Atlantic cod (Gadus morhua) is a large, cold-adapted teleost that sustains long-standing commercial fisheries and incipient aquaculture1,2. Here we present the genome sequence of Atlantic cod, showing evidence for complex thermal adaptations in its haemoglobin gene cluster and an unusual immune architecture compared to other sequenced vertebrates. The genome assembly was obtained exclusively by 454 sequencing of shotgun and paired-end libraries, and automated annotation identified 22,154 genes. The major histocompatibility complex (MHC) II is a conserved feature of the adaptive immune system of jawed vertebrates3,4, but we show that Atlantic cod has lost the genes for MHCII, CD4 and Ii that are essential for the function of this pathway. Nevertheless, Atlantic cod is not exceptionally susceptible to disease under natural conditions5. We find a highly expanded number of MHCI genes and a unique composition of its Toll-like receptor (TLR) families. This suggests how the Atlantic cod immune system has evolved compensatory mechanisms within both adaptive and innate immunity in the absence of MHCII. These observations affect fundamental assumptions about the evolution of the adaptive immune system and its components in vertebrates.

Motivation: The commercial launch of 454 pyrosequencing in 2005 was a milestone in genome sequencing in terms of performance and cost. Throughout the three available releases, average read lengths have increased to ∼500 base pairs and are thus approaching read lengths obtained from traditional Sanger sequencing. Study design of sequencing projects would benefit from being able to simulate experiments.Results: We explore 454 raw data to investigate its characteristics and derive empirical distributions for the flow values generated by pyrosequencing. Based on our findings, we implement Flowsim, a simulator that generates realistic pyrosequencing data files of arbitrary size from a given set of input DNA sequences. We finally use our simulator to examine the impact of sequence lengths on the results of concrete whole-genome assemblies, and we suggest its use in planning of sequencing projects, benchmarking of assembly methods and other fields.Availability: Flowsim is freely available under the General Public License from http://blog.malde.org/index.php/flowsim/Contact: susanne.balzer@imr.no; ketil.malde@imr.no

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Alkylating agents are widely used chemotherapeutics in the treatment of many cancers, including leukemia, lymphoma, multiple myeloma, sarcoma, lung, breast and ovarian cancer. Melphalan is the most commonly used chemotherapeutic agent against multiple myeloma. However, despite a 70–80% initial response rate, virtually all patients eventually relapse due to the emergence of drug-resistant tumour cells. By using global proteomic and transcriptomic profiling on melphalan sensitive and resistant RPMI8226 cell lines followed by functional assays, we discovered changes in cellular processes and pathways not previously associated with melphalan resistance in multiple myeloma cells, including a metabolic switch conforming to the Warburg effect (aerobic glycolysis), and an elevated oxidative stress response mediated by VEGF/IL8-signaling. In addition, up-regulated aldo-keto reductase levels of the AKR1C family involved in prostaglandin synthesis contribute to the resistant phenotype. Finally, selected metabolic and oxidative stress response enzymes were targeted by inhibitors, several of which displayed a selective cytotoxicity against the melphalan-resistant cells and should be further explored to elucidate their potential to overcome melphalan resistance.

Background: The four heterogeneous childhood cancers, neuroblastoma, non-Hodgkin lymphoma, rhabdomyosarcoma, and Ewing sarcoma present a similar histology of small round blue cell tumor (SRBCT) and thus often leads to misdiagnosis. Identification of biomarkers for distinguishing these cancers is a well studied problem. Existing methods typically evaluate each gene separately and do not take into account the nonlinear interaction between genes and the tools that are used to design the diagnostic prediction system. Consequently, more genes are usually identified as necessary for prediction. We propose a general scheme for finding a small set of biomarkers to design a diagnostic system for accurate classification of the cancer subgroups. We use multilayer networks with online gene selection ability and relational fuzzy clustering to identify a small set of biomarkers for accurate classification of the training and blind test cases of a well studied data set.

The polymeric immunoglobulin receptor (pIgR) plays a pivotal role in mucosal immune protection by transporting secretory immunoglobulins to mucosal epithelia, and protecting them from proteolytic degradation. It has been reported that a homolog of the pIgR has a similar role in teleost fish. Considering the role pIgR has in mucosal defenses, this study was initiated to characterize a possible pIgR homolog in Atlantic salmon (Salmo salar) and its relatedness to pIgR of other vertebrates and similar molecules. Two pIgR-like cDNAs and genes of Atlantic salmon (Salsal pIgR and Salsal pIgRL) were cloned and analyzed. In addition, we gathered sequence information of CMRF35-like molecules (CLM) 1, 7, and 8 (designated as CD300 in humans) and made a comparative evaluation to that of the Salsal pIgR and Salsal pIgRL polypeptides. Salsal pIgR and Salsal pIgRL, like pIgR in other teleosts, are composed of two IG V domains, a connecting, a transmembrane, and a cytoplasmic region. The same holds true for Atlantic salmon CLM1 and CLM7, except that they possess putative immunoreceptor tyrosine-based inhibitory motifs (ITIM) in their cytoplasmic tails. The abundance of Salsal pIgR transcript is significantly higher than Salsal pIgRL and CLM in the skin, while Salsal pIgRL transcripts were abundant in the gills, depicting their possible tissue-specific role in mucosal immunity. To further highlight the roles of these molecules in cutaneous mucosal defence, we compared their transcriptional changes in salmon skin and spleen infected with the ectoparasite Lepeophtheirus salmonis which targets skin and mucus of salmonid fish (sampled 3, 14 and 28 days post infection (dpi)). Salsal pIgR and Salsal pIgRL transcripts significantly increased after 14dpi in skin and spleen. CLM1 was up-regulated in skin and down-regulated in spleen, possibly indicating that CLM1 expressing cells had migrated to the target site. Homology modeling using human pIgR domain 1 (PDB 1xed) identified structurally equivalent residues on both Salsal pIgR and Salsal pIgRL, and the same domain disulphide bridge topology. Cysteines 42 and 50 (IMGT numbering) are 7 residues apart in all V domains of Salsal pIgR, Salsal pIgRL, and mammalian [D1].

Given the association between high aerobic capacity and the prevention of metabolic diseases, elucidating the mechanisms by which high aerobic capacity regulates whole-body metabolic homeostasis is a major research challenge. Oxidative post-translational modifications (Ox-PTMs) of proteins can regulate cellular homeostasis in skeletal and cardiac muscles, but the relationship between Ox-PTMs and intrinsic components of oxidative energy metabolism is still unclear. Here, we evaluated the Ox-PTM profile in cardiac and skeletal muscles of rats bred for low (LCR) and high (HCR) intrinsic aerobic capacity. Redox proteomics screening revealed different cysteine (Cys) Ox-PTM profile between HCR and LCR rats. HCR showed a higher number of oxidized Cys residues in skeletal muscle compared to LCR, while the opposite was observed in the heart. Most proteins with differentially oxidized Cys residues in the skeletal muscle are important regulators of oxidative metabolism. The most oxidized protein in the skeletal muscle of HCR rats was malate dehydrogenase (MDH1). HCR showed higher MDH1 activity compared to LCR in skeletal, but not cardiac muscle. These novel findings indicate a clear association between Cys Ox-PTMs and aerobic capacity, leading to novel insights into the role of Ox-PTMs as an essential signal to maintain metabolic homeostasis.

Xenorhabdus nematophila secretes insecticidal proteins to kill its larval prey. We have isolated an ϳ58-kDa GroEL homolog, secreted in the culture medium through outer membrane vesicles. The protein was orally insecticidal to the major crop pest Helicoverpa armigera with an LC 50 of ϳ3.6 g/g diet.