bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of Bmi-1 is a prognostic marker in bladder cancer
Authors: Qin Zi-Ke , Yang Jian-An , Ye Yun-lin , Zhang Xing , Xu Li-Hua , Zhou Fang-Jian , Han Hui , Liu Zuo-Wei , Song Li-Bing , Zeng Mu-Sheng
Published: February 2009

Background

The molecular mechanisms of the development and progression of bladder cancer are poorly understood. The objective of this study was to analyze the expression of Bmi-1 protein and its clinical significance in human bladder cancer.

Methods

We examined the expression of Bmi-1 mRNA and Bmi-1 protein by RT-PCR and Western blot, respectively in 14 paired bladder cancers and the adjacent normal tissues. The expression of Bmi-1 protein in 137 specimens of bladder cancer and 30 specimens of adjacent normal bladder tissue was determined by immunohistochemistry. Statistical analyses were applied to test the relationship between expression of Bmi-1, and clinicopathologic features and prognosis.

Results

Expression of Bmi-1 mRNA and protein was higher in bladder cancers than in the adjacent normal tissues in 14 paired samples (P < 0.01). By immunohistochemical examination, five of 30 adjacent normal bladder specimens (16.7%) versus 75 of 137 bladder cancers (54.3%) showed Bmi-1 protein expression (P < 0.05). Bmi-1 protein expression was intense in 20.6%, 54.3%, and 78.8% of tumors of histopathological stages G1, G2, and G3, respectively (P < 0.05). Expression of Bmi-1 protein was greater in invasive bladder cancers than in superficial bladder cancers (81.5% versus 32.5%, P < 0.05). In invasive bladder cancers, the expression of Bmi-1 protein in progression-free cancers was similar to that of cancers that have progressed (80.0% versus 82.4%, P > 0.5). In superficial bladder cancers, the expression of Bmi-1 protein in recurrent cases was higher than in recurrence-free cases (62.5% versus 13.7%, P < 0.05). Bmi-1 expression was positively correlated with tumor classification and TNM stage (P < 0.05), but not with tumor number (P > 0.05). Five-year survival in the group with higher Bmi-1 expression was 50.8%, while it was 78.5% in the group with lower Bmi-1 expression (P < 0.05). Patients with higher Bmi-1 expression had shorter survival time, whereas patients with lower Bmi-1 expression had longer survival time (P < 0.05).

Conclusion

Expression of Bmi-1 was greater in bladder cancers than in the adjacent normal tissues. The examination of Bmi-1 protein expression is potentially valuable in prognostic evaluation of bladder cancer.
Influence of HFE variants and cellular iron on monocyte chemoattractant protein-1
Authors: Mitchell Ryan M , Lee Sang Y , Randazzo William T , Simmons Zachary , Connor James R
Published: February 2009

Background

Polymorphisms in theMHC class 1-likegene known asHFEhave been proposed as genetic modifiers of neurodegenerative diseases that include neuroinflammation as part of the disease process. Variants ofHFEare relatively common in the general population and are most commonly associated with iron overload, but can promote subclinical cellular iron loading even in the absence of clinically identified disease. The effects of the variants as well as the resulting cellular iron dyshomeostasis potentially impact a number of disease-associated pathways. We tested the hypothesis that the two most common HFE variants, H63D and C282Y, would affect cellular secretion of cytokines and trophic factors.

Methods

We screened a panel of cytokines and trophic factors using a multiplexed immunoassay in human neuroblastoma SH-SY5Y cells expressing different variants of HFE. The influence of cellular iron secretion on the potent chemokine monocyte chemoattractant protein-1 (MCP-1) was assessed using ferric ammonium citrate and the iron chelator, desferroxamine. Additionally, an antioxidant, Trolox, and an anti-inflammatory, minocycline, were tested for their effects on MCP-1 secretion in the presence of HFE variants.

Results

Expression of the HFE variants altered the labile iron pool in SH-SY5Y cells. Of the panel of cytokines and trophic factors analyzed, only the release of MCP-1 was affected by the HFE variants. We further examined the relationship between iron and MCP-1 and found MCP-1 secretion tightly associated with intracellular iron status. A potential direct effect of HFE is considered because, despite having similar levels of intracellular iron, the association between HFE genotype and MCP-1 expression was different for the H63D and C282Y HFE variants. Moreover, HFE genotype was a factor in the effect of minocycline, a multifaceted antibiotic used in treating a number of neurologic conditions associated with inflammation, on MCP-1 secretion.

Conclusion

Our results demonstrate that HFE polymorphisms influence the synthesis and release of MCP-1. The mechanism of action involves cellular iron status but it appears there could be additional influences such as ER stress. Finally, these data demonstrate a pharmacogenetic effect of HFE polymorphisms on the ability of minocycline to inhibit MCP-1 secretion.
Intra- and inter-individual variation of BIS-index® and Entropy® during controlled sedation with midazolam/remifentanil and dexmedetomidine/remifentanil in healthy volunteers: an interventional study
Authors: Haenggi Matthias , Ypparila-Wolters Heidi , Hauser Kathrin , Caviezel Claudio , Takala Jukka , Korhonen Ilkka , Jakob Stephan M
Published: February 2009

Introduction

We studied intra-individual and inter-individual variability of two online sedation monitors, BIS® and Entropy®, in volunteers under sedation.

Methods

Ten healthy volunteers were sedated in a stepwise manner with doses of either midazolam and remifentanil or dexmedetomidine and remifentanil. One week later the procedure was repeated with the remaining drug combination. The doses were adjusted to achieve three different sedation levels (Ramsay Scores 2, 3 and 4) and controlled by a computer-driven drug-delivery system to maintain stable plasma concentrations of the drugs. At each level of sedation, BIS® and Entropy® (response entropy and state entropy) values were recorded for 20 minutes. Baseline recordings were obtained before the sedative medications were administered.

Results

Both inter-individual and intra-individual variability increased as the sedation level deepened. Entropy® values showed greater variability than BIS® values, and the variability was greater during dexmedetomidine/remifentanil sedation than during midazolam/remifentanil sedation.

Conclusions

The large intra-individual and inter-individual variability of BIS® and Entropy® values in sedated volunteers makes the determination of sedation levels by processed electroencephalogram (EEG) variables impossible. Reports in the literature which draw conclusions based on processed EEG variables obtained from sedated intensive care unit (ICU) patients may be inaccurate due to this variability.

Trial registration

clinicaltrials.gov Nr. NCT00641563.
Commercialization, patenting and genomics: researcher perspectives
Authors: Murdoch CJ , Caulfield Timothy
Published: February 2009

The impact of commercialization and patenting pressure on genomics research is still a topic of considerable debate in academic, policy and popular literature. We interviewed genomic researchers to see if their perspectives offered fresh insights. Regional Genome Canada centers provided us with relevant researcher contact information, and in-depth structured interviews were conducted. Researcher perspectives were sharply divided, with both support and concern for commercialization regimes surfacing in interviews. Data withholding and publication delays were commonly reported, but the aggressive enforcement of patents was not. There are parallels to the Stem Cell community in Canada in these respects. Genomic researchers, as individuals directly implicated in the field of controversy, have developed varied and often novel insights which should be incorporated into the ongoing debates surrounding commercialization and patenting. Many researchers continue to raise concerns, particularly in relation to data withholding, thus emphasizing the need for a continued exploration of the complex issues associated with commercialization and patenting.
Christine de Pizan, Isabeau of Bavaria, and Female Regency
Authors: Adams Tracy
Published: February 2009

What motivated Christine de Pizan's Book of the City of Ladies? This essay argues that the poet's defenses of women were intended to train readers how to envisage the role of Queen Isabeau of Bavaria, who presided over the royal council when her husband, King Charles VI, suffered bouts of madness. Christine's examples of women who ruled in the name of their husbands, sons, and fathers and her references to the ultimate coregent, the Virgin Mary, support female coregency as outlined in Charles VI's ordinances, that is, coregency by a sure guardian of royal authority against the threats posed by the king's male relatives. Although Christine insisted on the female aptitude for power, she never urged that women be allowed to rule in their own names, nor did she appeal for powers that they did not already possess under customary law as representatives of their husbands, sons, or fathers.
“A Reserved Place”? English Catholic Exiles and Contested Space in Late-Sixteenth-Century Paris
Authors: Gibbons Katy
Published: February 2009

English and Scottish Catholic exiles interacted with the complex urban environment of late-sixteenth-century Paris in a variety of ways. Historians usually concentrate on their contribution to the radical polemic that accompanied the rise of the Catholic League. This approach can be complemented with an examination of the ways in which they established or claimed physical space for themselves. The parish church of Saints-Cosme-et-Damien and Collège Mignon were key venues for such efforts. Both were themselves contested spaces within the French capital. In pursuing space for themselves on the Left Bank, the exiles became embroiled in the confessional conflicts of the sixteenth century. The strategies that they and other competing parties employed drew on established precedent while also taking advantage of contemporary jurisdictional quarrels within Paris and of wider religious and political instability. In fact, the already contested nature of these spaces offered new opportunities to the exiles.
An Ambiguous Monument: Dakar's Colonial Cathedral of the Souvenir Africain
Authors: Foster Elizabeth A.
Published: February 2009

This article explores the conception, construction, and consecration of Dakar's cathedral of the Souvenir Africain between 1910 and 1936 and charts the evolution of the project in the context of religious and political “tensions of empire” in Senegal and in France. The Catholic mission of Senegambia billed the project as a patriotic memorial to the French who had died colonizing Africa and, after World War I, to all the African and French troops who had died fighting for France in Europe. The cathedral formed part of the missionaries' sustained and unsuccessful effort to convince the colonial administration of the value of their Catholic “civilizing mission.” The lavish consecration in 1936 appeared to demonstrate that the Catholic mission and the colonial administration were close allies, but it in fact obscured their fundamentally different agendas, reflecting instead a metropolitan-based ideal of a “plus grande France.” The Souvenir Africain was thus an ambiguous monument that represented two uneasy pairings: that of the Catholic Church and the colonial state, and that of French colonialists and the Africans they ruled.
Les Annales de Lucien Febvre À Fernand Braudel: Entre Épopée Coloniale Et Opposition Orient/Occident
Authors: Paligot Carole Reynaud
Published: February 2009

Les fondateurs et directeurs des Annales ont largement partagé la culture coloniale de leur temps. A travers ses comptes rendus et en intégrant des collaborateurs issus du monde colonial, la revue a accordé une large place à la colonisation. Prestige de la Grande France, admiration pour l'épopée coloniale et l'œuvre des colons, mission civilisatrice, opposition séculaire entre l'Orient et l'Occident caractérisent les articles de la revue qui intègre ainsi pleinement l'idéologie coloniale de l'époque. Lucien Febvre, Marc Bloch et Fernand Braudel ont accordé un grand crédit aux écrits de figures emblématiques de la culture coloniale de l'époque, Henri Labouret, Emile-Félix Gautier, Augustin Bernard mais aussi à la psychologie des peuples d'André Siegfried. Jusqu'à l'arrivée d'une nouvelle génération dans les années 1950, la revue a été peu attentive aux premières critiques dénonçant les abus de la colonisation, tout comme aux premières manifestations nationalistes.
BMP canonical Smad signaling throughSmad1andSmad5is required for endochondral bone formation
Authors: Retting Kelsey N. , Song Buer , Yoon Byeong S. , Lyons Karen M.
Published: February 2009

Bone morphogenetic protein (BMP) signaling is required for endochondral bone formation. However, whether or not the effects of BMPs are mediated via canonical Smad pathways or through noncanonical pathways is unknown. In this study we have determined the role of receptor Smads 1, 5 and 8 in chondrogenesis. Deletion of individual Smads results in viable and fertile mice. Combined loss of Smads 1, 5 and 8, however, results in severe chondrodysplasia. Smad1/5CKO (cartilage-specific knockout)mutant mice are nearly identical to Smad1/5CKO;Smad8-/- mutants, indicating that Smads 1 and 5 have overlapping functions and are more important than Smad8 in cartilage. The Smad1/5CKO phenotype is more severe than that of Smad4CKO mice, challenging the dogma, at least in chondrocytes, that Smad4 is required to mediate Smad signaling through BMP pathways. The chondrodysplasia in Smad1/5CKO mice is accompanied by imbalances in cross-talk between the BMP, FGF and Ihh/PTHrP pathways. We show that Ihh is a direct target of BMP pathways in chondrocytes, and that FGF exerts antagonistic effects on Ihhexpression. Finally, we tested whether FGF exerts its antagonistic effects directly through Smad linker phosphorylation. The results support the alternative conclusion that the effects of FGFs on BMP signaling are indirect in vivo.
Increased RNAi is related to intracellular release of siRNA via a covalently attached signal peptide
Authors: Detzer Anke , Overhoff Marita , Wünsche Winfried , Rompf Maria , Turner John J. , Ivanova Gabriela D. , Gait Michael J. , Sczakiel Georg
Published: February 2009

In the last decade short interfering RNA (siRNA) became an important means for functional genomics and the development of gene-specific drugs. However, major technical hurdles in the application of siRNA include its cellular delivery followed by its intracellular trafficking and its release in order to enter the RNA interference (RNAi) machinery. The novel phosphorothioate-stimulated cellular uptake of siRNA contrasts other known delivery systems because it involves a caveosomal pathway in which large amounts of siRNA are delivered to the perinuclear environment, leading to measurable though moderate target suppression. Limited efficacy seems to be related to intracellular trapping of siRNA. To study the role of intracellular trafficking of siRNA for biological effectiveness we studied whether a signal peptide for trans-membrane transport of bacterial protein toxins, which is covalently attached to siRNA, can promote its release from the perinuclear space into the cytoplasm and thereby enhance its biological effectiveness. We show that attachment of the peptide TQIENLKEKG to lamin A/C-directed siRNA improves target inhibition after its PS-stimulated delivery. This is related to increased efflux of the siRNA–peptide conjugate from the ER-specific perinuclear sites. In summary, this study strongly suggests that intracellular release of siRNA leads to increased biological effectiveness. Thus covalent peptide–siRNA conjugates are proposed as new tools to study the relationship between intracellular transport and efficacy of siRNA.
A fast selenium derivatization strategy for crystallization and phasing of RNA structures
Authors: Olieric Vincent , Rieder Ulrike , Lang Kathrin , Serganov Alexander , Schulze-Briese Clemens , Micura Ronald , Dumas Philippe , Ennifar Eric
Published: February 2009

Site-specific 2′-methylseleno RNA labeling is a promising tool for tackling the phase problem in RNA crystallography. We have developed an efficient strategy for crystallization and structure determination of RNA and RNA/protein complexes based on preliminary crystallization screening of 2′-OCH3-modified RNA sequences, prior to the replacement of 2′-OCH3 groups with their 2′-SeCH3 counterparts. The method exploits the similar crystallization properties of 2′-OCH3- and 2′-SeCH3-modified RNAs and has been successfully validated for two test cases. In addition, our data show that 2′-SeCH3-modified RNA have an increased resistance to X-ray radiolysis in comparison with commonly used 5-halogen-modified RNA, which permits collection of experimental electron density maps of remarkable quality.
How Electronic Spreadsheets Changed the World
Authors: Hesse Rick , Scerno Deborah Hesse
Published: February 2009

In How the Irish Saved Civilization, Tom Cahill contended that during the dark ages the monks were responsible not only for writing and preserving the Bible but for other great works, including mathematics texts [Cahill, T. 1995. How the Irish Saved Civilization: From the Fall of Rome to the Rise of Medieval Europe. Doubleday, New York]. In much the same way, we have seen that electronic spreadsheets have changed (although perhaps not saved) our world in the last 25 years. The first author, who has over 40 years of experience in teaching quantitative analysis (management science, operations research, decision sciences, and statistics) at eight US universities, has been using spreadsheets for over 20 years. The second author, with almost 15 years of spreadsheet experience, witnessed the exponential growth of personal computers and their associated programs starting in her college days in the mid-1980s. While she majored in computer science, the emphasis was on programming. However, many who were in school at that time realized that the growth area would be in programs, not in programming; therefore, they spent their time using Mac computers and learning word processing and spreadsheets. When the second author returned to school for her master's in science, she observed a love/hate relationship with spreadsheets in the multiple fields of science in which she worked. In this paper, we offer our personal perspective on this ubiquitous and useful tool that has unquestionably changed the world.
A Summary of Deliberations on Strategic Planning for Continuous Quality Improvement in Laboratory Medicine
Authors: Grzybicki Dana Marie , Shahangian Shahram , Pollock Anne M. , Raab Stephen S.
Published: February 2009

On September 24–26, 2007, the Centers for Disease Control and Prevention convened the 2007 Institute on Critical Issues in Health Laboratory Practice: Managing for Better Health to develop an action plan for change for the immediate and long-term future. A wide variety of stakeholders, including pathologists, pathologist extenders, clinicians, and researchers, examined means to improve laboratory service communication, quality parameters, and potential future laboratory contributions to health care. In this summary document, we present the identified gaps, barriers, and proposed action plans for improvement for laboratory medicine in the 6 quality domains identified by the Institute of Medicine: safety, effectiveness, patient centeredness, timeliness, efficiency, and equity. Five major recommendations emerged from concluding discussions and included focusing on preanalytic and postanalytic processes as areas of potential quality improvement and recruiting a multidisciplinary group of nonlaboratory stakeholders to work with laboratory personnel to achieve improvement goals.
Challenges and Pitfalls of Morphologic Identification of Fungal Infections in Histologic and Cytologic Specimens
Authors: Sangoi Ankur R. , Rogers William M. , Longacre Teri A. , Montoya Jose G. , Baron Ellen Jo , Banaei Niaz
Published: February 2009

Despite the advantages of providing an early presumptive diagnosis, fungal classification by histopathology can be difficult and may lead to diagnostic error. To assess the accuracy of histologic diagnosis of fungal infections vs culture (“gold standard”), we performed a 10-year retrospective review at our institution. Of the 47 of 338 positive mold and yeast cultures with concurrent surgical pathology evaluation without known history of a fungal infection, 37 (79%) were correctly identified based on morphologic features in histologic and/or cytologic specimens. The 10 discrepant diagnoses (21%) included misidentification of septate and nonseptate hyphal organisms and yeast forms. Errors resulted from morphologic mimics, use of inappropriate terminology, and incomplete knowledge in mycology. The accuracy did not correlate with preceding antifungal therapy (P = .14) or use of special stains (P = .34) and was not operator-dependent. Among 8 discrepancies with clinical follow-up available, 2 potential adverse clinical consequences resulted. While histopathologic identification of fungi in tissue sections and cytologic preparations is prone to error, implementation of a standardized reporting format should improve diagnostic accuracy and prevent adverse outcomes.
Flow Cytometry Can Diagnose Classical Hodgkin Lymphoma in Lymph Nodes With High Sensitivity and Specificity
Authors: Fromm Jonathan R. , Thomas Anju , Wood Brent L.
Published: February 2009

The diagnosis of classical Hodgkin lymphoma (CHL) has been made in tissue sections as attempts to identify neoplastic Hodgkin and Reed Sternberg (HRS) cells in lymph nodes by flow cytometry (FC) have been unsuccessful. However, we have recently demonstrated that HRS cells can be identified by FC, often present as T-cell–HRS-cell rosettes. In this study, we examined the usefulness of a novel 9-color (CD95–Pacific blue/CD64–fluorescein isothiocyanate/CD30-phycoerythrin [PE]/CD45-PE–Texas red/CD40–PE cyanine [Cy]5.5/CD20-PECy7/CD15-allophycocyanin [APC]/CD71-APC–AlexaFluor A700/CD5-APC-Cy7), single tube FC assay to diagnose CHL in lymph nodes. We used the FC assay to determine diagnostic sensitivity and specificity in 279 blindly identified and 141 selected (for specimen type or cytopreparation morphologic features suggesting CHL) tissues. Of the 53 morphologically defined CHL cases identified (10 in the unselected group; 43 in the selected group), the FC assay diagnostic sensitivity and specificity were 88.7% and 100%, respectively. With the current availability of 8 (or more) color clinical flow cytometers, this assay can now be applied to routinely immunophenotype and confirm a diagnosis of CHL or as an adjunct to immunohistochemical analysis.
Activating children's thinking skills (ACTS): The effects of an infusion approach to teaching thinking in primary schools
Authors: Dewey Jessica , Bento Janet
Published: February 2009

BackgroundRecent interest in the teaching of thinking skills within education has led to an increase in thinking skills packages available to schools. However many of these are not based on scientific evaluation (DfEE, 1999). This paper endeavours to examine the effectiveness of one approach, that of infusion, to teaching thinking.

AimsTo investigate the impact of an infusion methodology, activating children's thinking skills (ACTS), on the cognitive, social, and emotional development of children in Year 4–6 in primary schools. This is a sister project to research being conducted in Northern Ireland (McGuinness, 2006).

SampleThe study involved 404 children from 8 primary schools in one local authority. These were divided into 160 in the experimental group and 244 in the waiting list control group.

MethodsA quasi‐experimental design was used with pre‐, post‐, and delayed post‐tests to ascertain changes in children's cognitive abilities, self‐perceptions, and social/behavioural skills using quantitative measures. In addition qualitative techniques were used with pupils and teachers to evaluate effectiveness.

ResultsThe experimental group made significantly greater gains in cognitive ability skills over a 2 year period compared to the waiting list control. Qualitative data demonstrated a positive impact on children's social and emotional development. In addition teacher professional development was reported to be enhanced.

ConclusionsThis research indicated that children's cognitive abilities can be developed following a 2 year period of the ACTS infusion intervention. While some positive effects were evidenced on the social and emotional development of children, further study will be necessary to examine these in more detail.
Time perspective and attitude‐behaviour consistency in future‐oriented behaviours
Authors: Rabinovich Anna , Morton Thomas , Postmes Tom
Published: February 2009

The authors propose that the salience of a distant‐future time perspective, compared to a near‐future time perspective, should increase attitude‐behaviour and attitude‐intention consistency for future‐oriented behaviours. To test this prediction, time perspective was experimentally manipulated in three studies. Across studies, participants in the distant‐future time perspective condition demonstrated a strong positive relationship between attitudes towards future‐oriented behaviours (saving and environmental protection) and corresponding intentions, as well as between attitudes and behaviour. In the near‐future time perspective condition, the relationship between attitudes and intentions and attitudes and behaviour was significantly weaker than in the distant‐future time perspective condition. The theoretical implications of these results and suggestions for future research are discussed.
Repetitive exploration towards locations that no longer carry a target in patients with neglect
Authors: Nys Gudrun M. S. , Stuart Marije , Dijkerman H. Chris
Published: February 2009

About 50% of neglect patients show ipsilesional target re‐exploration on neglect tasks and in daily life. The present study examines whether omissions and revisitings are due to disengagement failure from visible stimuli on the ipsilesional side. Thirteen patients with neglect and nine healthy controls were tested with three versions of the Bells test on touch screen, i.e. a standard cancellation in which targets have to be marked, an erase cancellation in which targets have to be erased, and a condition in which all items (including distracters) have to be erased. Whereas omissions decreased in the full‐erase condition, revisitings were the most prominent in this condition. Our study shows that neglect patients also return to previously visited locations which no longer carry a target.
Estimation of Subgrade Soils Resilient Modulus from in-situ Devices Test Results
Authors: Mohammad Louay N. , Nazzal Munir D. , Abu-Farsakh Murad Y. , Alshibli Khalid
Published: February 2009

Field and laboratory testing programs were conducted to develop resilient modulus prediction models for application in the design and evaluation procedures of pavement structures. The field testing program included conducting several in-situ tests such as Geogauge, Light Falling Weight Deflectometer, and Dynamic Cone Penetrometer (DCP). The laboratory program consisted of performing repeated load triaxial resilient modulus tests, physical properties, and compaction tests on soil samples obtained from tested sections. A total of four subgrade soil types at different moisture-dry unit weight levels were considered. Comprehensive statistical analyses were conducted on the field and laboratory test results. Two sets of models were developed. The first set (direct model) directly relates the laboratory measured resilient modulus values with the results of each of the three in-situ devices, whereas the second set (soil property model) incorporates soil properties in addition to the results of each of the three in-situ devices. A good agreement was observed between the predicted and measured values of the resilient modulus. Furthermore, the results showed that the resilient modulus prediction was enhanced when the soil properties were included as variables within the models. Among the models developed, the DCP-soil property model had the best prediction of resilient modulus followed by the DCP-direct model. The effectiveness of the DCP models were further evaluated during a forensic analysis of pavement section failure in a highway within Louisiana.
Loss of the Cholesterol-Binding Protein Prominin-1/CD133 Causes Disk Dysmorphogenesis and Photoreceptor Degeneration
Authors: Zacchigna Serena , Oh Hideyasu , Wilsch-Bräuninger Michaela , Missol-Kolka Ewa , Jászai József , Jansen Sandra , Tanimoto Naoyuki , Tonagel Felix , Seeliger Mathias , Huttner Wieland B. , Corbeil Denis , Dewerchin Mieke , Vinckier Stefan , Moons Lieve , Carmeliet Peter
Published: February 2009

Prominin-1/CD133 (Prom-1) is a commonly used marker of neuronal, vascular, hematopoietic and other stem cells, yet little is known about its biological role and importancein vivo. Here, we show that loss of Prom-1 results in progressive degeneration of mature photoreceptors with complete loss of vision. Despite the expression of Prom-1 on endothelial progenitors, photoreceptor degeneration was not attributable to retinal vessel defects, but caused by intrinsic photoreceptor defects in disk formation, outer segment morphogenesis, and associated with visual pigment sorting and phototransduction abnormalities. These findings shed novel insight on how Prom-1 regulates neural retinal development and phototransduction in vertebrates.
Cerebral Microglia Recruit Monocytes into the Brain in Response to Tumor Necrosis Factorα Signaling during Peripheral Organ Inflammation
Authors: D'Mello Charlotte , Le Tai , Swain Mark G.
Published: February 2009

In inflammatory diseases occurring outside the CNS, communication between the periphery and the brain via humoral and/or neural routes results in central neural changes and associated behavioral alterations. We have recently identified another immune-to-CNS communication pathway in the setting of organ-centered peripheral inflammation: namely, the entrance of immune cells into the brain. In our current study, using a mouse model of inflammatory liver injury, we have confirmed the significant infiltration of activated monocytes into the brain in mice with hepatic inflammation and have defined the mechanism that mediates this trafficking of monocytes. Specifically, we show that in the presence of hepatic inflammation, mice demonstrate elevated cerebral monocyte chemoattractant protein (MCP)-1 levels, as well as increased numbers of circulating CCR2-expressing monocytes. Cerebral recruitment of monocytes was abolished in inflamed mice that lacked MCP-1/CCL2 or CCR2. Furthermore, in mice with hepatic inflammation, microglia were activated and produced MCP-1/CCL2 before cerebral monocyte infiltration. Moreover, peripheral tumor necrosis factor (TNF)α signaling was required to stimulate microglia to produce MCP-1/CCL2. TNFα signaling via TNF receptor 1 (TNFR1) is required for these observed effects since in TNFR1 deficient mice with hepatic inflammation, microglial expression of MCP-1/CCL2 and cerebral monocyte recruitment were both markedly inhibited, whereas there was no inhibition in TNFR2 deficient mice. Our results identify the existence of a novel immune-to-CNS communication pathway occurring in the setting of peripheral organ-centered inflammation which may have specific implications for the development of alterations in cerebral neurotransmission commonly encountered in numerous inflammatory diseases occurring outside the CNS.
Broadband Coding with Dynamic Synapses
Authors: Lindner Benjamin , Gangloff Dorian , Longtin André , Lewis John E.
Published: February 2009

Short-term synaptic plasticity (STP) can significantly alter the amplitudes of synaptic responses in ways that depend on presynaptic history. Thus, it is widely assumed that STP acts as a filter for specific patterns of presynaptic inputs, and as a result can play key roles in neuronal information processing. To evaluate this assumption and directly quantify the effects of STP on information transmission, we consider a population of independent synaptic inputs to a model neuron. We show using standard information theoretic approaches that the changes in synaptic response amplitude resulting from STP interact with the related effects on fluctuations in membrane conductance, such that information transmission is broadband (no frequency-dependent filtering occurs), regardless of whether synaptic depression or facilitation dominates. Interestingly, this broadband transmission is preserved in the postsynaptic spike train as long as the postsynaptic neuron's baseline firing rate is relatively high; in contrast, low baseline firing rates lead to STP-dependent effects. Thus, background inputs that control the firing state of a postsynaptic neuron can gate the effects of STP on information transmission.
Human Cortical Organization for Processing Vocalizations Indicates Representation of Harmonic Structure as a Signal Attribute
Authors: Lewis James W. , Talkington William J. , Walker Nathan A. , Spirou George A. , Jajosky Audrey , Frum Chris , Brefczynski-Lewis Julie A.
Published: February 2009

The ability to detect and rapidly process harmonic sounds, which in nature are typical of animal vocalizations and speech, can be critical for communication among conspecifics and for survival. Single-unit studies have reported neurons in auditory cortex sensitive to specific combinations of frequencies (e.g., harmonics), theorized to rapidly abstract or filter for specific structures of incoming sounds, where large ensembles of such neurons may constitute spectral templates. We studied the contribution of harmonic structure to activation of putative spectral templates in human auditory cortex by using a wide variety of animal vocalizations, as well as artificially constructed iterated rippled noises (IRNs). Both the IRNs and vocalization sounds were quantitatively characterized by calculating a global harmonics-to-noise ratio (HNR). Using functional MRI, we identified HNR-sensitive regions when presenting either artificial IRNs and/or recordings of natural animal vocalizations. This activation included regions situated between functionally defined primary auditory cortices and regions preferential for processing human nonverbal vocalizations or speech sounds. These results demonstrate that the HNR of sound reflects an important second-order acoustic signal attribute that parametrically activates distinct pathways of human auditory cortex. Thus, these results provide novel support for the presence of spectral templates, which may subserve a major role in the hierarchical processing of vocalizations as a distinct category of behaviorally relevant sound.
Genetics of Brain Fiber Architecture and Intellectual Performance
Authors: Chiang Ming-Chang , Barysheva Marina , Shattuck David W. , Lee Agatha D. , Madsen Sarah K. , Avedissian Christina , Klunder Andrea D. , Toga Arthur W. , McMahon Katie L. , de Zubicaray Greig I. , Wright Margaret J. , Srivastava Anuj , Balov Nikolay , Thompson Paul M.
Published: February 2009

The study is the first to analyze genetic and environmental factors that affect brain fiber architecture and its genetic linkage with cognitive function. We assessed white matter integrity voxelwise using diffusion tensor imaging at high magnetic field (4 Tesla), in 92 identical and fraternal twins. White matter integrity, quantified using fractional anisotropy (FA), was used to fit structural equation models (SEM) at each point in the brain, generating three-dimensional maps of heritability. We visualized the anatomical profile of correlations between white matter integrity and full-scale, verbal, and performance intelligence quotients (FIQ, VIQ, and PIQ). White matter integrity (FA) was under strong genetic control and was highly heritable in bilateral frontal (a2= 0.55,p= 0.04, left;a2= 0.74,p= 0.006, right), bilateral parietal (a2= 0.85,p< 0.001, left;a2= 0.84,p< 0.001, right), and left occipital (a2= 0.76,p= 0.003) lobes, and was correlated with FIQ and PIQ in the cingulum, optic radiations, superior fronto-occipital fasciculus, internal capsule, callosal isthmus, and thecorona radiata(p= 0.04 for FIQ andp= 0.01 for PIQ, corrected for multiple comparisons). In a cross-trait mapping approach, common genetic factors mediated the correlation between IQ and white matter integrity, suggesting a common physiological mechanism for both, and common genetic determination. These genetic brain maps reveal heritable aspects of white matter integrity and should expedite the discovery of single-nucleotide polymorphisms affecting fiber connectivity and cognition.
Suppression of Oct4 by Germ Cell Nuclear Factor Restricts Pluripotency and Promotes Neural Stem Cell Development in the Early Neural Lineage
Authors: Akamatsu Wado , DeVeale Brian , Okano Hideyuki , Cooney Austin J , van der Kooy Derek
Published: February 2009

The earliest murine neural stem cells are leukemia inhibitory factor (LIF)-dependent, primitive neural stem cells, which can be isolated from embryonic stem cells or early embryos. These primitive neural stem cells have the ability to differentiate to non-neural tissues and transition into FGF2-dependent, definitive neural stem cells between embryonic day 7.5 and 8.5in vivo, accompanied by a decrease in non-neural competency. We found that Oct4 is expressed in LIF-dependent primitive neural stem cells and suppressed in FGF-dependent definitive neural stem cells. In mice lackinggerm cell nuclear factor(GCNF), a transcriptional repressor of Oct4, generation of definitive neural stem cells was dramatically suppressed, accompanied by a sustained expression of Oct4 in the early neuroectoderm. Knockdown of Oct4 inGCNF−/−neural stem cells rescued theGCNF−/−phenotype. Overexpession of Oct4 blocked the differentiation of primitive to definitive neural stem cells, but did not induce the dedifferentiation of definitive to primitive neural stem cells. These results suggested that primitive neural stem cells develop into definitive neural stem cells by means of GCNF induced suppression of Oct4. The Oct4 promoter was methylated during the development from primitive neural stem cell to definitive neural stem cell, while these neural stem cells lose their pluripotency through a GCNF dependent mechanism. Thus, the suppression of Oct4 by GCNF is important for the transition from primitive to definitive neural stem cells and restriction of the non-neural competency in the early neural stem cell lineage.
Regulation of Persistent Na Current by Interactions between β Subunits of Voltage-Gated Na Channels
Authors: Aman Teresa K. , Grieco-Calub Tina M. , Chen Chunling , Rusconi Raffaella , Slat Emily A. , Isom Lori L. , Raman Indira M.
Published: February 2009

The β subunits of voltage-gated Na channels (Scnxb) regulate the gating of pore-forming α subunits, as well as their trafficking and localization. In heterologous expression systems, β1, β2, and β3 subunits influence inactivation and persistent current in different ways. To test how the β4 protein regulates Na channel gating, we transfected β4 into HEK (human embryonic kidney) cells stably expressing NaV1.1. Unlike a free peptide with a sequence from the β4 cytoplasmic domain, the full-length β4 protein did not block open channels. Instead, β4 expression favored open states by shifting activation curves negative, decreasing the slope of the inactivation curve, and increasing the percentage of noninactivating current. Consequently, persistent current tripled in amplitude. Expression of β1 or chimeric subunits including the β1 extracellular domain, however, favored inactivation. Coexpressing NaV1.1 and β4 with β1 produced tiny persistent currents, indicating that β1 overcomes the effects of β4 in heterotrimeric channels. In contrast, β1C121W, which contains an extracellular epilepsy-associated mutation, did not counteract the destabilization of inactivation by β4 and also required unusually large depolarizations for channel opening. In cultured hippocampal neurons transfected with β4, persistent current was slightly but significantly increased. Moreover, in β4-expressing neurons fromScn1bandScn1b/Scn2bnull mice, entry into inactivated states was slowed. These data suggest that β1 and β4 have antagonistic roles, the former favoring inactivation, and the latter favoring activation. Because increased Na channel availability may facilitate action potential firing, these results suggest a mechanism for seizure susceptibility of both mice and humans with disrupted β1 subunits.
TheDrosophilaFragile X Mental Retardation Gene Regulates Sleep Need
Authors: Bushey Daniel , Tononi Giulio , Cirelli Chiara
Published: February 2009

Sleep need is affected by developmental stage and neuronal plasticity, but the underlying mechanisms remain unclear. The fragile X mental retardation geneFmr1, whose loss-of-function mutation causes the most common form of inherited mental retardation in humans, is involved in synaptogenesis and synaptic plasticity, and its expression depends on both developmental stage and waking experience.Fmr1is highly conserved across species andDrosophilamutants carryingdFmr1loss-of-function or gain-of-function mutations are well characterized: amorphs have overgrown dendritic trees with larger synaptic boutons, developmental defects in pruning, and enhanced neurotransmission, while hypermorphs show opposite defects, including dendritic and axonal underbranching and loss of synapse differentiation. We find here thatdFmr1amorphs are long sleepers and hypermorphs are short sleepers, while both show increased locomotor activity and shortened lifespan. Both amorphs and hypermorphs also show abnormal sleep homeostasis, with impaired waking performance and no sleep rebound after sleep deprivation. An impairment in the circadian regulation of sleep cannot account for the altered sleep phenotype ofdFmr1mutants, nor can an abnormal activation of glutamatergic metabotropic receptors. Moreover, overexpression ofdFmr1throughout the mushroom bodies is sufficient to reduce sleep. Finally,dFmr1protein levels are modulated by both developmental stage and behavioral state, with increased expression immediately after eclosure and after prolonged wakefulness. Thus,dFmr1expression dose-dependently affects both sleep and synapses, suggesting that changes in sleep time indFmr1mutants may derive from changes in synaptic physiology.
The Involvement of Hypothalamic Sleep Pathways in General Anesthesia: Testing the Hypothesis Using the GABAAReceptor β3N265M Knock-In Mouse
Authors: Zecharia Anna Y. , Nelson Laura E. , Gent Thomas C. , Schumacher Mark , Jurd Rachel , Rudolph Uwe , Brickley Stephen G. , Maze Mervyn , Franks Nicholas P.
Published: February 2009

The GABAAreceptor has been identified as the single most important target for the intravenous anesthetic propofol. How effects at this receptor are then translated into a loss of consciousness, however, remains a mystery. One possibility is that anesthetics act on natural sleep pathways. Here, we test this hypothesis by exploring the anesthetic sensitivities of GABAergic synaptic currents in three specific brain nuclei that are known to be involved in sleep. Using whole-cell electrophysiology, we have recorded GABAergic IPSCs from the tuberomammillary nucleus (TMN), the perifornical area (Pef), and the locus ceruleus (LC) in brain slices from both wild-type mice and mice that carry a specific mutation in the GABAAreceptor β3subunit (N265M), which greatly reduces their sensitivity to propofol, but not to the neurosteroid alphaxalone. We find that thisin vivopattern of anesthetic sensitivity is mirrored in the hypothalamic TMN and Pef nuclei, consistent with their role as direct anesthetic targets. In contrast, anesthetic sensitivity in the LC was unaffected by the β3N265M mutation, ruling out this nucleus as a major target for propofol. In support of the hypothesis that orexinergic neurons in the Pef are involved in propofol anesthesia, we further show that these neurons are selectively inhibited by GABAergic drugsin vivoduring anesthesia, and that a modulation in the activity of Pef neurons alone can affect loss of righting reflex. Overall, our results support the idea that GABAergic anesthetics such as propofol exert their effects, at least in part, by modulating hypothalamic sleep pathways.
Rodent Habenulo–Interpeduncular Pathway Expresses a Large Variety of Uncommon nAChR Subtypes, But Only the α3β4 and α3β3β4 Subtypes Mediate Acetylcholine Release
Authors: Grady Sharon R. , Moretti Milena , Zoli Michele , Marks Michael J. , Zanardi Alessio , Pucci Luca , Clementi Francesco , Gotti Cecilia
Published: February 2009

Recent studies suggest that the neuronal nicotinic receptors (nAChRs) present in the habenulo–interpeduncular (Hb–IPn) system can modulate the reinforcing effect of addictive drugs and the anxiolytic effect of nicotine. Hb and IPn neurons express mRNAs for most nAChR subunits, thus making it difficult to establish the subunit composition of functional receptors. We used immunoprecipitation and immunopurification studies performed in rat and wild-type (+/+) and β2 knock-out (−/−) mice to establish that the Hb and IPn contain significant β2* and β4* populations of nAChR receptors (each of which is heterogeneous). The β4* nAChR are more highly expressed in the IPn. We also identified novel native subtypes (α2β2*, α4β3β2*, α3β3β4*, α6β3β4*). Our studies on IPn synaptosomes obtained from +/+ and α2, α4, α5, α6, α7, β2, β3, and β4−/−mice show that only the α3β4 and α3β3β4 subtypes facilitate acetylcholine (ACh) release. Ligand binding, immunoprecipitation, and Western blotting studies in β3−/−mice showed that, in the IPn of these mice, there is a concomitant reduction of ACh release and α3β4* receptors, whereas the receptor number remains the same in the Hb. We suggest that, in habenular cholinergic neurons, the β3 subunit may be important for transporting the α3β4* subtype from the medial habenula to the IPn. Overall, these studies highlight the presence of a wealth of uncommon nAChR subtypes in the Hb–IPn system and identify α3β4 and α3β3β4, transported from the Hb and highly enriched in the IPn, as the subtypes modulating ACh release in the IPn.
Evidence That Oxytocin Exerts Anxiolytic Effects via Oxytocin Receptor Expressed in Serotonergic Neurons in Mice
Authors: Yoshida Masahide , Takayanagi Yuki , Inoue Kiyoshi , Kimura Tadashi , Young Larry J. , Onaka Tatsushi , Nishimori Katsuhiko
Published: February 2009

The oxytocin receptor has been implicated in the regulation of reproductive physiology as well as social and emotional behaviors. The neurochemical mechanisms by which oxytocin receptor modulates social and emotional behavior remains elusive, in part because of a lack of sensitive and selective antibodies for cellular localization. To more precisely characterize oxytocin receptor-expressing neurons within the brain, we generated an oxytocin receptor-reporter mouse in which part of the oxytocin receptor gene was replaced with Venus cDNA (a variant of yellow fluorescent protein). Examination of the Venus expression revealed that, in the raphe nuclei, about one-half of tryptophan hydroxylase-immunoreactive neurons were positive for Venus, suggesting a potential role for oxytocin in the modulation of serotonin release. Oxytocin infusion facilitated serotonin release within the median raphe nucleus and reduced anxiety-related behavior. Infusion of a 5-HT2A/2Creceptor antagonist blocked the anxiolytic effect of oxytocin, suggesting that oxytocin receptor activation in serotonergic neurons mediates the anxiolytic effects of oxytocin. This is the first demonstration that oxytocin may regulate serotonin release and exert anxiolytic effects via direct activation of oxytocin receptor expressed in serotonergic neurons of the raphe nuclei. These results also have important implications for psychiatric disorders such as autism and depression in which both the oxytocin and serotonin systems have been implicated.