bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome‐wide analysis and molecular dissection of the SPL gene family in Salvia miltiorrhiza
Authors: Zhang Linsu , Wu Bin , Zhao Degang , Li Caili , Shao Fenjuan , Lu Shanfa 
Published: October 2013

AbstractSQUAMOSA promoter binding protein‐likes (SPLs) are plant‐specific transcription factors playing vital regulatory roles in plant growth and development. There is no information about SPLs in Salvia miltiorrhiza (Danshen), a significant medicinal plant widely used in Traditional Chinese medicine (TCM) for >1,700 years and an emerging model plant for TCM studies. Through genome‐wide identification and subsequent molecular cloning, we identified a total 15 SmSPLs with divergent sequence features, gene structures, and motifs. Comparative analysis showed sequence conservation between SmSPLs and their Arabidopsis counterparts. A phylogenetic tree clusters SmSPLs into six groups. Many of the motifs identified commonly exist in a group/subgroup, implying their functional redundancy. Eight SmSPLs were predicted and experimentally validated to be targets of miR156/157. SmSPLs were differentially expressed in various tissues of S. milltiorrhiza. The expression of miR156/157‐targeted SmSPLs was increased with the maturation of S. miltiorrhiza, whereas the expression of miR156/157 was decreased, confirming the regulatory roles of miR156/157 in SmSPLs and suggesting the functions of SmSPLs in S. miltiorrhiza development. The expression of miR156/157 was negatively correlated with miR172 during the maturation of S. miltiorrhiza. The results indicate the significance and complexity of SmSPL‐, miR156‐, and miR172‐mediated regulation of developmental timing in S. miltiorrhiza.
Prevalence of aggressive challenging behaviours in intellectual disability and its relationship to personality status: Jamaican study
Authors: Tyrer P. , Oliver P. , Tarabi S. A. 
Published: October 2013

AbstractBackgroundBoth the classification of personality disorder in intellectual disability (ID) and its identification in practice are deemed to be difficult. A simpler approach to classification and its relationship to challenging behaviours were tested in an adult Jamaican population with ID.MethodThe study was carried out in Kingston, Jamaica, as part of a programme of field trials to determine the utility of the proposed revision of personality disorders in the 11th Revision of the International Classification of Diseases (ICD‐11), in a population of adults with ID living with their families or in supported care homes. Thirty‐eight people with borderline (n = 5), mild (n = 16), moderate (n = 14) and severe (n = 3) ID were assessed at face‐to‐face interview and with relatives or staff using the provisional criteria for severity of personality disorder and its associated domain traits, and challenging behaviour was assessed using the Problem Behaviour Check List (PBCL) (a 5‐point, 7‐item scale).ResultsUsing the severity scale 18 patients (47%) had no personality disorder, 7 (18%) had personality difficulty, 9 (24%) had mild personality disorder, and 4 (11%) had moderate personality disorder. None of the sample had severe personality disorder in which there is high risk of harm to self or others. Of the four major trait domains, provisionally named anankastic, detached, emotional and dissocial, three were evenly distributed in those with personality disturbance with the antagonistic (antisocial) trait less commonly shown (6 only). Scores on the PBCL were higher in those with increasing severity of personality disorder (P = 0.03) and those in the antagonistic personality trait domain had the highest PCL scores.ConclusionsDespite previous difficulties in assessing personality disorder in intellectual difficulties the ICD‐11 classification was easy to administer in practice in this population, and the higher problem behaviour scores in those with greater severity of personality disturbance support its construct validity.
Time‐dependent reduction of structural complexity of the buccal epithelial cell nuclei after treatment with silver nanoparticles
Authors: PANTIC I. , PAUNOVIC J. , PEROVIC M. , CATTANI C. , PANTIC S. , SUZIC S. , NESIC D. , BASTA‐JOVANOVIC G. 
Published: October 2013

SummaryRecent studies have suggested that silver nanoparticles (AgNPs) may affect cell DNA structure in in vitro conditions. In this paper, we present the results indicating that AgNPs change nuclear complexity properties in isolated human epithelial buccal cells in a time‐dependent manner. Epithelial buccal cells were plated in special tissue culture chamber / slides and were kept at 37°C in an RPMI 1640 cell culture medium supplemented with L‐glutamine. The cells were treated with colloidal silver nanoparticles suspended in RPMI 1640 medium at the concentration 15 mg L−1. Digital micrographs of the cell nuclei in a sample of 30 cells were created at five different time steps: before the treatment (controls), immediately after the treatment, as well as 15 , 30 and 60 min after the treatment with AgNPs. For each nuclear structure, values of fractal dimension, lacunarity, circularity, as well as parameters of grey level co‐occurrence matrix (GLCM) texture, were determined. The results indicate time‐dependent reduction of structural complexity in the cell nuclei after the contact with AgNPs. These findings further suggest that AgNPs, at concentrations present in today's over‐the‐counter drug products, might have significant effects on the cell genetic material.
A conserved sequence in calmodulin regulated spectrin‐associated protein 1 links its interaction with spectrin and calmodulin to neurite outgrowth
Authors: King Mikayala D. A. , Phillips Gareth W. , Bignone Paola A. , Hayes Nandini V. L. , Pinder Jennifer C. , Baines Anthony J. 
Published: October 2013

AbstractCalmodulin regulated spectrin‐associated protein 1 (CAMSAP1) is a vertebrate microtubule‐binding protein, and a representative of a family of cytoskeletal proteins that arose with animals. We reported previously that the central region of the protein, which contains no recognized functional domain, inhibited neurite outgrowth when over‐expressed in PC12 cells [Baines et al., Mol. Biol. Evol. 26 (2009), p. 2005]. The CKK domain (DUF1781) binds microtubules and defines the CAMSAP/ssp4 family of animal proteins (Baines et al. 2009). In the central region, three short well‐conserved regions are characteristic of CAMSAP‐family members. One of these, CAMSAP‐conserved region 1 (CC1), bound to both βIIΣ1‐spectrin and Ca2+/calmodulin in vitro. The binding of Ca2+/calmodulin inhibited spectrin binding. Transient expression of CC1 in PC12 cells inhibited neurite outgrowth. siRNA knockdown of CAMSAP1 inhibited neurite outgrowth in PC12 cells or primary cerebellar granule cells: this could be rescued in PC12 cells by wild‐type CAMSAP1‐enhanced green fluorescent protein, but not by a CC1 mutant. We conclude that CC1 represents a functional region of CAMSAP1, which links spectrin‐binding to neurite outgrowth.
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Knockdown of the cytoskeletal protein CAMSAP1 using siRNA inhibited NGF‐induced (nerve growth factor) neurite outgrowth from PC12 cells, and axon production by cerebellar granule cells in culture. This activity is linked to a spectrin‐ and Ca2+/calmodulin‐binding region (CC1), since over‐expression of isolated CC1 inhibited neurite production from PC12 cells. We previously showed that CAMSAP1 binds microtubules at the C‐terminal CKK domain. Our data indicates CAMSAP1 is a cytoskeletal interconnector required for neurite and axon production.
CaMKII represses transcriptionally active β‐catenin to mediate acute ethanol neurodegeneration and can phosphorylate β‐catenin
Authors: Flentke George R. , Garic Ana , Hernandez Marcos , Smith Susan M. 
Published: October 2013

AbstractPrenatal ethanol exposure causes persistent neurodevelopmental deficits by inducing apoptosis within neuronal progenitors including the neural crest. The cellular signaling events underlying this apoptosis are unclear. Using an established chick embryo model, we previously identified ethanol's activation of calmodulin‐dependent protein kinase II (CaMKII) as a crucial early step in this pathway. Here, we report that CaMKII is pro‐apoptotic because it mediates the loss of transcriptionally active β‐catenin, which normally provides trophic support to these cells. β‐catenin over‐expression normalized cell survival in ethanol's presence. CaMKII inhibition similarly restored β‐catenin content and transcriptional activity within ethanol‐treated cells and prevented their cell death. In contrast, inhibition of alternative effectors known to destabilize β‐catenin, including glycogen synthase kinase‐3β, Protein Kinase C, JNK, and calpain, failed to normalize cell survival and β‐catenin activity in ethanol's presence. Importantly, we found that purified CaMKII can directly phosphorylate β‐catenin. Using targeted mutagenesis we identified CaMKII phosphorylation sites within human β‐catenin at T332, T472, and S552. This is the first demonstration that β‐catenin is a phosphorylation target of CaMKII and represents a novel mechanism by which calcium signals could regulate β‐catenin‐dependent transcription. These results inform ethanol's neurotoxicity and offer unexpected insights into other neurodevelopmental and neurodegenerative disorders having dysregulated calcium or β‐catenin signaling.
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We proposed that ethanol initiates apoptosis in early neuroprogenitors through an intracellular calcium transient that activates CaMKII, which in turn destabilizes transcriptionally‐active beta‐catenin, perhaps through direct phosphorylation at Thr332, Thr472 and Ser552. This represents a novel mechanism of calcium‐modulation of Wnt signaling and of ethanol's neurotoxicity.
The secretogranin II gene is a signal integrator of glutamate and dopamine inputs
Authors: Iwase Katsuro , Ishihara Akinori , Yoshimura Shuntaro , Andoh Yoshio , Kato Masaki , Seki Naohiko , Matsumoto Eriko , Hiwasa Takaki , Muller Dominique , Fukunaga Kohji , Takiguchi Masaki 
Published: October 2013

AbstractCooperative gene regulation by different neurotransmitters likely underlies the long‐term forms of associative learning and memory, but this mechanism largely remains to be elucidated. Following cDNA microarray analysis for genes regulated by Ca2+ or cAMP, we found that the secretogranin II gene (Scg2) was cooperatively activated by glutamate and dopamine in primary cultured mouse hippocampal neurons. The Ca2+ chelator 1,2‐bis(2‐aminophenoxy)ethane‐N,N,N’,N’‐tetraacetic acid acetoxymethyl ester (BAPTA‐AM) and the mitogen‐activated protein kinase (MAPK) kinase (MEK) inhibitor PD98059 prevented Scg2 activation by glutamate or dopamine; thus, the Ca2+/MEK pathway is predicted to include a convergence point(s) of glutamatergic and dopaminergic signaling. Unexpectedly, the protein kinase A inhibitor KT5720 enhanced Scg2 activation by dopamine. The protein‐synthesis inhibitor cycloheximide also enhanced Scg2 activation, and the proteasome inhibitor ZLLLH diminished the KT5720‐mediated augmentation of Scg2 activation. These results are concordant with the notion that dopaminergic input leads to accumulation of a KT5720‐sensitive transcriptional repressor, which is short‐lived because of rapid degradation by proteasomes. This repression pathway may effectively limit the time window permissive to Scg2 activation by in‐phase glutamate and dopamine inputs via the Ca2+/MEK pathway. We propose that the regulatory system of Scg2 expression is equipped with machinery that is refined for the signal integration of in‐phase synaptic inputs.
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We proposed hypothetical mechanism for the regulation of the secretogranin II gene as a signal integrator of glutamate and dopamine inputs. Glutamate or dopamine activates the Ca2+/MEK/ERK pathway, which thus contributes to the signal integration. Concurrently, activation of the PKA inhibitor KT5720‐sensitive pathway by dopamine leads to accumulation of the repressor protein X that is otherwise susceptible to proteasome degradation. This repression system may determine the time window permissive to the cooperative activation by in‐phase glutamate and dopamine inputs.
EphrinA/EphA‐induced ectodomain shedding of neural cell adhesion molecule regulates growth cone repulsion through ADAM10 metalloprotease
Authors: Brennaman Leann H. , Moss Marcia L. , Maness Patricia F. 
Published: October 2013

AbstractEphrinA/EphA‐dependent axon repulsion is crucial for synaptic targeting in developing neurons but downstream molecular mechanisms remain obscure. Here, it is shown that ephrinA5/EphA3 triggers proteolysis of the neural cell adhesion molecule (NCAM) by the metalloprotease a disintegrin and metalloprotease (ADAM)10 to promote growth cone collapse in neurons from mouse neocortex. EphrinA5 induced ADAM10 activity to promote ectodomain shedding of polysialic acid‐NCAM in cortical neuron cultures, releasing a ~ 250 kDa soluble fragment consisting of most of its extracellular region. NCAM shedding was dependent on ADAM10 and EphA3 kinase activity as shown in HEK293T cells transfected with dominant negative ADAM10 and kinase‐inactive EphA3 (K653R) mutants. Purified ADAM10 cleaved NCAM at a sequence within the E‐F loop of the second fibronectin type III domain (Leu671‐Lys672/Ser673‐Leu674) identified by mass spectrometry. Mutations of NCAM within the ADAM10 cleavage sequence prevented EphA3‐induced shedding of NCAM in HEK293T cells. EphrinA5‐induced growth cone collapse was dependent on ADAM10 activity, was inhibited in cortical cultures from NCAM null mice, and was rescued by WT but not ADAM10 cleavage site mutants of NCAM. Regulated proteolysis of NCAM through the ephrin5/EphA3/ADAM10 mechanism likely impacts synapse development, and may lead to excess NCAM shedding when disrupted, as implicated in neurodevelopmental disorders such as schizophrenia.
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PSA‐NCAM and ephrinA/EphA3 coordinately regulate inhibitory synapse development. Here, we have found that ephrinA5 stimulates EphA3 kinase and ADAM10 activity to promote PSA‐NCAM cleavage at a site in its second FNIII repeat, which regulates ephrinA5‐induced growth cone collapse in GABAergic and non‐GABAergic neurons. These findings identify a new regulatory mechanism which may contribute to inhibitory connectivity.
Cathepsin E generates a sumoylated intracellular fragment of the cell adhesion molecule L1 to promote neuronal and Schwann cell migration as well as myelination
Authors: Lutz David , Wolters‐Eisfeld Gerrit , Schachner Melitta , Kleene Ralf 
Published: October 2013

AbstractThe cell adhesion molecule L1 regulates cellular responses in the developing and adult nervous system. Here, we show that stimulation of cultured mouse cerebellar neurons by a function‐triggering L1 antibody leads to cathepsin E‐mediated generation of a sumoylated 30 kDa L1 fragment (L1‐30) and to import of L1‐30 into the nucleus. Mutation of the sumoylation site at K1172 or the cathepsin E cleavage site at E1167 abolishes generation of L1‐30, while mutation of the nuclear localization signal at K1147 prevents nuclear import of L1‐30. Moreover, the aspartyl protease inhibitor pepstatin impairs the generation of L1‐30 and inhibits L1‐induced migration of cerebellar neurons and Schwann cells as well as L1‐dependent in vitro myelination on axons of dorsal root ganglion neurons by Schwann cells. L1‐stimulated migration of HEK293 cells expressing L1 with mutated cathepsin E cleavage site is diminished in comparison to migration of cells expressing non‐mutated L1. In addition, L1‐stimulated migration of HEK293 cells expressing non‐mutated L1 is also abolished upon knock‐down of cathepsin E expression and enhanced by over‐expression of cathepsin E. The findings of the present study indicate that generation and nuclear import of L1‐30 regulate neuronal and Schwann cell migration as well as myelination.
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Cell adhesion molecule L1 regulates cellular responses in the developing and adult nervous system. L1 stimulation triggers sumoylation and cleavage of L1, thus generating the L1‐70 fragment (1) which is cleaved by cathepsin E (2) yielding the L1‐30 fragment that is imported to the nucleus (3), may bind to DNA and/or nuclear proteins (4), to regulate diverse cellular functions.
GABAA receptor transmembrane amino acids are critical for alcohol action: disulfide cross‐linking and alkyl methanethiosulfonate labeling reveal relative location of binding sites
Authors: Borghese Cecilia M. , Hicks Jessica A. , Lapid Daniel J. , Trudell James R. , Harris R. Adron 
Published: October 2013

AbstractAlcohols and inhaled anesthetics modulate GABAA receptor (GABAAR) function via putative binding sites within the transmembrane regions. The relative position of the amino acids lining these sites could be either inter‐ or intra‐subunit. We introduced cysteines in relevant TM locations and tested the proximity of cysteine pairs using oxidizing and reducing agents to induce or break disulfide bridges between cysteines, and thus change GABA‐mediated currents in wild‐type and mutant α1β2γ2 GABAARs expressed in Xenopus laevis oocytes. We tested for: (i) inter‐subunit cross‐linking: a cysteine located in α1TM1 [either α1(Q229C) or α1(L232C)] was paired with a cysteine in different positions of β2TM2 and TM3; (ii) intra‐subunit cross‐linking: a cysteine located either in β2TM1 [β2(T225C)] or in TM2 [β2(N265C)] was paired with a cysteine in different locations along β2TM3. Three inter‐subunit cysteine pairs and four intra‐subunits cross‐linked. In three intra‐subunit cysteine combinations, the alcohol effect was reduced by oxidizing agents, suggesting intra‐subunit alcohol binding. We conclude that the structure of the alcohol binding site changes during activation and that potentiation or inhibition by binding at inter‐ or intra‐subunit sites is determined by the specific receptor and ligand.
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Alcohols modulate GABAA receptor function. The relative location of alcohol binding pockets in transmembrane domains was assessed by substituting critical amino acids with cysteines, and testing GABA responses and alcohol modulation before and after crosslinking double cysteine mutants and labeling single cysteine mutants. Lines show absence of crosslinking (red), and crosslinking that modified GABA responses (black) and alcohol modulation (grey).
Blocking the apolipoprotein E/Amyloid β interaction in triple transgenic mice ameliorates Alzheimer's disease related amyloid β and tau pathology
Authors: Liu Shan , Breitbart Ariel , Sun Yanjie , Mehta Pankaj D. , Boutajangout Allal , Scholtzova Henrieta , Wisniewski Thomas 
Published: October 2013

AbstractInheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late‐onset Alzheimer's disease (AD). Studies have shown that the binding between apoE and amyloid‐β (Aβ) peptides occurs at residues 244–272 of apoE and residues 12–28 of Aβ. ApoE4 has been implicated in promoting Aβ deposition and impairing clearance of Aβ. We hypothesized that blocking the apoE/Aβ interaction would serve as an effective new approach to AD therapy. We have previously shown that treatment with Aβ12‐28P can reduce amyloid plaques in APP/PS1 transgenic (Tg) mice and vascular amyloid in TgSwDI mice with congophilic amyloid angiopathy. In the present study, we investigated whether the Aβ12‐28P elicits a therapeutic effect on tau‐related pathology in addition to amyloid pathology using old triple transgenic AD mice (3xTg, with PS1M146V, APPSwe and tauP30IL transgenes) with established pathology from the ages of 21 to 26 months. We show that treatment with Aβ12‐28P substantially reduces tau pathology both immunohistochemically and biochemically, as well as reducing the amyloid burden and suppressing the activation of astrocytes and microglia. These affects correlate with a behavioral amelioration in the treated Tg mice.
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The apolipoprotein E (apoE)/amyloid beta (Aβ) interaction plays an important role in the aggregation and clearance of Aβ. We show that the apoE/Aβ binding blocker, Aβ12‐28P, elicits a therapeutic effect on tau related pathology, in addition to amyloid deposition, in 3xTg Alzheimer's disease model mice. These affects correlate with a behavioral amelioration in the treated Tg mice. We believe this presents a novel therapeutic approach for AD.
Paradoxical Effect of Gonadotrophin‐Inhibiting Hormone to Negatively Regulate Neuropeptide Y Neurones in Mouse Arcuate Nucleus
Authors: Jacobi J. S. , Coleman H. A. , Enriori P. J. , Parkington H. C. , Li Q. , Pereira A. , Cowley M. A. , Clarke I. J. 
Published: October 2013

Regulation of reproduction and energy homeostasis are linked, although our understanding of the central neural mechanisms subserving this connection is incomplete. Gonadotrophin‐inhibiting hormone (GnIH) is a neuropeptide that negatively regulates reproduction and stimulates food intake. Neuropeptide Y (NPY) and products of the pro‐opiomelanocortin (POMC) precursor (β‐endorphin melanocortins) are appetite regulating peptides produced in the neurones of the arcuate nucleus; these peptides also regulate reproduction. In the present study, we determined the effects of GnIH on NPY and POMC neurones. Using brain slices from mice with transgenes for fluorescent tags in the two types of neurone and patch clamp electrophysiology, a predominant inhibitory effect of GnIH was observed. GnIH (100 nm) inhibited the firing rate in POMC cells, confirming the results of previous studies and consistent with the stimulatory effect of GnIH on food intake. Paradoxically (i.e. because both GnIH and NPY stimulate food intake), GnIH also had a predominantly inhibitory effect on action potential activity in NPY cells. GnIH also inhibited the secretion of NPY and α‐melanocyte‐stimulating hormone secretion in incubated hypothalamic blocks. GnIH (100 ng) injected into the cerebral ventricles of mice did not increase the number of NPY cells that were positively immunostained for c‐Fos. Finally, dual label immunocytochemistry showed that 20% of NPY neurones had close contacts from GnIH fibres/varicosities. In conclusion, we confirm a negative effect of GnIH on POMC cells and demonstrate a paradoxical reduction of electrophysiological and functional activity in NPY cells.