bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct expression of C1q‐like family mRNAs in mouse brain and biochemical characterization of their encoded proteins
Authors: Iijima Takatoshi , Miura Eriko , Watanabe Masahiko , Yuzaki Michisuke 
Published: April 2010

AbstractMany members of the C1q family, including complement C1q and adiponectin, and the structurally related tumor necrosis factor family are secreted and play crucial roles in intercellular signaling. Among them, the Cbln (precerebellin) and C1q‐like (C1ql) subfamilies are highly and predominantly expressed in the central nervous system. Although the Cbln subfamily serve as essential trans‐neuronal regulators of synaptic integrity in the cerebellum, the functions of the C1ql subfamily (C1ql1–C1ql4) remain unexplored. Here, we investigated the gene expression of the C1ql subfamily in the adult and developing mouse brain by reverse transcriptase‐polymerase chain reaction and high‐resolution in‐situ hybridization. In the adult brain, C1ql1–C1ql3 mRNAs were mainly expressed in neurons but weak expression was seen in glia‐like structures in the adult brain. The C1ql1 mRNA was predominantly expressed in the inferior olive, whereas the C1ql2 and C1ql3 mRNAs were strongly coexpressed in the dentate gyrus. Although the C1ql1 and C1ql3 mRNAs were detectable as early as embryonic day 13, the C1ql2 mRNA was observed at later embryonic stages. The C1ql1 mRNA was also expressed transiently in the external granular layer of the cerebellum. Biochemical characterization in heterologous cells revealed that all of the C1ql subfamily proteins were secreted and they formed both homomeric and heteromeric complexes. They also formed hexameric and higher‐order complexes via their N‐terminal cysteine residues. These results suggest that, like Cbln, the C1ql subfamily has distinct spatial and temporal expression patterns and may play diverse roles by forming homomeric and heteromeric complexes in the central nervous system.
First diabetes prevalence study in Portugal: PREVADIAB study
Authors: Gardete‐Correia L. , Boavida J. M. , Raposo J. F. , Mesquita A. C. , Fona C. , Carvalho R. , Massano‐Cardoso S. 
Published: April 2010

Diabet. Med. 27, 879–881 (2010)AbstractAims  Diabetes is a growing worldwide problem. Ascertaining its prevalence is vital as a starting point to establish and measure the success of health interventions. This study aimed to determine the prevalence of Type 2 diabetes and ‘pre‐diabetes’, defined as impaired fasting glucose and impaired glucose tolerance, in the Portuguese population aged between 20 and 79 years.Methods  Considering the number of inhabitants between 20 and 79 years old, statistical units were selected that were representative regionally and nationally. The total sample comprised 5167 subjects. National prevalence was calculated. Analyses were performed on all those without previously known diabetes using World Health Organization reference diagnostic criteria.Results  We found a diabetes prevalence of 11.7% (95% confidence interval 10.8–12.6%), with a significant difference between men (14.2%; 95% confidence interval 12.5–15.5%) and women (9.5%; 95% confidence interval 8.5–10.6%). While 6.6% of the subjects had previously been diagnosed with diabetes, 5.1% were undiagnosed. By age groups, 2.4% of the population between 20 and 39 years, 12.6% of people from 40 to 59 years old and 26.3% of those aged between 60 and 79 years had diabetes. Prevalence of ‘pre‐diabetes’ (impaired fasting glucose, impaired glucose tolerance or both) in the population was 23.3%.Conclusions  Diabetes has a high prevalence in Portugal. If ‘pre‐diabetes’ is also considered, about one‐third (34.9%) of the population aged 20–79 years is affected. A greater number of males were found to have diabetes. We detected a high percentage of people with undiagnosed diabetes (43.6%).
Analysis of RET, ZEB2, EDN3 and GDNF Genomic Rearrangements in Central Congenital Hyperventilation Syndrome Patients by Multiplex Ligation‐dependent Probe Amplification
Authors: Serra Alexandre , Görgens Heike , Alhadad Karin , Fitze Guido , Schackert Hans K. 
Published: April 2010

SummaryCentral congenital hypoventilation syndrome (CCHS) is an autonomous control disease producing hypoventilation, high PaCO2, and low PaO2 during quiet sleep. The main gene variants detected in CCHS are mutations in the PHOX2b gene in up to 97% of isolated cases. However, CCHS is sometimes associated with autonomic diseases such as Hirschsprung disease (HSCR). Since genomic rearrangements in particularly sensitive areas of the RET protooncogene and/or associated genes may account for the CCHS/HSCR phenotype in patients without other detectable RET variants, the aim of the present study was to identify rearrangements in the coding sequence of RET as well as in three HSCR‐associated genes (ZEB2, EDN3 and GDNF) in CCHS/HSCR patients by using Multiplex Ligation‐dependent Probe Amplification (MLPA). We have screened 27 CCHS and 11 CCHS/HSCR patients for genomic rearrangements in RET, ZEB2, EDN3 and GDNF and did not identify any deletion or amplification in these four genes in all patients. We conclude that genomic rearrangements in RET are rare and were not responsible for the CCHS/HSCR phenotype in individuals without identifiable germline RET variants in our group of patients, yet this possibility cannot be excluded altogether given the size of the cohort.
A longitudinal investigation of early reading and language skills in children with poor reading comprehension
Authors: Nation Kate , Cocksey Joanne , Taylor Jo S.H. , Bishop Dorothy V.M. 
Published: April 2010

Background:  Poor comprehenders have difficulty comprehending connected text, despite having age‐appropriate levels of reading accuracy and fluency. We used a longitudinal design to examine earlier reading and language skills in children identified as poor comprehenders in mid‐childhood.Method:  Two hundred and forty‐two children began the study at age 5. Further assessments of language and reading skill were made at 5.5, 6, 7 and 8 years. At age 8, fifteen children met criteria for being a poor comprehender and were compared to 15 control children both concurrently and prospectively.Results:  Poor comprehenders showed normal reading accuracy and fluency at all ages. Reading comprehension was poor at each time point and, notably, showed minimal increases in raw score between 6 and 8 years. Phonological skills were generally normal throughout, but mild impairments in expressive and receptive language, listening comprehension and grammatical understanding were seen at all ages.Conclusions:  Children identified as poor comprehenders at 8 years showed the same reading profile throughout earlier development. Their difficulties with the non‐phonological aspects of oral language were present at school entry and persisted through childhood, showing that the oral language weaknesses seen in poor comprehenders in mid‐childhood are not a simple consequence of their reading comprehension impairment.
Attentional networks in children and adolescents with autism spectrum disorder
Authors: Keehn Brandon , Lincoln Alan J. , Müller Ralph‐Axel , Townsend Jeanne 
Published: April 2010

Background:  Individuals diagnosed with autism spectrum disorder (ASD) exhibit lifelong abnormalities in the adaptive allocation of visual attention. The ubiquitous nature of attentional impairments in ASD has led some authors to hypothesize that atypical attentional modulation may be a factor in the development of higher‐level sociocommunicative deficits.Method:  Participants were 20 children with ASD and 20 age‐ and Nonverbal IQ‐matched typically developing (TD) children. We used the Attention Network Test (ANT) to investigate the efficiency and independence of three discrete attentional networks: alerting, orienting, and executive control. Additionally, we sought to investigate the relationship between each attentional network and measures of sociocommunicative symptom severity in children with ASD.Results:  Results indicate that the orienting, but not alerting or executive control, networks may be impaired in children with ASD. In contrast to TD children, correlational analyses suggest that the alerting and executive control networks may not function as independently in children with ASD. Additionally, an association was found between the alerting network and social impairment and between the executive control network and IQ in children with ASD.Conclusions:  The results provide further evidence of an impairment in the visuospatial orienting network in ASD and suggest that there may be greater interdependence of alerting and executive control networks in ASD. Furthermore, decreased ability to efficiently modulate levels of alertness was related to increased sociocommunicative deficits, suggesting that domain‐general attentional function may be associated with ASD symptomatology.
A novel antagonist of the prostaglandin E2 EP4 receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models
Authors: Chen Q , Muramoto K , Masaaki N , Ding Y , Yang H , Mackey M , Li W , Inoue Y , Ackermann K , Shirota H , Matsumoto I , Spyvee M , Schiller S , Sumida T , Gusovsky F , Lamphier M 
Published: April 2010

Background and purpose:  Rheumatoid arthritis (RA) is an autoimmune disorder involving subsets of activated T cells, in particular T helper (Th) 1 and Th17 cells, which infiltrate and damage tissues and induce inflammation. Prostaglandin E2 (PGE2) enhances the Th17 response, exacerbates collagen‐induced arthritis (CIA) and promotes inflammatory pain. The current study investigated whether selective antagonism of the PGE2 EP4 receptor would suppress Th1/Th17 cell development and inflammatory arthritis in animal models of RA.Experimental approach:  Effects of PGE2 and a novel EP4 receptor antagonist ER‐819762 on Th1 differentiation, interleukin‐23 (IL‐23) production by dendritic cells (DCs), and Th17 development were assessed in vitro. The effect of ER‐819762 was evaluated in CIA and glucose‐6‐phosphate isomerase (GPI)‐induced arthritis models. In addition, the effects of ER‐819762 on pain were evaluated in a model of chronic inflammatory pain induced by complete Freund's adjuvant (CFA) in the rat.Key results:  Stimulation of the EP4 receptor enhanced Th1 differentiation via phosphatidylinositol 3 kinase signalling, selectively promoted Th17 cell expansion, and induced IL‐23 secretion by activated DCs, effects suppressed by ER‐819762 or anti‐PGE2 antibody. Oral administration of ER‐19762 suppressed Th1 and Th17 cytokine production, suppressed disease in collagen‐ and GPI‐induced arthritis in mice, and suppressed CFA‐induced inflammatory pain in rats.Conclusion and implications:  PGE2 stimulates EP4 receptors to promote Th1 differentiation and Th17 expansion and is critically involved in development of arthritis in two animal models. Selective suppression of EP4 receptor signalling may have therapeutic value in RA both by modifying inflammatory arthritis and by relieving pain.
Spinal glial TLR4‐mediated nociception and production of prostaglandin E2and TNF
Authors: Saito O , Svensson CI , Buczynski MW , Wegner K , Hua X‐Y , Codeluppi S , Schaloske RH , Deems RA , Dennis EA , Yaksh TL 
Published: April 2010

Background and purpose: Toll‐like receptor 4 (TLR4) expressed on spinal microglia and astrocytes has been suggested to play an important role in the regulation of pain signalling. The purpose of the present work was to examine the links between TLR4, glial activation and spinal release of prostaglandin E2(PGE2) and tumour necrosis factor (TNF), and the role these factors play in TLR4‐induced tactile allodynia.Experimental approach: Toll‐like receptor 4 was activated by intrathecal (i.t.) injection of lipopolysaccharide (LPS) and KDO2‐Lipid A (KDO2) to rats. Tactile allodynia was assessed using von Frey filaments and cerebrospinal fluid collected through spinal dialysis and lumbar puncture. PGE2and TNF levels were measured by mass spectometry andelisa. Minocycline and pentoxifylline (glia inhibitors), etanercept (TNF‐blocker) and ketorolac (COX‐inhibitor) were given i.t. prior to injection of the TLR4‐agonists, in order to determine if these agents alter TLR4‐mediated nociception and the spinal release of PGE2and TNF.Key results: Spinal administration of LPS and KDO2produced a dose‐dependent tactile allodynia, which was attenuated by pentoxifylline, minocycline and etanercept but not ketorolac. Both TLR4 agonists induced the spinal release of PGE2and TNF. Intrathecal pentoxifylline blunted PGE2and TNF release, while i.t. minocycline only prevented the spinal release of TNF. The release of PGE2induced by LPS and KDO2was attenuated by i.t. administration of ketorolac.Conclusions and implications: Activation of TLR4 induces tactile allodynia, which is probably mediated by TNF released by activated spinal glia.
Acute activation of eNOS by statins involves scavenger receptor‐B1, G protein subunit Gi, phospholipase C and calcium influx
Authors: Datar R , Kaesemeyer WH , Chandra S , Fulton DJ , Caldwell RW 
Published: April 2010

Background and purpose:  Statins (HMG CoA reductase inhibitors) have beneficial effects independent of reducing cholesterol synthesis and this includes their ability to acutely activate endothelial nitric oxide synthase (eNOS). The mechanism by which this occurs is largely unknown and thus we characterized the pathways by which statins activate NOS, including involvement of scavenger receptor‐B1 (SR‐B1), which is expressed in endothelial cells and maintains cholesterol concentrations.Experimental approach:  Nitric oxide production was monitored in bovine aortic endothelial cells (BAECs) exposed to lovastatin (LOV) or pravastatin (PRA) for 10–20 min, alone or following pre‐exposure to the end product of HMG‐CoA reductase (mevalonate), G protein inhibitors (pertussis/cholera toxins), phospholipase C (PLC) inhibitor (U‐73122), or intracellular and extracellular calcium chelators – BAPTA‐AM and EGTA (respectively), or a function blocking antibody to SR‐B1.Key results:  Both statins increased NO production in a rapid, dose‐dependent and HMG‐CoA reductase‐independent manner. Inhibiting Gi protein or PLC almost completely blocked statin‐induced NO generation. Additionally, removing extracellular calcium inhibited statin‐induced NO production. COS‐7 cells co‐transfected with eNOS and SR‐B1 increased NO production when exposed to LOV or high‐density lipoprotein (HDL), an agonist of SR‐B1. These effects were not observed in COS‐7 cells with eNOS alone or co‐transfected with bradykinin receptor 2, indicating specificity for SR‐B1. Further, pretreatment of BAEC with blocking antibody for SR‐B1 blocked NO responses to statins and HDL.Conclusions and implications:  LOV and PRA acutely activate eNOS through pathways that include the cell surface receptor SR‐B1, Gi protein, phosholipase C and entry of extracellular calcium into endothelial cells.
Depression‐resistant endophenotype in mice overexpressing cannabinoid CB2 receptors
Authors: García‐Gutiérrez MS , Pérez‐Ortiz JM , Gutiérrez‐Adán A , Manzanares J 
Published: April 2010

Background and purpose:  The present study evaluated the role of CB2 receptors in the regulation of depressive‐like behaviours. Transgenic mice overexpressing the CB2 receptor (CB2xP) were challenged with different types of acute and chronic experimental paradigms to evaluate their response in terms of depressive‐like behaviours.Experimental approach:  Tail suspension test (TST), novelty‐suppressed feeding test (NSFT) and unpredictable chronic mild stress tests (CMS) were carried out in CB2xP mice. Furthermore, acute and chronic antidepressant‐like effects of the CB2 receptor‐antagonist AM630 were evaluated by means of the forced swimming test (FST) and CMS, respectively, in wild‐type (WT) and CB2xP mice. CB2 gene expression, brain‐derived neurotrophic factor (BDNF) gene and protein expressions were studied in mice exposed to CMS by real‐time PCR and immunohistochemistry, respectively.Key results:  Overexpression of CB2 receptors resulted in decreased depressive‐like behaviours in the TST and NSFT. CMS failed to alter the TST and sucrose consumption in CB2xP mice. In addition, no changes in BDNF gene and protein expression were observed in stressed CB2xP mice. Interestingly, acute administration of AM630 (1 and 3 mg·kg−1, i.p.) exerted antidepressant‐like effects on the FST in WT, but not in CB2xP mice. Chronic administration of AM630 for 4 weeks (1 mg·kg−1; twice daily, i.p.) blocked the effects of CMS on TST, sucrose intake, CB2 receptor gene, BDNF gene and protein expression in WT mice.Conclusion and implications:  Taken together, these results suggest that increased CB2 receptor expression significantly reduced depressive‐related behaviours and that the CB2 receptor could be a new potential therapeutic target for depressive‐related disorders.
Symptomatic and neuroprotective effects following activation of nigral group III metabotropic glutamate receptors in rodent models of Parkinson's disease
Authors: Austin PJ , Betts MJ , Broadstock M , O'Neill MJ , Mitchell SN , Duty S 
Published: April 2010

Background and purpose:  Increased glutamatergic innervation of the substantia nigra pars reticulata (SNpr) and pars compacta (SNpc) may contribute to the motor deficits and neurodegeneration, respectively, in Parkinson's disease (PD). This study aimed to establish whether activation of pre‐synaptic group III metabotropic glutamate (mGlu) receptors reduced glutamate release in the SN, and provided symptomatic or neuroprotective relief in animal models of PD.Experimental approach:  Broad‐spectrum group III mGlu receptor agonists, O‐phospho‐l‐serine (l‐SOP) and l‐2‐amino‐4‐phosphonobutyrate (l‐AP4), were assessed for their ability to inhibit KCl‐evoked [3H]‐d‐aspartate release in rat nigral prisms or inhibit KCl‐evoked endogenous glutamate release in the SNpr in vivo using microdialysis. Reversal of akinesia in reserpine‐treated rats was assessed following intranigral injection of l‐SOP and l‐AP4. Finally, the neuroprotective effect of 7 days' supra‐nigral treatment with l‐AP4 was examined in 6‐hydroxydopamine (6‐OHDA)‐lesioned rats.Key results:  l‐SOP and l‐AP4 inhibited [3H]‐d‐aspartate release by 33 and 44% respectively. These effects were blocked by the selective group III mGlu antagonist (RS)‐α‐cyclopropyl‐4‐phosphonophenylglycine (CPPG). l‐SOP also reduced glutamate release in the SNpr in vivo by 48%. Injection of l‐SOP and l‐AP4 into the SNpr reversed reserpine‐induced akinesia. Following administration above the SNpc, l‐AP4 provided neurochemical, histological and functional protection against 6‐OHDA lesion of the nigrostriatal tract. Pretreatment with CPPG inhibited these effects.Conclusions and implications:  These findings highlight group III mGlu receptors in the SN as potential targets for providing both symptomatic and neuroprotective relief in PD, and indicate that inhibition of glutamate release in the SN may underlie these effects.
Modulation of the apelin/APJ system in heart failure and atherosclerosis in man
Authors: Pitkin Sarah L , Maguire Janet J , Kuc Rhoda E , Davenport Anthony P 
Published: April 2010

Background and purpose:  The aim of this study was to determine whether the apelin/APJ system is altered in human cardiovascular disease by investigating whether the expression of apelin or its receptor is altered at the protein level.Experimental approach:  Radioligand binding studies were used to determine apelin receptor density in human cardiac tissues. Apelin peptide levels in cardiovascular tissues were determined by radioimmunoassay. In vitro pharmacology was used to assess vasoactive properties of apelin in human coronary artery. Localization of apelin and its receptor in coronary artery was determined using immunohistochemistry.Key results:  Apelin receptor density was significantly decreased in left ventricle from patients with dilated cardiomyopathy or ischaemic heart disease compared with controls, but apelin peptide levels remained unchanged. Apelin was up‐regulated in human atherosclerotic coronary artery and this additional peptide localized to the plaque, colocalizing with markers for macrophages and smooth muscle cells. Apelin potently constricted human coronary artery.Conclusions and implications:  We have detected changes in the apelin/APJ system in human diseased cardiac and vascular tissue. The decrease in receptor density in heart failure may limit the positive inotropic actions of apelin, contributing to contractile dysfunction. The contribution of the increased apelin levels in atherosclerotic coronary artery to disease progression remains to be determined. These data suggest a potential role for the apelin/APJ system in human cardiovascular disease.
Identification of sites responsible for the potentiating effect of niflumic acid on ClC‐Ka kidney chloride channels
Authors: Zifarelli G , Liantonio A , Gradogna A , Picollo A , Gramegna G , De Bellis M , Murgia AR , Babini E , Conte Camerino D , Pusch M 
Published: April 2010

Background and purpose: ClC‐K kidney Cl–channels are important for renal and inner ear transepithelial Cl–transport, and are potentially interesting pharmacological targets. They are modulated by niflumic acid (NFA), a non‐steroidal anti‐inflammatory drug, in a biphasic way: NFA activates ClC‐Ka at low concentrations, but blocks the channel above ∼1 mM. We attempted to identify the amino acids involved in the activation of ClC‐Ka by NFA.Experimental approach: We used site‐directed mutagenesis and two‐electrode voltage clamp analysis of wild‐type and mutant channels expressed inXenopusoocytes. Guided by the crystal structure of a bacterial CLC homolog, we screened 97 ClC‐Ka mutations for alterations of NFA effects.Key results: Mutations of five residues significantly reduced the potentiating effect of NFA. Two of these (G167A and F213A) drastically altered general gating properties and are unlikely to be involved in NFA binding. The three remaining mutants (L155A, G345S and A349E) severely impaired or abolished NFA potentiation.Conclusions and implications: The three key residues identified (L155, G345, A349) are localized in two different protein regions that, based on the crystal structure of bacterial CLC homologs, are expected to be exposed to the extracellular side of the channel, relatively close to each other, and are thus good candidates for being part of the potentiating NFA binding site. Alternatively, the protein region identified mediates conformational changes following NFA binding. Our results are an important step towards the development of ClC‐Ka activators for treating Bartter syndrome types III and IV with residual channel activity.