bluuebunny/crossref_metadata_2025 huggingface dataset:
Review: Structural determinants of pattern recognition by lung collectins
Authors: Seaton Barbara A. , Crouch Erika C. , McCormack Francis X. , Head James F. , Hartshorn Kevan L. , Mendelsohn Richard
Published: April 2010

Host defense roles for the lung collectins, surfactant protein A (SP-A) and surfactant protein D (SP-D), were first suspected in the 1980s when molecular characterization revealed their sequence homology to the acute phase reactant of serum, mannose-binding lectin. Surfactant protein A and SP-D have since been shown to play diverse and important roles in innate immunity and pulmonary homeostasis. Their location in surfactant ideally positions them to interact with air-space pathogens. Despite extensive structural similarity, the two proteins show many functional differences and considerable divergence in their interactions with microbial surface components, surfactant lipids, and other ligands. Recent crystallographic studies have provided many new insights relating to these observed differences. Although both proteins can participate in calcium-dependent interactions with sugars and other polyols, they display significant differences in the spatial orientation, charge, and hydrophobicity of their binding surfaces. Surfactant protein D appears particularly adapted to interactions with complex carbohydrates and anionic phospholipids, such as phosphatidylinositol. By contrast, SP-A shows features consistent with its preference for lipid ligands, including lipid A and the major surfactant lipid, dipalmitoylphosphatidylcholine. Current research suggests that structural biology approaches will help to elucidate the molecular basis of pulmonary collectin—ligand recognition and facilitate development of new therapeutics based upon SP-A and SP-D.
Service Failures in Restaurants
Authors: Young Namkung  , Soocheong Jang
Published: April 2010

A multistage approach for restaurant service enables managers to determine and focus on the most critical stage of service failure to reduce customer dissatisfaction and defection. A survey of 491 diners in the United States assessed customer reaction to failures in the follow four service stages: (1) reception, (2) ordering, (3) meal consumption, and (4) checkout. The study found that in both casual dining and fine dining restaurants, service failure in stage 3 (consumption) most strongly diminishes overall customer satisfaction, followed by stage 4 (payment and exiting), stage 2 (order taking and delivery), and finally stage 1 (greeting and seating). The relative impact of service failure on behavioral intentions varies by service stage and restaurant type. In casual dining restaurants, service failure in stage 3 had the most effect in diminishing diners’ intent to come back and willingness to recommend the restaurant to others, followed by service failure in stage 4. On the other hand, for fine dining restaurants, service failure in stage 2 was the most critical influence on diners’ likelihood of returning. Additionally, stage 4 was the most important determinant in fine restaurant diners’ willingness to recommend the restaurant to others.
Commonly used prophylactic vaccines as an alternative for synthetically produced TLR ligands to mature monocyte-derived dendritic cells
Authors: Schreibelt Gerty , Benitez-Ribas Daniel , Schuurhuis Danita , Lambeck Annechien J. A. , van Hout-Kuijer Maaike , Schaft Niels , Punt Cornelis J. A. , Figdor Carl G. , Adema Gosse J. , de Vries I. Jolanda M.
Published: April 2010

Currently dendritic cell (DC)–based vaccines are explored in clinical trials, predominantly in cancer patients. Murine studies showed that only maturation with Toll-like receptor (TLR) ligands generates mature DCs that produce interleukin-12 and promote optimal T-cell help. Unfortunately, the limited availability of clinical-grade TLR ligands significantly hampers the translation of these findings into DC-based vaccines. Therefore, we explored 15 commonly used preventive vaccines as a possible source of TLR ligands. We have identified a cocktail of the vaccines BCG-SSI, Influvac, and Typhim that contains TLR ligands and is capable of optimally maturing DCs. These DCs (vaccine DCs) showed high expression of CD80, CD86, and CD83 and secreted interleukin-12. Although vaccine DCs exhibited an impaired migratory capacity, this could be restored by addition of prostaglandin E2 (PGE2; vaccine PGE2 DCs). Vaccine PGE2 DCs are potent inducers of T-cell proliferation and induce Th1 polarization. In addition, vaccine PGE2 DCs are potent inducers of tumor antigen-specific CD8+ effector T cells. Finally, vaccine PGE2–induced DC maturation is compatible with different antigen-loading strategies, including RNA electroporation. These data thus identify a new clinical application for a mixture of commonly used preventive vaccines in the generation of Th1-inducing clinical-grade mature DCs.
Telomere dysfunction-induced foci arise with the onset of telomeric deletions and complex chromosomal aberrations in resistant chronic lymphocytic leukemia cells
Authors: Brugat Thibaut , Nguyen-Khac Florence , Grelier Aurore , Merle-Béral Hélène , Delic Jozo
Published: April 2010

In somatic cells, eroded telomeres can induce DNA double-strand break signaling, leading to a form of replicative senescence or apoptosis, both of which are barriers to tumorigenesis. However, cancer cells might display telomere dysfunctions which in conjunction with defects in DNA repair and apoptosis, enables them to circumvent these pathways. Chronic lymphocytic leukemia (CLL) cells exhibit telomere dysfunction, and a subset of these cells are resistant to DNA damage-induced apoptosis and display short telomeres. We show here that these cells exhibit significant resection of their protective telomeric 3′ single-stranded overhangs and an increased number of telomere-induced foci containing γH2AX and 53BP1. Chromatin immunoprecipitation and immunofluorescence experiments demonstrated increased levels of telomeric Ku70 and phospho-S2056-DNA-PKcs, 2 essential components of the mammalian nonhomologous end-joining DNA repair system. Notably, these CLL cells display deletions of telomeric signals on one or 2 chromatids in parallel with 11q22 deletions, or with 13q14 deletions associated with another chromosomal aberration or with a complex karyotype. Taken together, our results indicate that a subset of CLL cells from patients with an unfavorable clinical outcome harbor a novel type of chromosomal aberration resulting from telomere dysfunction.
Variations in morphology and PSII photosynthetic capabilities during the early development of tetraspores of Gracilaria vermiculophylla (Ohmi) Papenfuss (Gracilariales, Rhodophyta)
Authors: Xie Xiujun , Wang Guangce , Pan Guanghua , Gao Shan , Xu Pu , Zhu Jianyi
Published: April 2010

Background

Red algae are primitive photosynthetic eukaryotes, whose spores are ideal subjects for studies of photosynthesis and development. Although the development of red alga spores has received considerable research attention, few studies have focused on the detailed morphological and photosynthetic changes that occur during the early development of tetraspores ofGracilaria vermiculophylla(Ohmi) Papenfuss (Gracilariales, Rhodophyta). Herein, we documented these changes in this species of red algae.

Results

In the tetraspores, we observed two types of division, cruciate and zonate, and both could develop into multicellular bodies (disks). During the first 84 hours, tetraspores divided several times, but the diameter of the disks changed very little; thereafter, the diameter increased significantly. Scanning electron microscopy observations and analysis of histological sections revealed that the natural shape of the disk remains tapered over time, and the erect frond grows from the central protrusion of the disk. Cultivation of tissue from excised disks demonstrated that the central protrusion of the disk is essential for initiation of the erect frond. Photosynthetic (i.e., PSII) activities were measured using chlorophyll fluorescence analysis. The results indicated that freshly released tetraspores retained limited PSII photosynthetic capabilities; when the tetraspores attached to a substrate, those capabilities increased significantly. In the disk, the PSII activity of both marginal and central cells was similar, although some degree of morphological polarity was present; the PSII photosynthetic capabilities in young germling exhibited an apico-basal gradient.

Conclusions

Attachment of tetraspores to a substrate significantly enhanced their PSII photosynthetic capabilities, and triggered further development. The central protrusion of the disk is the growth point, may have transfer of nutritive material with the marginal cells. Within the young germling, the hetero-distribution of PSII photosynthetic capabilities might be due to the differences in cell functions.
Large impact of the apoplast on somatic embryogenesis in Cyclamen persicum offers possibilities for improved developmental control in vitro
Authors: Hoenemann Claudia , Richardt Sandra , Krüger Katja , Zimmer Andreas D , Hohe Annette , Rensing Stefan A
Published: April 2010

Background

Clonal propagation is highly desired especially for valuable horticultural crops. The method with the potentially highest multiplication rate is regeneration via somatic embryogenesis. However, this mode of propagation is often hampered by the occurrence of developmental aberrations and non-embryogenic callus. Therefore, the developmental process of somatic embryogenesis was analysed in the ornamental crop Cyclamen persicum by expression profiling, comparing different developmental stages of embryogenic cell cultures, zygotic vs. somatic embryos and embryogenic vs. non-embryogenic cell cultures.

Results

The analysis was based on a cDNA microarray representing 1,216 transcripts and was exemplarily validated by realtime PCR. For this purpose relative transcript abundances of homologues of a putative receptor kinase, two different glutathione S-transferases (GST), a xyloglucan endotransglycosylase (XET) and a peroxidase (POX) were quantitatively measured by realtime PCR for three different comparisons. In total, 417 genes were found to be differentially expressed. Gene Ontology annotation revealed that transcripts coding for enzymes that are active in the extracellular compartment (apoplast) were significantly overrepresented in several comparisons. The expression profiling results are underpinned by thorough histological analyses of somatic and zygotic embryos.

Conclusions

The putative underlying physiological processes are discussed and hypotheses on improvement of the protocol for in vitro somatic embryogenesis in Cyclamen persicum are deduced. A set of physiological markers is proposed for efficient molecular control of the process of somatic embryogenesis in C. persicum. The general suitability of expression profiling for the development and improvement of micropropagation methods is discussed.
Association and interaction of PPAR-complex gene variants with latent traits of left ventricular diastolic function
Authors: Juang Jyh-Ming Jimmy , de las Fuentes Lisa , Waggoner Alan D , Gu C Charles , Dávila-Román Víctor G
Published: April 2010

Background

Abnormalities in myocardial metabolism and/or regulatory genes have been implicated in left ventricular systolic dysfunction. However, the extent to which these modulate left ventricular diastolic function (LVDF) is uncertain.

Methods

Independent component analysis was applied to extract latent LVDF traits from 14 measured echocardiography-derived endophenotypes of LVDF in 403 Caucasians. Genetic association was assessed between measured and latent LVDF traits and 64 single nucleotide polymorphisms (SNPs) in three peroxisome proliferator-activated receptor (PPAR)-complex genes involved in the transcriptional regulation of fatty acid metabolism.

Results

By linear regression analysis, 7 SNPs (4 in PPARA, 2 in PPARGC1A, 1 in PPARG) were significantly associated with the latent LVDF trait, whereas a range of 0-4 SNPs were associated with each of the 14 measured echocardiography-derived endophenotypes. Frequency distribution of P values showed a greater proportion of significant associations with the latent LVDF trait than for the measured endophenotypes, suggesting that analyses of the latent trait improved detection of the genetic underpinnings of LVDF. Ridge regression was applied to investigate within-gene and gene-gene interactions. In the within-gene analysis, there were five significant pair-wise interactions in PPARGC1A and none in PPARA or PPARG. In the gene-gene analysis, significant interactions were found between rs4253655 in PPARA and rs1873532 (p = 0.02) and rs7672915 (p = 0.02), both in PPARGC1A, and between rs1151996 in PPARG and rs4697046 in PPARGC1A (p = 0.01).

Conclusions

Myocardial metabolism PPAR-complex genes, including within and between genes interactions, may play an important role modulating left ventricular diastolic function.
Analysis of gene expression in prostate cancer epithelial and interstitial stromal cells using laser capture microdissection
Authors: Gregg Jennifer L , Brown Kathleen E , Mintz Eric M , Piontkivska Helen , Fraizer Gail C
Published: April 2010

Background

The prostate gland represents a multifaceted system in which prostate epithelia and stroma have distinct physiological roles. To understand the interaction between stroma and glandular epithelia, it is essential to delineate the gene expression profiles of these two tissue types in prostate cancer. Most studies have compared tumor and normal samples by performing global expression analysis using a mixture of cell populations. This report presents the first study of prostate tumor tissue that examines patterns of differential expression between specific cell types using laser capture microdissection (LCM).

Methods

LCM was used to isolate distinct cell-type populations and identify their gene expression differences using oligonucleotide microarrays. Ten differentially expressed genes were then analyzed in paired tumor and non-neoplastic prostate tissues by quantitative real-time PCR. Expression patterns of the transcription factors, WT1 and EGR1, were further compared in established prostate cell lines. WT1 protein expression was also examined in prostate tissue microarrays using immunohistochemistry.

Results

The two-step method of laser capture and microarray analysis identified nearly 500 genes whose expression levels were significantly different in prostate epithelial versus stromal tissues. Several genes expressed in epithelial cells (WT1, GATA2, and FGFR-3) were more highly expressed in neoplastic than in non-neoplastic tissues; conversely several genes expressed in stromal cells (CCL5, CXCL13, IGF-1, FGF-2, and IGFBP3) were more highly expressed in non-neoplastic than in neoplastic tissues. Notably, EGR1 was also differentially expressed between epithelial and stromal tissues. Expression of WT1 and EGR1 in cell lines was consistent with these patterns of differential expression. Importantly, WT1 protein expression was demonstrated in tumor tissues and was absent in normal and benign tissues.

Conclusions

The prostate represents a complex mix of cell types and there is a need to analyze distinct cell populations to better understand their potential interactions. In the present study, LCM and microarray analysis were used to identify novel gene expression patterns in prostate cell populations, including identification of WT1 expression in epithelial cells. The relevance of WT1 expression in prostate cancer was confirmed by analysis of tumor tissue and cell lines, suggesting a potential role for WT1 in prostate tumorigenesis.
Noncutaneous malignant melanoma: a prognostic model from a retrospective multicenter study
Authors: Kim Hyo Song , Kim Eun Kyoung , Jun Hyun Jung , Oh Sung Yong , Park Keon Woo , Lim Do Hyoung , Lee Soon Il , Kim Jung Han , Kim Kyoung Mee , Lee Dae Ho , Lee Jeeyun
Published: April 2010

Background

We performed multicenter study to define clinical characteristics of noncutaneous melanomas and to establish prognostic factors patients who received curative resection.

Methods

Of the 141 patients who were diagnosed of non-cutaneous melanoma at 4 institutions in Korea between June 1992 and May 2005, 129 (91.5%) satisfied the selection criteria.

Results

Of the 129 noncutaneous melanoma patients, 14 patients had ocular melanoma and 115 patients had mucosal melanoma. For mucosal melanoma, anorectum was the most common anatomic site (n = 39, 30.2%) which was followed by nasal cavity (n = 30, 23.3%), genitourinary (n = 21, 16.3%), oral cavity (n = 14, 10.9%), upper gastrointestinal tract (n = 6, 4.7%) and maxillary sinus (n = 5, 3.9%) in the order of frequency. With the median 64.5 (range 4.3-213.0) months follow-up, the median overall survival were 24.4 months (95% CI 13.2-35.5) for all patients, and 34.6 (95% CI 24.5-44.7) months for curatively resected mucosal melanoma patients. Adverse prognostic factors of survival for 87 curatively resected mucosal melanoma patients were complete resection (R1 resection margin), and age > 50 years. For 14 ocular melanoma, Survival outcome was much better than mucosal melanoma with 73.3% of 2 year OS and 51.2 months of median OS (P = .04).

Conclusion

Prognosis differed according to primary sites of noncutaneous melanoma. Based on our study, noncutaneous melanoma patients should be treated differently to improve survival outcome.
Parametric Study of Externally Loaded Rotating Discs under Shrink Fit
Authors: Bhowmick S , Misra D , Saha K N
Published: April 2010

The present work proposes a numerical method, using a variational principle, to investigate the behaviour of shrink-fitted rotating discs carrying attached masses. Locked-up stresses are released due to shrink fit at a certain angular speed, and when the speed is increased further, a limit is reached when the maximum induced stress in the disc attains yield stress value. Taking the radial displacement field as unknown and assuming a series approximation of the unknown field following Galerkin's principle, the solution of the governing differential equation is obtained. The release speed and the limit angular speed of the disc are calculated for various system parameters and reported in the dimensionless form. The analysis is carried out for various disc geometries, and the effects of geometry and loading parameters on the stress and deformation states are also investigated.
The effect of aluminium content on morphology, size, volume fraction, and number of graphite nodules in ductile cast iron
Authors: Shayesteh-Zeraati A , Naser-Zoshki H , Kiani-Rashid A R , Yousef-Sani M R
Published: April 2010

The effect of aluminium content on the formation mechanism, volume fraction, morphology, and particle size distribution of graphite has been investigated. Addition of aluminium to ductile iron causes some fundamental changes in iron—carbon phase diagrams and, as a result, improves graphite formation during eutectic transformation. Results reveal that aluminium compounds have been formed in the core of graphite nodules; thus aluminium plays an important role in the formation of graphite nodules. Furthermore, it is indicated that an increase in the aluminium content also leads to an increase in the number of graphite nodules and a decrease in the nodule size. By using electron probe microanalysis, the segregation of aluminium and silicon between graphite nodules has been studied.
Differential effects of nucleotide analogs on scanning-dependent initiation and elongation of mammalian mRNA translation in vitro
Authors: Aspden Julie L. , Jackson Richard J.
Published: April 2010

Codon–anticodon interactions are central to both the initiation and elongation phases of eukaryotic mRNA translation. The obvious difference is that the interaction takes place in the ribosomal A-site during elongation, whereas the 40S ribosomal subunit and associated initiation factors scan the mRNA sequence in search of an initiation codon with Met-tRNAi bound in the P-site, ceasing once codon–anticodon interaction is established at the AUG. As an indirect test of whether the two mechanisms of mRNA sequence inspection are basically similar or not, the effects of six different uridine analog substitutions in the mRNA were examined in reticulocyte lysate translation assays and 80S initiation complex formation assays. Four constructs, each with the same reporter coding sequence, were used, differing in whether the initiation codon was AUG or ACG, and in whether the 5′-UTR had U residues or not. Three analogs (5-bromoU, 5-aminoallylU, and pseudoU) inhibited both elongation and initiation, but the other three had striking differential effects. Ribothymidine had a negligible effect on elongation but caused a ∼50% inhibition of initiation, with little effect on actual AUG recognition, which implies that inhibition must have occurred at some earlier step in initiation. In complete contrast, 2′ deoxyU was prohibitive to elongation but had no effect on initiation, and 4-thioU actually stimulated initiation but quite strongly inhibited elongation processivity. These results show that the detailed mechanisms of inspection of the mRNA sequence during scanning-dependent initiation and elongation must be considerably different.
The General Election – How Surgeons can get Involved
Authors: Stebbing Richard
Published: April 2010

General elections are a crucial and defining part of UK politics and are undoubtedly one of the busiest times in public affairs. But what actually goes on during this period? How does the Royal College of Surgeons get involved? Why is this general election particularly significant? And what can surgeons do to engage with politicians?
Clinical outcomes, quality improvement and professional recertification: lessons from UK cardiac surgery
Authors: Bridgewater Ben , Nicholas Owen , Hamilton Leslie , Cooper Graham
Published: April 2010

At the time of writing this paper, mortality outcomes for cardiac surgeons in the UK are being updated on the Care Quality Commission (CQC) website. The initial clamour for results to become available followed events in paediatric cardiac surgery at Bristol and recommendations from the subsequent inquiry (see http://www.bristol-inquiry.org.uk/). A decade later these published data remain unique in British medicine. More recently legislation was introduced to regulate healthcare professionals and outcomes data will form part of the evidence required. What are the lessons from cardiac surgery?
Contradictions in the (still) gendered structure of Portuguese newspapers' production and discourse
Authors: Pinto-Coelho Zara , Mota-Ribeiro Silvana
Published: April 2010

This article discusses the access of women to Portuguese newspapers against the background of a more general debate over the role of the media in the (re)production of gender inequalities in western societies. On one hand, we stress the qualitative and quantitative developments of women's
participation as journalists in newspapers, by comparing the results of previous investigation in the Portuguese context with the statistics of our own research and with the statistics provided by the last Global Media Monitoring Project (GMMP) and by The International Federation of Journalists.
In addition, we show how gender inequalities are manifested and (re)produced in and by newspaper texts and images, by combining Critical Discourse Analysis and visual social semiotics and by comparing our results with the ones provided by the GMMP. We analyse relevant structural written and
visual categories and their implications in terms of gender ideologies and inequalities in one daily edition of Portuguese quality newspapers.
Stone, granite and concrete: three images of the urban under Franco
Authors: Muoz-Rojas Olivia
Published: April 2010

This article proposes three images of the urban for examining the reconstruction, architecture and planning discourses in the aftermath of the Spanish Civil War. The city of stone, the city of granite and the city of concrete reveal the Falangists' preference for certain construction
materials because of their symbolic and material association with the perceived historical sources of the New Spain the Roman and Hapsburg Empires and the ideal of a technically functional nation. In order to illustrate these images, this article succinctly reviews the post-war transformations
of three selected sites: the Avinguda de la Catedral in Barcelona, the Montaa del Prncipe Po in Madrid and the bridges of Bilbao, together with the discourses that accompanied these developments.
Ignoring the Elephant in the Room: A Neural Circuit to Downregulate Salience
Authors: Mevorach Carmel , Hodsoll John , Allen Harriet , Shalev Lilach , Humphreys Glyn
Published: April 2010

How do we ignore stimuli that are salient but irrelevant when our task is to select a lower salient stimulus? Since bottom–up processes favor high saliency, detection of a low-salient target in the presence of highly salient distractors requires top–down attentional guidance. Previous studies have demonstrated that top–down attention can modulate perceptual processing and also that the control of attention is driven by frontoparietal regions. However, to date, there is no direct evidence on the cause and effect relationship between control regions and perceptual processing. Here, we report the first evidence demonstrating a neural circuit for the downregulation of salient distractors when a low-salient target is selected, combining brain imaging using functional magnetic resonance imaging with brain stimulation by transcranial magnetic stimulation. Using these combined techniques, we were able to identify a cause and effect relationship in the suppression of saliency, based on an interaction between the left intraparietal sulcus (IPS) and a region implicated in visual processing in our task (the left occipital pole). In particular, low-salient stimuli were selected by the left IPS suppressing early visual areas that would otherwise respond to a high-saliency distractor in the task. Apart from providing a first documentation of the neural circuit supporting selection by saliency, these data can be critical for understanding the underlying causes of problems in ignoring irrelevant salience that are found in both acquired and neurodevelopmental disorders (e.g., attention deficit/hyperactivity disorder or autism).
Burst-Induced Anti-Hebbian Depression Acts through Short-Term Synaptic Dynamics to Cancel Redundant Sensory Signals
Authors: Harvey-Girard Erik , Lewis John , Maler Leonard
Published: April 2010

Weakly electric fish can enhance the detection and localization of important signals such as those of prey in part by cancellation of redundant spatially diffuse electric signals due to, e.g., their tail bending. The cancellation mechanism is based on descending input, conveyed by parallel fibers emanating from cerebellar granule cells, that produces a negative image of the global low-frequency signals in pyramidal cells within the first-order electrosensory region, the electrosensory lateral line lobe (ELL). Here we demonstrate that the parallel fiber synaptic input to ELL pyramidal cell undergoes long-term depression (LTD) whenever both parallel fiber afferents and their target cells are stimulated to produce paired burst discharges. Paired large bursts (4-4) induce robust LTD over pre–post delays of up to ±50 ms, whereas smaller bursts (2-2) induce weaker LTD. Single spikes (either presynaptic or postsynaptic) paired with bursts did not induce LTD. Tetanic presynaptic stimulation was also ineffective in inducing LTD. Thus, we have demonstrated a form of anti-Hebbian LTD that depends on the temporal correlation of burst discharge. We then demonstrated that the burst-induced LTD is postsynaptic and requires the NR2B subunit of the NMDA receptor, elevation of postsynaptic Ca2+, and activation of CaMKIIβ. A model incorporating local inhibitory circuitry and previously identified short-term presynaptic potentiation of the parallel fiber synapses further suggests that the combination of burst-induced LTD, presynaptic potentiation, and local inhibition may be sufficient to explain the generation of the negative image and cancellation of redundant sensory input by ELL pyramidal cells.
The Death Receptor Antagonist FLIP-L Interacts with Trk and Is Necessary for Neurite Outgrowth Induced by Neurotrophins
Authors: Moubarak Rana S. , Solé Carme , Pascual Marta , Gutierrez Humberto , Llovera Marta , Pérez-García M. José , Gozzelino Raffaella , Segura Miguel F. , Iglesias-Guimarais Victoria , Reix Stéphanie , Soler Rosa M. , Davies Alun M. , Soriano Eduardo , Yuste Victor J. , Comella Joan X.
Published: April 2010

FLICE-inhibitory protein (FLIP) is an endogenous inhibitor of the signaling pathway triggered by the activation of death receptors. Here, we reveal a novel biological function for the long form of FLIP (FLIP-L) in neuronal differentiation, which can be dissociated from its antiapoptotic role. We show that FLIP-L is expressed in different regions of the mouse embryonic nervous system. Immunohistochemistry of mouse brain sections at different stages reveals that, in neurons, FLIP is expressed early during the embryonic neuronal development (embryonic day 16) and decreases at later stages (postnatal days 5–15), when its expression is essentially detected in glial cells. FLIP-L overexpression significantly enhances neurotrophin-induced neurite outgrowth in motoneurons, superior cervical ganglion neurons, and PC12 cells. Conversely, the downregulation of FLIP-L protein levels by specific RNA interference significantly reduces neurite outgrowth, even in the presence of the appropriate neurotrophin stimulus. Moreover, NGF-dependent activation of two main intracellular pathways involved in the regulation of neurite outgrowth, extracellular signal-regulated kinases (ERKs) and nuclear factor κB (NF-κB), is impaired when endogenous FLIP-L is downregulated, although TrkA remains activated. Finally, we demonstrate that FLIP-L interacts with TrkA, and not with p75NTR, in an NGF-dependent manner, and endogenous FLIP-L interacts with TrkB in whole-brain lysates from embryonic day 15 mice embryos. Altogether, we uncover a new role for FLIP-L as an unexpected critical player in neurotrophin-induced mitogen-activated protein kinase/ERK- and NF-κB-mediated control of neurite growth in developing neurons.
Norrin Mediates Neuroprotective Effects on Retinal Ganglion Cells via Activation of the Wnt/β-Catenin Signaling Pathway and the Induction of Neuroprotective Growth Factors in Müller Cells
Authors: Seitz Roswitha , Hackl Simon , Seibuchner Thomas , Tamm Ernst R. , Ohlmann Andreas
Published: April 2010

Norrin is a secreted protein that binds to frizzled 4 and controls development of capillaries in retina and inner ear. We provide evidence that Norrin has distinct neuroprotective properties that are independent from its effects on vascular development. The function of Norrin was investigated in a mouse model of excitotoxic retinal ganglion cell (RGC) damage after intravitreal injection of NMDA, and in cultured Müller glia or immortalized RGC-5 cells. Intravitreal injection of Norrin significantly increased the number of surviving RGC axons in the optic nerve and decreased apoptotic death of retinal neurons following NMDA-mediated damage. This effect could be blocked by adding dickkopf (DKK)-1, an inhibitor of the Wnt/β-catenin signaling pathway. Treatment of eyes with combined Norrin/NMDA activated Wnt/β-catenin signaling and increased the retinal expression of leukemia inhibitory factor and endothelin-2, as well as that of neurotrophic growth factors such as fibroblast growth factor-2, brain-derived neurotrophic factor, lens epithelium-derived growth factor, and ciliary neurotrophic factor. A similar activation of Wnt/β-catenin signaling and an increased expression of neurotrophic factors was observed in cultured Müller cells after treatment with Norrin, effects that again could be blocked by adding DKK-1. In addition, conditioned cell culture medium of Norrin-treated Müller cells increased survival of differentiated RGC-5 cells. We conclude that Norrin has pronounced neuroprotective properties on retinal neurons with the distinct potential to decrease the damaging effects of NMDA-induced RGC loss. The effects of Norrin involve activation of Wnt/β-catenin signaling and subsequent induction of neurotrophic growth factors in Müller cells.
CNS Leptin Action Modulates Immune Response and Survival in Sepsis
Authors: Tschöp Johannes , Nogueiras Ruben , Haas-Lockie Sarah , Kasten Kevin R. , Castañeda Tamara R. , Huber Nadine , Guanciale Kelsey , Perez-Tilve Diego , Habegger Kirk , Ottaway Nickki , Woods Stephen C. , Oldfield Brian , Clarke Iain , Chua Streamson , Farooqi I. Sadaf , O'Rahilly Stephen , Caldwell Charles C. , Tschöp Matthias H.
Published: April 2010

Sepsis describes a complex clinical syndrome that results from an infection, setting off a cascade of systemic inflammatory responses that can lead to multiple organ failure and death. Leptin is a 16 kDa adipokine that, among its multiple known effects, is involved in regulating immune function. Here we demonstrate that leptin deficiency inob/obmice leads to higher mortality and more severe organ damage in a standard model of sepsis in mice [cecal ligation and puncture (CLP)]. Moreover, systemic leptin replacement improved the immune response to CLP. Based on the molecular mechanisms of leptin regulation of energy metabolism and reproductive function, we hypothesized that leptin acts in the CNS to efficiently coordinate peripheral immune defense in sepsis. We now report that leptin signaling in the brain increases survival during sepsis in leptin-deficient as well as in wild-type mice and that endogenous CNS leptin action is required for an adequate systemic immune response. These findings reveal the existence of a relevant neuroendocrine control of systemic immune defense and suggest a possible therapeutic potential for leptin analogs in infectious disease.
Dysregulation of Dopamine Transporters via Dopamine D2Autoreceptors Triggers Anomalous Dopamine Efflux Associated with Attention-Deficit Hyperactivity Disorder
Authors: Bowton Erica , Saunders Christine , Erreger Kevin , Sakrikar Dhananjay , Matthies Heinrich J. , Sen Namita , Jessen Tammy , Colbran Roger J. , Caron Marc G. , Javitch Jonathan A. , Blakely Randy D. , Galli Aurelio
Published: April 2010

The neurotransmitter dopamine (DA) modulates brain circuits involved in attention, reward, and motor activity. Synaptic DA homeostasis is primarily controlled via two presynaptic regulatory mechanisms, DA D2receptor (D2R)-mediated inhibition of DA synthesis and release, and DA transporter (DAT)-mediated DA clearance. D2Rs can physically associate with DAT and regulate DAT function, linking DA release and reuptake to a common mechanism. We have established that the attention-deficit hyperactivity disorder-associated human DAT coding variant Ala559Val (hDAT A559V) results in anomalous DA efflux (ADE) similar to that caused by amphetamine-like psychostimulants. Here, we show that tonic activation of D2R provides support for hDAT A559V-mediated ADE. We determine in hDAT A559V a pertussis toxin-sensitive, CaMKII-dependent phosphorylation mechanism that supports D2R-driven DA efflux. These studies identify a signaling network downstream of D2R activation, normally constraining DA action at synapses, that may be altered by DAT mutation to impact risk for DA-related disorders.
Genetic Variation inFGF20Modulates Hippocampal Biology
Authors: Lemaitre Herve , Mattay Venkata S. , Sambataro Fabio , Verchinski Beth , Straub Richard E. , Callicott Joseph H. , Kittappa Raja , Hyde Thomas M. , Lipska Barbara K. , Kleinman Joel E. , McKay Ronald , Weinberger Daniel R.
Published: April 2010

We explored the effect of single-nucleotide polymorphisms (SNPs) in the fibroblast growth factor 20 gene (FGF20) associated with risk for Parkinson's disease on brain structure and function in a large sample of healthy young-adult human subjects and also in elderly subjects to look at the interaction between genetic variations and age (N= 237; 116 men; 18–87 years). We analyzed high-resolution anatomical magnetic resonance images using voxel-based morphometry, a quantitative neuroanatomical technique. We also measured FGF20 mRNA expression in postmortem human brain tissue to determine the molecular correlates of these SNPs (N= 108; 72 men; 18–74 years). We found that the T allele carriers of rs12720208 in the 3′-untranslated region had relatively larger hippocampal volume (p= 0.0059) and diminished verbal episodic memory (p= 0.048) and showed steeper decreases of hippocampal volume with normal aging (p= 0.026). In postmortem brain, T allele carriers had greater expression of hippocampalFGF20mRNA (p= 0.037), consistent with a previously characterized microRNA mechanism. The C allele matches a predicted miR-433 microRNA binding domain, whereas the T allele disrupts it, resulting in higherFGF20protein translation. The strong FGF20 genetic effects in hippocampus are presumably mediated by activation of the FGFR1 (FGF receptor 1), which is expressed in mammalian brain most abundantly in the hippocampus. These associations, from mRNA expression to brain morphology to cognition and an interaction with aging, confirm a role of FGF20 in human brain structure and function during development and aging.
Parallel Input Channels to Mouse Primary Visual Cortex
Authors: Gao Enquan , DeAngelis Gregory C. , Burkhalter Andreas
Published: April 2010

It is generally accepted that in mammals visual information is sent to the brain along functionally specialized parallel pathways, but whether the mouse visual system uses similar processing strategies is not known. It is important to resolve this issue because the mouse brain provides a tractable system for developing a cellular and molecular understanding of disorders affecting spatiotemporal visual processing. We have used single-unit recordings in mouse primary visual cortex to study whether individual neurons are more sensitive to one set of sensory cues than another. Our quantitative analyses show that neurons with short response latencies have low spatial acuity and high sensitivity to contrast, temporal frequency, and speed, whereas neurons with long latencies have high spatial acuity, low sensitivities to contrast, temporal frequency, and speed. These correlations suggest that neurons in mouse V1 receive inputs from a weighted combination of parallel afferent pathways with distinct spatiotemporal sensitivities.
Bone mineral density acquisition in peripubertal female rhythmic gymnasts is directly associated with plasma IGF1/IGF-binding protein 3 ratio
Authors: Maïmoun Laurent , Coste Olivier , Galtier Florence , Mura Thibault , Mariano-Goulart Denis , Paris Françoise , Sultan Charles
Published: April 2010

Objectives

Intense physical activity in peripubertal girls may delay menarche and cause menstrual disorders and estrogen deficiency, particularly in sport disciplines that require strict weight control. It may also have a deleterious effect on bone mass acquisition. The aim of this study was to determine the time-course of bone mass accretion in peripubertal elite female rhythmic gymnasts (FRGs) over a 1-year period, as well as the anthropometric and hormone parameters that could be helpful for predicting bone mineral density (BMD) gain.

Methods and design

We conducted a 1-year follow-up study in 29 FRGs (10.7–16.1 years old). Whole body composition and BMD of the whole body, proximal femur, lumbar spine, mid-radius, and skull were measured by dual energy X-ray absorptiometry (DXA). Moreover, baseline growth- and bone metabolism-related hormones such as IGF1, IGF-binding protein 3 (IGFBP3), leptin, and bone markers were measured.

Results

BMD increased significantly at all bone sites throughout puberty, particularly between Tanner stages II and IV–V (P=0.025 toP<0.001). The IGF1 level, IGF1/IGFBP3 ratio, and leptin level were higher in late pubertal stages (i.e. IV–V) compared with early stage (i.e. I). In simple and multivariate analyses, only the IGF1/IGFBP3 ratio was strongly correlated with the BMD change at all bone sites (r=0.49,P=0.02 tor=0.77,P<0.0001).

Conclusion

This 1-year follow-up study of peripubertal FRGs showed that BMD gain was maximal around Tanner stage III. The plasma IGF1/IGFBP3 ratio was associated with bone mass acquisition in this period, and it may thus serve as a surrogate marker of bone mass gain in this population.
Early Human Bone Response to Laser Metal Sintering Surface Topography: A Histologic Report
Authors: Mangano Carlo , Piattelli Adriano , d'Avila Susana , Iezzi Giovanna , Mangano Francesco , Onuma Tatiana , Shibli Jamil Awad
Published: April 2010

This histologic report evaluated the early human bone response to a direct laser metal sintering implant surface retrieved after a short period of healing. A selective laser sintering procedure using a Ti-6Al-4V alloy powder with a particle size of 25–45 µm prepared this surface topography. One experimental microimplant was inserted into the anterior mandible of a patient during conventional implant surgery of the jaw. The microimplant and surrounding tissues were removed after 2 months of unloaded healing and were prepared for histomorphometric analysis. Histologically, the peri-implant bone appeared in close contact with the implant surface, whereas marrow spaces could be detected in other areas along with prominently stained cement lines. The mean of bone-to-implant contact was 69.51%. The results of this histologic report suggest that the laser metal sintering surface could be a promising alternative to conventional implant surface topographies.
Advanced Glycation Endproducts and Rat Dental Implant Osseointegration
Authors: Quintero David G. , Winger Julia N. , Khashaba Rania , Borke James L.
Published: April 2010

Advanced glycation endproducts (AGEs) are a diverse group of molecular adducts formed in environments high in reducing sugars that accumulate with aging and in diabetes. This study tests the hypothesis that AGEs inhibit the stabile osseointegration of dental implants through tissue interactions that interfere with bone turnover and compromise the biomechanical properties at the bone-implant interface. Maxillary first molars were extracted from 32 rats and allowed to heal for 4 weeks. Titanium implants (1 mm × 3 mm) were placed in the healed sockets of 2 groups of 16 rats consisting of 8 rats injected 3 times/wk for 1 month with AGE (prepared from glucose and lysine) and 8 rats injected with vehicle as a control. AGE injections continued for an additional 14 or 28 days before sacrifice. X-ray images, blood, and tissues were collected to examine bone/implant contact ratio, serum pyridinoline ([PYD] a collagen breakdown marker), osteocalcin ([OSC] a bone formation marker), and for immunohistochemistry with antibodies to AGE and the bone turnover-marker protein matrix metalloproteinase1. Compared with the AGE-treated groups, the controls showed significantly higher bone/implant contact at both 14- and 28-day time points. PYD (P < .05) and OSC (trend) levels from controls showed decreases at 28 days when compared with AGE-treated groups. Immunohistochemistry with AGE-specific and bone turnover marker antibodies showed stronger staining associated with the implant/tissue interface in AGE-treated rats. Our studies indicate an association between AGE and inhibition of bone turnover, suggesting that the formation of AGE in high glycemic conditions, such as diabetes, may contribute to a slower rate of osseointegration that negatively affects implant stability.
Free Gingival Graft Immobilization: A Pilot Study on a Newly Designed Stent
Authors: Hassani Ali , Sadrimanesh Roozbeh , Vahdati Seyed Aliakbar , Sadr-eshkevari Pooyan
Published: April 2010

The presence of adequate gingiva with firm attachment to the underlying periosteum and bone is important for the overall long-term success of implant-supported oral rehabilitation. In the presence of an atrophic edentulous mandible, peri-implant soft tissue management is a challenging task. Therefore, mucosal grafts are sometimes necessary in patients with insufficient attached gingiva around abutments. Immobilization of this graft is mandatory for its survival. The study design included 5 edentulous patients with inadequate attached gingival zone, all candidates for implant surgery and free gingival graft. In the first surgery the implants were inserted, and in the second operation a free gingival graft was obtained from the palate and sutured to the mandibular site. A newly designed stent was applied for the stabilization of the graft. Two to 3 weeks after the second surgery, the stents were removed and the attached gingival width was measured. Long-term evaluations were performed to follow the survival of the graft. All grafts were intact at the time of stent removal. In all cases, the long-term evaluations revealed adequate attached gingiva around the implant. It may be concluded that immobilization of free gingival graft in the recipient site increases its success rate and its survival rate. The application of the newly designed stent can serve as a proper and easy immobilizer for peri-implant soft tissue management.
Immediate Placement of Dental Implants Into Fresh Extraction Socket in the Maxillary Anterior Region: A Case Report
Authors: Park Jun-Beom
Published: April 2010

The loss of the buccal alveolar plate following tooth extraction in the maxillary anterior may lead to palatal implant positioning with esthetic complications. Immediate placement of dental implants has been suggested because it may preclude dramatic postextraction bone loss. In this report, the harmony of soft and hard tissue was achieved by immediate implant placement with bone augmentation in an esthetically challenging situation.
Saethre-Chotzen Syndrome: A Case Report
Authors: Peña William A. , Slavotinek Anne , Oberoi Snehlata
Published: April 2010

Saethre-Chotzen syndrome (acrocephalosyndactyly type III) is a craniosynostosis syndrome inherited in an autosomal dominant manner. Although similar to the other craniosynostosis syndromes in its clinical presentation, this syndrome is caused by a mutation in the TWIST1 gene. The TWIST1 gene product is a transcription factor containing a basic helix-loop-helix (bHLH) domain important in the development of the head and limbs. Clinical features of this syndrome include unilateral or bilateral coronal synostosis, ptosis, low-set ears, hearing loss, hypertelorism, maxillary hypoplasia, deviated nasal septum, broad great toes, clinodactyly, and syndactyly. We report a young girl with clinical features of Saethre-Chotzen syndrome who has a previously undescribed sequence variant in the TWIST1 gene, corresponding to p.R191 M. The location of the altered amino acid in the Twist-box of TWIST1, the high conservation of this amino acid between different species, and the phenotype of the child all support a pathogenic role for this novel TWIST1 sequence alteration.