bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of genes influencing skeletal phenotypes in congenic P/NP rats
Authors: Alam Imranul , Carr Lucinda G , Liang Tiebing , Liu Yunlong , Edenberg Howard J , Econs Michael J , Turner Charles H
Published: February 2010

We previously showed that alcohol-preferring (P) rats have higher bone density than alcohol-nonpreferring (NP) rats. Genetic mapping in P and NP rats identified a major quantitative trait locus (QTL) between 4q22 and 4q34 for alcohol preference. At the same location, several QTLs linked to bone density and structure were detected in Fischer 344 (F344) and Lewis (LEW) rats, suggesting that bone mass and strength genes might cosegregate with genes that regulate alcohol preference. The aim of this study was to identify the genes segregating for skeletal phenotypes in congenic P and NP rats. Transfer of the NP chromosome 4 QTL into the P background (P.NP) significantly decreased areal bone mineral density (aBMD) and volumetric bone mineral density (vBMD) at several skeletal sites, whereas transfer of the P chromosome 4 QTL into the NP background (NP.P) significantly increased bone mineral content (BMC) and aBMD in the same skeletal sites. Microarray analysis from the femurs using Affymetrix Rat Genome arrays revealed 53 genes that were differentially expressed among the rat strains with a false discovery rate (FDR) of less than 10%. Nine candidate genes were found to be strongly correlated (r2 > 0.50) with bone mass at multiple skeletal sites. The top three candidate genes, neuropeptide Y (Npy), α synuclein (Snca), and sepiapterin reductase (Spr), were confirmed using real-time quantitative PCR (qPCR). Ingenuity pathway analysis revealed relationships among the candidate genes related to bone metabolism involving β-estradiol, interferon-γ, and a voltage-gated calcium channel. We identified several candidate genes, including some novel genes on chromosome 4 segregating for skeletal phenotypes in reciprocal congenic P and NP rats. © 2010 American Society for Bone and Mineral Research
RECK‐mediated inhibition of glioma migration and invasion
Authors: Silveira Corrêa Tatiana C. , Massaro Renato Ramos , Brohem Carla Abdo , Taboga Sebastião Roberto , Lamers Marcelo Lazzaron , Santos Marinilce Fagundes , Maria‐Engler Silvya Stuchi
Published: February 2010

RECK is an anti‐tumoral gene whose activity has been associated with its inhibitory effects regulating MMP‐2, MMP‐9, and MT1‐MMP. RECK level decreases as gliobastoma progresses, varying from less invasive grade II gliomas to very invasive human glioblastoma multiforme (GBM). Since RECK expression and glioma invasiveness show an inverse correlation, the aim of the present study is to investigate whether RECK expression would inhibit glioma invasive behavior. We conducted this study to explore forced RECK expression in the highly invasive T98G human GBM cell line. Expression levels as well as protein levels of RECK, MMP‐2, MMP‐9, and MT1‐MMP were assessed by qPCR and immunoblotting in T98G/RECK+ cells. The invasion and migration capacity of RECK+ cells was inhibited in transwell and wound assays. Dramatic cytoskeleton modifications were observed in the T98G/RECK+ cells, when compared to control cells, such as the abundance of stress fibers (contractile actin–myosin II bundles) and alteration of lamellipodia. T98G/RECK+ cells also displayed phosphorylated focal adhesion kinase (P‐FAK) in mature focal adhesions associated with stress fibers; whereas P‐FAK in control cells was mostly associated with immature focal complexes. Interestingly, the RECK protein was predominantly localized at the leading edge of migrating cells, associated with membrane ruffles. Unexpectedly, introduced expression of RECK effectively inhibited the invasive process through rearrangement of actin filaments, promoting a decrease in migratory ability. This work has associated RECK tumor‐suppressing activity with the inhibition of motility and invasion in this GBM model, which are two glioma characteristics responsible for the inefficiency of current available treatments. J. Cell. Biochem. 110: 52–61, 2010. © 2010 Wiley‐Liss, Inc.
Control of intestinal promoter activity of the cellular migratory regulator gene ELMO3 by CDX2 and SP1
Authors: Coskun Mehmet , Boyd Mette , Olsen Jørgen , Troelsen Jesper T.
Published: February 2010

An important aspect of the cellular differentiation in the intestine is the migration of epithelial cells from the crypt to the villus tip. As homeodomaine transcription factor CDX2 has been suggested to influence cell migration, we performed a genome‐wide promoter analysis for CDX2 binding in the differentiated human intestinal cancer cell line Caco‐2 in order to identify CDX2‐regulated genes involved in cellular migration. The engulfment and cell motility 3 (ELMO3) gene was identified as a potential CDX2 target gene. ELMO3 is an essential upstream regulator of the GTP‐binding protein RAC during cell migration. However, no information is available about the transcriptional regulation of the ELMO3 gene. The aim of this study was to investigate the potential role of CDX2 in the regulation of the ELMO3 promoter activity. Electrophoretic mobility shift assays showed that CDX2 bound to conserved CDX2 sequences and mutations of the CDX2‐binding sites, significantly reduced the promoter activity. Reporter gene assays demonstrated that the region mediating ELMO3 basal transcriptional activity to be located between −270 and −31 bp. Sequence analysis revealed no typical TATA‐box, but four GC‐rich sequences. In vitro analyses (electrophoretic mobility shift assays and promoter analyses) demonstrate that the SP1‐binding sites are likely to play an important role in regulating the ELMO3 promoter activity. Furthermore, we showed here that CDX2 and SP1 can activate the ELMO3 promoter. Taken together, the present study reports the first characterization of the ELMO3 promoter and suggests a significant role of CDX2 in the basal transcriptional regulation of the intestine‐specific expression of ELMO3, possibly through interaction with SP1. J. Cell. Biochem. 109: 1118–1128, 2010. © 2010 Wiley‐Liss, Inc.
Breviscapine protects against cardiac hypertrophy through blocking PKC‐α‐dependent signaling
Authors: Yan Ling , Huang He , Tang Qi‐Zhu , Zhu Li‐Hua , Wang Lang , Liu Chen , Bian Zhou‐Yan , Li Hongliang
Published: February 2010

Breviscapine is a mixture of flavonoid glycosides extracted from the Chinese herbs. Previous studies have shown that breviscapine possesses comprehensive pharmacological functions. However, very little is known about whether breviscapine have protective role on cardiac hypertrophy. The aim of the present study was to determine whether breviscapine attenuates cardiac hypertrophy induced by angiotensin II (Ang II) in cultured neonatal rat cardiac myocytes in vitro and pressure‐overload‐induced cardiac hypertrophy in mice in vivo. Our data demonstrated that breviscapine (2.5–15 µM) dose‐dependently blocked cardiac hypertrophy induced by Ang II (1 µM) in vitro. The results further revealed that breviscapine (50 mg/kg/day) prevented cardiac hypertrophy induced by aortic banding as assessed by heart weight/body weight and lung weight/body weight ratios, echocardiographic parameters, and gene expression of hypertrophic markers. The inhibitory effect of breviscapine on cardiac hypertrophy is mediated by disrupting PKC‐α‐dependent ERK1/2 and PI3K/AKT signaling. Further studies showed that breviscapine inhibited inflammation by blocking NF‐κB signaling, and attenuated fibrosis and collagen synthesis through abrogating Smad2/3 signaling. Therefore, these findings indicate that breviscapine, which is a potentially safe and inexpensive therapy for clinical use, has protective potential in targeting cardiac hypertrophy and fibrosis through suppression of PKC‐α‐dependent signaling. J. Cell. Biochem. 109: 1158–1171, 2010. © 2010 Wiley‐Liss, Inc.
Alcohol and PRAS40 knockdown decrease mTOR activity and protein synthesis via AMPK signaling and changes in mTORC1 interaction
Authors: Hong‐Brown Ly Q. , Brown C. Randell , Kazi Abid A. , Huber Danuta S. , Pruznak Anne M. , Lang Charles H.
Published: February 2010

The mTORC1 protein kinase complex consists of mTOR, raptor, mLST8/GβL and PRAS40. Previously, we reported that mTOR plays an important role in regulating protein synthesis in response to alcohol (EtOH). However, the mechanisms by which EtOH regulates mTORC1 activity have not been established. Here, we investigated the effect of EtOH on the phosphorylation and interaction of components of mTORC1 in C2C12 myocytes. We also examined the specific role that PRAS40 plays in this process. Incubation of myocytes with EtOH (100 mM, 24 h) increased raptor and PRAS40 phosphorylation. Likewise, there were increased levels of the PRAS40 upstream regulators Akt and IRS‐1. EtOH also caused changes in mTORC1 protein–protein interactions. EtOH enhanced the binding of raptor and PRAS40 with mTOR. These alterations occurred in concert with increased binding of 14‐3‐3 to raptor, while the PRAS40 and 14‐3‐3 interaction was not affected. The shRNA knockdown (KD) of PRAS40 decreased protein synthesis similarly to EtOH. PRAS40 KD increased raptor phosphorylation and its association with 14‐3‐3, whereas decreased GβL–mTOR binding. The effects of EtOH and PRAS40 KD were mediated by AMPK. Both factors increased in vitro AMPK activity towards the substrate raptor. In addition, KD enhanced the activity of AMPK towards TSC2. Collectively, our results indicate that EtOH stabilizes the association of raptor, PRAS40, and GβL with mTOR, while likewise increasing the interaction of raptor with 14‐3‐3. These data suggest a possible mechanism for the inhibitory effects of EtOH on mTOR kinase activity and protein synthesis in myocytes. J. Cell. Biochem. 109: 1172–1184, 2010. © 2010 Wiley‐Liss, Inc.
Promiscuity of translocation partners in multiple myeloma
Authors: Martin Lorri D. , Belch Andrew R. , Pilarski Linda M.
Published: February 2010

Multiple myeloma (MM) is characterized by karyotypic instability, including chromosomal translocations involving the IGH locus. MM cells display a promiscuity of translocation partners, only some of which are recurrent. We propose that several factors, including temporal and spatial nuclear positioning of potential partner loci, “off‐target” IGH diversification mechanisms, and aberrant repair pathways contribute to the promiscuity of translocation partners in MM. We speculate that in MM, IGH diversification processes [V(D)J recombination, somatic hypermutation, and class switch recombination] in B cells may not be restricted to specific stages of B‐cell development or within specific immune tissues, but may occur in different temporal “windows.” Before or during MM evolution, off‐target activities of the enzymes involved in IGH modification processes may contribute to the generation of double‐strand breaks (DSB) in translocation partner loci. In the parent B cells from which MM originates, spatial proximity within the nucleus of IGH and potential translocation partners contributes to the selection of a translocation partner and the clinical frequency at which a specific translocation occurs. The spatial proximity of IGH and specific translocation partners may be temporal and contribute not only to partner selection but also to the promiscuity of partners seen in MM. Lastly, aberrant repair mechanisms in MM progenitors (including the possibility that a Ku 86 variant allows for positional instability at DSBs) may also contribute to the promiscuity of chromosome translocation partners in MM. J. Cell. Biochem. 109: 1085–1094, 2010. © 2010 Wiley‐Liss, Inc.
Inhibition of glycogen synthase kinase‐3β promotes nuclear export of the androgen receptor through a CRM1‐dependent mechanism in prostate cancer cell lines
Authors: Schütz Stefanie V. , Cronauer Marcus V. , Rinnab Ludwig
Published: February 2010

The androgen receptor (AR) is a ligand‐dependent transcription factor belonging to the steroid hormone receptor superfamily. Under normal conditions, in the absence of a ligand, the AR is localized to the cytoplasm and is actively transported into the nucleus upon binding of androgens. In advanced prostate cancer (PCa) cell lines, an increased sensitivity to dihydrotestosterone (DHT), enabling the cells to proliferate under sub‐physiological levels of androgens, has been associated with increased stability and nuclear localization of the AR. There is experimental evidence that the glycogen synthase kinase‐3β (GSK‐3β), a multifunctional serine/threonine kinase is involved in estrogen and AR stability. As demonstrated in the following study by immunoprecipitation analysis, GSK‐3β binds to the AR forming complexes in the cytoplasm and in the nucleus. Furthermore, inhibition of GSK‐3β activity by pharmacological inhibitors like the maleimide SB216761, the chloromethyl‐thienyl‐ketone GSK‐3 inhibitor VI or the aminopyrazol GSK‐3 inhibitor XIII in cells grown in the presence of DHT triggered a rapid nuclear export of endogenous AR as well as of green fluorescent AR‐EosFP. The nuclear export of AR following GSK‐3β inhibition could be blocked by leptomycin B suggesting a CRM1‐dependent export mechanism. This assumption is supported by the localization of a putative CRM1 binding site at the C‐terminus of the AR protein. The results suggest that GSK‐3β is an important element not only in AR stability but also significantly alters nuclear translocation of the AR, thereby modulating the androgenic response of human PCa cells. J. Cell. Biochem. 109: 1192–1200, 2010. © 2010 Wiley‐Liss, Inc.
Overexpression of Par‐4 sensitizes TRAIL‐induced apoptosis via inactivation of NF‐κB and Akt signaling pathways in renal cancer cells
Authors: Lee Tae‐Jin , Jang Ji‐Hoon , Noh Hyo‐Jeong , Park Eun‐Jung , Choi Kyeong‐Sook , Kwon Taeg‐Kyu
Published: February 2010

The prostate‐apoptosis‐response‐gene‐4 (Par‐4) is up‐regulated in prostate cells undergoing programmed cell death. Furthermore, Par‐4 protein has been shown to function as an effector of cell death in response to various apoptotic stimuli that trigger mitochondria and membrane receptor‐mediated cell death pathways. In this study, we investigated how Par‐4 modulates TRAIL‐mediated apoptosis in TRAIL‐resistant Caki cells. Par‐4 overexpressing cells were strikingly sensitive to apoptosis induced by TRAIL compared with control cells. Par‐4 overexpressing Caki cells treated with TRAIL showed an increased activation of the initiator caspase‐8 and the effector caspase‐3, together with an enforced cleavage of XIAP and c‐FLIP. TRAIL‐induced reduction of XIAP and c‐FLIP protein levels in Par‐4 overexpressing cells was prevented by z‐VAD pretreatment. In addition, the surface DR5 protein level was increased in TRAIL‐treated Par‐4 overexpressing cells. Interestingly, even though a deletion of leucine zipper domain in Par‐4 recovered Bcl‐2 level to basal level induced by wild type Par‐4, it partly decreased sensitivity to TRAIL in Caki cells. In addition, exposure of Caki/Par‐4 cells to TRAIL led to reduction of phosphorylated Akt levels, but deletion of leucine zipper domain of Par‐4 did not affect these phosphorylated Akt levels. In conclusion, we here provide evidence that ectopic expression of Par‐4 sensitizes Caki cells to TRAIL via modulation of multiple targets, including DR5, Bcl‐2, Akt, and NF‐κB. J. Cell. Biochem. 109: 885–895, 2010. © 2010 Wiley‐Liss, Inc.
Improving the accuracy of predicting disulfide connectivity by feature selection
Authors: Zhu Lin , Yang Jie , Song Jiang‐Ning , Chou Kuo‐Chen , Shen Hong‐Bin
Published: February 2010

Disulfide bonds are primary covalent cross‐links formed between two cysteine residues in the same or different protein polypeptide chains, which play important roles in the folding and stability of proteins. However, computational prediction of disulfide connectivity directly from protein primary sequences is challenging due to the nonlocal nature of disulfide bonds in the context of sequences, and the number of possible disulfide patterns grows exponentially when the number of cysteine residues increases. In the previous studies, disulfide connectivity prediction was usually performed in high‐dimensional feature space, which can cause a variety of problems in statistical learning, such as the dimension disaster, overfitting, and feature redundancy. In this study, we propose an efficient feature selection technique for analyzing the importance of each feature component. On the basis of this approach, we selected the most important features for predicting the connectivity pattern of intra‐chain disulfide bonds. Our results have shown that the high‐dimensional features contain redundant information, and the prediction performance can be further improved when these high‐dimensional features are reduced to a lower but more compact dimensional space. Our results also indicate that the global protein features contribute little to the formation and prediction of disulfide bonds, while the local sequential and structural information play important roles. All these findings provide important insights for structural studies of disulfide‐rich proteins. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010
Investigation of excited‐state properties of fluorene–thiophene oligomers by the SAC‐CI theoretical approach
Authors: Poolmee Potjaman , Hannongbua Supa
Published: February 2010

Excited states of fluorene‐ethylenedioxythiophene (FEDOT) and fluorene‐S,S‐dioxide‐thiophene (FTSO2) monomers and dimers were studied by the symmetry‐adapted cluster (SAC)‐configuration interaction (CI) method. The absorption and emission peaks observed in the experimental spectra were theoretically assigned. The first three excited states of the optimized conformers, and the conformers of several torsional angles, were computed by SAC‐CI/D95(d). Accurate absorption spectra were simulated by taking the thermal average for the conformers of torsional angles from 0° to 90°. The conformers of torsional angles 0°, 15°, and 30° mainly contributed to the absorption spectra. The full width at half‐maximum of the FEDOT absorption band is 0.60 eV (4839 cm−1), which agrees very well with the experimental value of 0.61 eV (4900 cm−1). The maximum absorption wavelength is located at 303 nm, which is close to those of the experimental band (327 nm). The calculated absorption spectrum of FTSO2 showed two bands in the range of 225–450 nm. This agrees very well with the available experimental spectrum of a polymer of FTSO2, where two bands are detected. The excited‐state geometries were investigated by CIS/6‐31G(d). These showed a quinoid‐type structure which exhibited a shortening of the inter‐ring distance (0.06 Å for FEDOT and 0.04 Å for FTSO2). The calculated emission energy of FEDOT is 3.43 eV, which agrees very well with the available experimental data (3.46 eV). The fwhmE is about 0.49 eV (3952 cm−1), while the experimental fwhm is 0.43 eV (3500 cm−1). For FTSO2, two bands were also found in the emission spectrum. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010
Time‐dependent density functional theory study on the hydrogen bonding‐induced twisted intramolecular charge‐transfer excited states of 2‐(4′‐N,N‐dimethylaminophenyl)imidazo[4,5‐b]pyridine
Authors: Yin Shu‐Hui , Liu Yufang , Zhang Wei , Guo Ming‐Xing , Song Peng
Published: February 2010

In this work, the time‐dependent density functional theory (TDDFT) method was carried out to investigate the hydrogen‐bonded intramolecular charge‐transfer excited state of 2‐(4′‐N,N‐dimethylaminophenyl)imidazo[4,5‐b]pyridine (DMAPIP) in methanol (MeOH) solvent. All the geometric conformations of the ground state and locally excited (LE) state and the twisted intramolecular charge‐transfer (TICT) state for isolated DMAPIP and its hydrogen‐bonded complexes have been optimized. At the same time, the absorption and fluorescence spectra of DMAPIP and the hydrogen‐bonded complexes in different electronic states are also calculated. We theoretically demonstrated for the first time that the intermolecular hydrogen bond formed between DMAPIP and MeOH can induce the formation of the TICT state for DMAPIP in MeOH solvent. Therefore, the two components at 414 and 506 nm observed in the fluorescence spectra of DMAPIP in MeOH solvent were reassigned in this work. The fluorescence peak at 414 nm is confirmed to be the LE state. Furthermore, the red‐shifted shoulder at 506 nm should be originated from the hydrogen‐bonded TICT excited state. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010
27 ps DFT molecular dynamics simulation of α‐maltose: A reduced basis set study
Authors: Schnupf Udo , Willett J. L. , Momany Frank A.
Published: February 2010

DFT molecular dynamics simulations are time intensive when carried out on carbohydrates such as α‐maltose. In a recent publication (Momany et al., J. Mol. Struct. THEOCHEM, submitted) forces for dynamics were generated from B3LYP/6‐31+G* electronic structure calculations. The implicit solvent method COSMO was applied to simulate the solution environment. Here we present a modification of the DFT method that keeps the critical aspects of the larger basis set (B3LYP/6‐31+G*) while allowing the less‐essential atom interactions to be calculated using a smaller basis set, thus allowing for faster completion without sacrificing the interactions dictating the hydrogen bonding networks in α‐maltose. In previous studies, the gg′‐gg‐c solvated form quickly converged to the “r” form during a 5 ps dynamics run. This important conformational transition is tested by carrying out a long 27 ps simulation. The trend for the “r” conformer to be most stable during dynamics when fully solvated, is confirmed, resulting in ∼20/80% c/r population. Further, the study shows that considerable molecular end effects are important, the reducing end being fairly stable, the O6H pointing at the O5, while the nonreducing end moves freely to take on different conformations. Some “kink” and transition state forms are populated during the simulation. The average H1′···H4 distance of 2.28 Å confirms that the syn form is the primary glycosidic conformation, while the average C1′O1′C4 bond angle was 118.8°, in excellent agreement with experimental values. The length of this simulation allowed the evaluation of vibrational frequencies by Fourier transform of the velocity correlation function, taken from different time segments along the simulation path. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010
Convergent and divergent validity of the relationship profile test: investigating the relationship with attachment, interpersonal distress and psychological health
Authors: Haggerty Greg , Blake Margaret , Siefert Caleb J.
Published: February 2010

The present study looked to illustrate the convergent and divergent validity of the Relationship Profile Test (RPT), which is a 30‐item self‐report measuring destructive overdependence, dysfunctional detachment, and healthy dependence. The RPT items are written to draw upon Bornstein's (1992, 1993) 4‐component model as well as other essential components of the dimension in question (Bornstein et al., 2003). The results reveal that the subscales of the RPT are related in predictable ways to scores on measures of adult attachment, interpersonal distress, and psychological health and well‐being. The clinical implications of the results and the assessment of dependency in the clinical setting are discussed. © 2010 Wiley Periodicals, Inc. J Clin Psychol 66: 1–14, 2010.
Epigenetically regulated clonal heritability of CTA expression profiles in human melanoma
Authors: Fratta Elisabetta , Sigalotti Luca , Colizzi Francesca , Covre Alessia , Nicolay Hugues JMG , Danielli Riccardo , Fonsatti Ester , Altomonte Maresa , Calabrò Luana , Coral Sandra , Maio Michele
Published: February 2010

The intratumoral heterogeneity of cancer testis antigens (CTA) expression, which is driven by promoter methylation status, may hamper the effectiveness of CTA‐directed vaccination of melanoma patients. Thus, we investigated whether the intratumoral heterogeneity of CTA expression is inherited at cellular level, or evolves throughout cellular replication, leading to a phenotypically unstable tumor cell population with reduced immunogenicity and/or able to escape immune control. Utilizing a previously characterized ex vivo clonal model of intratumoral heterogeneity of CTA expression in melanoma, Mel 313 MAGE‐A3‐low clone 5 (clone 5M3‐low) and MAGE‐A3‐high clone 14 (clone 14M3‐high) were sub‐cloned and analyzed for CTA profile. Molecular assays demonstrated that levels of MAGE‐A3 expression were highly conserved among generated sub‐clones, as compared to parental clones. A similar behavior was identified for an extensive panel of other CTA investigated. Inherited levels of MAGE‐A3 expression correlated with the extent of promoter methylation among clone 5M3‐low and clone 14M3‐high sub‐clones analyzed. Treatment of clone 5M3‐low with a DNA hypomethylating agent (DHA) resulted in an up‐regulated expression of MAGE‐A3, which was inherited at single cell level, being still detectable at day 60 in its sub‐clones. Bisulfite sequencing demonstrated that also MAGE‐A3 promoter methylation status was inherited among sub‐clones generated from DHA‐treated clone 5M3‐low and strictly correlated with MAGE‐A3 expression levels in investigated sub‐clones. Similar results were obtained for additional CTA studied. Altogether our findings demonstrate that constitutive and DHA‐modified CTA profiles of melanoma cells are clonally inherited throughout cellular replications, thus providing relevant insights to improve the effectiveness of CTA‐based immunotherapy. J. Cell. Physiol. 223: 352–358, 2010. © 2010 Wiley‐Liss, Inc.
Decreased levels of Cx43 gap junctions result in ameloblast dysregulation and enamel hypoplasia inGja1Jrt/+mice
Authors: Toth K. , Shao Q. , Lorentz R. , Laird D.W.
Published: February 2010

Coordinated differentiation of the ameloblast cell layer is essential to enamel matrix protein deposition and subsequent mineralization. It has been hypothesized that this process is governed by Cx43‐based gap junctional intercellular communication as oculodentodigital dysplasia (ODDD) patients harboring autosomal‐dominant mutations in Cx43 exhibit enamel defects typically resulting in early adulthood tooth loss. To assess the role of Cx43 in tooth development we employ a mouse model of ODDD that harbors a G60S Cx43 mutant,Gja1Jrt/+, and appears to exhibit tooth abnormalities that mimic the human disease. We found that total Cx43 plaques at all stages of ameloblast differentiation, as well as within the supporting cell layers, were greatly reduced inGja1Jrt/+incisors compared to wild‐type littermate controls. To characterize theGja1Jrt/+mouse tooth phenotype, mice were sacrificed prior to tooth eruption (postnatal day 7), weaning (postnatal day 21), and adulthood (2 months postnatal). A severely disorganizedGja1Jrt/+mouse ameloblast layer and abnormal accumulation of amelogenin were observed at stages when the cells were active in secretion and mineralization. Differences in enamel thickness became more apparent after tooth eruption and incisor exposure to the oral cavity suggesting that enamel integrity is compromised, leading to rapid erosion. Additional analysis of incisors from mutant mice revealed that they were longer with a thicker dentin layer than their wild‐type littermates, which may reflect a mechanical stress response to the depleted enamel layer. Together, these data show that reduced levels of Cx43 gap junctions result in ameloblast dysregulation, enamel hypoplasia, and secondary tissue responses. J. Cell. Physiol. 223:601–609, 2010. © 2010 Wiley‐Liss, Inc.
Electric power in nanoscale devices with full Coulomb interaction
Authors: Albareda G. , Alarcón A. , Oriols X.
Published: February 2010

An accurate reformulation of the electric power in quasi‐ballistic (classical or quantum) scenarios is deduced within an explicit many‐particle treatment of the Coulomb interaction. The traditional definition of the electric power is compared with the new formulation presented here for classical bulk, quantum well and quantum wire double‐gate MOSFETs by means of 3D many‐electron Monte Carlo simulations. The accurate results with the many‐electron approach show not‐negligible discrepancies when compared with the conventional definition. Such small discrepancies become very important when the single‐transistor power is multiplied by the huge number of transistors present in the state‐of‐the‐art integrated circuits. Copyright © 2010 John Wiley & Sons, Ltd.
Functional central nervous system myelin repair in an adult mouse model of demyelination caused by proteolipid protein overexpression
Authors: Espinosa‐Jeffrey A. , Hitoshi S. , Zhao P. , Awosika O. , Agbo C. , Olaniyan E. , Garcia J. , Valera R. , Thomassian A. , Chang‐Wei R. , Yamaguchi M. , de Vellis J. , Ikenaka K.
Published: February 2010

Two types of interventions to remyelinate the adult demyelinated central nervous system were investigated in heterozygous transgenic mice overexpressing the proteolipid protein gene. 1) A cocktail of trophic factors, “TS1,” was directed toward the activation of the endogenous pool of neural progenitors to increase the number of myelinating oligodendrocytes (OL) in the brain. 2) A combinatorial approach in which OL progenitors were coinjected with TS1 into the corpus callosum of wild‐type and He4e transgenic mice that displayed hindlimb paralysis. The levels of locomotor ability in these mice were evaluated after a single treatment. The data showed that a single administration of either one of the interventions had similar therapeutic effects, alleviating the symptoms of demyelination and leading to the recovery of hindlimb function. Histological and immunofluorescent examination of brain sections showed extensive remyelination that was sufficient to reverse hindlimb paralysis in transgenic mice. When the interventions were administered prior to hindlimb paralysis, He4e mice were able to walk up to 1 year of age without paralysis. © 2010 Wiley‐Liss, Inc.
NRAGE is a negative regulator of nerve growth factor‐stimulated neurite outgrowth in PC12 cells mediated through TrkA‐ERK signaling
Authors: Feng Zhenhua , Li Kaizhen , Liu Mei , Wen Chuanjun
Published: February 2010

NRAGE, also denominated as MAGE‐D1 or Dlxin‐1, is firstly identified as a molecule interacting with NGF low affinity receptor p75NTR. It facilitates cell cycle arrest and NGF‐dependent neuronal apoptosis. Here we report that NRAGE is downregulated while p75NTR is upregulated during the process of NGF‐induced neuronal differentiation of PC12 cells. Knockdown of NRAGE by RNA interference accelerates NGF‐mediated neurite outgrowth. In addition, in the NRAGE‐suppressed cells, NGF‐induced ERK activation is increased and this activation is MEK‐dependent. Conversely, NRAGE overexpression significantly represses NGF‐induced ERK activation. Further studies revealed that NRAGE downregulates TrkA expression through a post‐transcriptional manner and thereby blocks NGF‐induced TrkA phosphrylation at tyrosine‐490. Altogether, these data indicate for the first time that NRAGE is an endogenous inhibitor for NGF‐induced neuronal differentiation of PC12 cells by regulating TrkA‐ERK signaling. © 2010 Wiley‐Liss, Inc.
Induction of parkinsonism‐related proteins in the spinal motor neurons of transgenic mouse carrying a mutant SOD1 gene
Authors: Morimoto Nobutoshi , Nagai Makiko , Miyazaki Kazunori , Ohta Yasuyuki , Kurata Tomoko , Takehisa Yasushi , Ikeda Yoshio , Matsuura Tohru , Asanuma Masato , Abe Koji
Published: February 2010

Amyotrophic lateral sclerosis is a progressive and fatal disease caused by selective death of motor neurons, and a number of these patients carry mutations in the superoxide dismutase 1 (SOD1) gene involved in ameliorating oxidative stress. Recent studies indicate that oxidative stress and disruption of mitochondrial homeostasis is a common mechanism for motor neuron degeneration in amyotrophic lateral sclerosis and the loss of midbrain dopamine neurons in Parkinson's disease. Therefore, the present study investigated the presence and alterations of familial Parkinson's disease‐related proteins, PINK1 and DJ‐1, in spinal motor neurons of G93ASOD1 transgenic mouse model of amyotrophic lateral sclerosis. Following onset of disease, PINK1 and DJ‐1 protein expression increased in the spinal motor neurons. The activated form of p53 also increased and translocated to the nuclei of spinal motor neurons, followed by increased expression of p53‐activated gene 608 (PAG608). This is the first report demonstrating that increased expression of PAG608 correlates with activation of phosphorylated p53 in spinal motor neurons of an amyotrophic lateral sclerosis model. These results provide further evidence of the profound correlations between spinal motor neurons of amyotrophic lateral sclerosis and parkinsonism‐related proteins. © 2010 Wiley‐Liss, Inc.
The comparison of mouse full metallothionein‐1 versus α and β domains and metallothionein‐1‐to‐3 mutation following traumatic brain injury reveals different biological motifs
Authors: Manso Yasmina , Serra Montserrat , Comes Gemma , Giralt Mercedes , Carrasco Javier , Cols Neus , Vašák Milan , González‐Duarte Pilar , Hidalgo Juan
Published: February 2010

Traumatic injury to the brain is one of the leading causes of injury‐related death or disability, but current therapies are limited. Previously it has been shown that the antioxidant proteins metallothioneins (MTs) are potent neuroprotective factors in animal models of brain injury. The exogenous administration of MTs causes effects consistent with the roles proposed from studies in knock‐out mice. We herewith report the results comparing full mouse MT‐1 with the independent α and β domains, alone or together, in a cryoinjury model. The lesion of the cortex caused the mice to perform worse in the horizontal ladder beam and the rota‐rod tests; all the proteins showed a modest effect in the former test, while only full MT‐1 improved the performance of animals in the rota‐rod, and the α domain showed a rather detrimental effect. Gene expression analysis by RNA protection assay demonstrated that all proteins may alter the expression of host‐response genes such as GFAP, Mac1 and ICAM, in some cases being the β domain more effective than the α domain or even the full MT‐1. A MT‐1‐to‐MT‐3 mutation blunted some but not all the effects caused by the normal MT‐1, and in some cases increased its potency. Thus, splitting the two MT‐1 domains do not seem to eliminate all MT functions but certainly modifies them, and different motifs seem to be present in the protein underlying such functions. © 2010 Wiley‐Liss, Inc.
Inflammasome signaling at the heart of central nervous system pathology
Authors: Chakraborty Swarupa , Kaushik Deepak Kumar , Gupta Malvika , Basu Anirban
Published: February 2010

Neuroinflammation is a complex innate response of neural tissue against harmful effects of diverse stimuli viz., pathogens, damaged cells and irritants within the Central Nervous System (CNS). Studies show that multiple inflammatory mediators including cytokines, chemokines and prostaglandins are elevated in the Cerebrospinal Fluid (CSF) and in post‐mortem brain tissues of patients with history of neuroinflammatory conditions as well as neurodegenerative disorders like Alzheimer's disease, Parkinson's disease and Multiple Sclerosis. The innate immunity mediators in the brain, namely microglia and astrocytes, express certain Pattern Recognition Receptors (PRRs), which are always on ‘high‐alert’ for pathogens or other inflammatory triggers and participate in the assembly and activation of the inflammasome. The inflammasome orchestrates the activation of the precursors of proinflammatory caspases, which in turn, cleave the precursor forms of interleukin‐1β, IL‐18 and IL‐33 into their active forms; the secretion of which leads to a potent inflammatory response, and/or influences the release of toxins from glial and endothelial cells. Altered expression of inflammasome mediators can either promote or inhibit neurodegenerative processes. Therefore, modulating the inflammasome machinery seems a better combat strategy than summarily suppressing all inflammation in most neuroinflammatory conditions. In the current review we have surveyed the identified triggers and pathways of inflammasome activation and the following events which ultimately accomplish the innate inflammatory response in the CNS, with a goal to provide an analytical insight into disease pathogenesis that might provide cues for devising novel therapeutic strategies. © 2010 Wiley‐Liss, Inc.
Thyroid hormone enhances transected axonal regeneration and muscle reinnervation following rat sciatic nerve injury
Authors: Panaite Petrica‐Adrian , Barakat‐Walter Ibtissam
Published: February 2010

Improvement of nerve regeneration and functional recovery following nerve injury is a challenging problem in clinical research. We have already shown that following rat sciatic nerve transection, the local administration of triiodothyronine (T3) significantly increased the number and the myelination of regenerated axons. Functional recovery is a sum of the number of regenerated axons and reinnervation of denervated peripheral targets. In the present study, we investigated whether the increased number of regenerated axons by T3‐treatment is linked to improved reinnervation of hind limb muscles. After transection of rat sciatic nerves, silicone or biodegradable nerve guides were implanted and filled with either T3 or phosphate buffer solution (PBS). Neuromuscular junctions (NMJs) were analyzed on gastrocnemius and plantar muscle sections stained with rhodamine α‐bungarotoxin and neurofilament antibody. Four weeks after surgery, most end‐plates (EPs) of operated limbs were still denervated and no effect of T3 on muscle reinnervation was detected at this stage of nerve repair. In contrast, after 14 weeks of nerve regeneration, T3 clearly enhanced the reinnervation of gastrocnemius and plantar EPs, demonstrated by significantly higher recovery of size and shape complexity of reinnervated EPs and also by increased acetylcholine receptor (AChRs) density on post synaptic membranes compared to PBS‐treated EPs. The stimulating effect of T3 on EP reinnervation is confirmed by a higher index of compound muscle action potentials recorded in gastrocnemius muscles. In conclusion, our results provide for the first time strong evidence that T3 enhances the restoration of NMJ structure and improves synaptic transmission. © 2010 Wiley‐Liss, Inc.
DMXB (GTS‐21) ameliorates the cognitive deficits in beta amyloid injected mice through preventing the dysfunction of alpha7 nicotinic receptor
Authors: Chen Lei , Wang Haofei , Zhang Zhuo , Li Zhen , He Danjun , Sokabe Masahiro , Chen Ling
Published: February 2010

Intracerebroventricular injection of beta‐amyloid25–35(Aβ25–35) in mice leads to cognitive deficits with the dysfunction of α7 nicotinic acetylcholine receptor (α7nAChR) within 1–2 weeks in a dose‐dependent manner. The present study focused on the effect of DMXB, a selective α7nAChR agonist, on Aβ25–35(3 nmol)‐impaired spatial memory and α7nAChR function. We found that the treatment with DMXB on days 1–10 after Aβ25–35injection dose‐dependently prevented Aβ25–35‐induced impairment of acquisition performance and probe trail test in Morris water maze. Importantly, the treatment with DMXB (1 mg/kg) perfectly prevented Aβ25–35‐induced depression of α7nAChR response, which was associated with improving the probability of presynaptic glutamate release and the induction of high‐frequency stimulation (HFS)‐dependent long‐term potentiation (LTP) in hippocampal Schaffer collaterale‐CA1 synapse. Furthermore, although either the basal level of extracellular signal‐regulated kinase 2 (ERK2) or its phosphorylation in the hippocampus had no difference between control and Aβ25–35mice, the Aβ25–35injection significantly attenuated HFS‐triggered increase in ERK2 phosphorylation. The treatment with DMXB also rescued the ERK2 phosphorylation triggered by HFS in Aβ25–35mice that is required for LTP induction. This study firstly provides in vivo evidence that the anti‐amnesic effect of DMXB is likely due to preventing the Aβ25–35‐induced dysfunction of α7nAChR. © 2010 Wiley‐Liss, Inc.
Dynamin 1 depletion and memory deficits in rats treated with Aβ and cerebral ischemia
Authors: Watanabe Takuya , Iwasaki Katsunori , Takasaki Kotaro , Yamagata Norito , Fujino Mutsumi , Nogami Ai , Ii Miyuki , Katsurabayashi Shutaro , Mishima Kenichi , Fujiwara Michihiro
Published: February 2010

Alzheimer's disease (AD) is progressive dementia with senile plaques composed of β‐amyloid (Aβ). Recent studies suggest that synaptic dysfunction is one of the earliest events in the pathogenesis of AD. Here we provide the first experimental evidence that a change in the level of dynamin 1 induced by Aβ correlates with memory impairment in vivo. We treated rats with transient cerebral ischemia with oligomeric forms of Aβ (Aβ oligomers), including dimers, trimers, and tetramers, intracerebroventricularly. The combination of Aβ oligomers and cerebral ischemia, but not cerebral ischemia alone, significantly impaired memory and decreased the level of dynamin 1, which plays a critical role in synaptic vesicle recycling, but did not affect the levels of other synaptic proteins, such as synaptophysin and synaptobrevin, in the hippocampus. Furthermore, the N‐methyl‐D‐aspartate (NMDA) receptor antagonist memantine prevented memory impairment and dynamin 1 degradation, suggesting that these changes might be mediated by NMDA receptors. These results suggest that Aβ oligomers induce memory impairment via dynamin 1 degradation, which may imply that dynamin 1 degradation is one of the causes of synaptic dysfunction in AD. © 2010 Wiley‐Liss, Inc.
Oligodendrogenesis in iron‐deficient rats: Effect of apotransferrin
Authors: Rosato‐Siri M.V. , Badaracco M.E. , Ortiz E.H. , Belforte N. , Clausi M. Guardia , Soto E.F. , Bernabeu R. , Pasquini J.M.
Published: February 2010

In rats, iron deficiency produces an alteration in myelin formation. However, there is limited information on the effects of this condition on oligodendroglial cell (OLGc) proliferation and maturation. In the present study, we further analyzed the hypomyelination associated with iron deficiency by studying the dynamics of oligodendrogenesis. Rats were fed control (40 mg Fe/kg) or iron‐deficient (4 mg Fe/kg) diets from gestation day 5 until postnatal day 3 (P3) or 11 (P11). OLGc proliferation, migration and differentiation were investigated before and after an intracranial injection of apotransferrin at 3 days of age (P3). The proliferating cell population was evaluated at P3. Iron‐deficient (ID) animals showed an increase in the oligodendrocyte precursors cell (OPC) population in comparison with controls. The overall pattern of migration of cells labeled with BrdU was investigated at P11. Iron deficiency increased the amount of BrdU+ cells in the corpus callosum (CC) and decreased OLGc maturation and myelin formation. Changes in nerve conduction were analyzed by measuring visual evoked potentials. Latency and amplitude were significantly disturbed in ID rats compared with controls. Both parameters were substantially normalized when animals were treated with a single intracranial injection of 350 ng apotransferrin (aTf). The current results give support to the idea that iron deficiency increases the number of proliferating and undifferentiated cells in the CC compared with the control. Treatment with aTf almost completely reverted the effects of iron deficiency, both changing the migration pattern and increasing the number of mature cells in the CC and myelin formation. © 2010 Wiley‐Liss, Inc.
Reinterpreting the magnetic resonance signs of hemodynamic impairment in the brains of multiple sclerosis patients from the perspective of a recent discovery of outflow block in the extracranial veins
Authors: Simka Marian , Zaniewski Maciej
Published: February 2010

Multiple sclerosis patients examined with perfusion magnetic resonance (MR) imaging techniques have been found to have patterns of abnormal blood flow. These include prolonged mean transit time, a trend toward decreased cerebral blood flow in the area of plaques, and decreased cerebral blood flow and prolonged mean transit time within normal‐appearing white matter. In‐creased cerebral blood flow and volume and decreased mean transit time (compared with the baseline values before the relapse) were found to precede the development of plaques. In addition, susceptibility‐weighted imaging utilizing deoxyhemoglobin as the contrast has revealed that venous blood in cerebral veins of multiple sclerosis patients is less deoxygenated compared with healthy controls. All these findings were traditionally interpreted as a sign of local flow disturbances mediated by inflammatory and neurodegenerative processes. However, recent findings of significant stenoses in the extracranial veins that drain the brain and spinal cord shed new light on these MR results. With the assumption that a majority, if not all, of multiple sclerosis patients exhibit such extracranial venous obstacles, the perfusion MR images of multiple sclerosis patients should be reinterpreted. Perhaps ongoing MR studies with respect to extracranial venous hemodynamics may decipher some of the unsolved puzzles related to this neurologic disease. © 2010 Wiley‐Liss, Inc.
Climatological onset dates of summer monsoon over Myanmar
Authors: Htway Ohnmar , Matsumoto Jun
Published: February 2010

Asian summer monsoon is the predominant climate system in Myanmar and nearly 90% of total rainfalls are from summer monsoon. The timing of monsoon onset is of importance to the agricultural sector and water replenishment. However, there is a lack of systematic method to detect the climatological monsoon onset dates of Myanmar. In this study, the climatology of the summer monsoon onset over Myanmar is defined using the mean pentad precipitation data of 29 stations from 1968 to 2000. As a result, the climatological monsoon onset dates over Myanmar are on 18th May (the middle date of pentad number 28) in the southern and central Myanmar and on 28th May (the middle date of pentad number 30) in the northern Myanmar. These climatological onset dates in two areas of Myanmar are confirmed by examining seven meteorological parameters of the observed station data and ERA40 re‐analysis data during the period between 21st April and 9th June. Copyright © 2010 Royal Meteorological Society