bluuebunny/crossref_metadata_2025 huggingface dataset:
X-Linked Creatine Transporter Deficiency Presenting as a Mitochondrial Disorder
Authors: Hathaway Samantha C. , Friez Michael , Limbo Kimberly , Parker Colette , Salomons Gajja S. , Vockley Jerry , Wood Tim , Abdul-Rahman Omar A.
Published: May 2010

X-linked creatine transporter defect is caused by mutations in SLC6A8 at Xq28, which encodes the sodium-dependent creatine transporter. Reduction in creatine uptake results in elevated urine creatine and CSF creatine deficiency, which can be detected on magnetic resonance spectroscopy. We report a patient who was initially suspected of having a mitochondrial disorder but was later found to have a creatine transporter defect. The abnormal laboratory study results seen in this patient suggesting a mitochondrial cytopathy could be due to excess mitochondrial stress as well as the mitochondrial inclusion bodies. This report looks at the mitochondrial presentation of the creatine transporter deficiency.
Prevalence and Predictors of Posttraumatic Stress Disorder Among Victims of Violence Applying for State Compensation
Authors: Kunst Maarten , Winkel Frans Willem , Bogaerts Stefan
Published: May 2010

Many studies have focused on the predictive value of victims’ emotions experienced shortly after violence exposure to identify those vulnerable for development of posttraumatic stress disorder (PTSD). However, many victims remain unidentified during the initial recovery phase, yet may still be highly in need of psychological help after substantial time since victimization has passed. Professionals involved in the settlement of civil damage claims filed by victims of violence may play an important role in referring victims with current psychological problems to appropriate treatment services, as they are likely to maintain relations with victims until all compensation possibilities have been exhausted. As an exploratory examination of this topic, the current study investigates the potential utility of file characteristics as predictors of chronic PTSD among 686 victims of violence who had applied for state compensation with the Dutch Victim Compensation Fund (DVCF) in 2006. Identification of significant predictors is preceded by estimating prevalence rates of PTSD. Results indicate that approximately 1 of 2 victims applying for state compensation in the Netherlands still have PTSD many years after victimization and claim settlement. Age, female sex, time since victimization, acquaintance with the perpetrator, violence-related hospitalization, and compensation for immaterial damage prove to be predictive of PTSD, although female sex and immaterial damage compensation fail to reach significance after adjusting for recalled peritraumatic distress severity. Implications for policy practice as well as strengths and limitations of the study are discussed.
Cutaneous manifestations and serological findings in 260 patients with systemic lupus erythematosus
Authors: Grönhagen CM , Gunnarsson I. , Svenungsson E. , Nyberg F.
Published: May 2010

The prevalence and prognostic value of cutaneous manifestations in patients with systemic lupus erythematosus (SLE) is not clear due to a lack of distinct criteria. Our aim was to investigate the prevalence of cutaneous manifestations in SLE patients according to strict dermatological classification, compare the results with other studies and to assess differences in serological markers between patients with and without cutaneous lupus erythematosus (CLE). Secondary aims were to investigate the validity of the criteria ‘malar rash’ and ‘photosensitivity’ for SLE diagnosis. We included 260 consecutive SLE patients, and 164 with skin complaints were examined by a dermatologist. CLE was found in 23% of the 260 SLE patients. There was agreement on the presence of malar rash in only 60% of patients seen by both rheumatologists and dermatologists. A history of polymorphous light eruption (PLE) was found in 42% of patients. Raynaud’s phenomenon was significantly more common in patients with CLE. In addition, four malignant melanomas were found. Based on our findings, we suggest that the American College of Rheumatology (ACR) criteria for SLE diagnosis include histopathologically confirmed CLE as one criterion, and that the criteria photosensitivity and malar rash should be re-defined. Regular examination by a dermatologist is called for in SLE patients.
Mathematical analysis of antigen selection in somatically mutated immunoglobulin genes associated with autoimmunity
Authors: MacDonald CM , Boursier L. , D'Cruz DP , Dunn-Walters DK , Spencer J.
Published: May 2010

Affinity maturation is a process by which low-affinity antibodies are transformed into highly specific antibodies in germinal centres. This process occurs by hypermutation of immunoglobulin heavy chain variable (IgH V) region genes followed by selection for high-affinity variants. It has been proposed that statistical tests can identify affinity maturation and antigen selection by analysing the frequency of replacement and silent mutations in the complementarity determining regions (CDRs) that contact antigen and the framework regions (FRs) that encode structural integrity. In this study three different methods that have been proposed for detecting selection: the binomial test, the multinomial test and the focused binomial test, have been assessed for their reliability and ability to detect selection in human IgH V genes. We observe first that no statistical test is able to identify selection in the CDR antigen-binding sites, second that tests can reliably detect selection in the FR and third that antibodies from nasal biopsies from patients with Wegener’s granulomatosis and pathogenic antibodies from systemic lupus erythematosus do not appear to be as stringently selected for structural integrity as other groups of functional sequences.
C3a, TNF-α and interleukin myocardial expression in a case of fatal sudden cardiac failure during clinic reactivation of systemic lupus erythematosus
Authors: Pomara C. , Neri M. , Bello S. , Pennella A. , Turillazzi E. , Fineschi V.
Published: May 2010

Isolated myocarditis, or dilated cardiomyopathy, is a rare and usually late clinical manifestation of systemic lupus erythematosus (SLE). Increased levels of complement split products are associated with disease activity. Injury of the vascular endothelium due to complement activation and immune complexes may contribute to the vasculopathy in SLE. We present a case of sudden cardiac failure and death in a 28-year-old Caucasian man, during reactivation of SLE. To explain the sudden cardiac failure, we looked for anti-tumour necrosis factor (TNF)-∝ and anti-interleukin (IL) expression in cardiac cells, and anti-complement (anti-C)3a in small cardiac vessels. The immunohistochemical examination of heart specimens revealed a strong positive reaction in cardiac myocytes for antibodies anti-TNF-∝ and IL-8, and a milder positive reaction for antibodies anti-IL-15 and IL-10. A strong positive reaction of C3a in small cardiac vessels was observed in all specimens. Furthermore, the expression of CD4 and CD8 showed a strong positive reaction in pericardium and valvular endocardium, and a lesser positivity in myocardial specimens. TNF appears to have played a major proinflammatory role in this fatal case.
MALT lymphoma of the lacrimal gland in the context of systemic lupus erythematosus: complete remission after treatment with rituximab
Authors: Tektonidou MG
Published: May 2010

Mucosa-associated lymphoid tissue (MALT) lymphoma of the lacrimal glands has been reported in only two patients with systemic lupus erythematosus (SLE) in the literature. We describe a 41-year-old female with SLE who had multiple relapses and remissions of her disease during the last 20 years and developed a right eyelid swelling. Magnetic resonance imaging showed a lesion in the right lacrimal gland with increased enhancement on T1- and T2-weighted images after intravenous contrast administration, and the biopsy of lacrimal gland was consistent with the diagnosis of marginal zone B-cell lymphoma of MALT type. The patient received treatment with four once-weekly doses of rituximab 375 mg/m2 every 6 months for 2 years resulting in complete remission. Lacrimal gland MALT lymphoma is mainly treated with local radiotherapy, or chemotherapy in cases with systemic lymphoma. This is the first case of rituximab treatment in a patient with SLE who developed lacrimal gland MALT lymphoma, resulting in complete durable remission.
Core and Peripheral Values
Authors: Sharabi Moshe , Harpaz Itzhak
Published: May 2010

The longitudinal research presented here is unique, having examined a model of stability and change in work values of the same people over the course of time. The purpose was to reflect the changes in work values that occurred in Israel during this period. The research focused on three domains: work goals, job satisfaction, and work centrality. Following an analysis of research literature, a model of work values was examined by the LISREL method. Instrumental and expressive goals effected work centrality both directly and indirectly (through job satisfaction as mediating factor). While in 1981 only the positive effect of expressive goals on work centrality was significant, the 1993 analysis revealed that beyond the positive effect of expressive goals, there is also significant negative effect of instrumental goals on work centrality. Our research shows that the main changes occurred in peripheral values (work goals) as compared with the stability of core values (work centrality). Slight changes occurred in semi-peripheral values (job satisfaction).
Development of a New Finite Element for the Analysis of Sandwich Beams with Soft Core
Authors: Sudhakar V. , Vijayaraju K. , Gopalakrishnan S.
Published: May 2010

A new super convergent sandwich beam finite element formulation is presented in this article. This element is a two-nodded, six degrees of freedom (dof) per node (3 dof u0, w, φ for top and bottom face sheets each), which assumes that all the axial and flexural loads are taken by face sheets, while the core takes only the shear loads. The beam element is formulated based on first-order shear deformation theory for the face sheets and the core displacements are assumed to vary linearly across the thickness. A number of numerical experiments involving static, free vibration, and wave propagation analysis examples are solved with an aim to show the super convergent property of the formulated element. The examples presented in this article consider both metallic and composite face sheets. The formulated element is verified in most cases with the results available in the published literature.
Social status and the pursuit of positive social identity: Systematic domains of intergroup differentiation and discrimination for high- and low-status groups
Authors: Oldmeadow Julian A. , Fiske Susan T.
Published: May 2010

Research on intergroup discrimination has focused on the cognitive and motivational mechanisms involved, but the role of stereotype content has been neglected. Drawing on social identity theory and stereotype content research, the current studies investigated the role of stereotype content in intergroup differentiation and discrimination. Across two studies, students from high- and low-status groups differentiated themselves positively on stereotypes of competence and warmth respectively, and in allocations of resources in domains relevant to competence (academics, research) and warmth (sports, community outreach). Furthermore, there was evidence that discrimination by high- and low-status groups was driven by their respective stereotypes of competence and warmth. It is argued that stereotypes of competence and warmth, derived from status and power relations between groups, define the domains in which groups pursue positively distinct identities.
Feasibility of Radiofrequency Ablation for the Treatment of Chronic Radiation Proctitis
Authors: Nikfarjam Mehrdad , Faulx Ashley , Laughinghouse Michelle , Marks Jeffrey M.
Published: May 2010

Background. Chronic radiation proctitis can be difficult to manage. Radiofrequency ablation has recently been shown to be effective in the management of gastric antral vascular ectasia and Barrett’s esophagus, but its utility in the treatment of chronic radiation proctitis is undetermined. Method. A 77-year-old man with extensive chronic radiation proctitis had continued bleeding despite argon plasma coagulation. The HALO90 radiofrequency system (BÂRRX Medical, Sunnyvale, CA) was used for treatment regions of proctitis at an energy density of 12 J/cm2. Results. At monthly intervals, over 3 months, radiofrequency ablation was performed with a mean of 7 regions ablated at a time. The mean treatment time was 29 minutes. There was no significant bleeding after the first treatment session. The patient was symptom free at 6 months follow-up with minimal evidence of residual mucosal abnormalities. Conclusions. Radiofrequency ablation appears feasible for treatment of refractory chronic radiation proctitis, with further studies required.
Bloodless Liver Resection Using Needle Arrays Under Alternating Electromagnetic Fields
Authors: Shan Yan-Shen , Zuchini Roberto , Tsai Hung-Wen , Lin Pin-Wen , Lee Gwo-Bin , Lin Xi-Zhang
Published: May 2010

Background/Aim: Hemostasis is a major difficulty associated with hepatectomies. The authors designed a new thermal surgery system to reduce blood loss. Methods: The newly designed system consists of an alternating magnetic field generator and stainless steel needle arrays with thermosensitive bands. Lanyu pigs were used: 4 for the Kelly crushing method and 4 for the newly designed method. The procedures used were S4-S5 segmentectomies or left lateral segmentectomies, after which the amount of blood loss and operation times were compared. The pigs were observed for 4 weeks, after which liver pathologies were studied. Results: The blood loss in the method proposed by the authors was almost 0 mL, whereas with the Kelly crushing method it was 116 ± 35 mL. The method proposed in this study can save 15 to 25 minutes of operation time. The resected liver margins exhibited prominent apoptosis and fibrotic change in the remnant livers. Conclusions: The method proposed is a novel new way of performing thermal surgery.
Fully Laparoscopic Colorectal Anastomosis Involving Percutaneous Endoluminal Colonic Anvil Control (PECAC)
Authors: Leroy Joël , Costantino Federico , Cahill Ronan A. , Donnatelli G.F. , Kawai M. , Hurng Sheng WU  , Marescaux Jacques
Published: May 2010

Introduction: A novel technique for secure placement of the anvil for mechanical stapled anastomosis in the proximal colon without exteriorization of the bowel is described. Methods: After standard laparoscopic segmental colonic mobilization, a needle-cannula from a percutaneous endoscopic gastrostomy kit is passed under direct endoscopic vision transparietally into the colon at the site intended for anvil placement. A wire passed through the cannula into the colon is then withdrawn endoscopically per ano. The stapler anvil is fixed to the wire and pulled back along the intestine before being positioned by traction through the needle puncture site. After distal specimen transection, a standard stapled anastomosis is performed. Results: The technique is illustrated in 2 patients undergoing laparoscopic sigmoidectomy by either a single port or a multiport procedure with transanal specimen extraction. Conclusion: By positioning the anvil without colon exteriorization, this technique enables pure intraperitoneal colonic anastomoses that may advance natural orifice operating.
In Practice
Authors: Hay Lizzy
Published: May 2010

According to the most recent data from the UNESCO Institute for Statistics, there are an estimated 759 million adults lacking minimum literacy skills in the world. Health literacy, however, is not just about people’s ability to read and understand health information but also includes the capacity to obtain, process and engage in basic health information and services and subsequently making suitable health decisions.
Total Therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy
Authors: van Rhee Frits , Szymonifka Jackie , Anaissie Elias , Nair Bijay , Waheed Sarah , Alsayed Yazan , Petty Nathan , Shaughnessy John D. , Hoering Antje , Crowley John , Barlogie Bart
Published: May 2010

The impact of cumulative dosing and premature drug discontinuation (PMDD) of bortezomib (V), thalidomide (T), and dexamethasone (D) on overall survival (OS), event-free survival (EFS), time to next therapy, and post-relapse survival in Total Therapy 3 were examined, using time-dependent methodology, relevant to induction, peritransplantation, consolidation, and maintenance phases. Univariately, OS and EFS were longer in case higher doses were used of all agents during induction, consolidation (except T), and maintenance (except V and T). The favorable OS and EFS impact of D induction dosing provided the rationale for examining the expression of glucocorticoid receptor NR3C1, top-tertile levels of which significantly prolonged OS and EFS and rendered outcomes independent of D and T dosing, whereas T and D, but not V, dosing was critical to outcome improvement in the bottom-tertile NR3C1 setting. PMDD of V was an independent highly adverse feature for OS (hazard ratio = 6.44; P < .001), whereas PMDD of both T and D independently imparted shorter time to next therapy. The absence of adverse effects on postrelapse survival of dosing of any VTD components and indeed a benefit from V supports the use up-front of all active agents in a dose-dense and dose-intense fashion, as practiced in Total Therapy 3, toward maximizing myeloma survival.
Functional conservation of a forebrain enhancer from the elephant shark (Callorhinchus milii) in zebrafish and mice
Authors: MacDonald Ryan B , Debiais-Thibaud Mélanie , Martin Kyle , Poitras Luc , Tay Boon-Hui , Venkatesh Byrappa , Ekker Marc
Published: May 2010

Background

The phylogenetic position of the elephant shark (Callorhinchus milii ) is particularly relevant to study the evolution of genes and gene regulation in vertebrates. Here we examine the evolution of Dlx homeobox gene regulation during vertebrate embryonic development with a particular focus on the forebrain. We first identified the elephant shark sequence orthologous to the URE2 cis -regulatory element of the mouse Dlx1/Dlx2 locus (herein named CmURE2). We then conducted a comparative study of the sequence and enhancer activity of CmURE2 with that of orthologous regulatory sequences from zebrafish and mouse.

Results

The CmURE2 sequence shows a high percentage of identity with its mouse and zebrafish counterparts but is overall more similar to mouse URE2 (MmURE2) than to zebrafish URE2 (DrURE2). In transgenic zebrafish and mouse embryos, CmURE2 displayed enhancer activity in the forebrain that overlapped with that of DrURE2 and MmURE2. However, we detected notable differences in the activity of the three sequences in the diencephalon. Outside of the forebrain, CmURE2 shows enhancer activity in areas such as the pharyngeal arches and dorsal root ganglia where its' counterparts are also active.

Conclusions

Our transgenic assays show that part of the URE2 enhancer activity is conserved throughout jawed vertebrates but also that new characteristics have evolved in the different groups. Our study demonstrates that the elephant shark is a useful outgroup to study the evolution of regulatory mechanisms in vertebrates and to address how changes in the sequence of cis -regulatory elements translate into changes in their regulatory activity.
Validation of dot blot hybridization and denaturing high performance liquid chromatography as reliable methods for TP53 codon 72 genotyping in molecular epidemiologic studies
Authors: Rabachini Tatiana , Trottier Helen , Franco Eduardo L , Villa Luisa L
Published: May 2010

Background

Mutations in TP53 are common events during carcinogenesis. In addition to gene mutations, several reports have focused on TP53 polymorphisms as risk factors for malignant disease. Many studies have highlighted that the status of the TP53 codon 72 polymorphism could influence cancer susceptibility. However, the results have been inconsistent and various methodological features can contribute to departures from Hardy-Weinberg equilibrium, a condition that may influence the disease risk estimates. The most widely accepted method of detecting genotyping error is to confirm genotypes by sequencing and/or via a separate method.

Results

We developed two new genotyping methods for TP53 codon 72 polymorphism detection: Denaturing High Performance Liquid Chromatography (DHPLC) and Dot Blot hybridization. These methods were compared with Restriction Fragment Length Polymorphism (RFLP) using two different restriction enzymes. We observed high agreement among all methodologies assayed. Dot-blot hybridization and DHPLC results were more highly concordant with each other than when either of these methods was compared with RFLP.

Conclusions

Although variations may occur, our results indicate that DHPLC and Dot Blot hybridization can be used as reliable screening methods for TP53 codon 72 polymorphism detection, especially in molecular epidemiologic studies, where high throughput methodologies are required.
Genetic Structure of the Spanish Population
Authors: Gayán Javier , Galan José J , González-Pérez Antonio , Sáez María Eugenia , Martínez-Larrad María Teresa , Zabena Carina , Rivero M Carmen , Salinas Ana , Ramírez-Lorca Reposo , Morón Francisco J , Royo Jose Luis , Moreno-Rey Concha , Velasco Juan , Carrasco José M , Molero Eva , Ochoa Carolina , Ochoa María Dolores , Gutiérrez Marta , Reina Mercedes , Pascual Rocío , Romo-Astorga Alejandro , Susillo-González Juan Luis , Vázquez Enrique , Real Luis M , Ruiz Agustín , Serrano-Ríos Manuel
Published: May 2010

Background

Genetic admixture is a common caveat for genetic association analysis. Therefore, it is important to characterize the genetic structure of the population under study to control for this kind of potential bias.

Results

In this study we have sampled over 800 unrelated individuals from the population of Spain, and have genotyped them with a genome-wide coverage. We have carried out linkage disequilibrium, haplotype, population structure and copy-number variation (CNV) analyses, and have compared these estimates of the Spanish population with existing data from similar efforts.

Conclusions

In general, the Spanish population is similar to the Western and Northern Europeans, but has a more diverse haplotypic structure. Moreover, the Spanish population is also largely homogeneous within itself, although patterns of micro-structure may be able to predict locations of origin from distant regions. Finally, we also present the first characterization of a CNV map of the Spanish population. These results and original data are made available to the scientific community.
The prevalence of rheumatic diseases in central Greece: a population survey
Authors: Anagnostopoulos Ioannis , Zinzaras Elias , Alexiou Ioannis , Papathanasiou Aphrodite A , Davas Evangelos , Koutroumpas Athanasios , Barouta Georgia , Sakkas Lazaros I
Published: May 2010

Background

Rheumatic diseases are a major health and financial burden for societies. The prevalence of rheumatic diseases may change over time, and therefore, we sought to estimate the prevalence of rheumatic diseases in an adult population of central Greece.

Methods

In this prospective cross-sectional population survey, a random sample of adult population was drawn from poll catalogues of a region in central Greece. A postal questionnaire was sent to 3,528 people for the presence of any rheumatic disease. All positive cases were further confirmed by clinical examination using the American College of Rheumatoloy criteria. Multiple regression analysis was used to assess risk factors for rheumatic diseases.

Results

The response rate was 48.3% (1,705 answers). Four hundred and twenty individuals (24.6%) had a rheumatic disease. The prevalence of rheumatoid arthritis was 0.58% (95% confidence interval [CI], 0.32-0.87), of psoriatic arthritis was 0.35% (95% CI, 0.33-1.13), of ankylosing spondylitis was 0.29% (95% CI, 0.28-0.94), of primary Sjögren's syndrome was 0.23% (95% CI, 0.22-0.75) and of systemic lupus erythematosus was 0.11% (95% CI, 0.11-0.37). One individual had systemic sclerosis (prevalence, 0.058%), 1 individual had dermatomyositis (prevalence, 0.058%; 95% CI, 0.05-0.18), 2 individuals had vasculitis (prevalence 0.11%; 95% CI, 0.11-0.37), 81 individuals had gout (prevalence, 4.75%; 95% CI, 4.41-5.13), and 304 individuals had osteoarthritis (OA) (prevalence 17.82%; 95% CI, 16.50-19.34). Gout was associated with male gender, diabetes mellitus, and hypertension, and OA was associated with age, female gender, and hypertension.

Conclusions

Rheumatic diseases are common in central Greece, affecting nearly a quarter of adult population. OA and gout are the most common joint disorders.
Myc interacts with Max and Miz1 to repress C/EBPδ promoter activity and gene expression
Authors: Si Junling , Yu Xueyan , Zhang Yingjie , DeWille James W.
Published: May 2010

Background

"Loss of function" alterations in CCAAT/Enhancer Binding Proteinδ (C/EBPδ) have been reported in a number of human cancers including breast, prostate and cervical cancer, hepatocellular carcinoma and acute myeloid leukemia. C/EBPδ gene transcription is induced during cellular quiescence and repressed during active cell cycle progression. C/EBPδ exhibits tumor suppressor gene properties including reduced expression in cancer cell lines and tumors and promoter methylation silencing.

We previously reported that C/EBPδ expression is inversely correlated with c-Myc (Myc) expression. Aberrant Myc expression is common in cancer and transcriptional repression is a major mechanism of Myc oncogenesis. A number of tumor suppressor genes are targets of Myc transcriptional repression including C/EBPα, p15
INK 4, p21
CIP 1, p27
KIP 1and p57
KIP 2. This study investigated the mechanisms underlying Myc repression of C/EBPδ expression.

Results

Myc represses C/EBPδ promoter activity in nontransformed mammary epithelial cells in a dose-dependent manner that requires Myc Box II, Basic Region and HLH/LZ domains. Chromatin Immunoprecipitation (ChIP) assays demonstrate that Myc, Miz1 and Max are associated with the C/EBPδ promoter in proliferating cells, when C/EBPδ expression is repressed. EMSAs demonstrate that Miz1 binds to a 30 bp region (-100 to -70) of the C/EBPδ promoter which contains a putative transcription initiator (Inr) element. Miz1 functions exclusively as a repressor of C/EBPδ promoter activity. Miz1 siRNA expression or expression of a Miz1 binding deficient Myc (MycV394D) construct reduces Myc repression of C/EBPδ promoter activity. Max siRNA expression, or expression of a Myc construct lacking the HLH/LZ (Max interacting) region, also reduces Myc repression of C/EBPδ promoter activity. Miz1 and Max siRNA treatments attenuate Myc repression of endogenous C/EBPδ expression. Myc Box II interacting proteins RuvBl1 (Pontin, TIP49) and RuvBl2 (Reptin, TIP48) enhances Myc repression of C/EBPδ promoter activity.

Conclusion

Myc represses C/EBPδ expression by associating with the C/EBPδ proximal promoter as a transient component of a repressive complex that includes Max and Miz1. RuvBl1 and RuvBl2 enhance Myc repression of C/EBPδ promoter activity. These results identify protein interactions that mediate Myc repression of C/EBPδ, and possibly other tumor suppressor genes, and suggest new therapeutic targets to block Myc transcriptional repression and oncogenic function.
Role of Leukotriene Receptor Antagonists in the Treatment of Exercise-Induced Bronchoconstriction: A Review
Authors: Philteos George S , Davis Beth E , Cockcroft Donald W , Marciniuk Darcy D
Published: May 2010

Asthma is a very common disorder that still causes significant morbidity and mortality. A high percentage of individuals with asthma also experience exercise-induced bronchoconstriction (EIB). This article reviews the current literature and updates the reader on the safety, efficacy, and clinical applications of leukotriene modifiers in the treatment of EIB.
Eukaryotic gene invasion by a bacterial mobile insertion sequence element IS2 during cloning into a plasmid vector
Authors: Senejani Alireza G , Sweasy Joann B
Published: May 2010

Escherichia coli (E. coli) are commonly used as hosts for DNA cloning and sequencing. Upon transformation of E. coli with recombined vector carrying a gene of interest, the bacteria multiply the gene of interest while maintaining the integrity of its content. During the subcloning of a mouse genomic fragment into a plasmid vector, we noticed that the size of the insert increased significantly upon replication in E. coli. The sequence of the insert was determined and found to contain a novel DNA sequence within the mouse genomic insert. A BLAST search of GenBank revealed the novel sequence to be that of the Insertion Sequence 2 (IS2) element from E. coli that was likely inserted during replication in that organism. Importantly, a detailed search of GenBank shows that the IS2 is present within many eukaryotic nucleotide sequences, and in many cases, has been annotated as being part of the protein. The results of this study suggest that one must perform additional careful analysis of the sequence results using BLAST comparisons, and further verification of gene annotation before submission into the GenBank.
Defective Artemis causes mild telomere dysfunction
Authors: Yasaei Hemad , Slijepcevic Predrag
Published: May 2010

Background

Repair of DNA double strand breaks by non-homologous end joining (NHEJ) requires several proteins including Ku, DNA-PKcs, Artemis, XRCC4, Ligase IV and XLF. Two of these proteins, namely Ku and DNA-PKcs, are also involved in maintenance of telomeres, chromosome end-structures. In contrast, cells defective in Ligase IV and XRCC4 do not show changes in telomere length or function suggesting that these proteins are not involved in telomere maintenance. Since a mouse study indicated that defective Artemis may cause telomere dysfunction we investigated the effects of defective Artemis on telomere maintenance in human cells.

Results

We observed significantly elevated frequencies of telomeric fusions in two primary fibroblast cell lines established from Artemis defective patients relative to the control cell line. The frequencies of telomeric fusions increased after exposure of Artemis defective cells to ionizing radiation. Furthermore, we observed increased incidence of DNA damage at telomeres in Artemis defective cells that underwent more than 32 population doublings using the TIF (Telomere dysfunction Induced Foci) assay. We have also inhibited the expression levels of DNA-PKcs in Artemis defective cell lines by either using synthetic inhibitor (IC86621) or RNAi and observed their greater sensitivity to telomere dysfunction relative to control cells.

Conclusion

These results suggest that defective Artemis causes a mild telomere dysfunction phenotype in human cell lines.
Inhibition of poly (ADP-Ribose) polymerase-1 in telomerase deficient mouse embryonic fibroblasts increases arsenite-induced genome instability
Authors: Gurung Resham L , Balakrishnan Lakshmidevi , Bhattacharjee Rabindra N , Manikandan Jayapal , Swaminathan Srividya , Hande M Prakash
Published: May 2010

Background

The telomerase enzyme is a viable target for anti-cancer therapy given the innate differences in telomerase activity between tumour cells and normal somatic cells. However, the time lag between telomerase inhibition and telomeres becoming critically short to trigger cell death, allows cancer cells to acquire drug resistance. Inhibition of DNA repair pathways along with telomerase could be an alternative strategy to enhance anti-tumour effects and circumvent the possibility of drug resistance. Poly (ADP-Ribose) Polymerase-1 (PARP-1), an important DNA damage sensor and a DNA repair factor, has important roles in maintaining telomeres and chromosomal stability. In this study, the effects of combined inhibition of PARP-1 and telomerase in mouse embryonic fibroblasts (MEFs) following sodium arsenite exposure (a carcinogen and potent DNA damaging agent), were evaluated.

Results

Inhibition of PARP in telomerase deficient MEFs induced an increase in arsenite-induced DNA damage as compared to control cells. Combined inhibition also resulted in enhanced genomic instability, demonstrated by elevated micronuclei induction and chromosomal aberrations with decreased cell survival. In addition, telomerase inhibition in PARP-1 deficient MEFs led to greater telomere shortening and increased genomic instability.

Conclusions

Our study demonstrated that the co-inhibition of PARP-1 and telomerase in MEFs rendered cells more susceptible to DNA damaging agents. Hence, these results offer support for the use of combined inhibition of PARP-1 and telomerase as a strategy to minimise the problems associated with long-term telomerase inhibition in cancer therapeutics.
Tmem176B and Tmem176A are associated with the immature state of dendritic cells
Authors: Condamine Thomas , Le Texier Laetitia , Howie Duncan , Lavault Amelie , Hill Marcelo , Halary Frank , Cobbold Steve , Waldmann Herman , Cuturi Maria-Cristina , Chiffoleau Elise
Published: May 2010

Knock-down of the expression of Tmem176B and Tmem176A in immature DC leads to increase of the DC stimulatory properties.

DCs play a central role in the development of innate and adaptive immunity but also in the induction and maintenance of immune tolerance. Identification of factors that govern DC activation, their maturation state, and their capacity to induce proinflammatory or tolerogeneic responses therefore represents a crucial aim of research. We previously identified a new molecule, Tmem176B (which we named TORID initially), as highly expressed in a model of allograft tolerance in the rat. We showed that its overexpression in rat DCs blocked their maturation, suggesting a role for this molecule in the maturation process. To characterize the function of Tmem176B further, we used a split-ubiquitin yeast, two-hybrid system to identify interacting partners and found that Tmem176B associated with itself but also with Tmem176A, a membrane protein similar to Tmem176B. Interestingly, these two molecules showed similar mRNA expression patterns among various murine tissues and immune cells and were both down-regulated following DC maturation. In addition, we showed that in using RNAi, these molecules are both involved in the maintenance of the immature state of the DCs. Taken together, these data suggest that Tmem176B and Tmem176A associate to form multimers and restrain DC maturation. Therefore, these two molecules may represent valid targets to regulate DC function.
Impaired-Inactivation of FoxO1 Contributes to Glucose-Mediated Increases in Serum Very Low-Density Lipoprotein
Authors: Wu Ke , Cappel David , Martinez Melissa , Stafford John M.
Published: May 2010

For patients with diabetes, insulin resistance and hyperglycemia both contribute to increased serum triglyceride in the form of very low-density lipoprotein (VLDL). Our objective was to define the insulin conditions in which hyperglycemia promotes increased serum VLDL in vivo. We performed hyperglycemic-hyperinsulinemic clamp studies and hyperglycemic-hypoinsulinemic clamp studies in rats, with metabolic tracers for glucose flux and de novo fatty acid synthesis. When blood glucose was clamped at hyperglycemia (17 mm) for 2 h under hyperinsulinemic conditions (4 mU/kg · min), serum VLDL levels were not increased compared with baseline. We speculated that hyperinsulinemia minimized glucose-mediated VLDL changes and performed hyperglycemic-hypoinsulinemic clamp studies in which insulin was clamped near fasting levels with somatostatin (17 mm blood glucose, 0.25 mU/kg · min insulin). Under low-insulin conditions, serum VLDL levels were increased 4.7-fold after hyperglycemia, and forkhead box O1 (FoxO1) was not excluded from the nucleus of liver cells. We tested the extent that impaired inactivation of FoxO1 by insulin was sufficient for glucose to promote increased serum VLDL. We found that, when the ability of insulin to inactivate FoxO1 is blocked after adenoviral delivery of constitutively active FoxO1, glucose increased serum VLDL triglyceride when given both by ip glucose tolerance testing (3.5-fold increase) and by a hyperglycemic clamp (4.6-fold). Under both experimental conditions in which insulin signaling to FoxO1 was impaired, we found increased activation of carbohydrate response element binding protein. These data suggest that glucose more potently promotes increased serum VLDL when insulin action is impaired, with either low insulin levels or disrupted downstream signaling to the transcription factor FoxO1.
Androgen and Src signaling regulate centrosome activity
Authors: Colello Diane , Reverte Carlos G. , Ward Rachel , Jones Christopher W. , Magidson Valentin , Khodjakov Alexey , LaFlamme Susan E.
Published: May 2010

Microtubules nucleated from γ-tubulin ring complexes located at the centrosome regulate the localization of organelles, promote vesicular transport and direct cell migration. Although several signaling mechanisms have been identified that regulate microtubule dynamics during interphase, signaling pathways that promote microtubule nucleation remain elusive. We assayed microtubule regrowth following nocodazole washout in human fibroblasts and CHO-K1 cells adhered to fibronectin in either normal serum-free medium or the serum-free, growth-promoting medium, CCM1, which contains IGF1 and androgen, as well as other nutrients. The results indicate that integrin-mediated adhesion is not sufficient to promote rapid microtubule regrowth in either cell type. The addition of androgen, but not IGF1, for 5 minutes was sufficient to promote rapid regrowth and this occurred by a mechanism requiring the androgen receptor. Since Src is a component of the cytoplasmic androgen-receptor-signaling complex, we examined its role using Src siRNA, the Src kinase inhibitor SU6656, and the expression of a constitutively active Src mutant. The data show that Src signaling is both required and sufficient to promote rapid microtubule regrowth in cells adhered to fibronectin. Measurement of the density of microtubules close to the centrosome and the rates of GFP-EB1-labeled microtubules emanating from the centrosome indicated that Src signaling promotes microtubule nucleation. Furthermore, recovery of GFP–γ-tubulin at the centrosome following photobleaching and measurements of endogenous γ-tubulin levels at the centrosome showed that androgen and Src signaling regulate the levels of centrosomal γ-tubulin. Thus, we propose that androgen and Src signaling regulate microtubule nucleation during interphase by promoting the centrosomal localization of γ-tubulin.
Nuclear factor-κB signaling and ezrin are essential for L1-mediated metastasis of colon cancer cells
Authors: Gavert Nancy , Ben-Shmuel Amir , Lemmon Vance , Brabletz Thomas , Ben-Ze'ev Avri
Published: May 2010

Hyperactivation of β-catenin–T-cell-factor (TCF)-regulated gene transcription is a hallmark of colorectal cancer (CRC). The cell-neural adhesion molecule L1CAM (hereafter referred to as L1) is a target of β-catenin–TCF, exclusively expressed at the CRC invasive front in humans. L1 overexpression in CRC cells increases cell growth and motility, and promotes liver metastasis. Genes induced by L1 are also expressed in human CRC tissue but the mechanisms by which L1 confers metastasis are still unknown. We found that signaling by the nuclear factor κB (NF-κB) is essential, because inhibition of signaling by the inhibitor of κB super repressor (IκB-SR) blocked L1-mediated metastasis. Overexpression of the NF-κB p65 subunit was sufficient to increase CRC cell proliferation, motility and metastasis. Binding of the L1 cytodomain to ezrin – a cytoskeleton-crosslinking protein – is necessary for metastasis because when binding to L1 was interrupted or ezrin gene expression was suppressed with specific shRNA, metastasis did not occur. L1 and ezrin bound to and mediated the phosphorylation of IκB. We also observed a complex containing IκB, L1 and ezrin in the juxtamembrane region of CRC cells. Furthermore, we found that L1, ezrin and phosphorylated p65 are co-expressed at the invasive front in human CRC tissue, indicating that L1-mediated activation of NF-κB signaling involving ezrin is a major route of CRC progression.
Reaction to the birth of a child with cleft lip or cleft palate in Zimbabwe
Authors: Mzezewa S , Muchemwa F C
Published: May 2010

Cleft lip and palate (CLP) is often a distressful abnormality for both mother and child. In our setting, CLP is generally associated with witchcraft or ancestral spirits. The mother is often accused of infidelity during pregnancy. We wanted to determine the feelings of parents and the wider public towards CLP babies, to establish what parents believed were the causes of CLP and to establish the postpartum marital status. One hundred and twenty-four parents were prospectively included in the study. They were interviewed using a structured questionnaire. One hundred and fifteen mothers and four fathers said they loved their babies. Thirty-eight parents attributed CLP to witchcraft. Nineteen percent of the mothers were divorced. The responses to our questionnaire show that although CLP babies are loved by their parents, the condition is associated with stigma and superstition.
Column Generation with Dynamic Duty Selection for Railway Crew Rescheduling
Authors: Potthoff Daniel , Huisman Dennis , Desaulniers Guy
Published: May 2010

The Dutch railway network experiences about three large disruptions per day on average. In this paper, we present an algorithm to reschedule the crews when such a disruption occurs. The algorithm is based on column generation techniques combined with Lagrangian heuristics. Since the number of duties is very large in practical instances, we first define a core problem of tractable size. If some tasks remain uncovered in the solution of the core problem, we perform a neighborhood exploration to improve the solution. Computational experiments with real-life instances show that our method is capable of producing good solutions within a couple of minutes of computation time.
When gesture does and does not promote learning
Authors: Goldin-Meadow Susan
Published: May 2010

Speakers move their hands when they talk—they gesture. These gestures can signal whether the speaker is ready to learn a particular task and, in this sense, provide a window onto the speaker's knowledge. But gesture can do more than reflect knowledge. It can play a role in changing knowledge in at least two ways: indirectly through its effects on communication with the learner, and directly through its effects on the learner's cognition. Gesturing is, however, not limited to learners. Speakers who are proficient in a task also gesture. Their gestures have a different relation to speech than the gestures that novices produce, and seem to support cognition rather than change it. Gesturing can thus serve as a tool for thinking and for learning.
Incidental verbatim memory for language
Authors: Gurevich Olga , Johnson Matthew A. , Goldberg Adele E.
Published: May 2010

It is widely believed that explicit verbatim memory for language is virtually nonexistent except in certain circumstances, for example if participants are warned they are to receive a memory test, if the language is ‘interactive’ (emotion-laden), or if the texts are exceedingly short and memory is tested immediately. The present experiments revisit the question of verbatim memory for language and demonstrate that participants do reliably recognize and recall full sentences that they are exposed to only once at above chance rates (Experiments 1 and 3). The texts are 300 words long, non-interactive, and no advanced warning of a memory test is given. Verbatim memory is demonstrated even when lexical content and memory for gist are controlled for (Experiments 2 and 4). The most striking finding is one of incidental recall: even after a six-day delay, participants reliably reproduce sentences they have heard before when asked to describe scenes, even though they are not asked to recall what they had heard (Experiment 5).
Disembodying cognition
Authors: Chatterjee Anjan
Published: May 2010

The idea that concepts are embodied by our motor and sensory systems is popular in current theorizing about cognition. Embodied cognition accounts come in different versions and are often contrasted with a purely symbolic amodal view of cognition. Simulation, or the hypothesis that concepts simulate the sensory and motor experience of real world encounters with instances of those concepts, has been prominent in psychology and cognitive neuroscience. Here, with a focus on spatial thought and language, I review some of the evidence cited in support of simulation versions of embodied cognition accounts. While these data are extremely interesting and many of the experiments are elegant, knowing how to best interpret the results is often far from clear. I point out that a quick acceptance of embodied accounts runs the danger of ignoring alternate hypotheses and not scrutinizing neuroscience data critically. I also review recent work from my lab that raises questions about the nature of sensory motor grounding in spatial thought and language. In my view, the question of whether or not cognition is grounded is more fruitfully replaced by questions about gradations in this grounding. A focus on disembodying cognition, or on graded grounding, opens the way to think about how humans abstract. Within neuroscience, I propose that three functional anatomic axes help frame questions about the graded nature of grounded cognition. First, are questions of laterality differences. Do association cortices in both hemispheres instantiate the same kind of sensory or motor information? Second, are questions about ventral dorsal axes. Do neuronal ensembles along this axis shift from conceptual representations of objects to the relationships between objects? Third, are questions about gradients centripetally from sensory and motor cortices towards and within perisylvian cortices. How does sensory and perceptual information become more language-like and then get transformed into language proper?
Striatal Overexpression of ΔFosB Reproduces Chronic Levodopa-Induced Involuntary Movements
Authors: Cao Xuebing , Yasuda Toru , Uthayathas Subramaniam , Watts Ray L. , Mouradian M. Maral , Mochizuki Hideki , Papa Stella M.
Published: May 2010

Long-term dopamine replacement therapy in Parkinson's disease leads to the development of disabling involuntary movements named dyskinesias that are related to adaptive changes in striatal signaling pathways. The chronic transcription factor ΔFosB, which is overexpressed in striatal neurons after chronic dopaminergic drug exposure, is suspected to mediate these adaptive changes. Here, we sought to demonstrate the ability of ΔFosB to lead directly to the abnormal motor responses associated with chronic dopaminergic therapy. Using rAAV (recombinant adenoassociated virus) viral vectors, high levels of ΔFosB expression were induced in the striatum of dopamine-denervated rats naive of chronic drug administration. Transgenic ΔFosB overexpression reproduced the entire spectrum of altered motor behaviors in response to acute levodopa tests, including different types of abnormal involuntary movements and hypersensitivity of rotational responses that are typically associated with chronic levodopa treatment. JunD, the usual protein partner of ΔFosB binding to AP-1 (activator protein-1) sites of genes, remained unchanged in rats with high ΔFosB expression induced by viral vectors. These findings demonstrate that the increase of striatal ΔFosB in the evolution of chronically treated Parkinson's disease may be a trigger for the development of abnormal responsiveness to dopamine and the emergence of involuntary movements.