bluuebunny/crossref_metadata_2025 huggingface dataset:
Divergent and nonuniform gene expression patterns in mouse brain
Authors: Morris John A. , Royall Joshua J. , Bertagnolli Darren , Boe Andrew F. , Burnell Josh J. , Byrnes Emi J. , Copeland Cathy , Desta Tsega , Fischer Shanna R. , Goldy Jeff , Glattfelder Katie J. , Kidney Jolene M. , Lemon Tracy , Orta Geralyn J. , Parry Sheana E. , Pathak Sayan D. , Pearson Owen C. , Reding Melissa , Shapouri Sheila , Smith Kimberly A. , Soden Chad , Solan Beth M. , Weller John , Takahashi Joseph S. , Overly Caroline C. , Lein Ed S. , Hawrylycz Michael J. , Hohmann John G. , Jones Allan R.
Published: October 2010

Considerable progress has been made in understanding variations in gene sequence and expression level associated with phenotype, yet how genetic diversity translates into complex phenotypic differences remains poorly understood. Here, we examine the relationship between genetic background and spatial patterns of gene expression across seven strains of mice, providing the most extensive cellular-resolution comparative analysis of gene expression in the mammalian brain to date. Using comprehensive brainwide anatomic coverage (more than 200 brain regions), we applied in situ hybridization to analyze the spatial expression patterns of 49 genes encoding well-known pharmaceutical drug targets. Remarkably, over 50% of the genes examined showed interstrain expression variation. In addition, the variability was nonuniformly distributed across strain and neuroanatomic region, suggesting certain organizing principles. First, the degree of expression variance among strains mirrors genealogic relationships. Second, expression pattern differences were concentrated in higher-order brain regions such as the cortex and hippocampus. Divergence in gene expression patterns across the brain could contribute significantly to variations in behavior and responses to neuroactive drugs in laboratory mouse strains and may help to explain individual differences in human responsiveness to neuroactive drugs.
Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis
Authors: Everaerts Wouter , Zhen Xiaoguang , Ghosh Debapriya , Vriens Joris , Gevaert Thomas , Gilbert James P. , Hayward Neil J. , McNamara Colleen R. , Xue Fenqin , Moran Magdalene M. , Strassmaier Timothy , Uykal Eda , Owsianik Grzegorz , Vennekens Rudi , De Ridder Dirk , Nilius Bernd , Fanger Christopher M. , Voets Thomas
Published: October 2010

Reduced functional bladder capacity and concomitant increased micturition frequency (pollakisuria) are common lower urinary tract symptoms associated with conditions such as cystitis, prostatic hyperplasia, neurological disease, and overactive bladder syndrome. These symptoms can profoundly affect the quality of life of afflicted individuals, but available pharmacological treatments are often unsatisfactory. Recent work has demonstrated that the cation channel TRPV4 is highly expressed in urothelial cells and plays a role in sensing the normal filling state of the bladder. In this article, we show that the development of cystitis-induced bladder dysfunction is strongly impaired in

Trpv4
−/−

mice. Moreover, we describe HC-067047, a previously uncharacterized, potent, and selective TRPV4 antagonist that increases functional bladder capacity and reduces micturition frequency in WT mice and rats with cystitis. HC-067047 did not affect bladder function in

Trpv4
−/−

mice, demonstrating that its in vivo effects are on target. These results indicate that TRPV4 antagonists may provide a promising means of treating bladder dysfunction.
Mucosal host immune response predicts the severity and duration of herpes simplex virus-2 genital tract shedding episodes
Authors: Schiffer Joshua T. , Abu-Raddad Laith , Mark Karen E. , Zhu Jia , Selke Stacy , Koelle David M. , Wald Anna , Corey Lawrence
Published: October 2010

Herpes simplex virus-2 (HSV-2) shedding episodes in humans vary markedly in duration and virologic titer within an infected person over time, an observation that is unexplained. To evaluate whether host or virological factors more closely accounted for this variability, we combined measures of viral replication and CD8+lymphocyte density in genital biopsies, with a stochastic mathematical model of HSV-2 infection. Model simulations reproduced quantities of virus and duration of shedding detected in 1,003 episodes among 386 persons. In the simulations, local CD8+lymphocyte density in the mucosa at episode onset predicted peak HSV DNA copy number and whether genital lesions or subclinical shedding occurred. High density of CD8+T cells in the mucosa correlated with decreased infected cell lifespan and fewer infected epithelial cells before episode clearance. If infected cell lifespan increased by 15 min because of CD8+lymphocyte decay, then there was potential for a thousandfold increase in the number of infected cells. The model suggests that the rate of containment of infected cells by the peripheral mucosal immune system is the major driver of duration and severity of HSV-2 reactivation in the immunocompetent host.
3-Ketoacyl thiolase delays aging ofCaenorhabditis elegansand is required for lifespan extension mediated bysir-2.1
Authors: Berdichevsky Alina , Nedelcu Simona , Boulias Konstantinos , Bishop Nicholas A. , Guarente Leonard , Horvitz H. Robert
Published: October 2010

Studies of long-livedCaenorhabditis elegansmutants have identified several genes that function to limit lifespan, i.e., loss-of-function mutations in these genes promote longevity. By contrast, little is known about genes that normally act to delay aging and that when mutated cause premature aging (progeria). To seek such genes, we performed a genetic screen forC. elegansmutants that age prematurely. We found that loss-of-function mutations of the ketoacyl thiolase genekat-1result in an increased accumulation of the lipofuscin-like fluorescent aging pigment, shortened lifespan, early behavioral decline, and other abnormalities characteristic of premature aging. These findings suggest thatkat-1acts to delayC. elegansaging.kat-1encodes a conserved metabolic enzyme that catalyzes the last step of fatty acid oxidation and was previously shown to regulate fat accumulation in worms. We observed thatkat-1is required for the extension of lifespan and enhanced thermotolerance mediated by extra copies of the deacetylase genesir-2.1.kat-1acts independently of other known pathways that affect longevity. Our findings suggest that defects in fatty acid oxidation can limit lifespan and accelerate aging inC. elegansand thatkat-1-mediated fatty acid oxidation is crucial for overexpressedsir-2.1to delay aging.
CLOCK and BMAL1 regulate
MyoD
and are necessary for maintenance of skeletal muscle phenotype and function
Authors: Andrews Jessica L. , Zhang Xiping , McCarthy John J. , McDearmon Erin L. , Hornberger Troy A. , Russell Brenda , Campbell Kenneth S. , Arbogast Sandrine , Reid Michael B. , Walker John R. , Hogenesch John B. , Takahashi Joseph S. , Esser Karyn A.
Published: October 2010

MyoD
, a master regulator of myogenesis, exhibits a circadian rhythm in its mRNA and protein levels, suggesting a possible role in the daily maintenance of muscle phenotype and function. We report that
MyoD
is a direct target of the circadian transcriptional activators CLOCK and BMAL1, which bind in a rhythmic manner to the core enhancer of the
MyoD
promoter. Skeletal muscle of
Clock

Δ19

and

Bmal1
−/−

mutant mice exhibited ∼30% reductions in normalized maximal force. A similar reduction in force was observed at the single-fiber level. Electron microscopy (EM) showed that the myofilament architecture was disrupted in skeletal muscle of
Clock

Δ19

,

Bmal1
−/−

, and

MyoD
−/−

mice. The alteration in myofilament organization was associated with decreased expression of actin, myosins, titin, and several
MyoD
target genes. EM analysis also demonstrated that muscle from both
Clock

Δ19

and

Bmal1
−/−

mice had a 40% reduction in mitochondrial volume. The remaining mitochondria in these mutant mice displayed aberrant morphology and increased uncoupling of respiration. This mitochondrial pathology was not seen in muscle of

MyoD
−/−

mice. We suggest that altered expression of both
Pgc-1α
and
Pgc-1β
in
Clock

Δ19

and

Bmal1
−/−

mice may underlie this pathology. Taken together, our results demonstrate that disruption of CLOCK or BMAL1 leads to structural and functional alterations at the cellular level in skeletal muscle. The identification of
MyoD
as a clock-controlled gene provides a mechanism by which the circadian clock may generate a muscle-specific circadian transcriptome in an adaptive role for the daily maintenance of adult skeletal muscle.
The association between reality‐based beliefs and indirectly experienced traumatization
Authors: Shiri Shimon , Wexler Isaiah D. , Schwartz Isabella , Kadari Michal , Kreitler Shulamith
Published: October 2010

R The purpose of the study was to examine the association between belief types and the magnitude of indirect traumatization. Specific types of beliefs were defined in terms of the cognitive orientation theory, which is a cognitive‐motivational approach to the understanding, predicting, and changing of behaviors. Belief types that were analyzed included beliefs about self, general beliefs, beliefs about norms, and goal beliefs as they relate to personal growth. Study participants included 38 rescuers (body handlers), 37 nurses, and 31 rehabilitation workers who treated injured civilians that had been exposed to politically motivated violence. The Cognitive Orientation for Posttraumatic Growth Scale was used to assess beliefs about personal growth. The Revised Posttraumatic Stress Disorder Inventory was administered to evaluate indirect traumatization. The results indicate that three of the four belief types related to personal growth were associated with the level of indirect traumatization. Optimistic and positive beliefs about self and general beliefs were associated with a lower level of indirect traumatization symptomatology, suggesting that these types of beliefs may counteract indirect traumatization. On the other hand, stronger goal beliefs were associated with greater indirect traumatization. The negative association between positive goal beliefs and indirect trauma may be related to the gap the individual perceives between the hoped‐for ideals and the trauma‐stricken reality. These results indicate the importance of cognitive beliefs and their possible role in determining the response to indirect traumatization.
PICMI: mapping point mutations on genomes
Authors: Le Pera Loredana , Marcatili Paolo , Tramontano Anna
Published: October 2010

Motivation: Several international collaborations and local projects are producing extensive catalogues of genomic variations that are supplementing existing collections such as the OMIM catalogue. The flood of this type of data will keep increasing and, especially, it will be relevant to a wider user base, including not only molecular biologists, geneticists and bioinformaticians, but also clinical researchers. Mapping the observed variations, sometimes only described at the amino acid level, on a genome, identifying whether they affect a gene and—if so—whether they also affect different isoforms of the same gene, is a time consuming and often frustrating task.

Results: The PICMI server is an easy to use tool for quickly mapping one or more amino acid or nucleotide variations on a genome and its products, including alternatively spliced isoforms.

Availability: The server is available at www.biocomputing.it/picmi

Contact:  anna.tramontano@uniromal.it
Investigating the correlations among the chemical structures, bioactivity profiles and molecular targets of small molecules
Authors: Cheng Tiejun , Wang Yanli , Bryant Stephen H.
Published: October 2010

Motivation: Most of the previous data mining studies based on the NCI-60 dataset, due to its intrinsic cell-based nature, can hardly provide insights into the molecular targets for screened compounds. On the other hand, the abundant information of the compound–target associations in PubChem can offer extensive experimental evidence of molecular targets for tested compounds. Therefore, by taking advantages of the data from both public repositories, one may investigate the correlations between the bioactivity profiles of small molecules from the NCI-60 dataset (cellular level) and their patterns of interactions with relevant protein targets from PubChem (molecular level) simultaneously.

Results: We investigated a set of 37 small molecules by providing links among their bioactivity profiles, protein targets and chemical structures. Hierarchical clustering of compounds was carried out based on their bioactivity profiles. We found that compounds were clustered into groups with similar mode of actions, which strongly correlated with chemical structures. Furthermore, we observed that compounds similar in bioactivity profiles also shared similar patterns of interactions with relevant protein targets, especially when chemical structures were related. The current work presents a new strategy for combining and data mining the NCI-60 dataset and PubChem. This analysis shows that bioactivity profile comparison can provide insights into the mode of actions at the molecular level, thus will facilitate the knowledge-based discovery of novel compounds with desired pharmacological properties.

Availability: The bioactivity profiling data and the target annotation information are publicly available in the PubChem BioAssay database (ftp://ftp.ncbi.nlm.nih.gov/pubchem/Bioassay/).

Contact:  ywang@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov

Supplementary information:  Supplementary data are available at Bioinformatics online.
Graph-based Word Sense Disambiguation of biomedical documents
Authors: Agirre Eneko , Soroa Aitor , Stevenson Mark
Published: October 2010

Motivation: Word Sense Disambiguation (WSD), automatically identifying the meaning of ambiguous words in context, is an important stage of text processing. This article presents a graph-based approach to WSD in the biomedical domain. The method is unsupervised and does not require any labeled training data. It makes use of knowledge from the Unified Medical Language System (UMLS) Metathesaurus which is represented as a graph. A state-of-the-art algorithm, Personalized PageRank, is used to perform WSD.

Results: When evaluated on the NLM-WSD dataset, the algorithm outperforms other methods that rely on the UMLS Metathesaurus alone.

Availability: The WSD system is open source licensed and available from http://ixa2.si.ehu.es/ukb/. The UMLS, MetaMap program and NLM-WSD corpus are available from the National Library of Medicine http://www.nlm.nih.gov/research/umls/, http://mmtx.nlm.nih.gov and http://wsd.nlm.nih.gov. Software to convert the NLM-WSD corpus into a format that can be used by our WSD system is available from http://www.dcs.shef.ac.uk/∼marks/biomedical_wsd under open source license.

Contact:  m.stevenson@dcs.shef.ac.uk
GPCRRD: G protein-coupled receptor spatial restraint database for 3D structure modeling and function annotation
Authors: Zhang Jian , Zhang Yang
Published: October 2010

Summary: G protein-coupled receptors (GPCRs) comprise the largest family of integral membrane proteins. They are the most important class of drug targets. While there exist crystal structures for only a very few GPCR sequences, numerous experiments have been performed on GPCRs to identify the critical residues and motifs. GPCRRD database is designed to systematically collect all experimental restraints (including residue orientation, contact and distance maps) available from the literature and primary GPCR resources using an automated text mining algorithm combined with manual validation, with the purpose of assisting GPCR 3D structure modeling and function annotation. The current dataset contains thousands of spatial restraints from mutagenesis, disulfide mapping distances, electron cryo-microscopy and Fourier-transform infrared spectroscopy experiments.

Availability:  http://zhanglab.ccmb.med.umich.edu/GPCRRD/

Contact:  zhng@umich.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
A classification model for G-to-A hypermutation in hepatitis B virus ultra-deep pyrosequencing reads
Authors: Reuman Elizabeth C. , Margeridon-Thermet Severine , Caudill Harrison B. , Liu Tommy , Borroto-Esoda Katyna , Svarovskaia Evguenia S. , Holmes Susan P. , Shafer Robert W.
Published: October 2010

Motivation: G → A hypermutation is an innate antiviral defense mechanism, mediated by host enzymes, which leads to the mutational impairment of viruses. Sensitive and specific identification of host-mediated G → A hypermutation is a novel sequence analysis challenge, particularly for viral deep sequencing studies. For example, two of the most common hepatitis B virus (HBV) reverse transcriptase (RT) drug-resistance mutations, A181T and M204I, arise from G → A changes and are routinely detected as low-abundance variants in nearly all HBV deep sequencing samples.

Results: We developed a classification model using measures of G → A excess and predicted indicators of lethal mutation and applied this model to 325 920 unique deep sequencing reads from plasma virus samples from 45 drug treatment-naïve HBV-infected individuals. The 2.9% of sequence reads that were classified as hypermutated by our model included most of the reads with A181T and/or M204I, indicating the usefulness of this model for distinguishing viral adaptive changes from host-mediated viral editing.

Availability: Source code and sequence data are available at http://hivdb.stanford.edu/pages/resources.html.

Contact:  ereuman@stanfordalumni.org

Supplementary information:  Supplementary data are available at Bioinformatics online.
IgA antibodies to Chlamydia trachomatis and metabolic syndrome
Authors: Sehnem Luciele , Bodanese Luiz Carlos , Repetto Giuseppe , Staub Henrique L.
Published: October 2010

Chlamydia pneumoniae may trigger atherogenesis. Chlamydia trachomatis (CT) can also induce endothelial activation. However, its role in metabolic syndrome (METS), a proatherogenic entity, has remained unexplored. In this study the frequencies of IgA and IgG anti‐CT antibodies were evaluated by immunoenzymatic assay in METS patients and healthy controls. The survey included 238 individuals (148 with METS). The mean age was 59.7 years. IgA anti‐CT antibodies were found significantly more frequently in METS patients (16.9%) than in controls (5.6%) (P= 0.015). The role of such IgA response in METS should be further investigated.
Differentiating new cannabis use from residual urinary cannabinoid excretion in chronic, daily cannabis users
Authors: Schwilke Eugene W. , Gullberg Rod G. , Darwin William D. , Chiang C. Nora , Cadet Jean Lud , Gorelick David A. , Pope Harrison G. , Huestis Marilyn A.
Published: October 2010

Aims To develop and validate empirically a mathematical model for identifying new cannabis use in chronic, daily cannabis smokers.

Design Models were based on urinary creatinine‐normalized (CN) cannabinoid excretion in chronic cannabis smokers.

Setting For model development, participants resided on a secure research unit for 30 days. For model validation, participants were abstinent with daily observed urine specimens for 28 days.

Participants A total of 48 (model development) and 67 (model validation) daily cannabis smokers were recruited.

Measurements All voided urine was collected and analyzed for 11‐nor‐9‐carboxy‐Δ9‐tetrahydrocannabinol (THCCOOH) by gas chromatography‐mass spectrometry (GCMS; limit of quantification 2.5 ng/ml) and creatinine (mg/ml). Urine THCCOOH was normalized to creatinine, yielding ng/mg CN‐THCCOOH concentrations. Urine concentration ratios were determined from 123 513 specimen pairs collected 2–30 days apart.

Findings A mono‐exponential model (with two parameters, initial urine specimen CN‐THCCOOH concentration and time between specimens), based on the Marquardt–Levenberg algorithm, provided a reasonable data fit. Prediction intervals with varying probability levels (80, 90, 95, 99%) provide upper ratio limits for each urine specimen pair. Ratios above these limits suggest cannabis re‐use. Disproportionate numbers of ratios were higher than expected for some participants, prompting development of two additional rules that avoid misidentification of re‐use in participants with unusual CN‐THCCOOH excretion patterns.

Conclusions For the first time, a validated model is available to aid in the differentiation of new cannabis use from residual creatinine‐normalized 11‐nor‐9‐carboxy‐Δ9‐tetrahydrocannabinol (CN‐THCCOOH) excretion in chronic, daily cannabis users. These models are valuable for clinicians, toxicologists and drug treatment staff and work‐place, military and criminal justice drug‐testing programs.
The effects of itopride on oesophageal motility and lower oesophageal sphincter function in man
Authors: Scarpellini E. , Vos R. , Blondeau K. , Boecxstaens V. , Farré R. , Gasbarrini A. , Tack J.
Published: October 2010

Aliment Pharmacol Ther 2011; 33: 99–105

Background  Itopride is a new prokinetic agent that combines antidopaminergic and cholinesterase inhibitory actions. Previous studies suggested that itopride improves heartburn in functional dyspepsia, and decreases oesophageal acid exposure in gastro‐oesophageal reflux disease. It remains unclear whether this effect is due to effects of itopride on the lower oesophageal sphincter (LES).

Aims  To study the effects of itopride on fasting and postprandial LES function in healthy subjects.

Methods  Twelve healthy volunteers (five men; 32.6 ± 2.0 years) underwent three oesophageal sleeve manometry studies after 3 days premedication with itopride 50 mg, itopride 100 mg or placebo t.d.s. Drug was administered after 30 min and a standardized meal was administered after 90 min, with measurements continuing to 120 min postprandially. Throughout the study, 10 wet swallows were administered at 30‐min intervals, and gastrointestinal symptoms were scored on 100 mm visual analogue scales at 15‐min intervals.

Results  Lower oesophageal sphincter resting pressures, swallow‐induced relaxations and the amplitude or duration of peristaltic contractions were not altered by both doses of itopride, at all time points. Itopride pre‐treatment inhibited the meal‐induced rise of transient LES relaxations (TLESRs).

Conclusions  Itopride inhibits TLESRs without significantly affecting oesophageal peristaltic function or LES pressure. These observations support further studies with itopride in gastro‐oesophageal reflux disease.
Risk stratification of normotensive patients with acute symptomatic pulmonary embolism
Authors: Jiménez David , Aujesky Drahomir , Yusen Roger D.
Published: October 2010

Treatment guidelines recommend strong consideration of thrombolysis in patients with acute symptomatic pulmonary embolism (PE) that present with arterial hypotension or shock because of the high risk of death in this setting. For haemodynamically stable patients with PE, the categorization of risk for subgroups may assist with decision‐making regarding PE therapy. Clinical models [e.g. Pulmonary Embolism Severity Index (PESI)] may accurately identify those at low risk of overall death in the first 3 months after the diagnosis of PE, and such patients might benefit from an abbreviated hospital stay or outpatient therapy. Though some evidence suggests that a subset of high‐risk normotensive patients with PE may have a reasonable risk to benefit ratio for thrombolytic therapy, single markers of right ventricular dysfunction (e.g. echocardiography, spiral computed tomography, or brain natriuretic peptide testing) and myocardial injury (e.g. cardiac troponin T or I testing) have an insufficient positive predictive value for PE‐specific mortality to drive decision‐making toward such therapy. Recommendations for outpatient treatment or thrombolytic therapy for patients with PE necessitate further development of prognostic models and conduct of clinical trials that assess various treatment strategies.
Square‐mesh codend length and selectivity in southeastern Australian stow nets
Authors: BROADHURST M. K. , MILLAR R. B.
Published: October 2010

Abstract  The relationship between the amount of square mesh in codends and selectivity was investigated for an Australian penaeid stow‐net fishery. Three lengths (3, 2 and 1 m) of square‐mesh codend made from 27‐mm mesh hung on the bar were alternately tested with a conventional 34‐mm diamond‐mesh design during two covered‐codend experiments. Compared with the conventional codend, the square‐mesh configurations incrementally selected school prawns, Metapenaeus macleayi (Haswell) across narrower selection ranges (SR) and mostly at greater sizes at 50% retention (L50), while retaining fewer fish. Irrespective of the mesh configuration or square‐mesh codend length, there were significant differences between experiments (attributed to water flow) and impacts of catch weight on the selectivity of school prawns. Both variables had a negative relationship with L50, while water flow similarly affected SR. This study reaffirms the utility of square‐mesh codends as a key input control for managing the selectivity of penaeid‐catching gears.
Changes in life history and ecological characteristics of coral reef fish catch composition with increasing fishery management
Authors: MCCLANAHAN T. R. , HICKS C. C.
Published: October 2010

Abstract  Length, life history and ecological characteristics of landed fish communities were studied over a 10‐year period to test theories of fishing disturbance during a time of increased gear and closure management in heavily utilised fisheries. It was predicted that with greater management restrictions: (1) the earliest and fastest responses in the fishery will be seen in those species with faster turnovers, or relatively lower vulnerabilities to fishing; (2) the fishery would transition to a landed catch with higher mean trophic levels, and greater mean body lengths. In addition, the removal of a non‐selective, small‐mesh seine nets should benefit the catch of gears that previously had the greatest species selectivity overlap with the seine net. Many predictions were supported, although maximum lengths and lengths at maturity responded more rapidly than anticipated. The response to eliminating the non‐selective seine net was a more rapid increase in sizes caught by gears with a larger overlap in size (hook and lines) than species selectivity (gill nets). The simultaneous comparison of management systems over time indicates that open‐access fishing grounds can benefit from restrictions imposed in adjacent fishing grounds. The study indicated that multi‐species coral reef fisheries management objectives of maximising yields, as well as maintaining the fish community’s life‐history diversity, require management trade‐offs that balance local socio‐economic and biodiversity needs.
Expression of aberrantly glycosylated Mucin‐1 in ovarian cancer
Authors: Van Elssen Catharina H M J , Frings Peter W H , Bot Freek J , Van de Vijver Koen K , Huls Mariska B , Meek Bob , Hupperets Pierre , Germeraad Wilfred T V , Bos Gerard M J
Published: October 2010

Van Elssen C H M J, Frings P W H, Bot F J, Van de Vijver K K, Huls M B, Meek B, Hupperets P, Germeraad W T V & Bos G M J (2010) Histopathology57, 597–606 Expression of aberrantly glycosylated Mucin‐1 in ovarian cancer

Aims:  Mucin 1 (MUC1) is an important tumour‐associated antigen (TAA), both overexpressed and aberrantly glycosylated in adenocarcinomas. The aim of this study was to examine the MUC1‐glycosylation status of primary ovarian adenocarcinomas and metastatic lesions.

Methods and results:  Paraffin‐embedded tissue sections of 37 primary ovarian adenocarcinomas representing all histotypes (22 serous, five mucinous, two clear‐cell, eight endometrioid), four serous borderline tumours with intraepithelial carcinoma, seven sections of ovarian endometriosis and 13 metastatic lesions were analysed by immunohistochemistry. Non‐neoplastic ovarian surface epithelium and serous cystadenomas were used as controls. All epithelia expressed MUC1 protein. Of primary tumours, 76% expressed the differentiation‐dependent glycoform and 84% the cancer‐associated glycoform (Tn/Sialyl‐Tn‐epitopes). In metastatic lesions this was 77% and 85%, respectively. Notably, in 57% of ovarian endometriosis and 75% of intraepithelial lesions, the cancer‐associated MUC1 epitopes were expressed, whereas normal ovarian surface epithelium and serous cystadenomas did not express these epitopes.

Conclusions:  The underglycosylated MUC1 epitopes are expressed by all histotypes of primary ovarian adenocarcinomas, by the vast majority of metastatic lesions and by possible ovarian cancer precursor lesions, but not by normal ovarian tissue. These results indicate that MUC1‐associated Tn/STn‐epitopes are important targets for immunotherapy and diagnostic imaging in ovarian cancer patients.
Lack of RUNX3 inactivation in columnar cell lesions of breast
Authors: Subramaniam Manish Mani , Chan Jason Yongsheng , Omar Mohd Feroz Mohd , Ito Kosei , Ito Yoshiaki , Yeoh Khay Guan , Salto‐Tellez Manuel , Putti Thomas Choudary
Published: October 2010

Subramaniam M M, Chan J Y, Omar M F M, Ito K, Ito Y, Yeoh K G, Salto‐Tellez M & Putti T C (2010) Histopathology57, 555–563 Lack of RUNX3 inactivation in columnar cell lesions of breast

Aims:  Ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) exhibit frequent RUNX3 inactivation by promoter hypermethylation and protein mislocalization. The aim of this study was to analyse columnar cell lesions (CCLs) to further characterize RUNX3 involvement in breast carcinogenesis.

Methods and results:  RUNX3 expression and methylation was analysed by immunohistochemistry and methylation‐specific polymerase chain reaction (PCR), respectively, in 75 CCLs. Our previously reported DCIS and IDC data were also included. Consistent with terminal duct lobular units (TDLUs) (73 of 75, 97%), active nuclear RUNX3 protein was observed in 73 of 75 (97%) CCLs [columnar cell change, 46 of 48 (96%); columnar cell hyperplasia, 12 of 12 (100%) and flat epithelial atypia, 15 of 15 (100%). In contrast to matched TDLUs from cancer specimens [four of 40 (10%)] and CCLs, significantly inactivated RUNX3 expression was detected in DCIS [17 of 20 (85%)] and IDC [18 of 20 (90%)] (all P < 0.001). RUNX3 methylation was more frequent in DCIS [15 of 20 (75%)] and IDC [16 of 20 (80%)] than CCLs [(none of 20 (0%)] and matched TDLUs [one of 10 (10%)] from cancer patients (all P < 0.001).

Conclusions:  RUNX3 inactivation occurs specifically in DCIS and IDC cells. In addition, RUNX3 inactivation may not be a common association between CCLs and breast carcinomas.
A large trophic quilt
Authors: Lewinsohn Thomas M.
Published: October 2010

image

[ Assembling a tropical plant‐herbivore web requires thousands of person‐hours of field sampling and rearing, and thousands more to mount, sort and when possible identify hundreds of different herbivorous species. The decision, early on, to organize a stable team of highly involved and committed parataxonomists [Y. Basset et al. (2000) Bioscience, 50, 899‐908], who attend to these massive routines, was as essential to the entire enterprise as the engagement of expert taxonomists to cover major groups of herbivorous insects. Image credit: New Guinea Binatang Research Center. ]

V. Novotny, S. E. Miller, L. Baje, S. Balagawi, Y. Basset, L. Cizek, K.J. Craft, F. Dem, R.A.I. Drew, J. Huclr, J. Leps, O.T. Lewis, R. Pokon, A.J.A. Stewart, G.A. Samuelson & G.D. Weiblen (2010) Guild‐specific patterns of species richness and host specialization in plant–herbivore food webs from a tropical forest. Journal of Animal Ecology, 79, 1193–1203.

Plants and invertebrate herbivores are major constituents of terrestrial food webs. Identifying component species and tracing their interactions in highly diverse communities are a monumental task. Novotny et al. 2010 present the first broad conspectus of herbivore–plant interactions in a forest in Papua New Guinea. In more than 15 years, nearly 7000 feeding links were traced between about 200 plants and 1500 insect herbivores. Although staggering, these figures might represent only 15% of the total herbivore richness and interaction diversity in that lowland forest. Standardized comparisons also showed distinctive specialization and diversification patterns in different feeding guilds, restricting the possibility of using any single guild as surrogate for the entire assemblage.
Viewpoint: Economic evaluation of package of care interventions employing clinical guidelines
Authors: Barasa Edwine W. , English Mike
Published: October 2010

Increasingly attention is shifting towards delivering essential packages of care, often based on clinical practice guidelines, as a means to improve maternal, child and newborn survival in low‐income settings. Cost effectiveness analysis (CEA), allied to the evaluation of less complex intervention, has become an increasingly important tool for priority setting. Arguably such analyses should be extended to inform decisions around the deployment of more complex interventions. In the discussion, we illustrate some of the challenges facing the extension of CEA to this area. We suggest that there are both practical and methodological challenges to overcome when conducting economic evaluation for packages of care interventions that incorporate clinical guidelines. Some might be overcome by developing specific guidance on approaches, for example clarity in identifying relevant costs. Some require consensus on methods. The greatest challenge, however, lies in how to incorporate, as measures of effectiveness, process measures of service quality. Questions on which measures to use, how multiple measures might be combined, how improvements in one area might be compared with those in another and what value is associated with improvement in health worker practices are yet to be answered.
Predictive diagnostic value of the tourniquet test for the diagnosis of dengue infection in adults
Authors: Mayxay Mayfong , Phetsouvanh Rattanaphone , Moore Catrin E , Chansamouth Vilada , Vongsouvath Manivanh , Sisouphone Syho , Vongphachanh Pankham , Thaojaikong Thaksinaporn , Thongpaseuth Soulignasack , Phongmany Simmaly , Keolouangkhot Valy , Strobel Michel , Newton Paul N.
Published: October 2010

Objective  To examine the accuracy of the admission tourniquet test in the diagnosis of dengue infection among Lao adults.

Methods  Prospective assessment of the predictive diagnostic value of the tourniquet test for the diagnosis of dengue infection, as defined by IgM, IgG and NS1 ELISAs (Panbio Ltd, Australia), among Lao adult inpatients with clinically suspected dengue infection.

Results  Of 234 patients with clinically suspected dengue infection on admission, 73% were serologically confirmed to have dengue, while 64 patients with negative dengue serology were diagnosed as having scrub typhus (39%), murine typhus (11%), undetermined typhus (12%), Japanese encephalitis virus (5%), undetermined flavivirus (5%) and typhoid fever (3%); 25% had no identifiable aetiology. The tourniquet test was positive in 29.1% (95% CI = 23.2–34.9%) of all patients and in 34.1% (95% CI = 27.0–41.2%) of dengue‐seropositive patients, in 32.7% (95% CI = 23.5–41.8) of those with dengue fever and in 36.4% (95% CI = 24.7–48.0) of those with dengue haemorrhagic fever. Interobserver agreement for the tourniquet test was 90.2% (95% CI = 86.4–94.0) (Kappa = 0.76). Using ELISAs as the diagnostic gold standard, the sensitivity of the tourniquet test was 33.5–34%; its specificity was 84–91%. The positive and negative predictive values were 85–90% and 32.5–34%, respectively.

Conclusions  The admission tourniquet test has low sensitivity and adds relatively little value to the diagnosis of dengue among Lao adult inpatients with suspected dengue. Although a positive tourniquet test suggests dengue and that treatment of alternative diagnoses may not be needed, a negative test result does not exclude dengue.
Ryanodine receptors selectively contribute to the formation of taste‐evoked calcium signals in mouse taste cells
Authors: Rebello Michelle R. , Medler Kathryn F.
Published: October 2010

The peripheral taste system uses multiple signaling pathways to transduce a stimulus into an output signal that activates afferent neurons. All of these signaling pathways depend on transient increases in intracellular calcium, but current understanding of these calcium signals is not well developed. Using molecular and physiological techniques, this study establishes that ryanodine receptors (RyRs), specifically isoform 1, are expressed in taste cells and that their physiological function differs among cell types employing different signaling pathways. RyR1 contributes to some taste‐evoked signals that rely on calcium release from internal stores but can also supplement the calcium signal that is initiated by opening voltage‐gated calcium channels. In taste cells expressing both signaling pathways, RyR1 contributes to the depolarization‐induced calcium signal but not to the calcium signal that depends on calcium release from stores. These data suggest that RyR1 is an important regulator of calcium signaling and that its physiological role in taste cells is dictated by the nature of the calcium signaling mechanisms expressed.
Diagnostic performance of chromoendoscopy and narrow band imaging for colonic neoplasms: a meta‐analysis
Authors: Kobayashi Y. , Hayashino Y. , Jackson J. L. , Takagaki N. , Hinotsu S. , Kawakami K.
Published: October 2010

Aim  We conducted a meta‐analysis to compare the diagnostic test performance of chromoendoscopy and narrow band imaging (NBI) for colonic neoplasms.

Method  MEDLINE, EMBASE and the Cochrane Library were searched (1966 to March 2009). Articles were included if: (i) chromoendoscopy or NBI was used, (ii) sensitivity and specificity were reported; (iii) absolute numbers of true‐positive, false‐positive, true‐negative and false‐negative results were provided or could be calculated; and (iv) pathology was used as the reference standard. Sensitivity and specificity were pooled using random effects model. Secondary analyses were conducted by limiting the studies in which magnifying endoscopy was used alone as a diagnostic modality, and polyp size and macroscopic appearance of lesions were not considered.

Results  Of 1342 screened articles, 27 met the inclusion criteria. Pooled sensitivity for chromoendoscopy and NBI was 0.94 (95% CI, 0.92–0.95) and 0.94 (0.91–0.97), and specificity was 0.82 (0.77–0.88) and 0.86 (0.83–0.89), respectively. There were no differences in sensitivity (P = 0.99) or specificity (P = 0.54) between the two methods. In the secondary analysis, pooled sensitivity for choromoendoscopy and NBI was 0.93 (95% CI, 0.90–0.97) and 0.96 (0.93–0.99) and specificity was 0.80 (0.73–0.87) and 0.85 (0.78–0.92). respectively. Overall, the pooled false‐negative rate was 0.057 (95% CI, 0.040–0.73) for chromoendoscopy and 0.057 (95% CI, 0.028–0.085) for NBI.

Conclusion  Chromoendoscopy and NBI had similar diagnostic test characteristics in the assessment of colonic neoplasms; however, the false‐negative rate for both methods of 5.7% is an unacceptably high rate and currently therefore, neither method is ready for general use.
Emotional Prosperity and the Stiglitz Commission
Authors: Oswald Andrew J.
Published: October 2010

This article argues — in line with the proposals of the recent Stiglitz Commission on the Measurement of Economic Performance and Social Progress — that we should now be measuring a nation's emotional prosperity rather than its economic prosperity (i.e. we ought to focus on the level of mental well‐being, not on the number of pounds in people's bank accounts). The article reviews recent ideas in this field. It also describes seven recent studies that, worryingly, suggest that emotional prosperity may be declining through time. For labour‐market specialists, a key question for future research is how much this downward trend can be traced back to increased pressures in working life. That question currently remains open.
Characterization of β‐adrenoceptor‐mediated relaxation signals in isolated pulmonary artery of Dahl salt‐sensitive hypertensive and normotensive rats
Authors: Ford C. A. , Mahajan P. , Tabrizchi R.
Published: October 2010

1 Relaxant responses to isoprenaline (ISO) were studied in the pulmonary arteries of normotensive and hypertensive Dahl salt‐sensitive rats. Rats were fed either a high‐salt (4.0%) or low‐salt (0.14%) diet for 5 weeks. Animals fed a high‐salt diet (167/123 ± 2/2 mmHg) had a significantly higher blood pressure compared to those fed a low‐salt diet (127/87 ± 2/2 mmHg).

2 Isoprenaline‐elicited relaxations were not significantly different in tissues from hypertensive compared to normotensive animals. Responses to ISO were significantly attenuated in denuded tissues and substantially more so in hypertensive compared to normotensive animals. While relaxant responses to ISO were resistant to inhibition byNω‐nitro‐l‐arginine methyl ester, indomethacin, glibenclamide or a combination of barium chloride and ouabain, they were inhibited by Rp‐cAMP, anandamide and acidic buffer. The inhibitory impact of anandamide and acidic buffer was significantly greater in tissues from hypertensivevs.normotensive rats.

3 The resting membrane potential (Em) of smooth muscle cells was −67.0 ± 0.7 mV (n = 43 cells) and −66.6 ± 0.8 mV (n = 55 cells) in pulmonary arteries from hypertensive and normotensive rats, respectively. Isoprenaline produced hyperpolarization ofEmwhich was significant in the blood vessels of hypertensive (−71.6 ± 0.8 mV;n = 29 cells) but not normotensive (−68.1 ± 0.7 mV;n = 49 cells) rats.

4 The endothelium plays a critical role in β‐adrenoceptor‐mediated relaxation but nitric oxide is not the mediator for the response. It is possible that the greater hyperpolarization caused by ISO in blood vessels from hypertensive compared to normotensive rats is mediated by activation of TASK‐1 channels.
Wintering Snowy OwlsBubo scandiacusintegrate plumage colour, behaviour and their environment to maximize efficacy of visual displays
Authors: BORTOLOTTI GARY R. , STOFFEL MARTEN J. , GALVÁN ISMAEL
Published: October 2010

For a comprehensive understanding of the evolution of animal signals, it is necessary to understand how the performance of visual displays is maximized to get the most possible attention from receivers. We assessed whether the white plumage of Snowy OwlsBubo scandiacusfunctioned as a social signal and, if so, how coloration and behavioural adaptations enhance signal efficacy. Signalling theory predicts that: (1) the colour properties of plumage should vary across the body, with the brightest parts being those involved in visual display performance; (2) specific displays calling attention to or enhancing detection or conspicuousness to conspecifics should be evident; and (3) location of the signallers should be such that signal efficacy is optimized. All three predictions were supported. The brightest areas of the plumage (particularly the face, throat and upper breast) were always unspotted, and white is particularly effective in open habitats characteristic of this species. The birds displayed a specific posture and orientated toward the sun preferentially on sunny days, and Owls with the whitest (least spotted) plumage displayed more and signalled more frequently from perches on the ground, where albedo from the snow may enhance the visual display. Snowy Owls integrate coloration, behaviour and environment through habitat selection to maximize the efficacy of their visual displays.
The Impact of Financial Reporting Quality on Debt Contracting: Evidence from Internal Control Weakness Reports
Authors: COSTELLO ANNA M. , WITTENBERG‐MOERMAN* REGINA
Published: October 2010

We examine the effect of financial reporting quality on the trade‐off between monitoring mechanisms used by lenders. We rely on Sarbanes‐Oxley internal control reports to measure financial reporting quality. We find that when a firm experiences a material internal control weakness, lenders decrease their use of financial covenants and financial‐ratio‐based performance pricing provisions and substitute them with alternatives, such as price and security protections and credit‐rating‐based performance pricing provisions. We also find that changes in debt contract design following internal control weaknesses are substantially different from those following restatements, where lenders impose tighter monitoring on managers’ actions, but do not decrease their use of financial statement numbers.
Altered aquaporin expression and role in apoptosis during hepatic stellate cell activation
Authors: Lakner Ashley M. , Walling Tracy L. , McKillop Iain H. , Schrum Laura W.
Published: October 2010

Background: Hepatic stellate cells (HSCs) are effector cells of hepatic fibrosis contributing to excessive collagen deposition and scar matrix formation. Sustained HSC activation leads to hepatic cirrhosis, a leading cause of liver‐related death. Reversal of hepatic fibrosis has been attributed to the induction of HSC apoptosis. Aquaporins (AQPs) are critical proteinacious channels that mediate cellular water loss during the initiation and progression of apoptosis.

Aims: This study examined AQP expression in quiescent and activated HSCs and determined the responsiveness to AQP‐dependent apoptosis.

Methods: Aquaporin gene and protein expressions in quiescent and activated HSCs were determined by reverse transcription polymerase chain reaction and Western blot analyses. AQP function was determined by cell swelling and apoptotic assays in the absence and presence of HgCl2, a non‐specific AQP inhibitor.

Results: In this study, we report that activated HSCs showed no detectable expression of AQP 1, 5, 8, 9 and 12 mRNAs but expression was observed in quiescent HSCs. Similarly, AQP 0, 1, 8 and 9 protein was not detected in activated HSCs but was measured in quiescent HSCs. Dual fluorescent immunohistochemistry confirmed that AQP expression is decreased in activated HSCs in a model of liver injury. Functional studies demonstrated that quiescent HSCs were highly susceptible to osmotic challenge and apoptotic stimulus, whereas activated HSCs were less responsive. Finally, apoptosis was abrogated by the inhibition of AQP‐dependent water movement.

Conclusions: These findings demonstrate that increased resistance to apoptosis in activated HSCs is due, at least in part, to the changes in AQP expression and function that occur following HSC activation.