem, although the T-type Ca2+ channel was more sensitive to nicergoline. 5. The inhibitory effects of nicergoline and nicardipine on the T-type Ca2+ current were voltage-, time-, and use-dependent, and the inhibition increased with a decrease in the external Ca2+ concentration. Diltiazem showed only a use-dependent block.

Rapid Recycling of Ca2+ between IP3-Sensitive Stores and Lysosomes

PubMed Central

López Sanjurjo, Cristina I.; Tovey, Stephen C.; Taylor, Colin W.

2014-01-01

Inositol 1,4,5-trisphosphate (IP3) evokes release of Ca2+ from the endoplasmic reticulum (ER), but the resulting Ca2+ signals are shaped by interactions with additional intracellular organelles. Bafilomycin A1, which prevents lysosomal Ca2+ uptake by inhibiting H+ pumping into lysosomes, increased the amplitude of the initial Ca2+ signals evoked by carbachol in human embryonic kidney (HEK) cells. Carbachol alone and carbachol in combination with parathyroid hormone (PTH) evoke Ca2+ release from distinct IP3-sensitive Ca2+ stores in HEK cells stably expressing human type 1 PTH receptors. Bafilomycin A1 similarly exaggerated the Ca2+ signals evoked by carbachol or carbachol with PTH, indicating that Ca2+ released from distinct IP3-sensitive Ca2+ stores is sequestered by lysosomes. The Ca2+ signals resulting from store-operated Ca2+ entry, whether evoked by thapsigargin or carbachol, were unaffected by bafilomycin A1. Using Gd3+ (1 mM) to inhibit both Ca2+ entry and Ca2+ extrusion, HEK cells were repetitively stimulated with carbachol to assess the effectiveness of Ca2+ recycling to the ER after IP3-evoked Ca2+ release. Blocking lysosomal Ca2+ uptake with bafilomycin A1 increased the amplitude of each carbachol-evoked Ca2+ signal without affecting the rate of Ca2+ recycling to the ER. This suggests that Ca2+ accumulated by lysosomes is rapidly returned to the ER. We conclude that lysosomes rapidly, reversibly and selectively accumulate the Ca2+ released by IP3 receptors residing within distinct Ca2+ stores, but not the Ca2+ entering cells via receptor-regulated, store-operated Ca2+ entry pathways. PMID:25337829

Rapid recycling of Ca2+ between IP3-sensitive stores and lysosomes.

PubMed

López Sanjurjo, Cristina I; Tovey, Stephen C; Taylor, Colin W

2014-01-01

Inositol 1,4,5-trisphosphate (IP3) evokes release of Ca2+ from the endoplasmic reticulum (ER), but the resulting Ca2+ signals are shaped by interactions with additional intracellular organelles. Bafilomycin A1, which prevents lysosomal Ca2+ uptake by inhibiting H+ pumping into lysosomes, increased the amplitude of the initial Ca2+ signals evoked by carbachol in human embryonic kidney (HEK) cells. Carbachol alone and carbachol in combination with parathyroid hormone (PTH) evoke Ca2+ release from distinct IP3-sensitive Ca2+ stores in HEK cells stably expressing human type 1 PTH receptors. Bafilomycin A1 similarly exaggerated the Ca2+ signals evoked by carbachol or carbachol with PTH, indicating that Ca2+ released from distinct IP3-sensitive Ca2+ stores is sequestered by lysosomes. The Ca2+ signals resulting from store-operated Ca2+ entry, whether evoked by thapsigargin or carbachol, were unaffected by bafilomycin A1. Using Gd3+ (1 mM) to inhibit both Ca2+ entry and Ca2+ extrusion, HEK cells were repetitively stimulated with carbachol to assess the effectiveness of Ca2+ recycling to the ER after IP3-evoked Ca2+ release. Blocking lysosomal Ca2+ uptake with bafilomycin A1 increased the amplitude of each carbachol-evoked Ca2+ signal without affecting the rate of Ca2+ recycling to the ER. This suggests that Ca2+ accumulated by lysosomes is rapidly returned to the ER. We conclude that lysosomes rapidly, reversibly and selectively accumulate the Ca2+ released by IP3 receptors residing within distinct Ca2+ stores, but not the Ca2+ entering cells via receptor-regulated, store-operated Ca2+ entry pathways.

Recombination luminescence of CaSO4:Tb3+ and CaSO4:Gd3+phosphors

NASA Astrophysics Data System (ADS)

Kudryavtseva, Irina; Lushchik, Aleksandr; Maaroos, Aarne; Azmaganbetova, Zhannur; Nurakhmetov, Turlybek; Salikhoja, Zhussupbek

2012-08-01

A comparative study of the excitation of luminescence by VUV radiation as well as of thermally and photostimulated luminescence has been carried out for CaSO4:Tb3+ and CaSO4:Gd3+ phosphors, where Na+ or F- ions are used for charge compensation. The distinction in hole processes for the phosphors with Na+ or F- compensators is determined by the differing thermal stability of the holes localized at/near Tb3+Na+ and Gd3+Na+ (up to 100-160 K) or at/near Tb3+F- V Ca and Gd3+F- V Ca centers involving also a cation vacancy (up to 400-550 K). Tunnel luminescence in the pairs of localized electrons and holes nearby Tb3+ or Gd3+ has been detected. The mechanisms of electron-hole, hole-electron and tunnel recombination luminescence as well as a subsequent released energy transfer to RE3+ ions are considered.

Angiotensin II upregulates K(Ca)3.1 channels and stimulates cell proliferation in rat cardiac fibroblasts.

PubMed

Wang, Li-Ping; Wang, Yan; Zhao, Li-Mei; Li, Gui-Rong; Deng, Xiu-Ling

2013-05-15

The proliferation of cardiac fibroblasts is implicated in the pathogenesis of myocardial remodeling and fibrosis. Intermediate-conductance calcium-activated K⁺ channels (K(Ca)3.1 channels) have important roles in cell proliferation. However, it is unknown whether angiotensin II (Ang II), a potent profibrotic molecule, would regulate K(Ca)3.1 channels in cardiac fibroblasts and participate in cell proliferation. In the present study, we investigated whether K(Ca)3.1 channels were regulated by Ang II, and how the channel activity mediated cell proliferation in cultured adult rat cardiac fibroblasts using electrophysiology and biochemical approaches. It was found that mRNA, protein, and current density of K(Ca)3.1 channels were greatly enhanced in cultured cardiac fibroblasts treated with 1 μM Ang II, and the effects were countered by the angiotensin type 1 receptor (AT₁R) blocker losartan, the p38-MAPK inhibitor SB203580, the ERK1/2 inhibitor PD98059, and the PI3K/Akt inhibitor LY294002. Ang II stimulated cell proliferation and the effect was antagonized by the K(Ca)3.1 blocker TRAM-34 and siRNA targeting K(Ca)3.1. In addition, Ang II-induced increase of K(Ca)3.1 expression was attenuated by transfection of activator protein-1 (AP-1) decoy oligodeoxynucleotides. These results demonstrate for the first time that Ang II stimulates cell proliferation mediated by upregulating K(Ca)3.1 channels via interacting with the AT₁R and activating AP-1 complex through ERK1/2, p38-MAPK and PI3K/Akt signaling pathways in cultured adult rat cardiac fibroblasts. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Microstructures and Mechanical Study of Mg Alloy Foam Based on Mg-Zn-Ca-CaCO3 System

NASA Astrophysics Data System (ADS)

Erryani, A.; Pramuji, F.; Annur, D.; Amal, M. I.; Kartika, I.

2017-05-01

Magnesium alloy, a material that has potential to use some applications such as aerospace components, computer parts, and mobile phones. Magnesium alloy can also be a popular candidate as an orthopedic implant material for biodegradability, non-toxicity, and mechanical and physical properties that are excellent. Magnesium, one of the main macro elements required for the proper functioning of the human organism, is used to test the materials for biodegradable implants. The main objective of this study was to find out the microstructure, and mechanical characteristics of the Mg-Ca-Zn-CaCO3 alloy as porous implant materials are biodegradable. The presence of CaCO3 on the alloy functions as a foaming agent expected to produce gas bubbles during manufacturing process taken place that will form pores in the alloy. Mg-Ca-Zn-CaCO3 alloy was made by powder metallurgy method with three variations of composition (96Mg-Ca-3Zn-CaCO3, 91Mg-Ca-3Zn-5CaCO3, and 86Mg-Ca-3Zn-10CaCO3 wt%). Milling process was by using a shaker mill for 2 hours to produce a powder size distribution which was more homogeneous. The mixed powder was uniaxially pressed at a pressure of 100 MPa for 2 minutes and 200 MPa for 3 minutes into green compacts with dimensions of 10 mm in diameter and 10 mm in length. The sintering process was carried out at 650°C with a variation of holding time of 10 and 15 hours, and then the specimens were cooled down at room temperature. Microstructural analysis was performed by using X-Ray diffraction technique and Scanning electron microscopy equipped with an energy disperse spectrometry (EDS). The mechanical characteristics were analyzed by using Universal Testing Machine. The density and porosity of specimen were further measured by using Archimedes method. The results show that the optimum microstructure and mechanical characteristics are the holding time of 10 hours. The value of compression was 208.398 N/mm2, the density was 1.63 g/cc and a porosity was 18% on the

Regulation of IP 3 Receptors by IP 3 and Ca 2+

NASA Astrophysics Data System (ADS)

Taylor, Colin W.; Swatton, Jane E.

Inositol 1,4,5-trisphosphate ( IP 3) receptors are intracellular Ca 2+ channels that mediate release of Ca 2+ from intracellular stores. The channels are oligomeric assemblies of four subunits, each of which has an N-terminal IP 3-binding domain and each of which contributes to formation of the Ca 2+ channel. In mammals, three different genes encode IP 3 receptors subunits and the type 1 receptor (and perhaps the type 2 receptor) is also expressed as splice variants. Further diversity arises from assembly of the receptor in hetero- and homo-tetrameric channels. The subtypes differ in their expression and regulation, but they share the key property of being regulated by both IP3 and cytosolic Ca 2+. All three mammalian IP 3 subtypes, and probably also the IP 3 receptors expressed in invertebrates, are biphasically regulated by cytosolic Ca2+, although the underlying mechanisms appear to differ between subtypes. The interactions between IP 3 and Ca 2+ in controlling IP 3 receptor gating, and the physiological significance of such regulation will be reviewed.

Ca 3d unoccupied states in Bi2Sr2CaCu2O8 investigated by Ca L2,3 x-ray-absorption near-edge structure

NASA Astrophysics Data System (ADS)

Borg, A.; King, P. L.; Pianetta, P.; Lindau, I.; Mitzi, D. B.; Kapitulnik, A.; Soldatov, A. V.; della Longa, S.; Bianconi, A.

1992-10-01

The high-resolution Ca L2,3 x-ray-absorption near-edge-structure (XANES) spectrum of a Bi2Sr2CaCu2O8 single crystal has been measured by use of a magnetic-projection x-ray microscope probing a surface area of 200×200 μm2. The Ca L2,3 XANES spectrum is analyzed by performing a multiple-scattering XANES calculation in real space and comparing the results with the spectrum of CaF2. Good agreement between the calculated and experimental crystal-field splitting Δf of the Ca 3d final states is found and the splitting is shown to be smaller by 0.5 eV than in the initial state. The Ca 3d partial density of states is found to be close to the Fermi level in the initial state. The Ca-O(in plane) distance is shown to be a critical parameter associated with the shift of the Ca 3d states relative to the Fermi level; in particular, we have studied the effect of the out-of-plane dimpling mode of the in-plane oxygen atoms O(in plane) that will move the Ca 3d states on or off the Fermi level. This mode can therefore play a role in modulating the charge transfer between the two CuO2 planes separated by the Ca ions.

The 3R polymorph of CaSi{sub 2}

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nedumkandathil, Reji; Benson, Daryn E.; Grins, Jekabs

The Zintl phase CaSi{sub 2} commonly occurs in the 6R structure where puckered hexagon layers of Si atoms are stacked in an AA′BB′CC′ fashion. In this study we show that sintering of CaSi{sub 2} in a hydrogen atmosphere (30 bar) at temperatures between 200 and 700 °C transforms 6R-CaSi{sub 2} quantitatively into 3R-CaSi{sub 2}. In the 3R polymorph (space group R-3m (no. 166), a=3.8284(1), c=15.8966(4), Z=3) puckered hexagon layers are stacked in an ABC fashion. The volume per formula unit is about 3% larger compared to 6R-CaSi{sub 2}. First principles density functional calculations reveal that 6R and 3R-CaSi{sub 2} aremore » energetically degenerate at zero Kelvin. With increasing temperature 6R-CaSi{sub 2} stabilizes over 3R because of its higher entropy. This suggests that 3R-CaSi{sub 2} should revert to 6R at elevated temperatures, which however is not observed up to 800 °C. 3R-CaSi{sub 2} may be stabilized by small amounts of incorporated hydrogen and/or defects. - Graphical abstract: The common 6R form of CaSi{sub 2} can be transformed quantitatively into 3R-CaSi{sub 2} upon sintering in a hydrogen atmosphere. - Highlights: • Quantitative and reproducible bulk synthesis of the rare 3R polymorph of CaSi{sub 2}. • Clarification of the energetic relation between 3R and conventional 6R form. • 3R-CaSi{sub 2} is presumably stabilized by small amounts of incorporated hydrogen and/or defects.« less

Carcinogenesis of PIK3CA

PubMed Central

2013-01-01

PIK3CA is the most frequently mutated oncogene in human cancers. PIK3CA is phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha. It controls cell growth, proliferation, motility, survival, differentiation and intracellular trafficking. In most of human cancer alteration occurred frequently in the alpha isoform of phosphatidylinositol 3 kinase. PIK3CA mutations were most frequent in endometrial, ovarian, colorectal, breast, cervical, squamous cell cancer of the head and neck, chondroma, thyroid carcinoma and in cancer family syndrome. Inhibition of PI3K signaling can diminish cell proliferation, and in some circumstances, promote cell death. Consequently, components of this pathway present attractive targets for cancer therapeutics. A number of PI3K pathway inhibitors have been developed and used. PI3K inhibitors (both pan-PI3K and isoform-specific PI3K inhibitors), dual PI3K-mTOR inhibitors that are catalytic site inhibitors of the p110 isoforms and mTOR (the kinase component of both mTORC1 and mTORC2), mTOR catalytic site inhibitors, and AKT inhibitors are the most advanced in the clinic. They are approved for the treatment of several carcinomas. PMID:23768168

Comparison of the diagnostic accuracy of CA27.29 and CA15.3 in primary breast cancer.

PubMed

Gion, M; Mione, R; Leon, A E; Dittadi, R

1999-05-01

A new, fully automated method that measures the breast cancer-associated glycoprotein CA27.29 has become commercially available. The aim of the present study was to compare this CA27.29 assay with the assay that measures CA15.3 in primary breast cancer. The study was performed retrospectively on preoperative serum samples collected from 275 patients with untreated primary breast cancer (154 node positive and 121 node negative). Eighty-three healthy control subjects were also evaluated. CA27.29 was measured using the fully automated Chiron Diagnostics immunochemiluminescent system (ACS:180 BR). CA15.3 was measured with a manual immunoradiometric method (Centocor CA15.3 RIA). In healthy subjects, CA15.3 was significantly higher than CA27.29 (P <0. 0001). On the other hand, in breast cancer patients CA27.29 was higher than CA15.3 (P = 0.013). The mean value found in the control group plus 2 SD was chosen as the positive/negative cutoff point. The overall positivity rates were 34.9% for CA27.29 and 22.5% for CA15.3. The area under the ROC curve was greater (P <0.001) for CA27. 29 (0.72) than for CA15.3 (0.61). Both markers showed a statistically significant, direct relationship, with pathological stage being higher in node-positive than in node-negative cases and in larger than in smaller tumors. Neither CA27.29 nor CA15.3 showed significant associations with age, menopausal status, or tumor receptor status. CA27.29 discriminates primary breast cancer from healthy subjects better than CA15.3, especially in patients with limited disease. Prospective studies are necessary to confirm this conclusion. Copyright 1999 American Association for Clinical Chemistry.

Synthesis of the new compound CaFe(CO 3) 2 and experimental constraints on the (Ca,Fe)CO 3 join

NASA Astrophysics Data System (ADS)

Davidson, Paula M.; Symmes, Gregory H.; Cohen, Barbara A.; Reeder, Richard J.; Lindsley, Donald H.

1993-12-01

Synthesis of the new (disordered) compound CaFe(CO 3) 2 has been achieved with the use of Fe-substituted CaCO 3(Cc ss) + Ca-substituted FeCO 3(Sid ss) as starting materials, and high CO 2 pressures. High pressure (20-30 kbar) is needed to stabilize FeCO 3 to sufficiently high temperatures for disordered CaFe(CO 3) 2 to form. Experiments provide reversed compositions of coexisting disordered phases in the CaFe join and locate the solvus temperature for CaFe(C) 3) 2 between 815 and 845°C at 30 kbars. Calculated phase relations predict that the stability of ordered CaFe(CO 3) 2 is limited to T < ˜450°C by the breakdown to Cc ss + Sid ss. A comparison of the unit-cell volume measured for disordered CaFe(CO 3) 2 vs. that estimated for ordered CaFe(CO 3) 2 suggests that increasing pressure stabilizes the disordered phase.

Formation of ternary CaUO2(CO3)3(2-) and Ca2UO2(CO3)3(aq) complexes under neutral to weakly alkaline conditions.

PubMed

Lee, Jun-Yeop; Yun, Jong-Il

2013-07-21

The chemical behavior of ternary Ca-UO2-CO3 complexes was investigated by using time-resolved laser fluorescence spectroscopy (TRLFS) in combination with EDTA complexation at pH 7-9. A novel TRLFS revealed two distinct fluorescence lifetimes of 12.7 ± 0.2 ns and 29.2 ± 0.4 ns for uranyl complexes which were formed increasingly dependent upon the calcium ion concentration, even though nearly indistinguishable fluorescence peak shapes and positions were measured for both Ca-UO2-CO3 complexes. For identifying the stoichiometric number of complexed calcium ions, slope analysis in terms of relative fluorescence intensity versus calcium concentration was employed in a combination with the complexation reaction of CaEDTA(2-) by adding EDTA. The formation of CaUO2(CO3)3(2-) and Ca2UO2(CO3)3(aq) was identified under given conditions and their formation constants were determined at I = 0.1 M Na/HClO4 medium, and extrapolated to infinitely dilute solution using specific ion interaction theory (SIT). As a result, the formation constants for CaUO2(CO3)3(2-) and Ca2UO2(CO3)3(aq) were found to be log β113(0) = 27.27 ± 0.14 and log β213(0) = 29.81 ± 0.19, respectively, providing that the ternary Ca-UO2-CO3 complexes were predominant uranium(vi) species at neutral to weakly alkaline pH in the presence of Ca(2+) and CO3(2-) ions.

Thermoelectric properties of Ca(1-x-y)Dy(x)CeyMnO3 for power generation.

PubMed

Park, K; Lee, G W; Jung, J; Kim, S-J; Lim, Y-S; Choi, S-M; Seo, W-S

2011-08-01

The sintered Ca(1-x-y)Dy(x)CeyMnO3 bodies were a single phase with a perovskite structure without any impurity phases. The calculated crystallite sizes of the Ca(1-x-y)Dy(x)CeyMnO3 were in the range of 43.3 to 63.3 nm. The composition significantly affected their microstructural and thermoelectric characteristics. The doped Dy led to both an increase in the electrical conductivity as well as the absolute value of the Seebeck coefficient, resulting in an enhanced power factor. The highest power factor (5.1 x 10(-4) Wm(-1) K(-2)) was obtained for Ca(0.8)Dy(0.2)MnO3 at 800 degrees C. In this study, we systematically discussed the thermoelectric properties of the Ca(1-x-y)Dy(x)CeyMnO3, with respect to the substitution of Dy and/or Ce for Ca.

Long term potentiation, but not depression, in interlamellar hippocampus CA1.

PubMed

Sun, Duk-Gyu; Kang, Hyeri; Tetteh, Hannah; Su, Junfeng; Lee, Jihwan; Park, Sung-Won; He, Jufang; Jo, Jihoon; Yang, Sungchil; Yang, Sunggu

2018-03-26

Synaptic plasticity in the lamellar CA3 to CA1 circuitry has been extensively studied while interlamellar CA1 to CA1 connections have not yet received much attention. One of our earlier studies demonstrated that axons of CA1 pyramidal neurons project to neighboring CA1 neurons, implicating information transfer along a longitudinal interlamellar network. Still, it remains unclear whether long-term synaptic plasticity is present within this longitudinal CA1 network. Here, we investigate long-term synaptic plasticity between CA1 pyramidal cells, using in vitro and in vivo extracellular recordings and 3D holography glutamate uncaging. We found that the CA1-CA1 network exhibits NMDA receptor-dependent long-term potentiation (LTP) without direction or layer selectivity. By contrast, we find no significant long-term depression (LTD) under various LTD induction protocols. These results implicate unique synaptic properties in the longitudinal projection suggesting that the interlamellar CA1 network could be a promising structure for hippocampus-related information processing and brain diseases.

The synthesis and crystal structure of α-Ca 3UO 6

NASA Astrophysics Data System (ADS)

Holc, J.; Golic̆, L.

1983-07-01

Single crystals of α-Ca 3UO 6 were grown from a UO 3CaCl 2CaO melt by the slow cooling method from 950°C. The crystal structure was determined by means of X-ray diffraction with R = 0.032 and Rw = 0.019. The structure of α-Ca 3UO 6 is of Mg 3TeO 6 type. α-Ca 3UO 6 is rhombohedral with a = 6.729 (1)Å, α = 90.30 (1)°, Z = 2, Dc = 4.955 g/cm 3, Dm = 4.79 g/cm 3, space group R overline3. Uranium and calcium atoms are six-coordinated. At 1200°C rhombohedral α-Ca 3UO 6 irreversibly transforms to monoclinic β-Ca 3UO 6.

Ca(5)Zr(3)F(22).

PubMed

Oudahmane, Abdelghani; El-Ghozzi, Malika; Avignant, Daniel

2012-04-01

Single crystals of Ca(5)Zr(3)F(22), penta-calcium trizirconium docosafluoride, were obtained unexpectedly by solid-state reaction between CaF(2) and ZrF(4) in the presence of AgF. The structure of the title compound is isotypic with that of Sr(5)Zr(3)F(22) and can be described as being composed of layers with composition [Zr(3)F(20)](8-) made up from two different [ZrF(8)](4-) square anti-prisms (one with site symmetry 2) by corner-sharing. The layers extending parallel to the (001) plane are further linked by Ca(2+) cations, forming a three-dimensional network. Amongst the four crystallographically different Ca(2+) ions, three are located on twofold rotation axes. The Ca(2+) ions exhibit coordination numbers ranging from 8 to 12, depending on the cut off, with very distorted fluorine environments. Two of the Ca(2+) ions occupy inter-stices between the layers whereas the other two are located in void spaces of the [Zr(3)F(20)](8-) layer and alternate with the two Zr atoms along [010]. The crystal under investigation was an inversion twin.

Ca2+-independent Activation of Ca2+/Calmodulin-dependent Protein Kinase II Bound to the C-terminal Domain of CaV2.1 Calcium Channels*

PubMed Central

Magupalli, Venkat G.; Mochida, Sumiko; Yan, Jin; Jiang, Xin; Westenbroek, Ruth E.; Nairn, Angus C.; Scheuer, Todd; Catterall, William A.

2013-01-01

Ca2+/calmodulin-dependent protein kinase II (CaMKII) forms a major component of the postsynaptic density where its functions in synaptic plasticity are well established, but its presynaptic actions are poorly defined. Here we show that CaMKII binds directly to the C-terminal domain of CaV2.1 channels. Binding is enhanced by autophosphorylation, and the kinase-channel signaling complex persists after dephosphorylation and removal of the Ca2+/CaM stimulus. Autophosphorylated CaMKII can bind the CaV2.1 channel and synapsin-1 simultaneously. CaMKII binding to CaV2.1 channels induces Ca2+-independent activity of the kinase, which phosphorylates the enzyme itself as well as the neuronal substrate synapsin-1. Facilitation and inactivation of CaV2.1 channels by binding of Ca2+/CaM mediates short term synaptic plasticity in transfected superior cervical ganglion neurons, and these regulatory effects are prevented by a competing peptide and the endogenous brain inhibitor CaMKIIN, which blocks binding of CaMKII to CaV2.1 channels. These results define the functional properties of a signaling complex of CaMKII and CaV2.1 channels in which both binding partners are persistently activated by their association, and they further suggest that this complex is important in presynaptic terminals in regulating protein phosphorylation and short term synaptic plasticity. PMID:23255606

Removal of area CA3 from hippocampal slices induces postsynaptic plasticity at Schaffer collateral synapses that normalizes CA1 pyramidal cell discharge.

PubMed

Dumas, Theodore C; Uttaro, Michael R; Barriga, Carolina; Brinkley, Tiffany; Halavi, Maryam; Wright, Susan N; Ferrante, Michele; Evans, Rebekah C; Hawes, Sarah L; Sanders, Erin M

2018-06-21

Neural networks that undergo acute insults display remarkable reorganization. This injury related plasticity is thought to permit recovery of function in the face of damage that cannot be reversed. Previously, an increase in the transmission strength at Schaffer collateral to CA1 pyramidal cell synapses was observed after long-term activity reduction in organotypic hippocampal slices. Here we report that, following acute preparation of adult rat hippocampal slices and surgical removal of area CA3, input to area CA1 was reduced and Schaffer collateral synapses underwent functional strengthening. This increase in synaptic strength was limited to Schaffer collateral inputs (no alteration to temporoammonic synapses) and acted to normalize postsynaptic discharge, supporting a homeostatic or compensatory response. Short-term plasticity was not altered, but an increase in immunohistochemical labeling of GluA1 subunits was observed in the stratum radiatum (but not stratum moleculare), suggesting increased numbers of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and a postsynaptic locus of expression. Combined, these data support the idea that, in response to the reduction in presynaptic activity caused by removal of area CA3, Schaffer collateral synapses undergo a relatively rapid increase in functional efficacy likely supported by insertion of more AMPARs, which maintains postsynaptic excitability in CA1 pyramidal neurons. This novel fast compensatory plasticity exhibits properties that would allow it to maintain optimal network activity levels in the hippocampus, a brain structure lauded for its ongoing experience-dependent malleability. Copyright © 2018 Elsevier B.V. All rights reserved.

Modeling Ca2+ Feedback on a Single Inositol 1,4,5-Trisphosphate Receptor and Its Modulation by Ca2+ Buffers

PubMed Central

Shuai, Jianwei; Pearson, John E.; Parker, Ian

2008-01-01

The inositol 1,4,5-trisphosphate receptor/channel (IP3R) is a major regulator of intracellular Ca2+ signaling, and liberates Ca2+ ions from the endoplasmic reticulum in response to binding at cytosolic sites for both IP3 and Ca2+. Although the steady-state gating properties of the IP3R have been extensively studied and modeled under conditions of fixed [IP3] and [Ca2+], little is known about how Ca2+ flux through a channel may modulate the gating of that same channel by feedback onto activating and inhibitory Ca2+ binding sites. We thus simulated the dynamics of Ca2+ self-feedback on monomeric and tetrameric IP3R models. A major conclusion is that self-activation depends crucially on stationary cytosolic Ca2+ buffers that slow the collapse of the local [Ca2+] microdomain after closure. This promotes burst-like reopenings by the rebinding of Ca2+ to the activating site; whereas inhibitory actions are substantially independent of stationary buffers but are strongly dependent on the location of the inhibitory Ca2+ binding site on the IP3R in relation to the channel pore. PMID:18641077

Colossal magnetoresistance accompanied with magnetorelaxor behavior in phase-separated Ca1-xCexMnO3 thin films and CaMnO3/Ca0.92Ce0.08MnO3 superlattices

NASA Astrophysics Data System (ADS)

Xiang, P.-H.; Yamada, H.; Sawa, A.; Akoh, H.

2010-03-01

We report on the transport properties of electron-doped manganite Ca1-xCexMnO3 (CCMO, 0≤x≤0.08) films and superlattices composed of insulating layers CaMnO3 (CMO) and Ca0.92Ce0.08MnO3 (CCMO8), deposited on nearly lattice-matched NdAlO3 substrates. The CCMO (x =0.06 and 0.07) films show colossal magnetoresistance (CMR) accompanied with magnetorelaxor behavior, which can be ascribed to the phase separation of canted G-type antiferromagnetic metal and C-type antiferromagnetic insulator. The (CMO)m/(CCMO8)n superlattices with 4≤m, n ≤8 (unit cells) resemble the solid-solution CCMO (x =0.06 and 0.07) films in CMR and magnetorelaxor behavior, suggesting that the phase separation takes place in the superlattices. The CMR and magnetorelaxor behavior of the (CMO)m/(CCMO8)n superlattices strongly depend on the thicknesses of constituent CMO and CCMO8 layers. The origin of the phase separation in the superlattices is discussed in terms of the charge transfer and the phase competition at the interfaces.

CaCO3-III and CaCO3-VI, high-pressure polymorphs of calcite: Possible host structures for carbon in the Earth's mantle

NASA Astrophysics Data System (ADS)

Merlini, M.; Hanfland, M.; Crichton, W. A.

2012-06-01

Calcite, CaCO3, undergoes several high pressure phase transitions. We report here the crystal structure determination of the CaCO3-III and CaCO3-VI high-pressure polymorphs obtained by single-crystal synchrotron X-ray diffraction. This new technical development at synchrotron beamlines currently affords the possibility of collecting single-crystal data suitable for structure determination in-situ at non-ambient conditions, even after multiphase transitions. CaCO3-III, observed in the pressure range 2.5-15 GPa, is triclinic, and it presents two closely related structural modifications, one, CaCO3-III, with 50 atoms in the unit cell [a=6.281(1) Å, b=7.507(2) Å, c=12.516(3) Å, α=93.76(2)°, β=98.95(2)°, γ=106.49(2)°, V=555.26(20) Å3 at 2.8 GPa], the second, CaCO3-IIIb, with 20 atoms [a=6.144(3) Å, b=6.3715(14) Å, c=6.3759(15) Å, α= 93.84(2)°, β=107.34(3)°, γ=107.16(3)°, V=224.33(13) Å3 at 3.1 GPa]. Different pressure-time experimental paths can stabilise one or the other polymorph. Both structures are characterised by the presence of non-coplanar CO3 groups. The densities of CaCO3-III (2.99 g/cm3 at 2.8 GPa) and CaCO3-IIIb (2.96 g/cm3 at 3.1 GPa) are lower than aragonite, in agreement with the currently accepted view of aragonite as the thermodynamically stable Ca-carbonate phase at these pressures. The presence of different cation sites, with variable volume and coordination number (7-9), suggests however that these structures have the potential to accommodate cations with different sizes without introducing major structural strain. Indeed, this structure can be adopted by natural Ca-rich carbonates, which often exhibit compositions deviating from pure calcite. Mg-calcites are found both in nature (Frezzotti et al., 2011) and in experimental syntheses at conditions corresponding to deep subduction environments (Poli et al., 2009). At these conditions, the low pressure rhombohedral calcite structure is most unlikely to be stable, and, at the same

The CaGeO3 Ca3Fe2Ge3O12 garnet join: an experimental study

NASA Astrophysics Data System (ADS)

Iezzi, Gianluca; Boffa-Ballaran, Tiziana; McCammon, Catherine; Langenhorst, Falko

2005-06-01

Germanate garnets are often used as isostructural analogues of silicate garnets to provide insight into the crystal chemistry and symmetry of the less accessible natural garnet solid solutions. We synthesised two series of germanate garnets at 3 GPa along the joinVIIICa3VI(CaGe)IVGe3O12 VIIICa3VIFe2IVGe3O12 at 900 °C and 1,100 °C. Samples with compositions close to the CaGeO3 end-member consist of tetragonal garnet with a small amount of triclinic CaGe2O5. Samples with nominal compositions between XFe=0.4 and 1.0 consist of a mixture of tetragonal and cubic garnets; whereas, single-phase cubic garnets were obtained for compositions with XFe>1.2 (XFe gives the iron content expressed in atoms per formula unit, and varies between 0 and 2 along the join). Run products which were primarily single-phase garnet were investigated using Mössbauer spectroscopy. Spectra from samples synthesised at 1,100°C consist of one well-resolved doublet that can be assigned to Fe3+ in the octahedral site of the garnet structure. A second doublet, present primarily in samples synthesised at 900°C, can be assigned to Fe2+ at the octahedral sites of the garnet structure. The relative abundance of Fe2+ decreases with increasing iron content. Transmission electron microscopy analyses confirm this tendency and show that the garnets are essentially defect-free. The unit-cell parameters of tetragonal VIIICa3VI(CaGe)IVGe3O3 garnet decrease with increasing synthesis temperature, and the deviation from cubic symmetry becomes smaller. Cubic garnets show a linear decrease of unit-cell parameter with increasing iron content. The results are discussed in the context of iron incorporation into VIIIMg3VI(MgSi)IVSi3O3 majorite.

Electric Field Control of Interfacial Ferromagnetism in CaMnO3/CaRuO3 Heterostructures

NASA Astrophysics Data System (ADS)

Grutter, A. J.; Kirby, B. J.; Gray, M. T.; Flint, C. L.; Alaan, U. S.; Suzuki, Y.; Borchers, J. A.

2015-07-01

New mechanisms for achieving direct electric field control of ferromagnetism are highly desirable in the development of functional magnetic interfaces. To that end, we have probed the electric field dependence of the emergent ferromagnetic layer at CaRuO3/CaMnO3 interfaces in bilayers fabricated on SrTiO3. Using polarized neutron reflectometry, we are able to detect the ferromagnetic signal arising from a single atomic monolayer of CaMnO3, manifested as a spin asymmetry in the reflectivity. We find that the application of an electric field of 600 kV /m across the bilayer induces a significant increase in this spin asymmetry. Modeling of the reflectivity suggests that this increase corresponds to a transition from canted antiferromagnetism to full ferromagnetic alignment of the Mn4 + ions at the interface. This increase from 1 μB to 2.5 - 3.0 μB per Mn is indicative of a strong magnetoelectric coupling effect, and such direct electric field control of the magnetization at an interface has significant potential for spintronic applications.

Structures of Ca(V) Ca**2+/CaM-IQ Domain Complexes Reveal Binding Modes That Underlie Calcium-Dependent Inactivation And Facilitation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, E.Y.; Rumpf, C.H.; Fujiwara, Y.

2009-05-20

Calcium influx drives two opposing voltage-activated calcium channel (Ca{sub V}) self-modulatory processes: calcium-dependent inactivation (CDI) and calcium-dependent facilitation (CDF). Specific Ca{sup 2+}/calmodulin (Ca{sup 2+}/CaM) lobes produce CDI and CDF through interactions with the Ca{sub V}{alpha}{sub 1} subunit IQ domain. Curiously, Ca{sup 2+}/CaM lobe modulation polarity appears inverted between Ca{sub V}1s and Ca{sub V}2s. Here, we present crystal structures of Ca{sub V}2.1, Ca{sub V}2.2, and Ca{sub V}2.3 Ca{sup 2+}/CaM-IQ domain complexes. All display binding orientations opposite to Ca{sub V}1.2 with a physical reversal of the CaM lobe positions relative to the IQ {alpha}-helix. Titration calorimetry reveals lobe competition for a high-affinitymore » site common to Ca{sub V}1 and Ca{sub V}2 IQ domains that is occupied by the CDI lobe in the structures. Electrophysiological experiments demonstrate that the N-terminal Ca{sub V}2 Ca{sup 2+}/C-lobe anchors affect CDF. Together, the data unveil the remarkable structural plasticity at the heart of Ca{sub V} feedback modulation and indicate that Ca{sub V}1 and Ca{sub V}2 IQ domains bear a dedicated CDF site that exchanges Ca{sup 2+}/CaM lobe occupants.« less

Calmodulin-dependent gating of Ca(v)1.2 calcium channels in the absence of Ca(v)beta subunits.

PubMed

Ravindran, Arippa; Lao, Qi Zong; Harry, Jo Beth; Abrahimi, Parwiz; Kobrinsky, Evgeny; Soldatov, Nikolai M

2008-06-10

It is generally accepted that to generate calcium currents in response to depolarization, Ca(v)1.2 calcium channels require association of the pore-forming alpha(1C) subunit with accessory Ca(v)beta and alpha(2)delta subunits. A single calmodulin (CaM) molecule is tethered to the C-terminal alpha(1C)-LA/IQ region and mediates Ca2+-dependent inactivation of the channel. Ca(v)beta subunits are stably associated with the alpha(1C)-interaction domain site of the cytoplasmic linker between internal repeats I and II and also interact dynamically, in a Ca2+-dependent manner, with the alpha(1C)-IQ region. Here, we describe a surprising discovery that coexpression of exogenous CaM (CaM(ex)) with alpha(1C)/alpha(2)delta in COS1 cells in the absence of Ca(v)beta subunits stimulates the plasma membrane targeting of alpha(1C), facilitates calcium channel gating, and supports Ca2+-dependent inactivation. Neither real-time PCR with primers complementary to monkey Ca(v)beta subunits nor coimmunoprecipitation analysis with exogenous alpha(1C) revealed an induction of endogenous Ca(v)beta subunits that could be linked to the effect of CaM(ex). Coexpression of a calcium-insensitive CaM mutant CaM(1234) also facilitated gating of Ca(v)beta-free Ca(v)1.2 channels but did not support Ca2+-dependent inactivation. Our results show there is a functional matchup between CaM(ex) and Ca(v)beta subunits that, in the absence of Ca(v)beta, renders Ca2+ channel gating facilitated by CaM molecules other than the one tethered to LA/IQ to support Ca2+-dependent inactivation. Thus, coexpression of CaM(ex) creates conditions when the channel gating, voltage- and Ca2+-dependent inactivation, and plasma-membrane targeting occur in the absence of Ca(v)beta. We suggest that CaM(ex) affects specific Ca(v)beta-free conformations of the channel that are not available to endogenous CaM.

Role of Caspase-3 Cleaved IP3R1 on Ca2+ Homeostasis and Developmental Competence of Mouse Oocytes and Eggs

PubMed Central

Zhang, Nan; Fissore, Rafael. A.

2014-01-01

Apoptosis in most cell types is accompanied by altered Ca2+ homeostasis. During apoptosis, caspase-3 mediated cleavage of the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) generates a 95-kDa C-terminal fragment (C-IP3R1), which represents the channel domain of the receptor. Aged mouse eggs display abnormal Ca2+ homeostasis and express C-IP3R1, although whether or not C-IP3R1 expression contributes to Ca2+ misregulation or a decrease in developmental competency is unknown. We sought to answer these questions by injecting in mouse oocytes and eggs cRNAs encoding CIP3R1. We found that: 1) expression of C-IP3R1 in eggs lowered the Ca2+ content of the endoplasmic reticulum (ER), although, as C-IP3R1 is quickly degraded at this stage, its expression did not impair pre-implantation embryo development; 2) expression of CIP3R1 in eggs enhanced fragmentation associated with aging; 3) endogenous IP3R1 is required for aging associated apoptosis, as its down-regulation prevented fragmentation, and expression of C-IP3R1 in eggs with downregulated IP3R1 partly restored fragmentation; 4) C-IP3R1 expression in GV oocytes resulted in persistent levels of protein, which abolished the increase in the ER releasable Ca2+ pool that occurs during maturation, undermined the Ca2+ oscillatory ability of matured eggs and their activation potential. Collectively, this study supports a role for IP3R1 and C-IP3R1 in regulating Ca2+ homeostasis and the ER Ca2+ content during oocyte maturation. Nevertheless, the role of C-IP3R1 on Ca2+ homeostasis in aged eggs seems minor, as in MII eggs the majority of endogenous IP3R1 remains intact and C-IP3R1 undergoes rapid turnover. PMID:24692207

New anticancer drug candidates sulfonamides as selective hCA IX or hCA XII inhibitors.

PubMed

Gul, Halise Inci; Yamali, Cem; Sakagami, Hiroshi; Angeli, Andrea; Leitans, Janis; Kazaks, Andris; Tars, Kaspars; Ozgun, Dilan Ozmen; Supuran, Claudiu T

2018-04-01

In this study, new 4-[3-(aryl)-5-substitutedphenyl-4,5-dihydro-1H-pyrazole-1-yl]benzensulfonamides (19-36) were synthesized and evaluated their cytotoxic/anticancer and CA inhibitory effects. According to results obtained, the compounds 34 (4-[5-(2,3,4-trimethoxyphenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-yl] benzensulfonamide, Potency-Selectivity Expression (PSE) = 141) and 36 (4-[5-(3,4,5-trimethoxyphenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-yl]benzensulfonamide, PSE = 54.5) were found the leader anticancer compounds with the highest PSE values. In CA inhibitory studies, the compounds 36 and 24 (4-[5-(3,4,5-trimethoxyphenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-yl]benzensulfonamide) were found the leader CA inhibitors depending on selectivity ratios. The compound 36 was a selective inhibitor of hCA XII isoenzyme (hCA I/hCA XII = 1250 and hCA II/hCA XII = 224) while the compound 24 was a selective inhibitor of hCA IX isoenzyme (hCA I/hCA IX = 161 and hCA II/hCA IX = 177). The compounds 24, 34, and 36 can be considered to develop new anticancer drug candidates. Copyright © 2018 Elsevier Inc. All rights reserved.

Seawater Mg/Ca controls polymorph mineralogy of microbial CaCO3: a potential proxy for calcite-aragonite seas in Precambrian time.

PubMed

Ries, J B; Anderson, M A; Hill, R T

2008-03-01

A previously published hydrothermal brine-river water mixing model driven by ocean crust production suggests that the molar Mg/Ca ratio of seawater (mMg/Ca(sw)) has varied significantly (approximately 1.0-5.2) over Precambrian time, resulting in six intervals of aragonite-favouring seas (mMg/Ca(sw) > 2) and five intervals of calcite-favouring seas (mMg/Ca(sw) < 2) since the Late Archaean. To evaluate the viability of microbial carbonates as mineralogical proxy for Precambrian calcite-aragonite seas, calcifying microbial marine biofilms were cultured in experimental seawaters formulated over the range of Mg/Ca ratios believed to have characterized Precambrian seawater. Biofilms cultured in experimental aragonite seawater (mMg/Ca(sw) = 5.2) precipitated primarily aragonite with lesser amounts of high-Mg calcite (mMg/Ca(calcite) = 0.16), while biofilms cultured in experimental calcite seawater (mMg/Ca(sw) = 1.5) precipitated exclusively lower magnesian calcite (mMg/Ca(calcite) = 0.06). Furthermore, Mg/Ca(calcite )varied proportionally with Mg/Ca(sw). This nearly abiotic mineralogical response of the biofilm CaCO3 to altered Mg/Ca(sw) is consistent with the assertion that biofilm calcification proceeds more through the elevation of , via metabolic removal of CO2 and/or H+, than through the elevation of Ca2+, which would alter the Mg/Ca ratio of the biofilm's calcifying fluid causing its pattern of CaCO3 polymorph precipitation (aragonite vs. calcite; Mg-incorporation in calcite) to deviate from that of abiotic calcification. If previous assertions are correct that the physicochemical properties of Precambrian seawater were such that Mg/Ca(sw) was the primary variable influencing CaCO3 polymorph mineralogy, then the observed response of the biofilms' CaCO3 polymorph mineralogy to variations in Mg/Ca(sw), combined with the ubiquity of such microbial carbonates in Precambrian strata, suggests that the original polymorph mineralogy and Mg/Ca(calcite )of well

Close Association of Carbonic Anhydrase (CA2a and CA15a), Na+/H+ Exchanger (Nhe3b), and Ammonia Transporter Rhcg1 in Zebrafish Ionocytes Responsible for Na+ Uptake

PubMed Central

Ito, Yusuke; Kobayashi, Sayako; Nakamura, Nobuhiro; Miyagi, Hisako; Esaki, Masahiro; Hoshijima, Kazuyuki; Hirose, Shigehisa

2013-01-01

Freshwater (FW) fishes actively absorb salt from their environment to tolerate low salinities. We previously reported that vacuolar-type H+-ATPase/mitochondrion-rich cells (H-MRCs) on the skin epithelium of zebrafish larvae (Danio rerio) are primary sites for Na+ uptake. In this study, in an attempt to clarify the mechanism for the Na+ uptake, we performed a systematic analysis of gene expression patterns of zebrafish carbonic anhydrase (CA) isoforms and found that, of 12 CA isoforms, CA2a and CA15a are highly expressed in H-MRCs at larval stages. The ca2a and ca15a mRNA expression were salinity-dependent; they were upregulated in 0.03 mM Na+ water whereas ca15a but not ca2a was down-regulated in 70 mM Na+ water. Immunohistochemistry demonstrated cytoplasmic distribution of CA2a and apical membrane localization of CA15a. Furthermore, cell surface immunofluorescence staining revealed external surface localization of CA15a. Depletion of either CA2a or CA15a expression by Morpholino antisense oligonucleotides resulted in a significant decrease in Na+ accumulation in H-MRCs. An in situ proximity ligation assay demonstrated a very close association of CA2a, CA15a, Na+/H+ exchanger 3b (Nhe3b), and Rhcg1 ammonia transporter in H-MRC. Our findings suggest that CA2a, CA15a, and Rhcg1 play a key role in Na+uptake under FW conditions by forming a transport metabolon with Nhe3b. PMID:23565095

Electric Field Control of the Ferromagnetic CaRuO3 /CaMnO3 Interface

NASA Astrophysics Data System (ADS)

Grutter, Alexander; Kirby, Brian; Gray, Matthew; Flint, Charles; Suzuki, Yuri; Borchers, Julie

2015-03-01

Electric field control of magnetism has been recognized as one of the most important goals in nanoscale magnetics research. The most popular routes towards achieving magnetoelectric (ME) coupling have focused on heterostructures incorporating multiferroics or ferroelectrics. Such studies often rely on voltage induced distortion to induce strain in the magnetic film and alter the magnetic properties. However, successful attempts to induce ME coupling without multiferroicity or magnetoelasticity remain relatively rare. The ferromagnetic interface between the antiferromagnetic insulator CaMnO3 and the paramagnetic metal CaRuO3 is a promising candidate for direct magnetization control. This interfacial ferroagnetism is stabilized through the competition between interfacial double exchange and antiferromagnetic superexchange between adjacent Mn4+ so that the system is expected to be very sensitive to small changes in interfacial carrier density. Using polarized neutron reflectometry, we have probed the electric field dependence of the interfacial magnetization of CaRuO3/CaMnO3 bilayers deposited on SrTiO3. We find that electric fields of +/-8 kV/m are sufficient to switch the interfaces from largely ferromagnetic to completely antiferromagnetic.

Probing the electronic properties of ternary AnM3n−1B2n (n = 1: A = Ca, Sr; M = Rh, Ir and n = 3: A = Ca, Sr; M = Rh) phases: observation of superconductivity

PubMed Central

Takeya, Hiroyuki; ElMassalami, Mohammed; Terrazos, Luis A; Rapp, Raul E; Capaz, Rodrigo B; Fujii, Hiroki; Takano, Yoshihiko; Doerr, Mathias; Granovsky, Sergey A

2013-01-01

We follow the evolution of the electronic properties of the titled homologous series when n as well as the atomic type of A and M are varied where for n = 1, A = Ca, Sr and M = Rh, Ir while for n = 3, A = Ca, Sr and M = Rh. The crystal structure of n = 1 members is known to be CaRh2B2-type (Fddd), while that of n = 3 is Ca3Rh8B6-type (Fmmm); the latter can be visualized as a stacking of structural fragments from AM3B2 (P6/mmm) and AM2B2. The metallic properties of the n = 1 and 3 members are distinctly different: on the one hand, the n = 1 members are characterized by a linear coefficient of the electronic specific heat γ ≈ 3 mJ mol−1 K−2, a Debye temperature θD ≈ 300 K, a normal conductivity down to 2 K and a relatively strong linear magnetoresistivity for fields up to 150 kOe. The n = 3 family, on the other hand, exhibits γ ≈ 18 mJ mol−1 K−2, θD ≈ 330 K, a weak linear magnetoresistivity and an onset of superconductivity (for Ca3Rh8B6, Tc = 4.0 K and Hc2 = 14.5 kOe, while for Sr3Rh8 B6, Tc = 3.4 K and Hc2 ≈ 4.0 kOe). These remarkable differences are consistent with the findings of the electronic band structures and density of state (DOS) calculations. In particular, satisfactory agreement between the measured and calculated γ was obtained. Furthermore, the Fermi level, EF, of Ca3Rh8B6 lies at almost the top of a pronounced local DOS peak, while that of CaRh2B2 lies at a local valley: this is the main reason behind the differences between the, e.g., superconducting properties. Finally, although all atoms contribute to the DOS at EF, the contribution of the Rh atoms is the strongest. PMID:27877576

Function of a STIM1 Homologue in C. elegans: Evidence that Store-operated Ca2+ Entry Is Not Essential for Oscillatory Ca2+ Signaling and ER Ca2+ Homeostasis

PubMed Central

Yan, Xiaohui; Xing, Juan; Lorin-Nebel, Catherine; Estevez, Ana Y.; Nehrke, Keith; Lamitina, Todd; Strange, Kevin

2006-01-01

1,4,5-trisphosphate (IP3)-dependent Ca2+ signaling regulates gonad function, fertility, and rhythmic posterior body wall muscle contraction (pBoc) required for defecation in Caenorhabditis elegans. Store-operated Ca2+ entry (SOCE) is activated during endoplasmic reticulum (ER) Ca2+ store depletion and is believed to be an essential and ubiquitous component of Ca2+ signaling pathways. SOCE is thought to function to refill Ca2+ stores and modulate Ca2+ signals. Recently, stromal interaction molecule 1 (STIM1) was identified as a putative ER Ca2+ sensor that regulates SOCE. We cloned a full-length C. elegans stim-1 cDNA that encodes a 530–amino acid protein with ∼21% sequence identity to human STIM1. Green fluorescent protein (GFP)–tagged STIM-1 is expressed in the intestine, gonad sheath cells, and spermatheca. Knockdown of stim-1 expression by RNA interference (RNAi) causes sterility due to loss of sheath cell and spermatheca contractile activity required for ovulation. Transgenic worms expressing a STIM-1 EF-hand mutant that constitutively activates SOCE in Drosophila and mammalian cells are sterile and exhibit severe pBoc arrhythmia. stim-1 RNAi dramatically reduces STIM-1∷GFP expression, suppresses the EF-hand mutation–induced pBoc arrhythmia, and inhibits intestinal store-operated Ca2+ (SOC) channels. However, stim-1 RNAi surprisingly has no effect on pBoc rhythm, which is controlled by intestinal oscillatory Ca2+ signaling, in wild type and IP3 signaling mutant worms, and has no effect on intestinal Ca2+ oscillations and waves. Depletion of intestinal Ca2+ stores by RNAi knockdown of the ER Ca2+ pump triggers the ER unfolded protein response (UPR). In contrast, stim-1 RNAi fails to induce the UPR. Our studies provide the first detailed characterization of STIM-1 function in an intact animal and suggest that SOCE is not essential for certain oscillatory Ca2+ signaling processes and for maintenance of store Ca2+ levels in C. elegans. These findings

Function of a STIM1 homologue in C. elegans: evidence that store-operated Ca2+ entry is not essential for oscillatory Ca2+ signaling and ER Ca2+ homeostasis.

PubMed

Yan, Xiaohui; Xing, Juan; Lorin-Nebel, Catherine; Estevez, Ana Y; Nehrke, Keith; Lamitina, Todd; Strange, Kevin

2006-10-01

1,4,5-trisphosphate (IP(3))-dependent Ca(2+) signaling regulates gonad function, fertility, and rhythmic posterior body wall muscle contraction (pBoc) required for defecation in Caenorhabditis elegans. Store-operated Ca(2+) entry (SOCE) is activated during endoplasmic reticulum (ER) Ca(2+) store depletion and is believed to be an essential and ubiquitous component of Ca(2+) signaling pathways. SOCE is thought to function to refill Ca(2+) stores and modulate Ca(2+) signals. Recently, stromal interaction molecule 1 (STIM1) was identified as a putative ER Ca(2+) sensor that regulates SOCE. We cloned a full-length C. elegans stim-1 cDNA that encodes a 530-amino acid protein with approximately 21% sequence identity to human STIM1. Green fluorescent protein (GFP)-tagged STIM-1 is expressed in the intestine, gonad sheath cells, and spermatheca. Knockdown of stim-1 expression by RNA interference (RNAi) causes sterility due to loss of sheath cell and spermatheca contractile activity required for ovulation. Transgenic worms expressing a STIM-1 EF-hand mutant that constitutively activates SOCE in Drosophila and mammalian cells are sterile and exhibit severe pBoc arrhythmia. stim-1 RNAi dramatically reduces STIM-1GFP expression, suppresses the EF-hand mutation-induced pBoc arrhythmia, and inhibits intestinal store-operated Ca(2+) (SOC) channels. However, stim-1 RNAi surprisingly has no effect on pBoc rhythm, which is controlled by intestinal oscillatory Ca(2+) signaling, in wild type and IP(3) signaling mutant worms, and has no effect on intestinal Ca(2+) oscillations and waves. Depletion of intestinal Ca(2+) stores by RNAi knockdown of the ER Ca(2+) pump triggers the ER unfolded protein response (UPR). In contrast, stim-1 RNAi fails to induce the UPR. Our studies provide the first detailed characterization of STIM-1 function in an intact animal and suggest that SOCE is not essential for certain oscillatory Ca(2+) signaling processes and for maintenance of store Ca(2+) levels

IP/sub 3/ stimulates CA/sup + +/ efflux from fusogenic carrot protoplasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rincon, M.; Boss, W.F.

1986-04-01

Polyphosphoinositide breakdown plays an important role in signal transduction in animal cells (Berridge and Irvine, 1984, Nature, 312:315). Upon stimulation, phospholipase C hydrolyzes phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate (IP/sub 3/) and diacylglycerol both of which act as cellular second messengers. IP/sub 3/ mobilizes Ca/sup + +/ from internal stores, hence the cytosolic free Ca/sup + +/ concentration increases and those physiological activities regulated by Ca/sup + +/ are stimulated. To test if plant cells also responded to IP/sub 3/, Ca/sup + +/ efflux studies were done with fusogenic carrot protoplasts released in EGTA. The protoplasts were preloaded with /sup 45/Ca/supmore » + +/ placed in a Ca/sup + +/-free medium, and efflux determined as /sup 45/Ca/sup + +/ loss from the protoplasts. IP/sub 3/ (10-20..mu..M) caused enhanced /sup 45/Ca/sup + +/ efflux and the response was sustained for at least 15 min. In plants, as in animals, the observed IP/sub 3/-enhanced /sup 45/Ca/sup + +/ efflux suggested that IP/sub 3/ released Ca/sup + +/ from internal stores, and the increased free cytosolic Ca/sup + +/ activated Ca/sup + +/ pumping mechanisms which restored the Ca/sup + +/ concentration in the cytosol to the normal level.« less

Improper origin of polar displacements at CaTiO3 and CaMnO3 twin walls

NASA Astrophysics Data System (ADS)

Barone, Paolo; Di Sante, Domenico; Picozzi, Silvia

2014-04-01

Recent interest in novel functionalities arising at domain walls of ferroic materials naturally calls for a microscopic understanding. To this end, first-principles calculations have been performed in order to provide solid evidence of polar distortions in the twin walls of nonpolar CaTiO3 and magnetic CaMnO3. We show that such polar displacements arise from rotation and/or tilting octahedral distortions—cooperatively acting at the twin wall in both considered systems—rather than from a proper secondary ferroelectric instability, as often believed. Our results are in excellent agreement with experimental observations of domain walls in CaTiO3. In addition, we show that magnetic properties at the twin wall in CaMnO3 are also modified, thus suggesting an unexplored route to achieve and detect multiferroic ordering in a single-phase material.

K(Ca)3.1 channel downregulation and impaired endothelium-derived hyperpolarization-type relaxation in pulmonary arteries from chronically hypoxic rats.

PubMed

Kroigaard, Christel; Kudryavtseva, Olga; Dalsgaard, Thomas; Wandall-Frostholm, Christine; Olesen, Søren-Peter; Simonsen, Ulf

2013-04-01

Calcium-activated potassium channels of small (K(Ca)2, SK) and intermediate (K(Ca)3.1, IK) conductance are involved in endothelium-dependent relaxation of pulmonary arteries. We hypothesized that the function and expression of K(Ca)2 and K(Ca)3.1 increase as a compensatory mechanism to counteract hypoxia-induced pulmonary hypertension in rats. For functional studies, pulmonary arteries were mounted in microvascular myographs for isometric tension recordings. The K(Ca) channel expression was evaluated by immunoblotting and quantitative PCR. Although ACh induced similar relaxations, the ACh-induced relaxations were abolished by the combined inhibition of nitric oxide synthase (by L-nitro-arginine, L-NOARG), cyclo-oxygenase (by indomethacin) and soluble guanylate cyclase (by ODQ) in pulmonary arteries from hypoxic rats, whereas 20 ± 6% (n = 8) maximal relaxation in response to ACh persisted in arteries from normoxic rats. Inhibiting Na(+),K(+)-ATPase with ouabain or blocking K(Ca)2 and K(Ca)3.1 channels reduced the persisting ACh-induced relaxation. In the presence of L-NOARG and indomethacin, a novel K(Ca)2 and K(Ca)3.1 channel activator, NS4591, induced concentration- and endothelium-dependent relaxations, which were markedly reduced in arteries from chronically hypoxic rats compared with arteries from normoxic rats. The mRNA levels of K(Ca)2.3 and K(Ca)3.1 were unaltered, whereas K(Ca)2.3 protein expression was upregulated and K(Ca)3.1 protein expression downregulated in pulmonary arteries from rats exposed to hypoxia. In conclusion, endothelium-dependent relaxation was conserved in pulmonary arteries from chronically hypoxic rats, while endothelium-derived hyperpolarization (EDH)-type relaxation was impaired in chronically hypoxic pulmonary small arteries despite upregulation of K(Ca)2.3 channels. Since impaired EDH-type relaxation was accompanied by K(Ca)3.1 channel protein downregulation, these findings suggest that K(Ca)3.1 channels are important for the

Functional reconstitution of the mitochondrial Ca2+/H+ antiporter Letm1.

PubMed

Tsai, Ming-Feng; Jiang, Dawei; Zhao, Linlin; Clapham, David; Miller, Christopher

2014-01-01

The leucine zipper, EF hand-containing transmembrane protein 1 (Letm1) gene encodes a mitochondrial inner membrane protein, whose depletion severely perturbs mitochondrial Ca(2+) and K(+) homeostasis. Here we expressed, purified, and reconstituted human Letm1 protein in liposomes. Using Ca(2+) fluorophore and (45)Ca(2+)-based assays, we demonstrate directly that Letm1 is a Ca(2+) transporter, with apparent affinities of cations in the sequence of Ca(2+) ≈ Mn(2+) > Gd(3+) ≈ La(3+) > Sr(2+) > Ba(2+), Mg(2+), K(+), Na(+). Kinetic analysis yields a Letm1 turnover rate of 2 Ca(2+)/s and a Km of ∼25 µM. Further experiments show that Letm1 mediates electroneutral 1 Ca(2+)/2 H(+) antiport. Letm1 is insensitive to ruthenium red, an inhibitor of the mitochondrial calcium uniporter, and CGP-37157, an inhibitor of the mitochondrial Na(+)/Ca(2+) exchanger. Functional properties of Letm1 described here are remarkably similar to those of the H(+)-dependent Ca(2+) transport mechanism identified in intact mitochondria.

Effect of replacement of Ca by Zn on the structure and optical property of CaTiO3:Eu(3+) red phosphor prepared by sol-gel method.

PubMed

Wang, Yulong; Zhang, Wentao; Zhang, Peicong; Li, Junfeng; Long, Jianping

2015-08-01

Eu(3+)-doped calcium titanate red phosphors, Ca(1-x)Znx TiO3:Eu(3+), were prepared by the sol-gel method. The structure of prepared Ca(1-x)Znx TiO3:Eu(3+) phosphors were investigated by X-ray diffraction and infrared spectra. Due to the (5) D0  → (7) F1-3 electron transitions of Eu(3+) ions, photoluminescence spectra showed a red emission at about 619 nm under excitation of 397 nm and 465 nm, respectively. When zinc was added to the host, the luminescent intensity of Ca(1-x)ZnxTiO3:Eu(3+) was markedly improved several fold compared with that of CaTiO3:Eu(3+). Ca0.9Zn0.1TiO3:Eu(3+) also had higher luminescence intensity than the commercially available Y2 O3:Eu(3+) phosphors under UV light excitation. Copyright © 2014 John Wiley & Sons, Ltd.

Probing the electronic properties of ternary A n M3n-1B2n (n = 1: A = Ca, Sr; M = Rh, Ir and n = 3: A = Ca, Sr; M = Rh) phases: observation of superconductivity.

PubMed

Takeya, Hiroyuki; ElMassalami, Mohammed; Terrazos, Luis A; Rapp, Raul E; Capaz, Rodrigo B; Fujii, Hiroki; Takano, Yoshihiko; Doerr, Mathias; Granovsky, Sergey A

2013-06-01

We follow the evolution of the electronic properties of the titled homologous series when n as well as the atomic type of A and M are varied where for n = 1, A = Ca, Sr and M = Rh, Ir while for n = 3, A = Ca, Sr and M = Rh. The crystal structure of n = 1 members is known to be CaRh 2 B 2 -type ( Fddd ), while that of n = 3 is Ca 3 Rh 8 B 6 -type ( Fmmm ); the latter can be visualized as a stacking of structural fragments from AM 3 B 2 ( P 6/ mmm ) and AM 2 B 2 . The metallic properties of the n = 1 and 3 members are distinctly different: on the one hand, the n = 1 members are characterized by a linear coefficient of the electronic specific heat γ ≈ 3 mJ mol -1 K -2 , a Debye temperature θ D ≈ 300 K, a normal conductivity down to 2 K and a relatively strong linear magnetoresistivity for fields up to 150 kOe. The n = 3 family, on the other hand, exhibits γ ≈ 18 mJ mol -1 K -2 , θ D ≈ 330 K, a weak linear magnetoresistivity and an onset of superconductivity (for Ca 3 Rh 8 B 6 , T c = 4.0 K and H c2 = 14.5 kOe, while for Sr 3 Rh 8 B 6 , T c = 3.4 K and H c2 ≈ 4.0 kOe). These remarkable differences are consistent with the findings of the electronic band structures and density of state (DOS) calculations. In particular, satisfactory agreement between the measured and calculated γ was obtained. Furthermore, the Fermi level, E F , of Ca 3 Rh 8 B 6 lies at almost the top of a pronounced local DOS peak, while that of CaRh 2 B 2 lies at a local valley: this is the main reason behind the differences between the, e.g., superconducting properties. Finally, although all atoms contribute to the DOS at E F , the contribution of the Rh atoms is the strongest.

Measurement of mitochondrial Ca2+ transport mediated by three transport proteins: VDAC1, the Na+/Ca2+ exchanger, and the Ca2+ uniporter.

PubMed

Ben-Hail, Danya; Palty, Raz; Shoshan-Barmatz, Varda

2014-02-01

Ca(2+) is a ubiquitous cellular signal, with changes in intracellular Ca(2+) concentration not only stimulating a number of intercellular events but also triggering cell death pathways, including apoptosis. Mitochondrial Ca(2+) uptake and release play pivotal roles in cellular physiology by regulating intracellular Ca(2+) signaling, energy metabolism and cell death. Ca(2+) transport across the inner and outer mitochondrial membranes is mediated by several proteins, including channels, antiporters, and a uniporter. In this article, we present the background to several methods now established for assaying mitochondrial Ca(2+) transport activity across both mitochondrial membranes. The first of these is Ca(2+) transport mediated by the outer mitochondrial protein, the voltage-dependent anion-selective channel protein 1 (VDAC1, also known as porin 1), both as a purified protein reconstituted into a planar lipid bilayer (PLB) or into liposomes and as a mitochondrial membrane-embedded protein. The second method involves isolated mitochondria for assaying the activity of an inner mitochondrial membrane transport protein, the mitochondrial Ca(2+) uniporter (MCU) that transports Ca(2+) and is powered by the steep mitochondrial membrane potential. In the event of Ca(2+) overload, this leads to opening of the mitochondrial permeability transition pore (MPTP) and cell death. The third method describes how Na(+)-dependent mitochondrial Ca(2+) efflux mediated by mitochondrial NCLX, a member of the Na(+)/Ca(2+) exchanger superfamily, can be assayed in digitonin-permeabilized HEK-293 cells. The Ca(2+)-transport assays can be performed under various conditions and in combination with inhibitors, allowing detailed characterization of the transport activity of interest.

Mouse osteoblastic cell line (MC3T3-E1) expresses extracellular calcium (Ca2+o)-sensing receptor and its agonists stimulate chemotaxis and proliferation of MC3T3-E1 cells

NASA Technical Reports Server (NTRS)

Yamaguchi, T.; Chattopadhyay, N.; Kifor, O.; Butters, R. R. Jr; Sugimoto, T.; Brown, E. M.; O'Malley, B. W. (Principal Investigator)

1998-01-01

The calcium-sensing receptor (CaR) is a G protein-coupled receptor that plays key roles in extracellular calcium ion (Ca2+o) homeostasis in parathyroid gland and kidney. Osteoblasts appear at sites of osteoclastic bone resorption during bone remodeling in the "reversal" phase following osteoclastic resorption and preceding bone formation. Bone resorption produces substantial local increases in Ca2+o that could provide a signal for osteoblasts in the vicinity, leading us to determine whether such osteoblasts express the CaR. In this study, we used the mouse osteoblastic, clonal cell line MC3T3-E1. Both immunocytochemistry and Western blot analysis, using an antiserum specific for the CaR, detected CaR protein in MC3T3-E1 cells. We also identified CaR transcripts in MC3T3-E1 cells by Northern analysis using a CaR-specific riboprobe and by reverse transcription-polymerase chain reaction with CaR-specific primers, followed by nucleotide sequencing of the amplified products. Exposure of MC3T3-E1 cells to high Ca2+o (up to 4.8 mM) or the polycationic CaR agonists, neomycin and gadolinium (Gd3+), stimulated both chemotaxis and DNA synthesis in MC3T3-E1 cells. Therefore, taken together, our data strongly suggest that the osteoblastic cell line MC3T3-E1 possesses both CaR protein and mRNA very similar, if not identical, to those in parathyroid and kidney. Furthermore, the CaR in these osteoblasts could play a key role in regulating bone turnover by stimulating the proliferation and migration of such cells to sites of bone resorption as a result of local release of Ca2+o.

Rice-like hollow nano-CaCO3 synthesis

NASA Astrophysics Data System (ADS)

Ulkeryildiz, Eda; Kilic, Sevgi; Ozdemir, Ekrem

2016-09-01

We have shown that Ca(OH)2 solution is a natural stabilizer for CaCO3 particles. We designed a CO2 bubbling crystallization reactor to produce nano-CaCO3 particles in homogenous size distribution without aggregation. In the experimental set-up, the crystallization region was separated from the stabilization region. The produced nanoparticles were removed from the crystallization region into the stabilization region before aggregation or crystal growth. It was shown that rice-like hollow nano-CaCO3 particles in about 250 nm in size were produced with almost monodispersed size distribution. The particles started to dissolve through their edges as CO2 bubbles were injected, which opened-up the pores inside the particles. At the late stages of crystallization, the open pores were closed as a result of dissolution-recrystallization of the newly synthesized CaCO3 particles. These particles were stable in Ca(OH)2 solution and no aggregation was detected. The present methodology can be used in drug encapsulation into inorganic CaCO3 particles for cancer treatment with some modifications.

Nature of potential barrier in (Ca 1/4,Cu 3/4)TiO 3 polycrystalline perovskite

NASA Astrophysics Data System (ADS)

Marques, V. P. B.; Bueno, P. R.; Simões, A. Z.; Cilense, M.; Varela, J. A.; Longo, E.; Leite, E. R.

2006-04-01

The nonohmic electrical features of (Ca 1/4,Cu 3/4)TiO 3 perovskite ceramics, which have very strong gigantic dielectric is believed originate from potential barriers at the grain boundaries. In the present study, we used the admittance and impedance spectroscopy technique to investigate (Ca 1/4,Cu 3/4)TiO 3 perovskite ceramics with low nonohmic electrical properties. The study was conducted under two different conditions: on as-sintered ceramics and on ceramics thermally treated in an oxygen-rich atmosphere. The results confirm that thermal treatment in oxygen-rich atmospheres influence the nonohmic properties. Annealing at oxygen-rich atmospheres improve the nonohmic behavior and annealing at oxygen-poor atmospheres decrease the nonohmic properties, a behavior already reported for common metal oxide nonohmic devices and here firstly evidenced for the (Ca 1/4,Cu 3/4)TiO 3 perovskite related materials. The results show that oxygen also influences the capacitance values at low frequencies, a behavior that is indicative of the Schottky-type nature of the potential barrier.

Presynaptic kainate receptor-mediated facilitation of glutamate release involves Ca2+ -calmodulin at mossy fiber-CA3 synapses.

PubMed

Andrade-Talavera, Yuniesky; Duque-Feria, Paloma; Negrete-Díaz, José Vicente; Sihra, Talvinder S; Flores, Gonzalo; Rodríguez-Moreno, Antonio

2012-09-01

Presynaptic kainate receptors (KARs) modulate the release of glutamate at synapses established between mossy fibers (MF) and CA3 pyramidal cells in the hippocampus. The activation of KAR by low, nanomolar, kainate concentrations facilitates glutamate release. KAR-mediated facilitation of glutamate release involves the activation of an adenylate cyclase/cyclic adenosine monophosphate/protein kinase A cascade at MF-CA3 synapses. Here, we studied the mechanisms by which KAR activation produces this facilitation of glutamate release in slices and synaptosomes. We find that the facilitation of glutamate release mediated by KAR activation requires an increase in Ca(2+) levels in the cytosol and the formation of a Ca(2+) -calmodulin complex to activate adenylate cyclase. The increase in cytosolic Ca(2+) underpinning this modulation is achieved, both, by Ca(2+) entering via Ca(2+) -permeable KARs and, by the mobilization of intraterminal Ca(2+) stores. Finally, we find that, congruent with the Ca(2+) -calmodulin support of KAR-mediated facilitation of glutamate release, induction of long-term potentiation at MF-CA3 synapses has an obligate requirement for Ca(2+) -calmodulin activity. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Pepper protein phosphatase type 2C, CaADIP1 and its interacting partner CaRLP1 antagonistically regulate ABA signalling and drought response.

PubMed

Lim, Chae Woo; Lee, Sung Chul

2016-07-01

Abscisic acid (ABA) is a key phytohormone that regulates plant growth and developmental processes, including seed germination and stomatal closing. Here, we report the identification and functional characterization of a novel type 2C protein phosphatase, CaADIP1 (Capsicum annuum ABA and Drought-Induced Protein phosphatase 1). The expression of CaADIP1 was induced in pepper leaves by ABA, drought and NaCl treatments. Arabidopsis plants overexpressing CaADIP1 (CaADIP1-OX) exhibited an ABA-hyposensitive and drought-susceptible phenotype. We used a yeast two-hybrid screening assay to identify CaRLP1 (Capsicum annuum RCAR-Like Protein 1), which interacts with CaADIP1 in the cytoplasm and nucleus. In contrast to CaADIP1-OX plants, CaRLP1-OX plants displayed an ABA-hypersensitive and drought-tolerant phenotype, which was characterized by low levels of transpirational water loss and increased expression of stress-responsive genes relative to those of wild-type plants. In CaADIP1-OX/CaRLP1-OX double transgenic plants, ectopic expression of the CaRLP1 gene led to strong suppression of CaADIP1-induced ABA hyposensitivity during the germinative and post-germinative stages, indicating that CaADIP1 and CaRLP1 act in the same signalling pathway and CaADIP1 functions downstream of CaRLP1. Our results indicate that CaADIP1 and its interacting partner CaRLP1 antagonistically regulate the ABA-dependent defense signalling response to drought stress. © 2016 John Wiley & Sons Ltd.

Na(+)/Ca(2+) exchange regulates Ca(2+)-dependent duodenal mucosal ion transport and HCO(3)(-) secretion in mice.

PubMed

Dong, Hui; Sellers, Zachary M; Smith, Anders; Chow, Jimmy Y C; Barrett, Kim E

2005-03-01

Stimulation of muscarinic receptors in duodenal mucosa raises intracellular Ca(2+), which regulates ion transport, including HCO(3)(-) secretion. However, the underlying Ca(2+) handling mechanisms are poorly understood. The aim of the present study was to determine whether Na(+)/Ca(2+) exchanger (NCX) plays a role in the regulation of duodenal mucosal ion transport and HCO(3)(-) secretion by controlling Ca(2+) homeostasis. Mouse duodenal mucosa was mounted in Ussing chambers. Net ion transport was assessed as short-circuit current (I(sc)), and HCO(3)(-) secretion was determined by pH-stat. Expression of NCX in duodenal mucosae was analyzed by Western blot, and cytosolic Ca(2+) in duodenocytes was measured by fura 2. Carbachol (100 muM) increased I(sc) in a biphasic manner: an initial transient peak within 2 min and a later sustained plateau starting at 10 min. Carbachol-induced HCO(3)(-) secretion peaked at 10 min. 2-Aminoethoxydiphenylborate (2-APB, 100 muM) or LiCl (30 mM) significantly reduced the initial peak in I(sc) by 51 or 47%, respectively, and abolished the plateau phase of I(sc) without affecting HCO(3)(-) secretion induced by carbachol. Ryanodine (100 muM), caffeine (10 mM), and nifedipine (10 muM) had no effect on either response to carbachol. In contrast, nickel (5 mM) and KB-R7943 (10-30 muM) significantly inhibited carbachol-induced increases in duodenal mucosal I(sc) and HCO(3)(-) secretion. Western blot analysis showed expression of NCX1 proteins in duodenal mucosae, and functional NCX in duodenocytes was demonstrated in Ca(2+) imaging experiments where Na(+) depletion elicited Ca(2+) entry via the reversed mode of NCX. These results indicate that NCX contributes to the regulation of Ca(2+)-dependent duodenal mucosal ion transport and HCO(3)(-) secretion that results from stimulation of muscarinic receptors.

46 CFR 7.125 - Point Vincente, CA to Point Conception, CA.

Code of Federal Regulations, 2010 CFR

2010-10-01

... BOUNDARY LINES Pacific Coast § 7.125 Point Vincente, CA to Point Conception, CA. (a) A line drawn from Redondo Beach East Jetty Light “2” to Redondo Beach West Jetty Light “3”. (b) A line drawn from Marina Del... 46 Shipping 1 2010-10-01 2010-10-01 false Point Vincente, CA to Point Conception, CA. 7.125...

46 CFR 7.125 - Point Vincente, CA to Point Conception, CA.

Code of Federal Regulations, 2012 CFR

2012-10-01

... BOUNDARY LINES Pacific Coast § 7.125 Point Vincente, CA to Point Conception, CA. (a) A line drawn from Redondo Beach East Jetty Light “2” to Redondo Beach West Jetty Light “3”. (b) A line drawn from Marina Del... 46 Shipping 1 2012-10-01 2012-10-01 false Point Vincente, CA to Point Conception, CA. 7.125...

46 CFR 7.125 - Point Vincente, CA to Point Conception, CA.

Code of Federal Regulations, 2013 CFR

2013-10-01

... BOUNDARY LINES Pacific Coast § 7.125 Point Vincente, CA to Point Conception, CA. (a) A line drawn from Redondo Beach East Jetty Light “2” to Redondo Beach West Jetty Light “3”. (b) A line drawn from Marina Del... 46 Shipping 1 2013-10-01 2013-10-01 false Point Vincente, CA to Point Conception, CA. 7.125...

46 CFR 7.125 - Point Vincente, CA to Point Conception, CA.

Code of Federal Regulations, 2014 CFR

2014-10-01

... BOUNDARY LINES Pacific Coast § 7.125 Point Vincente, CA to Point Conception, CA. (a) A line drawn from Redondo Beach East Jetty Light “2” to Redondo Beach West Jetty Light “3”. (b) A line drawn from Marina Del... 46 Shipping 1 2014-10-01 2014-10-01 false Point Vincente, CA to Point Conception, CA. 7.125...

46 CFR 7.125 - Point Vincente, CA to Point Conception, CA.

Code of Federal Regulations, 2011 CFR

2011-10-01

... BOUNDARY LINES Pacific Coast § 7.125 Point Vincente, CA to Point Conception, CA. (a) A line drawn from Redondo Beach East Jetty Light “2” to Redondo Beach West Jetty Light “3”. (b) A line drawn from Marina Del... 46 Shipping 1 2011-10-01 2011-10-01 false Point Vincente, CA to Point Conception, CA. 7.125...

Potentiation of inositol trisphosphate-induced Ca2+ mobilization in Xenopus oocytes by cytosolic Ca2+.

PubMed Central

Yao, Y; Parker, I

1992-01-01

1. The ability of cytosolic Ca2+ ions to modulate inositol 1,4,5-trisphosphate (Insp3)-induced Ca2+ liberation from intracellular stores was studied in Xenopus oocytes using light flash photolysis of caged InsP3. Changes in cytosolic free Ca2+ level were effected by inducing Ca2+ entry through ionophore and voltage-gated plasma membrane channels and by injection of Ca2+ through a micropipette. Their effects on Ca2+ liberation were monitored by video imaging of Fluo-3 fluorescence and by voltage clamp recording of Ca(2+)-activated membrane Cl- currents. 2. Treatment of oocytes with the Ca2+ ionophores A23187 and ionomycin caused a transient elevation of cytosolic Ca2+ level when cells were bathed in Ca(2+)-free solution, which probably arose because of release of Ca2+ from intracellular stores. 3. Membrane current and Fluo-3 Ca2+ signals evoked by photoreleased InsP3 in ionophore-treated oocytes were potentiated when the intracellular Ca2+ level was elevated by raising the Ca2+ level in the bathing solution. 4. Responses to photoreleased InsP3 were similarly potentiated following activation of Ca2+ entry through voltage-gated Ca2+ channels expressed in the plasma membrane. 5. Ca(2+)-activated membrane currents evoked by depolarization developed a delayed 'hump' component during sustained photorelease of InsP3, probably because Ca2+ ions entering through the membrane channels triggered liberation of Ca2+ from intracellular stores. 6. Ba2+ and Sr2+ ions were able to substitute for Ca2+ in potentiating InsP3-mediated Ca2+ liberation. 7. Gradual photorelease of InsP3 by weak photolysis light evoked Ca2+ liberation that began at particular foci and then propagated throughout, but not beyond that area of the oocyte exposed to the light. Local elevations of intracellular Ca2+ produced by microinjection of Ca2+ acted as new foci for the initiation of Ca2+ liberation by InsP3. 8. In resting oocytes, intracellular injections of Ca2+ resulted only in localized elevation of

Distribution of calcium channel Ca(V)1.3 immunoreactivity in the rat spinal cord and brain stem.

PubMed

Sukiasyan, N; Hultborn, H; Zhang, M

2009-03-03

The function of local networks in the CNS depends upon both the connectivity between neurons and their intrinsic properties. An intrinsic property of spinal motoneurons is the presence of persistent inward currents (PICs), which are mediated by non-inactivating calcium (mainly Ca(V)1.3) and/or sodium channels and serve to amplify neuronal input signals. It is of fundamental importance for the prediction of network function to determine the distribution of neurons possessing the ion channels that produce PICs. Although the distribution pattern of Ca(V)1.3 immunoreactivity (Ca(V)1.3-IR) has been studied in some specific central nervous regions in some species, so far no systematic investigations have been performed in both the rat spinal cord and brain stem. In the present study this issue was investigated by immunohistochemistry. The results indicated that the Ca(V)1.3-IR neurons were widely distributed across different parts of the spinal cord and the brain stem although with variable labeling intensities. In the spinal gray matter large neurons in the ventral horn (presumably motoneurons) tended to display higher levels of immunoreactivity than smaller neurons in the dorsal horn. In the white matter, a subset of glial cells labeled by an oligodendrocyte marker was also Ca(V)1.3-positive. In the brain stem, neurons in the motor nuclei appeared to have higher levels of immunoreactivity than those in the sensory nuclei. Moreover, a number of nuclei containing monoaminergic cells, for example the locus coeruleus, were also strongly immunoreactive. Ca(V)1.3-IR was consistently detected in the neuronal perikarya regardless of the neuronal type. However, in the large neurons in the spinal ventral horn and the cranial motor nuclei the Ca(V)1.3-IR was clearly detectable in first and second order dendrites. These results indicate that in the rat spinal cord and brain stem Ca(V)1.3 is probably a common calcium channel used by many kinds of neurons to facilitate the neuronal

Oestrogen directly inhibits the cardiovascular L-type Ca{sup 2+} channel Ca{sub v}1.2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ullrich, Nina D.; Koschak, Alexandra; MacLeod, Kenneth T.

2007-09-21

Oestrogen can modify the contractile function of vascular smooth muscle and cardiomyocytes. The negative inotropic actions of oestrogen on the heart and coronary vasculature appear to be mediated by L-type Ca{sup 2+} channel (Ca{sub v}1.2) inhibition, but the underlying mechanisms remain elusive. We tested the hypothesis that oestrogen directly inhibits the cardiovascular L-type Ca{sup 2+} current, I {sub CaL}. The effect of oestrogen on I {sub CaL} was measured in Ca{sub v}1.2-transfected HEK-293 cells using the whole-cell patch-clamp technique. The current revealed typical activation and inactivation profiles of nifedipine- and cadmium-sensitive I {sub CaL}. Oestrogen (50 {mu}M) rapidly reduced Imore » {sub CaL} by 50% and shifted voltage-dependent activation and availability to more negative potentials. Furthermore, oestrogen blocked the Ca{sup 2+} channel in a rate-dependent way, exhibiting higher efficiency of block at higher stimulation frequencies. Our data suggest that oestrogen inhibits I {sub CaL} through direct interaction of the steroid with the channel protein.« less

Subpopulation of store-operated Ca2+ channels regulate Ca2+-induced Ca2+ release in non-excitable cells.

PubMed

Yao, Jian; Li, Qin; Chen, Jin; Muallem, Shmuel

2004-05-14

Ca2+-induced Ca2+ release (CICR) is a well characterized activity in skeletal and cardiac muscles mediated by the ryanodine receptors. The present study demonstrates CICR in the non-excitable parotid acinar cells, which resembles the mechanism described in cardiac myocytes. Partial depletion of internal Ca2+ stores leads to a minimal activation of Ca2+ influx. Ca2+ influx through this pathway results in an explosive mobilization of Ca2+ from the majority of the stores by CICR. Thus, stimulation of parotid acinar cells in Ca2+ -free medium with 0.5 microm carbachol releases approximately 5% of the Ca2+ mobilizable by 1 mm carbachol. Addition of external Ca2+ induced the same Ca2+ release observed in maximally stimulated cells. Similar results were obtained by a short treatment with 2.5-10 microm cyclopiazonic acid, an inhibitor of the sarco/endoplasmic reticulum Ca2+ ATPase pump. The Ca2+ release induced by the addition of external Ca2+ was largely independent of IP(3)Rs because it was reduced by only approximately 30% by the inhibition of the inositol 1,4,5-trisphosphate receptors with caffeine or heparin. Measurements of Ca2+ -activated outward current and [Ca2+](i) suggested that most CICR triggered by Ca2+ influx occurred away from the plasma membrane. Measurement of the response to several concentrations of cyclopiazonic acid revealed that Ca2+ influx that regulates CICR is associated with a selective portion of the internal Ca2+ pool. The minimal activation of Ca2+ influx by partial store depletion was confirmed by the measurement of Mn2+ influx. Inhibition of Ca2+ influx with SKF96365 or 2-aminoethoxydiphenyl borate prevented activation of CICR observed on addition of external Ca2+. These findings provide evidence for activation of CICR by Ca2+ influx in non-excitable cells, demonstrate a previously unrecognized role for Ca2+ influx in triggering CICR, and indicate that CICR in non-excitable cells resembles CICR in cardiac myocytes with the exception that in

PIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinoma.

PubMed

Ross, R L; McPherson, H R; Kettlewell, L; Shnyder, S D; Hurst, C D; Alder, O; Knowles, M A

2016-07-28

Many urothelial carcinomas (UC) contain activating PIK3CA mutations. In telomerase-immortalized normal urothelial cells (TERT-NHUC), ectopic expression of mutant PIK3CA induces PI3K pathway activation, cell proliferation and cell migration. However, it is not clear whether advanced UC tumors are PIK3CA-dependent and whether PI3K pathway inhibition is a good therapeutic option in such cases. We used retrovirus-mediated delivery of shRNA to knock down mutant PIK3CA in UC cell lines and assessed effects on pathway activation, cell proliferation, migration and tumorigenicity. The effect of the class I PI3K inhibitor GDC-0941 was assessed in a panel of UC cell lines with a range of known molecular alterations in the PI3K pathway. Specific knockdown of PIK3CA inhibited proliferation, migration, anchorage-independent growth and in vivo tumor growth of cells with PIK3CA mutations. Sensitivity to GDC-0941 was dependent on hotspot PIK3CA mutation status. Cells with rare PIK3CA mutations and co-occurring TSC1 or PTEN mutations were less sensitive. Furthermore, downstream PI3K pathway alterations in TSC1 or PTEN or co-occurring AKT1 and RAS gene mutations were associated with GDC-0941 resistance. Mutant PIK3CA is a potent oncogenic driver in many UC cell lines and may represent a valuable therapeutic target in advanced bladder cancer.

Effects of addition of Bi2Ca2Co2O y on the thermoelectric properties of Ca3Co4O9 polycrystalline ceramics

NASA Astrophysics Data System (ADS)

Feng, Ningbo; Liao, Y. W.; Lu, Y.; He, Y.; Jin, Y. R.; Liu, X. R.

2018-06-01

Thermoelectric properties of Ca3Co4O9 polycrystalline ceramics with sheet grains were optimized by adding Bi2Ca2Co2O y phase. Therefore, the (1 - x) Ca3Co4O9/ x Bi2Ca2Co2O y (0 ≤ x ≤ 1) composites were prepared. The phase constitution and micro-structure of the samples were analyzed by XRD and SEM, respectively. With the addition of Bi2Ca2Co2O y , the apparent density D a and the relative density D r of the samples continuously increases. When x ≤ 0.4, the electrical resistivity of the samples declines, however, when x ≥ 0.4, the electrical resistivity of the samples increases. The Seebeck coefficient of the samples grows with the increase of the x monotonously. The power factor of the 0.6 Ca3Co4O9/0.4 Bi2Ca2Co2O y samples reaches 0.24 mW m-1K-2 at 973 K. Thermal conductivity κ of the 0.6 Ca3Co4O9/0.4 Bi2Ca2Co2O y monotonously decreases with the temperature rising, achieving the minimum about 1.34 W m-1K-1 at 973 K. The ZT of 0.6 Ca3Co4O9/0.4 Bi2Ca2Co2O y composites gets to 0.18, which is comparable to that of most doped Ca3Co4O9 polycrystalline ceramics, implying higher ZT can be realized by combining the strategy of doping and introducing the Bi2Ca2Co2O y .

Alcohol Withdrawal-Induced Seizure Susceptibility is Associated with an Upregulation of CaV1.3 Channels in the Rat Inferior Colliculus

PubMed Central

Akinfiresoye, Luli R.; Allard, Joanne S.; Lovinger, David M.

2015-01-01

Background: We previously reported increased current density through L-type voltage-gated Ca2+ (CaV1) channels in inferior colliculus (IC) neurons during alcohol withdrawal. However, the molecular correlate of this increased CaV1 current is currently unknown. Methods: Rats received three daily doses of ethanol every 8 hours for 4 consecutive days; control rats received vehicle. The IC was dissected at various time intervals following alcohol withdrawal, and the mRNA and protein levels of the CaV1.3 and CaV1.2 α1 subunits were measured. In separate experiments, rats were tested for their susceptibility to alcohol withdrawal–induced seizures (AWS) 3, 24, and 48 hours after alcohol withdrawal. Results: In the alcohol-treated group, AWS were observed 24 hours after withdrawal; no seizures were observed at 3 or 48 hours. No seizures were observed at any time in the control-treated rats. Compared to control-treated rats, the mRNA level of the CaV1.3 α1 subunit was increased 1.4-fold, 1.9-fold, and 1.3-fold at 3, 24, and 48 hours, respectively. In contrast, the mRNA level of the CaV1.2 α1 subunit increased 1.5-fold and 1.4-fold at 24 and 48 hours, respectively. At 24 hours, Western blot analyses revealed that the levels of the CaV1.3 and CaV1.2 α1 subunits increased by 52% and 32%, respectively, 24 hours after alcohol withdrawal. In contrast, the CaV1.2 and CaV1.3 α1 subunits were not altered at either 3 or 48 hours during alcohol withdrawal. Conclusions: Expression of the CaV1.3 α1 subunit increased in parallel with AWS development, suggesting that altered L-type CaV1.3 channel expression is an important feature of AWS pathogenesis. PMID:25556199

Concordance analysis of paired cancer antigen (CA) 15-3 and 27.29 testing.

PubMed

Lin, David C; Genzen, Jonathan R

2018-01-01

Cancer antigens (CA) 15-3 and 27.29 are used in the clinical management of many breast cancer patients. Given that immunoassays for CA 15-3 and CA 27.29 target epitopes on the same glycoprotein-Mucin 1 (MUC1)-the present analysis was conducted to evaluate the potential concordance of tumor marker results when both tests were ordered by providers on the same specimens. A retrospective limited dataset of paired CA 15-3 (Roche Diagnostics) and CA 27.29 (Siemens Diagnostics) test results was obtained from a national clinical reference laboratory. Concordance according to reference interval (RI) status and percent (%) change between consecutive test results was analyzed. 37,652 paired results from 12,470 distinct patients were obtained. The correlation between CA 15-3 and CA 27.29 results was high (correlation coefficient: Pearson, 0.967), although across the dataset a significant difference between CA 15-3 and CA 27.29 results was observed (P < 0.05). RI concordance between CA 15-3 and CA 27.29 results was observed in 93.7% of pairs (35,280 of 37,652). Correlation was also observed in the % change of CA 15-3 and CA 27.29 results between consecutive specimens for individual patients. Using doubling or halving thresholds (i.e., 100% increase or 50% decrease), concordance in % change was observed between CA 15-3 and CA 27.29 in approximately 90% of cases. Individual patient results trended similarly across both markers over time. While generally concordant, CA 15-3 and CA 27.29 results should not be used interchangeably. The present report provides no evidence for added value in performing both tests routinely for individual patients.

Single orthorhombic b axis orientation and antiferromagnetic ordering type in multiferroic CaMnO3 thin film with La0.67Ca0.33MnO3 buffer layer

NASA Astrophysics Data System (ADS)

Wang, F.; Dong, B. J.; Zhang, Y. Q.; Liu, W.; Zhang, H. R.; Bai, Y.; Li, S. K.; Yang, T.; Sun, J. R.; Wang, Z. J.; Zhang, Z. D.

2017-09-01

The detailed crystal structure and antiferromagnetic properties of a 42 nm thick CaMnO3 film grown on a LaAlO3 substrate with a 9 nm La0.67Ca0.33MnO3 buffer layer have been investigated. Compared with a CaMnO3 film directly grown on a LaAlO3 substrate, only one kind of orthorhombic b axis orientation along the [100] axis of the substrate is observed in the CaMnO3 film with a La0.67Ca0.33MnO3 buffer layer. To determine the antiferromagnetic ordering type of our CaMnO3 film with a buffer layer, the first-principles calculations were carried out with the results, indicating that the CaMnO3 film, even under a tensile strain of 1.9%, is still a compensated G-type antiferromagnetic order, the same as the bulk. Moreover, the exchange bias effect is observed at the interface of the CaMnO3/La0.67Ca0.33MnO3 film, further confirming the antiferromagnetic ordering of the CaMnO3 film with a buffer layer. In addition, it is concluded that the exchange bias effect originates from the spin glass state at the La0.67Ca0.33MnO3/CaMnO3 interface, which arises from a competition between the double-exchange ferromagnetic La0.67Ca0.33MnO3 and super-exchange antiferromagnetic CaMnO3 below the spin glass freezing temperature.

The site of net absorption of Ca from the intestinal tract of growing pigs and effect of phytic acid, Ca level and Ca source on Ca digestibility.

PubMed

González-Vega, J Caroline; Walk, Carrie L; Liu, Yanhong; Stein, Hans H

2014-01-01

An experiment was conducted to test the hypothesis that the standardised digestibility of Ca in calcium carbonate and Lithothamnium calcareum Ca is not different regardless of the level of dietary Ca, and that phytic acid affects the digestibility of Ca in these two ingredients to the same degree. The objectives were to determine where in the intestinal tract Ca absorption takes place and if there are measurable quantities of basal endogenous Ca fluxes in the stomach, small intestine or large intestine. Diets contained calcium carbonate or L. calcareum Ca as the sole source of Ca, 0% or 1% phytic acid and 0.4% or 0.8% Ca. A Ca-free diet was also formulated and used to measure endogenous fluxes and losses of Ca. Nine growing pigs (initial body weight 23.8 ± 1.3 kg) were cannulated in the duodenum and in the distal ileum, and faecal, ileal and duodenal samples were collected. Duodenal endogenous fluxes of Ca were greater (p < 0.05) than ileal endogenous fluxes and total tract endogenous losses of Ca, but ileal endogenous fluxes were less (p < 0.05) than total tract endogenous losses. Standardised digestibility of Ca was not affected by the level of phytic acid, but decreased (p < 0.05) as Ca level increased in L. calcareum Ca diets, but that was not the case if calcium carbonate was the source of Ca (interaction, p < 0.05). The standardised duodenal digestibility (SDD), standardised ileal digestibility (SID) and standardised total tract digestibility (STTD) of Ca were not different if calcium carbonate was the source of dietary Ca. However, the STTD of Ca in L. calcareum Ca was greater (p < 0.05) than the SID and SDD of Ca. The SDD, SID and STTD of Ca in calcium carbonate were greater (p < 0.05) than those of L. calcareum Ca. In conclusion, under the conditions of this experiment, standardised digestibility of Ca is not affected by the level of phytic acid, but may be affected by dietary Ca level depending on the Ca source. Calcium from calcium carbonate is mostly

A role for CA3 in social recognition memory.

PubMed

Chiang, Ming-Ching; Huang, Arthur J Y; Wintzer, Marie E; Ohshima, Toshio; McHugh, Thomas J

2018-02-02

Social recognition memory is crucial for survival across species, underlying the need to correctly identify conspecifics, mates and potential enemies. In humans the hippocampus is engaged in social and episodic memory, however the circuit mechanisms of social memory in rodent models has only recently come under scrutiny. Work in mice has established that the dorsal CA2 and ventral CA1 regions play critical roles, however a more comprehensive comparative analyses of the circuits and mechanisms required has not been reported. Here we employ conditional genetics to examine the differential contributions of the hippocampal subfields to social memory. We find that the deletion of NMDA receptor subunit 1 gene (NR1), which abolishes NMDA receptor synaptic plasticity, in CA3 pyramidal cells led to deficits in social memory; however, mice lacking the same gene in DG granule cells performed indistinguishable from controls. Further, we use conditional pharmacogenetic inhibition to demonstrate that activity in ventral, but not dorsal, CA3 is necessary for the encoding of a social memory. These findings demonstrated CA3 pyramidal cell plasticity and transmission contribute to the encoding of social stimuli and help further identify the distinct circuits underlying the role of the hippocampus in social memory. Copyright © 2018 Elsevier B.V. All rights reserved.

PGC-1{alpha} accelerates cytosolic Ca{sup 2+} clearance without disturbing Ca{sup 2+} homeostasis in cardiac myocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Min, E-mail: chenminyx@gmail.com; Yunnan Centers for Diseases Prevention and Control, Kunming 650022; Wang, Yanru

2010-06-11

Energy metabolism and Ca{sup 2+} handling serve critical roles in cardiac physiology and pathophysiology. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1{alpha}) is a multi-functional coactivator that is involved in the regulation of cardiac mitochondrial functional capacity and cellular energy metabolism. However, the regulation of PGC-1{alpha} in cardiac Ca{sup 2+} signaling has not been fully elucidated. To address this issue, we combined confocal line-scan imaging with off-line imaging processing to characterize calcium signaling in cultured adult rat ventricular myocytes expressing PGC-1{alpha} via adenoviral transduction. Our data shows that overexpressing PGC-1{alpha} improved myocyte contractility without increasing the amplitude of Ca{sup 2+}more » transients, suggesting that myofilament sensitivity to Ca{sup 2+} increased. Interestingly, the decay kinetics of global Ca{sup 2+} transients and Ca{sup 2+} waves accelerated in PGC-1{alpha}-expressing cells, but the decay rate of caffeine-elicited Ca{sup 2+} transients showed no significant change. This suggests that sarcoplasmic reticulum (SR) Ca{sup 2+}-ATPase (SERCA2a), but not Na{sup +}/Ca{sup 2+} exchange (NCX) contribute to PGC-1{alpha}-induced cytosolic Ca{sup 2+} clearance. Furthermore, PGC-1{alpha} induced the expression of SERCA2a in cultured cardiac myocytes. Importantly, overexpressing PGC-1{alpha} did not disturb cardiac Ca{sup 2+} homeostasis, because SR Ca{sup 2+} load and the propensity for Ca{sup 2+} waves remained unchanged. These data suggest that PGC-1{alpha} can ameliorate cardiac Ca{sup 2+} cycling and improve cardiac work output in response to physiological stress. Unraveling the PGC-1{alpha}-calcium handing pathway sheds new light on the role of PGC-1{alpha} in the therapy of cardiac diseases.« less

Interaction of peridotite with Ca-rich carbonatite melt at 3.1 and 6.5 GPa: Implication for merwinite formation in upper mantle, and for the metasomatic origin of sublithospheric diamonds with Ca-rich suite of inclusions

NASA Astrophysics Data System (ADS)

Sharygin, Igor S.; Shatskiy, Anton; Litasov, Konstantin D.; Golovin, Alexander V.; Ohtani, Eiji; Pokhilenko, Nikolay P.

2018-03-01

We performed an experimental study, designed to reproduce the formation of an unusual merwinite + olivine-bearing mantle assemblage recently described as a part of a Ca-rich suite of inclusions in sublithospheric diamonds, through the interaction of peridotite with an alkali-rich Ca-carbonatite melt, derived from deeply subducted oceanic crust. In the first set of experiments, we studied the reaction between powdered Mg-silicates, olivine and orthopyroxene, and a model Ca-carbonate melt (molar Na:K:Ca = 1:1:2), in a homogeneous mixture, at 3.1 and 6.5 GPa. In these equilibration experiments, we observed the formation of a merwinite + olivine-bearing assemblage at 3.1 GPa and 1200 °C and at 6.5 GPa and 1300-1400 °C. The melts coexisting with this assemblage have a low Si and high Ca content (Ca# = molar 100 × Ca/(Ca + Mg) > 0.57). In the second set of experiments, we investigated reaction rims produced by interaction of the same Ca-carbonate melt (molar Na:K:Ca = 1:1:2) with Mg-silicate, olivine and orthopyroxene, single crystals at 3.1 GPa and 1300 °C and at 6.5 GPa and 1400 °C. The interaction of the Ca-carbonate melt with olivine leads to merwinite formation through the expected reaction: 2Mg2SiO4 (olivine) + 6CaCO3 (liquid) = Ca3MgSi2O8 (merwinite) + 3CaMg(CO3)2 (liquid). Thus, our experiments confirm the idea that merwinite in the upper mantle may originate via interaction of peridotite with Ca-rich carbonatite melt, and that diamonds hosting merwinite may have a metasomatic origin. It is remarkable that the interaction of the Ca-carbonate melt with orthopyroxene crystals does not produce merwinite both at 3.1 and 6.5 GPa. This indicates that olivine grain boundaries are preferable for merwinite formation in the upper mantle.

γCaMKII shuttles Ca2+/CaM to the nucleus to trigger CREB phosphorylation and gene expression

PubMed Central

Ma, Huan; Groth, Rachel D.; Cohen, Samuel M.; Emery, John F.; Li, Bo-Xing; Hoedt, Esthelle; Zhang, Guo-An; Neubert, Thomas A.; Tsien, Richard W.

2014-01-01

SUMMARY Activity-dependent CREB phosphorylation and gene expression are critical for long-term neuronal plasticity. Local signaling at CaV1 channels triggers these events but how information is relayed onward to the nucleus remains unclear. Here we report a novel mechanism that mediates long-distance communication within cells: a shuttle that transports Ca2+/calmodulin from the surface membrane to the nucleus. We show that the shuttle protein is γCaMKII, that its phosphorylation at Thr287 by βCaMKII protects the Ca2+/CaM signal, and that CaN triggers its nuclear translocation. Both βCaMKII and CaN act in close proximity to CaV1 channels, supporting their dominance, while γCaMKII operates as a carrier, not as a kinase. Upon arrival within the nucleus, Ca2+/CaM activates CaMKK and its substrate CaMKIV, the CREB kinase. This mechanism resolves longstanding puzzles about CaM/CaMK-dependent signaling to the nucleus. The significance of the mechanism is emphasized by dysregulation of CaV1, γCaMKII, βCaMKII and CaN in multiple neuropsychiatric disorders. PMID:25303525

The initial 41Ca/40Ca ratios in two type A Ca-Al-rich inclusions: Implications for the origin of short-lived 41Ca

NASA Astrophysics Data System (ADS)

Liu, Ming-Chang

2017-03-01

This paper reports new 41Ca-41K isotopic data for two Type A CAIs, NWA 3118 #1Nb (Compact Type A) and Vigarano 3138 F8 (Fluffy Type A), from reduced CV3 chondrites. The NWA CAI is found to have carried live 41Ca at the level of (4.6 ± 1.9) ×10-9 , consistent with the proposed Solar System initial 41Ca /40Ca = 4.2 ×10-9 by Liu et al. (2012a). On the other hand, the Vigarano CAI does not have resolvable radiogenic 41K excesses that can be attributed to the decay of 41Ca. Combined with the 26Al data that have been reported for these two CAIs, we infer that the 41Ca distribution was not homogeneous when 26Al was widespread at the canonical level of 26Al /27Al = 5.2 ×10-5 . Such a 41Ca heterogeneity can be understood under two astrophysical contexts: in situ charged particle irradiation by the protoSun in the solar nebula that had inherited some baseline 10Be abundance from the molecular cloud, and Solar System formation in a molecular cloud enriched in 26Al and 41Ca contaminated by massive star winds. That said, more high quality 41Ca data are still needed to better understand the origin of this radionuclide.

Regulation of RYR1 activity by Ca(2+) and calmodulin

NASA Technical Reports Server (NTRS)

Rodney, G. G.; Williams, B. Y.; Strasburg, G. M.; Beckingham, K.; Hamilton, S. L.

2000-01-01

The skeletal muscle calcium release channel (RYR1) is a Ca(2+)-binding protein that is regulated by another Ca(2+)-binding protein, calmodulin. The functional consequences of calmodulin's interaction with RYR1 are dependent on Ca(2+) concentration. At nanomolar Ca(2+) concentrations, calmodulin is an activator, but at micromolar Ca(2+) concentrations, calmodulin is an inhibitor of RYR1. This raises the question of whether the Ca(2+)-dependent effects of calmodulin on RYR1 function are due to Ca(2+) binding to calmodulin, RYR1, or both. To distinguish the effects of Ca(2+) binding to calmodulin from those of Ca(2+) binding to RYR1, a mutant calmodulin that cannot bind Ca(2+) was used to evaluate the effects of Ca(2+)-free calmodulin on Ca(2+)-bound RYR1. We demonstrate that Ca(2+)-free calmodulin enhances the affinity of RYR1 for Ca(2+) while Ca(2+) binding to calmodulin converts calmodulin from an activator to an inhibitor. Furthermore, Ca(2+) binding to RYR1 enhances its affinity for both Ca(2+)-free and Ca(2+)-bound calmodulin.

Size-driven magnetic transitions in La1/3Ca2/3MnO3 nanoparticles

NASA Astrophysics Data System (ADS)

Markovich, V.; Fita, I.; Wisniewski, A.; Mogilyansky, D.; Puzniak, R.; Titelman, L.; Gorodetsky, G.

2010-09-01

Magnetic properties of electron-doped La1/3Ca2/3MnO3 manganite nanoparticles with average particle size ranging from 12 to 42 nm, prepared by the glycine-nitrate method, have been investigated in temperature range 5-300 K and in magnetic fields up to 90 kOe. Reduction in the particle size suppresses antiferromagnetism and decreases the Néel temperature. In contrast to bulk crystals, the charge ordering does not occur in all studied nanoparticles, while a weak ferromagnetism appears above 200 K. Low temperature magnetic hysteresis loops indicate upon exchange bias effect displayed by horizontal and vertical shifts in field cooled processes. The spontaneous and remanent magnetization at low temperature shows a relatively complex variation with particle size. The size-induced structural/magnetic disorder drives the La1/3Ca2/3MnO3 nanoparticles to a pronounced glassy behavior for the smallest 12 nm particles, as evidenced by large difference between zero field cooled and field cooled magnetization, frequency dependent ac-susceptibility, as well as characteristic slowing down in the spin dynamics. Time evolution of magnetization recorded in magnetic fields after field cooling to low temperatures exhibits pronounced relaxation and a very noisy behavior that may be caused by formation of some collective states. Magnetic properties of the nanoparticle samples are compared with those of La0.2Ca0.8MnO3 nanoparticles. These results shed some light on the coupling between charges and spin degrees of freedom in antiferromagnetic manganite nanoparticles.

The interhemispheric CA1 circuit governs rapid generalisation but not fear memory.

PubMed

Zhou, Heng; Xiong, Gui-Jing; Jing, Liang; Song, Ning-Ning; Pu, De-Lin; Tang, Xun; He, Xiao-Bing; Xu, Fu-Qiang; Huang, Jing-Fei; Li, Ling-Jiang; Richter-Levin, Gal; Mao, Rong-Rong; Zhou, Qi-Xin; Ding, Yu-Qiang; Xu, Lin

2017-12-19

Encoding specificity theory predicts most effective recall by the original conditions at encoding, while generalization endows recall flexibly under circumstances which deviate from the originals. The CA1 regions have been implicated in memory and generalization but whether and which locally separated mechanisms are involved is not clear. We report here that fear memory is quickly formed, but generalization develops gradually over 24 h. Generalization but not fear memory is impaired by inhibiting ipsilateral (ips) or contralateral (con) CA1, and by optogenetic silencing of the ipsCA1 projections onto conCA1. By contrast, in vivo fEPSP recordings reveal that ipsCA1-conCA1 synaptic efficacy is increased with delay over 24 h when generalization is formed but it is unchanged if generalization is disrupted. Direct excitation of ipsCA1-conCA1 synapses using chemogenetic hM3Dq facilitates generalization formation. Thus, rapid generalization is an active process dependent on bilateral CA1 regions, and encoded by gradual synaptic learning in ipsCA1-conCA1 circuit.

Tissue-selective restriction of RNA editing of CaV1.3 by splicing factor SRSF9.

PubMed

Huang, Hua; Kapeli, Katannya; Jin, Wenhao; Wong, Yuk Peng; Arumugam, Thiruma Valavan; Koh, Joanne Huifen; Srimasorn, Sumitra; Mallilankaraman, Karthik; Chua, John Jia En; Yeo, Gene W; Soong, Tuck Wah

2018-05-04

Adenosine DeAminases acting on RNA (ADAR) catalyzes adenosine-to-inosine (A-to-I) conversion within RNA duplex structures. While A-to-I editing is often dynamically regulated in a spatial-temporal manner, the mechanisms underlying its tissue-selective restriction remain elusive. We have previously reported that transcripts of voltage-gated calcium channel CaV1.3 are subject to brain-selective A-to-I RNA editing by ADAR2. Here, we show that editing of CaV1.3 mRNA is dependent on a 40 bp RNA duplex formed between exon 41 and an evolutionarily conserved editing site complementary sequence (ECS) located within the preceding intron. Heterologous expression of a mouse minigene that contained the ECS, intermediate intronic sequence and exon 41 with ADAR2 yielded robust editing. Interestingly, editing of CaV1.3 was potently inhibited by serine/arginine-rich splicing factor 9 (SRSF9). Mechanistically, the inhibitory effect of SRSF9 required direct RNA interaction. Selective down-regulation of SRSF9 in neurons provides a basis for the neuron-specific editing of CaV1.3 transcripts.

Effect of Ca2+ Ions on Electrical Properties of Ba1-x Ca x Ti0.90Sn0.10O3-0.05Y2O3 Ceramics

NASA Astrophysics Data System (ADS)

Chen, Zhi-hui; Li, Zhi-wei; Ding, Jian-ning; Zhao, Tian-xiang; Qiu, Jian-hua; Zhu, Ke-qian; Xu, Jiu-jun; Zhang, Bing

2018-03-01

Ba1-x Ca x Ti0.90Sn0.10O3-0.05Y2O3 (BCTSY) lead-free piezoceramics with x = 0.02 to 0.10 have been fabricated by solid-state sintering method at 1420°C. The effects of Ca2+ ions on the microstructure and electrical properties of the samples were studied. X-ray diffraction analysis showed that all samples possessed pure perovskite structure with Ca2+ ions diffused into the matrix lattice. The rhombohedral phase and tetragonal phase coexisted in the composition range of 0.02 < x < 0.06. The microstructure of BCTSY ceramic became more homogeneous with addition of Ca2+ ions, and the average grain size of the samples decreased from 97 μm (x = 0.02) to 18 μm (x = 0.10). Addition of Ca2+ remarkably improved the piezoelectric properties, enhanced the dielectric frequency dispersion, and increased the Curie temperature of the ceramics. The piezoelectric properties of the ceramics were optimized at x = 0.04 with d 33 and K p values of 579 pC/N and 52.7%, respectively.

Effect of Ca2+ Ions on Electrical Properties of Ba1- x Ca x Ti0.90Sn0.10O3-0.05Y2O3 Ceramics

NASA Astrophysics Data System (ADS)

Chen, Zhi-hui; Li, Zhi-wei; Ding, Jian-ning; Zhao, Tian-xiang; Qiu, Jian-hua; Zhu, Ke-qian; Xu, Jiu-jun; Zhang, Bing

2018-07-01

Ba1- x Ca x Ti0.90Sn0.10O3-0.05Y2O3 (BCTSY) lead-free piezoceramics with x = 0.02 to 0.10 have been fabricated by solid-state sintering method at 1420°C. The effects of Ca2+ ions on the microstructure and electrical properties of the samples were studied. X-ray diffraction analysis showed that all samples possessed pure perovskite structure with Ca2+ ions diffused into the matrix lattice. The rhombohedral phase and tetragonal phase coexisted in the composition range of 0.02 < x < 0.06. The microstructure of BCTSY ceramic became more homogeneous with addition of Ca2+ ions, and the average grain size of the samples decreased from 97 μm ( x = 0.02) to 18 μm ( x = 0.10). Addition of Ca2+ remarkably improved the piezoelectric properties, enhanced the dielectric frequency dispersion, and increased the Curie temperature of the ceramics. The piezoelectric properties of the ceramics were optimized at x = 0.04 with d 33 and K p values of 579 pC/N and 52.7%, respectively.

Ca2+-driven intestinal HCO(3)(-) secretion and CaCO3 precipitation in the European flounder in vivo: influences on acid-base regulation and blood gas transport.

PubMed

Cooper, Christopher A; Whittamore, Jonathan M; Wilson, Rod W

2010-04-01

Marine teleost fish continuously ingest seawater to prevent dehydration and their intestines absorb fluid by mechanisms linked to three separate driving forces: 1) cotransport of NaCl from the gut fluid; 2) bicarbonate (HCO(3)(-)) secretion and Cl(-) absorption via Cl(-)/HCO(3)(-) exchange fueled by metabolic CO(2); and 3) alkaline precipitation of Ca(2+) as insoluble CaCO(3), which aids H(2)O absorption). The latter two processes involve high rates of epithelial HCO(3)(-) secretion stimulated by intestinal Ca(2+) and can drive a major portion of water absorption. At higher salinities and ambient Ca(2+) concentrations the osmoregulatory role of intestinal HCO(3)(-) secretion is amplified, but this has repercussions for other physiological processes, in particular, respiratory gas transport (as it is fueled by metabolic CO(2)) and acid-base regulation (as intestinal cells must export H(+) into the blood to balance apical HCO(3)(-) secretion). The flounder intestine was perfused in vivo with salines containing 10, 40, or 90 mM Ca(2+). Increasing the luminal Ca(2+) concentration caused a large elevation in intestinal HCO(3)(-) production and excretion. Additionally, blood pH decreased (-0.13 pH units) and plasma partial pressure of CO(2) (Pco(2)) levels were elevated (+1.16 mmHg) at the highest Ca perfusate level after 3 days of perfusion. Increasing the perfusate [Ca(2+)] also produced proportional increases in net acid excretion via the gills. When the net intestinal flux of all ions across the intestine was calculated, there was a greater absorption of anions than cations. This missing cation flux was assumed to be protons, which vary with an almost 1:1 relationship with net acid excretion via the gill. This study illustrates the intimate link between intestinal HCO(3)(-) production and osmoregulation with acid-base balance and respiratory gas exchange and the specific controlling role of ingested Ca(2+) independent of any other ion or overall osmolality in marine

Genesis of interictal spikes in the CA1: a computational investigation

PubMed Central

Ratnadurai-Giridharan, Shivakeshavan; Stefanescu, Roxana A.; Khargonekar, Pramod P.; Carney, Paul R.; Talathi, Sachin S.

2014-01-01

Interictal spikes (IISs) are spontaneous high amplitude, short time duration <400 ms events often observed in electroencephalographs (EEG) of epileptic patients. In vitro analysis of resected mesial temporal lobe tissue from patients with refractory temporal lobe epilepsy has revealed the presence of IIS in the CA1 subfield. In this paper, we develop a biophysically relevant network model of the CA1 subfield and investigate how changes in the network properties influence the susceptibility of CA1 to exhibit an IIS. We present a novel template based approach to identify conditions under which synchronization of paroxysmal depolarization shift (PDS) events evoked in CA1 pyramidal (Py) cells can trigger an IIS. The results from this analysis are used to identify the synaptic parameters of a minimal network model that is capable of generating PDS in response to afferent synaptic input. The minimal network model parameters are then incorporated into a detailed network model of the CA1 subfield in order to address the following questions: (1) How does the formation of an IIS in the CA1 depend on the degree of sprouting (recurrent connections) between the CA1 Py cells and the fraction of CA3 Shaffer collateral (SC) connections onto the CA1 Py cells? and (2) Is synchronous afferent input from the SC essential for the CA1 to exhibit IIS? Our results suggest that the CA1 subfield with low recurrent connectivity (absence of sprouting), mimicking the topology of a normal brain, has a very low probability of producing an IIS except when a large fraction of CA1 neurons (>80%) receives a barrage of quasi-synchronous afferent input (input occurring within a temporal window of ≤24 ms) via the SC. However, as we increase the recurrent connectivity of the CA1 (Psprout > 40); mimicking sprouting in a pathological CA1 network, the CA1 can exhibit IIS even in the absence of a barrage of quasi-synchronous afferents from the SC (input occurring within temporal window >80 ms) and a low

Genesis of interictal spikes in the CA1: a computational investigation.

PubMed

Ratnadurai-Giridharan, Shivakeshavan; Stefanescu, Roxana A; Khargonekar, Pramod P; Carney, Paul R; Talathi, Sachin S

2014-01-01

Interictal spikes (IISs) are spontaneous high amplitude, short time duration <400 ms events often observed in electroencephalographs (EEG) of epileptic patients. In vitro analysis of resected mesial temporal lobe tissue from patients with refractory temporal lobe epilepsy has revealed the presence of IIS in the CA1 subfield. In this paper, we develop a biophysically relevant network model of the CA1 subfield and investigate how changes in the network properties influence the susceptibility of CA1 to exhibit an IIS. We present a novel template based approach to identify conditions under which synchronization of paroxysmal depolarization shift (PDS) events evoked in CA1 pyramidal (Py) cells can trigger an IIS. The results from this analysis are used to identify the synaptic parameters of a minimal network model that is capable of generating PDS in response to afferent synaptic input. The minimal network model parameters are then incorporated into a detailed network model of the CA1 subfield in order to address the following questions: (1) How does the formation of an IIS in the CA1 depend on the degree of sprouting (recurrent connections) between the CA1 Py cells and the fraction of CA3 Shaffer collateral (SC) connections onto the CA1 Py cells? and (2) Is synchronous afferent input from the SC essential for the CA1 to exhibit IIS? Our results suggest that the CA1 subfield with low recurrent connectivity (absence of sprouting), mimicking the topology of a normal brain, has a very low probability of producing an IIS except when a large fraction of CA1 neurons (>80%) receives a barrage of quasi-synchronous afferent input (input occurring within a temporal window of ≤24 ms) via the SC. However, as we increase the recurrent connectivity of the CA1 (P sprout > 40); mimicking sprouting in a pathological CA1 network, the CA1 can exhibit IIS even in the absence of a barrage of quasi-synchronous afferents from the SC (input occurring within temporal window >80 ms) and a low

Fluctuation conductivity in the superconducting compound Bi1.7Pb0.3Sr2Ca2Cu3Oy

NASA Astrophysics Data System (ADS)

Aliev, V. M.; Ragimov, J. A.; Selim-zade, R. I.; Damirova, S. Z.; Tairov, B. A.

2017-12-01

A study of how the partial substitution of Bi with Pb impacts the mechanism of excess conductivity in a Bi-Sr-Ca-Cu-O system. It is found that such a substitution leads to an increase in the critical temperature of the Bi1.7Pb0.3Sr2Ca2Cu3Oy(B2) sample, in comparison to Bi2Sr2CaCu2Ox (B1) [Tc (B2) = 100.09 K and Tc (B1) = 90.5 K, respectively]. At the same time, the resistivity ρ of the sample B2 in the normal phase decreases by almost 1.5 times in comparison to B1. The mechanism responsible for the generation of excess conductivity in cuprate HTSCs Bi2Sr2CaCu2Ox and Bi1.7Pb0.3Sr2Ca2Cu3Oy is examined using the local pair model with consideration of the Aslamazov-Larkin theory, near Tc. The temperature T0 of the transition from the 2D fluctuation region to the 3D (i.e., the temperature of the 2D-3D crossover), is also determined. The coherence length ξc(0) along the c axis of fluctuation Cooper pairs is calculated. It is shown that the partial substitution of Bi with Pb in the Bi-Sr-Ca-Cu-O system leads to a decrease in ξc(0) by a factor of 1.3 (4.205 and 3.254 Å, respectively), and that there is a narrowing of both the region of pseudogap existence and the region of superconducting fluctuations near Tc. The temperature dependence of the pseudogap Δ*(T) and the value Δ*(Tc) are determined, and the temperatures Tm, which correspond to the maximum of the pseudogap as a function of temperature in these materials, are estimated. The pseudogap maxima in samples B1 and B2 are found to be 61.06 and 38.18 meV, respectively.

Fabrication of Hybrid Capsules via CaCO3 Crystallization on Degradable Coacervate Droplets.

PubMed

Komatsu, Syuuhei; Ikedo, Yui; Asoh, Taka-Aki; Ishihara, Ryo; Kikuchi, Akihiko

2018-04-03

Organic-inorganic CaCO 3 capsules were prepared by crystallization of CaCO 3 on Pickering emulsion prepared using coacervate droplets made from thermoresponsive and degradable poly(2-methylene-1,3-dioxepane- co-2-hydroxyethyl acrylate) (poly(MDO- co-HEA)) in sole aqueous medium. The diameters of CaCO 3 -based Pickering emulsion could be controlled by varying several parameters: diameter of CaCO 3 powders, initial polymer concentration, and copolymer composition. The CaCO 3 Pickering emulsion was able to load low-molecular-weight hydrophobic substances at temperatures above the lower critical solution temperature (LCST) due to formation of polymer-concentrated phases, i.e., coacervate droplets. The diameter of CaCO 3 capsules prepared by crystallization also depended on the diameter of the CaCO 3 Pickering emulsion. The CaCO 3 shell was composed of calcite-type crystals, the most stable polymorph among known CaCO 3 crystals. The facially prepared CaCO 3 capsules are valuable for use in functional biomaterials, such as drug delivery carriers and cell culture scaffolds for noninvasive bone-regenerative medicine.

Filling the holes in the CaFe4As3 structure: Synthesis and magnetism of CaCo5As3

NASA Astrophysics Data System (ADS)

Rosa, P. F. S.; Scott, B. L.; Ronning, F.; Bauer, E. D.; Thompson, J. D.

2017-07-01

Here, we investigate single crystals of CaCo5As3 by means of single-crystal x-ray diffraction, microprobe, magnetic susceptibility, heat capacity, and pressure-dependent transport measurements. CaCo5As3 shares the same structure of CaFe4As3 with an additional Co atom filling a lattice vacancy and undergoes a magnetic transition at TM=16 K associated with a frustrated magnetic order. CaCo5As3 displays metallic behavior and its Sommerfeld coefficient (γ =70 mJ/mol K2) indicates a moderate enhancement of electron-electron correlations. Transport data under pressures to 2.5 GPa reveal a suppression of TM at a rate of -0.008 K/GPa. First-principles electronic structure calculations show a complex three-dimensional band structure and magnetic moments that depend on the local environment at each Co site. Our results are compared with previous data on CaFe4As3 and provide a scenario for a magnetically frustrated ground state in this family of compounds.

Increased Ca2+ signaling through CaV1.2 promotes bone formation and prevents estrogen deficiency–induced bone loss

PubMed Central

Cao, Chike; Barnett, Adam S.; Mirando, Anthony J.; Rouse, Douglas; Mun, Se Hwan; Park-Min, Kyung-Hyun; McNulty, Amy L.; Karner, Courtney M.; Hilton, Matthew J.

2017-01-01

While the prevalence of osteoporosis is growing rapidly with population aging, therapeutic options remain limited. Here, we identify potentially novel roles for CaV1.2 L-type voltage–gated Ca2+ channels in osteogenesis and exploit a transgenic gain-of-function mutant CaV1.2 to stem bone loss in ovariectomized female mice. We show that endogenous CaV1.2 is expressed in developing bone within proliferating chondrocytes and osteoblasts. Using primary BM stromal cell (BMSC) cultures, we found that Ca2+ influx through CaV1.2 activates osteogenic transcriptional programs and promotes mineralization. We used Prx1-, Col2a1-, or Col1a1-Cre drivers to express an inactivation-deficient CaV1.2 mutant in chondrogenic and/or osteogenic precursors in vivo and found that the resulting increased Ca2+ influx markedly thickened bone not only by promoting osteogenesis, but also by inhibiting osteoclast activity through increased osteoprotegerin secretion from osteoblasts. Activating the CaV1.2 mutant in osteoblasts at the time of ovariectomy stemmed bone loss. Together, these data highlight roles for CaV1.2 in bone and demonstrate the potential dual anabolic and anticatabolic therapeutic actions of tissue-specific CaV1.2 activation in osteoblasts. PMID:29202453

Increased Ca2+ signaling through CaV1.2 promotes bone formation and prevents estrogen deficiency-induced bone loss.

PubMed

Cao, Chike; Ren, Yinshi; Barnett, Adam S; Mirando, Anthony J; Rouse, Douglas; Mun, Se Hwan; Park-Min, Kyung-Hyun; McNulty, Amy L; Guilak, Farshid; Karner, Courtney M; Hilton, Matthew J; Pitt, Geoffrey S

2017-11-16

While the prevalence of osteoporosis is growing rapidly with population aging, therapeutic options remain limited. Here, we identify potentially novel roles for CaV1.2 L-type voltage-gated Ca2+ channels in osteogenesis and exploit a transgenic gain-of-function mutant CaV1.2 to stem bone loss in ovariectomized female mice. We show that endogenous CaV1.2 is expressed in developing bone within proliferating chondrocytes and osteoblasts. Using primary BM stromal cell (BMSC) cultures, we found that Ca2+ influx through CaV1.2 activates osteogenic transcriptional programs and promotes mineralization. We used Prx1-, Col2a1-, or Col1a1-Cre drivers to express an inactivation-deficient CaV1.2 mutant in chondrogenic and/or osteogenic precursors in vivo and found that the resulting increased Ca2+ influx markedly thickened bone not only by promoting osteogenesis, but also by inhibiting osteoclast activity through increased osteoprotegerin secretion from osteoblasts. Activating the CaV1.2 mutant in osteoblasts at the time of ovariectomy stemmed bone loss. Together, these data highlight roles for CaV1.2 in bone and demonstrate the potential dual anabolic and anticatabolic therapeutic actions of tissue-specific CaV1.2 activation in osteoblasts.

Hippocampal CA1 Ripples as Inhibitory Transients

PubMed Central

Krishnan, Giri P; Fellous, Jean-Marc; Bazhenov, Maxim

2016-01-01

Memories are stored and consolidated as a result of a dialogue between the hippocampus and cortex during sleep. Neurons active during behavior reactivate in both structures during sleep, in conjunction with characteristic brain oscillations that may form the neural substrate of memory consolidation. In the hippocampus, replay occurs within sharp wave-ripples: short bouts of high-frequency activity in area CA1 caused by excitatory activation from area CA3. In this work, we develop a computational model of ripple generation, motivated by in vivo rat data showing that ripples have a broad frequency distribution, exponential inter-arrival times and yet highly non-variable durations. Our study predicts that ripples are not persistent oscillations but result from a transient network behavior, induced by input from CA3, in which the high frequency synchronous firing of perisomatic interneurons does not depend on the time scale of synaptic inhibition. We found that noise-induced loss of synchrony among CA1 interneurons dynamically constrains individual ripple duration. Our study proposes a novel mechanism of hippocampal ripple generation consistent with a broad range of experimental data, and highlights the role of noise in regulating the duration of input-driven oscillatory spiking in an inhibitory network. PMID:27093059

Functional analysis of the pepper protein phosphatase, CaAIPP1, and its interacting partner CaAIRF1: Modulation of ABA signalling and the drought stress response.

PubMed

Baek, Woonhee; Lim, Chae Woo; Lee, Sung Chul

2017-10-01

Plant adaptive responses to abiotic stress are coordinated by restriction of plant growth and development. The plant hormone abscisic acid (ABA) is the key regulator of the response to abiotic stress, and its sensitivity determines abiotic stress tolerance levels. We previously showed that the E3 ubiquitin ligase CaAIRF1 functions as a positive regulator of ABA and drought stress via modulation of transcription and stability of the type 2C protein phosphatase CaADIP1. Here, we report the identification and functional analysis of a novel-type 2C phosphatase, CaAIPP1 (Capsicum annuum CaAIRF1 Interacting Protein Phosphatase 1). CaAIPP1 interacted with and was ubiquitinated by CaAIRF1. CaAIPP1 gene expression in pepper leaves was induced by ABA and drought. CaAIPP1 degradation was faster in crude protein extracts from ABA-treated pepper plants than in those from control plants. CaAIPP1-overexpressing plants displayed an ABA-hyposensitive phenotype during seed germination and seedling growth. Moreover, these plants exhibited a drought-sensitive phenotype characterized by high levels of transpirational water loss via decreased stomatal closure and reduced leaf temperatures. Our data indicate that CaAIPP1 is a negative regulator of the drought stress response via ABA-mediated signalling. Our findings provide a valuable insight into the plant defence mechanism that operates during drought stress. © 2017 John Wiley & Sons Ltd.

Probing structural changes in Ca(1-x)Nd2x/3TiO3 ceramics by Raman spectroscopy

NASA Astrophysics Data System (ADS)

Lowndes, Robert; Deluca, Marco; Azough, Feridoon; Freer, Robert

2013-01-01

Ceramics in the system Ca(1-x)Nd2x/3TiO3, intended for mobile communication applications, exhibit grossly non-linear variations in microwave dielectric properties with composition. There is evidence of a structural transition and the formation of vacancies on the A-site of the perovskite structure. High density, single phase perovskite Ca(1-x)Nd2x/3TiO3 ceramics have been prepared by the mixed oxide route. Raman spectroscopy was used to investigate the structural variations, which impact on dielectric properties. The Raman spectra show that with increasing Nd content, there is a transition from an ordered structure, to a disordered arrangement of cations and vacancies, and back to an ordered arrangement in Ca0.1Nd0.6TiO3. A structural phase transition from orthorhombic Pbnm to monoclinic C2/m coincides with the order-disorder transition at Ca0.1Nd0.6TiO3. Polarized Raman spectroscopy facilitated the assignment of the Raman modes and investigation of the role of importance of domain structures. Large variation in the plane angles was attributed to differences in domain structures. Differences in the angular dependence of the Raman modes with Nd content reflect changes in the preferred orientation of the domains from lamellar twins, to wedge shaped and back to lamellar twins.

Phosphorylation sites in the Hook domain of CaVβ subunits differentially modulate CaV1.2 channel function.

PubMed

Brunet, Sylvain; Emrick, Michelle A; Sadilek, Martin; Scheuer, Todd; Catterall, William A

2015-10-01

Regulation of L-type calcium current is critical for the development, function, and regulation of many cell types. Ca(V)1.2 channels that conduct L-type calcium currents are regulated by many protein kinases, but the sites of action of these kinases remain unknown in most cases. We combined mass spectrometry (LC-MS/MS) and whole-cell patch clamp techniques in order to identify sites of phosphorylation of Ca(V)β subunits in vivo and test the impact of mutations of those sites on Ca(V)1.2 channel function in vitro. Using the Ca(V)1.1 channel purified from rabbit skeletal muscle as a substrate for phosphoproteomic analysis, we found that Ser(193) and Thr(205) in the HOOK domain of Ca(V)β1a subunits were both phosphorylated in vivo. Ser(193) is located in a potential consensus sequence for casein kinase II, but it was not phosphorylated in vitro by that kinase. In contrast, Thr(205) is located in a consensus sequence for cAMP-dependent phosphorylation, and it was robustly phosphorylated in vitro by PKA. These two sites are conserved in multiple Ca(V)β subunit isoforms, including the principal Ca(V)β subunit of cardiac Ca(V)1.2 channels, Ca(V)β2b. In order to assess potential modulatory effects of phosphorylation at these sites separately from the effects of phosphorylation of the α11.2 subunit, we inserted phosphomimetic or phosphoinhibitory mutations in Ca(V)β2b and analyzed their effects on Ca(V)1.2 channel function in transfected nonmuscle cells. The phosphomimetic mutation Ca(V)β2b(S152E) decreased peak channel currents and shifted the voltage dependence of both activation and inactivation to more positive membrane potentials. The phosphoinhibitory mutation Ca(V)β2b(S152A) had opposite effects. There were no differences in peak Ca(V)1.2 currents or voltage dependence between the phosphomimetic mutation Ca(V)β2b(T164D) and the phosphoinhibitory mutation Ca(V)β2b(T164A). However, calcium-dependent inactivation was significantly increased for the

Systems Modeling of Ca2+ Homeostasis and Mobilization in Platelets Mediated by IP3 and Store-Operated Ca2+ Entry

PubMed Central

Dolan, Andrew T.; Diamond, Scott L.

2014-01-01

Resting platelets maintain a stable level of low cytoplasmic calcium ([Ca2+]cyt) and high dense tubular system calcium ([Ca2+]dts). During thrombosis, activators cause a transient rise in inositol trisphosphate (IP3) to trigger calcium mobilization from stores and elevation of [Ca2+]cyt. Another major source of [Ca2+]cyt elevation is store-operated calcium entry (SOCE) through plasmalemmal calcium channels that open in response to store depletion as [Ca2+]dts drops. A 34-species systems model employed kinetics describing IP3-receptor, DTS-plasmalemma puncta formation, SOCE via assembly of STIM1 and Orai1, and the plasmalemma and sarco/endoplasmic reticulum Ca2+-ATPases. Four constraints were imposed: calcium homeostasis before activation; stable in zero extracellular calcium; IP3-activatable; and functional SOCE. Using a Monte Carlo method to sample three unknown parameters and nine initial concentrations in a 12-dimensional space near measured or expected values, we found that model configurations that were responsive to stimuli and demonstrated significant SOCE required high inner membrane electric potential (>−70 mV) and low resting IP3 concentrations. The absence of puncta in resting cells was required to prevent spontaneous store depletion in calcium-free media. Ten-fold increases in IP3 caused saturated calcium mobilization. This systems model represents a critical step in being able to predict platelets’ phenotypes during hemostasis or thrombosis. PMID:24806937

Functional Properties of a Newly Identified C-terminal Splice Variant of Cav1.3 L-type Ca2+ Channels*

PubMed Central

Bock, Gabriella; Gebhart, Mathias; Scharinger, Anja; Jangsangthong, Wanchana; Busquet, Perrine; Poggiani, Chiara; Sartori, Simone; Mangoni, Matteo E.; Sinnegger-Brauns, Martina J.; Herzig, Stefan; Striessnig, Jörg; Koschak, Alexandra

2011-01-01

An intramolecular interaction between a distal (DCRD) and a proximal regulatory domain (PCRD) within the C terminus of long Cav1.3 L-type Ca2+ channels (Cav1.3L) is a major determinant of their voltage- and Ca2+-dependent gating kinetics. Removal of these regulatory domains by alternative splicing generates Cav1.342A channels that activate at a more negative voltage range and exhibit more pronounced Ca2+-dependent inactivation. Here we describe the discovery of a novel short splice variant (Cav1.343S) that is expressed at high levels in the brain but not in the heart. It lacks the DCRD but, in contrast to Cav1.342A, still contains PCRD. When expressed together with α2δ1 and β3 subunits in tsA-201 cells, Cav1.343S also activated at more negative voltages like Cav1.342A but Ca2+-dependent inactivation was less pronounced. Single channel recordings revealed much higher channel open probabilities for both short splice variants as compared with Cav1.3L. The presence of the proximal C terminus in Cav1.343S channels preserved their modulation by distal C terminus-containing Cav1.3- and Cav1.2-derived C-terminal peptides. Removal of the C-terminal modulation by alternative splicing also induced a faster decay of Ca2+ influx during electrical activities mimicking trains of neuronal action potentials. Our findings extend the spectrum of functionally diverse Cav1.3 L-type channels produced by tissue-specific alternative splicing. This diversity may help to fine tune Ca2+ channel signaling and, in the case of short variants lacking a functional C-terminal modulation, prevent excessive Ca2+ accumulation during burst firing in neurons. This may be especially important in neurons that are affected by Ca2+-induced neurodegenerative processes. PMID:21998310

Perirhinal cortical inactivation impairs object-in-place memory and disrupts task-dependent firing in hippocampal CA1, but not in CA3.

PubMed

Lee, Inah; Park, Seong-Beom

2013-01-01

Objects and their locations can associatively define an event and a conjoint representation of object-place can form an event memory. Remembering how to respond to a certain object in a spatial context is dependent on both hippocampus and perirhinal cortex (PER). However, the relative functional contributions of the two regions are largely unknown in object-place associative memory. We investigated the PER influence on hippocampal firing in a goal-directed object-place memory task by comparing the firing patterns of CA1 and CA3 of the dorsal hippocampus between conditions of PER muscimol inactivation and vehicle control infusions. Rats were required to choose one of the two objects in a specific spatial context (regardless of the object positions in the context), which was shown to be dependent on both hippocampus and PER. Inactivation of PER with muscimol (MUS) severely disrupted performance of well-trained rats, resulting in response bias (i.e., choosing any object on a particular side). MUS did not significantly alter the baseline firing rates of hippocampal neurons. We measured the similarity in firing patterns between two trial conditions in which the same target objects were chosen on opposite sides within the same arm [object-in-place (O-P) strategy] and compared the results with the similarity in firing between two trial conditions in which the rat chose any object encountered on a particular side [response-in-place (R-P) strategy]. We found that the similarity in firing patterns for O-P trials was significantly reduced with MUS compared to control conditions (CTs). Importantly, this was largely because MUS injections affected the O-P firing patterns in CA1 neurons, but not in CA3. The results suggest that PER is critical for goal-directed organization of object-place associative memory in the hippocampus presumably by influencing how object information is associated with spatial information in CA1 according to task demand.

Quantification of the functional expression of the Ca2+ -activated K+ channel KCa 3.1 on microglia from adult human neocortical tissue.

PubMed

Blomster, Linda V; Strøbaek, Dorte; Hougaard, Charlotte; Klein, Jessica; Pinborg, Lars H; Mikkelsen, Jens D; Christophersen, Palle

2016-12-01

The K Ca 3.1 channel (KCNN4) is an important modulator of microglia responses in rodents, but no information exists on functional expression on microglia from human adults. We isolated and cultured microglia (max 1% astrocytes, no neurons or oligodendrocytes) from neocortex surgically removed from epilepsy patients and employed electrophysiological whole-cell measurements and selective pharmacological tools to elucidate functional expression of K Ca 3.1. The channel expression was demonstrated as a significant increase in the voltage-independent current by NS309, a K Ca 3.1/K Ca 2 activator, followed by full inhibition upon co-application with NS6180, a highly selective K Ca 3.1 inhibitor. A major fraction (79%) of unstimulated human microglia expressed K Ca 3.1, and the difference in current between full activation and inhibition (ΔK Ca 3.1) was estimated at 292 ± 48 pA at -40 mV (n = 75), which equals at least 585 channels per cell. Serial K Ca 3.1 activation/inhibition significantly hyperpolarized/depolarized the membrane potential. The isolated human microglia were potently activated by lipopolysaccharide (LPS) shown as a prominent increase in TNF-α production. However, incubation with LPS neither changed the K Ca 3.1 current nor the fraction of K Ca 3.1 expressing cells. In contrast, the anti-inflammatory cytokine IL-4 slightly increased the K Ca 3.1 current per cell, but as the membrane area also increased, there was no significant change in channel density. A large fraction of the microglia also expressed a voltage-dependent current sensitive to the K Ca 1.1 modulators NS1619 and Paxilline and an inward-rectifying current with the characteristics of a K ir channel. The high functional expression of K Ca 3.1 in microglia from epilepsy patients accentuates the need for further investigations of its role in neuropathological processes. GLIA 2016;64:2065-2078. © 2016 Wiley Periodicals, Inc.

The investigation of minoxidil-induced [Ca2+]i rises and non-Ca2+-triggered cell death in PC3 human prostate cancer cells.

PubMed

Chen, I-Shu; Chou, Chiang-Ting; Liu, Yuan-Yuarn; Yu, Chia-Cheng; Liang, Wei-Zhe; Kuo, Chun-Chi; Shieh, Pochuen; Kuo, Daih-Huang; Chen, Fu-An; Jan, Chung-Ren

2017-02-01

Minoxidil is clinically used to prevent hair loss. However, its effect on Ca 2+ homeostasis in prostate cancer cells is unclear. This study explored the effect of minoxidil on cytosolic-free Ca 2+ levels ([Ca 2+ ] i ) and cell viability in PC3 human prostate cancer cells. Minoxidil at concentrations between 200 and 800 μM evoked [Ca 2+ ] i rises in a concentration-dependent manner. This Ca 2+ signal was inhibited by 60% by removal of extracellular Ca 2+ . Minoxidil-induced Ca 2+ influx was confirmed by Mn 2+ -induced quench of fura-2 fluorescence. Pre-treatment with the protein kinase C (PKC) inhibitor GF109203X, PKC activator phorbol 12-myristate 13 acetate (PMA), nifedipine and SKF96365 inhibited minoxidil-induced Ca 2+ signal in Ca 2+ containing medium by 60%. Treatment with the endoplasmic reticulum Ca 2+ pump inhibitor 2,5-ditert-butylhydroquinone (BHQ) in Ca 2+ -free medium abolished minoxidil-induced [Ca 2+ ] i rises. Conversely, treatment with minoxidil abolished BHQ-induced [Ca 2+ ] i rises. Inhibition of phospholipase C (PLC) with U73122 abolished minoxidil-evoked [Ca 2+ ] i rises. Overnight treatment with minoxidil killed cells at concentrations of 200-600 μM in a concentration-dependent fashion. Chelation of cytosolic Ca 2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/AM (BAPTA/AM) did not prevent minoxidil's cytotoxicity. Together, in PC3 cells, minoxidil induced [Ca 2+ ] i rises that involved Ca 2+ entry through PKC-regulated store-operated Ca 2+ channels and PLC-dependent Ca 2+ release from the endoplasmic reticulum. Minoxidil-induced cytotoxicity in a Ca 2+ -independent manner.

First principles study of structural, electronic and optical properties of perovskites CaZrO3 and CaHfO3 in cubic phase

NASA Astrophysics Data System (ADS)

Hoat, D. M.; Silva, J. F. Rivas; Blas, A. Méndez

2018-07-01

In this work, we present the first principles calculations for structural, electronic and optical properties of perovskites CaZrO3 and CaHfO3 using the full-potential linearized augmented plane wave method (FP-LAPW) within the framework of density functional theory (DFT) as implemented in WIEN2k package. The exchange-correlation potential is treated with local density approximation (LDA) and generalized gradient approximation (GGA-PBE and PBESol). Additionally, the Tran Blaha modified Becke-Johnson exchange potential (mBJ) also is employed for electronic and optical calculations due to that it gives very accurate band gap of solids. Our obtained structural parameters are in good agreement with experimental datas and other theoretical results. The energy band gap obtained with mBJ is 4.56 eV for CaZrO3 and 5.27 eV for CaHfO3. The hybridization of states of O atom with those of Zr and Hf atoms in CaZrO3 and CaHfO3, respectively, is observed. The spin-orbit coupling effect on electronic properties of considered compounds also is investigated. Finally, the linear optical properties of CaZrO3 and CaHfO3 are derived from their complex dielectric function calculated with mBJ potential for wide energy range up to 45 eV, and all of them analyzed in details.

Akt activation by Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) in ovarian cancer cells.

PubMed

Gocher, Angela M; Azabdaftari, Gissou; Euscher, Lindsey M; Dai, Shuhang; Karacosta, Loukia G; Franke, Thomas F; Edelman, Arthur M

2017-08-25

Hyperactivation of Akt is associated with oncogenic changes in the growth, survival, and chemoresistance of cancer cells. The PI3K/phosphoinositide-dependent kinase (PDK) 1 pathway represents the canonical mechanism for phosphorylation of Akt at its primary activation site, Thr-308. We observed that Ca 2+ /calmodulin (CaM)-dependent protein kinase kinase 2 (β) (CaMKK2) is highly expressed in high-grade serous ovarian cancer, and we investigated its role in Akt activation in ovarian cancer (OVCa) cell lines (OVCAR-3, SKOV-3, and Caov-3). Knockdown or pharmacological inhibition of CaMKK2 produced phenotypes expected of Akt inhibition, including reductions in cell growth and cell viability and in the regulation of Akt downstream targets involved in G 1 /S transition and apoptosis. CaMKK2 knockdown or inhibition decreased Akt phosphorylation at Thr-308 and Ser-473 to extents similar to those of PDK1 knockdown or PI3K inhibition. Combined CaMKK2 and PDK1 knockdown or CaMKK and PI3K inhibition, respectively, produced additive effects on p-Akt and cell growth, consistent with direct Akt phosphorylation by CaMKK2. This conclusion was supported by the absence of effects of CaMKK2 knockdown/inhibition on alternative means of activating Akt via p-Akt Thr-450, p-PDK1 Ser-241, or p-IRS1 Ser-636/639. Recombinant CaMKK2 directly activated recombinant Akt by phosphorylation at Thr-308 in a Ca 2+ /CaM-dependent manner. In OVCa cells, p-Akt Thr-308 was significantly inhibited by intracellular Ca 2+ i chelation or CaM inhibition. Ionomycin-induced Ca 2+ influx promoted p-Akt, an effect blocked by PDK1, and/or CaMKK2, siRNAs, and by PI3K and/or CaMKK inhibitors. CaMKK2 knockdown potentiated the effects of the chemotherapeutic drugs carboplatin and PX-866 to reduce proliferation and survival of OVCa cells. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Ca2+-driven intestinal HCO3− secretion and CaCO3 precipitation in the European flounder in vivo: influences on acid-base regulation and blood gas transport

PubMed Central

Cooper, Christopher A.; Whittamore, Jonathan M.

2010-01-01

Marine teleost fish continuously ingest seawater to prevent dehydration and their intestines absorb fluid by mechanisms linked to three separate driving forces: 1) cotransport of NaCl from the gut fluid; 2) bicarbonate (HCO3−) secretion and Cl− absorption via Cl−/HCO3− exchange fueled by metabolic CO2; and 3) alkaline precipitation of Ca2+ as insoluble CaCO3, which aids H2O absorption). The latter two processes involve high rates of epithelial HCO3− secretion stimulated by intestinal Ca2+ and can drive a major portion of water absorption. At higher salinities and ambient Ca2+ concentrations the osmoregulatory role of intestinal HCO3− secretion is amplified, but this has repercussions for other physiological processes, in particular, respiratory gas transport (as it is fueled by metabolic CO2) and acid-base regulation (as intestinal cells must export H+ into the blood to balance apical HCO3− secretion). The flounder intestine was perfused in vivo with salines containing 10, 40, or 90 mM Ca2+. Increasing the luminal Ca2+ concentration caused a large elevation in intestinal HCO3− production and excretion. Additionally, blood pH decreased (−0.13 pH units) and plasma partial pressure of CO2 (Pco2) levels were elevated (+1.16 mmHg) at the highest Ca perfusate level after 3 days of perfusion. Increasing the perfusate [Ca2+] also produced proportional increases in net acid excretion via the gills. When the net intestinal flux of all ions across the intestine was calculated, there was a greater absorption of anions than cations. This missing cation flux was assumed to be protons, which vary with an almost 1:1 relationship with net acid excretion via the gill. This study illustrates the intimate link between intestinal HCO3− production and osmoregulation with acid-base balance and respiratory gas exchange and the specific controlling role of ingested Ca2+ independent of any other ion or overall osmolality in marine teleost fish. PMID:20130227

Buffer kinetics shape the spatiotemporal patterns of IP3-evoked Ca2+ signals

PubMed Central

Dargan, Sheila L; Parker, Ian

2003-01-01

Ca2+ liberation through inositol 1,4,5-trisphosphate receptors (IP3Rs) plays a universal role in cell regulation, and specificity of cell signalling is achieved through the spatiotemporal patterning of Ca2+ signals. IP3Rs display Ca2+-induced Ca2+ release (CICR), but are grouped in clusters so that regenerative Ca2+ signals may remain localized to individual clusters, or propagate globally between clusters by successive cycles of Ca2+ diffusion and CICR. We used confocal microscopy and photoreleased IP3 in Xenopus oocytes to study how these properties are modulated by mobile cytosolic Ca2+ buffers. EGTA (a buffer with slow ‘on-rate’) speeded Ca2+ signals and ‘balkanized’ Ca2+ waves by dissociating them into local signals. In contrast, BAPTA (a fast buffer with similar affinity) slowed Ca2+ responses and promoted ‘globalization’ of spatially uniform Ca2+ signals. These actions are likely to arise through differential effects on Ca2+ feedback within and between IP3R clusters, because Ca2+ signals evoked by influx through voltage-gated channels were little affected. We propose that cell-specific expression of Ca2+-binding proteins with distinct kinetics may shape the time course and spatial distribution of IP3-evoked Ca2+ signals for specific physiological roles. PMID:14555715

Origin of colossal dielectric response of CaCu3Ti4O12 studied by using CaTiO3/CaCu3Ti4O12/CaTiO3 multilayer thin films

NASA Astrophysics Data System (ADS)

Mitsugi, Masakazu; Asanuma, Shutaro; Uesu, Yoshiaki; Fukunaga, Mamoru; Kobayashi, Wataru; Terasaki, Ichiro

2007-06-01

To elucidate the origin of the colossal dielectric response (CDR) of CaCu3Ti4O12 (CCTO), multilayer thin films of CCTO interposed in insulating CaTiO3 (CTO) were synthesized using a pulsed laser deposition technique. The capacitance C of CTO/CCTO/CTO films with different layer thicknesses is measured. After removing the capacitance of CTO by extrapolating C to zero CTO thickness, the real part of dielectric constant of CCTO is estimated to be 329-435, which is much smaller than the reported value for CCTO thin films. This fact indicates that the CDR of CCTO is extrinsic and originates from an internal barrier layer capacitor.

PIK3CA Mutations in Mucinous Cystic Neoplasms of the Pancreas

PubMed Central

Garcia-Carracedo, Dario; Chen, Zong-Ming; Qiu, Wanglong; Huang, Alicia S.; Tang, Sophia M.; Hruban, Ralph H.; Su, Gloria H.

2014-01-01

Objectives Mucinous cystic neoplasms (MCNs) are rare, potentially curable, mucin-producing neoplasms of the pancreas. We have previously reported PIK3CA (phosphoinositide-3-kinase catalytic subunit, p110α) mutations in intraductal papillary mucinous neoplasms, another mucin-producing neoplasm of the pancreas. In this study, we analyzed the presence of PIK3CA and AKT1/PKB (V-akt murine thymoma viral oncogene homolog 1) hot-spot mutations in MCN specimens. Methods Using the genomic DNA sequencing of tumor tissues isolated by laser capture microdissection, we evaluated 15 well-characterized MCNs for the E542K, E545K(exon 9), and H1047R (exon 20) hot-spotmutations in the PIK3CA gene and the E17K mutation in the AKT1 gene. Results A hot-spotmutation (E545K) of the PIK3CA gene was detected in 1 of the 15 MCNs and further confirmed by a mutant-enriched method. Interestingly, this mutation was found to be present only in the high-grade but not in low-grade dysplastic epithelium obtained from this neoplasm and coexisted with a KRASG12D mutation. No mutations were identified in the AKT1 gene. Conclusions Our data, when combined with previous reports on intraductal papillary mucinous neoplasms, indicate that oncogenic activation of the PI3K pathway involving PIK3CA gene mutations can contribute to the progression of mucin-producing neoplasms but not pancreatic intraepithelial neoplasia. PIK3CA status could be useful for understanding their progression to malignancy. PMID:24518503

Determination of MUC1 in sera of ovarian cancer patients and in sera of patients with benign changes of the ovaries with CA15-3, CA27.29, and PankoMab.

PubMed

Jeschke, Udo; Wiest, Irmi; Schumacher, Anamur Lan; Kupka, Markus; Rack, Brigitte; Stahn, Renate; Karsten, Uwe; Mayr, Doris; Friese, Klaus; Dian, Darius

2012-05-01

Mucin 1 (MUC1) is a high molecular weight transmembrane glycoprotein with unique properties which is used as a tumour marker in sera of ovarian cancer patients. The common test kit for the cancer antigen 15-3 (CA15-3) is not sufficient for the discrimination between sera from healthy individuals and sera from patients with benign changes of the ovaries. In this study, the newly developed anti-MUC1 antibody PankoMab was tested in normal and patient sera with an ELISA, and the obtained data were compared against data from experiments using the commercial kits for CA15-3 and CA27.29. Sera of 123 patients diagnosed with benign or malignant changes of the ovaries were obtained before surgery. CA15-3 was analysed with an automated ELISA system (Immulite 2000). CA27.29 was measured with the ST AIA-PACK CA27.29 for the AIA-600II-Analyzer (Tosoh Bioscience, Belgium). The release of MUC1 fragments carrying the TA-MUC1 epitope was analysed with an ELISA using the PankoMab antibody. Using the already established markers CA15-3 and CA27.29, significant differences between benign and malignant changes of the ovaries were found. The same result was obtained with the newly developed TA-MUC1 test. In contrast to CA15-3 and CA27.29, however, the median of TA-MUC1 was lower in sera from patients with ovarian cancer compared to sera from patients with benign diseases of the ovary. However, sera of patients with benign ovarian diseases had significantly higher TA-MUC1 values compared to sera of healthy individuals. The risk score of TA-MUC1 achieved an area under the curve (AUC) of 78.4% in receiver operating characteristic (ROC) curves and a sensitivity of 37% for the prediction of ovarian disease, at 95% specificity. In this study we employed an additional marker for MUC1 which recognizes a more tumour-specific MUC1 epitope (TA-MUC1). We obtained results showing significant differences between detection in benign and malignant ovarian diseases. Although the mean MUC1 values were

Regulation of the voltage-gated Ca2+ channel CaVα2δ-1 subunit expression by the transcription factor Egr-1.

PubMed

González-Ramírez, Ricardo; Martínez-Hernández, Elizabeth; Sandoval, Alejandro; Gómez-Mora, Kimberly; Felix, Ricardo

2018-04-23

It is well known that the Ca V α 2 δ auxiliary subunit regulates the density of high voltage-activated Ca 2+ channels in the plasma membrane and that alterations in their functional expression might have implications in the pathophysiology of diverse human diseases such as neuropathic pain. However, little is known concerning the transcriptional regulation of this protein. We previously characterized the promoter of Ca V α 2 δ, and here we report its regulation by the transcription factor Egr-1. Using the neuroblastoma N1E-115 cells, we found that Egr-1 interacts specifically with its binding site in the promoter, affecting the transcriptional regulation of Ca V α 2 δ. Overexpression and knockdown analysis of Egr-1 showed significant changes in the transcriptional activity of the Ca V α 2 δ promoter. Egr-1 also regulated the expression of Ca V α 2 δ at the level of protein. Also, functional studies showed that Egr-1 knockdown significantly decreases Ca 2+ currents in dorsal root ganglion (DRG) neurons, while overexpression of the transcription factor increased Ca 2+ currents in the F11 cell line, a hybrid of DRG and N18TG2 neuroblastoma cells. Studying the effects of Egr-1 on the transcriptional expression of Ca V α 2 δ could help to understand the regulatory mechanisms of this protein in both health and disease. Copyright © 2018 Elsevier B.V. All rights reserved.

Epigallocatechin-3-gallate increases intracellular [Ca2+] in U87 cells mainly by influx of extracellular Ca2+ and partly by release of intracellular stores.

PubMed

Kim, Hee Jung; Yum, Keun Sang; Sung, Jong-Ho; Rhie, Duck-Joo; Kim, Myung-Jun; Min, Do Sik; Hahn, Sang June; Kim, Myung-Suk; Jo, Yang-Hyeok; Yoon, Shin Hee

2004-02-01

Green tea has been receiving considerable attention as a possible preventive agent against cancer and cardiovascular disease. Epigallocatechin-3-gallate (EGCG) is a major polyphenol component of green tea. Using digital calcium imaging and an assay for [3H]-inositol phosphates, we determined whether EGCG increases intracellular [Ca2+] ([Ca2+]i) in non-excitable human astrocytoma U87 cells. EGCG induced concentration-dependent increases in [Ca2+]i. The EGCG-induced [Ca2+]i increases were reduced to 20.9% of control by removal of extracellular Ca2+. The increases were also inhibited markedly by treatment with the non-specific Ca2+ channel inhibitors cobalt (3 mM) for 3 min and lanthanum (1 mM) for 5 min. The increases were not significantly inhibited by treatment for 10 min with the L-type Ca2+ channel blocker nifedipine (100 nM). Treatment with the inhibitor of endoplasmic reticulum Ca2+-ATPase thapsigargin (1 micro M) also significantly inhibited the EGCG-induced [Ca2+]i increases. Treatment for 15 min with the phospholipase C (PLC) inhibitor neomycin (300 micro M) attenuated the increases significantly, while the tyrosine kinase inhibitor genistein (30 micro M) had no effect. EGCG increased [3H]-inositol phosphates formation via PLC activation. Treatment for 10 min with mefenamic acid (100 micro M) and flufenamic acid (100 micro M), derivatives of diphenylamine-2-carboxylate, blocked the EGCG-induced [Ca2+]i increase in non-treated and thapsigargin-treated cells but indomethacin (100 micro M) did not affect the increases. Collectively, these data suggest that EGCG increases [Ca2+]i in non-excitable U87 cells mainly by eliciting influx of extracellular Ca2+ and partly by mobilizing intracellular Ca2+ stores by PLC activation. The EGCG-induced [Ca2+]i influx is mediated mainly through channels sensitive to diphenylamine-2-carboxylate derivatives.

Infrared spectroscopic study of CaFe0.7Co0.3O3

NASA Astrophysics Data System (ADS)

Zhang, C. X.; Xia, H. L.; Dai, Y. M.; Qiu, Z. Y.; Sui, Q. T.; Long, Y. W.; Qiu, X. G.

2017-08-01

Temperature-dependent infrared spectroscopy has been investigated for CaFe0.7Co0.3O3 which undergoes a ferromagnetic transition at TC≈177 K . It is observed that the spectral weight is transferred from ˜4800 -14 000 cm-1 to ˜0 -4800 cm-1 as the temperature is lowered around TC. Such a large-range spectral weight transfer is attributed to the Hund's interaction. The phonons in CaFe0.7Co0.3O3 show minor asymmetric line shapes, implying relatively weak electron-phonon coupling compared with the parent compound CaFeO3. The optical conductivity also reveals a broad peak structure in the range of ˜700 -1500 cm-1. Fit by the model of single-polaron absorption, the broad peak is interpreted by the excitation of polarons. From the fitting parameters of the polaron peak, we estimate the electron-phonon coupling constant α ˜ 0.4 -0.5 , implying that CaFe0.7Co0.3O3 falls into the weak-coupling regime.

Epitaxial growth of lithium fluoride on the (1 1 1) surface of CaF 2

NASA Astrophysics Data System (ADS)

Klumpp, St; Dabringhaus, H.

1999-08-01

Growth of lithium fluoride by molecular beam epitaxy on the (1 1 1) surface of calcium fluoride crystals was studied by TEM and LEED for crystal temperatures from 400 to 773 K and impinging lithium fluoride fluxes from 3×10 11 to 3×10 14 cm -2 s -1. Growth starts, usually, at the <1 1 0> steps on the (1 1 1) surface of CaF 2. For larger step distances and at later growth stages also growth on the terraces between the steps is found. Preferably, longish, roof-like crystallites are formed, which can be interpreted by growth of LiF(2 0 1¯)[0 1 0] parallel to CaF 2(1 1 1)[ 1¯ 0 1]. To a lesser extent square crystallites, i.e. growth with LiF(0 0 1), and, rarely, three-folded pyramidal crystallites, i.e. growth with LiF(1 1 1) parallel to CaF 2(1 1 1), are observed. While the pyramidal crystallites show strict epitaxial orientation with LiF[ 1¯ 0 1]‖CaF 2[ 1¯ 0 1] and LiF[ 1¯ 0 1]‖CaF 2[1 2¯ 1], only about 80% of the square crystallites exhibit an epitaxial alignment, where LiF[1 0 0]‖CaF 2[ 1¯ 0 1] is preferred to LiF[1 1 0]‖CaF 2[ 1¯ 0 1]. The epitaxial relationships are discussed on the basis of theoretically calculated adsorption positions of the lithium fluoride monomer and dimer on the terrace and at the steps of the CaF 2(1 1 1) surface.

Regulation of gene expression by dietary Ca2+ in kidneys of 25-hydroxyvitamin D3-1 alpha-hydroxylase knockout mice.

PubMed

Hoenderop, Joost G J; Chon, Helena; Gkika, Dimitra; Bluyssen, Hans A R; Holstege, Frank C P; St-Arnaud, Rene; Braam, Branko; Bindels, Rene J M

2004-02-01

Pseudovitamin D deficiency rickets (PDDR) is an autosomal disease, characterized by undetectable levels of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), rickets and secondary hyperparathyroidism. Mice in which the 25-hydroxyvitamin D3-1 alpha-hydroxylase (1 alpha-OHase) gene was inactivated, presented the same clinical phenotype as patients with PDDR. cDNA Microarray technology was used on kidneys of 1 alpha-OHase knockout mice to study the expression profile of renal genes in this Ca2+-related disorder. Genome wide molecular events that occur during the rescue of these mice by high dietary Ca2+ intake were studied by the use of 15K cDNA microarray chips. 1 alpha-OHase knockout mice fed a normal Ca2+ diet developed severe hypocalcemia, rickets and died with an average life span of 12 +/- 2 weeks. Intriguingly, 1 alpha-OHase-/- mice supplemented with an enriched Ca2+ diet were normocalcemic and not significantly different from wild-type mice. Inactivation of the 1 alpha-OHase gene resulted in a significant regulation of +/- 1000 genes, whereas dietary Ca2+ supplementation of the 1 alpha-OHase-/- mice revealed +/- 2000 controlled genes. Interestingly, 557 transcripts were regulated in both situations implicating the involvement in the dietary Ca2+-mediated rescue mechanism of the 1 alpha-OHase-/- mice. Conspicuous regulated genes encoded for signaling molecules like the PDZ-domain containing protein channel interacting protein, FK binding protein type 4, kinases, and importantly Ca2+ transporting proteins including the Na+-Ca2+ exchanger, calbindin-D28K and the Ca2+ sensor calmodulin. Dietary Ca2+ intake normalized disturbances in the Ca2+ homeostasis due to vitamin D deficiency that were accompanied by the regulation of a subset of renal genes, including well-known renal Ca2+ transport protein genes, but also genes not previously identified as playing a role in renal Ca2+ handling.

High-pressure compressibility and vibrational properties of (Ca,Mn)CO 3

DOE PAGES

Liu, Jin; Caracas, Razvan; Fan, Dawei; ...

2016-12-01

Knowledge of potential carbon carriers such as carbonates is critical for our understanding of the deep-carbon cycle and related geological processes within the planet. Here we investigated the high-pressure behavior of (Ca,Mn)CO 3 up to 75 GPa by synchrotron single-crystal X-ray diffraction, laser Raman spectroscopy, and theoretical calculations. MnCO 3-rich carbonate underwent a structural phase transition from the CaCO 3-I structure into the CaCO 3-VI structure at 45–48 GPa, while CaCO 3-rich carbonate transformed into CaCO 3-III and CaCO 3-VI at approximately 2 and 15 GPa, respectively. The equation of state and vibrational properties of MnCO 3-rich and CaCO 3-richmore » carbonates changed dramatically across the phase transition. The CaCO 3-VI-structured CaCO 3-rich and MnCO 3-rich carbonates were stable at room temperature up to at least 53 and 75 GPa, respectively. In conclusion, the addition of smaller cations (e.g., Mn 2+, Mg 2+, and Fe 2+) can enlarge the stability field of the CaCO 3-I phase as well as increase the pressure of the structural transition into the CaCO 3-VI phase.« less

A distinct entorhinal cortex to hippocampal CA1 direct circuit for olfactory associative learning.

PubMed

Li, Yiding; Xu, Jiamin; Liu, Yafeng; Zhu, Jia; Liu, Nan; Zeng, Wenbo; Huang, Ning; Rasch, Malte J; Jiang, Haifei; Gu, Xiang; Li, Xiang; Luo, Minhua; Li, Chengyu; Teng, Junlin; Chen, Jianguo; Zeng, Shaoqun; Lin, Longnian; Zhang, Xiaohui

2017-04-01

Lateral and medial parts of entorhinal cortex (EC) convey nonspatial 'what' and spatial 'where' information, respectively, into hippocampal CA1, via both the indirect EC layer 2→ hippocampal dentate gyrus→CA3→CA1 and the direct EC layer 3→CA1 paths. However, it remains elusive how the direct path transfers distinct information and contributes to hippocampal learning functions. Here we report that lateral EC projection neurons selectively form direct excitatory synapses onto a subpopulation of morphologically complex, calbindin-expressing pyramidal cells (PCs) in the dorsal CA1 (dCA1), while medial EC neurons uniformly innervate all dCA1 PCs. Optogenetically inactivating the distinct lateral EC-dCA1 connections or the postsynaptic dCA1 calbindin-expressing PC activity slows olfactory associative learning. Moreover, optetrode recordings reveal that dCA1 calbindin-expressing PCs develop more selective spiking responses to odor cues during learning. Thus, our results identify a direct lateral EC→dCA1 circuit that is required for olfactory associative learning.

Apo states of calmodulin and CaBP1 control CaV1 voltage-gated calcium channel function through direct competition for the IQ domain.

PubMed

Findeisen, Felix; Rumpf, Christine H; Minor, Daniel L

2013-09-09

In neurons, binding of calmodulin (CaM) or calcium-binding protein 1 (CaBP1) to the CaV1 (L-type) voltage-gated calcium channel IQ domain endows the channel with diametrically opposed properties. CaM causes calcium-dependent inactivation and limits calcium entry, whereas CaBP1 blocks calcium-dependent inactivation (CDI) and allows sustained calcium influx. Here, we combine isothermal titration calorimetry with cell-based functional measurements and mathematical modeling to show that these calcium sensors behave in a competitive manner that is explained quantitatively by their apo-state binding affinities for the IQ domain. This competition can be completely blocked by covalent tethering of CaM to the channel. Further, we show that Ca(2+)/CaM has a sub-picomolar affinity for the IQ domain that is achieved without drastic alteration of calcium-binding properties. The observation that the apo forms of CaM and CaBP1 compete with each other demonstrates a simple mechanism for direct modulation of CaV1 function and suggests a means by which excitable cells may dynamically tune CaV activity. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Apo-states of calmodulin and CaBP1 control CaV1 voltage-gated calcium channel function through direct competition for the IQ domain

PubMed Central

Findeisen, Felix; Rumpf, Christine; Minor, Daniel L.

2013-01-01

In neurons, binding of calmodulin (CaM) or calcium-binding protein 1 (CaBP1) to the CaV1 (L-type) voltage-gated calcium channel IQ domain endows the channel with diametrically opposed properties. CaM causes calcium-dependent inactivation (CDI) and limits calcium entry, whereas CaBP1 blocks CDI and allows sustained calcium influx. Here, we combine isothermal titration calorimetry (ITC) with cell-based functional measurements and mathematical modeling to show that these calcium sensors behave in a competitive manner that is explained quantitatively by their apo-state binding affinities for the IQ domain. This competition can be completely blocked by covalent tethering of CaM to the channel. Further, we show that Ca2+/CaM has a sub-picomolar affinity for the IQ domain that is achieved without drastic alteration of calcium binding properties. The observation that the apo-forms of CaM and CaBP1 compete with each other demonstrates a simple mechanism for direct modulation of CaV1 function and suggests a means by which excitable cells may dynamically tune CaV activity. PMID:23811053

2:1 Charge disproportionation in perovskite-structure oxide La{sub 1/3}Ca{sub 2/3}FeO{sub 3} with unusually-high-valence Fe{sup 3.67+}

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guo, Haichuan; Hosaka, Yoshiteru; Seki, Hayato

La{sub 1/3}Ca{sub 2/3}FeO{sub 3} with unusually-high-valence Fe{sup 3.67+} was synthesized at a high pressure and high temperature. The compound crystallizes in a √2a×2a×√2a perovskite cell in which the La and Ca ions at the A site are disordered. At 217 K the Fe{sup 3.67+} shows charge disproportionation to Fe{sup 3+} and Fe{sup 5+} in a ratio of 2:1, and this disproportionation is accompanied by transitions in magnetic and transport properties. The charge-disproportionated Fe{sup 3+} and Fe{sup 5+} are arranged along the <111> direction of the cubic perovskite cell. The local electronic and magnetic environments of Fe in La{sub 1/3}Ca{sub 2/3}FeO{submore » 3} are quite similar to those of Fe in La{sub 1/3}Sr{sub 2/3}FeO{sub 3}, and the 2:1 charge disproportionation pattern of Fe{sup 3+} and Fe{sup 5+} in La{sub 1/3}Ca{sub 2/3}FeO{sub 3} is also the same as that in La{sub 1/3}Sr{sub 2/3}FeO{sub 3}. - Graphical abstract: The perovskite-structure oxide La{sub 1/3}Ca{sub 2/3}FeO{sub 3} with unusually-high-valence Fe{sup 3.67+} shows charge disproportionation to Fe{sup 3+} and Fe{sup 5+} in a ratio of 2:1, and the charge-disproportionated Fe{sup 3+} and Fe{sup 5+} are arranged along the <111> direction of the cubic perovskite cell. - Highlights: • La{sub 1/3}Ca{sub 2/3}FeO{sub 3} with unusually-high-valence Fe{sup 3.67+} was synthesized at a high pressure and high temperature. • At 217 K the Fe{sup 3.67+} shows charge disproportionation (CD) to Fe{sup 3+} and Fe{sup 5+} in a ratio of 2:1. • The charge-disproportionated Fe{sup 3+} and Fe{sup 5+} are arranged along the <111> direction of the cubic perovskite cell. • The disproportionation is accompanied by transitions in magnetic and transport properties.« less

Proximal clustering between BK and CaV1.3 channels promotes functional coupling and BK channel activation at low voltage

PubMed Central

Vivas, Oscar; Moreno, Claudia M; Santana, Luis F; Hille, Bertil

2017-01-01

CaV-channel dependent activation of BK channels is critical for feedback control of both calcium influx and cell excitability. Here we addressed the functional and spatial interaction between BK and CaV1.3 channels, unique CaV1 channels that activate at low voltages. We found that when BK and CaV1.3 channels were co-expressed in the same cell, BK channels started activating near −50 mV, ~30 mV more negative than for activation of co-expressed BK and high-voltage activated CaV2.2 channels. In addition, single-molecule localization microscopy revealed striking clusters of CaV1.3 channels surrounding clusters of BK channels and forming a multi-channel complex both in a heterologous system and in rat hippocampal and sympathetic neurons. We propose that this spatial arrangement allows tight tracking between local BK channel activation and the gating of CaV1.3 channels at quite negative membrane potentials, facilitating the regulation of neuronal excitability at voltages close to the threshold to fire action potentials. DOI: http://dx.doi.org/10.7554/eLife.28029.001 PMID:28665272

Regulation of L-type CaV1.3 channel activity and insulin secretion by the cGMP-PKG signaling pathway

PubMed Central

Sandoval, Alejandro; Duran, Paz; Gandini, María A.; Andrade, Arturo; Almanza, Angélica; Kaja, Simon; Felix, Ricardo

2018-01-01

cGMP is a second messenger widely used in the nervous system and other tissues. One of the major effectors for cGMP is the serine/threonine protein kinase, cGMP-dependent protein kinase (PKG), which catalyzes the phosphorylation of a variety of proteins including ion channels. Previously, it has been shown that the cGMP-PKG signaling pathway inhibits Ca2+ currents in rat vestibular hair cells and chromaffin cells. This current allegedly flow through voltage-gated CaV1.3L-type Ca2+ channels, and is important for controlling vestibular hair cell sensory function and catecholamine secretion, respectively. Here, we show that native L-type channels in the insulin-secreting RIN-m5F cell line, and recombinant CaV1.3 channels heterologously expressed in HEK-293 cells, are regulatory targets of the cGMP-PKG signaling cascade. Our results indicate that the CaVα1 ion-conducting subunit of the CaV1.3 channels is highly expressed in RIN-m5F cells and that the application of 8-Br-cGMP, a membrane-permeable analogue of cGMP, significantly inhibits Ca2+ macroscopic currents and impair insulin release stimulated with high K+. In addition, KT-5823, a specific inhibitor of PKG, prevents the current inhibition generated by 8-Br-cGMP in the heterologous expression system. Interestingly, mutating the putative phosphorylation sites to residues resistant to phosphorylation showed that the relevant PKG sites for CaV1.3 L-type channel regulation centers on two amino acid residues, Ser793 and Ser860, located in the intracellular loop connecting the II and III repeats of the CaVα1 pore-forming subunit of the channel. These findings unveil a novel mechanism for how the cGMP-PKG signaling pathway may regulate CaV1.3 channels and contribute to regulate insulin secretion. PMID:28807144

Analysis of ESR1 and PIK3CA mutations in plasma cell-free DNA from ER-positive breast cancer patients.

PubMed

Takeshita, Takashi; Yamamoto, Yutaka; Yamamoto-Ibusuki, Mutsuko; Tomiguchi, Mai; Sueta, Aiko; Murakami, Keiichi; Omoto, Yoko; Iwase, Hirotaka

2017-08-08

The measurement of ESR1 and PIK3CA mutations in plasma cell-free DNA (cfDNA) has been studied as a non-invasive method to quickly assess and monitor endocrine therapy (ET) resistant metastatic breast cancer (MBC) patients. The subjects of this retrospective study were a total of 185 plasma samples from 86 estrogen receptor-positive BC patients, of which 151 plasma samples were from 69 MBC patients and 34 plasma samples were from 17 primary BC (PBC) patients. We developed multiplex droplet digital PCR assays to verify the clinical significance of ESR1 and PIK3CA mutations both in a snapshot and serially in these patients. cfDNA ESR1 and PIK3CA mutations were found in 28.9% and 24.6 % of MBC patients, respectively. The relation between ESR1 or PIK3CA mutations and clinical features showed that ESR1 mutations occurred mostly in patients previously treated by ET, which was not the case for PIK3CA mutations. The analysis of the clinical impact of those mutations on subsequent lines of treatment for the 69 MBC patients revealed that both ESR1 and PIK3CA mutations detection were related to a shorter duration of ET effectiveness in univariate analysis but only for ESR1 mutations in multivariate analysis. The monitoring of cfDNA in a subset of 52 patients showed that loss of ESR1 mutations was related to a longer duration of response, which was not the case for PIK3CA mutations. We have demonstrated the clinical significance of on-treatment ESR1 mutations both in a snapshot and serially in comparison with PIK3CA mutations.

Insulin-mediated upregulation of K(Ca)3.1 channels promotes cell migration and proliferation in rat vascular smooth muscle.

PubMed

Su, Xing-Li; Wang, Yan; Zhang, Wei; Zhao, Li-Mei; Li, Gui-Rong; Deng, Xiu-Ling

2011-07-01

The detailed molecular mechanisms underlying pathogenesis of various vascular diseases such as atherosclerosis are not fully understood in type-2 diabetes. The present study was designed to investigate whether insulin regulates K(Ca)3.1 channels and participates in vasculopathy in type-2 diabetes. A rat model with experimental insulin-resistant type-2 diabetes was used for detecting pathological changes in the aorta wall, and cultured vascular smooth muscle cells (VSMCs) were employed to investigate the regulation of K(Ca)3.1 channels by insulin and roles of K(Ca)3.1 channels in cell migration and proliferation using molecular biology and electrophysiology. Early pathological changes were observed and expression of K(Ca)3.1 channels increased in the aorta wall of the type 2 diabetic rats. K(Ca)3.1 channel mRNA, protein levels and current density were greatly enhanced in cultured VSMCs treated with insulin, and the effects were countered in the cells treated with the ERK1/2 inhibitor PD98059, but not the p38-MAPK inhibitor SB203580. In addition, insulin stimulated cell migration and proliferation in cultured VSMCs, and the effects were fully reversed in the cells treated with the K(Ca)3.1 blocker TRAM-34 or PD98059, but not SB203580. These results demonstrate the novel information that insulin increases expression of K(Ca)3.1 channels by stimulating ERK1/2 phosphorylation thereby promoting migration and proliferation of VSMCs, which likely play at least a partial role in the development of vasculopathy in type-2 diabetes. Copyright © 2011 Elsevier Ltd. All rights reserved.

Crystal structure and electrical conductivity of lanthanum-calcium chromites-titanates La 1-xCa xCr 1-yTi yO 3-δ ( x=0-1, y=0-1)

NASA Astrophysics Data System (ADS)

Vashook, V.; Vasylechko, L.; Zosel, J.; Gruner, W.; Ullmann, H.; Guth, U.

2004-10-01

Five series of perovskite-type compounds in the system La1-xCaxCr1-yTiyO3 with the nominal compositions y = 0 , x = 0 - 0.5 ; y = 0.2 , x = 0.2 - 0.8 ; y = 0.5 , x = 0.5 - 1.0 ; y = 0.8 , x = 0.6 - 1.0 and y = 1 , x = 0.8 - 1 were synthesized by a ceramic technique in air (final heating 1350 °C). On the basis of the X-ray analysis of the samples with (Ca/Ti)⩾1, the phase diagram of the CaTiO3-LaCrIIIO3-CaCrIVO3 quasi-ternary system was constructed. Extended solid solution with a wide homogeneity range is formed in the quasi-ternary system CaCrIVO3-CaTiO3-LaCrIIIO3. The solid solution La(1-x‧-y)Ca(x‧+y)CrIVx‧CrIII(1-x‧-y)TiyO3 exists by up to 0.6-0.7 mol fractions of CaCrIVO3 (x‧ < 0.6 - 0.7) at the experimental conditions. The crystal structure of the compounds is orthorhombic in the space group Pbnm at room temperature. The lattice parameters and the average interatomic distances of the samples within the solid solution ranges decrease uniformly with increasing Ca content. Outside the quasi-ternary system, the nominal compositions La0.1Ca0.9TiO3, La0.2Ca0.8TiO3, La0.4Ca0.6Cr0.2Ti0.8O3 and La0.3Ca0.7Cr0.2Ti0.8O3 in the system La1-xCaxCr1-yTiyO3 were found as single phases with an orthorhombic structure. In the temperature range between 850 and 1000 °C, the synthesized single-phase compositions are stable at pO2=6×10-16-0.21×105 Pa. Oxygen stoichiometry and electrical conductivity of the separate compounds were investigated as functions of temperature and oxygen partial pressure. The chemical stability of these oxides with respect to oxygen release during thermal dissociation decreases with increasing Ca-content. At 900 °C and oxygen partial pressure 1×10-15-0.21×105 Pa, the compounds with x > y (acceptor doped) are p-type semiconductors and those with x < y (donor doped) and x = y are n-type semiconductors. The type and level of electrical conductivity are functions of the concentration ratios of cations occupying the B-sites of the perovskite

Dielectric properties and nonlinear I-V electrical behavior of (Li1+, Al3+) co-doped CaCu3Ti4O12 ceramics

NASA Astrophysics Data System (ADS)

Sun, Li; Ni, Qing; Guo, Jianqin; Cao, Ensi; Hao, Wentao; Zhang, Yongjia; Ju, Lin

2018-06-01

(Li1+, Al3+) co-doped CaCu3Ti4O12 ceramics (CaCu3-2 x Li x Al x Ti4O12, x = 0.05, 0.1, 0.15) were prepared by a sol-gel method and were sintered at 1020-1080 °C for 8 h to improve the geometric microstructure, dielectric and nonlinear I-V electrical properties. Notably, very high dielectric constant of 1 × 105 with good dielectric-frequency as well as dielectric-temperature stability can be achieved in CaCu2.8Li0.1Al0.1Ti4O12 ceramic sintered at 1060 °C. The average grain sizes, resistivity and the non-Ohmic properties are also improved compared to pure CaCu3Ti4O12. These results indicate that (Li1+, Al3+) co-doping at the Cu2+ site can improve the dielectric properties of CaCu3Ti4O12, supporting the internal barrier layer capacitance effect of Schottky barriers at grain boundaries.

Gene of the month: PIK3CA.

PubMed

Lai, K; Killingsworth, M C; Lee, C S

2015-04-01

PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K) which through its role in the PI3K/Akt pathway is important for the regulation of important cellular functions such as proliferation, metabolism and protein synthesis, angiogenesis and apoptosis. Mutations in PIK3CA are known to be involved in a wide range of human cancers and mutant PIK3CA is thought to act as an oncogene. The specific PIK3CA inhibitor, NVP-BYL719, has displayed promising results in cancer therapy and is currently under clinical trials. Furthermore, PI3K regulates autophagy, a cellular process that recycles proteins and organelles through lysosomal degradation and has recently been recognised as an attractive therapeutic target due to its pro- and anti-cancer properties. Several studies have attempted to investigate the effects of combining the inhibition of both PI3K and autophagy in cancer therapy, and an in vivo model has demonstrated that the combined use of a concomitant PI3K and autophagy inhibitor induced apoptosis in glioma cells. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Influence of Li3BO3 additives on the Li+ conductivity and stability of Ca/Ta-substituted Li6.55(La2.95Ca0.05)(Zr1.5Ta0.5)O12 electrolytes

NASA Astrophysics Data System (ADS)

Zhang, L. C.; Yang, J. F.; Gao, Y. X.; Wang, X. P.; Fang, Q. F.; Chen, C. H.

2017-07-01

The cubic Ca/Ta-substituted Li6.55(La2.95Ca0.05)(Zr1.5Ta0.5)O12 (LLCZTO) electrolytes were synthesized at 800 °C with Li3BO3 as additives. The optimal amount of Li3BO3 and its influences on the microstructure, crystal structures, Li+ conductivity and the stability of the Li6.55(La2.95Ca0.05)(Zr1.5Ta0.5)O12 were studied by SEM, XRD and EIS. Among all the samples, when the molar ratio of Li3BO3 to the Li6.55(La2.95Ca0.05)(Zr1.5Ta0.5)O12 is 4:5, the highest Li+ conductivity of 1.33 × 10-4 S cm-1 at 30 °C is obtained. When the LLCZTO samples are exposed in air, the Li+ conductivity is deteriorated possibly owing to the side reactions between the LLCZTO and the H2O or CO2 in the air. The Li3BO3 addition can alleviate such deterioration of the Li+ conductivity.

Chronic renal failure induces cell death in rat hippocampal CA1 via upregulation of αCaMKII/NR2A synaptic complex and phosphorylated GluR1-containing AMPA receptor cascades.

PubMed

Kim, Jong Wan; Ha, Gyoung Yim; Jung, Yong Wook

2014-09-01

N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propinoic acid (AMPA) receptors bound to postsynaptic density-95 (PSD-95) and α isoform of calcium/calmodulin-dependent protein kinase II (αCaMKII) is fundamentally involved in the regulation of working memory. The aim of present study was to investigate the alterations of NMDA and AMPA receptors responsible for hippocampal synaptic dysfunction and selective neuronal cell death after chronic renal failure (CRF) which may be associated with impairment of working memory. Altered interactions between NMDA and AMPA receptors and PSD-95 and αCaMKII were analyzed in the cornu ammonis (CA) 1 and CA3/dentate gyrus (DG) subfields of the uremic rat hippocampi using the immunoblotting and immunoprecipitation methods. Uremia induced by CRF produced necrotic cell death and decreased neuronal nucleoli protein levels in the hippocampal CA1 subfield, but not in the CA3/DG subfields. The CA1 subfields of CRF rats exhibited significant decreases and increases, respectively, in the expressions of PSD-95/NR2B and αCaMKII/NR2A synaptic complex. Moreover, increased phosphorylation of glutamate receptor type 1 (GluR1) AMPA receptor at ser831 was observed in the CA1 subfield after CRF. These hippocampal CA1 neuronal vulnerability may be responsible for memory dysfunction after CRF as mediated by an increase in NR2A-containing NMDA receptors bound to αCaMKII and subsequent activation of GluR1-containing AMPA receptors caused by the phosphorylation of GluR1 at ser831.

Analysis of ESR1 and PIK3CA mutations in plasma cell-free DNA from ER-positive breast cancer patients

PubMed Central

Takeshita, Takashi; Yamamoto, Yutaka; Yamamoto-Ibusuki, Mutsuko; Tomiguchi, Mai; Sueta, Aiko; Murakami, Keiichi; Omoto, Yoko; Iwase, Hirotaka

2017-01-01

Background The measurement of ESR1 and PIK3CA mutations in plasma cell-free DNA (cfDNA) has been studied as a non-invasive method to quickly assess and monitor endocrine therapy (ET) resistant metastatic breast cancer (MBC) patients. Methods The subjects of this retrospective study were a total of 185 plasma samples from 86 estrogen receptor-positive BC patients, of which 151 plasma samples were from 69 MBC patients and 34 plasma samples were from 17 primary BC (PBC) patients. We developed multiplex droplet digital PCR assays to verify the clinical significance of ESR1 and PIK3CA mutations both in a snapshot and serially in these patients. Results cfDNA ESR1 and PIK3CA mutations were found in 28.9% and 24.6 % of MBC patients, respectively. The relation between ESR1 or PIK3CA mutations and clinical features showed that ESR1 mutations occurred mostly in patients previously treated by ET, which was not the case for PIK3CA mutations. The analysis of the clinical impact of those mutations on subsequent lines of treatment for the 69 MBC patients revealed that both ESR1 and PIK3CA mutations detection were related to a shorter duration of ET effectiveness in univariate analysis but only for ESR1 mutations in multivariate analysis. The monitoring of cfDNA in a subset of 52 patients showed that loss of ESR1 mutations was related to a longer duration of response, which was not the case for PIK3CA mutations. Conclusions We have demonstrated the clinical significance of on-treatment ESR1 mutations both in a snapshot and serially in comparison with PIK3CA mutations. PMID:28881720

Identification of Glycosylation Sites Essential for Surface Expression of the CaVα2δ1 Subunit and Modulation of the Cardiac CaV1.2 Channel Activity*

PubMed Central

Tétreault, Marie-Philippe; Bourdin, Benoîte; Briot, Julie; Segura, Emilie; Lesage, Sylvie; Fiset, Céline; Parent, Lucie

2016-01-01

Alteration in the L-type current density is one aspect of the electrical remodeling observed in patients suffering from cardiac arrhythmias. Changes in channel function could result from variations in the protein biogenesis, stability, post-translational modification, and/or trafficking in any of the regulatory subunits forming cardiac L-type Ca2+ channel complexes. CaVα2δ1 is potentially the most heavily N-glycosylated subunit in the cardiac L-type CaV1.2 channel complex. Here, we show that enzymatic removal of N-glycans produced a 50-kDa shift in the mobility of cardiac and recombinant CaVα2δ1 proteins. This change was also observed upon simultaneous mutation of the 16 Asn sites. Nonetheless, the mutation of only 6/16 sites was sufficient to significantly 1) reduce the steady-state cell surface fluorescence of CaVα2δ1 as characterized by two-color flow cytometry assays and confocal imaging; 2) decrease protein stability estimated from cycloheximide chase assays; and 3) prevent the CaVα2δ1-mediated increase in the peak current density and voltage-dependent gating of CaV1.2. Reversing the N348Q and N812Q mutations in the non-operational sextuplet Asn mutant protein partially restored CaVα2δ1 function. Single mutation N663Q and double mutations N348Q/N468Q, N348Q/N812Q, and N468Q/N812Q decreased protein stability/synthesis and nearly abolished steady-state cell surface density of CaVα2δ1 as well as the CaVα2δ1-induced up-regulation of L-type currents. These results demonstrate that Asn-663 and to a lesser extent Asn-348, Asn-468, and Asn-812 contribute to protein stability/synthesis of CaVα2δ1, and furthermore that N-glycosylation of CaVα2δ1 is essential to produce functional L-type Ca2+ channels. PMID:26742847

Immunohistochemical Analysis of Activin Receptor-Like Kinase 1 (ACVRL1/ALK1) Expression in the Rat and Human Hippocampus: Decline in CA3 During Progression of Alzheimer's Disease.

PubMed

Adams, Stephanie L; Benayoun, Laurent; Tilton, Kathy; Mellott, Tiffany J; Seshadri, Sudha; Blusztajn, Jan Krzysztof; Delalle, Ivana

2018-01-01

The pathophysiology of Alzheimer's disease (AD) includes signaling defects mediated by the transforming growth factor β-bone morphogenetic protein-growth and differentiation factor (TGFβ-BMP-GDF) family of proteins. In animal models of AD, administration of BMP9/GDF2 improves memory and reduces amyloidosis. The best characterized type I receptor of BMP9 is ALK1. We characterized ALK1 expression in the hippocampus using immunohistochemistry. In the rat, ALK1 immunoreactivity was found in CA pyramidal neurons, most frequently and robustly in the CA2 and CA3 fields. In addition, there were sporadic ALK1-immunoreactive cells in the stratum oriens, mainly in CA1. The ALK1 expression pattern in human hippocampus was similar to that of rat. Pyramidal neurons within the CA2, CA3, and CA4 were strongly ALK1-immunoreactive in hippocampi of cognitively intact subjects with no neurofibrillary tangles. ALK1 signal was found in the axons of alveus and fimbria, and in the neuropil across CA fields. Relatively strongest ALK1 neuropil signal was observed in CA1 where pyramidal neurons were occasionally ALK1-immunoractive. As in the rat, horizontally oriented neurons in the stratum oriens of CA1 were both ALK1- and GAD67-immunoreactive. Analysis of ALK1 immunoreactivity across stages of AD pathology revealed that disease progression was characterized by overall reduction of the ALK1 signal in CA3 in advanced, but not early, stages of AD. These data suggest that the CA3 pyramidal neurons may remain responsive to the ALK1 ligands, e.g., BMP9, during initial stages of AD and that ALK1 may constitute a therapeutic target in early and moderate AD.

Dentate network activity is necessary for spatial working memory by supporting CA3 sharp-wave ripple generation and prospective firing of CA3 neurons.

PubMed

Sasaki, Takuya; Piatti, Verónica C; Hwaun, Ernie; Ahmadi, Siavash; Lisman, John E; Leutgeb, Stefan; Leutgeb, Jill K

2018-02-01

Complex spatial working memory tasks have been shown to require both hippocampal sharp-wave ripple (SWR) activity and dentate gyrus (DG) neuronal activity. We therefore asked whether DG inputs to CA3 contribute to spatial working memory by promoting SWR generation. Recordings from DG and CA3 while rats performed a dentate-dependent working memory task on an eight-arm radial maze revealed that the activity of dentate neurons and the incidence rate of SWRs both increased during reward consumption. We then found reduced reward-related CA3 SWR generation without direct input from dentate granule neurons. Furthermore, CA3 cells with place fields in not-yet-visited arms preferentially fired during SWRs at reward locations, and these prospective CA3 firing patterns were more pronounced for correct trials and were dentate-dependent. These results indicate that coordination of CA3 neuronal activity patterns by DG is necessary for the generation of neuronal firing patterns that support goal-directed behavior and memory.

Low-Temperature Sintering Li3Mg1.8Ca0.2NbO6 Microwave Dielectric Ceramics with LMZBS Glass

NASA Astrophysics Data System (ADS)

Wang, Gang; Zhang, Huaiwu; Liu, Cheng; Su, Hua; Jia, Lijun; Li, Jie; Huang, Xin; Gan, Gongwen

2018-05-01

Li3Mg1.8Ca0.2NbO6 ceramics doped with Li2O-MgO-ZnO-B2O3-SiO2 glass (LMZBS) were prepared via a solid-state route. The LMZBS glass effectively reduced the sintering temperature of Li3Mg1.8Ca0.2NbO6 ceramics to 950°C. The effects of the LMZBS glass on the sintering behavior, microstructures and microwave dielectric properties of Li3Mg1.8Ca0.2NbO6 ceramics are discussed in detail. Among all the LMZBS doped Li3Mg1.8Ca0.2NbO6 ceramics, the sample with 1 wt.% of LMZBS glass sintered at 950°C for 4 h exhibited good dielectric properties: ɛ r = 16.7, Q × f = 31,000 GHz (9.92 GHz), τ f = - 1.3 ppm/°C. The Li3Mg1.8Ca0.2NbO6 ceramics possessed excellent chemical compatibility with Ag electrodes, and could be applied in low temperature co-fired ceramics (LTCC) applications.

ESR1 and PIK3CA mutational status in serum and plasma from metastatic breast cancer patients: A comparative study.

PubMed

Takeshita, Takashi; Yamamoto, Yutaka; Yamamoto-Ibusuki, Mutsuko; Tomiguchi, Mai; Sueta, Aiko; Iwase, Hirotaka

2018-04-07

Plasma and serum cell-free DNA (cfDNA) are useful sources of tumor DNA, but comparative investigations of the tumor mutational status between them are rare. we performed droplet digital PCR assay for representative hotspot mutations in metastatic breast cancer (MBC) (ESR1 and PIK3CA) in serum and plasma cfDNA concurrently extracted from the blood of 33 estrogen receptor-positive MBC patients. ESR1 mutations in plasma cfDNA were found in 7 of the 33 patients; ESR1 mutations in serum cfDNA were detected in only one out of 7 patients with ESR1 mutations in plasma cfDNA. PIK3CA exon 9 and exon 20 mutations in plasma cfDNA were found in 3 and 7 out of the 33 patients, respectively; PIK3CA exon 9 mutations in serum cfDNA were detected in 2 out of 3 patients with PIK3CA exon 9 mutations in plasma cfDNA; PIK3CA exon 20 mutations in serum cfDNA were detected in 2 out of 7 patients with PIK3CA exon 20 mutations in plasma cfDNA. Here we show the higher frequency of ESR1 and PIK3CA mutations in the plasma than in the serum in 33 MBC patients; therefore, serum samples should not be considered the preferred source of cfDNA.

La 1-x Ca x MnO 3 semiconducting nanostructures: morphology and thermoelectric properties.

PubMed

Culebras, Mario; Torán, Raquel; Gómez, Clara M; Cantarero, Andrés

2014-01-01

Semiconducting metallic oxides, especially perosvkite materials, are great candidates for thermoelectric applications due to several advantages over traditionally metallic alloys such as low production costs and high chemical stability at high temperatures. Nanostructuration can be the key to develop highly efficient thermoelectric materials. In this work, La 1-x Ca x MnO 3 perosvkite nanostructures with Ca as a dopant have been synthesized by the hydrothermal method to be used in thermoelectric applications at room temperature. Several heat treatments have been made in all samples, leading to a change in their morphology and thermoelectric properties. The best thermoelectric efficiency has been obtained for a Ca content of x=0.5. The electrical conductivity and Seebeck coefficient are strongly related to the calcium content.

Differential effect of age on hippocampal subfields assessed using a new high-resolution 3T MR sequence.

PubMed

La Joie, Renaud; Fouquet, Marine; Mézenge, Florence; Landeau, Brigitte; Villain, Nicolas; Mevel, Katell; Pélerin, Alice; Eustache, Francis; Desgranges, Béatrice; Chételat, Gaël

2010-11-01

Recent advances in neuroimaging have highlighted the interest to differentiate hippocampal subfields for cognitive neurosciences and more notably in assessing the effects of normal and pathological aging. The main goal of the present study is to investigate the effects of normal aging onto the volume of the different hippocampal subfields. For this purpose, we developed a new magnetic resonance sequence together with reliable tracing guidelines to assess the volume of different subfields of the hippocampus using a 3 Tesla scanner, and estimated the validity of a simpler and less time-consuming method based on the widely-used automatic Voxel-Based Morphometry (VBM) technique. Three hippocampal regions of interest were delineated on the right and left hippocampi of 50 healthy subjects between 18 and 68 years old corresponding to the CA1, subiculum and other (including CA2-3-4 and Dentate Gyrus) subfields. A strong effect of age was found on the volume of the subiculum only, with a decrease paralleling that of the global gray matter volume, while CA1 and other subfields seemed relatively spared. Although less precise than the ROI-tracing technique, the VBM-based method appeared as a reliable alternative especially to distinguish CA1 and subiculum subfields. Our findings of a specific effect of age on the subiculum are consistent with the developmental hypothesis ("last-in first-out" theory). This contrasts with the predominant vulnerability of the CA1 subfield to Alzheimer's disease reported in several previous studies, suggesting that the assessment of hippocampal subfields may improve the discrimination between normal and pathological aging. Copyright 2010 Elsevier Inc. All rights reserved.

Novel CPVT-Associated Calmodulin Mutation in CALM3 (CALM3-A103V) Activates Arrhythmogenic Ca Waves and Sparks

PubMed Central

Gomez-Hurtado, Nieves; Boczek, Nicole J.; Kryshtal, Dmytro O.; Johnson, Christopher N.; Sun, Jennifer; Nitu, Florentin R.; Cornea, Razvan L.; Chazin, Walter J.; Calvert, Melissa L.; Tester, David J.; Ackerman, Michael J.; Knollmann, Bjorn C.

2016-01-01

Background Calmodulin (CaM) mutations are associated with severe forms of long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). We recently reported that CaM mutations were found in 13% of genotype-negative LQTS patients, but the prevalence of CaM mutations in genotype-negative CPVT patients is unknown. Here, we identify and characterize CaM mutations in 12 patients with genotype-negative but clinically-diagnosed CPVT. Methods and Results Mutational analysis of CALM1, CALM2 and CALM3 coding regions, in vitro measurement of CaM-Ca2+ (Ca) binding affinity, RyR2-CaM binding, Ca handling, L-type Ca current (LTCC) and action potential duration (APD). We identified a novel CaM mutation – A103V – in CALM3 in 1 of 12 patients (8%), a female who experienced episodes of exertion-induced syncope since age 10, had normal QT interval, and displayed ventricular ectopy during stress testing consistent with CPVT. A103V modestly lowered CaM Ca-binding affinity (3-fold reduction vs WT-CaM), but did not alter CaM binding to RyR2. In permeabilized cardiomyocytes, A103V-CaM (100 nM) promoted spontaneous Ca wave and spark activity, a cellular phenotype of RyR2 activation. Even a 1:3 mixture of A103V-CaM:WT-CaM activated Ca waves, demonstrating functional dominance. Compared to LQTS D96V-CaM, A103V-CaM had significantly less effects on LTCC inactivation and APD, and caused delayed after depolarizations (DADs) and triggered beats in intact cardiomyocytes. Conclusions We discovered a novel CPVT mutation in the CALM3 gene that shares functional characteristics with established CPVT-associated mutations in CALM1. A small proportion of A103V-CaM is sufficient to evoke arrhythmogenic Ca disturbances via RyR2 dysregulation, which explains the autosomal dominant inheritance. PMID:27516456

Stoichiometric requirements for trapping and gating of Ca2+ release-activated Ca2+ (CRAC) channels by stromal interaction molecule 1 (STIM1).

PubMed

Hoover, Paul J; Lewis, Richard S

2011-08-09

Store-operated Ca(2+) entry depends critically on physical interactions of the endoplasmic reticulum (ER) Ca(2+) sensor stromal interaction molecule 1 (STIM1) and the Ca(2+) release-activated Ca(2+) (CRAC) channel protein Orai1. Recent studies support a diffusion-trap mechanism in which ER Ca(2+) depletion causes STIM1 to accumulate at ER-plasma membrane (PM) junctions, where it binds to Orai1, trapping and activating mobile CRAC channels in the overlying PM. To determine the stoichiometric requirements for CRAC channel trapping and activation, we expressed mCherry-STIM1 and Orai1-GFP at varying ratios in HEK cells and quantified CRAC current (I(CRAC)) activation and the STIM1:Orai1 ratio at ER-PM junctions after store depletion. By competing for a limited amount of STIM1, high levels of Orai1 reduced the junctional STIM1:Orai1 ratio to a lower limit of 0.3-0.6, indicating that binding of one to two STIM1s is sufficient to immobilize the tetrameric CRAC channel at ER-PM junctions. In cells expressing a constant amount of STIM1, CRAC current was a highly nonlinear bell-shaped function of Orai1 expression and the minimum stoichiometry for channel trapping failed to evoke significant activation. Peak current occurred at a ratio of ∼2 STIM1:Orai1, suggesting that maximal CRAC channel activity requires binding of eight STIM1s to each channel. Further increases in Orai1 caused channel activity and fast Ca(2+)-dependent inactivation to decline in parallel. The data are well described by a model in which STIM1 binds to Orai1 with negative cooperativity and channels open with positive cooperativity as a result of stabilization of the open state by STIM1.

The Ca2+/Calmodulin/CaMKK2 Axis: Nature’s Metabolic CaMshaft

PubMed Central

Marcelo, Kathrina L.; Means, Anthony R.; York, Brian

2016-01-01

Calcium (Ca2+) is an essential ligand that binds its primary intracellular receptor Calmodulin (CaM) to trigger a variety of downstream processes and pathways. Central to the actions of Ca2+/CaM is the activation of a highly conserved Ca2+/CaM kinase (CaMK) cascade, which amplifies Ca2+ signals through a series of subsequent phosphorylation events. Proper regulation of Ca2+ flux is necessary for whole-body metabolism and disruption of Ca2+ homeostasis has been linked to a variety of metabolic diseases. Herein, we provide a synthesis of recent advances that highlight the roles of the Ca2+/CaM kinase axis in key metabolic tissues. An appreciation of this information is critical in order to understand the mechanisms by which Ca2+/CaM-dependent signaling contributes to metabolic homeostasis and disease. PMID:27449752

SNAP-25 in hippocampal CA3 region is required for long-term memory formation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hou Qiuling; Gao Xiang; Lu Qi

SNAP-25 is a synaptosomal protein of 25 kDa, a key component of synaptic vesicle-docking/fusion machinery, and plays a critical role in exocytosis and neurotransmitter release. We previously reported that SNAP-25 in the hippocampal CA1 region is involved in consolidation of contextual fear memory and water-maze spatial memory (Hou et al. European J Neuroscience, 20: 1593-1603, 2004). SNAP-25 is expressed not only in the CA1 region, but also in the CA3 region, and the SNAP-25 mRNA level in the CA3 region is higher than in the CA1 region. Here, we provide evidence that SNAP-25 in the CA3 region is also involvedmore » in learning/memory. Intra-CA3 infusion of SNAP-25 antisense oligonucleotide impaired both long-term contextual fear memory and water-maze spatial memory, with short-term memory intact. Furthermore, the SNAP-25 antisense oligonucleotide suppressed the long-term potentiation (LTP) of field excitatory post-synaptic potential (fEPSP) in the mossy-fiber pathway (DG-CA3 pathway), with no effect on paired-pulse facilitation of the fEPSP. These results are consistent with the notion that SNAP-25 in the hippocampal CA3 region is required for long-term memory formation.« less

Carbonic anhydrase inhibitors: in vitro inhibition of α isoforms (hCA I, hCA II, bCA III, hCA IV) by flavonoids.

PubMed

Ekinci, Derya; Karagoz, Lutfi; Ekinci, Deniz; Senturk, Murat; Supuran, Claudiu T

2013-04-01

A series of flavonoids, such as quercetin, catechin, apigenin, luteolin, morin, were investigated for their inhibitory effects against the metalloenzyme carbonic anhydrase (CA). The compounds were tested against four α-CA isozymes purified from human and bovine (hCA I, hCA II, bCA III, hCA IV) tissues. The four isozymes showed quite diverse inhibition profiles with these compounds. The flavonoids inhibited hCA I with K(I)-s in the range of 2.2-12.8 μM, hCA II with K(I)-s in the range of 0.74-6.2 μM, bCA III with K(I)-s in the range of 2.2-21.3 μM, and hCA IV with inhibition constants in the range of 4.4-15.7, with an esterase assay using 4-nitrophenyl acetate as substrate. Some simple phenols/sulfonamides were also investigated as standard inhibitors. The flavonoids incorporate phenol moieties which inhibit these CAs through a diverse, not yet determined inhibition mechanism, compared to classic inhibitors such as the sulfonamide/sulfamate ones.

PIK3CA-mutated melanoma cells rely on cooperative signaling through mTORC1/2 for sustained proliferation.

PubMed

Silva, Jillian M; Deuker, Marian M; Baguley, Bruce C; McMahon, Martin

2017-05-01

Malignant conversion of BRAF- or NRAS-mutated melanocytes into melanoma cells can be promoted by PI3'-lipid signaling. However, the mechanism by which PI3'-lipid signaling cooperates with mutationally activated BRAF or NRAS has not been adequately explored. Using human NRAS- or BRAF-mutated melanoma cells that co-express mutationally activated PIK3CA, we explored the contribution of PI3'-lipid signaling to cell proliferation. Despite mutational activation of PIK3CA, melanoma cells were more sensitive to the biochemical and antiproliferative effects of broader spectrum PI3K inhibitors than to an α-selective PI3K inhibitor. Combined pharmacological inhibition of MEK1/2 and PI3K signaling elicited more potent antiproliferative effects and greater inhibition of the cell division cycle compared to single-agent inhibition of either pathway alone. Analysis of signaling downstream of MEK1/2 or PI3K revealed that these pathways cooperate to regulate cell proliferation through mTORC1-mediated effects on ribosomal protein S6 and 4E-BP1 phosphorylation in an AKT-dependent manner. Although PI3K inhibition resulted in cytostatic effects on xenografted NRAS Q61H /PIK3CA H1047R melanoma, combined inhibition of MEK1/2 plus PI3K elicited significant melanoma regression. This study provides insights as to how mutationally activated PIK3CA acts in concert with MEK1/2 signaling to cooperatively regulate mTORC1/2 to sustain PIK3CA-mutated melanoma proliferation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Troponin T3 regulates nuclear localization of the calcium channel Ca{sub v}β{sub 1a} subunit in skeletal muscle

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Tan; Taylor, Jackson; Jiang, Yang

The voltage-gated calcium channel (Ca{sub v}) β{sub 1a} subunit (Ca{sub v}β{sub 1a}) plays an important role in excitation–contraction coupling (ECC), a process in the myoplasm that leads to muscle-force generation. Recently, we discovered that the Ca{sub v}β{sub 1a} subunit travels to the nucleus of skeletal muscle cells where it helps to regulate gene transcription. To determine how it travels to the nucleus, we performed a yeast two-hybrid screening of the mouse fast skeletal muscle cDNA library and identified an interaction with troponin T3 (TnT3), which we subsequently confirmed by co-immunoprecipitation and co-localization assays in mouse skeletal muscle in vivo andmore » in cultured C2C12 muscle cells. Interacting domains were mapped to the leucine zipper domain in TnT3 COOH-terminus (160–244 aa) and Ca{sub v}β{sub 1a} NH{sub 2}-terminus (1–99 aa), respectively. The double fluorescence assay in C2C12 cells co-expressing TnT3/DsRed and Ca{sub v}β{sub 1a}/YFP shows that TnT3 facilitates Ca{sub v}β{sub 1a} nuclear recruitment, suggesting that the two proteins play a heretofore unknown role during early muscle differentiation in addition to their classical role in ECC regulation. - Highlights: • Previously, we demonstrated that Ca{sub v}β{sub 1a} is a gene transcription regulator. • Here, we show that TnT3 interacts with Ca{sub v}β{sub 1a}. • We mapped TnT3 and Ca{sub v}β{sub 1a} interaction domain. • TnT3 facilitates Ca{sub v}β{sub 1a} nuclear enrichment. • The two proteins play a heretofore unknown role during early muscle differentiation.« less

Ca2+/Cation Antiporters (CaCA): Identification, Characterization and Expression Profiling in Bread Wheat (Triticum aestivum L.)

PubMed Central

Taneja, Mehak; Tyagi, Shivi; Sharma, Shailesh; Upadhyay, Santosh Kumar

2016-01-01

The Ca2+/cation antiporters (CaCA) superfamily proteins play vital function in Ca2+ ion homeostasis, which is an important event during development and defense response. Molecular characterization of these proteins has been performed in certain plants, but they are still not characterized in Triticum aestivum (bread wheat). Herein, we identified 34 TaCaCA superfamily proteins, which were classified into TaCAX, TaCCX, TaNCL, and TaMHX protein families based on their structural organization and evolutionary relation with earlier reported proteins. Since the T. aestivum comprises an allohexaploid genome, TaCaCA genes were derived from each A, B, and D subgenome and homeologous chromosome (HC), except chromosome-group 1. Majority of genes were derived from more than one HCs in each family that were considered as homeologous genes (HGs) due to their high similarity with each other. These HGs showed comparable gene and protein structures in terms of exon/intron organization and domain architecture. Majority of TaCaCA proteins comprised two Na_Ca_ex domains. However, TaNCLs consisted of an additional EF-hand domain with calcium binding motifs. Each TaCaCA protein family consisted of about 10 transmembrane and two α-repeat regions with specifically conserved signature motifs except TaNCL, which had single α-repeat. Variable expression of most of the TaCaCA genes during various developmental stages suggested their specified role in development. However, constitutively high expression of a few genes like TaCAX1-A and TaNCL1-B indicated their role throughout the plant growth and development. The modulated expression of certain genes during biotic (fungal infections) and abiotic stresses (heat, drought, salt) suggested their role in stress response. Majority of TaCCX and TaNCL family genes were found highly affected during various abiotic stresses. However, the role of individual gene needs to be established. The present study unfolded the opportunity for detail functional

Ca2+/Cation Antiporters (CaCA): Identification, Characterization and Expression Profiling in Bread Wheat (Triticum aestivum L.).

PubMed

Taneja, Mehak; Tyagi, Shivi; Sharma, Shailesh; Upadhyay, Santosh Kumar

2016-01-01

The Ca 2+ /cation antiporters (CaCA) superfamily proteins play vital function in Ca 2+ ion homeostasis, which is an important event during development and defense response. Molecular characterization of these proteins has been performed in certain plants, but they are still not characterized in Triticum aestivum (bread wheat). Herein, we identified 34 TaCaCA superfamily proteins, which were classified into TaCAX, TaCCX, TaNCL, and TaMHX protein families based on their structural organization and evolutionary relation with earlier reported proteins. Since the T. aestivum comprises an allohexaploid genome, TaCaCA genes were derived from each A, B, and D subgenome and homeologous chromosome (HC), except chromosome-group 1. Majority of genes were derived from more than one HCs in each family that were considered as homeologous genes (HGs) due to their high similarity with each other. These HGs showed comparable gene and protein structures in terms of exon/intron organization and domain architecture. Majority of TaCaCA proteins comprised two Na_Ca_ex domains. However, TaNCLs consisted of an additional EF-hand domain with calcium binding motifs. Each TaCaCA protein family consisted of about 10 transmembrane and two α-repeat regions with specifically conserved signature motifs except TaNCL, which had single α-repeat. Variable expression of most of the TaCaCA genes during various developmental stages suggested their specified role in development. However, constitutively high expression of a few genes like TaCAX1-A and TaNCL1-B indicated their role throughout the plant growth and development. The modulated expression of certain genes during biotic (fungal infections) and abiotic stresses (heat, drought, salt) suggested their role in stress response. Majority of TaCCX and TaNCL family genes were found highly affected during various abiotic stresses. However, the role of individual gene needs to be established. The present study unfolded the opportunity for detail

Cytosolic and mitochondrial [Ca2+] in whole hearts using indo-1 acetoxymethyl ester: effects of high extracellular Ca2+.

PubMed Central

Schreur, J H; Figueredo, V M; Miyamae, M; Shames, D M; Baker, A J; Camacho, S A

1996-01-01

Assessment of free cytosolic [Ca2+] ([Ca2+]c) using the acetoxymethyl ester (AM) form of indo-1 may be compromised by loading of indo-1 into noncytosolic compartments, primarily mitochondria. To determine the fraction of noncytosolic fluorescence in whole hearts loaded with indo-1 AM, Mn2+ was used to quench cytosolic fluorescence. Residual (i.e., noncytosolic) fluorescence was subtracted from the total fluorescence before calculating [Ca2+]c. Noncytosolic fluorescence was used to estimate mitochondrial [Ca2+]. In hearts paced at 5 Hz (N = 17), noncytosolic fluorescence was 0.61 +/- 0.06 and 0.56 +/- 0.07 of total fluorescence at lambda 385 and lambda 456, respectively. After taking into account noncytosolic fluorescence, systolic and diastolic [Ca2+]c was 673 +/- 72 and 132 +/- 9 nM, respectively, noncytosolic [Ca2+] was 183 +/- 36 nM and increased to 272 +/- 12 when extracellular Ca2+ was increased from 2 to 6 mM. This increase in noncytosolic [Ca2+] was inhibited by ruthenium red, a blocker of Ca2+ uptake by mitochondria. We conclude that cytosolic and mitochondrial [Ca2+] can be determined in whole hearts loaded with indo-1 AM by using Mn2+ to quench cytosolic fluorescence. PMID:8744296

Calculated and measured [Ca(2+)] in buffers used to calibrate Ca(2+) macroelectrodes.

PubMed

McGuigan, John A S; Stumpff, Friederike

2013-05-01

The ionized concentration of calcium in physiological buffers ([Ca(2+)]) is normally calculated using either tabulated constants or software programs. To investigate the accuracy of such calculations, the [Ca(2+)] in EGTA [ethylene glycol-bis(β-aminoethylether)-N,N,N|,N|-tetraacetic acid], BAPTA [1,2-bis(o-aminophenoxy) ethane-N,N,N|,N|-tetraacetic acid], HEDTA [N-(2-hydroxyethyl)-ethylenediamine-N,N|,N|-triacetic acid], and NTA [N,N-bis(carboxymethyl)glycine] buffers was estimated using the ligand optimization method, and these measured values were compared with calculated values. All measurements overlapped in the pCa range of 3.51 (NTA) to 8.12 (EGTA). In all four buffer solutions, there was no correlation between measured and calculated values; the calculated values differed among themselves by factors varying from 1.3 (NTA) to 6.9 (EGTA). Independent measurements of EGTA purity and the apparent dissociation constants for HEDTA and NTA were not significantly different from the values estimated by the ligand optimization method, further substantiating the method. Using two calibration solutions of pCa 2.0 and 3.01 and seven buffers in the pCa range of 4.0-7.5, calibration of a Ca(2+) electrode over the pCa range of 2.0-7.5 became a routine procedure. It is proposed that such Ca(2+) calibration/buffer solutions be internationally defined and made commercially available to allow the precise measurement of [Ca(2+)] in biology. Copyright © 2013 Elsevier Inc. All rights reserved.

Regulation of L-type CaV1.3 channel activity and insulin secretion by the cGMP-PKG signaling pathway.

PubMed

Sandoval, Alejandro; Duran, Paz; Gandini, María A; Andrade, Arturo; Almanza, Angélica; Kaja, Simon; Felix, Ricardo

2017-09-01

cGMP is a second messenger widely used in the nervous system and other tissues. One of the major effectors for cGMP is the serine/threonine protein kinase, cGMP-dependent protein kinase (PKG), which catalyzes the phosphorylation of a variety of proteins including ion channels. Previously, it has been shown that the cGMP-PKG signaling pathway inhibits Ca 2+ currents in rat vestibular hair cells and chromaffin cells. This current allegedly flow through voltage-gated Ca V 1.3L-type Ca 2+ channels, and is important for controlling vestibular hair cell sensory function and catecholamine secretion, respectively. Here, we show that native L-type channels in the insulin-secreting RIN-m5F cell line, and recombinant Ca V 1.3 channels heterologously expressed in HEK-293 cells, are regulatory targets of the cGMP-PKG signaling cascade. Our results indicate that the Ca V α 1 ion-conducting subunit of the Ca V 1.3 channels is highly expressed in RIN-m5F cells and that the application of 8-Br-cGMP, a membrane-permeable analogue of cGMP, significantly inhibits Ca 2+ macroscopic currents and impair insulin release stimulated with high K + . In addition, KT-5823, a specific inhibitor of PKG, prevents the current inhibition generated by 8-Br-cGMP in the heterologous expression system. Interestingly, mutating the putative phosphorylation sites to residues resistant to phosphorylation showed that the relevant PKG sites for Ca V 1.3 L-type channel regulation centers on two amino acid residues, Ser793 and Ser860, located in the intracellular loop connecting the II and III repeats of the Ca V α 1 pore-forming subunit of the channel. These findings unveil a novel mechanism for how the cGMP-PKG signaling pathway may regulate Ca V 1.3 channels and contribute to regulate insulin secretion. Copyright © 2017 Elsevier Ltd. All rights reserved.