bluuebunny/crossref_metadata_2025 huggingface dataset:
Behavioral and morphological asymmetries in chukar Alectoris chukar copulation
Authors: Delehanty David J. , Paasché O'Hearn Pamela
Published: June 2005

Birds often exhibit greater reproductive tract development on the left side than right side. Behavioral evidence from the three species for which data has been published indicates that these species copulate more frequently on the left side of females than on the right side. Missing from the literature are studies that compare asymmetry in copulation behavior to asymmetry in reproductive tract morphology of the same individuals of both sexes within a single species. To better understand the potential for cryptic sexual selection to influence avian copulation, we measured asymmetries in chukar Alectoris chukar copulation using 24 male and 29 female chukar brought into captivity from the wild. Chukar copulated (n=37) more from the left side (n=30) of females than the right side (n=7). The left testis of males was consistently greater in size, mass and volume than the right testis. The left ovary and oviduct of females was consistently functional with no observable development of the right ovary or oviduct. Left‐side bias in direction of copulation, larger left testes, and functional left vaginal openings may act in concert to deliver spermatozoa to the oviduct, promoting fertilization.
Oral pemphigus vulgaris in children and adolescents: a review of the literature and a case report
Authors: ARIYAWARDANA A. , TILAKARATNE W. M. , DISSANAYAKE M. , VITANAARACHCHI N. , BASNAYAKE L. K. , SITHEEQUE M. A. M. , RANASINGHE A. W.
Published: June 2005

This paper describes a case of oral pemphigus vulgaris (PV) in a child that was diagnosed in its early stages and managed successfully. The authors also report a literature review. Although oral PV in children and adolescents is extremely rare, it should be included in the differential diagnosis of oral ulcerative disease. It is of utmost importance to diagnose PV in children and adolescents in its initial stages in order to prevent the serious morbidity that may result from the disease, and to institute phamacotherapeutic measures so that they have the greatest effect. Furthermore, it is essential for dentists to be aware of the existence of PV in child and adolescent patients so that they may refer such cases for specialist management without undue delay.
Scanning electron micrograph analysis of hypomineralized enamel in permanent first molars
Authors: JÄLEVIK B. , DIETZ W. , NORÉN J. G.
Published: June 2005

First molars with cream‐ to yellow‐coloured demarcated opacities of the enamel, often in combination with severe loss of substance, are common in many child populations. The aetiology is obscure.

Aim and Method.  The aim of this study was to study the ultrastructure of the enamel of 10 affected teeth by means of scanning electron microscopy (SEM) in order to gain a better understanding of the clinical appearance and treatment problems of this condition, and to find some clues to its aetiology.

Results.  The basic enamel structure with enamel rods and interrod zones was found in porous parts of the enamel, as well as in normal parts, but the packing of the hydroxylapatite crystals seemed to be looser and less well organized in the porous parts. The border between normal and hypomineralized enamel was usually distinct, and followed the direction of the rods. The preserved basic structure indicates normal function of the ameloblasts during their secretion phase, but impaired function during their maturation stage.

Conclusion.  Considering the poor etch profile, it seems reasonable to recommend removal of all affected enamel surrounding the cavity, if possible, and to use a glass ionomer filling with its chemical bonding to tooth substrate, when restoring first molars with remaining affected enamel.
Despair and hopelessness in the context of HIV – a meta‐synthesis on qualitative research findings
Authors: Kylmä Jari
Published: June 2005

Aim. The aim of the study was to explore the concepts of despair and hopelessness in the context of human immunodeficiency virus based on previous studies.

Background. Some of the consequences of living with human immunodeficiency virus or as a significant other to a person with human immunodeficiency virus include despair and hopelessness.

Methods. The study is based on five earlier studies describing the dynamics of hope (including despair and hopelessness) in adult persons living with human immunodeficiency virus.

Results. Despair consists of two sub‐processes. The downward sub‐process of despair refers to stopping and being stuck in a situation, losing grip and sinking into a narrowing existence, focusing on impossibility and losing perspective of the future. Furthermore, the downward orientation means questioning the possibility of hope. The upward sub‐process of despair implies fighting against sinking and fighting to rise back up with a glimmer of hope. Hopelessness is the polar opposite of hope and includes sub‐processes of helplessly giving up everything (including hope) and living in emptiness in the face of an assumed non‐existing future, collapsing mentally, and becoming paralyzed without reason to live.

Conclusions. The results of this study support the findings of previous studies revealing that despair and hopelessness are possible elements in the life situation of persons living with human immunodeficiency virus and significant others to persons living with human immunodeficiency virus. The results of this study help to define the contents of despair and hopelessness, and help us to distinguish one from the other. The dual‐dimensionality of despair has not been pointed out in previous studies and in this way the present study offers new information about the phenomenon of despair.

Relevance to clinical practice. The findings of this study offer clinical guidelines on a conceptual level about how to detect these phenomena in persons living with human immunodeficiency virus and their significant others. Furthermore, the findings offer a starting point for interventions used to alleviate despair and hopelessness. Suggestions for suitable interventions are offered. The results of this study underline the clinical relevance of these phenomena in adding new information to the previously documented consequences of despair and hopelessness.
An assessment of intellectual disability among Aboriginal Australians
Authors: Glasson E. J. , Sullivan S. G. , Hussain R. , Bittles A. H.
Published: June 2005

Background The health and well‐being of Indigenous people is a significant global problem, and Aboriginal Australians suffer from a considerably higher burden of disease and lower life expectancy than the non‐Indigenous population. Intellectual disability (ID) can further compromise health, but there is little information that documents the prevalence of ID among indigenous populations. This study provides information on ID among the Aboriginal population of Western Australia.

Methods The Disability Services Commission (DSC) of Western Australia has maintained a statewide database of people with ID since 1953. Data on people of Aboriginal descent were extracted from the DSC database and linked to two other state‐based databases, the Hospital Morbidity Data System and the Deaths Registry, with additional linkage to the National Death Index. The linked data were used to assess the prevalence, survival patterns and causes of death in Aboriginal people with ID.

Results Although comprising 3.5% of the population, Aboriginal Australians represented 7.4% of all people registered for ID services. The level of ID was assessed as borderline or mild in 40.7% of cases, moderate in 19.9%, severe or profound in 12.1%, but had not been specified in 27.2% cases. Median survival was 55.1 years for men and 64.0 years for women, with a mean age at death (n = 102) of 19.6 years. The leading causes of death were respiratory diseases, diseases of the circulatory system, and accidents.

Conclusions The study presents unique population summary data for ID in the Aboriginal community of Western Australia. To provide appropriate prevention and intervention strategies, there is an urgent need for more detailed information on the prevalence and patterns of ID.
Determinants of early mortality and benefits of lamivudine therapy in patients with hepatitis B virus‐related decompensated liver cirrhosis
Authors: Tseng Po‐lin , Lu Sheng‐Nan , Tung Hung‐Da , Wang Jing‐Houng , Changchien Chi‐Sin , Lee Chuan‐Mo
Published: June 2005

Summary  Chronic hepatitis B infection (HBV) is a major health problem worldwide. The prognosis is grave for patients with HBV‐related decompensated liver cirrhosis (LC). We evaluated the effectiveness and the determinants of early mortality of lamivudine treatment in patients with HBV‐related decompensated LC. Thirty patients with HBV‐related decompensated LC and active viral replication were treated with lamivudine 100 mg daily for a median duration of 9 months. Among these patients, five patients died within 3 months. Two patients were lost to follow‐up at week 8 and 9. One patient was treated for <6 months. Twenty‐two patients were treated over 6 months. Univariate analysis revealed that the total bilirubin (P = 0.008), prothrombin time (P = 0.004), Child–Turcotte–Pugh score (P = 0.005), the model of efd‐stage liver disease score (P = 0.004) and stage III hepatic encephalopathy (P = 0.001) were predictive factors of early mortality. Multivariate analysis revealed that the independent factor associated with early mortality was stage III encephalopathy. Among 22 patients, liver function improved markedly after lamivudine therapy. Of the nine hepatitis B e antigen (HBeAg)‐positive patients, three had HBeAg seroconversion. Two patients had YMDD mutant and virological breakthrough at 41 and 46 weeks. One of the two had hepatocellular carcinoma and died of hepatic failure at week 125; the other received adefovir and is doing well. Lamivudine appeared to have benefits in viral suppression and significant improvement in liver function in patients with HBV‐related decompensated LC. As noted in prior studies, poor baseline liver function is associated with a poor prognosis in Asian patients with decompensated HBV cirrhosis treated with lamivudine.
Differentially expressed cellular genes following HBV: potential targets of anti‐HBV drugs?
Authors: Yang J. , Bo X. C. , Yao J. , Yang N. M. , Wang S. Q.
Published: June 2005

Summary.  The aim of the study was to screen for cellular genes that are differentially expressed following hepatitis B virus (HBV) infection, in an attempt to identify potential targets of anti‐HBV drugs. An oligonucleotide microarray containing 231 virus‐infection‐associated genes was prepared. Differential gene expression in HepG2.2.15 cells compared to control with HepG2 cells was analysed by this in‐house microarray. The change in gene expression in HepG2.2.15 cells treated by lamivudine on days 4 and 8 after exposure was also studied. Semi‐quantitative reverse transcriptase‐polymerase chain reaction (RT‐PCR) was used to comfirm the differentially expressed genes induced by HBV and lamivudine. There were 31 upregulated and four downregulated genes in HepG2.2.15 cells compared with the HepG2 control cells. Eleven genes were consistently altered by lamivudine at both time points. Of the 31 genes that were upregulated in HepG2.2.15 cells, there were seven genes which were downregulated by lamivudine. Of the four downregulated genes, there was one gene which was upregulated by lamivudine. Of the differentially expressed genes induced by HBV and lamivudine, the expression of five genes was confirmed by semi‐quantitative RT‐PCR. These results shed new light on the effects of HBV and lamivudine on cellular gene expression. Differentially expressed genes induced by HBV and lamivudine could potentially become new anti‐HBV drug targets in novel therapies.
Response to long‐term lamivudine treatment (up to 5 years) in patients with severe chronic hepatitis B, role of genotype and drug resistance
Authors: Moskovitz D. N. , Osiowy C. , Giles E. , Tomlinson G. , Heathcote E. J.
Published: June 2005

Summary.  Lamivudine is effective in suppressing viral replication, normalizing alanine aminotransferase (ALT), and improving histological appearance in HBe positive and negative hepatitis. It is unclear whether hepatitis B virus (HBV) genotype influences the response to lamivudine. We report the long‐term response of patients with chronic hepatitis B with and without cirrhosis at baseline treated with lamivudine according to HBV genotype. Retrospective review of charts of all patients treated with lamivudine monotherapy between 1993 and 2002. Response to therapy defined as ALT in the normal range, undetectable HBV DNA, and in the HBeAg positive group loss of HBeAg and/or the development of anti‐HBe. HBV DNA measured by the Digene Hybrid capture assay (sensitivity 1.4 × 106 copies/mL). YMDD mutation at rtL180M and rtM204V/I measured by restriction digest of amplified products. Genotyping performed by sequencing and phylogenetic tree analysis of the preS region of the virus genome. Seventy‐one patients treated with lamivudine for 6 months or more, 53 (75%) were male, average age 47 years, 38 (54%) were HBeAg+ and 33 (46%) HBeAg−. Mean baseline HBV DNA viral titre was 1280.2 copies/mL and 518 copies/mL respectively. Cirrhosis was present in 30 (42%). Sera were examined for YMDD mutations at last patient visit in 61 (86%), and were detected in 45 (74%), there being no association with a particular genotype. Data from up to 5 years on lamivudine indicated no difference in biochemical or virological response between genotypes. Cirrhosis was more prevalent with specific genotypes. We found no influence of HBV genotype on the development of resistance to lamivudine, however liver disease severity was influenced by genotype.
Liver enzymes elevation after HAART in HIV‐HCV co‐infection
Authors: Servin‐Abad L. , Molina E. , Baracco G. , Arosemena L. , Regev A. , Jeffers L. , Schiff E.
Published: June 2005

Summary.  Hepatitis C virus (HCV) co‐infection is common among human immunodeficiency virus (HIV) patients. The incidence and risk factors associated with hepatotoxicity in this population after high active antiretroviral therapy (HAART) is initiated are still not well‐understood. We argued to evaluate the incidence and risk factors associated with liver enzyme elevation (LEE) and their clinical significance. A retrospective chart review of patients who started HAART and had follow up at our centre for at least 1 year was undertaken. The frequency and severity of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation after treatment initiation were investigated and searched for clinical manifestations.

Between January 1996 and March 2002, 85 HIV‐HCV co‐infected patients began HAART and continued follow up for at least 1 year. The incidence of severe toxicity [grades 3 + 4 LEE: >5 and >10 times the upper limit of normal (ULN) of ALT or AST] was calculated at 4% per person‐years. There were no clinical manifestations of liver toxicity, and patients continued their treatment with a trend towards a decrease of their enzymes. No statistical differences in opportunistic infections or mortality were evident. The variables associated with severe hepatotoxicity were a higher baseline AST, higher international normalized ratio (INR) and lower albumin. A baseline AST < 2.1 ULN had a negative predictive value of 92% of leading to severe hepatotoxicity.

In HIV‐HCV co‐infected patients therefore, the group at a higher risk of developing higher transaminase elevations is the one with a higher baseline AST, higher INR and lower albumin.
Protein dynamics of bovine dentin phosphophoryn
Authors: Cross K.J. , Huq N.L. , Reynolds E.C.
Published: June 2005

Abstract:  Bovine dentin phosphophoryn (BDP), a protein rich in aspartyl (Asp) and o‐phosphoseryl [Ser(P)] residues, is synthesized by odontoblasts and believed to be involved in matrix‐mediated biomineralization of dentin. The elucidation of the structure–function relationship of phosphophoryn has been a challenge because of its high‐molecular weight, high negative charge, repetitive sequence, and lability. We have used the dynamic behavior of the 1H NMR signal at 600 MHz to provide insight into the molecular dynamics of phosphophoryn. Our results indicate that phosphophoryn is a molecule of uniformly high mobility, thus belonging to a recently identified class of intrinsically disordered proteins that are characterized by sequences of low complexity and rich in polar and charged residues. The significance of our results is that phosphophoryn, because of its uniform nature has the potential to be replaced by biomimetic synthetic peptide analogs that together with amorphous calcium phosphate may lead to the development of novel, nontoxic, apatite‐based dental restorative materials.
Furanoid sugar amino acids as dipeptide mimics in design of analogs of vasoactive intestinal peptide receptor binding inhibitor
Authors: Prasad S. , Mathur A. , Jaggi M. , Sharma R. , Gupta N. , Reddy V. R. , Sudhakar G. , Kumar S.U. , Kumar S.K. , Kunwar A. C , Chakraborty T. K.
Published: June 2005

Abstract:  In this study we describe the development of peptidomimetic analogs of the potent vasoactive intestinal peptide receptor binding inhibitor, Leu1 ‐Met2 ‐Tyr3 ‐Pro4 ‐Thr5 ‐Tyr6 ‐Leu7 ‐Lys8 ‐OH 1, by incorporating furanoid sugar amino acids (SAAs) 2‐4 into the molecule. The furanoid SAAs 2‐4 were used as dipeptide isosteres to replace Tyr3 ‐Pro4 or Pro4 ‐Thr5 in sequence 1. The resulting analogs 5‐9 were tested for their anti‐cancer activities in vitro, following the standard MTT assay on a panel of human cancer cell lines. One of the potent analogs, 6a was tested in vivo for tumor regression on primary colon tumor xenografted nude mice. Our experimental results suggest that many of these analogs show either retention or enhancement of biological activity.
Histochemical and Electron Microscopic Study on Motor Neurone Degeneration Following Transient Spinal Cord Ischaemia at Normothermic Conditions in Rabbits
Authors: Lee J.‐C. , Hwang I. K. , Park S.‐K. , Yoo K.‐Y. , Seo K. , Kang T.‐C. , Oh Y. S. , Won M. H.
Published: June 2005

This study was carried out to investigate the motor neurone degeneration in the ventral horn following transient spinal cord ischaemia at normothermic conditions in rabbits. Transient spinal cord ischaemia was induced by occlusion of the abdominal aorta underneath the left renal artery for 15 min at normothermia (38.7°C). Sections at the level of L7 were examined using histochemical and electron microscopic methods. Cresyl violet‐positive motor neurones began to reduce in number at 3 h after ischaemia reperfusion, and were not detectable at 48 h after ischaemia reperfusion. Acid fuchsin‐positive motor neurones were detected at 1 h after ischaemia reperfusion, significantly increased up to 6 h after the ischaemia reperfusion, and eventually disappeared by 48 h after ischaemia reperfusion. In electron microscopic findings, the disintegration of cytoplasmic membranes, and the disruption of mitochondria and endoplasmic reticulum were observed in motor neurones at 30 min after ischaemia reperfusion. Motor neurones showed necrotic findings with pyknotic degeneration at 1 h after ischaemia reperfusion. The necrotic degeneration became severer time dependently after ischaemia reperfusion. At 48 h after ischaemia reperfusion, cellular components were not detectable in motor neurones. In conclusion, we suggest that the degeneration pattern of motor neurones of the ischaemic spinal cord was necrotic after ischaemia reperfusion under normothermic conditions.
UNITED KINGDOM: CARING DIFFERENTLY: INTERMEDIATE CARE ‐ AN ALTERNATIVE APPROACH TO SERVICE PROVISION IN RESPONSE TO CLIENT NEED AND WORKFORCE CHANGES IN THE NHS
Authors: Vaughan Barbara
Published: June 2005

Introduction

The King's Fund is an independant organisation whose prime function is to support development of health and social services. The following paper outlines one aspect of its work which is concerned with the introduction of so called ‘intermediate care’ services for people who need help during the transition between medical dependance and personal independance, but who do not require the specialist medical expertise provided in an acute hospital setting. It is argued that currently there are few services specifically designed to meet this group of patients needs and a ‘black hole’ exists in service provision. The purpose of such a service is to provide intensive therapy in order to maximise their ability to live independently, improve the quality of their lives, and provide the opportunity for them to learn greater self‐care skills in order that they can manage their own health more effectively in the longer term.
Niche properties and geographical extent as predictors of species sensitivity to climate change
Authors: Thuiller Wilfried , Lavorel Sandra , Araújo Miguel B.
Published: June 2005

Aim  Bioclimatic envelope models are often used to make projections of species’ potential responses to climate change. It can be hypothesized that species with different kinds of distributions in environmental niche and geographical space may respond differently to changes in climate. Here, we compare projections of shifts in species ranges with simple descriptors of species niche (position and breadth) and geographical (range size) distributions.

Location  Europe.

Methods  The future distribution for 1200 European plant species were predicted by niche‐based models using seven climate variables known to have an important role in limiting plant species distributions. Ecological niche properties were estimated using a multivariate analysis. Species range changes were then related to species niche properties using generalized linear models.

Results  Generally, percentage of remaining suitable habitat in the future increased linearly with niche position and breadth. Increases in potential suitable habitat were associated with greater range size, and had a hump‐shaped relationship with niche position on temperature gradient. By relating species chorotypes to percentage of remaining or gained habitat, we highlighted biogeographical patterns of species sensitivity to climate change. These were clearly related to the degree of exposure according to regional patterns of projected climate change.

Main conclusion  This study highlights general patterns about the relationships between sensitivity of species to climate change and their ecological properties. There is a strong convergence between simple inferences based on ecological characteristics of species and projections by bioclimatic ‘envelope’ models, confirming macroecological assumptions about species sensitivity based on niche properties. These patterns appear to be most strongly driven by the exposure of species to climate change, with additional effects of species niche characteristics. We conclude that simple species niche properties are powerful indicators of species’ sensitivity to climate change.
The interspecific range size–body size relationship in Australian frogs
Authors: Murray Brad R. , Hose Grant C.
Published: June 2005

Aim There is substantial residual scatter about the positive range size–body size relationship in Australian frogs. We test whether species’ life history and abundance can account for this residual scatter.

Location Australia.

Methods Multiple regressions were performed using both cross‐species and independent contrasts analyses to determine whether clutch size, egg size and species abundance account for variation in range size over and above the effects of body size.

Results In both cross‐species and independents contrasts models with body size, clutch size and egg size as predictors, partialr2values revealed that only egg size was significantly and uniquely related to range size. Contrary to expectation, neither body size nor clutch size could account for significant variation in range size. Incorporating species abundance as a predictor in further multiple regression analysis demonstrated that while abundance accounted for a significant proportion of range size variation, the contribution of egg size was reduced but still significant. Notably, non‐significant relationships persisted between range size and both body size and clutch size.

Conclusions The weak positive correlation between body size and range size in Australian frogs disappears after accounting for species abundance and egg size. Our findings demonstrate that species with both high local abundance and small eggs occupy comparatively wider geographical ranges than species with low abundance and large eggs.
Amyloid beta peptide 1–40 enhances the action of Toll‐like receptor‐2 and ‐4 agonists but antagonizes Toll‐like receptor‐9‐induced inflammation in primary mouse microglial cell cultures
Authors: Lotz Miriam , Ebert Sandra , Esselmann Hermann , Iliev Asparouh I. , Prinz Marco , Wiazewicz Nicole , Wiltfang Jens , Gerber Joachim , Nau Roland
Published: June 2005

The interaction of endogenous and exogenous stimulators of innate immunity was examined in primary cultures of mouse microglial cells and macrophages after application of defined Toll‐like receptor (TLR) agonists [lipopolysaccharide (LPS) (TLR4), the synthetic lipopeptide Pam3Cys‐Ser‐Lys4 (Pam3Cys) (TLR2) and single‐stranded unmethylated CpG‐DNA (CpG) (TLR9)] alone and in combination with amyloid beta peptide (Abeta) 1–40. Abeta 1–40 stimulated microglial cells and macrophages primed by interferon‐γ in a dose‐dependent manner. Co‐administration of Abeta1–40 with LPS or Pam3Cys led to an additive release of nitric oxide (NO) and tumour necrosis factor alpha (TNF‐α). This may be one reason for the clinical deterioration frequently observed in patients with Alzheimer's disease during infections. In contrast, co‐application of Abeta1–40 with CpG led to a substantial decrease of NO and TNF‐ α release compared with stimulation with CpG alone. Abeta 1–40 and CpG did not co‐localize within the same subcellular compartment, making a direct physicochemical interaction as the cause of the observed antagonism very unlikely. This suggests that not all TLR agonists enhance the stimulatory effect of Abeta on innate immunity.
NADPH oxidase is required for NMDA receptor‐dependent activation of ERK in hippocampal area CA1
Authors: Kishida Kenneth T. , Pao Maryland , Holland Steven M. , Klann Eric
Published: June 2005

Previous studies have shown that N‐methyl‐d‐aspartate (NMDA) receptor activation results in production of reactive oxygen species (ROS) and activation of extracellular signal‐regulated kinase (ERK) in hippocampal area CA1. In addition, application of ROS to hippocampal slices has been shown to result in activation of ERK in area CA1. To determine whether these events were linked causally, we investigated whether ROS are required for NMDA receptor‐dependent activation of ERK. In agreement with previous studies, we found that treatment of hippocampal slices with NMDA resulted in activation of ERK in area CA1. The NMDA receptor‐dependent activation of ERK was either blocked or attenuated by a number of antioxidants, including the general antioxidant N‐acetyl‐l‐cysteine (L‐NAC), the superoxide‐scavenging enzyme superoxide dismutase (SOD), the membrane‐permeable SOD mimetic Mn(III) tetrakis (4‐benzoic acid) porphyrin (MnTBAP), the hydrogen peroxide‐scavenging enzyme catalase, and the catalase mimetic ebselen. The NMDA receptor‐dependent activation of ERK also was blocked by the NADPH oxidase inhibitor diphenylene iodonium (DPI) and was absent in mice that lacked p47phox, one of the required protein components of NADPH oxidase. Taken together, our results suggest that ROS production, especially superoxide production via NADPH oxidase, is required for NMDA receptor‐dependent activation of ERK in hippocampal area CA1.
Histone methylation at gene promoters is associated with developmental regulation and region‐specific expression of ionotropic and metabotropic glutamate receptors in human brain
Authors: Stadler Florian , Kolb Gabriele , Rubusch Lothar , Baker Stephen P. , Jones Edward G. , Akbarian Schahram
Published: June 2005

Glutamatergic signaling is regulated, in part, through differential expression of NMDA and AMPA/KA channel subunits and G protein‐coupled metabotropic receptors. In human brain, region‐specific expression patterns of glutamate receptor genes are maintained over the course of decades, suggesting a role for molecular mechanisms involved in long‐term regulation of transcription, including methylation of lysine residues at histone N‐terminal tails. Using a native chromatin immunoprecipitation assay, we studied histone methylation marks at proximal promoters of 16 ionotropic and metabotropic glutamate receptor genes (GRIN1,2A–D; GRIA1,3,4; GRIK2,4,5; GRM1,3,4,6,7 ) in cerebellar cortex collected across a wide age range from midgestation to 90 years old. Levels of di‐ and trimethylated histone H3‐lysine 4, which are associated with open chromatin and transcription, showed significant differences between promoters and a robust correlation with corresponding mRNA levels in immature and mature cerebellar cortex. In contrast, levels of trimethylated H3‐lysine 27 and H4‐lysine 20, two histone modifications defining silenced or condensed chromatin, did not correlate with transcription but were up‐regulated overall in adult cerebellum. Furthermore, differential gene expression patterns in prefrontal and cerebellar cortex were reflected by similar differences in H3‐lysine 4 methylation at promoters. Together, these findings suggest that histone lysine methylation at gene promoters is involved in developmental regulation and maintenance of region‐specific expression patterns of ionotropic and metabotropic glutamate receptors. The association of a specific epigenetic mark, H3‐(methyl)‐lysine 4, with the molecular architecture of glutamatergic signaling in human brain has potential implications for schizophrenia and other disorders with altered glutamate receptor function.
Cellular localization and subcellular distribution of Unc‐33‐like protein 6, a brain‐specific protein of the collapsin response mediator protein family that interacts with the neuronal glycine transporter 2
Authors: Horiuchi Masahisa , Loebrich Sven , Brandstaetter Johann Helmut , Kneussel Matthias , Betz Heinrich
Published: June 2005

Unc‐33‐like protein (Ulip)6, a brain‐specific phosphoprotein of the Ulip/collapsin response mediator protein family, was originally identified in our laboratory by yeast two‐hybrid screening using the cytoplasmic N‐terminal domain of the neuronal glycine transporter, glycine transporter (GlyT) 2, as a bait. Here, the interaction of Ulip6 with the N‐terminal domain of GlyT2 was found to be specific for this member of the Ulip/collapsin response mediator protein family and to involve amino acids 135–184 of GlyT2. In pull‐down assays and coimmunoprecipitation experiments with rat spinal cord extract, the presence of phosphatase inhibitors significantly enhanced binding of Ulip6 to GlyT2. Subcellular fractionation of spinal cord and retina homogenates at different developmental stages showed Ulip6 immunoreactivity to be associated with light vesicles that were distinct from GlyT2‐containing and synaptic vesicles. Immunocytochemistry revealed punctate Ulip6 immunoreactivity in both somatic regions and processes of cultured spinal neurones; no colocalization with GlyT2 or other synaptic marker proteins was found. In retina, which expresses only GlyT1 but not GlyT2, Ulip6 was detected in the inner plexiform layer and along the somata and processes of selected bipolar, amacrine and ganglion cells. Our data support a model in which Ulip6 transiently interacts with GlyT2 in a phosphorylation‐dependent manner.
AMPA receptor stimulation increases α5β1 integrin surface expression, adhesive function and signaling
Authors: Lin Ching‐Yi , Lynch Gary , Gall Christine M.
Published: June 2005

Integrin proteins are critical for stabilization of hippocampal long‐term potentiation but the mechanisms by which integrin activities are involved in synaptic transmission are not known. The present study tested whether activation of α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐proprionate (AMPA) class glutamate receptors increases surface expression of α5β1 integrin implicated in synaptic potentiation. Surface protein biotinylation assays demonstrated that AMPA treatment of COS7 cells expressing GluR1 homomeric AMPA receptors increased membrane insertion and steady‐state surface levels of α5 and β1 subunits. Treated cells exhibited increased adhesion to fibronectin‐ and anti‐α5‐coated substrates and tyrosine kinase signaling elicited by fibronectin‐substrate adhesion, as expected if new surface receptors are functional. Increased surface expression did not occur in calcium‐free medium and was blocked by the protein kinase C inhibitor chelerythrine chloride and the exocytosis inhibitor brefeldin A. AMPA treatment similarly increased α5 and β1 surface expression in dissociated neurons and cultured hippocampal slices. In both neuronal preparations AMPA‐induced integrin trafficking was blocked by combined antagonism of NMDA receptor and L‐type voltage‐sensitive calcium channel activities but was not induced by NMDA treatment alone. These results provide the first evidence that glutamate receptor activation increases integrin surface expression and function, and suggest a novel mechanism by which synaptic activity can engage a volley of new integrin signaling in coordination with, and probably involved in, stabilization of synaptic potentiation.
Retrovirally transduced NCAM140 facilitates neuronal fate choice of hippocampal progenitor cells
Authors: Kim Ju Hee , Lee Jung‐Ha , Park Jin‐Yong , Park Chang‐Hwan , Yun Chae‐Ok , Lee Sang‐Hun , Lee Yong‐Sung , Son Hyeon
Published: June 2005

Neural cell adhesion molecule (NCAM) influences proliferation and differentiation of neuronal cells. However, only a little is known about the downstream effects of NCAM signalling, such as alterations in gene transcription, which are associated with cell fate choice. To examine whether NCAM plays a role in cell fate choice during hippocampal neurogenesis, we performed a gain‐of‐function study, using a retroviral vector which contained full‐length NCAM140 cDNA and the marker gene EGFP, and found that NCAM140 promoted neurogenesis by activating proneural transcription activators with concurrent inhibition of gliogenesis. The enhanced transcript levels of proneural transcription factors in NCAM140‐transduced cells were down‐regulated by treatment of the cells with mitogen‐activated protein kinase kinase (MEK) inhibitor PD098059. Overall, these findings suggest that NCAM140 may facilitate hippocampal neurogenesis via regulation of proneurogenic transcription factors in an extracellular signal‐regulated kinase (ERK)‐dependent manner.
Proteomic identification of differentially expressed proteins in the aging murine olfactory system and transcriptional analysis of the associated genes
Authors: Poon H. Fai , Vaishnav Radhika A. , Butterfield D. Allan , Getchell Marilyn L. , Getchell Thomas V.
Published: June 2005

Decline in olfactory ability has been associated with aging as well as neurodegenerative disorders. The aim of this study was to gain fundamental insight into molecular events associated with the aging olfactory system. We report a comparative proteomic analysis of the olfactory epithelium (OE) and olfactory bulb (OB) of old (80‐week old) and young (6‐week old) mice with further analysis of age‐related differences in differentially expressed proteins at the mRNA level using real‐time RT–PCR. Nine proteins in the OE and 20 in the OB were differentially expressed in old and young mice; of these, aldolase 1, peptidyl prolyl isomerase A, mitochondrial aconitase 2, mitochondrial aldehyde dehydrogenase 2 and albumin 1 were identified in the OE; and ATP synthase isoform 1, enolase 1, ferritin heavy chain, malate dehydrogenase 1, tropomyosin alpha 3 chain and dynamin 1 were identified in the OB. At the transcriptional level, aconitase 2 in the OE and ferritin heavy chain 1 in the OB were differentially expressed with aging, in concordance with the proteomic data. Our results demonstrate an altered proteomic profile of the aged murine olfactory system. The identified proteins fall into three broadly defined functional categories: (i) metabolism, (ii) transport/motility and (iii) stress response. Our transcriptional analysis provides insight into possible mechanisms by which protein expression may be regulated in the OE and OB. The results are discussed in relation to the decrement in olfactory sensitivity with aging.
Reversal of non‐hydroxy : α‐hydroxy galactosylceramide ratio and unstable myelin in transgenic mice overexpressing UDP‐galactose : ceramide galactosyltransferase
Authors: Fewou Simon N. , Büssow Heinrich , Schaeren‐Wiemers Nicole , Vanier Marie T. , Macklin Wendy B. , Gieselmann Volkmar , Eckhardt Matthias
Published: June 2005

The sphingolipids galactosylceramide and sulfatide are important for the formation and maintenance of myelin. Transgenic mice overexpressing the galactosylceramide synthesizing enzyme UDP‐galactose : ceramide galactosyltransferase in oligodendrocytes display an up to four‐fold increase in UDP‐galactose : ceramide galactosyltransferase activity, which correlates with an increase in its products monogalactosyl diglyceride and non‐hydroxy fatty acid‐containing galactosylceramide. Surprisingly, however, we observed a concomitant decrease in α‐hydroxylated galactosylceramide such that total galactosylceramide in transgenic mice was almost unaltered. These data suggest that UDP‐galactose : ceramide galactosyltransferase activity does not limit total galactosylceramide level. Furthermore, the predominance of α‐hydroxylated galactosylceramide appeared to be determined by the extent to which non‐hydroxylated ceramide was galactosylated rather than by the higher affinity of UDP‐galactose : ceramide galactosyltransferase for α‐hydroxy fatty acid ceramide. The protein composition of myelin was unchanged with the exception of significant up‐regulation of the myelin and lymphocyte protein. Transgenic mice were able to form myelin, which, however, was apparently unstable and uncompacted. These mice developed a progressive hindlimb paralysis and demyelination in the CNS, demonstrating that tight control of UDP‐galactose : ceramide galactosyltransferase expression is essential for myelin maintenance.
Blockade of interleukin‐6 signaling aggravates ischemic cerebral damage in mice: possible involvement of Stat3 activation in the protection of neurons
Authors: Yamashita Toru , Sawamoto Kazunobu , Suzuki Shigeaki , Suzuki Norihiro , Adachi Kazuhide , Kawase Takeshi , Mihara Masahiko , Ohsugi Yoshiyuki , Abe Koji , Okano Hideyuki
Published: June 2005

Interleukin (IL)‐6 expression transiently increases in the acute phase of cerebral ischemia. To investigate the physiological significance of endogenous IL‐6 expression and to identify the main signal pathway for the action of IL‐6, we administered anti‐mouse IL‐6 receptor monoclonal antibody (IL‐6RA), which blocks IL‐6 signaling, to mice immediately after a 45‐min period of middle cerebral artery occlusion (MCAO). At 6 h after MCAO, IL‐6RA administration had resulted in a significant reduction in the amount of phosphorylated signal transducer and activator of transcription‐3 (Stat3) protein in the peri‐infarct area of the cortex. At 24 h after MCAO, blockade of IL‐6 signaling had led to an increase in number of apoptotic cells in the peri‐infarct area and enlargement of the size of the infarct, and it had adversely affected neurological function. These results suggest that endogenous IL‐6 plays a critical role in preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischemia and that its role may be mediated by Stat3 activation.
Down‐regulation of Dickkopf 3, a regulator of the Wnt signalling pathway, in elderly schizophrenic subjects
Authors: Ftouh Saoussen , Akbar Mohammed T. , Hirsch Steven R. , De Belleroche Jacqueline S.
Published: June 2005

The aetiology of schizophrenia is complex and the pathological mechanisms involved are still not fully understood. The aim of this project was to gain insight into the underlying molecular changes occurring in schizophrenia through the analysis of gene expression. Using suppression subtractive hybridization to isolate differentially expressed genes in superior temporal cortex (BA22), we detected one prominent sequence with reduced expression in schizophrenia and represented in at least nine clones. This was then selected for further validation. This 190‐bp partial transcript showed identity to part of the Dickkopf‐3 (Dkk3) gene sequence. Differential expression was initially confirmed in BA22 by slot blot hybridization where expression was decreased by 35% (p < 0.026). These results were further authenticated in a larger panel (12 control and 11 schizophrenia cases) using SYBR Green I real‐time quantitative RT–PCR, in which a 41% decrease in expression of Dkk3 mRNA in schizophrenia was obtained (p < 0.012). Furthermore, using in situ hybridization, Dkk3 mRNA was shown to be abundantly expressed in cortical neurones, with prominent expression in layers II/III and V/VI of BA22. Dkk3 belongs to a novel family of Dkk proteins, which have been shown to be potent inhibitors of the neurodevelopmental wingless (Wnt) signalling pathway, and is therefore a putative candidate for further investigation into the aetiology of schizophrenia.
The mechanism of SR95531 inhibition at GABAA receptors examined in human α1β1 and α1β1γ2S receptors
Authors: Lindquist Catarina E. L. , Laver Derek R. , Birnir Bryndis
Published: June 2005

We examined the interaction of GABA and the competitive inhibitor SR95531 at human α1β1γ2S and α1β1 GABAA receptors expressed in Sf9 cells. The efficacy and potency of inhibition depended on the relative timing of the GABA and SR95531 applications. In saturating (10 mm) GABA, the half‐inhibitory concentrations of SR95531 (IC50) when coapplied with GABA to α1β1γ2S or α1β1 receptors were 49 and 210 µm for the peak and 18 and 130 µm for the plateau current, respectively. Our data are explained by an inhibition mechanism in which SR95531 and GABA bind to two sites on the receptor where the binding of GABA allows channel opening but SR95531 does not. The SR95531 affinity for both receptor types was ∼200 nm and the binding rate was found to be 10‐fold faster than that for GABA. The dual binding‐site model gives insights into the differential effects of GABA and SR95531 on the peak and plateau currents. The model predicts the effect of SR95531 on GABA currents in the synapse (GABA concentration ∼ mm) and at extrasynaptic (GABA concentration ≤ µm) sites. The IC50 (50–100 nm) for the synaptic response to SR95531 was insensitive to the GABA affinity of the receptors whereas the IC50 (50–800 nm) for extrasynaptic inhibition correlated with the GABA affinity.
Two distinct regulatory mechanisms of neurotransmitter release by phosphatidylinositol 3‐kinase
Authors: Itakura Makoto , Yamamori Saori , Kuwahara Reiko , Sekiguchi Mariko , Takahashi Masami
Published: June 2005

Recent studies have indicated that various growth factors are involved in synaptic functions; however, the precise mechanisms remain unclear. In order to elucidate the molecular mechanisms of the growth factor‐mediated regulation of presynaptic functions, the effects of epidermal growth factor (EGF) and insulin‐like growth factor‐1 (IGF‐1) on neurotransmitter release were studied in rat PC12 cells. Brief treatment with EGF and IGF‐1 enhanced Ca2+‐dependent dopamine release in a concentration‐dependent manner. EGF activated both mitogen‐activated protein kinase (MAPK) and phosphatidylinositol 3‐kinase (PI3‐kinase) pathways, and the EGF‐dependent enhancement of DA release was suppressed by a MAPK kinase inhibitor as well as by PI3‐kinase inhibitors. In striking contrast, IGF‐1 activated the PI3‐kinase pathway but not the MAPK pathway, and IGF‐1‐dependent enhancement was suppressed by a PI3‐kinase inhibitor but not by a MAPK kinase inhibitor. The enhanced green fluorescent protein‐tagged pleckstrin homology (PH) domain of protein kinase B, which selectively binds to phosphatidylinositol 3,4‐bisphosphate and phosphatidylinositol 3,4,5‐triphosphate, was translocated to the plasma membrane after treatment with either EGF or NGF. By contrast, no significant redistribution was induced by IGF‐1. These results indicate that PI3‐kinase participates in the enhancement of neurotransmitter release by two distinct mechanisms: EGF and NGF activate PI3‐kinase in the plasma membrane, whereas IGF‐1 activates PI3‐kinase possibly in the intracellular membrane, leading to enhancement of neurotransmitter release in a MAPK‐dependent and ‐independent manner respectively.
Nightingales Luscinia megarhynchos in scrub habitats in the southern fens of East Anglia, England: associations with soil type and vegetation structure
Authors: WILSON A. M. , FULLER R. J. , DAY C. , SMITH G.
Published: June 2005

The southeast corner of the East Anglian Fens supports a large concentration of Nightingale Luscinia megarhynchos territories. A total of 382 territories were located in extensive surveys in 1999 and 2000, probably representing over 5% of the English population. Transect counts revealed that the Fenland population is restricted in distribution and is associated with localized thickets of scrub. The highest densities are found on humus‐rich soils, suggesting that soil type, in addition to habitat availability, may have a strong influence on the Nightingale's distribution in this region. This paper provides the first assessment of habitat requirements of the Nightingale in scrub, which now forms a principal habitat for the species in England. Detailed studies of the attributes of over 100 Nightingale territories revealed subtle differences in the vegetation structure of these thickets when compared with paired, unoccupied, but apparently similar thickets. The Nightingale territories tended to have a higher proportion of bare ground or short vegetation in the field layer under the canopy, whereas paired sites were more likely to have low field layer vegetation beneath the canopy. The bare ground within the thickets is a feature of shading beneath very dense foliage cover. Within Nightingale territories, low field layer volume and shrub twig volume at the thicket edges was higher than in unoccupied thickets. The differences detected in vegetation structure suggest that a dense and continuous canopy forming a shell over bare ground but with dense low foliage at thicket edges provides the ideal vegetation structure for Nightingales in scrub habitats. Our study suggests that Nightingales occupy scrub of a very specific structure, and specific stage in vegetation succession. This structure probably provides an optimal combination of foraging habitat, microclimate and cover from predators. It is suggested that humus‐rich soils may be preferred because they may support a particularly rich source of invertebrate food, but this remains to be tested empirically.