bluuebunny/crossref_metadata_2025 huggingface dataset:
Femtosecond laser treatment enhances DNA transfection efficiency in vivo
Authors: Tsen Shaw-Wei D , Wu Chao-Yi , Meneshian Avedis , Pai Sara I , Hung Chien-Fu , Wu T-C
Published: May 2009

Background

Gene therapy with plasmid DNA is emerging as a promising strategy for the treatment of many diseases. One of the major obstacles to such therapy is the poor transfection efficiency of DNA in vivo.

Methods

In this report, we employed a very low power, near-infrared femtosecond laser technique to enhance the transfection efficiency of intradermally and intratumorally administered DNA plasmid.

Results

We found that femtosecond laser treatment can significantly enhance the delivery of DNA into the skin and into established tumors in mice. In addition, we found that both laser power density as well as duration of laser treatment are critical parameters for augmenting DNA transfection efficiency. The femtosecond laser technique employs a relatively unfocused laser beam that maximizes the transfected area, minimizes damage to tissue and simplifies its implementation.

Conclusion

This femtosecond new laser technology represents a safe and innovative technology for enhancing DNA gene transfer in vivo.
Enhanced muscarinic M1 receptor gene expression in the corpus striatum of streptozotocin-induced diabetic rats
Authors: Gireesh G , Kumar T Peeyush , Mathew Jobin , Paulose CS
Published: May 2009

Acetylcholine (ACh), the first neurotransmitter to be identified, regulate the activities of central and peripheral functions through interactions with muscarinic receptors. Changes in muscarinic acetylcholine receptor (mAChR) have been implicated in the pathophysiology of many major diseases of the central nervous system (CNS). Previous reports from our laboratory on streptozotocin (STZ) induced diabetic rats showed down regulation of muscarinic M1 receptors in the brainstem, hypothalamus, cerebral cortex and pancreatic islets. In this study, we have investigated the changes of acetylcholine esterase (AChE) enzyme activity, total muscarinic and muscarinic M1 receptor binding and gene expression in the corpus striatum of STZ – diabetic rats and the insulin treated diabetic rats. The striatum, a neuronal nucleus intimately involved in motor behaviour, is one of the brain regions with the highest acetylcholine content. ACh has complex and clinically important actions in the striatum that are mediated predominantly by muscarinic receptors. We observed that insulin treatment brought back the decreased maximal velocity (Vmax) of acetylcholine esterase in the corpus striatum during diabetes to near control state. In diabetic rats there was a decrease in maximal number (Bmax) and affinity (Kd) of total muscarinic receptors whereas muscarinic M1 receptors were increased with decrease in affinity in diabetic rats. We observed that, in all cases, the binding parameters were reversed to near control by the treatment of diabetic rats with insulin. Real-time PCR experiment confirmed the increase in muscarinic M1 receptor gene expression and a similar reversal with insulin treatment. These results suggest the diabetes-induced changes of the cholinergic activity in the corpus striatum and the regulatory role of insulin on binding parameters and gene expression of total and muscarinic M1 receptors.
Requirement of focal adhesion kinase in branching tubulogenesis
Authors: Wei Wei-Chun , Kopec Anna K , Tang Ming-Jer
Published: May 2009

We previously demonstrated that α3β1 integrins are essential to hepatocyte growth factor (HGF)-independent branching tubulogenesis in Mardin-Darby Canine Kidney (MDCK) cells. However, the involvement of integrin downstream signaling molecules remains unclear. In the present study, we successfully isolated cell lines possessing different tubulogenic potentials from the MDCK cells; cyst clones (CA4, CA6) forming cystic structures when cultured in 0.3% type I collagen gel and mass clones (M610, M611, M612) forming aggregated masses. Cyst clones maintained cystic structure in 0.1% collagen gel, whereas mass clones spontaneously developed into tubules. Both clones exhibited various morphologies when cultured on a dish: cyst clones formed aggregated islands, while mass clones were more scattered and exhibited higher migration capacity. Among several focal adhesion machinery proteins examined, only the expression and phosphorylation level of focal adhesion kinase (FAK) in mass clones was higher than in cyst clones, while other proteins showed no obvious differences. However, overexpression of wild type FAK in CA6 cells did not facilitate branching tubule formation in 0.1% collagen gel. Targeted decrease in the expression level of FAK in M610 cells with the application of antisense cDNA resulted in a marked reduction of branching tubule formation in 0.1% collagen gel and showed a down-regulation of fibronectin assembly, which is known to promote tubulogenesis. In contrast, overexpression of wild type FAK in CA6 cells had no effect on fibronectin assembly. Taken together, our data demonstrates that FAK is required, but not sufficient for HGF-independent branching tubulogenesis in MDCK cells.
Mutagenesis identifies the critical amino acid residues of human endonuclease G involved in catalysis, magnesium coordination, and substrate specificity
Authors: Wu Shih-Lu , Li Chia-Cheng , Chen Jaw-Chyun , Chen Yi-Jin , Lin Ching-Ting , Ho Tin-Yun , Hsiang Chien-Yun
Published: May 2009

Background

Endonuclease G (EndoG), a member of DNA/RNA nonspecific ββα-Me-finger nucleases, is involved in apoptosis and normal cellular proliferation. In this study, we analyzed the critical amino acid residues of EndoG and proposed the catalytic mechanism of EndoG.

Methods

To identify the critical amino acid residues of human EndoG, we replaced the conserved histidine, asparagine, and arginine residues with alanine. The catalytic efficacies of Escherichia coli-expressed EndoG variants were further analyzed by kinetic studies.

Results

Diethyl pyrocarbonate modification assay revealed that histidine residues were involved in EndoG activity. His-141, Asn-163, and Asn-172 in the H-N-H motif of EndoG were critical for catalysis and substrate specificity. H141A mutant required a higher magnesium concentration to achieve its activity, suggesting the unique role of His-141 in both catalysis and magnesium coordination. Furthermore, an additional catalytic residue (Asn-251) and an additional metal ion binding site (Glu-271) of human EndoG were identified.

Conclusion

Based on the mutational analysis and homology modeling, we proposed that human EndoG shared a similar catalytic mechanism with nuclease A from Anabaena.
Differential protection against oxidative stress and nitric oxide overproduction in cardiovascular and pulmonary systems by propofol during endotoxemia
Authors: Liu Yen-Chin , Chang Alice YW , Tsai Yu-Chuan , Chan Julie YH
Published: May 2009

Background

Both overproduction of nitric oxide (NO) and oxidative injury of cardiovascular and pulmonary systems contribute to fatal cardiovascular depression during endotoxemia. We investigated in the present study the relative contribution of oxidative stress and NO to cardiovascular depression during different stages of endotoxemia, and delineated their roles in cardiovascular protective effects of a commonly used anesthetic propofol during endotoxemia.

Methods

Experimental endotoxemia was induced by systemic injection ofE. colilipopolysaccharide (LPS, 15 mg/kg) to Sprague-Dawley rats that were maintained under propofol (15 or 30 mg/kg/h, i.v.) anesthesia. Mean systemic arterial pressure (MSAP) and heart rate (HR) were monitored for 6 h after the endotoxin. Tissue level of NO was measured by chemical reduction-linked chemiluminescence and oxidative burst activity was determined using dihydroethidium method. Expression of NO synthase (NOS) was determined by immunoblotting. The Scheffé multiple range test was used for post hoc statistical analysis.

Results

Systemic injection of LPS (15 mg/kg) induced biphasic decreases in MSAP and HR. In the heart, lung and aorta, an abrupt increase in lipid peroxidation, our experimental index of oxidative tissue injury, was detected in early stage and sustained during late stage cardiovascular depression. LPS injection, on the other hand, induced a gradual increase in tissue nitrite and nitrate levels in the same organs that peaked during late stage endotoxemia. Propofol infusion (15 or 30 mg/kg/h, i.v.) significantly attenuated lipid peroxidation in the heart, lung and aorta during early and late stage endotoxemia. High dose (30 mg/kg/h, i.v.) propofol also reversed the LPS-induced inducible NO synthase (iNOS) upregulation and NO production in the aorta, alongside a significant amelioration of late stage cardiovascular depression and increase in survival time during endotoxemia.

Conclusion

Together these results suggest that oxidative injury and NO may play a differential role in LPS-induced cardiovascular depression. Oxidative tissue injury is associated with both early and late stage; whereas NO is engaged primarily in late stage cardiovascular depression. Moreover, propofol anesthesia may protect against fatal cardiovascular depression during endotoxemia by attenuating the late stage NO surge in the aorta, possibly via inhibition of iNOS upregulation by the endotoxin.
In silico miRNA prediction in metazoan genomes: balancing between sensitivity and specificity
Authors: van der Burgt Ate , Fiers Mark WJE , Nap Jan-Peter , van Ham Roeland CHJ
Published: May 2009

Background

MicroRNAs (miRNAs), short ~21-nucleotide RNA molecules, play an important role in post-transcriptional regulation of gene expression. The number of known miRNA hairpins registered in the miRBase database is rapidly increasing, but recent reports suggest that many miRNAs with restricted temporal or tissue-specific expression remain undiscovered. Various strategies for in silico miRNA identification have been proposed to facilitate miRNA discovery. Notably support vector machine (SVM) methods have recently gained popularity. However, a drawback of these methods is that they do not provide insight into the biological properties of miRNA sequences.

Results

We here propose a new strategy for miRNA hairpin prediction in which the likelihood that a genomic hairpin is a true miRNA hairpin is evaluated based on statistical distributions of observed biological variation of properties (descriptors) of known miRNA hairpins. These distributions are transformed into a single and continuous outcome classifier called the L score. Using a dataset of known miRNA hairpins from the miRBase database and an exhaustive set of genomic hairpins identified in the genome of Caenorhabditis elegans, a subset of 18 most informative descriptors was selected after detailed analysis of correlation among and discriminative power of individual descriptors. We show that the majority of previously identified miRNA hairpins have high L scores, that the method outperforms miRNA prediction by threshold filtering and that it is more transparent than SVM classifiers.

Conclusion

The L score is applicable as a prediction classifier with high sensitivity for novel miRNA hairpins. The L- score approach can be used to rank and select interesting miRNA hairpin candidates for downstream experimental analysis when coupled to a genome-wide set of in silico-identified hairpins or to facilitate the analysis of large sets of putative miRNA hairpin loci obtained in deep-sequencing efforts of small RNAs. Moreover, the in-depth analyses of miRNA hairpins descriptors preceding and determining the L score outcome could be used as an extension to miRBase entries to help increase the reliability and biological relevance of the miRNA registry.
Biases in Drosophila melanogaster protein trap screens
Authors: Aleksic Jelena , Lazic Ranko , Müller Ilka , Russell Steven R , Adryan Boris
Published: May 2009

Background

The ability to localise or follow endogenous proteins in real time in vivo is of tremendous utility for cell biology or systems biology studies. Protein trap screens utilise the random genomic insertion of a transposon-borne artificial reporter exon (e.g. encoding the green fluorescent protein, GFP) into an intron of an endogenous gene to generate a fluorescent fusion protein. Despite recent efforts aimed at achieving comprehensive coverage of the genes encoded in the Drosophila genome, the repertoire of genes that yield protein traps is still small.

Results

We analysed the collection of available protein trap lines in Drosophila melanogaster and identified potential biases that are likely to restrict genome coverage in protein trap screens. The protein trap screens investigated here primarily used P-element vectors and thus exhibit some of the same positional biases associated with this transposon that are evident from the comprehensive Drosophila Gene Disruption Project. We further found that protein trap target genes usually exhibit broad and persistent expression during embryonic development, which is likely to facilitate better detection. In addition, we investigated the likely influence of the GFP exon on host protein structure and found that protein trap insertions have a significant bias for exon-exon boundaries that encode disordered protein regions. 38.8% of GFP insertions land in disordered protein regions compared with only 23.4% in the case of non-trapping P-element insertions landing in coding sequence introns (p < 10-4). Interestingly, even in cases where protein domains are predicted, protein trap insertions frequently occur in regions encoding surface exposed areas that are likely to be functionally neutral. Considering the various biases observed, we predict that less than one third of intron-containing genes are likely to be amenable to trapping by the existing methods.

Conclusion

Our analyses suggest that the utility of P-element vectors for protein trap screens has largely been exhausted, and that approximately 2,800 genes may still be amenable using piggyBac vectors. Thus protein trap strategies based on current approaches are unlikely to offer true genome-wide coverage. We suggest that either transposons with reduced insertion bias or recombineering-based targeting techniques will be required for comprehensive genome coverage in Drosophila.
Toxoplasma seroprevalence in a rural population in France: detection of a household effect
Authors: Fromont Emmanuelle Gilot , Riche Benjamin , Rabilloud Muriel
Published: May 2009

Background

Toxoplasma gondii, the agent of toxoplasmosis, has a complex life cycle. In humans, the parasite may be acquired either through ingestion of contaminated meat or through oocysts present in the environment. The importance of each source of contamination varies locally according to the environment characteristics and to differences concerning human eating habits and the presence of cats; thus, the risk factors may be determined through fine-scale studies. Here, we searched for factors associated with seropositivity in the population of two adjacent villages in Lorraine region, France.

Methods

All voluntary inhabitants filled out a questionnaire and gave a blood sample. The seroprevalence was estimated globally and according to the inhabitants' ages using a cubic spline regression. A mixed logistic regression model was used to quantify the effect of individual and household factors on the probability of seropositivity.

Results

Based on serological results from 273 persons, we estimated seroprevalence to be 47% (95% confidence interval: 41 to 53%). That seroprevalence increased with age: the slope was the steepest up to the age of 40 years (OR = 2.48 per 10-year increment, 95% credibility interval: [1.29 to 5.09]), but that increase was not significant afterwards. The probability of seropositivity tended to be higher in men than in women (OR = 2.01, 95% credibility interval: [0.92 to 4.72]) and in subjects eating raw vegetables at least once a week than in the others (OR = 8.4, 95% credibility interval: [0.93 to 72.1]). These effects were close to statistical significance. The multivariable analysis highlighted a significant seroprevalence heterogeneity among households. That seroprevalence varied between 6 and 91% (5th and 95th percentile of the household seropositivity distribution).

Conclusion

The major finding is the household effect, with a strong heterogeneity of seroprevalence among households. This effect may be explained by common exposures of household members to local risk factors. Future work will quantify the link between the presence of oocysts in the soil and the seroprevalence of exposed households using a spatial analysis.
Expression of miR-21 and its targets (PTEN, PDCD4, TM1) in flat epithelial atypia of the breast in relation to ductal carcinoma in situ and invasive carcinoma
Authors: Qi Liqiang , Bart Joost , Tan Lu Ping , Platteel Inge , Sluis Tineke van der , Huitema Sippie , Harms Geert , Fu Li , Hollema Harry , Berg Anke van den
Published: May 2009

Background

Flat epithelial atypia (FEA) of the breast is characterised by a few layers of mildly atypical luminal epithelial cells. Genetic changes found in ductal carcinoma in situ (DCIS) and invasive ductal breast cancer (IDC) are also found in FEA, albeit at a lower concentration. So far, miRNA expression changes associated with invasive breast cancer, like miR-21, have not been studied in FEA.

Methods

We performed miRNA in-situ hybridization (ISH) on 15 cases with simultaneous presence of normal breast tissue, FEA and/or DCIS and 17 additional cases with IDC. Expression of the miR-21 targets PDCD4, TM1 and PTEN was investigated by immunohistochemistry.

Results

Two out of fifteen cases showed positive staining for miR-21 in normal breast ductal epithelium, seven out of fifteen cases were positive in the FEA component and nine out of twelve cases were positive in the DCIS component. A positive staining of miR-21 was observed in 15 of 17 IDC cases. In 12 cases all three components were present in one tissue block and an increase of miR-21 from normal breast to FEA and to DCIS was observed in five cases. In three cases the FEA component was negative, whereas the DCIS component was positive for miR-21. In three other cases, normal, FEA and DCIS components were negative for miR-21 and in the last case all three components were positive. Overall we observed a gradual increase in percentage of miR-21 positive cases from normal, to FEA, DCIS and IDC. Immunohistochemical staining for PTEN revealed no obvious changes in staining intensities in normal, FEA, DCIS and IDC. Cytoplasmic staining of PDCD4 increased from normal to IDC, whereas, the nuclear staining decreased. TM1 staining decreased from positive in normal breast to negative in most DCIS and IDC cases. In FEA, the staining pattern for TM1 was similar to normal breast tissue.

Conclusion

Upregulation of miR-21 from normal ductal epithelial cells of the breast to FEA, DCIS and IDC parallels morphologically defined carcinogenesis. No clear relation was observed between the staining pattern of miR-21 and its previously reported target genes.
Do serum biomarkers really measure breast cancer?
Authors: Jesneck Jonathan L , Mukherjee Sayan , Yurkovetsky Zoya , Clyde Merlise , Marks Jeffrey R , Lokshin Anna E , Lo Joseph Y
Published: May 2009

Background

Because screening mammography for breast cancer is less effective for premenopausal women, we investigated the feasibility of a diagnostic blood test using serum proteins.

Methods

This study used a set of 98 serum proteins and chose diagnostically relevant subsets via various feature-selection techniques. Because of significant noise in the data set, we applied iterated Bayesian model averaging to account for model selection uncertainty and to improve generalization performance. We assessed generalization performance using leave-one-out cross-validation (LOOCV) and receiver operating characteristic (ROC) curve analysis.

Results

The classifiers were able to distinguish normal tissue from breast cancer with a classification performance of AUC = 0.82 ± 0.04 with the proteins MIF, MMP-9, and MPO. The classifiers distinguished normal tissue from benign lesions similarly at AUC = 0.80 ± 0.05. However, the serum proteins of benign and malignant lesions were indistinguishable (AUC = 0.55 ± 0.06). The classification tasks of normal vs. cancer and normal vs. benign selected the same top feature: MIF, which suggests that the biomarkers indicated inflammatory response rather than cancer.

Conclusion

Overall, the selected serum proteins showed moderate ability for detecting lesions. However, they are probably more indicative of secondary effects such as inflammation rather than specific for malignancy.
Serum high mobility group box-1 (HMGB1) is closely associated with the clinical and pathologic features of gastric cancer
Authors: Chung Hye Won , Lee Sang-Guk , Kim Heejung , Hong Duck Jin , Chung Jae Bock , Stroncek David , Lim Jong-Baeck
Published: May 2009

Background

High mobility group box-1 (HMGB1) is a newly recognized factor regulating cancer cell tumorigenesis, expansion and invasion. We investigated the correlation between the serum HMGB1 levels and the clinical and pathologic features of gastric cancer and evaluated the validity of HMGB1 as a potential biomarker for the early diagnosis of gastric cancer.

Methods

A total of 227 subjects were classified into 5 disease groups according to the 'gastritis-dysplasia-carcinoma' sequence of gastric carcinogenesis and their serum levels of HMGB1 were analyzed by an enzyme-linked immunosorbent assay (ELISA) method. Clinical parameters, International Union Against Cancer (UICC) TNM stage, cancer size, differentiation or lymphatic invasion, vascular or perineural invasion and prognosis were used as analysis variables.

Results

The serum HMGB1 levels were significantly different among disease groups (ANOVA, p < 0.05) and HMGB1 levels tended to increase according to the progression of gastric carcinogenesis. Serum HMGB1 levels were significantly associated with depth of invasion, lymph node metastasis, tumor size, and poor prognosis (p < 0.05). However, HMGB1 levels were not associated with patient gender or age, differentiation of tumor cells, or lymphatic, vascular and perineural invasion, or the existence of distant metastasis in advanced cancer (p > 0.05). The sensitivity and specificity of serum HMGB1 was 71% and 67% (cut-off value of 5 ng/ml) for the diagnosis of early gastric cancer, and 70% and 64% (cut-off value of 4 ng/ml) for the diagnosis of high-risk lesions, respectively. These values were greater than those for carcinoembryonic antigen (CEA) (30–40% of sensitivity).

Conclusion

HMGB1 appears to be a useful serological biomarker for early diagnosis as well as evaluating the tumorigenesis, stage, and prognosis of gastric cancer.
Computational investigation of epithelial cell dynamic phenotype in vitro
Authors: Kim Sean HJ , Park Sunwoo , Mostov Keith , Debnath Jayanta , Hunt C Anthony
Published: May 2009

Background

When grown in three-dimensional (3D) cultures, epithelial cells typically form cystic organoids that recapitulate cardinal features of in vivo epithelial structures. Characterizing essential cell actions and their roles, which constitute the system's dynamic phenotype, is critical to gaining deeper insight into the cystogenesis phenomena.

Methods

Starting with an earlier in silico epithelial analogue (ISEA1) that validated for several Madin-Darby canine kidney (MDCK) epithelial cell culture attributes, we built a revised analogue (ISEA2) to increase overlap between analogue and cell culture traits. Both analogues used agent-based, discrete event methods. A set of axioms determined ISEA behaviors; together, they specified the analogue's operating principles. A new experimentation framework enabled tracking relative axiom use and roles during simulated cystogenesis along with establishment of the consequences of their disruption.

Results

ISEA2 consistently produced convex cystic structures in a simulated embedded culture. Axiom use measures provided detailed descriptions of the analogue's dynamic phenotype. Dysregulating key cell death and division axioms led to disorganized structures. Adhering to either axiom less than 80% of the time caused ISEA1 to form easily identified morphological changes. ISEA2 was more robust to identical dysregulation. Both dysregulated analogues exhibited characteristics that resembled those associated with an in vitro model of early glandular epithelial cancer.

Conclusion

We documented the causal chains of events, and their relative roles, responsible for simulated cystogenesis. The results stand as an early hypothesis–a theory–of how individual MDCK cell actions give rise to consistently roundish, cystic organoids.
CANnabinoid Receptor Type 2 Activation Induces a Microglial Anti-Inflammatory Phenotype and Reduces Migration via MKP Induction and ERK Dephosphorylation
Authors: Romero-Sandoval Edgar Alfonso , Horvath Ryan , Landry Russell P , DeLeo Joyce A
Published: May 2009

Background

Cannabinoid receptor type 2 (CBR2) inhibits microglial reactivity through a molecular mechanism yet to be elucidated. We hypothesized that CBR2 activation induces an anti-inflammatory phenotype in microglia by inhibiting extracellular signal-regulated kinase (ERK) pathway, via mitogen-activated protein kinase-phosphatase (MKP) induction. MKPs regulate mitogen activated protein kinases, but their role in the modulation of microglial phenotype is not fully understood.

Results

JWH015 (a CBR2 agonist) increased MKP-1 and MKP-3 expression, which in turn reduced p-ERK1/2 in LPS-stimulated primary microglia. These effects resulted in a significant reduction of tumor necrosis factor-α (TNF) expression and microglial migration. We confirmed the causative link of these findings by using MKP inhibitors. We found that the selective inhibition of MKP-1 by Ro-31-8220 and PSI2106, did not affect p-ERK expression in LPS+JWH015-treated microglia. However, the inhibition of both MKP-1 and MKP-3 by triptolide induced an increase in p-ERK expression and in microglial migration using LPS+JWH015-treated microglia.

Conclusion

Our results uncover a cellular microglial pathway triggered by CBR2 activation. These data suggest that the reduction of pro-inflammatory factors and microglial migration via MKP-3 induction is part of the mechanism of action of CBR2 agonists. These findings may have clinical implications for further drug development.
The cost and impact of male circumcision on HIV/AIDS in Botswana
Authors: Bollinger Lori A , Stover John , Musuka Godfrey , Fidzani Boga , Moeti Themba , Busang Lesego
Published: May 2009

The HIV/AIDS epidemic continues to be a major issue facing Botswana, with overall adult HIV prevalence estimated to be 25.7 percent in 2007. This paper estimates the cost and impact of the draft Ministry of Health male circumcision strategy using the UNAIDS/WHO Decision‐Makers' Programme Planning Tool (DMPPT). Demographic data and HIV prevalence estimates from the recent National AIDS Coordinating Agency estimations are used as input to the DMPPT to estimate the impact of scaling‐up male circumcision on the HIV/AIDS epidemic. These data are supplemented by programmatic information from the draft Botswana National Strategy for Safe Male Circumcision, including information on unit cost and program goals. Alternative scenarios were developed in consultation with stakeholders. Results suggest that scaling‐up adult and neonatal circumcision to reach 80% coverage by 2012 would result in averting almost 70,000 new HIV infections through 2025, at a total net cost of US$47 million across that same period. This results in an average cost per HIV infection averted of US$689. Changing the target year to 2015 and the scale‐up pattern to a linear pattern results in a more evenly‐distributed number of MCs required, and averts approximately 60,000 new HIV infections through 2025. Other scenarios explored include the effect of risk compensation and the impact of increasing coverage of general prevention interventions. Scaling‐up safe male circumcision has the potential to reduce the impact of HIV/AIDS in Botswana significantly; program design elements such as feasible patterns of scale‐up and inclusion of counselling are important in evaluating the overall success of the program.
DNA-like class R inhibitory oligonucleotides (INH-ODNs) preferentially block autoantigen-induced B-cell and dendritic cell activation in vitro and autoantibody production in lupus-prone MRL-Fas
lpr/lpr
mice in vivo
Authors: Lenert Petar , Yasuda Kei , Busconi Liliana , Nelson Patrice , Fleenor Courtney , Ratnabalasuriar Radhika S , Nagy Peter L , Ashman Robert F , Rifkin Ian R , Marshak-Rothstein Ann
Published: May 2009

Introduction

B cells have many different roles in systemic lupus erythematosus (SLE), ranging from autoantigen recognition and processing to effector functions (for example, autoantibody and cytokine secretion). Recent studies have shown that intracellular nucleic acid-sensing receptors, Toll-like receptor (TLR) 7 and TLR9, play an important role in the pathogenesis of SLE. Dual engagement of rheumatoid factor-specific AM14 B cells through the B-cell receptor (BCR) and TLR7/9 results in marked proliferation of autoimmune B cells. Thus, strategies to preferentially block innate activation through TLRs in autoimmune B cells may be preferred over non-selective B-cell depletion.

Methods

We have developed a new generation of DNA-like compounds named class R inhibitory oligonucleotides (INH-ODNs). We tested their effectiveness in autoimmune B cells and interferon-alpha-producing dendritic cells in vitro and in lupus-prone MRL-Fas
lpr/lpr
mice in vivo.

Results

Class R INH-ODNs have 10- to 30-fold higher inhibitory potency when autoreactive B cells are synergistically activated through the BCR and associated TLR7 or 9 than when stimulation occurs via non-BCR-engaged TLR7/9. Inhibition of TLR9 requires the presence of both CCT and GGG triplets in an INH-ODN, whereas the inhibition of the TLR7 pathway appears to be sequence-independent but dependent on the phosphorothioate backbone. This difference was also observed in the MRL-Fas
lpr/lpr
mice in vivo, where the prototypic class R INH-ODN was more effective in curtailing abnormal autoantibody secretion and prolonging survival.

Conclusions

The increased potency of class R INH-ODNs for autoreactive B cells and dendritic cells may be beneficial for lupus patients by providing pathway-specific inhibition yet allowing them to generate protective immune response when needed.
White matter microstructural impairments and genetic liability
to familial bipolar I disorder
Authors: Chaddock Christopher A. , Barker Gareth J. , Marshall Nicolette , Schulze Katja , Hall Mei Hua , Fern Adele , Walshe Muriel , Bramon Elvira , Chitnis Xavier A. , Murray Robin , McDonald Colm
Published: May 2009

Background

Subtle abnormalities in frontal white matter have been reported in
bipolar disorder.

Aims

To assess whether impaired integrity of white matter tracts is associated
with bipolar disorder and genetic liability for the disorder.

Method

A total of 19 patients with psychotic bipolar I disorder from multiply
affected families, 21 unaffected first-degree relatives and 18 comparison
individuals (controls) underwent diffusion tensor imaging. Whole brain
voxel-based analyses compared fractional anisotropy between patients and
relatives with controls, and its relationship with a quantitative measure
of genetic liability.

Results

Patients had decreased fractional anisotropy compared with controls in
the genu of the corpus callosum, right inferior longitudinal fasciculus
and left superior longitudinal fasciculus. Increased genetic liability
for bipolar disorder was associated with reduced fractional anisotropy
across distributed regions of white matter in patients and their
unaffected relatives.

Conclusions

Disturbed structural integrity within key intra- and interhemispheric
tracts characterises both bipolar disorder and genetic liability for this
illness.
Dual training in psychiatry: where now?
Authors: Oakley Clare , White Ollie , Bailey Sue
Published: May 2009

This is a time of rapid change in postgraduate training, the implications of which are wide ranging. This paper reviews the current situation regarding dual training in psychiatry. Included is an analysis of utilisation of dual training in psychiatric specialities gleaned via the College membership data and an examination of the current employment prospects in relation to dual training. the impact on dual training of Modernising Medical Careers (MMC), competency-based training and the possibility of a single Certificate of Completion of Training (CCT) in psychiatry is considered. Suggestions are then made for the way forward.
Mental health rehabilitation services in the UK in 2007
Authors: Mountain Debbie , Killaspy Helen , Holloway Frank
Published: May 2009

Aims and Method

A survey of UK consultants in rehabilitation psychiatry was carried out to investigate current service provision and changes over the past 3 years.

Results

Most services had undergone multiple changes, with an overall reduction in over half and an overall expansion in a minority. the proportion with low secure provision had doubled. Around a third reported reinvestment of rehabilitation resources into other specialist in-patient and community services.

Clinical Implications

Rehabilitation services are undergoing rapid change with diversion of resources into services that may lack rehabilitation expertise. This risks an increase in independent sector referrals for in-patient rehabilitation for those with complex needs. Expansion of community services should be balanced against the need for local in-patient rehabilitation services.
Mental Capacity Act 2005: views and experiences of learning disability psychiatrists
Authors: Sawhney Indermeet , Mukhopadhyay Abir , Karki Chuda
Published: May 2009

Aims and Method

Postal questionnaires were sent out to 66 learning disability psychiatrists to assess their knowledge and experience of the Mental Capacity Act 2005.

Results

A response rate of 55% (n = 36) was achieved; 22 (61%) respondents felt that patient care had improved; 16 (44%) felt workload had increased. Despite 79% (n = 23) of the respondents feeling that the training for the Act was adequate, only 19% (n = 7) were aware of the situations where patients had to be referred to the Independent Mental Capacity Advocate (IMCA) service and only 53% (n = 19) were aware that the Act currently does not cover patients who fall in the ‘Bournewood gap’.

Clinical Implications

Learning disability psychiatrists are still not conversant with significant parts of the Act and this raises questions about the adequacy of the training delivered. Implementing the Act should improve patient care but will have implications for the workload of professionals.
New Ways not working? Psychiatrists' attitudes
Authors: Dale Jenny , Milner Gabrielle
Published: May 2009

Aims and Method

A questionnaire survey of general adult psychiatric consultants and specialist registrars in the West Midlands was conducted to examine attitudes towards New Ways of Working (NWW) for psychiatrists; these were measured using a 5-point Likert scale. Participants were also asked about their own experiences of NWW. the data were analysed using Mann–Whitney U-test.

Results

The response rate was 31.2%. Attitudes were generally negative, particularly regarding the effect on patient care, the erosion of the professional role of the consultant and effect on quality of work life. the attitudes of those who did not have any direct experience of working to the NWW models were more negative than those who had direct experience of NWW.

Clinical Implications

There are significant concerns about NWW among consultants and specialist registrars. There is a need for further debate and research with regard to the proposals.
Effect of brief motivational interviewing on stigmatised attitudes towards mental illness
Authors: Luty Jason , Umoh Okon , Nuamah Francis
Published: May 2009

Aims and Method

Stigmatised attitudes among the general public towards people with mental illness are one of the main factors delaying such people from seeking treatment, hindering their recovery and rehabilitation. Our aim was to devise a simple motivational interviewing technique to reduce stigmatised attitudes towards people with schizophrenia and substance misuse. We conducted a randomised paired-design trial of 100 adults subjected to a 10 min motivational interview to reduce their stigmatised attitudes; we used the Attitudes to Mental Illness Questionnaire (AMIQ) to measure the effect of the various procedures on stigmatised attitudes.

Results

A small improvement in stigma scores was observed in attitudes towards people with alcoholism but not towards those with schizophrenia.

Clinical Implications

A brief intervention involving motivational interviewing can be used to challenge the stigma of mental disorders.
Changes to the Mental Health and Mental Capacity Acts: implications for patients and professionals
Authors: Hall Ian , Ali Afia
Published: May 2009

The new Mental Health Act 2007 for England and Wales has introduced substantial amendments to the 1983 Mental Health Act and has also amended the Mental Capacity Act 2005. Most provisions came into effect in November 2008. the introduction of supervised community treatment, changes to professional roles such as the role of ‘responsible clinician’, and the introduction of deprivation of liberty safeguards in the Mental Capacity Act are discussed. Many of the new safeguards in the Act are welcomed by clinicians and service user groups. However, other changes are more controversial and could potentially lead to an increase in the work load of clinicians.
The Early Reception of Neapolitan Partimento Theory in France
Authors: Cafiero Rosa
Published: May 2009

The tradition of the Neapolitan school of composition (in which the partimento and its teaching techniques played a significant role) had a major influence on musical training in Paris from the second half of the eighteenth century through the first half of the nineteenth century. This article focuses first on some significant witnesses of this era (Fedele Fenaroli and Emanuele Imbimbo, who followed the school of Francesco Durante) and then on an interpretation of the traditionally nonverbal rules of partimenti proposed by François-Joseph Fétis.
Partimenti in the Age of Romanticism
Authors: Stella Gaetano
Published: May 2009

The teaching of music composition in Italy during the nineteenth century continued to make great use of partimenti. But during the course of the century, partimenti gradually lost their importance as guides to improvisation, transforming instead into blueprints for a written-out practice. Prominent musicians and teachers like Pietro Raimondi, Pietro Platania, and Raimondo Boucheron tried to merge the partimento tradition with the harmonic and formal innovations of their own era. Raimondi and Platania, significant exponents of the late Neapolitan school of composition, searched for innovation from within their own tradition. Boucheron, in Milan, deeply influenced by French and German theorists, used partimenti as a medium through which he could introduce elements of Romantic harmony. The partimento lessons of all three display not only a musical sophistication that merits our attention today, but also an insider's perspective on issues in nineteenth-century Italian composition.
Regulation of leg size and shape by the Dachsous/Fat signalling pathway during regeneration
Authors: Bando Tetsuya , Mito Taro , Maeda Yuko , Nakamura Taro , Ito Fumiaki , Watanabe Takahito , Ohuchi Hideyo , Noji Sumihare
Published: May 2009

An amputated cricket leg regenerates all missing parts with normal size and shape, indicating that regenerating blastemal cells are aware of both their position and the normal size of the leg. However, the molecular mechanisms regulating this process remain elusive. Here, we use a cricket model to show that the Dachsous/Fat (Ds/Ft) signalling pathway is essential for leg regeneration. We found that knockdown of ft or dstranscripts by regeneration-dependent RNA interference (rdRNAi) suppressed proliferation of the regenerating cells along the proximodistal (PD) axis concomitantly with remodelling of the pre-existing stump, making the regenerated legs shorter than normal. By contrast, knockdown of the expanded (ex) or Merlin (Mer) transcripts induced over-proliferation of the regenerating cells, making the regenerated legs longer. These results are consistent with those obtained using rdRNAi during intercalary regeneration induced by leg transplantation. We present a model to explain our results in which the steepness of the Ds/Ft gradient controls growth along the PD axis of the regenerating leg.
Processing bodies are not required for mammalian nonsense-mediated mRNA decay
Authors: Stalder Lukas , Mühlemann Oliver
Published: May 2009

Nonsense-mediated mRNA decay (NMD) is a eukaryotic quality-control mechanism that recognizes and degrades mRNAs with premature termination codons (PTCs). In yeast, PTC-containing mRNAs are targeted to processing bodies (P-bodies), and yeast strains expressing an ATPase defective Upf1p mutant accumulate P-bodies. Here we show that in human cells, an ATPase-deficient UPF1 mutant and a fraction of UPF2 and UPF3b accumulate in cytoplasmic foci that co-localize with P-bodies. Depletion of the P-body component Ge-1, which prevents formation of microscopically detectable P-bodies, also impairs the localization of mutant UPF1, UPF2, and UPF3b in cytoplasmic foci. However, the accumulation of the ATPase-deficient UPF1 mutant in P-bodies is independent of UPF2, UPF3b, or SMG1, and the ATPase-deficient UPF1 mutant can localize into the P-bodies independent of its phosphorylation status. Most importantly, disruption of P-bodies by depletion of Ge-1 affects neither the mRNA levels of PTC-containing reporter genes nor endogenous NMD substrates. Consistent with the recently reported decapping-independent SMG6-mediated endonucleolytic decay of human nonsense mRNAs, our results imply that microscopically detectable P-bodies are not required for mammalian NMD.
Mediating wars and conflicts: North African TV audiences in the UK and the changing security landscape
Authors: Miladi Noureddine
Published: May 2009

This article examines television audiences' perceptions of the war on terrorism and the war on Iraq coverage by western as well as Arab media. It looks at how bilingual North African viewers in the United Kingdom perceive news reporting and what issues they raise vis--vis the repercussions
of mediating the war on their everyday existence, hence on social change in this country. Informed by sixteen interviews and family discussions among North African families in London, and the influential theoretical discussion offered by Edward Said's Orientalism, Fukuyama's end of history
and others, this work seeks to find out the extent to which the media can be seen as agents of social control or social change? To what extent can media messages play a role in social stability or instability? What role can the news coverage audiences get on their television screens via satellite
or terrestrial services contribute to their integration or alienation in the society they live in?

This study reveals that there is a changing perception of people's identity, which has been the result of a perceived biased coverage of their causes and the British government's unjust foreign
policy in various parts of the Arab and Muslim world. Meanings of Britishness and the notion of belonging have become to be questioned among some of the respondents. Even those holding British citizenship feel they are becoming more and more second-class citizens, excluded and segregated against.
Also, the lack of trust and perception of bias vis--vis western media highlights my respondents' changing loyalty towards Arab satellite TV. Arab television channels headed by Al-Jazeera have been seen as sources of more accurate information with which Arab audiences wish to identify.

This
article also argues that the issues raised here by the media's war coverage will have long-term negative repercussions on this North African minority, as well as British society at large. Social change will be characterized by the possible exclusion of Arab and Muslim communities instead of
including them in the wider British society. The sense of security, which is salient in people's discussions, will probably dominate the feature of British public debates for years to come.
Framing of Arab countries on American news networks following the September 11 attacks
Authors: Ibrahim Dina
Published: May 2009

Through close reading and an ideological critique of network news reports this study investigates network television coverage of Arab countries during the two weeks following the September 11, 2001 attacks. The framing of countries as either enemies or friends of the United States of
America was a recurring aspect of national network coverage immediately following 9/11. The analysis reveals distinct differences between portrayals of Egypt, Jordan, Saudi Arabia and Iraq on network news after the attacks. The networks marginalized public opinion in Jordan, Saudi Arabia and
Egypt, while emphasizing American military and diplomatic relations with these countries. Iraq, however, was discussed primarily in the context of a future invasion.
Die Vergütung des Insolvenzverwalters bei Unternehmensfortführung
Authors: Keller Ulrich
Published: May 2009

Nachdem der Bundesgerichtshof sich im Beschluss vom 24.5.2005 grundlegend zur Vergütung des Insolvenzverwalters bei Unternehmensfortführung in der Insolvenz geäußert hatte, sind zu Einzelfragen der Vergütung einige weitere Entscheidungen ergangen, die teils allgemein beachtenswert sind, teils einzelfallbezogen betrachtet werden müssen. Der jetzt vorliegende Beschluss vom 16.10.2008 präzisiert die Anwendung des § 1 Abs. 2 Nr. 4 Satz 2 lit. b) InsVV und schränkt sie gleichzeitig gegenüber früherer Rechtsprechung ein. Diese Rechtsprechung bedarf kritischer Betrachtung.
Smart Graphics in Medical VisualizationSmart Graphics in Medizinischen Visualisierungen
Authors: Muehler Konrad , Preim Bernhard
Published: May 2009

Smart graphics techniques have a great potential in supporting medical treatment planning and education. In particular, the use of high-level knowledge and carefully selected default values reduces the interaction effort in exploring complex 3D data sets. Automatic viewpoint selection techniques may support the exploration of patient-specific 3D models. Camera movements and other animation techniques allow to emphasize important anatomic structures and convey complex spatial relations. Illustrative rendering techniques and smart visibility techniques enable the expressive visualization of nested surfaces which is important, e. g., to understand the location of a tumor inside an organ. General smart graphics techniques, however, have to be carefully adapted to support medical applications. In-depth discussions of usage scenarios, requirements, priorities and preferences are therefore a prerequisite for successful developments. In this paper, we give an overview of smart medical visualizations.