Integration of gene expression data with prior knowledge for network analysis and validation

Background

Reconstruction of protein-protein interaction or metabolic networks based on expression data often involves in silico predictions, while on the other hand, there are unspecific networks of in vivo interactions derived from knowledge bases.We analyze networks designed to come as close as possible to data measured in vivo, both with respect to the set of nodes which were taken to be expressed in experiment as well as with respect to the interactions between them which were taken from manually curated databases

Results

A signaling network derived from the TRANSPATH database and a metabolic network derived from KEGG LIGAND are each filtered onto expression data from breast cancer (SAGE) considering different levels of restrictiveness in edge and vertex selection.We perform several validation steps, in particular we define pathway over-representation tests based on refined null models to recover functional modules. The prominent role of the spindle checkpoint-related pathways in breast cancer is exhibited. High-ranking key nodes cluster in functional groups retrieved from literature. Results are consistent between several functional and topological analyses and between signaling and metabolic aspects.

Conclusions

This construction involved as a crucial step the passage to a mammalian protein identifier format as well as to a reaction-based semantics of metabolism. This yielded good connectivity but also led to the need to perform benchmark tests to exclude loss of essential information. Such validation, albeit tedious due to limitations of existing methods, turned out to be informative, and in particular provided biological insights as well as information on the degrees of coherence of the networks despite fragmentation of experimental data.Key node analysis exploited the networks for potentially interesting proteins in view of drug target prediction.

     

Current status of iodine intake in Croatia--the results of 2009 survey

In 1996, due to persistence of mild to moderate iodine deficiency, new law on obligatory salt iodination with 25 mg of potassium iodide (KI) per kg of salt was implemented in Croatia. Along with a new law, a new program for monitoring of iodine prophylaxis was implemented. Investigations of goiter and iodine intake performed in 2002, demonstrated sufficient iodine intake in Croatia with overall median of urinary iodine concentration (UIC) for schoolchildren in Croatia of 140 microg/L. In 2002, thyroid volumes (TV) measured by ultrasound in schoolchildren from all four geographic regions of Croatia were for the first time within the normal range according to ICCIDD reference values. Nowadays, Croatia is internationally recognized as iodine sufficient country. The aim of the present study was to assess current status of iodine intake in Croatia. The investigation was carried out in 2009. A total of 386 schoolchildren aged 7-10 years from all four major geographic regions of Croatia, 103 euthyroid pregnant women and 36 women of child-bearing age from Zagreb, the capital, were included in the survey. Urinary iodine concentration (UIC) was measured in all participants. Thyroid volumes were measured by ultrasound in schoolchildren from the capital of Zagreb (N = 101) and the village of Rude (N = 56). In the time period 2002-2009, the content of KI was analyzed in 384 salt samples from Croatian salt plants and samples of imported salt. An overall median UIC for schoolchildren in Croatia was 248 microg/L. Median UIC in pregnant women was 159 microg/L, with 50% of samples below and under 150 microg/L. Median UIC in women of child-bearing age was 136 microg/L. Thyroid volumes in schoolchildren were within the normal range according to the new reference values. Mean value of KI/kg of salt in samples from Croatian salt plants was 25.5 mg/kg and 24.9 mg/kg in samples of imported salt. A total of 72/384 (18.8%) of salt samples didn't corresponded to the Croatian law on obligatory salt iodination. Presented data indicate sufficient iodine intake of the Croatian population. Current medians of UIC in schoolchildren in Croatia are significantly higher than medians measured in 2002. This indicates that other potential sources of iodine are present in Croatian diet that may contribute to overall iodine intake. Due to rising medians of UIC in schoolchildren in Croatia, it is important to conduct nutrition studies to identify potential sources of "silent prophylaxis" in order to avoid iodine excess.     

Mass‐flowering crops dilute pollinator abundance in agricultural landscapes across Europe

Mass‐flowering crops (MFCs) are increasingly cultivated and might influence pollinator communities in MFC fields and nearby semi‐natural habitats (SNHs). Across six European regions and 2 years, we assessed how landscape‐scale cover of MFCs affected pollinator densities in 408 MFC fields and adjacent SNHs. In MFC fields, densities of bumblebees, solitary bees, managed honeybees and hoverflies were negatively related to the cover of MFCs in the landscape. In SNHs, densities of bumblebees declined with increasing cover of MFCs but densities of honeybees increased. The densities of all pollinators were generally unrelated to the cover of SNHs in the landscape. Although MFC fields apparently attracted pollinators from SNHs, in landscapes with large areas of MFCs they became diluted. The resulting lower densities might negatively affect yields of pollinator‐dependent crops and the reproductive success of wild plants. An expansion of MFCs needs to be accompanied by pollinator‐supporting practices in agricultural landscapes.     

Genetic diversity of populations of <Emphasis Type="Italic">Merodon aureus</Emphasis> and <Emphasis Type="Italic">M. cinereus</Emphasis> species complexes (Diptera,Syrphidae): integrative taxonomy and implications for conservation priorities on the Balkan Peninsula

The genetic structure of 10 populations of the Merodon aureus group from the Balkan Peninsula was examined through allozyme electrophoresis and mitochondrial DNA sequencing of the cytochrome c oxidase subunit I (COI). Six diagnosable cryptic taxa were identified within the morphologically defined species M. aureus Fabricius, 1805 and M. cinereus (Fabricius, 1794), with clear separation of the populations (((M. aureus A + M. aureus B) + cinereus complex) + M. aureus C). The parsimony analysis of COI sequence data of the aureus–cinereus complex using Merodon avidus A species as an outgroup resulted in two main clades, (M. aureus A + M. aureus B) and ((M. aureus C + M. cinereus B + M. cinereus C) + M. cinereus A), which differed on average by 5.7%. The observed spatial distribution of the taxonomic diversity of the group suggested that these taxa originated from a common ancestral population in the Mediterranean. Identification of genetic uniqueness and genetic endemism emphasizes the importance of molecular markers and estimation of genetic diversity in recognition of conservation units. The primary goals of the conservation measures that we propose are the protection of phylogenetic lineages within the highly diverse M. aureus group taxa and conservation of the genetic variation through management of important areas.     

The effect of repeated daily measurements on paw withdrawal latencies in Hargreaves test

The hypothesis that repeated measurements during 4 subsequent days affect withdrawal latencies in Hargreaves test was investigated. Paw withdrawal latencies to radiant heat were determined in the control, tramadol or saline group of male Wistar rats. The control group (N=10) had no treatment. Tramadol group (N=7) and saline group (N=7) received one daily intraperitoneal injection of tramadol (15 mg/kg) or saline (0.9% NaCl), respectively. A significant decline in withdrawal latencies was observed in the control group on the day 2 to day 4, when compared to day 1 (p < 0.05 Bonferroni test). In the saline and tramadol groups, latencies remained stable from day 1 to day 4. During the entire testing period withdrawal latencies were 27-50% longer in tramadol group (p < 0.05 ANOVA) compared with the saline group. When compared to the control group, the effect of tramadol, was noted from the second to forth day (p < 0.01 Bonferroni test), but not on the first day. Finally, a tendency to decrement in withdrawal latencies existed on day 1 in the saline group compared with control group, but this difference does not reach significance. We conclude that one day of training affect withdrawal latencies in the Hargreaves test.     

The efficacy of cisapride vs. placebo and diet in patients with chronic constipation

The effects of cisapride (10 mg three times daily) on the stool evacuation characteristics, laxative consumption (symptom diary) and motility pattern (rectoanal manometry) were assessed in patients with chronic idiopathic constipation who fulfilled Rome II criteria. After a 14-day basal period on a diet rich in fiber (phase I), patients were treated with placebo (n = 20) or cisapride (n = 19) (phase II). Anorectal manometry was performed at the end of each phase. The study was controlled, randomized and double blind. Side effects related to the use of cisapride were noted and found to be mild. Cisapride and placebo increased stool frequency from 4 (1-11) to 7 (14-12) (p < 0.001) and from 4 (2-10) to 6 (2-11) (p < 0.05) per week, respectively. Straining was decreased from 69.0% to 39.7% in the cisapride (p < 0.0001) group, and from 79% to 35% (p < 0.0001) in the placebo group. Both cisapride and placebo decreased the feeling of incomplete evacuation from 91.7% to 37.5% (p < 0.0001) and from 82.7% to 39.2% (p < 0.0001), respectively. Cisapride reduced the need of laxatives and showed a tendency to normalize stool consistency but did not influence any other symptom or bowel motility parameter.     

CT perfusion and noncontrast CT in acute ischemic stroke diagnosing--is there influence on early thrombolytic therapy outcome?

The objective of this study was to compare noncontrast computed tomography (NCCT) and computed tomography perfusion (CTP) in early diagnosis of acute ischemic stroke and to define influence of these diagnostic procedures on early outcome of thrombolytic therapy (TLTH). The study included 45 patients, 35 patients submitted to NCCT and CTP and 10 patients who underwent only NCCT, before CTP was introduced. Based on the National Institute of Health Stroke Scale (NIHSS) score we compared early outcome of patients who received TLTH after NCCT only (group 1) with the early outcome of patients who received TLTH following NCCT and CTP (group 2). Statistically significant difference was found in acute stroke diagnosing between CTP and NCCT (p = 0.002). There were no statistically significant differences in TLTH early outcome between group 1 and group 2. In conclusion, CTP should be done regulary in patients presenting with acute ischemic stroke symptoms. More research needs to be done in defining exact influence of CTP implementation on the TLTH outcome.     

Starvation as cause of death in the Croatian Quarnero and hinterland between 1816 and 1825

Our aim is to investigate starvation as cause of death and social and demographic consequences in the Croatian Quarnero and its hinterland between 1816 and 1825, paying particular attention to the infamous "year of famine" 1817. Our sources were: registers of births, marriages, and deaths from 21 parishes kept at the Croatian State Archives in Rijeka and Zagreb. We collected and processed data for statistical analysis according to the date of baptism (birth), marriage, and death, and according to sex and age. Our focus was on recorded causes of death. Between 1816 and 1825, 15,701 children were baptised (born), and 11,021 people died. Starvation was recorded as cause of death in 255 cases, of which 198 were recorded in the infamous 1817. It was the only year with negative growth in virtually all parishes, with the birth-to-death ratio of 1147:1545. In 1817, the proportion of death by starvation to the total death rate was 12.8% for the entire area, with the highest share recorded in Veprinac (33.3%), Crikvenica (23.3%), and Kastav (15.8%). Death by starvation was more common in men than in women (56.7% vs. 43.3%, respectively). Age distribution was as follows; in the population below 20 years of age the death rate was 42 (16.5% of total deaths), but the most affected age group were infants and children aged 1-4 years (69.0%) whereas in adult population the death rate was 213 (83.5% of total deaths) and the most affected group were the elderly between 60 and 69 years (26.3%). Analysis shows lower birth and marriage rates between 1816 and 1818, followed by a steep rise and a plateau with minimal variation. This study shows that the Croatian Quarnero and its hinterland suffered a great famine in the early 19th century and 1817 in particular, which had left a deep mark on local demography, just like in the neighbouring parts of Croatia and Europe.