bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular evolution and genetics of the Saitohin gene and tau haplotype in Alzheimer's disease and argyrophilic grain disease
Authors: Conrad Chris , Vianna Cintia , Schultz Christian , Thal Dietmar R. , Ghebremedhin Estifanos , Lenz Jack , Braak Heiko , Davies Peter 
Published: May 2006

AbstractA single nucleotide polymorphism that results in an amino acid change (Q7R) has been identified in the Saitohin (STH) gene and was initially found to be over‐represented in the homozygous state in subjects with late‐onset Alzheimer's disease (AD). More extensive studies provide limited support for the association with AD, but confirm an association of the Q allele with progressive supranuclear palsy and argyrophilic grain disease. A homologous sequence was found in the appropriate location of the rat and mouse tau genes, but there was no open reading frame allowing STH expression in these species, suggesting relatively recent evolution of this gene. In some non‐human primates, the STH gene was identified, and this was found to differ from the human gene at two of 128 amino acids. All primates in which the STH gene was identified were homozygous for the R allele of STH, suggesting this is the ancestral allele. This observation was surprising, in that the Q allele is more common in human populations, and raises the possibility that natural selection has operated to favor individuals carrying this allele. The STH polymorphism is part of the tau gene haplotype, of which two major variants exist in human populations, the Q being part of the H1 haplotype and the R part of the H2 haplotype. More detailed studies confirm the H2 haplotype to be the ancestral tau gene. This situation is reminiscent of the evolution of the apolipoprotein (ApoE) gene, another locus that is potentially important for the risk of development of AD.
The association of CTLA-4 and HLA class II autoimmune risk genotype with regulatory T cell marker expression in 5-year-old children
Authors: Jonson C-O , Hedman M , Karlsson Faresjö M , Casas R , Ilonen J , Ludvigsson J , Vaarala O 
Published: May 2006

SummaryRegulatory T cells (Treg) are involved in the maintenance of peripheral tolerance by suppression of autoreactive lymphocytes that have avoided thymic depletion. The defective function of Treg cells has recently attracted attention in autoimmune diseases such as type 1 diabetes (T1D), rheumatoid arthritis and multiple sclerosis. Susceptibility to these diseases is associated with specific human leucocyte antigen (HLA) class II and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene polymorphisms. This study aimed to investigate the relationship between HLA class II and CTLA +49 A/G polymorphisms associated with susceptibility to T1D and the number and characteristics of Treg cells in children. Samples from 47 5-year-old children who participated in the All Babies in South-east Sweden (ABIS) follow-up study were grouped according to the presence of the T1D risk-associated HLA genotype (DQA1*0501–DQB1*0201, DQA1*0301–DQB1*0302) or neutral HLA genotypes. Lower percentages of CD4+ T cells (P = 0·03) and CD4+ CD25high cells (P = 0·06) expressing intracellular CTLA-4 were detected in samples from children with CTLA-4 +49GG compared to children with the +49AA genotype. Similarly, lower percentages of CD4+ (P = 0·002) and CD4+ CD25high (P = 0·002) cells expressing CTLA-4 were observed in children positive for HLA DQA1*0501–DQB1*0201 and DQA1*0301–DQB1*0302 (P = 0·04 for CD4+ and P = 0·02 for CD4+ CD25high) risk haplotypes when compared to children without these alleles. The percentage of CD25high cells among CD4+ cells was correlated inversely with CTLA-4 mRNA expression in PBMC (r = –0·56, P = 0·03). Decreased levels of CTLA-4 in CD4+ and CD4+ CD25high cells in individuals with CTLA-4 and HLA class II alleles associated with T1D may contribute to the initiation and/or progression of autoimmune response.
Role of BAFF and APRIL in human B‐cell chronic lymphocytic leukaemia
Authors: Haiat Stéphanie , Billard Christian , Quiney Claire , Ajchenbaum‐Cymbalista Florence , Kolb Jean‐Pierre 
Published: May 2006

SummaryB‐cell chronic lymphocytic leukaemia (B‐CLL) is the most prevalent leukaemia in Western countries and is characterized by the gradual accumulation in patients of small mature B cells. Since the vast majority of tumoral cells are quiescent, the accumulation mostly results from deficient apoptosis rather than from acute proliferation. Although the phenomenon is relevant in vivo, B‐CLL cells die rapidly in vitro as a consequence of apoptosis, suggesting a lack of essential growth factors in the culture medium. Indeed, the rate of B‐CLL cell death in vitro is modulated by different cytokines, some favouring the apoptotic process, others counteracting it. Two related members of the tumour necrosis factor family, BAFF (B‐cell activating factor of the TNF family) and APRIL (a proliferation‐inducing ligand), already known for their crucial role in normal B‐cell survival, differentiation and apoptosis, were recently shown to be expressed by B‐CLL cells. These molecules are able to protect the leukaemic cells against spontaneous and drug‐induced apoptosis via autocrine and/or paracrine pathways. This review will focus on the role of BAFF and APRIL in the survival of tumoral cells. It will discuss the expression of these molecules by B‐CLL cells, their regulation, transduction pathways and their effects on leukaemic cells. The design of reagents able to counteract the effects of these molecules seems to be a new promising therapeutic approach for B‐CLL and is already currently developed in the treatment of autoimmune diseases.
Interleukin‐5 regulates genes involved in B‐cell terminal maturation
Authors: Horikawa Keisuke , Takatsu Kiyoshi 
Published: May 2006

SummaryInterleukin (IL)‐5 induces CD38‐activated splenic B cells to differentiate into immunoglobulin M‐secreting cells and undergo µ to γ1 class switch recombination (CSR) at the DNA level, resulting in immunoglobulin G1 (IgG1) production. Interestingly, IL‐4, a well‐known IgG1‐inducing factor does not induce immunoglobulin production or µ to γ1 CSR in CD38‐activated B cells. In the present study, we implemented complementary DNA microarrays to investigate the contribution of IL‐5‐induced gene expression in CD38‐stimulated B cells to immunoglobulin‐secreting cell differentiation and µ to γ1 CSR. IL‐5 and IL‐4 stimulation of CD38‐activated B cells induced the expression of 418 and 289 genes, respectively, that consisted of several clusters. Surprisingly, IL‐5‐inducible 78 genes were redundantly regulated by IL‐4. IL‐5 and IL‐4 also suppressed the gene expression of 319 and 325 genes, respectively, 97 of which were overlapped. Genes critically regulated by IL‐5 include immunoglobulin‐related genes such as J chain and immunoglobulinκ, and genes involved in B‐cell maturation such as BCL6, activation‐induced cytidine deaminase (Aid) and B lymphocyte‐induced maturation protein‐1 (Blimp‐1) and tend to be induced slowly after IL‐5 stimulation. Intriguingly, among genes, the retroviral induction of Blimp‐1 and Aid in CD38‐activated B cells could induce IL‐4‐dependent maturation to Syndecan‐1+ antibody‐secreting cells and µ to γ1 CSR, respectively, in CD38‐activated B cells. Taken together, preferential Aid and Blimp‐1 expression plays a critical role in IL‐5‐induced immunoglobulin‐secreting cell differentiation and µ to γ1 CSR in CD38‐activated B cells.
Ticks have R2 retrotransposons but not the consensus transposon target site of other arthropods
Authors: Bunikis J. , Barbour A. G. 
Published: May 2006

AbstractSome copies of the large subunit rRNA genes (LSU rDNA) of most arthropods studied to date are inactivated by R‐element retrotransposons at a specific target region that is highly conserved in sequence across all kingdoms of organisms. Here we report finding R2 elements in low copy numbers in the LSU rDNA of hard and soft ticks. Although the elements were inserted at the same LSU rDNA location as in insects, there were substitutions in the consensus R2 endonuclease cleavage site in the ticks and some other parasitiform mites. The substituted region comprises a critical contact point with small subunit rRNA, but in vitro structure probing analysis revealed novel, presumably stabilizing base‐pairing.
Effect of chronic dietary ethanol in the promotion of N‐nitrosomethylbenzylamine‐induced esophageal carcinogenesis in rats
Authors: TSUTSUMI MIKIHIRO , GEORGE JOSEPH , ISHIZAWA KIYOHIRO , FUKUMURA ATUSHI , TAKASE SHUJIRO 
Published: May 2006

AbstractBackground:  The pathogenetic correlation between chronic alcohol consumption and development of esophageal cancer is not clear. The role of alcohol abuse in the carcinogenic action of N‐nitrosomethylbenzylamine, which induces tumors in the esophagus, has been evaluated.Methods:  Twenty male rats were fed liquid diets containing ethanol or carbohydrates for 30 weeks. N‐nitrosomethylbenzylamine (0.1 mg/kg, twice a week) was injected i.p. from the 9th to 19th week. The pair feeding was stopped at 9.00 am and N‐nitrosomethylbenzylamine was administered at 10.00 am. Ethanol was not detected in the blood at the time of injection. Liquid diets were provided again at 3 pm until 9 am next day. The animals were killed at the end of the 30th week. The esophagi were collected and examined for visible tumors. The tissue sections were stained for histology and CYP2E1expression.Results:  While 5–8 esophageal squamous polyps developed in all rats in the ethanol group, only one polyp each was formed in five out of the 10 rats in the control group. The size of the polyps was significantly larger in the ethanol group, when compared to the control group. Invasive squamous cell carcinoma was also observed in 50% of the animals in the ethanol group. Cytochrome P4502E1 (CYP2E1) staining demonstrated marked expression in the esophageal mucosa in the ethanol group, but not in the control group.Conclusions:  The increased expression of CYP2E1 induced by chronic ethanol consumption promotes the development of N‐nitrosomethylbenzylamine‐induced esophageal tumorigenesis. However, the molecular mechanism of the increased production of esophageal tumors during alternative administration of N‐nitrosomethylbenzylamine and ethanol is not clear.
Protection against glucose‐induced neuronal death by NAAG and GCP II inhibition is regulated by mGluR3
Authors: Berent‐Spillson Alison , Robinson Amanda M. , Golovoy David , Slusher Barbara , Rojas Camilo , Russell James W. 
Published: May 2006

AbstractGlutamate carboxypeptidase II (GCP II) inhibition has previously been shown to be protective against long‐term neuropathy in diabetic animals. In the current study, we have determined that the GCP II inhibitor 2‐(phosphonomethyl) pentanedioic acid (2‐PMPA) is protective against glucose‐induced programmed cell death (PCD) and neurite degeneration in dorsal root ganglion (DRG) neurons in a cell culture model of diabetic neuropathy. In this model, inhibition of caspase activation is mediated through the group II metabotropic glutamate receptor, mGluR3. 2‐PMPA neuroprotection is completely reversed by the mGluR3 antagonist (S)‐α‐ethylglutamic acid (EGLU). In contrast, group I and III mGluR inhibitors have no effect on 2‐PMPA neuroprotection. Furthermore, we show that two mGluR3 agonists, the direct agonist (2R,4R)‐4‐aminopyrrolidine‐2, 4‐dicarboxylate (APDC) and N‐acetyl‐aspartyl‐glutamate (NAAG) provide protection to neurons exposed to high glucose conditions, consistent with the concept that 2‐PMPA neuroprotection is mediated by increased NAAG activity. Inhibition of GCP II or mGluR3 may represent a novel mechanism to treat neuronal degeneration under high‐glucose conditions.
Putative endogenous mediators of preconditioning‐induced ischemic tolerance in rat brain identified by genomic and proteomic analysis
Authors: Dhodda Vinay K. , Sailor Kurt A. , Bowen Kellie K. , Vemuganti Raghu 
Published: May 2006

AbstractIn brain, a brief ischemic episode induces protection against a subsequent severe ischemic insult. This phenomenon is known as preconditioning‐induced neural ischemic tolerance. An understanding of the molecular mechanisms leading to preconditioning helps in identifying potential therapeutic targets for preventing the post‐stroke brain damage. The present study conducted the genomic and proteomic analysis of adult rat brain as a function of time following preconditioning induced by a 10‐min transient middle cerebral artery (MCA) occlusion. GeneChip analysis showed induction of 40 putative neuroprotective transcripts between 3 to 72 h after preconditioning. These included heat‐shock proteins, heme oxygenases, metallothioneins, signal transduction mediators, transcription factors, ion channels and apoptosis/plasticity‐related transcripts. Real‐time PCR confirmed the GeneChip data for the transcripts up‐regulated after preconditioning. Two‐dimensional gel electrophoresis combined with MALDI‐TOF analysis showed increased expression of HSP70, HSP27, HSP90, guanylyl cyclase, muskelin, platelet activating factor receptor and β‐actin at 24 h after preconditioning. HSP70 protein induction after preconditioning was localized in the cortical pyramidal neurons. The infarct volume induced by focal ischemia (1‐h MCA occlusion) was significantly smaller (by 38 ± 7%,p < 0.05) in rats subjected to preconditioning 3 days before the insult. Preconditioning also prevented several gene expression changes induced by focal ischemia.
Mitochondrial extracellular signal‐regulated kinases 1/2 (ERK1/2) are modulated during brain development
Authors: Alonso Mariana , Melani Mariana , Converso Daniela , Jaitovich Ariel , Paz Cristina , Carreras M. Cecilia , Medina Jorge H. , Poderoso Juan J. 
Published: May 2006

AbstractIntracellular activation and trafficking of extracellular signal‐regulated protein kinases (ERK) play a significant role in cell cycle progression, contributing to developmental brain activities. Additionally, mitochondria participate in cell signalling through energy‐linked functions, redox metabolism and activation of pro‐ or anti‐apoptotic proteins. The purpose of the present study was to analyze the presence of ERK1/2 in mitochondria during rat brain development. Immunoblotting, immune electron microscopy and activity assays demonstrated that ERK1/2 are present in fully active brain mitochondria at the outer membrane/intermembrane space fraction. Besides, it was observed that ERK1/2 translocation to brain mitochondria follows a developmental pattern which is maximal between E19‐P2 stages and afterwards declines at P3, just before maximal translocation to nucleus, and up to adulthood. Most of mitochondrial ERK1/2 were active; upstream phospho‐MAPK/ERK kinases (MEK1/2) were also detected in the brain organelles. Mitochondrial phospho‐ERK1/2 increased at 1 μm hydrogen peroxide (H2O2) concentration, but it decreased at higher 50–100 μm H2O2, almost disappearing after the organelles were maximally stimulated to produce H2O2 with antimycin. Our results suggest that developmental mitochondrial activation of ERK1/2 cascade contributes to its nuclear translocation effects, providing information about mitochondrial energetic and redox status to the proliferating/differentiating nuclear pathways.
Platelet‐activating factor receptor‐deficient mice are protected from experimental sleep apnea‐induced learning deficits
Authors: Row Barry W. , Kheirandish Leila , Li Richard C. , Guo Shang Z. , Brittian Kenneth R. , Hardy Mattie , Bazan Nicolas G. , Gozal David 
Published: May 2006

AbstractIntermittent hypoxia (IH) during sleep, a hallmark of sleep apnea, is associated with neurobehavioral impairments, regional neurodegeneration and increased oxidative stress and inflammation in rodents. Platelet‐activating factor (PAF) is an important mediator of both normal neural plasticity and brain injury. We report that mice deficient in the cell surface receptor for PAF (PAFR–/–), a bioactive mediator of oxidative stress and inflammation, are protected from the spatial reference learning deficits associated with IH. Furthermore, PAFR–/– exhibit attenuated elevations in inflammatory signaling (cyclo‐oxygenase‐2 and inducible nitric oxide synthase activities), degradation of the ubiquitin–proteasome pathway and apoptosis observed in wild‐type littermates (PAFR+/+) exposed to IH. Collectively, these findings indicate that inflammatory signaling and neurobehavioral impairments induced by IH are mediated through PAF receptors.
A Microdialysis Profile of Dynorphin A1–8 Release in the Rat Nucleus Accumbens Following Alcohol Administration
Authors: Marinelli Peter W. , Lam Minh , Bai Li , Quirion Rémi , Gianoulakis Christina 
Published: May 2006

Background: Pharmacological studies have implicated the endogenous opioid system in mediating alcohol intake. Other evidence has shown that alcohol administration can influence endorphinergic and enkephalinergic activity, while very few studies have examined its effect on dynorphinergic systems. The aim of the present study was to investigate the effect of alcohol administration or a mechanical stressor on extracellular levels of dynorphin A1–8 in the rat nucleus accumbens—a brain region that plays a significant role in the processes underlying reinforcement and stress.Methods: Male Sprague–Dawley rats were implanted with a microdialysis probe aimed at the shell region of the nucleus accumbens. Artificial cerebrospinal fluid was pumped at a rate of 1.5 μL/min in awake and freely moving animals and the dialysate was collected at 30‐minute intervals. In one experiment, following a baseline period, rats were injected intraperitoneally with either physiological saline or 1 of 3 doses of alcohol, 0.8, 1.6, or 3.2 g ethanol/kg body weight. In a second experiment, following a baseline period, rats were applied a clothespin to the base of their tail for 20 minutes. The levels of dynorphin A1–8 in the dialysate were analyzed with solid‐phase radioimmunoassay.Results: Relative to saline‐treated controls, an alcohol dose of 1.6 and 3.2 g/kg caused a transient increase in the extracellular levels of dynorphin A1–8 in the first 30 minutes of alcohol administration. However, the effect resulting from the high 3.2 g/kg dose was far more pronounced and more significant than with the moderate dose. There was no effect of tail pinch on dynorphin A1–8 levels in the nucleus accumbens.Conclusions: In this experiment, a very high dose of alcohol was especially capable of stimulating dynorphin A1–8 release in the nucleus accumbens. Dynorphin release in the accumbens has been previously associated with aversive stimuli and may thus reflect a system underlying the aversive properties of high‐dose alcohol administration. However, the lack of effect of tail‐pinch stress in the present study suggests that dynorphin A1–8 is not released in response to all forms of stressful/aversive stimuli.
Comparison of VTA Dopamine Neuron Activity in Lines of Rats Selectively Bred to Prefer or Avoid Alcohol
Authors: Morzorati Sandra L. , Marunde Rita L. 
Published: May 2006

Background:Studies comparing alcohol‐naïve alcohol‐preferring (P) and ‐nonpreferring (NP) rats indicate that high alcohol drinking is associated with an innate deficiency of the mesolimbic dopamine (DA) system. We previously reported that ventral tegmental area (VTA) DA neurons in alcohol‐naïve P rats burst fire more frequently than VTA DA neurons in alcohol‐naïve Wistar rats. We hypothesized that increased burst firing in P rats may represent a compensatory mechanism to maintain adequate levels of DA in terminal areas, such as the nucleus accumbens, despite the deficient mesolimbic DA system. The present study sought to extend our previous work and include NP rats and to determine whether differences in VTA DA neuron activity could be generalized to other rat lines selected for high and low alcohol preference, namely the high (HAD) and low (LAD) alcohol‐drinking rats.Methods:The extracellular activity of posterior VTA DA neurons was recorded in unanesthetized alcohol‐naïve rats from the P/NP and HAD/LAD lines. Firing frequencies, burst activity, and the number of DA neurons encountered per electrode track were compared.Results:Dopamine neurons in the posterior VTA of P rats had a greater percentage of action potentials in bursts and greater number of bursts compared with posterior VTA DA neurons in NP rats. There were no differences in VTA DA neuronal activity between both replicate lines of HAD and LAD rats.Conclusions:Burst activity of posterior VTA DA neurons distinguishes P from NP rats, but does not generalize to other lines of rats selectively bred at Indiana University for alcohol preference and nonpreference. Increased burst activity of DA neurons in the posterior VTA may be related to alcohol preference in P rats but is not necessary for high alcohol drinking.
Suicide Attempts Among Substance Use Disorder Patients: An Initial Step Toward a Decision Tree for Suicide Management
Authors: Tiet Quyen Q. , Ilgen Mark A. , Byrnes Hilary F. , Moos Rudolf H. 
Published: May 2006

Background: Little empirical data are available to develop profiles of patients who attempt suicide or to formulate a decision tree for suicide management. This study identifies profiles of patients who have a high risk of suicide attempt and takes a first step toward developing a decision tree to classify high‐risk patients.Methods: Based on a cross‐sectional, nationwide cohort of substance use disorder patients (N=34,251) in 150 Veterans Affairs (VA) facilities, a total of 5,671 patients who reported suicidal ideation in the 30 days before intake assessment were included in receiver operating characteristic (ROC) analyses to identify the 30‐day risk of an actual suicide attempt. Clinical diagnostic and Addiction Severity Index interview data were used.Results: Results provide an initial decision tree to classify high‐risk patients with sensitivity ranging from 0.33 to 0.89, and specificity, from 0.42 to 0.87. The factors included in the decision tree encompass history of prior suicide attempts, current drinking to intoxication, current cocaine use, first occasion of suicidal ideation, and difficulty controlling violent behavior.Conclusions: To our knowledge, this is the first attempt to use empirical data to provide information to eventually establish a decision tree for clinical management of patients with suicidal ideation. The findings show that profiles of patients who are at high risk of suicide attempts can be effectively identified using ROC, with relatively good sensitivity and specificity.
Possible Role of Nerve Growth Factor in the Pathogenesis of Alcohol Dependence
Authors: Yoon Su‐Jung , Roh Sungwon , Lee Heejin , Lee Ji‐Youl , Lee Bun‐Hee , Kim Yong‐Ku , Kim Dai‐Jin 
Published: May 2006

Background: Recent studies have raised the possibility that nerve growth factor (NGF) is abnormally regulated in the central nervous system (CNS) of animal models of chronic ethanol treatment. The goals of this study were to determine whether prolonged alcohol consumption is associated with the plasma NGF levels and to assess the effect of a positive family history of alcohol dependence on plasma NGF levels in the alcohol‐dependent patients.Methods: We used the enzyme‐linked immunosorbent assay (ELISA) to determine the concentrations of peripheral NGF in patients with alcohol dependence and in a control group.Results: The plasma NGF concentrations in the alcohol‐dependent patients were significantly lower than in the controls (71.9 vs 110.5 pg/mL, respectively). Moreover, the alcohol‐dependent patients with positive family histories showed a greater decrease in their NGF levels than those subjects with negative family histories (64.7 vs 83.3 pg/mL, respectively).Conclusions: Our study suggests that the NGF levels may be a trait marker for the development of alcohol dependence.