bluuebunny/crossref_metadata_2025 huggingface dataset:
Multilocus association mapping using generalized ridge logistic regression
Authors: Liu Zhe , Shen Yuanyuan , Ott Jurg
Published: September 2011

Background

In genome-wide association studies, it is widely accepted that multilocus methods are more powerful than testing single-nucleotide polymorphisms (SNPs) one at a time. Among statistical approaches considering many predictors simultaneously, scan statistics are an effective tool for detecting susceptibility genomic regions and mapping disease genes. In this study, inspired by the idea of scan statistics, we propose a novel sliding window-based method for identifying a parsimonious subset of contiguous SNPs that best predict disease status.

Results

Within each sliding window, we apply a forward model selection procedure using generalized ridge logistic regression for model fitness in each step. In power simulations, we compare the performance of our method with that of five other methods in current use. Averaging power over all the conditions considered, our method dominates the others. We also present two published datasets where our method is useful in causal SNP identification.

Conclusions

Our method can automatically combine genetic information in local genomic regions and allow for linkage disequilibrium between SNPs. It can overcome some defects of the scan statistics approach and will be very promising in genome-wide case-control association studies.
Genome-wide analysis of WRKY gene family in Cucumis sativus
Authors: Ling Jian , Jiang Weijie , Zhang Ying , Yu Hongjun , Mao Zhenchuan , Gu Xingfang , Huang Sanwen , Xie Bingyan
Published: September 2011

Background

WRKY proteins are a large family of transcriptional regulators in higher plant. They are involved in many biological processes, such as plant development, metabolism, and responses to biotic and abiotic stresses. Prior to the present study, only one full-length cucumber WRKY protein had been reported. The recent publication of the draft genome sequence of cucumber allowed us to conduct a genome-wide search for cucumber WRKY proteins, and to compare these positively identified proteins with their homologs in model plants, such asArabidopsis.

Results

We identified a total of 55 WRKY genes in the cucumber genome. According to structural features of their encoded proteins, the cucumber WRKY (CsWRKY) genes were classified into three groups (group 1-3). Analysis of expression profiles ofCsWRKYgenes indicated that 48 WRKY genes display differential expression either in their transcript abundance or in their expression patterns under normal growth conditions, and 23 WRKY genes were differentially expressed in response to at least one abiotic stresses (cold, drought or salinity). The expression profile of stress-inducibleCsWRKYgenes were correlated with those of their putativeArabidopsis WRKY (AtWRKY)orthologs, except for the group 3 WRKY genes. Interestingly, duplicated group 3AtWRKYgenes appear to have been under positive selection pressure during evolution. In contrast, there was no evidence of recent gene duplication or positive selection pressure amongCsWRKYgroup 3 genes, which may have led to the expressional divergence of group 3 orthologs.

Conclusions

Fifty-five WRKY genes were identified in cucumber and the structure of their encoded proteins, their expression, and their evolution were examined. Considering that there has been extensive expansion of group 3 WRKY genes in angiosperms, the occurrence of different evolutionary events could explain the functional divergence of these genes.
Single-nucleotide resolution analysis of the transcriptome structure of Clostridium beijerinckii NCIMB 8052 using RNA-Seq
Authors: Wang Yi , Li Xiangzhen , Mao Yuejian , Blaschek Hans P
Published: September 2011

Background

Clostridium beijerinckii is an important solvent producing microorganism. The genome of C. beijerinckii NCIMB 8052 has recently been sequenced. Although transcriptome structure is important in order to reveal the functional and regulatory architecture of the genome, the physical structure of transcriptome for this strain, such as the operon linkages and transcript boundaries are not well understood.

Results

In this study, we conducted a single-nucleotide resolution analysis of the C. beijerinckii NCIMB 8052 transcriptome using high-throughput RNA-Seq technology. We identified the transcription start sites and operon structure throughout the genome. We confirmed the structure of important gene operons involved in metabolic pathways for acid and solvent production in C. beijerinckii 8052, including pta-ack, ptb-buk, hbd-etfA-etfB-crt (bcs) and ald-ctfA-ctfB-adc (sol) operons; we also defined important operons related to chemotaxis/motility, transcriptional regulation, stress response and fatty acids biosynthesis along with others. We discovered 20 previously non-annotated regions with significant transcriptional activities and 15 genes whose translation start codons were likely mis-annotated. As a consequence, the accuracy of existing genome annotation was significantly enhanced. Furthermore, we identified 78 putative silent genes and 177 putative housekeeping genes based on normalized transcription measurement with the sequence data. We also observed that more than 30% of pseudogenes had significant transcriptional activities during the fermentation process. Strong correlations exist between the expression values derived from RNA-Seq analysis and microarray data or qRT-PCR results.

Conclusions

Transcriptome structural profiling in this research provided important supplemental information on the accuracy of genome annotation, and revealed additional gene functions and regulation in C. beijerinckii.
Characterization of the χψ subcomplex of Pseudomonas aeruginosa DNA polymerase III
Authors: El Houry Mignan Sirine , Witte Gregor , Naue Natalie , Curth Ute
Published: September 2011

Background

DNA polymerase III, the main enzyme responsible for bacterial DNA replication, is composed of three sub-assemblies: the polymerase core, the β-sliding clamp, and the clamp loader. During replication, single-stranded DNA-binding protein (SSB) coats and protects single-stranded DNA (ssDNA) and also interacts with the χψ heterodimer, a sub-complex of the clamp loader. Whereas the χ subunits of Escherichia coli and Pseudomonas aeruginosa are about 40% homologous, P. aeruginosa ψ is twice as large as its E. coli counterpart, and contains additional sequences. It was shown that P. aeruginosa χψ together with SSB increases the activity of its cognate clamp loader 25-fold at low salt. The E. coli clamp loader, however, is insensitive to the addition of its cognate χψ under similar conditions. In order to find out distinguishing properties within P. aeruginosa χψ which account for this higher stimulatory effect, we characterized P. aeruginosa χψ by a detailed structural and functional comparison with its E. coli counterpart.

Results

Using small-angle X-ray scattering, analytical ultracentrifugation, and homology-based modeling, we found the N-terminus of P. aeruginosa ψ to be unstructured. Under high salt conditions, the affinity of the χψ complexes from both organisms to their cognate SSB was similar. Under low salt conditions, P. aeruginosa χψ, contrary to E. coli χψ, binds to ssDNA via the N-terminus of ψ. Whereas it is also able to bind to double-stranded DNA, the affinity is somewhat reduced.

Conclusions

The binding to DNA, otherwise never reported for any other ψ protein, enhances the affinity of P. aeruginosa χψ towards the SSB/ssDNA complex and very likely contributes to the higher stimulatory effect of P. aeruginosa χψ on the clamp loader. We also observed DNA-binding activity for P. putida χψ, making this activity most probably a characteristic of the ψ proteins from the Pseudomonadaceae.
A randomized controlled trial to investigate the influence of low dose radiotherapy on immune stimulatory effects in liver metastases of colorectal cancer
Authors: Reissfelder Christoph , Timke Carmen , Schmitz-Winnenthal Hubertus , Rahbari Nuh N , Koch Moritz , Klug Felix , Roeder Falk , Edler Lutz , Debus Jürgen , Büchler Markus W , Beckhove Philipp , Huber Peter E , Weitz Jürgen
Published: September 2011

Background

Insufficient migration and activation of tumor specific effector T cells in the tumor is one of the main reasons for inadequate host anti-tumor immune response. External radiation seems to induce inflammation and activate the immune response. This phase I/II clinical trial aims to evaluate whether low dose single fraction radiotherapy can improve T cell associated antitumor immune response in patients with colorectal liver metastases.

Methods/Design

This is an investigator-initiated, prospective randomised, 4-armed, controlled Phase I/II trial. Patients undergoing elective hepatic resection due to colorectal cancer liver metastasis will be enrolled in the study. Patients will receive 0 Gy, 0.5 Gy, 2 Gy or 5 Gy radiation targeted to their liver metastasis. Radiation will be applied by external beam radiotherapy using a 6 MV linear accelerator (Linac) with intensity modulated radiotherapy (IMRT) technique two days prior to surgical resection. All patients admitted to the Department of General-, Visceral-, and Transplantion Surgery, University of Heidelberg for elective hepatic resection are consecutively screened for eligibility into this trial, and written informed consent is obtained before inclusion. The primary objective is to assess the effect of active local external beam radiation dose on, tumor infiltrating T cells as a surrogate parameter for antitumor activity. Secondary objectives include radiogenic treatment toxicity, postoperative morbidity and mortality, local tumor control and recurrence patterns, survival and quality of life. Furthermore, frequencies of systemic tumor reactive T cells in blood and bone marrow will be correlated with clinical outcome.

Discussion

This is a randomized controlled patient blinded trial to assess the safety and efficiency of low dose radiotherapy on metastasis infiltrating T cells and thus potentially enhance the antitumor immune response.

Trial registration

ClinicalTrials.gov: NCT01191632
Service user and carer experiences of seeking help for a first episode of psychosis: a UK qualitative study
Authors: Tanskanen Sanna , Morant Nicola , Hinton Mark , Lloyd-Evans Brynmor , Crosby Michelle , Killaspy Helen , Raine Rosalind , Pilling Stephen , Johnson Sonia
Published: September 2011

Background

Long duration of untreated psychosis (DUP) is associated with poor outcomes and low quality of life at first contact with mental health services. However, long DUP is common. In order to inform initiatives to reduce DUP, we investigated service users' and carers' experiences of the onset of psychosis and help-seeking in two multicultural, inner London boroughs and the roles of participants' social networks in their pathways to care.

Method

In-depth interviews were conducted with service users and carers from an early intervention service in North London, purposively sampled to achieve diversity in sociodemographic characteristics and DUP and to include service users in contact with community organisations during illness onset. Interviews covered respondents' understanding of and reaction to the onset of psychosis, their help-seeking attempts and the reactions of social networks and health services. Thematic analysis of interview transcripts was conducted.

Results

Multiple barriers to prompt treatment included not attributing problems to psychosis, worries about the stigma of mental illness and service contact, not knowing where to get help and unhelpful service responses. Help was often not sought until crisis point, despite considerable prior distress. The person experiencing symptoms was often the last to recognise them as mental illness. In an urban UK setting, where involved, workers in non-health community organisations were frequently willing to assist help-seeking but often lacked skills, time or knowledge to do so.

Conclusion

Even modest periods of untreated psychosis cause distress and disruption to individuals and their families. Early intervention services should prioritise early detection. Initiatives aimed at reducing DUP may succeed not by promoting swift service response alone, but also by targeting delays in initial help-seeking. Our study suggests that strategies for doing this may include addressing the stigma associated with psychosis and community education regarding symptoms and services, targeting not only young people developing illness but also a range of people in their networks, including staff in educational and community organisations. Initiatives to enhance the effective involvement of staff in community organisations working with young people in promoting help-seeking merit research.
Factors associated with chemical burns in Zhejiang province, China: An epidemiological study
Authors: Zhang Yuan H , Han Chun M , Chen Guo X , Ye Chun J , Jiang Rui M , Liu Li P , Ni Liang F
Published: September 2011

Background

Work-related burns are common among occupational injuries. Zhejiang Province is an industrial area with a high incidence of chemical burns. We aimed to survey epidemiological features of chemical burns in Zhejiang province to determine associated factors and acquire data for developing a strategy to prevent and treat chemical burns.

Methods

Questionnaires were developed, reviewed and validated by experts, and sent to 25 hospitals in Zhejiang province to prospectively collect data of 492 chemical burn patients admitted during one year from Sept. 1, 2008 to Aug. 31, 2009. Questions included victims' characteristics and general condition, injury location, causes of accident, causative chemicals, total body surface area burn, concomitant injuries, employee safety training, and awareness level of protective measures. Surveys were completed for each of burn patients by burn department personnel who interviewed the hospitalized patients.

Results

In this study, 417 victims (87.61%) got chemical burn at work, of which 355 victims (74.58%) worked in private or individual enterprises. Most frequent chemicals involved were hydrofluoric acid and sulfuric acid. Main causes of chemical injury accidents were inappropriate operation of equipment or handling of chemicals and absence of or failure to use effective individual protection.

Conclusions

Most chemical burns are preventable occupational injuries that can be attributed to inappropriate operation of equipment or handling of chemicals, lack of employee awareness about appropriate action and lack of effective protective equipment and training. Emphasis on safety education and protection for workers may help protect workers and prevent chemical burns.
Laboratory demonstration of a prozone-like effect in HRP2-detecting malaria rapid diagnostic tests: implications for clinical management
Authors: Luchavez Jennifer , Baker Joanne , Alcantara Sheila , Belizario Vicente , Cheng Qin , McCarthy James S , Bell David
Published: September 2011

Background

Malaria rapid diagnostic tests (RDTs) are now widely used for prompt on-site diagnosis in remote endemic areas where reliable microscopy is absent. Aberrant results, whereby negative test results occur at high parasite densities, have been variously reported for over a decade and have led to questions regarding the reliability of the tests in clinical use.

Methods

In the first trial, serial dilutions of recombinant HRP2 antigen were tested on an HRP2-detectiing RDT. In a second trial, serial dilutions of culture-derived Plasmodium falciparum parasites were tested against three HRP2-detecting RDTs.

Results

A prozone-like effect occurred in RDTs at a high concentration of the target antigen, histidine-rich protein-2 (above 15,000 ng/ml), a level that corresponds to more than 312000 parasites per μL. Similar results were noted on three RDT products using dilutions of cultured parasites up to a parasite density of 25%. While reduced line intensity was observed, no false negative results occurred.

Conclusions

These results suggest that false-negative malaria RDT results will rarely occur due to a prozone-like effect in high-density infections, and other causes are more likely. However, RDT line intensity is poorly indicative of parasite density in high-density infections and RDTs should, therefore, not be considered quantitative. Immediate management of suspected severe malaria should rely on clinical assessment or microscopy. Evaluation against high concentrations of antigen should be considered in malaria RDT product development and lot-release testing, to ensure that very weak or false negative results will not occur at antigen concentrations that might be seen clinically.
Single wall carbon nanotubes enter cells by endocytosis and not membrane penetration
Authors: Yaron Peter N , Holt Brian D , Short Philip A , Lösche Mathias , Islam Mohammad F , Dahl Kris Noel
Published: September 2011

Background

Carbon nanotubes are increasingly being tested for use in cellular applications. Determining the mode of entry is essential to control and regulate specific interactions with cells, to understand toxicological effects of nanotubes, and to develop nanotube-based cellular technologies. We investigated cellular uptake of Pluronic copolymer-stabilized, purified ~145 nm long single wall carbon nanotubes (SWCNTs) through a series of complementary cellular, cell-mimetic, and in vitro model membrane experiments.

Results

SWCNTs localized within fluorescently labeled endosomes, and confocal Raman spectroscopy showed a dramatic reduction in SWCNT uptake into cells at 4°C compared with 37°C. These data suggest energy-dependent endocytosis, as shown previously. We also examined the possibility for non-specific physical penetration of SWCNTs through the plasma membrane. Electrochemical impedance spectroscopy and Langmuir monolayer film balance measurements showed that Pluronic-stabilized SWCNTs associated with membranes but did not possess sufficient insertion energy to penetrate through the membrane. SWCNTs associated with vesicles made from plasma membranes but did not rupture the vesicles.

Conclusions

These measurements, combined, demonstrate that Pluronic-stabilized SWCNTs only enter cells via energy-dependent endocytosis, and association of SWCNTs to membrane likely increases uptake.
Impact of childhood trauma on functionality and quality of life in HIV-infected women
Authors: Troeman Zyrhea CE , Spies Georgina , Cherner Mariana , Archibald Sarah L , Fennema-Notestine Christine , Theilmann Rebecca J , Spottiswoode Bruce , Stein Dan J , Seedat Soraya
Published: September 2011

Background

While there are many published studies on HIV and functional limitations, there are few in the context of early abuse and its impact on functionality and Quality of Life (QoL) in HIV.

Methods

The present study focused on HIV in the context of childhood trauma and its impact on functionality and Quality of Life (QoL) by evaluating 85 HIV-positive (48 with childhood trauma and 37 without) and 52 HIV-negative (21 with childhood trauma and 31 without) South African women infected with Clade C HIV. QoL was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), the Patient's Assessment of Own Functioning Inventory (PAOFI), the Activities of Daily Living (ADL) scale and the Sheehan Disability Scale (SDS). Furthermore, participants were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) and the Childhood Trauma Questionnaire (CTQ).

Results

Subjects had a mean age of 30.1 years. After controlling for age, level of education and CES-D scores, analysis of covariance (ANCOVA) demonstrated significant individual effects of HIV status and childhood trauma on self-reported QoL. No significant interactional effects were evident. Functional limitation was, however, negatively correlated with CD4 lymphocyte count.

Conclusions

In assessing QoL in HIV-infected women, we were able to demonstrate the impact of childhood trauma on functional limitations in HIV.
Evaluation of the new AJCC staging system for resectable hepatocellular carcinoma
Authors: Cheng Chih H , Lee Chen F , Wu Tsung H , Chan Kun M , Chou Hong S , Wu Ting J , Yu Ming C , Chen Tse C , Lee Wei C , Chen Miin F
Published: September 2011

Background

The aim of this study was to assess the validity of the 7th edition of the American Joint Committee on Cancer (AJCC) TNM system (TNM-7) for patients undergoing hepatectomy for hepatocellular carcinoma (HCC).

Methods

Partial hepatectomies performed for 879 patients from 1993 to 2005 were retrospectively reviewed. Clinicopathological factors, surgical outcome, overall survival (OS), and disease-free survival (DFS) were analyzed to evaluate the predictive value of the TNM-7 staging system.

Results

According to the TNM-7 system, differences in five-year survival between stages I, II, and III were statistically significant. Subgroup analysis of stage III patients revealed that the difference between stages II and IIIA was not significant (OS, p = 0.246; DFS, p = 0.105). Further stratification of stages IIIA, IIIB and IIIC also did not reveal significant differences. Cox proportional hazard models of stage III analyses identified additional clinicopathological factors affecting patient survival: lack of tumor encapsulation, aspartate aminotransferase (AST) values > 68 U/L, and blood loss > 500 mL affected DFS whereas lack of tumor encapsulation, AST values > 68 U/L, blood loss > 500 mL, and serum α-fetoprotein (AFP) values > 200 ng/mL were independent factors impairing OS. Stage III factors including tumor thrombus, satellite lesions, and tumor rupture did not appear to influence survival in the stage III subgroup.

Conclusions

In terms of 5-year survival rates, the TNM-7 system is capable of stratifying post-hepatectomy HCC patients into stages I, II, and III but is unable to stratify stage III patients into stages IIIA, IIIB and IIIC. Lack of tumor encapsulation, AST values > 68 U/L, blood loss > 500 mL, and AFP values > 200 ng/mL are independent prognostic factors affecting long-term survival.
Extremely discrepant mutation spectrum of SLC26A4 between Chinese patients with isolated Mondini deformity and enlarged vestibular aqueduct
Authors: Huang Shasha , Han Dongyi , Yuan Yongyi , Wang Guojian , Kang Dongyang , Zhang Xin , Yan Xiaofei , Meng Xiaoxiao , Dong Min , Dai Pu
Published: September 2011

Background

Mutations in SLC26A4 cause Pendred syndrome (hearing loss with goiter) or DFNB4 (non-syndromic hearing loss with inner ear malformation, such as enlarged vestibular aqueduct or Mondini deformity). The relationship between mutations in SLC26A4 and Mondini deformity without enlarged vestibular aqueduct has not been studied in any Chinese deaf population. The purpose of this study was to assess whether mutations in the SLC26A4 gene cause Mondini deformity without an enlarged vestibular aqueduct (isolated Mondini deformity) in a Chinese population.

Methods

In total, 144 patients with sensorineural hearing loss were included and subjected to high-resolution temporal bone CT. Among them, 28 patients with isolated Mondini dysplasia (MD group), 50 patients with enlarged vestibular aqueduct with Mondini dysplasia (EVA with MD group), 50 patients with enlarged vestibular aqueduct without Mondini dysplasia (EVA group), and 16 patients with other types of inner ear malformations (IEM group) were identified. The coding exons of SLC26A4 were analyzed in all subjects.

Results

DNA sequence analysis of SLC26A4 was performed in all 144 patients. In the different groups, the detection rate of the SLC26A4 mutation differed. In the isolated MD group, only one single allelic mutation in SLC26A4 was found in one patient (1/28, 3.6%). In the EVA with MD group, biallelic and monoallelic SLC26A4 mutations were identified in 46 patients (46/50, 92.0%) and three patients (3/50, 6.0%), respectively. Also, in the EVA group, biallelic and monoallelic SLC26A4 mutations were identified in 46 patients (46/50, 92.0%) and three patients (3/50, 6.0%), respectively. These percentages were identical to those in the EVA plus MD group. Only two patients carried monoallelic mutations of the SLC26A4 gene in the IEM group (2/16, 12.5%). There were significant differences in the frequency of SLC26A4 mutation among the groups (P < 0.001). The detection rate of SLC26A4 mutation in the isolated MD group was significantly lower than in the EVA group (with or without MD; P < 0.001), and there was no significant difference in the detection rate of SLC26A4 between the MD group and IEM group (P > 0.5).

Conclusion

Although mutations in the SLC26A4 gene were frequently found in Chinese EVA patients with and without MD, there was no evidence to show a relationship between isolated MD and the SLC26A4 gene in the Chinese population examined. Hearing impairment in patients with isolated MD may be caused by factors other than mutations in the SLC26A4 gene.
Photoelectrochemical studies of DNA-tagged biomolecules on Au and Au/Ni/Au multilayer nanowires
Authors: Swaminathan Viswanathan , Liew Hwi Fen , Lew Wen Siang , Hu Lanying , Phan Anh Tuan
Published: September 2011

The use of nanowires (NWs) for labeling, sensing, and sorting is the basis of detecting biomolecules attached on NWs by optical and magnetic properties. In spite of many advantages, the use of biomolecules-attached NWs sensing by photoelectrochemical (PEC) study is almost non-existent. In this article, the PEC study of dye-attached single-stranded DNA on Au NWs and Au-Ni-Au multilayer NWs prepared by pulse electrodeposition are investigated. Owing to quantum-quenching effect, the multilayer Au NWs exhibit low optical absorbance when compared with Au NWs. The tagged Au NWs show good fluorescence (emission) at 570 nm, indicating significant improvement in the reflectivity. Optimum results obtained for tagged Au NWs attached on functionalized carbon electrodes and its PEC behavior is also presented. A twofold enhancement in photocurrent is observed with an average dark current of 10 μA for Au NWs coated on functionalized sensing electrode. The importance of these PEC and optical studies provides an inexpensive and facile processing platform for Au NWs that may be suitable for biolabeling applications.
On the solvability of discrete nonlinear Neumann problems involving the p(x)-Laplacian
Authors: Guiro Aboudramane , Nyanquini Ismael , Ouaro Stanislas
Published: September 2011

In this article, we prove the existence and uniqueness of solutions for a family of discrete boundary value problems for data f which belongs to a discrete Hilbert space W.

2010 Mathematics Subject Classification: 47A75; 35B38; 35P30; 34L05; 34L30.
Error-resilient video coding with end-to-end rate-distortion optimized at macroblock level
Authors: Xiao Jimin , Tillo Tammam , Lin Chunyu , Zhao Yao
Published: September 2011

Intra macroblock refreshment is an effective approach for error-resilient video coding. In this paper, in addition to intra coding, we propose to add two macroblock coding modes to enhance the transmission robustness of the coded bitstream, which are inter coding with redundant macroblock and intra coding with redundant macroblock. The selection of coding modes and the parameters for coding the redundant version of the macroblock are determined by the rate-distortion optimization. It is worth mentioning that the end-to-end distortion is employed in the optimization procedure, which considers the channel conditions. Extensive simulation results show that the proposed approach outperforms other error-resilient approaches significantly; for some video sequences, the average PSNR can be up to 4 dB higher than that of the Optimal Intra Refreshment approach.
Up-regulation of dorsal root ganglia BDNF and trkB receptor in inflammatory pain: an in vivo and in vitrostudy
Authors: Lin Ya-Tin , Ro Long-Sun , Wang Hung-Li , Chen Jin-Chung
Published: September 2011

Background

During inflammation, immune cells accumulate in damaged areas and release pro-inflammatory cytokines and neurotrophins. Brain-derived neurotrophic factor (BDNF) plays a neuromodulatory role in spinal cord dorsal horn via the post-synaptic tyrosine protein kinase B (trkB) receptor to facilitate pain transmission. However, the precise role of BDNF and trkB receptor in the primary sensory neurons of dorsal root ganglia (DRG) during inflammation remains to be clarified. The aim of this study was to investigate whether and how BDNF-trkB signaling in the DRG is involved in the process of inflammatory pain.

Methods

We used complete Freund's adjuvant- (CFA-) induced and tumor necrosis factor-α- (TNF-α-) induced inflammation in rat hindpaw as animal models of inflammatory pain. Quantification of protein and/or mRNA levels of pain mediators was performed in separate lumbar L3-L5 DRGs. The cellular mechanism of TNF-α-induced BDNF and/or trkB receptor expression was examined in primary DRG cultures collected from pooled L1-L6 DRGs. Calcitonin gene-related peptide (CGRP), BDNF and substance P release were also evaluated by enzyme immunoassay.

Results

CFA injection into rat hindpaw resulted in mechanical hyperalgesia and significant increases in levels of TNF-α in the inflamed tissues, along with enhancement of BDNF and trkB receptor as well as the pain mediators CGRP and transient receptor potential vanilloid receptor subtype 1 (TRPV1) in DRG. Direct injection of TNF-α into rat hindpaw resulted in similar effects with retrograde transport of TNF-α along the saphenous nerve to DRG during CFA-induced inflammation. Primary DRG cultures chronically treated with TNF-α showed significant enhancement of mRNA and protein levels of BDNF and trkB receptor, BDNF release and trkB-induced phospho-ERK1/2 signal. Moreover, CGRP and substance P release were enhanced in DRG cultures after chronic TNF-α treatment or acute BDNF stimulation. In addition, we found that BDNF up-regulated trkB expression in DRG cultures.

Conclusions

Based on our current experimental results, we conclude that inflammation and TNF-α up-regulate the BDNF-trkB system in DRG. This phenomenon suggests that up-regulation of BDNF in DRG may, in addition to its post-synaptic effect in spinal dorsal horn, act as an autocrine and/or paracrine signal to activate the pre-synaptic trkB receptor and regulate synaptic excitability in pain transmission, thereby contributing to the development of hyperalgesia.
Primitive neuroectodermal tumor of the cervix: a case report
Authors: Farzaneh Farah , Rezvani Hamidreza , Boroujeni Parisa Taherzadeh , Rahimi Farzaneh
Published: September 2011

Introduction

Peripheral primitive neuroectodermal tumor of the cervix uteri is extremely rare. Between 1987 and 2010, there were only nine cases reported in the English literature, with considerably different management policies.

Case presentation

A 45-year-old Iranian woman presented to our facility with a primitive neuroectodermal tumor of the cervix uteri. Her clinical stage IB2 tumor was treated successfully with chemotherapy. Our patient underwent radical hysterectomy. There was no trace of the tumor after four years of follow-up.

Conclusions

According to current knowledge, primitive neuroectodermal tumors belong to the Ewing's sarcoma family, and the improvement of treatment outcome in our patient was due to dose-intensive neoadjuvant chemotherapy, surgery and consolidation chemotherapy in accordance with the protocol for bony Ewing's sarcoma.
Diagnostic evaluation of three cardiac software packages using a consecutive group of patients
Authors: Johansson Lena , Lomsky Milan , Marving Jens , Ohlsson Mattias , Svensson Sven-Eric , Edenbrandt Lars
Published: September 2011

Purpose

The aim of this study was to compare the diagnostic performance of the three software packages 4DMSPECT (4DM), Emory Cardiac Toolbox (ECTb), and Cedars Quantitative Perfusion SPECT (QPS) for quantification of myocardial perfusion scintigram (MPS) using a large group of consecutive patients.

Methods

We studied 1,052 consecutive patients who underwent 2-day stress/rest 99mTc-sestamibi MPS studies. The reference/gold-standard classifications for the MPS studies were obtained from three physicians, with more than 25 years each of experience in nuclear cardiology, who re-evaluated all MPS images. Automatic processing was carried out using 4DM, ECTb, and QPS software packages. Total stress defect extent (TDE) and summed stress score (SSS) based on a 17-segment model were obtained from the software packages. Receiver-operating characteristic (ROC) analysis was performed.

Results

A total of 734 patients were classified as normal and the remaining 318 were classified as having infarction and/or ischemia. The performance of the software packages calculated as the area under the SSS ROC curve were 0.87 for 4DM, 0.80 for QPS, and 0.76 for ECTb (QPS vs. ECTb p = 0.03; other differences p < 0.0001). The area under the TDE ROC curve were 0.87 for 4DM, 0.82 for QPS, and 0.76 for ECTb (QPS vs. ECTb p = 0.0005; other differences p < 0.0001).

Conclusion

There are considerable differences in performance between the three software packages with 4DM showing the best performance and ECTb the worst. These differences in performance should be taken in consideration when software packages are used in clinical routine or in clinical studies.
Comprehensive comparison of three commercial human whole-exome capture platforms
Authors: Asan  , Xu Yu , Jiang Hui , Tyler-Smith Chris , Xue Yali , Jiang Tao , Wang Jiawei , Wu Mingzhi , Liu Xiao , Tian Geng , Wang Jun , Wang Jian , Yang Huangming , Zhang Xiuqing
Published: September 2011

Background

Exome sequencing, which allows the global analysis of protein coding sequences in the human genome, has become an effective and affordable approach to detecting causative genetic mutations in diseases. Currently, there are several commercial human exome capture platforms; however, the relative performances of these have not been characterized sufficiently to know which is best for a particular study.

Results

We comprehensively compared three platforms: NimbleGen's Sequence Capture Array and SeqCap EZ, and Agilent's SureSelect. We assessed their performance in a variety of ways, including number of genes covered and capture efficacy. Differences that may impact on the choice of platform were that Agilent SureSelect covered approximately 1,100 more genes, while NimbleGen provided better flanking sequence capture. Although all three platforms achieved similar capture specificity of targeted regions, the NimbleGen platforms showed better uniformity of coverage and greater genotype sensitivity at 30- to 100-fold sequencing depth. All three platforms showed similar power in exome SNP calling, including medically relevant SNPs. Compared with genotyping and whole-genome sequencing data, the three platforms achieved a similar accuracy of genotype assignment and SNP detection. Importantly, all three platforms showed similar levels of reproducibility, GC bias and reference allele bias.

Conclusions

We demonstrate key differences between the three platforms, particularly advantages of solutions over array capture and the importance of a large gene target set.
The rise and fall of the atypical antipsychotics
Authors: Kendall Tim
Published: September 2011

The antipsychotics brought hope and optimism to people with schizophrenia and to those who care for them. There have been successive classes of antipsychotics used by the pharmaceutical industry to persuade doctors and patients that ‘new’ is better. Evidence is growing that the primary purpose of these fabricated classes is for marketing. It is time we stopped using these expensive labels – they are all just antipsychotics.
Assessing the mental state through a blog: psychiatry in the 21st century?
Authors: Wuyts Philippe , Broome Matthew , McGuire Philip
Published: September 2011

Blogs have become increasingly popular over the past 15 years, especially with young people. In this editorial we discuss how the blogosphere is reshaping information exchange in healthcare. More specifically, blogs may change the doctor–patient relationship and provide clinically relevant information to mental health practitioners. However, the use of blogs as a source of clinical material raises ethical and legal issues.
Young people, self-harm and internet forums
Authors: Powell John
Published: September 2011

A generation of digital natives are living their lives in fundamentally different ways from previous generations. The rapid advance of the internet and mobile telephones, and the adoption of online social media, mean that substantial parts of the social lives of young people are played out in online settings. This has implications for how young people discuss and seek help for mental health problems. This commentary discusses the role of online forums for young people who self-harm. Practitioners need to understand the potential harms and benefits, and explore how benefits can be harnessed and harms minimised.
Partially redundant proneural function reveals the importance of timing during zebrafish olfactory neurogenesis
Authors: Madelaine Romain , Garric Laurence , Blader Patrick
Published: September 2011

Little is known about proneural gene function during olfactory neurogenesis in zebrafish. Here, we show that the zebrafish Atonal genes neurogenin1 (neurog1) and neurod4 are redundantly required for development of both early-born olfactory neurons (EONs) and later-born olfactory sensory neurons (OSNs). We show that neurod4 expression is initially absent in neurog1 mutant embryos but recovers and is sufficient for the delayed development of OSN. By contrast, EON numbers are significantly reduced in neurog1 mutant embryos despite the recovery of neurod4 expression. Our results suggest that a shortened time window for EON development causes this reduction; the last S-phase of EON is delayed in neurog1 mutant embryos but mutant EONs are all post-mitotic at the same stage as EONs in wild-type embryos. Finally, we show that expression of certain genes, such as robo2, is never detected in neurog1 mutant EONs. Failure of robo2 expression to recover correlates with defects in the fasciculation of neurog1 mutant olfactory axonal projections and in the organisation of proto-glomeruli because projections arrive at the olfactory bulb that are reminiscent of those in robo2 mutant embryos. We conclude that the duration of proneural expression in EON progenitors is crucial for correct development of the zebrafish olfactory system.
COUP-TFI promotes radial migration and proper morphology of callosal projection neurons by repressing Rnd2 expression
Authors: Alfano Christian , Viola Luigi , Heng Julian Ik-Tsen , Pirozzi Marinella , Clarkson Michael , Flore Gemma , De Maio Antonia , Schedl Andreas , Guillemot François , Studer Michèle
Published: September 2011

During corticogenesis, late-born callosal projection neurons (CPNs) acquire their laminar position through glia-guided radial migration and then undergo final differentiation. However, the mechanisms controlling radial migration and final morphology of CPNs are poorly defined. Here, we show that in COUP-TFI mutant mice CPNs are correctly specified, but are delayed in reaching the cortical plate and have morphological defects during migration. Interestingly, we observed that the rate of neuronal migration to the cortical plate normally follows a low-rostral to high-caudal gradient, similar to that described for COUP-TFI. This gradient is strongly impaired in COUP-TFI–/– brains. Moreover, the expression of the Rho-GTPase Rnd2, a modulator of radial migration, is complementary to both these gradients and strongly increases in the absence of COUP-TFI function. We show that COUP-TFI directly represses Rnd2 expression at the post-mitotic level along the rostrocaudal axis of the neocortex. Restoring correct Rnd2 levels in COUP-TFI–/– brains cell-autonomously rescues neuron radial migration and morphological transitions. We also observed impairments in axonal elongation and dendritic arborization of COUP-TFI-deficient CPNs, which were rescued by lowering Rnd2 expression levels. Thus, our data demonstrate that COUP-TFI modulates late-born neuron migration and favours proper differentiation of CPNs by finely regulating Rnd2 expression levels.
Neuronal Neuregulin 1 type III directs Schwann cell migration
Authors: Perlin Julie R. , Lush Mark E. , Stephens W. Zac , Piotrowski Tatjana , Talbot William S.
Published: September 2011

During peripheral nerve development, each segment of a myelinated axon is matched with a single Schwann cell. Tight regulation of Schwann cell movement, proliferation and differentiation is essential to ensure that these glial cells properly associate with axons. ErbB receptors are required for Schwann cell migration, but the operative ligand and its mechanism of action have remained unknown. We demonstrate that zebrafish Neuregulin 1 (Nrg1) type III, which signals through ErbB receptors, controls Schwann cell migration in addition to its previously known roles in proliferation and myelination. Chimera analyses indicate that ErbB receptors are required in all migrating Schwann cells, and that Nrg1 type III is required in neurons for migration. Surprisingly, expression of the ligand in a few axons is sufficient to induce migration along a chimeric nerve constituted largely of nrg1 type III mutant axons. These studies also reveal a mechanism that allows Schwann cells to fasciculate axons regardless of nrg1 type III expression. Time-lapse imaging of transgenic embryos demonstrated that misexpression of human NRG1 type III results in ectopic Schwann cell migration, allowing them to aberrantly enter the central nervous system. These results demonstrate that Nrg1 type III is an essential signal that controls Schwann cell migration to ensure that these glia are present in the correct numbers and positions in developing nerves.
Defective neuroepithelial cell cohesion affects tangential branchiomotor neuron migration in the zebrafish neural tube
Authors: Stockinger Petra , Maître Jean-Léon , Heisenberg Carl-Philipp
Published: September 2011

Facial branchiomotor neurons (FBMNs) in zebrafish and mouse embryonic hindbrain undergo a characteristic tangential migration from rhombomere (r) 4, where they are born, to r6/7. Cohesion among neuroepithelial cells (NCs) has been suggested to function in FBMN migration by inhibiting FBMNs positioned in the basal neuroepithelium such that they move apically between NCs towards the midline of the neuroepithelium instead of tangentially along the basal side of the neuroepithelium towards r6/7. However, direct experimental evaluation of this hypothesis is still lacking. Here, we have used a combination of biophysical cell adhesion measurements and high-resolution time-lapse microscopy to determine the role of NC cohesion in FBMN migration. We show that reducing NC cohesion by interfering with Cadherin 2 (Cdh2) activity results in FBMNs positioned at the basal side of the neuroepithelium moving apically towards the neural tube midline instead of tangentially towards r6/7. In embryos with strongly reduced NC cohesion, ectopic apical FBMN movement frequently results in fusion of the bilateral FBMN clusters over the apical midline of the neural tube. By contrast, reducing cohesion among FBMNs by interfering with Contactin 2 (Cntn2) expression in these cells has little effect on apical FBMN movement, but reduces the fusion of the bilateral FBMN clusters in embryos with strongly diminished NC cohesion. These data provide direct experimental evidence that NC cohesion functions in tangential FBMN migration by restricting their apical movement.
JAK/Stat signaling regulates heart precursor diversification inDrosophila
Authors: Johnson Aaron N. , Mokalled Mayssa H. , Haden Tom N. , Olson Eric N.
Published: September 2011

Intercellular signal transduction pathways regulate the NK-2 family of transcription factors in a conserved gene regulatory network that directs cardiogenesis in both flies and mammals. The Drosophila NK-2 protein Tinman (Tin) was recently shown to regulate Stat92E, the Janus kinase (JAK) and Signal transducer and activator of transcription (Stat) pathway effector, in the developing mesoderm. To understand whether the JAK/Stat pathway also regulates cardiogenesis, we performed a systematic characterization of JAK/Stat signaling during mesoderm development. Drosophila embryos with mutations in the JAK/Stat ligand upd or in Stat92E have non-functional hearts with luminal defects and inappropriate cell aggregations. Using strong Stat92E loss-of-function alleles, we show that the JAK/Stat pathway regulates tin expression prior to heart precursor cell diversification. tin expression can be subdivided into four phases and, in Stat92E mutant embryos, the broad phase 2 expression pattern in the dorsal mesoderm does not restrict to the constrained phase 3 pattern. These embryos also have an expanded pericardial cell domain. We show the E(spl)-C gene HLHm5 is expressed in a pattern complementary to tin during phase 3 and that this expression is JAK/Stat dependent. In addition, E(spl)-C mutant embryos phenocopy the cardiac defects of Stat92E embryos. Mechanistically, JAK/Stat signals activate E(spl)-C genes to restrict Tin expression and the subsequent expression of the T-box transcription factor H15 to direct heart precursor diversification. This study is the first to characterize a role for the JAK/Stat pathway during cardiogenesis and identifies an autoregulatory circuit in which tin limits its own expression domain.
Inducible nitric oxide synthase–nitric oxide signaling mediates the mitogenic activity of Rac1 during endochondral bone growth
Authors: Wang Guoyan , Yan Qian , Woods Anita , Aubrey Laura A. , Feng Qingping , Beier Frank
Published: September 2011

Coordinated proliferation and differentiation of growth plate chondrocytes controls endochondral bone growth and final height in humans, and disruption of this process results in diseases of the growing and adult skeleton, such as chondrodysplasias or osteoarthritis. We had shown recently that chondrocyte-specific deletion of the gene Rac1 in mice leads to severe dwarfism due to reduced chondrocyte proliferation, but the molecular pathways involved remained unclear. Here, we demonstrate that Rac1-deficient chondrocytes have severely reduced levels of inducible nitric oxide synthase (iNOS) protein and nitric oxide (NO) production. NO donors reversed the proliferative effects induced by Rac1 deficiency, whereas inhibition of NO production mimicked the effects of Rac1 loss of function. Examination of the growth plate of iNOS-deficient mice revealed reduced chondrocyte proliferation and expression of cyclin D1, resembling the phenotype of Rac1-deficient growth plates. Finally, we demonstrate that Rac1–NO signaling inhibits the expression of ATF3, a known suppressor of cyclin D1 expression in chondrocytes. In conclusion, our studies identify the iNOS–NO pathway as a novel mediator of mitogenic Rac1 signaling and indicate that it could be a target for growth disorder therapies.