Systematic construction of gene coexpression networks with applications to human T helper cell differentiation process

Motivation: Coexpression networks have recently emerged as anovel holistic approach to microarray data analysis and interpretation.Choosing an appropriate cutoff threshold, above which a gene–geneinteraction is considered as relevant, is a critical task inmost network-centric applications, especially when two or morenetworks are being compared. Results: We demonstrate that the performance of traditionalapproaches, which are based on a pre-defined cutoff or significancelevel, can vary drastically depending on the type of data andapplication. Therefore, we introduce a systematic procedurefor estimating a cutoff threshold of coexpression networks directlyfrom their topological properties. Both synthetic and real datasetsshow clear benefits of our data-driven approach under variouspractical circumstances. In particular, the procedure providesa robust estimate of individual degree distributions, even frommultiple microarray studies performed with different array platformsor experimental designs, which can be used to discriminate thecorresponding phenotypes. Application to human T helper celldifferentiation process provides useful insights into the componentsand interactions controlling this process, many of which wouldhave remained unidentified on the basis of expression changealone. Moreover, several human–mouse orthologs showedconserved topological changes in both systems, suggesting theirpotential importance in the differentiation process. Contact: laliel{at}utu.fi Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: David Rocke     

Profiling of Coumarins in Peucedanum palustre (L.) Moench Populations Growing in Finland

The coumarin composition of Peucedanum palustre (L.) Moench populations growing in Finland was investigated. A total of 132 flowering P. palustre specimens from 43 locations in southern and central Finland were collected, divided into root, stem, leaf, and umbel samples, and analyzed by HPLC. HPLC coupled to high‐resolution mass spectrometry was used to aid the identification of coumarins. A total of 13 coumarin‐structured compounds were quantitatively analyzed from the samples. The coumarin profile of root samples was found to differ from the aerial plant parts. The main coumarins in roots were oxypeucedanin and columbianadin. In aerial parts, peulustrin isomers were the most abundant coumarin components. Umbels and leaves also contained a considerable amount of umbelliprenin, which was only found in traces in roots. Based on hierarchical cluster analysis of the coumarin profiles, some populations shared common characteristics. The most distinct property connecting certain populations was their high peulustrin content. Another notable common property between some populations was the high umbelliprenin content in aerial plant parts. Some populations were clustered together due to their low overall coumarin content.     

The Use of a Five-stage Sequential Leaching Procedure for Risk Assessment of Heavy Metals in Waste Rock Utilized in Railway Ballast

A five-stage sequential leaching procedure was used to determine the distribution of 10 metals in three combination samples taken from waste rock material, originating from a Finnish zinc mine, and used as railway ballast in Northern Finland. The leaching procedure consists of the following five sequential fractions: a water-soluble fraction (H₂O), an exchangeable fraction (CH₃COOH), an easily reduced fraction (NH₂OH-HCl), an oxidizable fraction (H₂O₂ + CH₃COONH₄), and a residual fraction (HF + HNO₃ + HCl). The results show, in accordance with all earlier corresponding studies, that a sequential extraction procedure is very suitable for evaluating the effects of external conditions on the solubility of harmful heavy metals, and that external conditions have a large effect on their leachability/solubility, and therefore on their mobility, bioavailability, and environmental risk. In addition, the total concentration of each element is much larger than its solubility in each of the first four fractions (1)–(4) – the potential bioavailability fractions – because the highest concentrations of all metals occurred in the residual fraction (5). The conditions of this phase – three strong acids and strong, long-lasting shaking – are never possible in nature, and therefore the residual fraction is called the inert phase. Thus, the total concentrations of the heavy metals are poor measures of real environmental risk and give no information about the effect of external conditions on their solubility. In addition, the dependency of different elements on the external conditions differs.     

Operon flv4-flv2 provides cyanobacterial photosystem II with flexibility of electron transfer

Synechocystis sp PCC 6803 has four genes encoding flavodiiron proteins (FDPs; Flv1 to Flv4). Here, we investigated the flv4-flv2 operon encoding the Flv4, Sll0218, and Flv2 proteins, which are strongly expressed under low inorganic carbon conditions (i.e., air level of CO(2)) but become repressed at elevated CO(2) conditions. Different from FDP homodimers in anaerobic microbes, Synechocystis Flv2 and Flv4 form a heterodimer. It is located in cytoplasm but also has a high affinity to membrane in the presence of cations. Sll0218, on the contrary, resides in the thylakoid membrane in association with a high molecular mass protein complex. Sll0218 operates partially independently of Flv2/Flv4. It stabilizes the photosystem II (PSII) dimers, and according to biophysical measurements opens up a novel electron transfer pathway to the Flv2/Flv4 heterodimer from PSII. Constructed homology models suggest efficient electron transfer in heterodimeric Flv2/Flv4. It is suggested that Flv2/Flv4 binds to thylakoids in light, mediates electron transfer from PSII, and concomitantly regulates the association of phycobilisomes with PSII. The function of the flv4-flv2 operon provides many β-cyanobacteria with a so far unknown photoprotection mechanism that evolved in parallel with oxygen-evolving PSII.     

Gamma-secretase inhibitor treatment promotes VEGF-A-driven blood vessel growth and vascular leakage but disrupts neovascular perfusion

The Notch signaling pathway is essential for normal development due to its role in control of cell differentiation, proliferation and survival. It is also critically involved in tumorigenesis and cancer progression. A key enzyme in the activation of Notch signaling is the gamma-secretase protein complex and therefore, gamma-secretase inhibitors (GSIs)--originally developed for Alzheimer's disease--are now being evaluated in clinical trials for human malignancies. It is also clear that Notch plays an important role in angiogenesis driven by Vascular Endothelial Growth Factor A (VEGF-A)--a process instrumental for tumor growth and metastasis. The effect of GSIs on tumor vasculature has not been conclusively determined. Here we report that Compound X (CX), a GSI previously reported to potently inhibit Notch signaling in vitro and in vivo, promotes angiogenic sprouting in vitro and during developmental angiogenesis in mice. Furthermore, CX treatment suppresses tumor growth in a mouse model of renal carcinoma, leads to the formation of abnormal vessels and an increased tumor vascular density. Using a rabbit model of VEGF-A-driven angiogenesis in skeletal muscle, we demonstrate that CX treatment promotes abnormal blood vessel growth characterized by vessel occlusion, disrupted blood flow, and increased vascular leakage. Based on these findings, we propose a model for how GSIs and other Notch inhibitors disrupt tumor blood vessel perfusion, which might be useful for understanding this new class of anti-cancer agents.     

Cytology of the genus Artemisia (Anthemidae,Asteraceae) in the Western Himalayas

The present study revealed the varied frequency of natural chromosomal abnormalities in 13 populations pertaining to 9 species of the genus Artemisia L. from different localities of Himachal Pradesh (Western Himalaya). Intraspecific chromosome variability has been reported for the first time on worldwide basis in Artemisia vestita (2n = 2x = 36) and from India in A. macrocephala (2n = 2x = 18) and A. scoparia (2n = 2x = 36). Besides, B-chromosomes have been reported here for the first time in A. nilagirica and A. roxburghiana. Most of the populations show anomalous meiotic behaviour resulting in cytomixis, chromosomal stickiness, unoriented bivalents, formation of laggards and bridges which leads to abnormal microsporogenesis, and production of heterogeneous-sized fertile pollen grains along with reduced pollen fertility.