bluuebunny/crossref_metadata_2025 huggingface dataset:
Leaf angle in Chenopodium album is determined by two processes: induction and cessation of petiole curvature
Authors: FUJITA KEIKO , TAKAGI SHINGO , TERASHIMA ICHIRO
Published: April 2008

Petiole curvature is important in regulating light interception by the leaf. To dissect the determination processes of leaf angle, we irradiated the lamina or petiole of Chenopodium album L. with either one or two spots of actinic light, after dark adaptation. When the abaxial side of the petiole was irradiated with blue light, the petiole curvature increased, and under continuous irradiation, the curvature continued for up to 6 h. The rate of curvature increased with increasing blue light intensity. The curvature induced by irradiation of the abaxial side with blue light ceased when the adaxial side of the petiole was simultaneously irradiated with either blue or red light. When an inhibitor for photosynthesis, 3‐(3,4‐dichlorophenyl)‐1,1‐dimethylurea, was applied to the adaxial side of the petiole, the cessation of curvature caused by blue light was only weakly inhibited, while the cessation caused by red light was markedly inhibited. When the adaxial side of the petiole was irradiated alternately with red and far‐red light, the far‐red light antagonized the cessation of curvature caused by the red light. These results clearly show that the petiole curvature is controlled by two processes, the induction and the cessation of curvature. At least three photoreceptor systems, blue‐light receptor, photosynthesis and phytochrome, are involved in the reactions.
Historical tsunamis and storms recorded in a coastal lowland, Shizuoka Prefecture, along the Pacific Coast of Japan
Authors: KOMATSUBARA JUNKO , FUJIWARA OSAMU , TAKADA KEITA , SAWAI YUKI , AUNG THAN TIN , KAMATAKI TAKANOBU
Published: April 2008

Four sand units deposited by tsunamis and one sand unit deposited by storm surge(s) were identified in a muddy marsh succession in a narrow coastal lowland along the Pacific coast of central Japan. Tsunamis in ad 1498, 1605, 1707 and 1854 that were related to large subduction‐zone earthquakes along the Nankai Trough, and storm surges in 1680 and/or 1699 were responsible for the deposition of these sand units. These sand units are distinguished by lithofacies, sedimentary structures, grain‐size and mineral composition, and radiocarbon ages; their ages are supported by events in local historical records. The tsunami deposits in the study area are massive or parallel‐laminated sands, with associated intraclasts, gravels, draping mud layers and, rarely, a return‐flow subunit. The storm surge deposits are devoid of these characteristics, and are composed of groups of thin, current ripple‐laminated sand layers. The differences in sedimentary structures between the tsunami and storm surge deposits are attributed to the different characteristics of tsunami and storm waves.
Ethylene–auxin interactions regulate lateral root initiation and emergence in Arabidopsis thaliana
Authors: Ivanchenko Maria G. , Muday Gloria K. , Dubrovsky Joseph G.
Published: April 2008

Plant root systems display considerable plasticity in response to endogenous and environmental signals. Auxin stimulates pericycle cells within elongating primary roots to enter de novo organogenesis, leading to the establishment of new lateral root meristems. Crosstalk between auxin and ethylene in root elongation has been demonstrated, but interactions between these hormones in root branching are not well characterized. We find that enhanced ethylene synthesis, resulting from the application of low concentrations of the ethylene precursor 1‐aminocyclopropane‐1‐carboxylic acid (ACC), promotes the initiation of lateral root primordia. Treatment with higher doses of ACC strongly inhibits the ability of pericycle cells to initiate new lateral root primordia, but promotes the emergence of existing lateral root primordia: behaviour that is also seen in the eto1 mutation. These effects are correlated with decreased pericycle cell length and increased lateral root primordia cell width. When auxin is applied simultaneously with ACC, ACC is unable to prevent the auxin stimulation of lateral root formation in the root tissues formed prior to ACC exposure. However, in root tissues formed after transfer to ACC, in which elongation is reduced, auxin does not rescue the ethylene inhibition of primordia initiation, but instead increases it by several fold. Mutations that block auxin responses, slr1 and arf7 arf19, render initiation of lateral root primordia insensitive to the promoting effect of low ethylene levels, and mutations that inhibit ethylene‐stimulated auxin biosynthesis, wei2 and wei7, reduce the inhibitory effect of higher ethylene levels, consistent with ethylene regulating root branching through interactions with auxin.
Both ATM and ATR promote the efficient and accurate processing of programmed meiotic double‐strand breaks
Authors: Culligan Kevin M. , Britt Anne B.
Published: April 2008

The ATM and ATR protein kinases play central roles in the cellular response to double‐strand breaks (DSBs) by regulating DNA repair, cell‐cycle arrest and apoptosis. During meiosis, SPO11‐dependent DSBs are generated, initiating recombination between homologous chromosomes. Previous studies in mice and plants have shown that defects in ATM result in the appearance of abnormally fragmented chromosomes. However, the role of ATR in promoting normal meiosis has not yet been elucidated. Employing null Arabidopsis mutants of ATR and ATM, we demonstrate here that although atr mutants display no obvious defects in any phase of meiotic progression, the combination of defects in atr and atm exacerbates the fragmentation observed in the atm single mutant, prevents complete synapsis of chromosomes, and results in extensive and persistent interactions between non‐homologous DNAs. The observed non‐homologous interactions require the induction of programmed breaks: the combination of either the atm single or the atr atm double mutant with a spo11 defect eliminates the ectopic interactions observed in the double mutant, as well as significantly reducing the fragmentation seen in atm or in atr atm. Our results suggest that ATM is required for the efficient processing of SPO11‐dependent DSBs during meiosis. They also indicate that ATM and ATR act redundantly to inhibit sustained interactions between non‐homologous chromatids, and that these ectopic interactions require SPO11 activity.
The Medicago truncatula ortholog of Arabidopsis EIN2, sickle, is a negative regulator of symbiotic and pathogenic microbial associations
Authors: Varma Penmetsa R. , Uribe Pedro , Anderson Jonathan , Lichtenzveig Judith , Gish John‐Charles , Nam Young Woo , Engstrom Eric , Xu Kun , Sckisel Gail , Pereira Mariana , Baek Jong Min , Lopez‐Meyer Melina , Long Sharon R. , Harrison Maria J. , Singh Karam B. , Kiss Gyorgy B. , Cook Douglas R.
Published: April 2008

The plant hormone ethylene negatively regulates bacterial infection and nodule formation in legumes in response to symbiotic rhizobia, but the molecular mechanism(s) of ethylene action in symbiosis remain obscure. We have identified and characterized multiple mutant alleles of the MtSkl1 gene, which controls both ethylene sensitivity and nodule numbers. We show that this locus encodes the Medicago truncatula ortholog of the Arabidopsis ethylene signaling protein EIN2. In addition to the well‐characterized role of MtSkl1 in rhizobial symbiosis, we show that MtSkl1 is involved in regulating early phases of the symbiotic interaction with mycorrhizal fungi, and in mediating root responses to cytokinin. MtSkl1 also functions in the defense against Rhizoctonia solani and Phytophthora medicaginis, with the latter interaction likely to involve positive feedback amplification of ethylene biosynthesis. Overexpression of the C‐terminal domain of MtEIN2 is sufficient to block nodulation responses, consistent with previous reports in Arabidopsis on the activation of ethylene signaling. This same C‐terminal region is uniquely conserved throughout the EIN2 homologs of angiosperms, which is consistent with its role as a higher plant‐specific innovation essential to EIN2 function.
AtCYP38 ensures early biogenesis, correct assembly and sustenance of photosystem II
Authors: Sirpiö Sari , Khrouchtchova Anastassia , Allahverdiyeva Yagut , Hansson Maria , Fristedt Rikard , Vener Alexander V. , Scheller Henrik Vibe , Jensen Poul Erik , Haldrup Anna , Aro Eva‐Mari
Published: April 2008

AtCYP38 is a thylakoid lumen protein comprising the immunophilin domain and the phosphatase inhibitor module. Here we show the association of AtCYP38 with the photosystem II (PSII) monomer complex and address its functional role using AtCYP38‐deficient mutants. The dynamic greening process of etiolated leaves failed in the absence of AtCYP38, due to specific problems in the biogenesis of PSII complexes. Also the development of leaves under short‐day conditions was severely disturbed. Detailed biophysical and biochemical analysis of mature AtCYP38‐deficient plants from favorable growth conditions (long photoperiod) revealed: (i) intrinsic malfunction of PSII, which (ii) occurred on the donor side of PSII and (iii) was dependent on growing light intensity. AtCYP38 mutant plants also showed decreased accumulation of PSII, which was shown not to originate from impaired D1 synthesis or assembly of PSII monomers, dimers and supercomplexes as such but rather from the incorrect fine‐tuning of the oxygen‐evolving side of PSII. This, in turn, rendered PSII centers extremely susceptible to photoinhibition. AtCYP38 deficiency also drastically decreased the in vivo phosphorylation of PSII core proteins, probably related to the absence of the AtCYP38 phosphatase inhibitor domain. It is proposed that during PSII assembly AtCYP38 protein guides the proper folding of D1 (and CP43) into PSII, thereby enabling the correct assembly of the water‐splitting Mn4–Ca cluster even with high turnover of PSII.
Skin reactivity and local cell recruitment in human atopic and nonatopic subjects by CCL2/MCP‐1 and CCL3/MIP‐1α
Authors: Gaga M. , Ong Y.‐E. , Benyahia F. , Aizen M. , Barkans J. , Kay A. B.
Published: April 2008

Background:  Monocyte chemotactic protein (MCP‐1/CCL2), the ligand for CCR2 and CCR5, and macrophage inflammatory protein‐1α (MIP‐1α/CCL3), the ligand for CCR1 and CCR5, are potent chemo‐attractants in vitro and produce lesions in experimental animals, which resemble immediate and delayed‐type hypersensitivity (DTH) reactions. CCL3 induces mononuclear cell and granulocyte infiltration in human atopic and nonatopic skin. Whether CCL2 (MCP‐1) has comparable activity in man is uncertain as is the capacity of both the chemokines to elicit immediate‐ and DTH‐like reactions in humans.

Methods:  Inflammatory cells were counted by immunohistochemistry in 24 and 48‐h skin biopsies from atopics and nonatopics after intradermal injection of CCL2 and CCL3. Immediate (15 min) wheals‐and‐flares and delayed (24 and 48 h) indurations were also recorded.

Results:  Both chemokines induced immediate‐ (15 min) and delayed (24 and 48 h) reactions, which were associated with significant infiltrations of CD68+ macrophages, CD3+, CD4+ (but not CD8+) T cells, neutrophils, and eosinophils in biopsies from injection sites. CCL2, but not CCL3, also induced infiltration of basophils. Neither chemokine produced significant changes in the numbers of tryptase+ cutaneous mast cells. There were no differences in the pattern of skin reactivity or the numbers of infiltrating leukocytes in response to CCL2 and CCL3 between atopic and nonatopic subjects. In general, maximal infiltration of inflammatory cells was observed at the 24‐h, rather than the 48‐h, time point.

Conclusions:  CCL2 and CCL3 induce both immediate and delayed skin reactions in atopics and nonatopics, and evoke a similar profile of local T cell/macrophage and granulocyte recruitment which, in general, confirm previous in vitro findings and in vivo experimental animal data.
Distribution of Langerhans cells and mast cells within the human oral mucosa: new application sites of allergens in sublingual immunotherapy?
Authors: Allam J.‐P. , Stojanovski G. , Friedrichs N. , Peng W. , Bieber T. , Wenzel J. , Novak N.
Published: April 2008

Background:  Sublingual immunotherapy (SLIT) represents an alternative to subcutaneous immunotherapy. While antigen‐presenting cells such as Langerhans cells (LCs) are thought to contribute to the effectiveness of SLIT, mast cells (MCs) most likely account for adverse reactions such as sublingual edema. As little is known about LCs and MCs within the oral cavity, we investigated their distribution in search for mucosal sites with highest LCs and lowest MCs density.

Methods:  Biopsies were taken simultaneously from human vestibulum, bucca, palatum, lingua, sublingua, gingiva, and skin. Immunohistochemistry and flow cytometry were used to detect MCs, LCs and high affinity receptor for IgE (FcεRI) expression of LCs. Mixed lymphocyte reactions were performed to assess their stimulatory capacity.

Results:  Highest density of MCs was detected within the gingiva, while the lowest density of MCs was found within the palatum and lingua. However, sublingual MCs were located within glands, which might explain swelling of sublingual caruncle in some SLIT patients. Highest density of LCs was detected within the vestibular region with lowest density in sublingual region. Highest expression of FcεRI was detected on LCs within the vestibulum. Furthermore LCs from different regions displayed similar stimulatory capacity towards allogeneic T cells.

Conclusions:  In view of our data, different mucosal regions such as the vestibulum might represent alternative SLIT application sites with potent allergen uptake. Our data might serve as a basis for new application strategies for SLIT to enhance efficiency and reduce local adverse reactions.
Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment
Authors: Wollenberg A. , Reitamo S. , Girolomoni G. , Lahfa M. , Ruzicka T. , Healy E. , Giannetti A. , Bieber T. , Vyas J. , Deleuran M. ,   for the European Tacrolimus Ointment Study Group
Published: April 2008

Background:  Long‐term treatment for atopic dermatitis (AD) using low dose, intermittent, topical anti‐inflammatory agents may control acute disease and prevent relapses. This 12‐month, European, multicentre, randomized study investigated whether the proactive use of 0.1% tacrolimus ointment applied twice weekly can keep AD in remission and reduce the incidence of disease exacerbations (DE).

Methods:  During the initial open‐label period, 257 adults with AD applied 0.1% tacrolimus ointment twice daily (b.i.d.) for up to 6 weeks to affected areas. When an Investigator Global Assessment (IGA) score of ≤2 was achieved, the patient entered the disease control period (DCP) and was randomized to either proactive tacrolimus (n = 116) or vehicle ointment (n = 108) twice weekly for 12 months. Exacerbations were treated with 0.1% tacrolimus ointment b.i.d. until an IGA ≤2 was regained, then randomized treatment was restarted. The primary endpoint was the number of DEs during the DCP that required a substantial therapeutic intervention.

Results:  Proactive tacrolimus 0.1% ointment application significantly reduced the number of DEs requiring substantial therapeutic intervention (median difference 2; P < 0.001; Wilcoxon rank sum test), the percentage of DE treatment days (median difference: 15.2%; P < 0.001; Wilcoxon rank sum test) and increased the time to first DE (median 142 vs 15 days; P < 0.001; stratified log‐rank test). The adverse event profile was similar for the two treatment approaches.

Conclusion:  A 12‐month, twice weekly proactive tacrolimus ointment application was an effective treatment in most study patients which prevented, delayed and reduced the occurrence of AD exacerbations.
Mechanisms of asthma in Olympic athletes – practical implications
Authors: Haahtela T. , Malmberg P. , Moreira A.
Published: April 2008

Athletes’ symptoms may only occur in extreme conditions, which are far from normal. Exercise may increase ventilation up to 200 l/min for short periods in speed and power athletes, and for longer periods in endurance athletes such as swimmers and cross‐country skiers. Increasing proportions of young athletes are atopic, i.e. they show signs of IgE‐mediated allergy which is, along with the sport event (endurance sport), a major risk factor for asthma and respiratory symptoms. Mechanisms in the etiology and clinical phenotypes vary between disciplines and individuals, and it may be an oversimplification to discuss athlete’s asthma as a distinct and unambiguous disease. Nevertheless, the experience on Finnish Olympic athletes suggests at least two different clinical phenotypes, which may reflect different underlying mechanisms. The pattern of ‘classical asthma’ is characterized by early onset childhood asthma, methacholine responsiveness, atopy and signs of eosinophilic airway inflammation, reflected by increased exhaled nitric oxide levels. Another distinct phenotype includes late onset symptoms (during sports career), bronchial responsiveness to eucapnic hyperventilation test, but not necessarily to inhaled methacholine, and a variable association with atopic markers and nitric oxide. A mixed type of eosinophilic and neutrophilic airway inflammation seems to affect especially swimmers, ice‐hockey players, and cross‐country skiers. The inflammation may represent a multifactorial trauma, in which both allergic and irritant mechanisms play a role. There is a significant problem of both under‐ and overdiagnosing asthma in athletes and the need for objective testing is emphasized. Follow‐up studies are needed to assess the temporal relationship between asthma and competitive sporting, taking better into account individual disposition, environmental factors (exposure), intensity of training and potential confounders.
An evaluation of the cost‐effectiveness of omalizumab for the treatment of severe allergic asthma
Authors: Sullivan S. D. , Turk F.
Published: April 2008

Omalizumab is the first licensed anti‐immunoglobulin (Ig) E antibody shown to be effective for treatment of allergic (IgE‐mediated) asthma. Recent international guidelines recommend omalizumab as add‐on treatment to fixed dose inhaled corticosteroid (ICS) and long‐acting β2‐agonist (LABA) combination therapy. However, omalizumab is more expensive than other current asthma treatments and health and reimbursement authorities are increasingly demanding evidence of economic benefit to support pricing and formulary listing. The aims of this article are to (i) summarize data on the human and economic burden of severe asthma, (ii) summarize the efficacy data obtained for omalizumab in clinical trials in patients with inadequately controlled severe persistent allergic asthma despite high‐dose ICS plus a LABA, and (iii) discuss the cost‐effectiveness evidence published for omalizumab in this patient population. A wealth of evidence exists highlighting that the health, economic and societal burden of asthma is considerable and is highly skewed towards patients with severe asthma, particularly when asthma is inadequately controlled. Omalizumab is clinically beneficial in patients with severe persistent allergic asthma despite high‐dose ICS plus a LABA, particularly in a subgroup of patients who respond to therapy. In patients who respond to therapy, the cost‐effectiveness of omalizumab compares well with other biologic treatments for chronic illness.
How to assess disease activity in patients with chronic urticaria?
Authors: Młynek A. , Zalewska‐Janowska A. , Martus P. , Staubach P. , Zuberbier T. , Maurer M.
Published: April 2008

Background:  The current EAACI/GA²LEN/EDF guidelines recommend assessing disease activity in chronic urticaria (CU) by using an established and well‐defined symptom score, i.e. the urticaria activity score (UAS), which combines daily wheal numbers and pruritus intensity. However, this UAS has never been formally tested for its suitability in assessing CU activity.

Aim:  To determine the UAS correlation with quality of life (QoL) in CU patients and to compare the UAS to other symptom scores.

Methods:  Chronic urticaria symptoms (wheals, erythema, angioedema, pruritus) were assessed on seven consecutive days in 111 CU patients for their numbers, duration, size, and/or intensity. Quality of life was assessed by using the Dermatology Life Quality Index. Both, urticaria activity and QoL were determined before and after a 3‐week period, in which the patients followed a pseudoallergen‐low diet.

Results:  Urticaria activity score values correlated positively, albeit weakly, with QoL impairment in CU patients (r2 = 0.31, P < 0.05). Also, changes in QoL following a pseudoallergen‐low diet were reflected by the changes observed in the UAS (r2 = 0.30, P < 0.05). No significant differences were found comparing the QoL correlation of the UAS and other symptom scores combining up to four CU symptom qualities. Quality of life correlation with UAS values increased with the number of days the UAS was assessed and plateaued starting from the fourth consecutive day.

Conclusions:  Our findings back the current guideline recommendations to use the UAS for monitoring disease activity in CU patients. Urticaria activity score mean values of at least four consecutive days should be used.
ADHD as a (non) allergic hypersensitivity disorder: A hypothesis
Authors: Pelsser Lidy M. J. , Buitelaar Jan K. , Savelkoul Huub F. J.
Published: April 2008

Research data concerning the causal association between attention deficit hyperactivity disorder (ADHD) and allergies are conflicting. Allergic disorders, like asthma and eczema are clinical syndromes in which both genetic predisposition and environmental factors (pets, pollen and foods) contribute to its development. The hypothesis of ADHD, in some children also being an allergic disorder, is postulated based on comparison of the mechanisms underlying the development of ADHD and allergic disorders. According to the accepted terminology, ADHD may comply with the criteria of hypersensitivity, allergy and atopy. This hypothesis has to be thoroughly tested by randomized controlled trials using environmental triggers and immunologic research. As genes related to the immune system may be associated with ADHD, further genetic research is compulsory. Immunotherapeutic approaches, using immunotherapy and probiotics, can subsequently be implicated in the treatment of ADHD. If hypersensitivity to environmental stimuli like foods contributes to the development of ADHD, the assessment and treatment of ADHD will have to be reconsidered, thereby improving the quality of care for these patients.
Habitat‐dependent song divergence at subspecies level in the grey‐breasted wood‐wren
Authors: DINGLE C. , HALFWERK W. , SLABBEKOORN H.
Published: April 2008

Song divergence among populations can theoretically lead to reproductive divergence and speciation. Despite many studies, this theory is still controversial. Habitat differences have been shown to shape songs, but few studies have looked for a link between ecologically driven acoustic and genetic divergence. We tested whether environmental selection has driven song divergence in two genetically distinct, but hybridizing, subspecies of the grey‐breasted wood‐wren (Henicorhina leucophrys) in Ecuador. Several acoustic features showed significant divergence between the subspecies. Spectral song divergence correlated with ambient noise profiles which differed significantly between the habitats of both subspecies. Temporal song divergence also corresponded as expected to vegetation density. However, in terms of quantified levels of reverberations, we found no significant differences in habitat‐dependent sound transmission properties. We conclude that ecological niche segregation may explain acoustic divergence among the two wren subspecies. The resulting habitat‐dependent song divergence may have contributed to reproductive divergence by guiding assortative mating in parapatric conditions or just currently contribute to maintenance of reproductive isolation upon secondary contact.
Geographically variable selection inAmbystoma tigrinumvirus (Iridoviridae) throughout the western USA
Authors: RIDENHOUR B. J. , STORFER A. T.
Published: April 2008

We investigated spatially variable selection inAmbystoma tigrinumvirus (ATV) which causes frequent and geographically widespread epizootics of the tiger salamander,Ambystoma tigrinum. To test for evidence of selection, we sequenced several coding and noncoding regions from virus strains isolated from epizootics throughout western North America. Three of the sequenced regions contained homologues for genes putatively involved in host immune evasion and virulence: eIF‐2α, caspase activation and recruitment domain (CARD) and β‐OH‐steroid oxidoreductase. Selection analysis showed evidence of very strong purifying selection on eIF‐2α, purifying selection within certain viral clades on CARD and positive selection on β‐OH‐steroid oxidoreductase within certain clades. Analysis usingmultidivtimeand Tajima’s relative rate tests indicate accelerated rates of evolution within clades associated with anthropogenic movement. These clades also demonstrate greater spatial variability in selection, suggesting a lack of local adaptation (i.e. locally adapted populations should exhibit little to no selection because of absent or reduced variation in fitness once a fitness optimum is reached). Increased transfer of non‐native viral strains to naïve salamander populations, in conjunction with local maladaptation as a result of local selection pressures, may explain the spread and emergence of ATV epizootics inA. tigrinumin western North America.
Long‐lasting alteration in mesocorticolimbic structures after repeated social defeat stress in rats: time course of µ‐opioid receptor mRNA and FosB/ΔFosB immunoreactivity
Authors: Nikulina Ella M. , Arrillaga‐Romany Isabel , Miczek Klaus A. , Hammer Ronald P.
Published: April 2008

Social defeat stress is a salient stressor that induces neuroadaptive changes in the mesocorticolimbic dopaminergic system. Substantial evidence indicates that µ‐opioid receptors (MORs) modulate dopamine transmission in the ventral tegmental area (VTA). FosB/ΔFosB protein accumulation in dopaminergic projections during repeated treatments is thought to be involved in long‐term neuroplasticity. In this study we characterize the magnitude and time‐course of MOR mRNA expression and FosB/ΔFosB immunoreactivity in mesocorticolimbic regions following repeated social defeat stress. Effects of brief repeated social defeat stress or control handling procedures were studied in rats either 2 h after the last exposure, or 3, 7, 14, 21 and 28 days later. We found that MOR mRNA expression in the VTA doubled after the last stress compared with handling, and remained 30–70% higher until day 21. The number of FosB/ΔFosB‐labeled neurons in regions of the frontal cortex, nucleus accumbens (NAc) shell and core, and in the medial, central and basolateral amygdala increased significantly immediately after the last stress episode, and remained enhanced for 21 days. Another group of rats received bilateral intra‐VTA infusion of the MOR agonist, DAMGO, 7 days after the last stress. Prior social defeat stress augmented DAMGO‐induced Fos expression in the NAc shell, suggesting that Fos expression in this region might be the direct result of MOR activity in the VTA. Social defeat stress leads to an increased capacity for MOR activation in the VTA, which may be relevant to enduring FosB/ΔFosB expression in mesocorticolimbic areas and to the behaviorally sensitized response to psychostimulant drugs.
Emergence of spatial impairment in rats following specific cholinergic depletion of the medial septum combined with chronic stress
Authors: Craig Laura A. , Hong Nancy S. , Kopp Joelle , McDonald Robert J.
Published: April 2008

A consistent finding in patients suffering from Alzheimer's disease is a loss of the cholinergic neurons of the basal forebrain that project to the hippocampus. However, the role this depletion plays in the development of Alzheimer's disease remains unclear. The loss of this ascending neurotransmitter system could potentially render hippocampal neurons more susceptible to further insult, such as chronic stress, ultimately resulting in neuronal death and memory loss. We explored this possibility by using the highly specific toxin 192 IgG‐Saporin to destroy the majority of cholinergic activity in the septo‐hippocampal pathway in rats. Following depletion, rats were subjected to 2 weeks of restraint stress. Rats were divided into two groups and were tested either on a hippocampal‐dependent (water maze) task or a hippocampal‐independent task (fear conditioning to tone and context). We showed that cholinergic depletion or stress alone had no effect on the successful performance of either of the tasks. However, rats with a combination of cholinergic depletion and stress were significantly impaired on the water‐maze task. No deficits were apparent in the combined group that was tested on fear conditioning to tone or context, suggesting that this impairment is specific to spatial working memory. These rats had no obvious hippocampal neuronal loss or damage; however, there were likely subtle changes in hippocampal processing that led to the observed deficit on the hippocampal‐dependent task. These findings support our theory that cholinergic depletion of the medial septum increases hippocampal vulnerability to further insults such as stress.
Changes in effective connectivity of human superior parietal lobule under multisensory and unisensory stimulation
Authors: Moran R. J. , Molholm S. , Reilly R. B. , Foxe J. J.
Published: April 2008

Previous event‐related potential (ERP) studies have identified the superior parietal lobule (SPL) as actively multisensory. This study compares effective, or contextually active, connections to this region under unisensory and multisensory conditions. Effective connectivity, the influence of one brain region over another, during unisensory visual, unisensory auditory and multisensory audiovisual stimulation was investigated. ERPs were recorded from subdural electrodes placed over the parietal lobe of three patients while they conducted a rapid reaction‐time task. A generative model of interacting neuronal ensembles for ERPs was inverted in a scheme allowing investigation of the connections from and to the SPL, a multisensory processing area. Important features of the ensemble model include inhibitory and excitatory feedback connections to pyramidal cells and extrinsic input to the stellate cell pool, with extrinsic forward and backward connections delineated by laminar connection differences between ensembles. The framework embeds the SPL in a plausible connection of distinct neuronal ensembles mirroring the integrated brain regions involved in the response task. Bayesian model comparison was used to test competing feed‐forward and feed‐backward models of how the electrophysiological data were generated. Comparisons were performed between multisensory and unisensory data. Findings from three patients show differences in summed unisensory and multisensory ERPs that can be accounted for by a mediation of both forward and backward connections to the SPL. In particular, a negative gain in all forward and backward connections to the SPL from other regions was observed during the period of multisensory integration, while a positive gain was observed for forward projections that arise from the SPL.
Functional similarities between the P1 component and alpha oscillations
Authors: Freunberger Roman , Höller Yvonne , Griesmayr Birgit , Gruber Walter , Sauseng Paul , Klimesch Wolfgang
Published: April 2008

The present study attempts to demonstrate functional similarities between the P1 component of event‐related potentials and alpha oscillations that are predicted by the ‘alpha inhibition‐timing’ hypothesis. On the basis of findings showing that the frequency characteristic of the P1 component lies in the alpha range and that alpha oscillation is functionally associated with inhibition, we predict that the P1 component also reflects inhibitory processes. This hypothesis is tested in two experiments, a spatial‐cuing task and a visual‐semantic categorization task. The results of the cuing task demonstrate that in a similar way as alpha power, the P1 component is larger over task‐irrelevant ipsilateral sites. For the categorization task, we found that the P1 component, in a similar way to alpha oscillations, is larger for task‐irrelevant, distorted pictures. We conclude that the P1 component may be generated at least in part by evoked alpha oscillations and reflects inhibition in the sense of suppressing task‐irrelevant processes.
13‐cis‐retinoic acid alters the cellular morphology of slice‐cultured serotonergic neurons in the rat
Authors: Ishikawa Junko , Sutoh Chihiro , Ishikawa Akinori , Kagechika Hiroyuki , Hirano Hitoshi , Nakamura Shoji
Published: April 2008

Retinoids influence cellular processes such as differentiation, proliferation and apoptosis via retinoic acid receptor (RAR) and retinoid X receptor (RXR), and have therapeutic applications in several cancers and dermatologic diseases. Recent reports indicate that depression occasionally occurs in patients using the acne drug Accutane, the active component of which is 13‐cis‐retinoic acid (13‐cis‐RA). Although impairment of serotonin (5‐HT)‐expressing neurons, including morphologic changes, is thought to be associated with depressive symptoms, the effects of 13‐cis‐RA on 5‐HT neurons have not been examined. The present study demonstrated that 13‐cis‐RA alters the morphology of 5‐HT neurons in cultured rat midbrain slices. The 13‐cis‐RA‐induced changes were partially blocked by RXR and RAR antagonists. Furthermore, cotreatment with RAR and RXR agonists altered the morphology of 5‐HT neurons to a greater extent than the individual application of each agonist. The morphologic changes were completely blocked by RXR antagonist, whereas RAR antagonist partially blocked the effects. These results suggest that 13‐cis‐RA exerts its action on slice‐cultured 5‐HT neurons, at least in part, through specific retinoid receptors. Moreover, RXR has a greater influence on the morphology of 5‐HT neurons than RAR. The receptor‐mediated actions of 13‐cis‐RA presented here may provide a clue for further research on depression associated with the use of 13‐cis‐RA.
Disentangling neural structures for processing of high‐ and low‐speed visual motion
Authors: Lorteije Jeannette A. M. , Van Wezel Richard J. A. , Van Der Smagt Maarten J.
Published: April 2008

Human psychophysical and electrophysiological evidence suggests at least two separate visual motion pathways, one tuned to a lower and one tuned to a broader and partly overlapping range of higher speeds. It remains unclear whether these two different channels are represented by different cortical areas or by sub‐populations within a single area. We recorded evoked potentials at 59 scalp locations to the onset of a slow (3.5°/s) and fast (32°/s) moving test pattern, preceded by either a slow or fast adapting pattern that moved in either the same direction or opposite to the test motion. Baseline potentials were recorded for slow and fast moving test patterns after adaptation to a static pattern. Comparison of adapted responses with baseline responses revealed that the N2 peak around 180 ms after test stimulus onset was modulated by the preceding adaptation. This modulation depended on both direction and speed. Source localization of baseline potentials as well as direction‐independent motion adaptation revealed cortical areas activated by fast motion to be more dorsal, medial and posterior compared with neural structures underlying slow motion processing. For both speeds, the direction‐dependent component of this adaptation modulation occurred in the same area, located significantly more dorsally compared with neural structures that were adapted in a direction‐independent manner. These results demonstrate for the first time the cortical separation of more ventral areas selectively activated by visual motion at low speeds (and not high speeds) and dorsal motion‐sensitive cortical areas that are activated by both high and low speeds.
Functional analysis of human CNGA3 mutations associated with colour blindness suggests impaired surface expression of channel mutants A3R427C and A3R563C
Authors: Koeppen Katja , Reuter Peggy , Kohl Susanne , Baumann Britta , Ladewig Thomas , Wissinger Bernd
Published: April 2008

Mutations in the CNGA3 gene have been associated with complete and incomplete forms of total colour blindness (achromatopsia), a disorder characterized by reduced visual acuity, lack of colour discrimination, photophobia and nystagmus. CNGA3 encodes the A‐subunit of the cone photoreceptor cyclic nucleotide‐gated (CNG) channel, an essential component of the phototransduction cascade. Here we report the identification of three new CNGA3 mutations in patients with achromatopsia. To assess the pathogenicity of these newly identified and four previously reported mutations, mutant CNGA3 channels were heterologously expressed in a human embryonic kidney cell line (HEK293 cells) and functionally analysed using calcium imaging. Channels with the mutations R427C and R563C showed a response in imaging experiments and were subsequently characterized in‐depth with the patch‐clamp technique. The mutant channels were analysed as homooligomers and also as heterooligomers with the wild‐type B‐subunit present in native channels. Overall, cyclic guanosine monophosphate (cGMP) maximum currents of mutant channels were profoundly reduced in homo‐ and heteromers. Treatment with the chemical chaperone glycerol effectively increased macroscopic currents, presumably by enhancing surface expression of mutant channels as confirmed by immunocytochemistry. These results suggest decreased channel density in the cell membrane due to impaired folding or trafficking of the channel protein as the main pathogenic effect of the mutations R427C and R563C. Moreover, A3R427C homomers showed distinctly increased cGMP and cyclic adenosine monophosphate (cAMP) sensitivities as well as cAMP fractional currents that were raised to over 90% of cGMP maximum currents. Co‐expression of A3R427C with the B3 subunit compensated for most of these aberrant properties, apart from the reduced cGMP maximum currents.
Mechanical lesion activates newly identified NFATc1 in primary astrocytes: implication of ATP and purinergic receptors
Authors: Pérez‐Ortiz José M. , Serrano‐Pérez María C. , Pastor María D. , Martín Eduardo D. , Calvo Soledad , Rincón Mercedes , Tranque Pedro
Published: April 2008

Ca2+‐dependent calcineurin is upregulated in reactive astrocytes in neuroinflammatory models. Therefore, the fact that the nuclear factor of activated T cells (NFAT) is activated in response to calcineurin qualifies this family of transcription factors with immune functions as candidates to mediate astrogliosis. Brain trauma induces a neuroinflammatory state in which ATP is released from astrocytes, stimulating calcium signalling. Our goal here is to characterize NFATc1 and NFATc2 in mouse primary astrocyte cultures, also exploring the implication of NFAT in astrocyte activation by mechanical lesion. Quantitative reverse transcriptase‐polymerase chain reaction, Western blot analysis and immunofluorescence microscopy identified NFATc1 in astrocytes, but not NFATc2. Moreover, NFATc1 was expressed in the cytosol of resting astrocytes, whereas activation of the Ca2+‐calcineurin pathway by ionomycin translocated NFATc1 to the nucleus, which is a requirement for activation. The implication of astrocytic NFAT in brain trauma was analysed using an in vitro scratch lesion model. Mechanical lesion caused a rapid NFATc1 translocation that progressed throughout the culture as a gradient and was maintained for at least 4 h. We also demonstrate that ATP, released by lesion, is a potent inducer of NFATc1 translocation and activation. Moreover, the use of P2Y receptor modulators showed that such ATP action is mediated by stimulation of several Gq‐protein‐coupled P2Y purinergic receptors, among which P2Y1 and P2Y6 are included. In conclusion, this work provides evidence that newly identified NFATc1 is translocated in astrocytes in response to lesion following a pathway that involves ATP release and activation of metabotropic purinergic receptors.
Motor learning affects visual movement perception
Authors: Engel Annerose , Burke Michael , Fiehler Katja , Bien Siegfried , Rösler Frank
Published: April 2008

In the present study we investigated whether imitation of artificial movement trajectories of meaningless objects has an effect on how these trajectories are later perceptually processed within the human brain. During observation of a sequence of artificial object movements 10 participants (experimental group) actively imitated the trajectories during motor training and 10 participants (control group) solved a working memory task without motor training. The haemodynamic responses were recorded before and after the intervention while participants observed the movements and either had to detect colour changes of one of the objects (colour task, motor‐irrelevant) or had to judge whether the movement pattern could be imitated with the hands (simulation judgement task, motor‐relevant). The between‐group comparison of the post‐intervention haemodynamic responses revealed stronger activity for the motor training than for the control group during the simulation judgement task. This activity appeared in motor‐related areas (supplementary motor area and inferior parietal lobe) and in the occipito‐temporal area. During the colour task, the motor training group showed stronger activity in the occipital lobe. The control group did not reveal any stronger activity than the motor training group for either task. The results suggest that motor training has task‐specific effects on neural processes that are involved in perception of movements. Furthermore, they indicate that motor‐related areas are triggered by observed artificial object movements, but only if a motor‐relevant task is pursued.
Augmented brain 5‐HT crosses the blood–brain barrier through the 5‐HT transporter in rat
Authors: Nakatani Yasushi , Sato‐Suzuki Ikuko , Tsujino Naohisa , Nakasato Akane , Seki Yoshinari , Fumoto Masaki , Arita Hideho
Published: April 2008

The present study re‐evaluated an existing notion that serotonin (5‐hydroxytryptamine; 5‐HT) could not cross the brain to the circulating blood via the blood–brain barrier (BBB). To elevate brain 5‐HT alone, 5‐hydroxytryptophan (5‐HTP; 30–75 mg/kg) was administrated intravenously to anaesthetized rats that had undergone gastrointestinal and kidney resections along with liver inactivation (organs contributing to increasing blood 5‐HT after 5‐HTP administration). A microdialysis method and HPLC system were used to determine the brain 5‐HT levels in samples collected from the frontal cortex. Blood 5‐HT levels were determined from whole blood, not platelet‐poor plasma, collected from the central vein. We found that blood 5‐HT levels showed a significant augmentation whenever brain 5‐HT levels were significantly elevated after the administration of 5‐HTP in those rats with the abdominal surgical procedures. This elevation was abolished after pretreatment with a selective serotonin reuptake inhibitor (fluoxetine; 10 mg/kg i.v.), although brain 5‐HT levels remained augmented. These results indicate that augmented brain 5‐HT can cross the BBB through the 5‐HT transporter from the brain to the circulating blood.
Membrane properties of excitatory and inhibitory neurons in the rat prepositus hypoglossi nucleus
Authors: Shino Masato , Ozawa Seiji , Furuya Nobuhiko , Saito Yasuhiko
Published: April 2008

The prepositus hypoglossi nucleus (PHN) is thought to be a neural structure involved in transforming eye or head velocity signals into eye position signals for horizontal eye movements. In this study, we investigated the relationship between electrophysiological membrane properties and expression patterns of cellular markers for excitatory and inhibitory neurons by whole‐cell patch clamp recordings followed by reverse transcription polymerase chain reaction (RT‐PCR) analysis in rat brainstem slices. Three types of voltage response properties, namely afterhyperpolarization (AHP), firing pattern, and response to hyperpolarizing current pulses, were characterized in each neuron. Following RT‐PCR analysis, we identified PHN neurons as either glutamatergic (n = 22) or GABAergic (n = 43), although a small number of cholinergic (n = 2) and glycinergic neurons (n = 1) were also identified. Both glutamatergic and GABAergic neurons showed a wide variety of membrane properties; however, we found several characteristic relationships between neuronal type and membrane properties. Most neurons exhibiting (i) AHP without a slow component, (ii) a firing pattern with a delay in the generation of the first spike, (iii) a firing pattern with a transient burst and (iv) a firing pattern with a prolonged initial interspike interval were GABAergic. On the other hand, glutamatergic neurons were primarily characterized by a low firing rate. These results indicate that there is a close relationship between specific electrophysiological membrane properties and expression of chemical markers in some types of glutamatergic and GABAergic PHN neurons.
The role of RNA editing of the serotonin 2C receptor in a rat model of oro‐facial neuropathic pain
Authors: Nakae Aya , Nakai Kunihiro , Tanaka Tatsuya , Hagihira Saotoshi , Shibata Masahiko , Ueda Koichi , Masimo Takashi
Published: April 2008

We examined whether infraorbital nerve injury affected the RNA editing efficiency of the serotonin (5HT) 2C receptor in the cervical spinal cord, in association with increased pain thresholds, and whether a 5HT reuptake inhibitor (fluvoxamine; Depromel®, Meiji Seika, Tokyo, Japan) altered this editing. Accordingly, we injured rats with an infraorbital nerve loose ligation and examined the pain thresholds, mRNA and mRNA editing of the 5HT2C receptor. We evaluated changes in mRNA editing and 5HT2C mRNA expression using cloning along with sequence analysis and quantitative reverse transcription‐polymerase chain reaction to compare samples taken at post‐injury day 28 from spinal cord sites, including the trigeminal nucleus caudalis, in naive, sham and injured rats (groups of each type had also received fluvoxamine). 5HT2C receptor expression was maintained post‐injury. The RNA editing efficiency was statistically significantly lower at molecular sites A and B in ipsilateral spinal cord samples from injured rats than in bilateral samples from naive and sham rats, and in contralateral samples from injured rats. After injury, the proportional presence of two receptor isoforms changed, i.e. statistically significantly less VNV and significantly more INV and ISV. The proportions reverted after fluvoxamine administration. The post‐injury change might be evidence of a functional adaptation mechanism that increases the expression of 5HT2C mRNA isoforms that encode receptors that are more sensitive to 5HT. This would activate the brainstem–spinal descending 5HT systems and, in effect, suppress nociceptive signals from primary afferent neurons to the spinal trigeminal nucleus caudalis.