bluuebunny/crossref_metadata_2025 huggingface dataset:
Is There a Role for HTLV-1-Specific CTL in Adult T-Cell Leukemia/Lymphoma?
Authors: Rowan Aileen G. , Bangham Charles R. M.
Published: December 2011

ATLL is an aggressive malignancy of T cells that affects about 5% of individuals infected with HTLV-1. The precise mechanism of oncogenesis is not known, but there is evidence that two regulatory viral proteins, Tax and HBZ, are involved. A high set point proviral load is associated with development of ATLL or a chronic inflammatory condition, HAM/TSP. Several lines of evidence, including HLA class 1 association studies and in vitro killing assays, indicate that cytotoxic T lymphocytes are instrumental in determining this proviral load set point. Prior studies have focused chiefly on the CTL response to the immunodominant Tax protein: efficient lysis of Tax-expressing cells inversely correlates with proviral load in nonmalignant infection. However, a recent study showed that strong binding of peptides from HBZ, but not Tax, to HLA class 1 molecules was associated with a low proviral load and a reduced risk of developing HAM/TSP, indicating an important role for HBZ-specific CTL in determining infection outcome. In comparison with nonmalignant infection, HTLV-1-specific CTLs in ATLL patients are reduced in frequency and functionally deficient. Here we discuss the nature of protective CTL responses in nonmalignant HTLV-1 infection and explore the potential of CTLs to protect against ATLL.
Intracultural Variation in the Knowledge of Medicinal Plants in an Urban-Rural Community in the Atlantic Forest from Northeastern Brazil
Authors: Rangel de Almeida Cecília de Fátima Castelo Branco , Ramos Marcelo Alves , Silva Rafael Ricardo Vasconcelos , de Melo Joabe Gomes , Medeiros Maria Franco Trindade , Araújo Thiago Antonio de Sousa , de Almeida Alyson Luiz Santos , de Amorim Elba Lúcia Cavalcanti , Alves Rômulo Romeu da Nóbrega , de Albuquerque Ulysses Paulino
Published: December 2011

This study assessed the intracultural knowledge of the use of medicinal plants in an urban-rural community in an Atlantic forest fragment in northeastern Brazil. We examined the importance of native and exotic species and the effects of gender and age on that knowledge. We also compared data obtained from different groups of informants (local experts and general community). We conducted 194 interviews between June 2007 and January 2008, using the freelist technique and semistructured forms to collect ethnobotanical data. Information obtained from the community was compared with that from six local experts who participated in a survey in 2003. From a total of 209 ethnospecies, exotic and herbaceous plants presented higher richness. With respect to the number of citations, women and older informants were shown to know a higher number of medicinal plants. Comparing knowledge of local experts with that of the general community, we noted that experts know a similar wealth of plant families and therapeutic indications, but the community knows a greater species richness. These results indicate that local experts may provide useful information for studies that search for a quick diagnosis of the knowledge of a given community.
A Fault Injection Analysis of Linux Operating on an FPGA-Embedded Platform
Authors: Monson Joshua S. , Wirthlin Mike , Hutchings Brad
Published: December 2011

An FPGA-based Linux test-bed was constructed for the purpose of measuring its sensitivity to single-event upsets. The test-bed consists of two ML410 Xilinx development boards connected using a 124-pin custom connector board. The Design Under Test (DUT) consists of the “hard core” PowerPC, running the Linux OS and several peripherals implemented in “soft” (programmable) logic. Faults were injected via the Internal Configuration Access Port (ICAP). The experiments performed here demonstrate that the Linux-based system was sensitive to 199,584 or about 1.4 percent of all tested bits. Each sensitive bit in the bit-stream is mapped to the resource and user-module to which it configures. A density metric for comparing the reliability of modules within the system is presented. Using this density metric, we found that the most sensitive user module in the design was the PowerPC's direct connections to the DDR2 memory controller.
Clinical Molecular Imaging with Radiotracers: Current Status
Authors: Graham Michael M.
Published: December 2011

Molecular imaging is defined as the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems. Most clinical molecular imaging is currently done using radioisotope-labeled agents to define the activity of various metabolic pathways in vivo or to determine the distribution and density of various receptors relevant to human disease. This paper briefly reviews most of the commonly used radiopharmaceuticals in nuclear medicine, as well as newer agents that are likely to become available in the near future. The metabolic pathways include those relevant to the thyroid, parathyroid, heart, brain, bones, kidneys, liver, pancreas, adrenals and tumor. The receptor systems include agents useful in evaluating movement disorders, dementia, cardiac sympathetic enervation and neoangiogenesis. Receptor systems relevant to tumors include somatostatin receptors (neuroendocrine tumors), prostate-specific membrane antigen, carbonic anhydrase IX (renal cancer), and CD-20 (lymphoma). These agents, and newer agents that are being developed, are likely to become critical in the development of personalized medicine, where it will become increasingly important to determine whether a treatment that is targeted to a specific metabolic pathway or receptor is likely to be successful.
A New Diagnostic Scoring for Discrimination of Tuberculous and Bacterial Meningitis on the Basis of Clinical and Laboratory Findings
Authors: Ersoy Yasemin , Yetkin Funda , Bayraktar Mehmet Refik , Ersoy Yuksel , Yologlu Saim
Published: December 2011

Objectives: The aim of this study was to develop a new diagnostic index (DI) on the basis of clinical and laboratory findings including serum C-reactive protein (CRP) for tuberculous meningitis (TM) and bacterial meningitis (BM). Subjects and Methods: During a 7-year period, 96 adult patients with meningitis (30 with TM and 66 with BM) were studied retrospectively. Multivariate logistic regression analysis was performed to investigate the diagnostic value of clinical and laboratory parameters as independent predictors on discrimination of tuberculous from BM patients. Results: Six features predictive for diagnosis including age, CSF leukocyte count, PML dominance, length of illness, serum CRP level and blood WBC count were used. The DI model developed from these features had very high sensitivity and specificity rates of 100.0 and 95.4%, respectively. The sensitivity and speciﬁcity rates were 97.4 and 100%, respectively, in microbiologically proven cases. Conclusion: Our results suggested that this new DI which consists of simple clinical and laboratory parameters had the power to discriminate adult patients with documented tuberculous and BM (excluding Brucella meningitis). It should, however, be tested in prospective studies.
Turkish Women’s Self-Reported Knowledge and Behavior towards Oral Health during Pregnancy
Authors: Özen Buğra , Özer Levent , Başak Feridun , Altun Ceyhan , Açıkel Cengizhan
Published: December 2011

Objectives: The purpose of this study was to evaluate oral health care knowledge and behavior of women during pregnancy. Subjects and Methods: The study population consisted of 351 mothers with children under 3 months of age who presented at Gülhane Medical Academy’s Department of Pediatrics for a routine child check-up. Mothers were asked to complete a questionnaire about their knowledge and behavior regarding dental care during pregnancy. Results: All the women who participated in the study had dental insurance, and most of them had high levels of education. Of the 351 mothers, 263 (75%) had heard about possible connections between oral health and pregnancy outcome, and 165 (47%) believed tooth and periodontal problems could affect pregnancy outcome. However, 256 (73%) women still believed that calcium would be drawn out of their teeth by the developing baby, and 151 (43%) believed in the erroneous statement ‘A tooth for a baby’. 241 (68.7%) women had experienced oral health problems during pregnancy; however, only 48 (13.7%) visited a dentist during their pregnancy. Conclusions: Turkish women, despite having knowledge that adverse pregnancy events may be related to dental and periodontal problems, did not seek oral health care during pregnancy. This suggests the need to better educate medical providers to inform pregnant women to obtain oral health care during pregnancy.
Toward Real-Time Daily PQPF by an Analog Sorting Approach: Application to Flash-Flood Catchments
Authors: Marty Renaud , Zin Isabella , Obled Charles , Bontron Guillaume , Djerboua Abdelatif
Published: December 2011

Heavy-rainfall events are common in southern France and frequently result in devastating flash floods. Thus, an appropriate anticipation of future rainfall is required: for early flood warning, at least 12–24 h in advance; for alerting operational services, at least 2–3 days ahead. Precipitation forecasts are generally provided by numerical weather prediction models (NWP), and their associated uncertainty is generally estimated through an ensemble approach. Precipitation forecasts also have to be adapted to hydrological scales. This study describes an alternative approach to commonly used limited-area models. Probabilistic quantitative precipitation forecasts (PQPFs) are provided through an analog sorting technique, which directly links synoptic-scale NWP output to catchment-scale rainfall probability distributions. One issue concerns the latest developments in implementing a daily version of this technique into operational conditions. It is shown that the obtained PQPFs depend on the meteorological forecasts used for selecting analogous days and that the method has to be reoptimized when changing the source of synoptic forecasts, because of the NWP output uncertainties. Second, an evaluation of the PQPFs demonstrates that the analog technique performs well for early warning of heavy-rainfall events and provides useful information as potential input to a hydrological ensemble prediction system. It is shown that the obtained daily rainfall distributions can be unreliable. A statistical correction of the observed bias is proposed as a function of the no-rain frequency values, leading to a significant improvement in PQPF sharpness.
Tanning behaviors and determinants of solarium use among indoor office workers in Queensland, Australia
Authors: Gordon Louisa G. , Hirst Nicholas G. , Green Adèle C. , Neale Rachel E.
Published: December 2011

Using cross-sectional survey data from Brisbane, Australia, this study identifies prevalence and factors associated with indoor tanning in office workers. Over 12-months, 72/2867 (2.5%) survey participants used solaria. Twenty-eight sunbed users (39%) tanned outdoors and used spray-tans and 42 (58%) reported burns after indoor tanning. Results from regression modelling suggests the strongest predictors of sunbed use were beliefs that tanning was safer indoors than outdoors (OR 6.1, 95%CI: 2.6–14.0) and engaging in outdoor tanning (OR 4.1, 95%CI: 1.8–9.0). We recommend that health authorities promote health gains by reducing ultraviolet radiation exposure or substituting indoor tanning with a spray-on tan.
The legitimacy of the military, private military and security companies, and just war theory
Authors: Pattison James
Published: December 2011

The legitimacy of the military is frequently overlooked in standard accounts of jus ad bellum. Accordingly, this paper considers how the military should be organized. It proposes a normative conception of legitimacy – the ‘Moderate Instrumentalist Approach’ – that outlines the qualities that a military should possess. It then assesses the three leading ways of organizing the military according to this approach: the use of private military and security companies (PMSCs), a conscripted force and the all-volunteer force (AVF). The paper argues that the AVF, despite some notable problems, is the most legitimate way of organizing the military.
Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR
Authors: Borte Stephan , von Döbeln Ulrika , Fasth Anders , Wang Ning , Janzi Magdalena , Winiarski Jacek , Sack Ulrich , Pan-Hammarström Qiang , Borte Michael , Hammarström Lennart
Published: December 2011

Severe combined immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) are inborn errors of immune function that require prompt diagnosis and treatment to prevent life-threatening infections. The lack of functional T or B lymphocytes in these diseases serves as a diagnostic criterion and can be applied to neonatal screening. A robust triplex PCR method for quantitation of T-cell receptor excision circles (TRECs) and κ-deleting recombination excision circles (KRECs), using a single Guthrie card punch, was developed and validated in a cohort of 2560 anonymized newborn screening cards and in 49 original stored Guthrie cards from patients diagnosed with SCID, XLA, ataxia-telangiectasia, Nijmegen-breakage-syndrome, common variable immunodeficiency, immunoglobulin A deficiency, or X-linked hyper-IgMsyndrome. Simultaneous measurement of TREC and KREC copy numbers in Guthrie card samples readily identified patients with SCID, XLA, ataxia-telangiectasia and Nijmegen-breakage-syndrome and thus facilitates effective newborn screening for severe immunodeficiency syndromes characterized by the absence of T or B cells.
Network-based functional enrichment
Authors: Poirel Christopher L , Owens Clifford C , Murali T M
Published: December 2011

Background

Many methods have been developed to infer and reason about molecular interaction networks. These approaches often yield networks with hundreds or thousands of nodes and up to an order of magnitude more edges. It is often desirable to summarize the biological information in such networks. A very common approach is to use gene function enrichment analysis for this task. A major drawback of this method is that it ignores information about the edges in the network being analyzed, i.e., it treats the network simply as a set of genes. In this paper, we introduce a novel method for functional enrichment that explicitly takes network interactions into account.

Results

Our approach naturally generalizes Fisher’s exact test, a gene set-based technique. Given a function of interest, we compute the subgraph of the network induced by genes annotated to this function. We use the sequence of sizes of the connected components of this sub-network to estimate its connectivity. We estimate the statistical significance of the connectivity empirically by a permutation test. We present three applications of our method: i) determine which functions are enriched in a given network, ii) given a network and an interesting sub-network of genes within that network, determine which functions are enriched in the sub-network, and iii) given two networks, determine the functions for which the connectivity improves when we merge the second network into the first. Through these applications, we show that our approach is a natural alternative to network clustering algorithms.

Conclusions

We presented a novel approach to functional enrichment that takes into account the pairwise relationships among genes annotated by a particular function. Each of the three applications discovers highly relevant functions. We used our methods to study biological data from three different organisms. Our results demonstrate the wide applicability of our methods. Our algorithms are implemented in C++ and are freely available under the GNU General Public License at our supplementary website. Additionally, all our input data and results are available at http://bioinformatics.cs.vt.edu/~murali/supplements/2011-incob-nbe/.
Structure-based and ligand-based virtual screening of novel methyltransferase inhibitors of the dengue virus
Authors: Lim See Ven , Rahman Mohd Basyaruddin A , Tejo Bimo A
Published: December 2011

Background

The dengue virus is the most significant arthropod-borne human pathogen, and an increasing number of cases have been reported over the last few decades. Currently neither vaccines nor drugs against the dengue virus are available. NS5 methyltransferase (MTase), which is located on the surface of the dengue virus and assists in viral attachment to the host cell, is a promising antiviral target. In order to search for novel inhibitors of NS5 MTase, we performed a computer-aided virtual screening of more than 5 million commercially available chemical compounds using two approaches: i) structure-based screening using the crystal structure of NS5 MTase and ii) ligand-based screening using active ligands of NS5 MTase. Structure-based screening was performed using the LIDAEUS (LIgand Discovery At Edinburgh UniverSity) program. The ligand-based screening was carried out using the EDULISS (EDinburgh University LIgand Selection System) program.

Results

The selection of potential inhibitors of dengue NS5 MTase was based on two criteria: the compounds must bind to NS5 MTase with a higher affinity than that of active NS5 MTase ligands, such as ribavirin triphosphate (RTP) andS-adenosyl-L-homocysteine (SAH); and the compounds must interact with residues that are catalytically important for the function of NS5 MTase. We found several compounds that bind strongly to the RNA cap site and theS-adenosyl-L-methionine (SAM) binding site of NS5 MTase with better binding affinities than that of RTP and SAH. We analyzed the mode of binding for each compound to its binding site, and our results suggest that all compounds bind to their respective binding sites by interacting with, and thus blocking, residues that are vital for maintaining the catalytic activity of NS5 MTase.

Conclusions

We discovered several potential compounds that are active against dengue virus NS5 MTase through virtual screening using structure-based and ligand-based methods. These compounds were predicted to bind into the SAM binding site and the RNA cap site with higher affinities than SAH and RTP. These compounds are commercially available and can be purchased for further biological activity tests.
HabiSign: a novel approach for comparison of metagenomes and rapid identification of habitat-specific sequences
Authors: Ghosh Tarini Shankar , Mohammed Monzoorul Haque , Rajasingh Hannah , Chadaram Sudha , Mande Sharmila S
Published: December 2011

Background

One of the primary goals of comparative metagenomic projects is to study the differences in the microbial communities residing in diverse environments. Besides providing valuable insights into the inherent structure of the microbial populations, these studies have potential applications in several important areas of medical research like disease diagnostics, detection of pathogenic contamination and identification of hitherto unknown pathogens. Here we present a novel and rapid, alignment-free method called HabiSign, which utilizes patterns of tetra-nucleotide usage in microbial genomes to bring out the differences in the composition of both diverse and related microbial communities.

Results

Validation results show that the metagenomic signatures obtained using the HabiSign method are able to accurately cluster metagenomes at biome, phenotypic and species levels, as compared to an average tetranucleotide frequency based approach and the recently published dinucleotide relative abundance based approach. More importantly, the method is able to identify subsets of sequences that are specific to a particular habitat. Apart from this, being alignment-free, the method can rapidly compare and group multiple metagenomic data sets in a short span of time.

Conclusions

The proposed method is expected to have immense applicability in diverse areas of metagenomic research ranging from disease diagnostics and pathogen detection to bio-prospecting. A web-server for the HabiSign algorithm is available at http://metagenomics.atc.tcs.com/HabiSign/.
Interrogation of alternative splicing events in duplicated genes during evolution
Authors: Chen Ting-Wen , Wu Timothy H , Ng Wailap V , Lin Wen-Chang
Published: December 2011

Background

Gene duplication provides resources for developing novel genes and new functions while retaining the original functions. In addition, alternative splicing could increase the complexity of expression at the transcriptome and proteome level without increasing the number of gene copy in the genome. Duplication and alternative splicing are thought to work together to provide the diverse functions or expression patterns for eukaryotes. Previously, it was believed that duplication and alternative splicing were negatively correlated and probably interchangeable.

Results

We look into the relationship between occurrence of alternative splicing and duplication at different time after duplication events. We found duplication and alternative splicing were indeed inversely correlated if only recently duplicated genes were considered, but they became positively correlated when we took those ancient duplications into account. Specifically, for slightly or moderately duplicated genes with gene families containing 2 - 7 paralogs, genes were more likely to evolve alternative splicing and had on average a greater number of alternative splicing isoforms after long-term evolution compared to singleton genes. On the other hand, those large gene families (contain at least 8 paralogs) had a lower proportion of alternative splicing, and fewer alternative splicing isoforms on average even when ancient duplicated genes were taken into consideration. We also found these duplicated genes having alternative splicing were under tighter evolutionary constraints compared to those having no alternative splicing, and had an enrichment of genes that participate in molecular transducer activities.

Conclusions

We studied the association between occurrences of alternative splicing and gene duplication. Our results implicate that there are key differences in functions and evolutionary constraints among singleton genes or duplicated genes with or without alternative splicing incidences. It implies that the gene duplication and alternative splicing may have different functional significance in the evolution of speciation diversity.
DetoxiProt: an integrated database for detoxification proteins
Authors: Yang Zhen , Yu Ying , Yao Lei , Li Guangui , Wang Lin , Hu Yiyao , Wei Haibin , Wang Li , Hammami Riadh , Razavi Roxanne , Zhong Yang , Liang Xufang
Published: December 2011

Background

Detoxification proteins are a class of proteins for degradation and/or elimination of endogenous and exogenous toxins or medicines, as well as reactive oxygen species (ROS) produced by these materials. Most of these proteins are generated as a response to the stimulation of toxins or medicines. They are essential for the clearance of harmful substances and for maintenance of physiological balance in organisms. Thus, it is important to collect and integrate information on detoxification proteins.

Results

To store, retrieve and analyze the information related to their features and functions, we developed the DetoxiProt, a comprehensive database for annotation of these proteins. This database provides detailed introductions about different classes of the detoxification proteins. Extensive annotations of these proteins, including sequences, structures, features, inducers, inhibitors, substrates, chromosomal location, functional domains as well as physiological-biochemical properties were generated. Furthermore, pre-computed BLAST results, multiple sequence alignments and evolutionary trees for detoxification proteins are also provided for evolutionary study of conserved function and pathways. The current version of DetoxiProt contains 5956 protein entries distributed in 628 organisms. An easy to use web interface was designed, so that annotations about each detoxification protein can be retrieved by browsing with a specific method or by searching with different criteria.

Conclusions

DetoxiProt provides an effective and efficient way of accessing the detoxification protein sequences and other high-quality information. This database would be a valuable source for toxicologists, pharmacologists and medicinal chemists. DetoxiProt database is freely available at http://lifecenter.sgst.cn/detoxiprot/.
Comparative genomics study of polyhydroxyalkanoates (PHA) and ectoine relevant genes from Halomonas sp. TD01 revealed extensive horizontal gene transfer events and co-evolutionary relationships
Authors: Cai Lei , Tan Dan , Aibaidula Gulsimay , Dong Xin-Ran , Chen Jin-Chun , Tian Wei-Dong , Chen Guo-Qiang
Published: December 2011

Background

Halophilic bacteria have shown their significance in industrial production of polyhydroxyalkanoates (PHA) and are gaining more attention for genetic engineering modification. Yet, little information on the genomics and PHA related genes from halophilic bacteria have been disclosed so far.

Results

The draft genome of moderately halophilic bacterium, Halomonas sp. TD01, a strain of great potential for industrial production of short-chain-length polyhydroxyalkanoates (PHA), was analyzed through computational methods to reveal the osmoregulation mechanism and the evolutionary relationship of the enzymes relevant to PHA and ectoine syntheses. Genes involved in the metabolism of PHA and osmolytes were annotated and studied in silico. Although PHA synthase, depolymerase, regulator/repressor and phasin were all involved in PHA metabolic pathways, they demonstrated different horizontal gene transfer (HGT) events between the genomes of different strains. In contrast, co-occurrence of ectoine genes in the same genome was more frequently observed, and ectoine genes were more likely under coincidental horizontal gene transfer than PHA related genes. In addition, the adjacent organization of the homologues of PHA synthase phaC1 and PHA granule binding protein phaP was conserved in the strain TD01, which was also observed in some halophiles and non-halophiles exclusively from γ-proteobacteria. In contrast to haloarchaea, the proteome of Halomonas sp. TD01 did not show obvious inclination towards acidity relative to non-halophilic Escherichia coli MG1655, which signified that Halomonas sp. TD01 preferred the accumulation of organic osmolytes to ions in order to balance the intracellular osmotic pressure with the environment.

Conclusions

The accessibility of genome information would facilitate research on the genetic engineering of halophilic bacteria including Halomonas sp. TD01.
The apolipoprotein A-I mimetic peptide, ETC-642, reduces chronic vascular inflammation in the rabbit
Authors: Di Bartolo Belinda A , Vanags Laura Z , Tan Joanne TM , Bao Shisan , Rye Kerry-Anne , Barter Philip J , Bursill Christina A
Published: December 2011

Background

High-density lipoproteins (HDL) and their main apolipoprotein, apoA-I, exhibit anti-inflammatory properties. The development of peptides that mimic HDL apolipoproteins offers a promising strategy to reduce inflammatory disease. This study aimed to compare the anti-inflammatory effects of ETC-642, an apoA-I mimetic peptide, with that of discoidal reconstituted HDL (rHDL), consisting of full-length apoA-I complexed with phosphatidylcholine, in rabbits with chronic vascular inflammation.

Results

New Zealand White rabbits (n = 10/group) were placed on chow supplemented with 0.2% (w/w) cholesterol for 6-weeks. The animals received two infusions of saline, rHDL (8 mg/kg apoA-I) or ETC-642 (30 mg/kg peptide) on the third and fifth days of the final week. The infusions of rHDL and ETC-642 were able to significantly reduce cholesterol-induced expression of intracellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the thoracic aorta (p < 0.05). When isolated rabbit HDL was pre-incubated with human coronary artery endothelial cells (HCAECs), prior to stimulation with TNF-α, it was found that HDL from ETC-642 treated rabbits were more effective at inhibiting the TNF-α-induced increase in ICAM-1, VCAM-1 and p65 than HDL isolated from saline treated rabbits (p < 0.05). There were, however, no changes in HDL lipid composition between treatment groups.

Conclusions

Infusion of ETC-642 causes anti-inflammatory effects that are comparable to rHDL in an animal model of chronic vascular inflammation and highlights that apoA-I mimetic peptides present a viable strategy for the treatment of inflammatory disease.
Notch1 binds and induces degradation of Snail in hepatocellular carcinoma
Authors: Lim Seung-Oe , Kim Hyeon Seop , Quan Xiaoyuan , Ahn Sun-Min , Kim Hongtae , Hsieh David , Seong Je Kyung , Jung Guhung
Published: December 2011

Background

Hepatocellular carcinoma (HCC) is a common, highly invasive malignant tumor associated with a high mortality rate. We previously reported that the aberrant expression of Snail via activation of reactive oxygen species contributes to the invasive property of HCC, in part by downregulation of E-cadherin through both transcriptional repression and epigenetic modification of the E-cadherin promoter. Having demonstrated the ability of Snail to bind and recruit histone deacetylase 1 and DNA methyltransferase 1 in this context, we set out to look for other interactions that could affect its ability to promote oncogenic transformation and cancer cell invasion.

Results

Using cells that stably expressed Snail, we characterized Snail protein interactors by tandem affinity purification and mass spectrometry. Immunoprecipitation and subcellular colocalization studies were performed to confirm our identification of the Notch1 intracellular domain (NICD) as a novel Snail-binding partner. NICD interaction with Snail was found to induce ubiquitination and MDM2-dependent degradation of Snail. Interestingly, NICD inhibited Snail-dependent invasive properties in both HCC cells and mouse embryonic fibroblasts.

Conclusions

Our study demonstrates that NICD can oppose Snail-dependent HCC cell invasion by binding and inducing proteolytic degradation of Snail. Although Notch signaling and Snail are both widely considered tumor-promoting factors, our findings indicate that the individual oncogenic contribution of Notch1 and Snail in malignant systems should be interpreted carefully, particularly when they are conjointly expressed.
Residual HIV-1 DNA Flap-independent nuclear import of cPPT/CTS double mutant viruses does not support spreading infection
Authors: Iglesias Candela , Ringeard Mathieu , Di Nunzio Francesca , Fernandez Juliette , Gaudin Raphael , Souque Philippe , Charneau Pierre , Arhel Nathalie
Published: December 2011

Background

The human immunodeficiency virus type 1 (HIV-1) central DNA Flap is generated during reverse transcription as a result of (+) strand initiation at the central polypurine tract (cPPT) and termination after a ca. 100 bp strand displacement at the central termination sequence (CTS). The central DNA Flap is a determinant of HIV-1 nuclear import, however, neither cPPT nor CTS mutations entirely abolish nuclear import and infection. Therefore, to determine whether or not the DNA Flap is essential for HIV-1 nuclear import, we generated double mutant (DM) viruses, combining cPPT and CTS mutations to abolish DNA Flap formation.

Results

The combination of cPPT and CTS mutations reduced the proportion of viruses forming the central DNA Flap at the end of reverse transcription and further decreased virus infectivity in one-cycle titration assays. The most affected DM viruses were unable to establish a spreading infection in the highly permissive MT4 cell line, nor in human primary peripheral blood mononuclear cells (PBMCs), indicating that the DNA Flap is required for virus replication. Surprisingly, we found that DM viruses still maintained residual nuclear import levels, amounting to 5-15% of wild-type virus, as assessed by viral DNA circle quantification. Alu-PCR quantification of integrated viral genome also indicated 5-10% residual integration levels compared to wild-type virus.

Conclusion

This work establishes that the central DNA Flap is required for HIV-1 spreading infection but points to a residual DNA Flap independent nuclear import, whose functional significance remains unclear since it is not sufficient to support viral replication.
Schizophrenia medication adherence in a resource-poor setting: randomised controlled trial of supervised treatment in out-patients for schizophrenia (STOPS)
Authors: Farooq Saeed , Nazar Zahid , Irfan Muhammad , Akhter Javed , Gul Ejaz , Irfan Uma , Naeem Farooq
Published: December 2011

Background

Most people with schizophrenia in low- and middle-income (LAMI) countries receive minimal formal care, and there are high rates of non-adherence to medication.

Aims

To evaluate the effectiveness of an intervention that involves a family member in supervising medication administration – supervised treatment in out-patients for schizophrenia (STOPS) – in improving treatment adherence and clinical outcomes.

Method

Individuals (n = 110) with schizophrenia or schizoaffective disorders were allocated to STOPS or to treatment as usual (TAU) and followed up for 1 year. The primary outcome was adherence to the treatment regimen. Positive and Negative Syndrome Scale for Schizophrenia and Global Assessment of Functioning scores were also assessed.

Results

Participants in the STOPS group had better adherence (complete adherence: 37 (67.3%) in STOPS v. 25 (45.5%) in TAU; P<0.02) and significant improvement in symptoms and functioning.

Conclusions

STOPS may be useful in enhancing adherence to treatment for schizophrenia in LAMI countries.
Developing large-group teaching in child and adolescent psychiatry to undergraduate medical students
Authors: Vallance Aaron K. , Hill Victoria , Ani Cornelius , Doig Alex , Garralda Elena
Published: December 2011

Aims and method

We developed material for a lecture hall teaching programme in child and adolescent psychiatry for medical students. Although lecture hall settings are not traditionally seen as conducive to exploring concepts, debating positions and encouraging higher-order thinking, we aimed to integrate these processes into the programme alongside educational theory and teaching strategies. We evaluated student and teacher perception of the new material through questionnaires before and after the introduction of the teaching package.

Results

Six 1.5-hour teaching sessions were prepared. The evaluation study received 133 student and 4 teacher questionnaires on the previous teaching package, and 99 student and 7 teacher questionnaires on the new material. The questionnaires showed that the redesign resulted in significant improvements in various predefined measures, such as clarity and interactivity of the material.

Clinical implications

A vivid and memorable teaching programme is essential in shaping students' understanding of the concepts in child and adolescent psychiatry as well as potentially making the specialty more attractive to medical undergraduates.
Patients' knowledge about treatment for opiate dependence
Authors: Alves Paula , Winstock Adam
Published: December 2011

Aims and method

A cross-sectional survey was conducted to assess patient knowledge and information provision about opioid substitution treatment among individuals with opiate dependence receiving treatment at four treatment centres in South London.

Results

In total 118 people were recruited to the study. Participants answered a mean of 14 out of 34 questions assessing a range of factors such as medication, blood-borne viruses and overdose correctly. Participants overestimated their performance on average by almost 40%. Individuals with a history of previous treatments scored significantly higher than those in their first treatment episode. The majority reported having been given written information on most of the topics assessed.

Clinical implications

The results of this study highlight the need to improve education about opioid dependence and its treatment. Poorly informed patients are unlikely to make optimal treatment choices. Improving patients' knowledge and understanding about treatment may lead to better engagement, retention, treatment adherence and, ultimately, better health outcomes.
Do psychiatric inpatients know their rights? A re-audit on information given to inpatients at a London mental health trust about their rights and admission to hospital
Authors: Lomax G Alice , Raphael Frances , Pagliero James , Patel Rupal
Published: December 2011

This re-audit assessed whether wards at South West London and St Georges’ mental health trust (SWLSTG) met agreed standards regarding informing inpatients about their legal status in hospital and rights, following an initial audit in 2009. Three general adult wards were re-audited, and other general and specialist wards (addictions, eating disorders, deaf services and obsessive compulsive disorder) were added. One hundred and five people (61 informal, 44 detained under the Mental Health Act 1983, revised 2007) on 10 wards were interviewed using an agreed proforma. The re-audit of wards A–C showed improvement: 81.3% of informal inpatients were aware of their legal status, versus 54.2% in 2009 ( P = 0.101). Including new wards D–K, 90.2% knew their status ( P = 0.0002). Of the informal patients, 65.6% knew they could refuse treatment ( P = 0.0184) (on wards A–C, 68.8%, P = 0.105) versus 37.5% in 2009. Despite some improvement, the patient experience of informal admission or detention in hospital still sometimes crosses legal boundaries. This audit highlights the need to improve awareness of patient rights and demonstrated how local presentation of audit improves practice.
Evaluation of Proposed Lateral Load Pattern for Estimating Seismic Demands on RC-Tall Buildings with Shear Walls in Pushover Analysis
Authors: Faramarz Khoshnoudian , Mehdi Kafaeikivi
Published: December 2011

The nonlinear static procedure (NSP) is becoming preferred as it favourite by virtue of its simplicity rather than nonlinear time history analysis for building evaluation and design verification. However, NSP is restricted to only a single mode response, thus this is appropriate for low-rise buildings in which the behaviour is dominated by the first vibration mode. The use of FEMA force distributions has certain flaws when high-rise buildings are evaluated; since the seismic demands are greatly underestimated especially at top stories of tall buildings.

Hence, in this paper a new pushover procedure is proposed with takes into account higher mode effects. The procedure utilizes consecutive modal pushover (CMP) analyses using mode shapes obtained from a linear elastic analysis of the structure. The methodology is applied to three Reinforced Concrete frames with shear walls. It is demonstrated that the CMP procedure is able to estimate the seismic demands accurately enough and to overcome the shortcomings of FEMA load distributions when the higher mode effects are significant. Plastic hinge rotations are noticeably improved by this procedure when compared with those obtained by the MPA procedure and FEMA load distributions.
An Indeterminate Strut-Tie Model and Load Distribution Ratio for RC Deep Beams- (II) Validity Evaluation
Authors: Kim Byung-Hun , Yun Young-Mook
Published: December 2011

In this study, the ultimate strength of 234 simply supported reinforced concrete deep beams tested to shear failure was evaluated by the ACI 318M-08's strut-tie model approach implemented with the indeterminate strut-tie model and load distribution ratio of the companion paper. The ultimate strength of the deep beams was also estimated by using the experimental shear strength models, the theoretical shear strength models, and the current strut-tie model design codes. The validity of the presented indeterminate strut-tie model and load distribution ratio was examined through the comparison of the strength analysis results classified according to the primary design variables of shear span-to-effective depth ratio, flexural reinforcement ratio, and compressive strength of concrete. The present study associated with the indeterminate strut-tie model and load distribution ratio evaluated the ultimate strength of 234 deep beams fairly accurately compared with those by other approaches. In addition, the present approach reflected the effects of the primary design variables on the ultimate strength of deep beams consistently and accurately.
Dynamic Analysis of Concrete Gravity Dams Utilizing Two-Dimensional Modified Efficient Fluid Hyper-Element
Authors: Hojati Maryam , Lotfi Vahid
Published: December 2011

The accurate dynamic analysis of concrete gravity dams relies heavily on employing a two-dimensional semi-infinite fluid element. The usual method for calculating the impedance matrix of this fluid hyper-element is dependent on the solution of a complex eigen-value problem for each frequency. In the present study, a modified efficient procedure is proposed which simplifies this procedure significantly, and results in great computational time saving. Moreover, the accuracy of this technique is examined thoroughly and it is concluded that modified efficient procedure is extremely accurate under all practical conditions. It is also shown that the original efficient method proposed in a previous study can be considered as a special case of the present more general procedure.
Retrofit of Non-Ductile RC Frames with Precast Concrete (PC) Wall Panels
Authors: Baran Mehmet , Tankut Tugrul
Published: December 2011

An economic, structurally effective and practically applicable strengthening method had been developed for reinforced concrete (RC) framed buildings. This study presents the test results on strengthening of deficient RC frames by using high strength precast concrete (PC) panels. The idea of the method is to convert the existing hollow brick infill wall into a load carrying system by bonding PC panels on to the plastered hollow brick infills. For this purpose, six (two reference and four strengthened) one-third scale, one bay, two storey deficient RC frames were tested under reversed-cyclic lateral loads. Test frames were designed and constructed with common deficiencies observed in practice. Panels having two different shapes were used as strengthening agencies. Test results showed that both strength and stiffness of the test frames were significantly improved by the introduction of PC panels. Experimental results were compared with the analytical approaches suggested by the authors.
Structural Behavior of Mortarless Interlocking Load Bearing Hollow Block Wall Panel under Out-Of-Plane Loading
Authors: Safiee Nor Azizi , Jaafar Mohd Saleh , Alwathaf Ahmed Hasan , Noorzaei Jamaloddin , Abdulkadir Mohd. Razali
Published: December 2011

Experimental and numerical investigation of interlocking mortarless wall panels with 1.0 m height, 1.2 m width and 150 mm thickness are conducted. Behaviour of both hollow and partially grouted masonry wall panels is studied. The panels were tested under constant pre-compressive vertical load and out-of-plane lateral load. Lateral load carrying capacity, deflection at mid height, dry joint opening between block layers and mode of failure are investigated. Strain characteristics throughout the loading process are also monitored. A finite element analysis is presented for the system and a good agreement between the experimental and modelling results is achieved. Parametric study using the finite element model is also presented and the effect of different parameters; amount of pre-compressive load and slenderness ratio is studied. The study reveals that pre-compressive vertical load and reinforcement significantly affect the structural behaviour of mortarless walls under out-of-plane loading. Useful expressions for the capacity are obtained from the analysis.
Closed-Form Equations for Flange Force and Maximum Deflection of Box-Beams of Fiber Reinforced Polymer with Partial Shear Interaction between Webs and Flanges
Authors: Evernden M.C. , Mottram J.T.
Published: December 2011

Presented in the paper is the formulation of a governing second-order differential equation for the moment distribution along the length of a beam having two interfaces with partial shear interaction where two flange and two web components join to form the box shaped section. For practical applications such a closed-section beam of Fiber Reinforced Polymer (FRP) can be assembled from individual pultruded profiles using mechanical fasteners. This assembly approach can be used to construct deeper section sizes than can be achieved with a single pultrusion, and which can be transported in flat-pack units. In developing the governing equation for flexural response account is made of the finite connection stiffness at the web/flange interfaces by applying conventional elastic beam theory. The differential equation for the partial interaction problem is solved to formulate closed form equations for the flange force and the maximum deflection of a simply supported beam under four-point bending. A numerical parametric study is presented to show changes in beam performance indicators with the degree of shear interaction between the upper and lower bounds of full- and non-interaction. Results from a series of load tests using a three-layered prototype FRP beam are shown to be in good agreement. The theoretical predictions for maximum deflection are however found to be directly linked to the appropriateness of the measured connection stiffness entered into the closed-form equation.
Ubiquitin Homeostasis Is Critical for Synaptic Development and Function
Authors: Chen Ping-Chung , Bhattacharyya Bula J. , Hanna John , Minkel Heather , Wilson Julie A. , Finley Daniel , Miller Richard J. , Wilson Scott M.
Published: December 2011

The ubiquitin-proteasome system (UPS) controls protein abundance and is essential for many aspects of neuronal function. Inataxia(axJ) mice, profound neurological and synaptic defects result from a loss-of-function mutation in the proteasome-associated deubiquitinating enzymeUsp14, which is required for recycling ubiquitin from proteasomal substrates. Here, we show that transgenic complementation ofaxJmice with neuronally expressed ubiquitin prevents early postnatal lethality, restores muscle mass, and corrects developmental and functional deficits resulting from the loss of Usp14, demonstrating that ubiquitin deficiency is a major cause of the neurological defects observed in theaxJmice. We also show that proteasome components are normally induced during the first 2 weeks of postnatal development, which coincides with dramatic alterations in polyubiquitin chain formation. These data demonstrate a critical role for ubiquitin homeostasis in synaptic development and function, and show that ubiquitin deficiency may contribute to diseases characterized by synaptic dysfunction.
Neural Correlates of Trial-to-Trial Fluctuations in Response Caution
Authors: van Maanen Leendert , Brown Scott D. , Eichele Tom , Wagenmakers Eric-Jan , Ho Tiffany , Serences John , Forstmann Birte U.
Published: December 2011

Trial-to-trial variability in decision making can be caused by variability in information processing as well as by variability in response caution. In this paper, we study which neural components code for trial-to-trial adjustments in response caution using a new computational approach that quantifies response caution on a single-trial level. We found that the frontostriatal network updates the amount of response caution. In particular, when human participants were required to respond quickly, we found a positive correlation between trial-to-trial fluctuations in response caution and the hemodynamic response in the presupplementary motor area and dorsal anterior cingulate. In contrast, on trials that required a change from a speeded response mode to a more accurate response mode or vice versa, we found a positive correlation between response caution and hemodynamic response in the anterior cingulate proper. These results indicate that for each decision, response caution is set through corticobasal ganglia functioning, but that individual choices differ according to the mechanisms that trigger changes in response caution.