The patterns and dynamics of genomic instability in metastatic pancreatic cancer

Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97-98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2-M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.     

Discovering the Principle of Finality in Computational Machines

In this essay we argue that the notion of machine necessarily includes its being designed for a purpose. Therefore, being a mechanical system is not enough for being a machine. Since the experimental scientific method excludes any consideration of finality on methodological grounds, it is then also insufficient to fully understand what machines are. Instead in order to understand a machine it is first required to understand its purpose, along with its structure, in clear parallel with Aristotle’s final and formal causes. Obviously, purpose and structure are not machine components that can physically interact with other components; nonetheless they are essential to understanding their operation. This casts an interesting light on the relationship between mind and body: for just as an artifact’s finality and structure explain its operation, so also consciousness is the explanation—not the efficient cause—of specifically human behavior. What machines and human beings have in common is that, in order to understand them, it is necessary to appeal to the principle of finality. Yet while finality is given and extrinsic in the case of machines, we human beings are characterized by the ability to self-propose our own ends. Since the principle of finality is essential to understanding the production of machines, the traditional view in modern Western philosophy that finality lies beyond the scope of objective/scientific knowledge should be rectified to allow for a genuine science of the artificial. We think a correct understanding of final causality will overcome current resistance to this principle.     

Puff activity after heat shock in two species of the Drosophila obscura group

When individuals of Drosophila guanche are submitted to heat shock, five new puffs are induced. These puffs usually do not appear during normal development. Comparing these results with those obtained in Drosophila subobscura, also belonging to the obscura group, differences between the induced puffing pattern of both species have been found.     

VRK1 and AURKB form a complex that cross inhibit their kinase activity and the phosphorylation of histone H3 in the progression of mitosis

Regulation of cell division requires the integration of signals implicated in chromatin reorganization and coordination of its sequential changes in mitosis. Vaccinia-related kinase 1 (VRK1) and Aurora B (AURKB) are two nuclear kinases involved in different steps of cell division. We have studied whether there is any functional connection between these two nuclear kinases, which phosphorylate histone H3 in Thr3 and Ser10, respectively. VRK1 and AURKB are able to form a stable protein complex, which represents only a minor subpopulation of each kinase within the cell and is detected following nocodazole release. Each kinase is able to inhibit the kinase activity of the other kinase, as well as inhibit their specific phosphorylation of histone H3. In locations where the two kinases interact, there is a different pattern of histone modifications, indicating that there is a local difference in chromatin during mitosis because of the local complexes formed by these kinases and their asymmetric intracellular distribution. Depletion of VRK1 downregulates the gene expression of BIRC5 (survivin) that recognizes H3-T3ph, both are dependent on the activity of VRK1, and is recovered with kinase active murine VRK1, but not with a kinase-dead protein. The H3–Thr3ph–survivin complex is required for AURB recruitment, and their loss prevents the localization of ACA and AURKB in centromeres. The cross inhibition of the kinases at the end of mitosis might facilitate the formation of daughter cells. A sequential role for VRK1, AURKB, and haspin in the progression of mitosis is proposed.     

Stephonyx californiensis sp. nov. (Amphipoda: Lysianassoidea: Uristidae), a new bathyal scavenger species from the Central Gulf of California,Mexico, and comments on the bathymetric and geographic distribution of the Stephonyx species group

A new species of scavenger amphipod of the genus Stephonyx is described and illustrated. The specimen was caught at 1150 m depth with a modified rectangular lobster trap positioned on the sea bottom in the central Gulf of California, Mexico. The new species is characterised by the absence of eyes; the lateral cephalic lobes medially developed and acute; antennae subequal in length; gnathopod 1 chelate, dactylus simple with three distal stout setae, inner margin sinuous with minute setae; gnathopod 2 subchelate, carpus with ventral margin crenulate, propodus subovate, palm deeply excavate, and dactylus slightly shorter than palm; maxilliped inner plate laceolate, with seven marginal nodular robust setae, distally; telson, each lobe with two dorsal robust setae, distal margin truncated, with one penicillate and two simple setae, in addition to two short spines. Stephonyx californiensis sp. nov. is morphologically similar to S. arabiensis, S talismani, S. laqueus and S. perexcavatus. The new species increases the number of Stephonyx species around the world to 14, with one species inhabiting from the continental shelf to abyssal depths (to 3000 m), 11 species occurring in bathyal depths (201–2000 m), and two other species restricted to abyssal depths (2001–4000 m).

www.zoobank.org/urn:lsid:zoobank.org:pub:346C3B15-E56A-4E17-9C5F-C9FDBB2AED92     

Targeting mitochondria by α-tocopheryl succinate kills neuroblastoma cells irrespective of MycN oncogene expression

Amplification of the MycN oncogene characterizes a subset of highly aggressive neuroblastomas, the most common extracranial solid tumor of childhood. However, the significance of MycN amplification for tumor cell survival is controversial, since down-regulation of MycN was found to decrease markedly neuroblastoma sensitivity towards conventional anticancer drugs, cisplatin, and doxorubicin. Here, we show that a redox-silent analogue of vitamin E, α-tocopheryl succinate (α-TOS), which triggers apoptotic cell death via targeting mitochondria, can kill tumor cells irrespective of their MycN expression level. In cells overexpressing MycN, as well as cells in which MycN was switched off, α-TOS stimulated rapid entry of Ca(2+) into the cytosol, compromised Ca(2+) buffering capacity of the mitochondria and sensitized them towards mitochondrial permeability transition and subsequent apoptotic cell death. Prevention of mitochondrial Ca(2+) accumulation or chelation of cytosolic Ca(2+) rescued the cells. Thus, targeting mitochondria might be advantageous for the elimination of tumor cells with otherwise dormant apoptotic pathways.     

CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium

Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function. However, its relationship to disorders of the primary cilium, termed ciliopathies, has not been explored. Here we mapped a new locus for Joubert syndrome (JBTS), which we have designated as JBTS15, and identified causative mutations in CEP41, which encodes a 41-kDa centrosomal protein. We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme. Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mice and results in glutamylation defects in the ciliary axoneme. Our data identify CEP41 mutations as a cause of JBTS and implicate tubulin post-translational modification in the pathogenesis of human ciliary dysfunction.     

Anisakis simplex complex (Nematoda: Anisakidae) in zooplankton communities from temperate NE Atlantic waters

The euphausiid Nyctiphanes couchii and an unidentified mysid have been found, for the first time, with third-stage larvae (L₃) of the Anisakis simplex complex in the mesozooplanktonic community of the coastal upwelling system in Galicia (NW Spain). Parasite larvae were molecularly identified using the internal transcribed spacer (ITS) region. The prevalence of these parasites in the euphausiid population was 0.0019%. The existence of parasites in a variety of mesozooplankton organisms suggests that the transmission routes of A. simplex sensu stricto and A. pegrefii are wider than expected. The results suggest that these two Anisakis species are not specific to their intermediate hosts. Finally, the recruitment of A. simplex complex may be affected by oceanography, differing under upwelling or downwelling conditions.