bluuebunny/crossref_metadata_2025 huggingface dataset:
Systems biology approach to identify transcriptome reprogramming and candidate microRNA targets during the progression of polycystic kidney disease
Authors: Pandey Priyanka , Qin Shan , Ho Jacqueline , Zhou Jing , Kreidberg Jordan A
Published: April 2011

Background

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst formation throughout the kidney parenchyma. It is caused by mutations in either of two genes, PKD1 and PKD2. Mice that lack functional Pkd1 (Pkd1

-/-
), develop rapidly progressive cystic disease during embryogenesis, and serve as a model to study human ADPKD. Genome wide transcriptome reprogramming and the possible roles of micro-RNAs (miRNAs) that affect the initiation and progression of cyst formation in the Pkd1

-/-
have yet to be studied. miRNAs are small, regulatory non-coding RNAs, implicated in a wide spectrum of biological processes. Their expression levels are altered in several diseases including kidney cancer, diabetic nephropathy and PKD.

Results

We examined the molecular pathways that modulate renal cyst formation and growth in the Pkd1

-/-
model by performing global gene-expression profiling in embryonic kidneys at days 14.5 and 17.5. Gene Ontology and gene set enrichment analysis were used to identify overrepresented signaling pathways in Pkd1

-/-
kidneys. We found dysregulation of developmental, metabolic, and signaling pathways (e.g. Wnt, calcium, TGF-β and MAPK) in Pkd1

-/-
kidneys. Using a comparative transcriptomics approach, we determined similarities and differences with human ADPKD: ~50% overlap at the pathway level among the mis-regulated pathways was observed. By using computational approaches (TargetScan, miRanda, microT and miRDB), we then predicted miRNAs that were suggested to target the differentially expressed mRNAs. Differential expressions of 9 candidate miRNAs, miRs-10a, -30a-5p, -96, -126-5p, -182, -200a, -204, -429 and -488, and 16 genes were confirmed by qPCR. In addition, 14 candidate miRNA:mRNA reciprocal interactions were predicted. Several of the highly regulated genes and pathways were predicted as targets of miRNAs.

Conclusions

We have described global transcriptional reprogramming during the progression of PKD in the Pkd1

-/-
model. We propose a model for the cascade of signaling events involved in cyst formation and growth. Our results suggest that several miRNAs may be involved in regulating signaling pathways in ADPKD. We further describe novel putative miRNA:mRNA signatures in ADPKD, which will provide additional insights into the pathogenesis of this common genetic disease in humans.
Statistical Inference Methods for Sparse Biological Time Series Data
Authors: Ndukum Juliet , Fonseca Luís L , Santos Helena , Voit Eberhard O , Datta Susmita
Published: April 2011

Background

Comparing metabolic profiles under different biological perturbations has become a powerful approach to investigating the functioning of cells. The profiles can be taken as single snapshots of a system, but more information is gained if they are measured longitudinally over time. The results are short time series consisting of relatively sparse data that cannot be analyzed effectively with standard time series techniques, such as autocorrelation and frequency domain methods. In this work, we study longitudinal time series profiles of glucose consumption in the yeast Saccharomyces cerevisiae under different temperatures and preconditioning regimens, which we obtained with methods of in vivo nuclear magnetic resonance (NMR) spectroscopy. For the statistical analysis we first fit several nonlinear mixed effect regression models to the longitudinal profiles and then used an ANOVA likelihood ratio method in order to test for significant differences between the profiles.

Results

The proposed methods are capable of distinguishing metabolic time trends resulting from different treatments and associate significance levels to these differences. Among several nonlinear mixed-effects regression models tested, a three-parameter logistic function represents the data with highest accuracy. ANOVA and likelihood ratio tests suggest that there are significant differences between the glucose consumption rate profiles for cells that had been--or had not been--preconditioned by heat during growth. Furthermore, pair-wise t-tests reveal significant differences in the longitudinal profiles for glucose consumption rates between optimal conditions and heat stress, optimal and recovery conditions, and heat stress and recovery conditions (p-values <0.0001).

Conclusion

We have developed a nonlinear mixed effects model that is appropriate for the analysis of sparse metabolic and physiological time profiles. The model permits sound statistical inference procedures, based on ANOVA likelihood ratio tests, for testing the significance of differences between short time course data under different biological perturbations.
“It is her responsibility”: partner involvement in prevention of mother to child transmission of HIV programmes, northern Tanzania
Authors: Falnes Eli Fjeld , Moland Karen Marie , Tylleskär Thorkild , de Paoli Marina Manuela , Msuya Sia E , Engebretsen Ingunn MS
Published: April 2011

Background

Partner involvement has been deemed fundamental in prevention of mother to child transmission (PMTCT) programmes, but is difficult to achieve. This study aimed to explore acceptability of the PMTCT programme components and to identify structural and cultural challenges to male involvement.

Methods

The study was conducted during 2007‐2008 in rural and urban areas of Moshi in the Kilimanjaro region of Tanzania. Mixed methods were used, and included focus group discussions with fathers and mothers, in‐depth interviews with fathers, mothers and health personnel, and a survey of 426 mothers bringing their four‐week‐old infants for immunization at five reproductive and child health clinics.

Results

Routine testing for HIV of women at the antenatal clinic was highly acceptable and appreciated by men, while other programme components, notably partner testing, condom use and the infant feeding recommendations, were met with continued resistance. Very few men joined their wives for testing and thus missed out on PMTCT counselling. The main barriers reported were that women did not have the authority to request their husbands to test for HIV and that the arena for testing, the antenatal clinic, was defined as a typical female domain where men were out of place.

Conclusions

Deep‐seated ideas about gender roles and hierarchy are major obstacles to male participation in the PMTCT programme. Empowering women remains a huge challenge. Empowering men to participate by creating a space within the PMTCT programme that is male friendly should be feasible and should be highly prioritized for the PMTCT programme to achieve its potential.
Mammalian target of rapamycin and head and neck squamous cell carcinoma
Authors: Liao Yu-Min , Kim Charles , Yen Yun
Published: April 2011

Head and neck squamous cell carcinoma (HNSCC), a significant cause of cancer deaths worldwide, has multiple stepwise malignant evolutions. Mammalian target of rapamycin (mTOR) plays a critical role in tumor development, invasion, metastasis and angiogenesis that impact local recurrence and survival. mTOR can also act as a biomarker for personalized adjuvant therapy. In in vivo and in vitro studies, mTOR inhibitor suppresses tumor growth and sensitizes HNSCC to radiation, cytotoxic agents and epidermoid growth factor receptor inhibitors. We have reviewed the pathogenesis of HNSCC, mTOR pathway, mTOR inhibitor and the role of mTOR in HNSCC.
Gene expression profiles from discordant monozygotic twins suggest that molecular pathways are shared among multiple systemic autoimmune diseases
Authors: O'Hanlon Terrance P , Rider Lisa G , Gan Lu , Fannin Rick , Paules Richard S , Umbach David M , Weinberg Clarice R , Shah Ruchir R , Mav Deepak , Gourley Mark F , Miller Frederick W
Published: April 2011

Introduction

The objective of this study is to determine if multiple systemic autoimmune diseases (SAID) share gene expression pathways that could provide insights into pathogenic mechanisms common to these disorders.

Methods

RNA microarray analyses (Agilent Human 1A(V2) 20K oligo arrays) were used to quantify gene expression in peripheral blood cells from 20 monozygotic (MZ) twin pairs discordant for SAID. Six affected probands with systemic lupus erythematosus (SLE), six with rheumatoid arthritis (RA), eight with idiopathic inflammatory myopathies (IIM), and their same-gendered unaffected twins, were enrolled. Comparisons were made between discordant twin pairs and these were also each compared to 40 unrelated control subjects (matched 2:1 to each twin by age, gender and ethnicity) using statistical and molecular pathway analyses. Relative quantitative PCR was used to verify independently measures of differential gene expression assessed by microarray analysis.

Results

Probands and unrelated, matched controls differed significantly in gene expression for 104 probes corresponding to 92 identifiable genes (multiple-comparison adjusted P values < 0.1). Differentially expressed genes involved several overlapping pathways including immune responses (16%), signaling pathways (24%), transcription/translation regulators (26%), and metabolic functions (15%). Interferon (IFN)-response genes (IFI27, OASF, PLSCR1, EIF2AK2, TNFAIP6, and TNFSF10) were up-regulated in probands compared to unrelated controls. Many of the abnormally expressed genes played regulatory roles in multiple cellular pathways. We did not detect any probes expressed differentially in comparisons among the three SAID phenotypes. Similarly, we found no significant differences in gene expression when comparing probands to unaffected twins or unaffected twins to unrelated controls. Gene expression levels for unaffected twins appeared intermediate between that of probands and unrelated controls for 6535 probes (32% of the total probes) as would be expected by chance. By contrast, in unaffected twins intermediate ordering was observed for 84 of the 104 probes (81%) whose expression differed significantly between probands and unrelated controls.

Conclusions

Alterations in expression of a limited number of genes may influence the dysregulation of numerous, integrated immune response, cell signaling and regulatory pathways that are common to a number of SAID. Gene expression profiles in peripheral blood suggest that for genes in these critical pathways, unaffected twins may be in a transitional or intermediate state of immune dysregulation between twins with SAID and unrelated controls, perhaps predisposing them to the development of SAID given the necessary and sufficient environmental exposures.
Interleukin-17A differentially modulates BCG induction of cytokine production in human blood macrophages
Authors: Fang J W , Li James C B , Au K Y , Yim Howard C H , Lau Allan S Y
Published: April 2011

The pathogenesis of Mtb depends in part on cytokine cross-regulation between macrophages and T cells in host immunity. Th17 cells produce IL-17A to induce granuloma formation and to restrict mycobacterial dissemination. IL-17A also mediates cytokine responses induced by proinflammatory cytokines such as TNF-α. Our previous results showed that BCG induces IL-6, IL-10, and TNF-α via activity of protein kinases, including dsRNA-activated serine/threonine protein kinase and glycogen synthase kinase-3 in primary human monocytes. Therefore, we investigated whether IL-17A, upon its induction by BCG, plays an additional role to aid the production of downstream proinflammatory cytokines in macrophages. Here, we showed that IL-17A enhanced IL-6 mRNA and protein levels inducible by BCG in a time- and dose-dependent manner, whereas it had no effect on IL-10 and TNF-α production. We also demonstrated that IL-17A activated the phosphorylation of ERK1/2 triggered by BCG. With the use of a specific chemical inhibitor of a MAPK/ERK-activating kinase (MEK1/2), we confirmed the correlation between the enhanced ERK1/2 activation and augmented IL-6 production. Additionally, we revealed that IL-17A acts in concert with BCG-induced TNF-α to enhance the level of IL-6 synthesis. Taken together, our results suggest a significant role of IL-17A to serve as a modulator of cytokine expression in innate immune response during mycobacterial infection.
Has psychopharmacology got a future?
Authors: Cowen Philip J.
Published: April 2011

Fifty years ago pharmacological discoveries transformed psychiatry but progress since then has been relatively slow and there is unease about the role of industry. Despite this, the possibilities of pharmacological treatment have improved in recent years but exploiting developments for the benefit of patients requires psychotherapeutic skill as well as a high level of scientific knowledge.
Lithium in drinking water and suicide rates across the East of England
Authors: Kabacs Nikolett , Memon Anjum , Obinwa Thom , Stochl Jan , Perez Jesus
Published: April 2011

Lithium can be found naturally in drinking water. In clinical practice, it is widely used in pharmacological doses for the treatment of bipolar disorder; and may also prevent suicidal behaviour in people with mood disorders. In two studies, lithium levels in tap water have been significantly and negatively correlated with suicide. We measured lithium levels in tap water in the 47 subdivisions of the East of England and correlated these with the respective suicide standardised mortality ratio in each subdivision. We found no association between lithium in drinking water and suicide rates across the East of England from 2006 to 2008.
Evaluation of secondary post-traumatic stress disorder symptoms in the spouses of chemical warfare victims 20 years after the Iran–Iraq war
Authors: Ahmadi Khodabakhsh , Reshadatjoo Mahmood , Karami GholamReza , Sepehrvand Nariman , Ahmadi Pegah , Bazargan-Hejazi Shahrzad
Published: April 2011

Aims and method

Post-traumatic stress disorder (PTSD) has been reported in 90% of chemical warfare victims in previous studies. An individual's traumatic experience(s) may affect the lives of other family members as well. This cross-sectional case–control study compared the prevalence of PTSD symptoms in the husbands, the secondary PTSD symptoms in the wives and also aimed to identify if there was an association between the PTSD symptoms of the couples in the case group. Cases were 150 husband–wife couples where husbands were civilians exposed to chemical warfare; the controls were 156 husband–wife couples where there was no such exposure. Both cases and controls were recruited from Sardasht in Iran; this Kurdish city was attacked by four 250 kg sulphur mustard warheads in June 1987.

Results

Across three sets of cut-off points for the Mississippi Scale for Combat-Related PTSD symptomotology (<120 and ⩾121; <106 and ⩾107; and <65, 65–130 and > 130) wives in the case group demonstrated higher rates of PTSD symptoms than did those in the control group; the difference was statistically significant. Furthermore, husbands in the case group had a significantly higher overall mean score (123.0 (s.d. = 17.2)) than the husbands in the control group (112.3 (s.d. = 21.7); P<0.001, t = 4.80). There was no statistically significant association between the overall PTSD score of the husbands in the case group with that of their wives (P = 0.274, correlation coefficient 0.092).

Clinical implications

Husbands who were exposed to the chemical agents reported higher PTSD symptoms and there were higher rates of PTSD symptoms among the wives of individuals who were exposed to chemical warfare. Study results suggest the need for coordinated treatments, policy efforts and interventions to improve the wellbeing of chemical warfare victims and their caregiver wives.
Still tilting at windmills
Authors: Shorter Edward
Published: April 2011

Thomas Szasz's essay misses several key points about the undoubted changes that psychiatry has undergone since he wrote his original screed against the discipline in 1961. Szasz fails to recognise that the discipline today acknowledges a neurological basis for much psychiatric illness. Thus, his fulminations against psychiatry for treating ‘mental illness' is off-base. Szasz's original diatribe was heavily against psychoanalysis. Yet today Freud's doctrines can scarcely be said to play even a marginal role in psychiatry, and it is absurd to keep levelling the same old charges of 50 years ago. One has the feeling of looking at one of the last veterans of the Esperanto movement in confronting Szasz: lunacy at the time, bizarrely outdated today.
Increased Hepatic Insulin Sensitivity in Mice Lacking Inhibitory Leptin Receptor Signals
Authors: Tom Robby Zachariah , Sjögren Rasmus J. O. , Vieira Elaine , Glund Stephan , Iglesias-Gutiérrez Eduardo , Garcia-Roves Pablo M. , Myers Martin G. , Björnholm Marie
Published: April 2011

Leptin regulates food intake and energy expenditure by activating the long form of the leptin receptor (LepRb). Leptin also regulates glucose homeostasis by improving whole-body insulin sensitivity, but the mechanism remains undefined. Leptin action is mediated by phosphorylation of several tyrosine residues on LepRb. LepRb-Tyr985 plays an important role in the attenuation of LepRb signaling. We determined the contribution of LepRb-Tyr985-mediated signals to leptin action on insulin sensitivity using LepRb-Tyr985 mutant mice (l/l mice). Glucose tolerance and whole-body insulin-mediated glucose utilization were determined in wild-type (+/+) and l/l mice. Glucose tolerance was unaltered between female +/+ and l/l mice but enhanced in the male l/l mice. Serum insulin concentration was decreased at baseline and 15 min after a glucose injection in female l/l vs. +/+ mice (P < 0.05) but unaltered in the male l/l mice. However, basal and insulin-stimulated glucose transport in isolated soleus and extensor digitorum longus muscle was similar between +/+ and l/l mice, indicating skeletal muscle insulin sensitivity in vitro was not enhanced. Moreover, euglycemic-hyperinsulinemic clamps reveal hepatic, rather than peripheral, insulin sensitivity is enhanced in female l/l mice, whereas male l/l mice display both improved hepatic and peripheral insulin sensitivity. In conclusion, signals emanating from leptin receptor Tyr985 control hepatic insulin sensitivity in both female and male l/l mice. Lack of LepRb-Tyr985 signaling enhances whole-body insulin sensitivity partly through increased insulin action on the suppression of hepatic glucose production.
Oxytocin and Dopamine Stimulate Ghrelin Secretion by the Ghrelin-Producing Cell Line, MGN3-1 in Vitro
Authors: Iwakura Hiroshi , Ariyasu Hiroyuki , Hosoda Hiroshi , Yamada Go , Hosoda Kiminori , Nakao Kazuwa , Kangawa Kenji , Akamizu Takashi
Published: April 2011

To understand the physiological role of ghrelin, it is crucial to study both the actions of ghrelin and the regulation of ghrelin secretion. Although ghrelin actions have been extensively revealed, the direct factors regulating ghrelin secretion by ghrelin-producing cells (X/A-like cells), however, is not fully understood. In this study, we examined the effects of peptide hormones and neurotransmitters on in vitro ghrelin secretion by the recently developed ghrelin-producing cell line MGN3-1. Oxytocin and vasopressin significantly stimulated ghrelin secretion by MGN3-1 cells. Because MGN3-1 cells express only oxytocin receptor mRNA, not vasopressin receptor mRNA, oxytocin is the likely regulator, with the effect of vasopressin mediated by a cross-reaction. We also discovered that dopamine stimulates ghrelin secretion from MGN3-1 cells in a similar manner to the previously known ghrelin stimulators, epinephrine and norepinephrine. MGN3-1 cells expressed mRNA encoding dopamine receptors D1a and D2. The dopamine receptor D1 agonist fenoldopam stimulated ghrelin secretion, whereas the D2, D3 agonist bromocriptine did not. Furthermore, the D1 receptor antagonist SKF83566 attenuated the stimulatory effect of dopamine. These results indicate that the stimulatory effect of dopamine on ghrelin secretion is mediated by the D1a receptor. In conclusion, we identified two direct regulators of ghrelin, oxytocin and dopamine. These findings will provide new direction for further studies seeking to further understand the regulation of ghrelin secretion, which will in turn lead to greater understanding of the physiological role of ghrelin.
Metabolic Sensing and the Brain: Who, What, Where, and How?
Authors: Levin Barry E. , Magnan Christophe , Dunn-Meynell Ambrose , Le Foll Christelle
Published: April 2011

Unique subpopulations of specialized metabolic sensing neurons reside in a distributed network throughout the brain and respond to alterations in ambient levels of various metabolic substrates by altering their activity. Variations in local brain substrate levels reflect their transport across the blood- and cerebrospinal-brain barriers as well as local production by astrocytes. There are a number of mechanisms by which such metabolic sensing neurons alter their activity in response to changes in substrate levels, but it is clear that these neurons cannot be considered in isolation. They are heavily dependent on astrocyte and probably tanycyte metabolism and function but also respond to hormones (e.g. leptin and insulin) and cytokines that cross the blood-brain barrier from the periphery as well as hard-wired neural inputs from metabolic sensors in peripheral sites such as the hepatic portal vein, gastrointestinal tract, and carotid body. Thus, these specialized neurons are capable of monitoring and integrating multiple signals from the periphery as a means of regulating peripheral energy homeostasis.
Oxidative profile varies with personality in European greenfinches
Authors: Herborn Katherine A. , Coffey Jo , Larcombe Stephen D. , Alexander Lucille , Arnold Kathryn E.
Published: April 2011

Where behavioural responses differ consistently between individuals, this is termed ‘personality’. There is the suggestion, but with little supporting data, that personality traits reflect underlying variation in physiology. Here, we tested whether greenfinches Carduelis chloris differing in personality traits differed in various plasma indices of oxidative profile: antioxidant capacity (OXY), pro-oxidant status (reactive oxygen metabolites, ROMs), oxidative stress (OS) and an end-product of oxidative damage: malondialdehyde (MDA). We measured two personality traits: neophobia (latency to approach food near novel objects) and object exploration (latency to approach novel objects). These traits were uncorrelated. ROMs, OXY, OS and MDA were also uncorrelated with each other. Highly neophobic birds had lower OXY, higher ROMs and higher OS than less neophobic birds. Fast exploring birds had higher OXY than slow explorers, but did not differ in ROMs or OS. Variation in MDA was described by a quadratic relationship with neophobia: birds with extremely high or low neophobia had lower MDA than birds with intermediate neophobia, despite highly neophobic birds exhibiting lower OS than intermediately neophobic birds. Additively in that model, fast explorers had lower MDA than slower explorers. To conclude: first, personality types can differ in oxidative profile. Second, although physiological differences (e.g. hormonal stress responsiveness) between personality types generally range along a linear continuum, physiological costs may not. Finally, relationships with oxidative profile differed between neophobia and object exploration. Understanding how oxidative profile and thus physiological costs vary within and between personality traits may explain how differences in personality traits can predict fitness.
Molecular physiology and functional morphology of SO42– excretion by the kidney of seawater-adapted eels
Authors: Watanabe Taro , Takei Yoshio
Published: April 2011

Marine teleosts actively excrete SO42– and keep the plasma concentration of this ion much lower than that of environmental seawater (SW). We used the eel as a model to study the excretory mechanism of SO42– because this euryhaline species changes SO42– regulation drastically after transfer from freshwater (FW) to SW. Time-course studies showed that plasma SO42– concentration decreased 3 days after transfer of eels from FW to SW, while urine SO42– concentration increased on 1 day. Detailed analyses showed that urine SO42– concentration increased linearly from 6 h after SW transfer; however, this did not immediately translate to increased SO42– excretion because the volume of urine was decreased. We identified five SO42– transporters in the eel kidney. Three of these (Slc26a1, Slc26a6b and Slc26a6c) are expressed in both SW- and FW-acclimated eels while Slc26a6a and Slc13a1 are expressed in SW-acclimated eels and FW-acclimated eels, respectively. We showed that changes in Slc26a6a and Slc13a1 gene expression occurred 1–3 days after SW transfer. In SW eel kidneys, immunohistochemistry using specific antisera against each transporter protein showed that Slc26a6a and Slc26a6c are localized on the apical membrane of the P1 segment of the proximal tubule, while Slc26a6b is localized on the apical membrane and Slc26a1 on the basolateral membrane of the P2 segment. The current study revealed complex molecular mechanisms of SO42– excretion in the SW eel kidney that involve segment-specific localization of multiple Slc transporters in proximal tubules and modulation of their expression in different SO42– environments. This precise regulatory mechanism may endow the eel with euryhalinity.
Experimental evolution of sperm count in protandrous self-fertilizing hermaphrodites
Authors: Murray Rosalind L. , Cutter Asher D.
Published: April 2011

Sperm count evolution is driven by sexual selection, with an added role of selection on gamete resource allocation for hermaphrodite spermatogenesis. However, self-fertilization by hermaphrodites retards sexual selection and results in the evolution of reduced investment in sperm or pollen. In contrast to reproduction limited by female gametes (Bateman's Principle), self-fertilizing Caenorhabditis elegans hermaphrodites exhibit sperm-limited reproduction. Caenorhabditis elegans hermaphrodites are thought to experience a fitness trade-off between lifetime fecundity and generation time: longer sperm production decreases the risk of self-sperm depletion, but at the same time delays the onset of selfing and thus increases egg-to-egg generation time. Theory predicts that shorter larval development will favor lower sperm counts and longer development will favor more sperm. To investigate how developmental trajectories affect the evolution of sperm production, we performed experimental evolution by directly competing alleles controlling hermaphrodite sperm count, conducted under different environmental conditions that alter development time. Results are partially consistent with theory: rapid larval development generally favored alleles encoding production of few sperm. However, we identify some previously unrecognized simplifications of the theory and its application to our experimental system. In addition, we evaluated the generality of sperm limitation in C. elegans. Although optimal growth conditions yield sperm limitation, non-optimal conditions induce oocyte limitation, suggesting that this species might conform to Bateman's Principle under many natural settings. These findings demonstrate how developmental trajectories can shape the fitness landscape for the evolution of reproduction and sperm traits, even without sexual selection.
ATP distribution and localization of mitochondria in Suberites domuncula (Olivi 1792) tissue
Authors: Lukić-Bilela Lada , Perović-Ottstadt Sanja , Walenta Stefan , Natalio Filipe , Pleše Bruna , Link Thorben , Müller Werner E. G.
Published: April 2011

The metabolic energy state of sponge tissue in vivo is largely unknown. Quantitative bioluminescence-based imaging was used to analyze the ATP distribution of Suberites domuncula (Olivi 1792) tissue, in relation to differences between the cortex and the medulla. This method provides a quantitative picture of the ATP distribution closely reflecting the in vivo situation. The obtained data suggest that the highest ATP content occurs around channels in the sponge medulla. HPLC reverse-phase C-18, used for measurement of ATP content, established a value of 1.62 μmol ATP g–1 dry mass in sponge medulla, as opposed to 0.04 μmol ATP g–1 dry mass in the cortex, thus indicating a specific and defined energy distribution. These results correlate with the mitochondria localization, determined using primary antibodies against cytochrome oxidase c subunit 1 (COX1) (immunostaining), as well as with the distribution of arginine kinase (AK), essential for cellular energy metabolism (in situ hybridization with AK from S. domuncula; SDAK), in sponge sections. The highest energy consumption seemed to occur in choanocytes, the cells that drive the water through the channel system of the sponge body. Taken together, these results showed that the majority of energetic metabolism in S. domuncula occurs in the medulla, in the proximity of aqueous channels.
Histaminergic signaling in the central nervous system of Daphnia and a role for it in the control of phototactic behavior
Authors: McCoole Matthew D. , Baer Kevin N. , Christie Andrew E.
Published: April 2011

Daphnia magna and Daphnia pulex are well-established model organisms in the fields of ecotoxicology and toxicogenomics. Among the many assays used for determining the effects of environmental and anthropogenic stressors on these animals is monitoring for changes in their phototactic behavior. In most arthropods, histamine has been shown to play a key role in the visual system. Currently, nothing is known about histaminergic signaling in either D. magna or D. pulex. Here, a combination of immunohistochemistry and genome mining was used to identify and characterize the histaminergic systems in these daphnids. In addition, a behavioral assay was used to assess the role of histamine in their phototactic response to ultraviolet (UV) light exposure. An extensive network of histaminergic somata, axons and neuropil was identified via immunohistochemistry within the central nervous system of both daphnids, including labeling of putative photoreceptors in the compound eye and projections from these cells to the brain. Mining of the D. pulex genome using known Drosophila melanogaster proteins identified a putative ortholog of histidine decarboxylase (the rate-limiting biosynthetic enzyme for histamine), as well as two putative histamine-gated chloride channels (hclA and hclB orthologs). Exposure of D. magna to cimetidine, an H2 receptor antagonist known to block both hclA and hclB in D. melanogaster, inhibited their negative phototactic response to UV exposure in a reversible, time-dependent manner. Taken collectively, our results show that an extensive histaminergic system is present in Daphnia species, including the visual system, and that this amine is involved in the control of phototaxis in these animals.
Immigration and the Neighborhood
Authors: Saiz Albert , Wachter Susan
Published: April 2011

Within metropolitan areas, neighborhoods of growing immigrant settlement are becoming relatively less desirable to natives. We deploy a geographic diffusion model to instrument for the growth of immigrant density in a neighborhood. Our approach deals explicitly with potential unobservable shocks that may be correlated with proximity to immigrant enclaves. The evidence is consistent with a causal interpretation of an impact from growing immigrant density to native flight and relatively slower housing value appreciation. Further evidence indicates that these results are driven more by the demand for residential segregation based on ethnicity and education than by foreignness per se. (JEL I20, J11, J15, R23, Z13)
Naturally occurring, tumor-specific, therapeutic proteins
Authors: Argiris Konstantinos , Panethymitaki Chrysoula , Tavassoli Mahvash
Published: April 2011

The emerging approach to cancer treatment known as targeted therapies offers hope in improving the treatment of therapy-resistant cancers. Recent understanding of the molecular pathogenesis of cancer has led to the development of targeted novel drugs such as monoclonal antibodies, small molecule inhibitors, mimetics, antisense and small interference RNA-based strategies, among others. These compounds act on specific targets that are believed to contribute to the development and progression of cancers and resistance of tumors to conventional therapies. Delivered individually or combined with chemo‐ and/or radiotherapy, such novel drugs have produced significant responses in certain types of cancer. Among the most successful novel compounds are those which target tyrosine kinases (imatinib, trastuzumab, sinutinib, cetuximab). However, these compounds can cause severe side-effects as they inhibit pathways such as epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor, which are also important for normal functions in non-transformed cells. Recently, a number of proteins have been identified which show a remarkable tumor-specific cytotoxic activity. This toxicity is independent of tumor type or specific genetic changes such as p53, pRB or EGFR aberrations. These tumor-specific killer proteins are either derived from common human and animal viruses such as E1A, E4ORF4 and VP3 (apoptin) or of cellular origin, such as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) and MDA-7 (melanoma differentiation associated-7). This review aims to present a current overview of a selection of these proteins with preferential toxicity among cancer cells and will provide an insight into the possible mechanism of action, tumor specificity and their potential as novel tumor-specific cancer therapeutics.
Vascular rhexis in mice subjected to non-sustained myocardial ischemia and its therapeutic implications
Authors: Zaman A K M Tarikuz , French Christopher J , Spees Jeffrey L , Binbrek Azan S , Sobel Burton E
Published: April 2011

We previously described the death of vascular cells (vascular rhexis) following persistent coronary occlusion. The present study was designed to determine whether non-sustained ischemia can initiate vascular rhexis and if so, whether relatively brief ischemic insults are sufficient. C57BL6 mice were subjected to coronary ligation for 15 min or 3 h followed by reperfusion. Soluble fractions of left ventricular (LV) homogenates were obtained 48 h after the onset of transitory coronary occlusion. They were assayed by Western blotting for quantification of alpha smooth muscle actin ( α-SMA) and smooth muscle myosin heavy chain (SM-MHC) that we have shown reflect vascular rhexis delineated immunohistochemically. Non-sustained coronary occlusion for 3 h initiated vascular rhexis evident 45 h after reperfusion, but not earlier, as judged from Western blotting of α-SMA and SM-MHC. The number of small- and medium-sized vessels in the previously ischemic zones was reduced at 45 h after reperfusion as well. Thus, vascular rhexis occurs after ischemia as brief as 3 h but evolves slowly and is not evident for 45 h. The delayed disintegration of the vasculature makes it likely that it can be ameliorated by interventions initiated after non-sustained ischemia, rendering it an attractive target for diminution of phenomena such as late negative LV remodeling, and ‘no reflow.’
A Multiproduct Risk-Averse Newsvendor with Law-Invariant Coherent Measures of Risk
Authors: Choi Sungyong , Ruszczyński Andrzej , Zhao Yao
Published: April 2011

We consider a multiproduct risk-averse newsvendor under the law-invariant coherent measures of risk. We first establish several fundamental properties of the model regarding the convexity of the problem, the symmetry of the solution, and the impact of risk aversion. Specifically, we show that for identical products with independent demands, increased risk aversion leads to decreased orders. For a large but finite number of heterogeneous products with independent demands, we derive closed-form approximations for the optimal order quantities. The approximations are as simple to compute as the classical risk-neutral solutions. We also show that the risk-neutral solution is asymptotically optimal as the number of products tends to be infinity, and thus risk aversion has no impact in the limit. For a risk-averse newsvendor with dependent demands, we show that positively (negatively) dependent demands lead to lower (higher) optimal order quantities than independent demands. Using a numerical study, we examine the convergence rates of the approximations and develop additional insights into the interplay between dependent demands and risk aversion.
One-Switch Independence for Multiattribute Utility Functions
Authors: Abbas Ali E. , Bell David E.
Published: April 2011

Assessment of multiattribute utility functions is significantly simplified if it is possible to decompose the function into more manageable pieces. Utility independence is a powerful property that serves well for this purpose, but if it is not appropriate in a given situation, what options does the analyst have? We review some possibilities and propose a new independence assumption based on the one-switch property. We argue that it is a natural generalization of utility independence and show how it leads to tractable multiattribute utility functions.
Vitamin D Status and Response to Daily 400 IU Vitamin D3 and Weekly Alendronate 70 mg in Men and Women with Osteoporosis
Authors: Karaplis Andrew C , Chouha Fridon , Djandji Michel , Sampalis John S , Hanley David A
Published: April 2011

Background

Suboptimal vitamin D status is common in elderly individuals. However, the extent of vitamin D inadequacy in men and women being treated for osteoporosis in a family practice setting has not been well characterized.

Objective:

To describe the distribution of serum 25-hydroxyvitamin D (25-[OH] D) in Canadian men and postmenopausal women with osteoporosis taking 400 IU or less of vitamin D daily and to evaluate the safety, tolerability, and impact of vitamin D3 supplementation 400 IU daily taken concurrently with alendronate sodium 70 mg weekly.

Methods:

This was a prospective, single-cohort, open-label, multicenter study. Community-dwelling men and postmenopausal women with osteoporosis were recruited at 197 sites across Canada. Patients received vitamin D3 400 IU/day supplementation coadministered with alendronate 70 mg/wk for 16 weeks. The primary outcome was the distribution of serum 25-(OH) D at baseline. Secondary outcome measures included changes from baseline in serum 25-(OH) D levels, adherence to study treatments, and incidence of treatment-related adverse events (AEs).

Results:

Of the 681 patients included in the analysis, 485 (71.2%) completed the study. Patients were predominantly female (83.1%) with a mean (SD) age of 67.6 (10.7) years. At baseline, mean (SD) serum 25-(OH) D concentration was 25.4 (9.9) ng/mL and 68.0% of the patients had inadequate (less than 30 ng/mL) vitamin D status. At week 16, concentrations increased by 35.1% to 31.2 (9.2) ng/mL (p < 0.001) and the proportion of patients with inadequate 25-(OH) D levels was reduced to 47.0%. Adherence to the treatment regimen was high (greater than 95%). Gastrointestinal disorders were the most frequently reported (6.9%) treatment-related AEs.

Conclusions:

About two thirds of patients previously diagnosed with osteoporosis have inadequate vitamin D status. A treatment regimen consisting of alendronate 70 mg/wk administered with daily vitamin D3 400 IU supplementation significantly increased patients' serum 25-(OH) D levels, but 47% did not achieve optimal levels. These results support both the National Osteoporosis Foundation and Osteoporosis Canada recommendations for higher vitamin D supplement doses (at least 800 IU daily) in osteoporotic patients receiving pharmacologic therapy for osteoporosis and for monitoring their serum 25-(OH) D response.
Symptom Reporting Compared with Audiometry for the Detection of Cochleotoxicity in Patients on Long-Term Aminoglycoside Therapy
Authors: Palmay Lesley , Walker Sandra AN , Walker Scott E , Simor Andrew E
Published: April 2011

Background

Aminoglycoside-associated auditory toxicity (cochleotoxicity) is a major concern in patients receiving prolonged aminoglycoside therapy. There are no published data comparing symptom monitoring to audiometry testing for the detection of aminoglycoside-induced cochleotoxicity; thus, agreement regarding the optimal monitoring of these patients for early detection of this effect is lacking.

Objective:

To compare the sensitivity of symptom monitoring to that of audiometry in identifying cochleotoxicity in patients on prolonged aminoglycoside therapy.

Methods:

A retrospective chart review of adult inpatients at Sunnybrook Health Sciences Centre prescribed prolonged aminoglycoside therapy (≥21 days) who completed at least 1 audiometry test between January 1, 1999, and December 31, 2009, was conducted. Data pertaining to results of audiometry testing and development of symptoms of auditory toxicity were collected. Symptom monitoring was compared with audiology testing for the detection of cochleotoxicity.

Results:

Forty eligible patients were included for analysis. Audiometry was significantly better than symptom monitoring to identify early cochleotoxicity (absolute risk reduction = 17.5% and number needed to treat = 6; p = 0.023). Compared to audiometry, symptom monitoring has a sensitivity, negative predictive value, and accuracy for the detection of early cochleotoxicity of 61%, 75%, and 82%, respectively.

Conclusions:

Audiometry testing is significantly better than monitoring symptoms to identify early aminoglycoside-induced auditory toxicity in patients prescribed prolonged aminoglycoside therapy (≥21 days). Subclinical cochleotoxicity identified with audiometry may allow early termination of aminoglycoside therapy to prevent progression of cochlear damage to the audible frequency range.
A graph-theoretical model for ballistic conduction in single-molecule conductors
Authors: Fowler Patrick W. , Pickup Barry T. , Todorova Tsanka Z.
Published: April 2011

The tight-binding version of the source-and-sink potential (SSP) model of ballistic conduction can be cast in a graph-theoretical form where the transmission through a molecular wire depends on four characteristic polynomials: those of the molecular graph and the vertex-deleted subgraphs with one or both of the molecular vertices contacting the electrodes removed. This gives an explicit function for the dependence of transmission on energy, one that is well adapted for qualitative description of general classes of conductors and conduction behavior. It also leads directly to a selection-rule criterion for conduction in terms of counting zero roots of the polynomials, which for benzenoids and graphenes is shown to subsume literature approaches based on Kekulé structure counting, bond order, and frontier-orbital matching. As explicitly demonstrated here, the SSP transmission function agrees with that derived by the Green’s function (GF) method.
Investigating the effects of physiological bile acids on GLP-1 secretion and glucose tolerance in normal and GLP-1R-/- mice
Authors: Rafferty Eamon P. , Wylie Alastair R. , Hand Katharine H. , Elliott Chris E. , Grieve David J. , Green Brian D.
Published: April 2011

Physiological secretion of bile acids has previously been linked to the regulation of blood glucose. GLP-1 is an intestinal peptide hormone with important glucose-lowering actions, such as stimulation of insulin secretion and inhibition of glucagon secretion. In this investigation, we assessed the ability of several bile acid compounds to secrete GLP-1in vitroin STC-1 cells. Bile acids stimulated GLP-1 secretion from 3.3- to 6.2-fold but some were associated with cytolytic effects. Glycocholic and taurocholic acids were selected forin vivostudies in normal and GLP-1R-/-mice. Oral glucose tolerance tests revealed that glycocholic acid did not affect glucose excursions. However, taurocholic acid reduced glucose excursions by 40% in normal mice and by 27% in GLP-1R-/-mice, and plasma GLP-1 concentrations were significantly elevated 30 min post-gavage. Additional studies used incretin receptor antagonists to probe involvement of GLP-1 and GIP in taurocholic acid-induced glucose lowering. The findings suggest that bile acids partially aid glucose regulation by physiologically enhancing nutrient-induced GLP-1 secretion. However, GLP-1 secretion appears to be only part of the glucose-lowering mechanism and our studies indicate that the other major incretin GIP is not involved.
Poliovirus 3C proteinase inhibition by organotelluranes
Authors: Gouvea Iuri E. , Santos Jorge A.N. , Burlandy Fernanda M. , Tersariol Ivarne L.S. , da Silva Edson E. , Juliano Maria A. , Juliano Luiz , Cunha Rodrigo L.O.R.
Published: April 2011

The 3C proteinase, essential for human poliovirus (PV) replication, has unique characteristics as its three-dimensional structure resembles chymotrypsin, but its catalytic nucleophile is a cysteine SH group rather than the OH group of serine. Here, we describe the use of tellurium compounds as inhibitors of PV3C proteinase. A rapid, stoichiometric and covalent inactivation of PV3C was observed with both a chloro-telluroxetane and a bis-vinylic organotellurane. These compounds also inhibit human cathepsins B, L, S, and K with second order rate constants higher than those obtained for PV3C. Chloro-telluroxetane inhibits replication of PV in human embryonic rhabdomyosarcoma cells in the low micromolar range and below the toxic level for the host cells. Bis-vinylic organotellurane is more effective as antiviral agent but reduces the cell viability by 20% at 10 μm, a concentration almost completely inhibiting virus growth. This is the first description of inhibition of viral 3C proteinase with antiviral property by this class of compounds.
The role of cathepsin E in terminal differentiation of keratinocytes
Authors: Kawakubo Tomoyo , Yasukochi Atsushi , Okamoto Kuniaki , Okamoto Yoshiko , Nakamura Seiji , Yamamoto Kenji
Published: April 2011

Cathepsin E (CatE) is predominantly expressed in the rapidly regenerating gastric mucosal cells and epidermal keratinocytes, in addition to the immune system cells. However, the role of CatE in these cells remains unclear. Here we report a crucial role of CatE in keratinocyte terminal differentiation. CatE deficiency in mice induces abnormal keratinocyte differentiation in the epidermis and hair follicle, characterized by the significant expansion of corium and the reduction of subcutaneous tissue and hair follicle. In a model of skin papillomas formed in three different genotypes of syngeneic mice, CatE deficiency results in significantly reduced expression and altered localization of the keratinocyte differentiation induced proteins, keratin 1 and loricrin. Involvement of CatE in the regulation of the expression of epidermal differentiation specific proteins was corroborated byin vitrostudies with primary cultures of keratinocytes from the three different genotypes of mice. In wild-type keratinocytes after differentiation inducing stimuli, the CatE expression profile was compatible to those of the terminal differentiation marker genes tested. Overexpression of CatE in mice enhances the keratinocyte terminal differentiation process, whereas CatE deficiency results in delayed differentiation accompanying the reduced expression or the ectopic localization of the differentiation markers. Our findings suggest that in keratinocytes CatE is functionally linked to the expression of terminal differentiation markers, thereby regulating epidermis formation and homeostasis.