Transient dynamics of an altered large marine ecosystem

Overfishing of large-bodied benthic fishes and their subsequent population collapses on the Scotian Shelf of Canada's east coast and elsewhere resulted in restructuring of entire food webs now dominated by planktivorous, forage fish species and macroinvertebrates. Despite the imposition of strict management measures in force since the early 1990s, the Scotian Shelf ecosystem has not reverted back to its former structure. Here we provide evidence of the transient nature of this ecosystem and its current return path towards benthic fish species domination. The prolonged duration of the altered food web, and its current recovery, was and is being governed by the oscillatory, runaway consumption dynamics of the forage fish complex. These erupting forage species, which reached biomass levels 900% greater than those prevalent during the pre-collapse years of large benthic predators, are now in decline, having outstripped their zooplankton food supply. This dampening, and the associated reduction in the intensity of predation, was accompanied by lagged increases in species abundances at both lower and higher trophic levels, first witnessed in zooplankton and then in large-bodied predators, all consistent with a return towards the earlier ecosystem structure. We conclude that the reversibility of perturbed ecosystems can occur and that this bodes well for other collapsed fisheries.     

Antibodies to human serum amyloid P component eliminate visceral amyloid deposits

Accumulation of amyloid fibrils in the viscera and connective tissues causes systemic amyloidosis, which is responsible for about one in a thousand deaths in developed countries. Localized amyloid can also have serious consequences; for example, cerebral amyloid angiopathy is an important cause of haemorrhagic stroke. The clinical presentations of amyloidosis are extremely diverse and the diagnosis is rarely made before significant organ damage is present. There is therefore a major unmet need for therapy that safely promotes the clearance of established amyloid deposits. Over 20 different amyloid fibril proteins are responsible for different forms of clinically significant amyloidosis and treatments that substantially reduce the abundance of the respective amyloid fibril precursor proteins can arrest amyloid accumulation. Unfortunately, control of fibril-protein production is not possible in some forms of amyloidosis and in others it is often slow and hazardous. There is no therapy that directly targets amyloid deposits for enhanced clearance. However, all amyloid deposits contain the normal, non-fibrillar plasma glycoprotein, serum amyloid P component (SAP). Here we show that administration of anti-human-SAP antibodies to mice with amyloid deposits containing human SAP triggers a potent, complement-dependent, macrophage-derived giant cell reaction that swiftly removes massive visceral amyloid deposits without adverse effects. Anti-SAP-antibody treatment is clinically feasible because circulating human SAP can be depleted in patients by the bis-d-proline compound CPHPC, thereby enabling injected anti-SAP antibodies to reach residual SAP in the amyloid deposits. The unprecedented capacity of this novel combined therapy to eliminate amyloid deposits should be applicable to all forms of systemic and local amyloidosis.     

Maternal investment. Sex differences in avian yolk hormone levels

It has been suggested that female birds put more resources into eggs fathered by attractive males by laying larger eggs or by adding more testosterone, but this inference could be undermined if eggs of different sex are provisioned differently, as these studies did not control for sex differences. Here we compare hormone concentrations in the yolks of male and female eggs and find that these are significantly different. Our results indicate that it is premature to conclude that female birds invest more in eggs sired by a preferred male, and raise the possibility that yolk sex steroids may be part of the sex-determining process in birds.     

Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer

CpG island hypermethylation and global genomic hypomethylation are common epigenetic features of cancer cells. Less attention has been focused on histone modifications in cancer cells. We characterized post-translational modifications to histone H4 in a comprehensive panel of normal tissues, cancer cell lines and primary tumors. Using immunodetection, high-performance capillary electrophoresis and mass spectrometry, we found that cancer cells had a loss of monoacetylated and trimethylated forms of histone H4. These changes appeared early and accumulated during the tumorigenic process, as we showed in a mouse model of multistage skin carcinogenesis. The losses occurred predominantly at the acetylated Lys16 and trimethylated Lys20 residues of histone H4 and were associated with the hypomethylation of DNA repetitive sequences, a well-known characteristic of cancer cells. Our data suggest that the global loss of monoacetylation and trimethylation of histone H4 is a common hallmark of human tumor cells.     

Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy

The identification of somatic activating mutations in JAK2 (refs?1–4) and in the thrombopoietin receptor gene (MPL) in most patients with myeloproliferative neoplasm (MPN) led to the clinical development of JAK2 kinase inhibitors. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms but does not significantly decrease or eliminate the MPN clone in most patients with MPN. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic inhibition of JAK2. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK–STAT signalling and with heterodimerization between activated JAK2 and JAK1 or TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible: JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, in murine models and in patients treated with JAK2 inhibitors. RNA interference and pharmacological studies show that JAK2-inhibitor-persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors.