bluuebunny/crossref_metadata_2025 huggingface dataset:
Persistent Chlamydia Pneumoniae serology is related to decline in lung function in women but not in men. Effect of persistent Chlamydia pneumoniae infection on lung function
Authors: Gislason Thorarinn , Guðnason Vilmundur , Benediktsdottir Bryndis , Olafsson Isleifur , Aspelund Thor , Thjodleifsson Bjarni , Janson Christer
Published: August 2010

Background

Chlamydia pneumoniae (C pn) infection causes an acute inflammation in the respiratory system that may become persistent, but little is known about the long-term respiratory effects of C pn infections. Aim: To estimate the long term respiratory effects of C pn with change in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) as a main outcome variable.

Methods

The study comprised of 1109 subjects (500 men and 609 women, mean age 28 ± 6 years) that participated in the Reykjavik Heart Study of the Young. Spirometry and blood samples for measurements of IgG antibodies for C pn were done at inclusion and at the end of the follow-up period (mean follow-up time 27 ± 4 years).

Results

Having IgG against C pn at both examinations was significantly associated to a larger decrease in FEV1 (6 mL/year) and FVC (7 mL/year) in women but not in men. In women the association between C pn and larger FEV1 decline was only found in women that smoked at baseline where having C pn IgG was associated with 10 mL/year decline compared to smokers without C pn IgG. These results were still significant after adjustment for age, smoking and change in body weight.

Conclusion

Our results indicate that persistent C pn serology is related to increased decline in lung function in women but not in men. This effect was, however, primarily found in smoking women. This study is a further indication that the pathophysiological process leading to lung impairment may differ between men and women.
The haematopoietic GTPase RhoH modulates IL3 signalling through regulation of STAT activity and IL3 receptor expression
Authors: Gündogdu Mehtap S , Liu He , Metzdorf Daniela , Hildebrand Dagmar , Aigner Michael , Aktories Klaus , Heeg Klaus , Kubatzky Katharina F
Published: August 2010

Background

RhoH is a constitutively active member of the family of Rho GTPases. Its expression is restricted to the haematopoietic lineage, where it serves as a positive regulator for T cell selection and mast cell function and as a negative regulator for growth-related functions in other lineages. Here, we examined the activation of signal transducer and activator of transcription (STAT) proteins in response to stimulation with interleukin 3 (IL3).

Results

Using the murine IL3-dependent cell line BaF3 we investigated the influence of RhoH protein expression levels on IL3-mediated cellular responses. RhoH overexpressing cells showed lower sensitivity to IL3 and decreased STAT5 activation. SiRNA-mediated repression of RhoH gene expression led to an increase in proliferation and STAT5 activity which correlated with an increased number of IL3 receptor α chain molecules, also known as CD123, expressed at the cell surface. Interestingly, these findings could be reproduced using human THP-1 cells as a model system for acute myeloid leukaemia, where low RhoH levels are known to be an unfavourable prognostic marker. Overexpression of RhoH on the other hand caused an induction of STAT1 activity and western blot analysis revealed that activated STAT1 is phosphorylated on Tyr701. STAT1 is known to induce apoptosis or cell cycle arrest and we detected an upregulation of cyclin-dependent kinase inhibitors (CDKI) p21

Cip1
and p27

Kip1
in RhoH overexpressing BaF3 cells.

Conclusions

We propose that RhoH functions as a negative regulator for IL3-induced signals through modulation of the JAK-STAT pathway. High levels of RhoH allow the IL3-dependent activation of STAT1 causing decreased proliferation through upregulation of p21

Cip1
and p27

Kip1
. Low RhoH levels on the other hand led to an upregulation of IL3-dependent cell growth, STAT5 activity and an increase of CD123 surface expression, linking RhoH to a CD123/STAT5 phenotype that has been described in AML patients.
Prevalence of human papillomavirus infection and genotype distribution among high-risk Korean women for prospecting the strategy of vaccine development
Authors: Rhee Jee Eun , Shin Mi Yeong , Kim Choong Mo , Kee Hye Young , Chung Jae Keun , Min Sang-Kee , Kim Seong-Joon , Jang Dai-Ho , Kim Sung Soon , Choi Byeong-Sun
Published: August 2010

We investigated the prevalence of human papillomavirus (HPV) infection and the distribution of high-risk HPV genotypes among 2,308 high-risk Korean women to predict how much the current prophylactic HPV vaccines might affect the prevention of cervical cancer in Korea. HPV DNA was detected in 939 women (40.7%) but only one-third of women were positive for HPV-16 and/or HPV-18, the genotypes used for developing the HPV vaccines. Thus, the development of area-specific HPV vaccines based on dominant HPV genotypes in our country is needed for preventing HPV infection and the development of premalignant lesions in the cervix of Korean women.
Pericyte-specific expression of PDGF beta receptor in mouse models with normal and deficient PDGF beta receptor signaling
Authors: Winkler Ethan A , Bell Robert D , Zlokovic Berislav V
Published: August 2010

Background

Pericytes are integral members of the neurovascular unit. Using mouse models lacking endothelial-secreted platelet derived growth factor-B (PDGF-B) or platelet derived growth factor receptor beta (PDGFRβ) on pericytes, it has been demonstrated that PDGF-B/PDGFRβ interactions mediate pericyte recruitment to the vessel wall in the embryonic brain regulating the development of the cerebral microcirculation and the blood-brain barrier (BBB). Relatively little is known, however, about the roles of PDGF-B/PDGFRβ interactions and pericytes in the adult brain in part due to a lack of adequate and/or properly characterized experimental models. To address whether genetic disruption of PDGFRβ signaling would result in a pericyte-specific insult in adult mice, we studied the pattern and cellular distribution of PDGFRβ expression in the brain in adult control mice and F7 mice that express two hypomorphic Pdgfrβ alleles containing seven point mutations in the cytoplasmic domain of PDGFRβ that impair downstream PDGFRβ receptor signaling.

Results

Using dual fluorescent in situ hybridization, immunofluorescent staining for different cell types in the neurovascular unit, and a fluorescent in situ proximity ligation assay to visualize molecular PDGF-B/PDGFRβ interactions on brain tissue sections, we show for the first time that PDGFRβ is exclusively expressed in pericytes, and not in neurons, astrocytes or endothelial cells, in the adult brain of control 129S1/SvlmJ mice. PDGFRβ co-localized only with well-established pericyte markers such as Chondroitin Sulfate Proteoglycan NG2 and the xLacZ4 transgenic reporter. We next confirm pericyte-specific PDGFRβ expression in the brains of F7 mutants and show that these mice are viable in spite of substantial 40-60% reductions in regional pericyte coverage of brain capillaries.

Conclusions

Our data show that PDGFRβ is exclusively expressed in pericytes in the adult 129S1/Sv1mJ and F7 mouse brain. Moreover, our findings suggest that genetic disruption of PDGFRβ signaling results in a pericyte-specific insult in adult F7 mutants and will not exert a primary effect on neurons because PDGFRβ is not expressed in neurons of the adult 129S1/SvlmJ and F7 mouse brain. Therefore, mouse models with normal and deficient PDGFRβ signaling on a 129S1/SvlmJ background may effectively be used to deduce the specific roles of pericytes in maintaining the cerebral microcirculation and BBB integrity in the adult and aging brain as well as during neurodegenerative and brain vascular disorders.
Cyclosporine-A therapy-induced multiple bilateral breast and accessory axillary breast fibroadenomas: a case report
Authors: Darwish Ahmed , Nasr Ayman O , El Hassan Lamya A , Fahal Ahmed H
Published: August 2010

Introduction

Breast adenoma is common. However, in the setting of post-transplantation immune suppression it may be expressed differently.

Case presentation

A 35-year-old Sudanese woman, with a history of renal transplantation two and half years prior to presentation, was on a single immune suppression therapy in the form of cyclosporine-A since the transplantation. During a regular follow-up visit, she was noticed to have gingival hypertrophy and bilateral breast and axillary swellings. She underwent successful surgical resection of the bilateral fibroadenomas.

Conclusions

Cyclosporine-A therapy post renal transplantation is associated with an increased incidence of benign breast changes as fibroadenoma. Regular follow-up and appropriate selection of immunosuppressant therapy are essential in the post transplantation management of these patients.
Digital expression profiling of novel diatom transcripts provides insight into their biological functions
Authors: Maheswari Uma , Jabbari Kamel , Petit Jean-Louis , Porcel Betina M , Allen Andrew E , Cadoret Jean-Paul , De Martino Alessandra , Heijde Marc , Kaas Raymond , La Roche Julie , Lopez Pascal J , Martin-Jézéquel Véronique , Meichenin Agnès , Mock Thomas , Schnitzler Parker Micaela , Vardi Assaf , Armbrust E Virginia , Weissenbach Jean , Katinka Michaël , Bowler Chris
Published: August 2010

Background

Diatoms represent the predominant group of eukaryotic phytoplankton in the oceans and are responsible for around 20% of global photosynthesis. Two whole genome sequences are now available. Notwithstanding, our knowledge of diatom biology remains limited because only around half of their genes can be ascribed a function based onhomology-based methods. High throughput tools are needed, therefore, to associate functions with diatom-specific genes.

Results

We have performed a systematic analysis of 130,000 ESTs derived from Phaeodactylum tricornutum cells grown in 16 different conditions. These include different sources of nitrogen, different concentrations of carbon dioxide, silicate and iron, and abiotic stresses such as low temperature and low salinity. Based on unbiased statistical methods, we have catalogued transcripts with similar expression profiles and identified transcripts differentially expressed in response to specific treatments. Functional annotation of these transcripts provides insights into expression patterns of genes involved in various metabolic and regulatory pathways and into the roles of novel genes with unknown functions. Specific growth conditions could be associated with enhanced gene diversity, known gene product functions, and over-representation of novel transcripts. Comparative analysis of data from the other sequenced diatom, Thalassiosira pseudonana, helped identify several unique diatom genes that are specifically regulated under particular conditions, thus facilitating studies of gene function, genome annotation and the molecular basis of species diversity.

Conclusions

The digital gene expression database represents a new resource for identifying candidate diatom-specific genes involved in processes of major ecological relevance.
Chemokine expression and control of muscle cell migration during myogenesis
Authors: Griffin Christine A. , Apponi Luciano H. , Long Kimberly K. , Pavlath Grace K.
Published: August 2010

Adult regenerative myogenesis is vital for restoring normal tissue structure after muscle injury. Muscle regeneration is dependent on progenitor satellite cells, which proliferate in response to injury, and their progeny differentiate and undergo cell–cell fusion to form regenerating myofibers. Myogenic progenitor cells must be precisely regulated and positioned for proper cell fusion to occur. Chemokines are secreted proteins that share both leukocyte chemoattractant and cytokine-like behavior and affect the physiology of a number of cell types. We investigated the steady-state mRNA levels of 84 chemokines, chemokine receptors and signaling molecules, to obtain a comprehensive view of chemokine expression by muscle cells during myogenesis in vitro. A large number of chemokines and chemokine receptors were expressed by primary mouse muscle cells, especially during times of extensive cell–cell fusion. Furthermore, muscle cells exhibited different migratory behavior throughout myogenesis in vitro. One receptor–ligand pair, CXCR4–SDF-1α (CXCL12), regulated migration of both proliferating and terminally differentiated muscle cells, and was necessary for proper fusion of muscle cells. Given the large number of chemokines and chemokine receptors directly expressed by muscle cells, these proteins might have a greater role in myogenesis than previously appreciated.
Phosphorylation of STIM1 at ERK1/2 target sites modulates store-operated calcium entry
Authors: Pozo-Guisado Eulalia , Campbell David G. , Deak Maria , Álvarez-Barrientos Alberto , Morrice Nicholas A. , Álvarez Ignacio S. , Alessi Dario R. , Martín-Romero Francisco Javier
Published: August 2010

Store-operated calcium entry (SOCE) is an important Ca2+ entry pathway that regulates many cell functions. Upon store depletion, STIM1, a transmembrane protein located in the endoplasmic reticulum (ER), aggregates and relocates close to the plasma membrane (PM) where it activates store-operated calcium channels (SOCs). Although STIM1 was early defined as a phosphoprotein, the contribution of the phosphorylation has been elusive. In the present work, STIM1 was found to be a target of extracellular-signal-regulated kinases 1 and 2 (ERK1/2) in vitro, and we have defined the ERK1/2-phosphorylated sites on the STIM1 sequence. Using HEK293 cells stably transfected for the expression of tagged STIM1, we found that alanine substitution mutants of ERK1/2 target sites reduced SOCE significantly, suggesting that phosphorylation of these residues are required to fully accomplish SOCE. Indeed, the ERK1/2 inhibitors PD184352 and PD0325901 decreased SOCE in transfected cells. Conversely, 12-O-tetradecanoylphorbol-13-acetate, which activates ERK1/2, enhanced SOCE in cells expressing wild-type tagged STIM1, but did not potentiate Ca2+ influx in cells expressing serine to alanine mutations in ERK1/2 target sites of STIM1. Alanine substitution mutations decreased Ca2+ influx without disturbing the aggregation of STIM1 upon store depletion and without affecting the relocalization in ER–PM punctae. However, our results suggest that STIM1 phosphorylation at ERK1/2 target sites can modulate SOCE by altering STIM1 binding to SOCs, because a significant decrease in FRET efficiency was observed between alanine substitution mutants of STIM1–GFP and ORAI1–CFP.
Specific replication origins promote DNA amplification in fission yeast
Authors: Kiang Lee , Heichinger Christian , Watt Stephen , Bähler Jürg , Nurse Paul
Published: August 2010

To ensure equal replication of the genome in every eukaryotic cell cycle, replication origins fire only once each S phase and do not fire after passive replication. Failure in these controls can lead to local amplification, contributing to genome instability and the development of cancer. To identify features of replication origins important for such amplification, we have investigated origin firing and local genome amplification in the presence of excess helicase loaders Cdc18 and Cdt1 in fission yeast. We find that S phase controls are attenuated and coordination of origin firing is lost, resulting in local amplification. Specific origins are necessary for amplification but act only within a permissive chromosomal context. Origins associated with amplification are highly AT-rich, fire efficiently and early during mitotic S phase, and are located in large intergenic regions. We propose that these features predispose replication origins to re-fire within a single S phase, or to remain active after passive replication.
Isolation of a small vasohibin-binding protein (SVBP) and its role in vasohibin secretion
Authors: Suzuki Yasuhiro , Kobayashi Miho , Miyashita Hiroki , Ohta Hideki , Sonoda Hikaru , Sato Yasufumi
Published: August 2010

Upon stimulation with angiogenic factors, vascular endothelial cells (ECs) secrete a negative-feedback regulator of angiogenesis, vasohibin-1 (VASH1). Because VASH1 lacks a classical signal sequence, it is not clear how ECs secrete VASH1. We isolated a small vasohibin-binding protein (SVBP) composed of 66 amino acids. The level of Svbp mRNA was relatively high in the bone marrow, spleen and testes of mice. In cultured ECs, Vash1 mRNA was induced by VEGF, and Svbp mRNA was expressed constitutively. The interaction between VASH1 and SVBP was confirmed using the BIAcore system and immunoprecipitation analysis. Immunocytochemical analysis revealed that SVBP colocalized with VASH1 in ECs. In polarized epithelial cells, SVBP accumulated on the apical side, whereas VASH1 was present throughout the cells and partially colocalized with SVBP. Transfection of SVBP enhanced VASH1 secretion, whereas knockdown of endogenous SVBP markedly reduced VASH1 secretion. SVBP increased the solubility of VASH1 protein in detergent solution and inhibited the ubiquitylation of VASH1 protein. Moreover, co-transfection of SVBP significantly augmented the inhibitory effect of VASH1 on EC migration. These results indicate that SVBP acts as a secretory chaperone for VASH1 and contributes to the anti-angiogenic activity of VASH1.
A double heterozygote for familial hypercholesterolaemia and familial defective apolipoprotein B-100
Authors: Taylor Alison , Bayly Graham , Patel Kunjan , Yarram Laura , Williams Maggie , Hamilton-Shield Julian , Humphries Steve E , Norbury Gail
Published: August 2010

Autosomal dominant hypercholesterolaemia is genetically heterogeneous, but most commonly (∼93%) caused by mutations in low-density lipoprotein receptor (LDLR), where the disease is known as familial hypercholesterolaemia (FH), or apolipoprotein B-100 ( APOB) (∼5.5%), where the disease is known as familial defective APOB (FDB), while in ∼2% of patients the mutation is in the proprotein convertase subtilisin/kexin type 9 gene. Homozygous FH having inheritance of two LDLR mutations is a rare but recognized syndrome associated with an extreme hypercholesterolaemia and early-onset coronary artery disease. We present a 15-year-old girl with untreated total cholesterol levels of 8.8 mmol/L who was heterozygous for both the LDLR p.Leu479Pro and APOB p.Arg3527Gln mutation. Cascade testing confirmed the paternal origin of the LDLR mutation and revealed a maternal diagnosis of FDB. This case provides further evidence that the combined effect of an LDLR and an APOB mutation give rise to a phenotype more severe than either mutation alone and is more severe than homozygous FDB, but less severe than homozygous FH. It also highlights the need to consider the presence of additional mutations in families where relatives have varying phenotypes.
Feasibility of pathways for the organizational and quality aspects of the use of positron emission tomography in patients with suspected post-transplant lymphoma
Authors: Brepoels Lieselot , Verscuren Raf , Dierickx Daan , Verhoef Gregor
Published: August 2010

As nuclear physicians, we wanted to assess the opportunities and chances of success of clinical pathways in our daily clinical practice, and therefore, we initiated an integrated project concerning the use of positron emission tomography (PET) for the diagnosis of post-transplant lymphoma (post-transplant lymphoproliferative disorder [PTLD]). PTLD is a pathology that occurs typically after long-term immunosuppression in a transplant patient, and often behaves as an aggressive lymphoma. We evaluated the possible benefits of a clinical pathway through the evaluation of the accuracy and cost-effectiveness of PET in this setting. We looked at the difficulties during the development of such a clinical pathway and tried to predict its chances of success. We showed a high accuracy and a substantial financial benefit for the use of PET. Despite this clear benefit, the development of a clinical pathway including PET for diagnosis in PTLD is very difficult due to the very heterogeneous patient population, the urgent nature of the disease and the structure of the organization of the nuclear department. Consequently, the chances of success of such a pathway seem limited to us at this time point, and we propose a different management of the patients with suspicion of PTLD, namely through the development of a central disclosure point.
Hip and knee replacement continuum of care: combining clinical and functional outcome measurement
Authors: Bridgeman Tania , Skinner Harry , Zamansani Tahereh , Schulz Michele
Published: August 2010

The total number of hip and knee arthroplasties has been increasing steadily in the USA every year. The University of California Irvine recognized a high volume activity that could be improved with the implementation of clinical pathways. Data collection was obtained by monitoring the clinical path on 138 patients. Baseline preoperative data and telephonic postoperative data were collected at 90 days postdischarge utilizing quality-of-life/functionality validated tools. Clinical path utilization was 100%. Ambulation day 1 was at 80% for hips and 85% for knees. Blood transfusions were at 56% for hips and 36% for knees. These percentages are well above the US national reported value for autologous blood transfusions of 30%.

The short form 36 health survey questionnaire (SF-36) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) preoperative and postoperative data were available on 47 patients (35%) at 90 days. The WOMAC osteoarthritis index showed a percent mean difference improvement of 82% (pre = 35.8, post = 65.3). The SF-36 revealed statistical significance in physical functioning, role physical, social functioning, bodily pain, energy/vitality and mental health. In conclusion, clinical pathways are a reliable measure of health care. Analysis of clinical path variance and functional outcomes provide the necessary data for making sound business/health-care decisions.
Pregnant Women's Beliefs About Medications—A Study Among 866 Norwegian Women
Authors: Nordeng Hedvig , Koren Gideon , Einarson Adrienne
Published: August 2010

Background:

Beliefs about medication may impact a woman's decision to take a needed medication during pregnancy. While many women will be faced with decisions regarding medication use during pregnancy, there is a paucity of research on this topic in the literature.

Objective:

To study pregnant women's beliefs about medication and factors that determine those beliefs.

Methods:

A questionnaire was posted at the University of Oslo's Web site for Internet surveys for 5 weeks from mid-September 2008 through October 2008. Seven general statements from the “Beliefs about Medicines” questionnaire and 9 pregnancy-specific statements were used to assess pregnant women's attitudes toward medication use during pregnancy. Other information, such as sociodemographic background and personal medication use during pregnancy, was also collected.

Results:

A total of 866 pregnant women completed the questionnaire. Most women had a positive attitude toward medication in general, but believed pregnant women should be more restrictive regarding use than nonpregnant women. There was a significant association between women's education, occupation, and attitudes, with less educated women believing that medications in general were harmful and herbal remedies were safe, while women with a higher education were more reluctant to use any medication in pregnancy. Women with health-related occupations were more knowledgeable about the possible risks of untreated illness during pregnancy. There was also an association between pregnant women's attitudes and their use of prescribed penicillins and herbal remedies.

Conclusions:

Most pregnant women believe that medicines in general are helpful and safe to use. However, they are much more restrictive and unsure about use during pregnancy. Health-care professionals should be aware of such attitudes when advising a woman to take a needed medication during pregnancy.
Defects in Mitochondrial Axonal Transport and Membrane Potential without Increased Reactive Oxygen Species Production in aDrosophilaModel of Friedreich Ataxia
Authors: Shidara Yujiro , Hollenbeck Peter J.
Published: August 2010

Friedreich ataxia, a neurodegenerative disorder resulting from frataxin deficiency, is thought to involve progressive cellular damage from oxidative stress. InDrosophilalarvae with reduced frataxin expression (DfhIR), we evaluated possible mechanisms of cellular neuropathology by quantifying mitochondrial axonal transport, membrane potential (MMP), and reactive oxygen species (ROS) production in the DfhIR versus wild-type nervous system throughout development. Although dying-back neuropathy in DfhIR larvae did not occur until late third instar, reduced MMP was already apparent at second instar in the cell bodies, axons and neuromuscular junctions (NMJs) of segmental nerves. Defects in axonal transport of mitochondria appeared late in development in distal nerve of DfhIR larvae, with retrograde movement preferentially affected. As a result, by late third instar the neuromuscular junctions (NMJs) of DfhIR larvae accumulated a higher density of mitochondria, many of which were depolarized. Notably, increased ROS production was not detected in any neuronal region or developmental stage in DfhIR larvae. However, when challenged with antimycin A, neurons did respond with a larger increase in ROS. We propose that pathology in the frataxin-deficient nervous system involves decreased MMP and ATP production followed by failures of mitochondrial transport and NMJ function.
Theta Oscillations Reflect the Dynamics of Interference in Episodic Memory Retrieval
Authors: Staudigl Tobias , Hanslmayr Simon , Bäuml Karl-Heinz T.
Published: August 2010

Selectively retrieving episodic information from a cue often induces interference from related episodes. To promote successful retrieval of the target episode, such interference is resolved by inhibition, causing retrieval-induced forgetting of the related but irrelevant information. Passively studying the episodic information again (reexposure) does not show this effect. This study examined the hypothesis that brain oscillations in the theta band (5–9 Hz) reflect the dynamics of interference in selective memory retrieval, analyzing EEG data from 24 healthy human subjects (21 women, 3 men). High versus low levels of interference were investigated by comparing the effects of selective retrieval with the effects of reexposure of material, with the former, but not the latter, inducing interference. Moreover, we analyzed repeated cycles of selective retrieval and reexposure, assuming that interference is reduced by inhibition across retrieval cycles, but not across reexposure cycles. We found greater theta band activity in selective retrieval than in reexposure, and a reduction in theta amplitude from the first to the second cycle of retrieval predicting the amount of retrieval-induced forgetting; the sources of theta amplitude reduction across retrieval cycles were located in the anterior cingulate cortex. No difference in theta activity was found across repeated cycles of reexposure. The results suggest that higher levels of interference in episodic memory are indexed by more theta band activity, and that successful interference resolution via inhibition causes a reduction in theta amplitude. Thus, theta band activity can serve as a neural marker of the dynamics of interference in selective episodic retrieval.
Neural Predictors of Within-Subject Fluctuations in Attentional Control
Authors: Leber Andrew B.
Published: August 2010

Whether salient objects automatically capture attention has long been the subject of considerable controversy. A possible resolution, investigated in this functional magnetic resonance imaging (fMRI) study, is that observers vacillate between periods when attention capture is robust and when it is minimal. Human observers searched static displays for a target circle among nontarget squares; an irrelevant color singleton distractor appeared on 50% of trials. Behavioral results showed a distraction effect in which response times to distractor-present trials were slower than for distractor-absent trials. fMRI results confirmed that this distraction effect not only fluctuated within experimental sessions, but the momentary degree of distraction could be predicted in advance by pretrial activity in middle frontal gyrus. A second experiment ruled out an alternative account by which participants achieved resistance to capture by trading off search efficiency. Together, these data reveal that observers frequently exert the capacity to resist attentional distraction, although they do not to sustain this capacity for long periods of time.
Direct Innervation and Modulation of Orexin Neurons by Lateral Hypothalamic LepRb Neurons
Authors: Louis Gwendolyn W. , Leinninger Gina M. , Rhodes Christopher J. , Myers Martin G.
Published: August 2010

Leptin, the adipose-derived hormonal signal of body energy stores, acts via the leptin receptor (LepRb) on neurons in multiple brain regions. We previously identified LepRb neurons in the lateral hypothalamic area (LHA), which are distinct from neighboring leptin-regulated melanin-concentrating hormone (MCH)- or orexin (OX)-expressing cells. Neither the direct synaptic targets of LHA LepRb neurons nor their potential role in the regulation of other LHA neurons has been determined, however. We thus generated several adenoviral and transgenic systems in which cre recombinase promotes the expression of the tracer, WGA (wheat germ agglutinin), and used these in combination with LepRbcremice to determine the neuronal targets of LHA LepRb neurons. This analysis revealed that, although some LHA LepRb neurons project to dopamine neurons in the ventral tegmental area, LHA LepRb neurons also densely innervate the LHA where they directly synapse with OX, but not MCH, neurons. Indeed, few other LepRb neurons in the brain project to the OX-containing region of the mouse LHA, and direct leptin action via LHA LepRb neurons regulates gene expression in OX neurons. These findings thus reveal a major role for LHA leptin action in the modulation of OX neurons, suggesting the importance of LHA LepRb neurons in the regulation of OX signaling that is crucial to leptin action and metabolic control.
Unexpected Survival of Neurons of Origin of the Pyramidal Tract after Spinal Cord Injury
Authors: Nielson Jessica L. , Sears-Kraxberger Ilse , Strong Melissa K. , Wong Jamie K. , Willenberg Rafer , Steward Oswald
Published: August 2010

There is continuing controversy about whether the cells of origin of the corticospinal tract (CST) undergo retrograde cell death after spinal cord injury (SCI). All previous attempts to assess this have used imaging and/or histological techniques to assess upper motoneurons in the cerebral cortex. Here, we address the question in a novel way by assessing Wallerian degeneration and axon numbers in the medullary pyramid of Sprague Dawley rats after both acute SCI, either at cervical level 5 (C5) or thoracic level 9 (T9), and chronic SCI at T9. Our findings demonstrate that only a fraction of a percentage of the total axons in the medullary pyramid exhibit any sign of degeneration at any time after SCI—no more so than in uninjured control rats. Moreover, design-based counts of myelinated axons revealed no decrease in axon number in the medullary pyramid after SCI, regardless of injury level, severity, or time after injury. Spinal cord-injured rats had fewer myelinated axons in the medullary pyramid at 1 year after injury than aged matched controls, suggesting that injury may affect ongoing myelination of axons during aging. We conclude that SCI does not cause death of the CST cell bodies in the cortex; therefore, therapeutic strategies aimed at promoting axon regeneration of the CST in the spinal cord do not require a separate intervention to prevent retrograde degeneration of upper motoneurons in the cortex.
Target-Specific Encoding of Response Inhibition: Increased Contribution of AMPA to NMDA Receptors at Excitatory Synapses in the Prefrontal Cortex
Authors: Hayton Scott J. , Lovett-Barron Matthew , Dumont Eric C. , Olmstead Mary C.
Published: August 2010

Impulse control suppresses actions that are inappropriate in one context, but may be beneficial in others. The medial prefrontal cortex (mPFC) mediates this process by providing a top-down signal to inhibit competing responses, although the mechanism by which the mPFC acquires this ability is unknown. To that end, we examined synaptic changes in the mPFC associated with learning to inhibit an incorrect response. Rats were trained in a simple response inhibition task to withhold responding until a signal was presented. We then measured synaptic plasticity of excitatory synapses in the mPFC, using whole-cell patch-clamp recordings, in brain slices prepared from trained rats. Response inhibition training significantly increased the relative contribution of AMPA receptors to the overall EPSC in prelimbic, but not infralimbic, neurons of the mPFC. This potentiation of synaptic transmission closely paralleled the acquisition and extinction of response inhibition. Using a retrograde fluorescent tracer, we observed that these plastic changes were selective for efferents projecting to the ventral striatum, but not the dorsal striatum or amygdala. Therefore, we suggest that response inhibition is encoded by a selective strengthening of a subset of corticostriatal projections, uncovering a synaptic mechanism of impulse control. This information could be exploited in therapeutic interventions for disorders of impulse control, such as addiction, attention deficit–hyperactivity disorder, and schizophrenia.
Reward Prediction Error Coding in Dorsal Striatal Neurons
Authors: Oyama Kei , Hernádi István , Iijima Toshio , Tsutsui Ken-Ichiro
Published: August 2010

In the current theory of learning, the reward prediction error (RPE), the difference between expected and received reward, is thought to be a key factor in reward-based learning, working as a teaching signal. The activity of dopamine neurons is known to code RPE, and the release of dopamine is known to modify the strength of synaptic connectivity in the target neurons. A fundamental interest in current neuroscience concerns the origin of RPE signals in the brain. Here, we show that a group of rat striatal neurons show a clear parametric RPE coding similar to that of dopamine neurons when tested under probabilistic pavlovian conditioning. Together with the fact that striatum and dopamine neurons have strong direct and indirect fiber connections, the result suggests that the striatum plays an important role in coding RPE signal by cooperating with dopamine neurons.
In VivoNMDA Receptor Activation Accelerates Motor Unit Maturation, Protects Spinal Motor Neurons, and Enhances SMN2 Gene Expression in Severe Spinal Muscular Atrophy Mice
Authors: Biondi Olivier , Branchu Julien , Sanchez Gabriel , Lancelin Camille , Deforges Séverine , Lopes Philippe , Pariset Claude , Lécolle Sylvie , Côté Jocelyn , Chanoine Christophe , Charbonnier Frédéric
Published: August 2010

Spinal muscular atrophy (SMA), a lethal neurodegenerative disease that occurs in childhood, is caused by the misexpression of the survival of motor neuron (SMN) protein in motor neurons. It is still unclear whether activating motor units in SMA corrects the delay in the postnatal maturation of the motor unit resulting in an enhanced neuroprotection. In the present work, we demonstrate that an adequate NMDA receptor activation in a type 2 SMA mouse model significantly accelerated motor unit postnatal maturation, counteracted apoptosis in the spinal cord, and induced a marked increase of SMN expression resulting from a modification of SMN2 gene transcription pattern. These beneficial effects were dependent on the level of NMDA receptor activation since a treatment with high doses of NMDA led to an acceleration of the motor unit maturation but favored the apoptotic process and decreased SMN expression. In addition, these results suggest that the NMDA-induced acceleration of motor unit postnatal maturation occurred independently of SMN. The NMDA receptor activating treatment strongly extended the life span in two different mouse models of severe SMA. The analysis of the intracellular signaling cascade that lay downstream the activated NMDA receptor revealed an unexpected reactivation of the CaMKII/AKT/CREB (cAMP response element-binding protein) pathway that induced an enhanced SMN expression. Therefore, pharmacological activation of spinal NMDA receptors could constitute a useful strategy for both increasing SMN expression and limiting motor neuron death in SMA spinal cord.
Hippocampal Ripple-Contingent Training Accelerates Trace Eyeblink Conditioning and Retards Extinction in Rabbits
Authors: Nokia Miriam S. , Penttonen Markku , Wikgren Jan
Published: August 2010

There are at least two distinct oscillatory states of the hippocampus that are related to distinct behavioral patterns. Theta (4–12 Hz) oscillation has been suggested to indicate selective attention during which the animal concentrates on some features of the environment while suppressing reactivity to others. In contrast, sharp-wave ripples (∼200 Hz) can be seen in a state in which the hippocampus is at its most responsive to any kind of afferent stimulation. In addition, external stimulation tends to evoke and reset theta oscillation, the phase of which has been shown to modulate synaptic plasticity in the hippocampus. Theoretically, training on a hippocampus-dependent learning task contingent upon ripples could enhance learning rate due to elevated responsiveness and enhanced phase locking of the theta oscillation. We used a brain–computer interface to detect hippocampal ripples in rabbits to deliver trace eyeblink conditioning and extinction trials selectively contingent upon them. A yoked control group was trained regardless of their ongoing neural state. Ripple-contingent training expedited acquisition of the conditioned response early in training and evoked stronger theta-band phase locking to the conditioned stimulus. Surprisingly, ripple-contingent training also resulted in slower extinction in well trained animals. We suggest that the ongoing oscillatory activity in the hippocampus determines the extent to which a stimulus can induce a phase reset of the theta oscillation, which in turn is the determining factor of learning rate in trace eyeblink conditioning.
Rats Markedly Escalate Their Intake and Show a Persistent Susceptibility to Reinstatement Only When Cocaine Is Injected Rapidly
Authors: Wakabayashi Ken T. , Weiss Mark J. , Pickup Kristen N. , Robinson Terry E.
Published: August 2010

When drugs enter the brain rapidly, liability for addiction is increased, but why this is the case is not well understood. Here we examined the influence of varying the speed of intravenous cocaine delivery on self-administration behavior in rats given limited or extended opportunity to take drug. The speed of cocaine delivery had no effect on self-administration behavior when rats were given only 1 h each day to take cocaine. When given sixfold more time to take cocaine, rats that received cocaine rapidly (5–45 s) increased their total intake eightfold. However, rats that received cocaine more slowly (>90 s) did not avail themselves of the opportunity to take much more drug: they increased their intake only twofold. Furthermore, when tested 45 d after the last self-administration session, a drug-priming injection reinstated drug-seeking behavior only in rats that in the past had cocaine injected rapidly (5 s), and this was associated with a persistent suppression in the ability of cocaine to induce immediate early gene expression. Cocaine may be potentially more addictive when it reaches the brain rapidly because (1) this promotes a marked escalation in intake and (2) it renders individuals more susceptible to relapse long after the discontinuation of drug use. This is presumably because the rapid uptake of drug to the brain preferentially promotes persistent changes in brain systems that regulate motivation for drug, and continuing exposure to large amounts of drug produces a vicious cycle of additional maladaptive changes in brain and behavior.
Impaired Orthotopic Glioma Growth and Vascularization in Transgenic Mouse Models of Alzheimer's Disease
Authors: Paris Daniel , Ganey Nowel , Banasiak Magdalena , Laporte Vincent , Patel Nikunj , Mullan Myles , Murphy Susan F. , Yee Gi-Taek , Bachmeier Corbin , Ganey Christopher , Beaulieu-Abdelahad David , Mathura Venkatarajan S. , Brem Steven , Mullan Michael
Published: August 2010

Alzheimer's disease (AD) is the most common form of dementia among the aging population and is characterized pathologically by the progressive intracerebral accumulation of β-amyloid (Aβ) peptides and neurofibrillary tangles. The level of proangiogenic growth factors and inflammatory mediators with proangiogenic activity is known to be elevated in AD brains which has led to the supposition that the cerebrovasculature of AD patients is in a proangiogenic state. However, angiogenesis depends on the balance between proangiogenic and antiangiogenic factors and the brains of AD patients also show an accumulation of endostatin and Aβ peptides which have been shown to be antiangiogenic. To determine whether angiogenesis is compromised in the brains of two transgenic mouse models of AD overproducing Aβ peptides (Tg APPsw and Tg PS1/APPsw mice), we assessed the growth and vascularization of orthotopically implanted murine gliomas since they require a high degree of angiogenesis to sustain their growth. Our data reveal that intracranial tumor growth and angiogenesis is significantly reduced in Tg APPsw and Tg PS1/APPsw mice compared with their wild-type littermates. In addition, we show that Aβ inhibits the angiogenesis stimulated by glioma cells when cocultured with human brain microvascular cells on a Matrigel layer. Altogether our data suggest that the brain of transgenic mouse models of AD does not constitute a favorable environment to support neoangiogenesis and may explain why vascular insults synergistically precipitate the cognitive presentation of AD.
Alternative Splicing of Neuroligin Regulates the Rate of Presynaptic Differentiation
Authors: Lee Hanson , Dean Camin , Isacoff Ehud
Published: August 2010

Neuroligins (NLGs) and Neurexins (NRXs) are important adhesion molecules that promote synapse formation. Multiple splice variants of NLG and NRX exist, but their specific functions are unclear. Here we report that a surrogate postsynaptic cell expressing full-length NLG-1 triggers slow presynaptic differentiation in a contacting axon. In contrast, a version of NLG-1, which lacks insert B (NLG-1ΔB), induces rapid presynaptic differentiation, reaching the rate seen at native neuronal synapses. We show that this acceleration is attributed to the removal of the N-linked glycosylation site within insert B. NLG-1ΔB also increases synaptic density at neuro-neuronal synapses more than does full-length NLG-1. Other postsynaptic adhesion proteins, such as N-cadherin, EphB2, and SynCAM-1, alone or in combination with full-length NLG-1, do not trigger fast differentiation, suggesting that rapid presynaptic differentiation depends on a unique interaction of NLG-1ΔB with axonal proteins. Indeed, we find that NLG-1ΔB recruits more axonal α-NRX. Our results suggest that the engagement of α-NRX is a key to rapid induction of synapses at new sites of axo-dendritic contact.
Characterization of the Intracellular Localization, Processing, and Secretion of Two Glial Cell Line-Derived Neurotrophic Factor Splice Isoforms
Authors: Lonka-Nevalaita Liina , Lume Maria , Leppänen Satu , Jokitalo Eija , Peränen Johan , Saarma Mart
Published: August 2010

Endocrine and neuronal cells have highly developed secretion mechanisms, and the secretion can be either constitutive or regulated by physiological stimuli. In the constitutive pathway, intracellular transport vesicles undergo immediate fusion reactions after arrival at the target. In regulated secretion, vesicles accumulate near the target membrane until triggered to fuse, typically by a local rise in free Ca2+. In the present study, we characterize the processing and secretion mechanisms of the glial cell line-derived neurotrophic factor (GDNF). Although the function of GDNF has been extensively studied, very little is known about the basic cell biology of GDNF and its precursor forms (α)pro-GDNF and (β)pro-GDNF that have different pro-regions. Our results show that both (α)pro-GDNF and (β)pro-GDNF are secreted. We demonstrate that KCl-induced depolarization increases the secretion of (β)pro-GDNF and corresponding mature GDNF, but not (α)pro-GDNF and corresponding mature GDNF, to the cell medium in a Ca2+-dependent manner. In parallel with this, immunofluorescence analysis of cells show that (α)pro-GDNF/GDNF is localized mostly in the Golgi complex, whereas (β)pro-GDNF/GDNF is localized primarily in secretogranin II and Rab3A-positive vesicles of the regulated secretory pathway. In addition, we find that matrix metalloproteinases and plasmin that cleave pro-BDNF and pro-NGF are not responsible for the cleavage of pro-GDNF, whereas furin endoproteinase, PACE4, and proprotein convertases PC5A, PC5B, and PC7 can cleave pro-GDNF into mature GDNF. Thus, the processing and secretion mechanisms of GDNF are different from those of BDNF and NGF.
Periodicity and Evoked Responses in Motor Cortex
Authors: Reimer Jacob , Hatsopoulos Nicholas G.
Published: August 2010

Spiking in primary motor cortex (MI) exhibits a characteristic beta frequency periodicity, but the functional relevance of this rhythmic firing is controversial. We simultaneously recorded multiple single units and local field potentials in MI in two monkeys (Macaca mulatta) during continuous, self-paced movements to serially presented targets. We find that the appearance of each new target evokes precisely timed spiking in MI at a characteristic latency but that the exact timing of this response varies depending on its relationship to the phase of the ongoing beta range oscillation. As a result of this interaction between evoked spiking and endogenous beta periodicity, we find that the amount of information about target location encoded in the spiking of MI neurons is not simply a function of elapsed time but depends also on oscillatory phase. Our results suggest that periodicity may be an important feature of the early stages of sensorimotor processing in the cortical motor system.
Sex, Love, and Autonomy in the Teenage Sleepover
Authors: Schalet Amy
Published: August 2010

Karel Doorman, a soft-spoken civil servant in the Netherlands, keeps tabs on his teenage children's computer use and their jobs to make sure neither interferes with school performance or family time. But Karelwouldn't object if his daughter Heidiwere to have a sexual relationship.
Is Hooking Up Bad for Young Women?
Authors: Armstrong Elizabeth A. , Hamilton Laura , England Paula
Published: August 2010

“Girls can't be guys in matters of the heart, even though they think they can,” says Laura Sessions Stepp, author of Unhooked: HowYoung Women Pursue Sex, Delay Love, and Lose at Both, published in 2007. In her view, “hooking up”—casual sexual activity ranging from kissing to intercourse—places women at risk of “low self-esteem, depression, alcoholism, and eating disorders.” Stepp is only one of half a dozen journalists currently engaged in the business of detailing the dangers of casual sex.
Straight Girls Kissing
Authors: Rupp Leila J. , Taylor Verta
Published: August 2010

The phenomenon of presumably straight girls kissing and making out with other girls at college parties and at bars is everywhere in contemporary popular culture, from Katy Perry's hit song, “I Kissed a Girl,” to a Tyra Banks online poll on attitudes toward girls who kiss girls in bars, to AskMen.com 's “Top 10: Chick Kissing Scenes.” Why do girls who aren't lesbians kiss girls?