The origin of interspersed repeats in the human genome

Over a third of the human genome consists of interspersed repetitive sequences which are primarily degenerate copies of transposable elements. In the past year, the identities of many of these transposable elements were revealed. The emerging concept is that only three mechanisms of amplification are responsible for the vast majority of interspersed repeats and that with each autonomous element a number of dependent non-autonomous sequences have co-amplified.     

Introduced megafauna are rewilding the Anthropocene

Large herbivorous mammals, already greatly reduced by the late‐Pleistocene extinctions, continue to be threatened with decline. However, many herbivorous megafauna (body mass ≥ 100 kg) have populations outside their native ranges. We evaluate the distribution, diversity and threat status of introduced terrestrial megafauna worldwide and their contribution towards lost Pleistocene species richness. Of 76 megafauna species, 22 (～29%) have introduced populations; of these eleven (50%) are threatened or extinct in their native ranges. Introductions have increased megafauna species richness by between 10% (Africa) and 100% (Australia). Furthermore, between 15% (Asia) and 67% (Australia) of extinct species richness, from the late Pleistocene to today, have been numerically replaced by introduced megafauna. Much remains unknown about the ecology of introduced herbivores, but evidence suggests that these populations are rewilding modern ecosystems. We propose that attitudes towards introduced megafauna should allow for broader research and management goals.     

Inhibitor-2 induced M-phase arrest in <Emphasis Type="Italic">Xenopus</Emphasis> cycling egg extracts is dependent on MAPK activation

The evolutionarily-conserved protein phosphatase 1 (PP1) plays a central role in dephosphorylation of phosphoproteins during the M phase of the cell cycle. We demonstrate here that the PP1 inhibitor inhibitor-2 protein (Inh-2) induces an M-phase arrest in Xenopus cycling egg extracts. Interestingly, the characteristics of this M-phase arrest are similar to those of mitogen-activated protein kinase (p42MAPK)-induced M-phase arrest. This prompted us to investigate whether Inh-2-induced M-phase arrest was dependent on activation of the p42MAPK pathway. We demonstrate here that MAPK activity is required for Inh-2-induced M-phase arrest, as inhibition of MAPK by PD98059 allowed cycling extracts to exit M phase, despite the presence of Inh-2. We next investigated whether Inh-2 phosphorylation by the MAPK pathway was required to induce an M-phase arrest. We discovered that while p90Rsk (a MAPK protein required for M-phase arrest) is able to phosphorylate Inh-2, this phosphorylation is not required for Inh-2 function. Overall, our results suggest a novel mechanism linking p42MAPK and PP1 pathways during M phase of the cell cycle.     

IL-2 controls the stability of Foxp3 expression in TGF-beta-induced Foxp3+ T cells in vivo

Stimulation of naive mouse CD4(+)Foxp3(-) T cells in the presence of TGF-β results in the induction of Foxp3 expression and T suppressor function. However, Foxp3 expression in these induced regulatory T cells (iTreg) is unstable, raising the possibility that iTreg would not be useful for treatment of autoimmune diseases. To analyze the factors that control the stability of Foxp3 expression in iTreg, we generated OVA-specific iTreg from OT-II Foxp3-GFP knockin mice. Following transfer to normal C57BL/6 mice, OT-II GFP(+) cells maintained high levels of Foxp3 expression for 8 d. However, they rapidly lost Foxp3 expression upon stimulation with OVA in IFA in vivo. This unstable phenotype was associated with a strong methylation of the Treg-specific demethylated region within the Foxp3 locus. Administration of IL-2/anti-IL-2 complexes expanded the numbers of transferred Foxp3(+) iTreg in the absence of Ag challenge. Notably, when the iTreg were stimulated with Ag, treatment with IL-2/anti-IL-2 complexes stabilized Foxp3 expression and resulted in enhanced demethylation of the Treg-specific demethylated region. Conversely, neutralization of IL-2 or disruption of its signaling by deletion of Stat5 diminished the level of Foxp3 expression resulting in decreased suppressor function of the iTreg in vivo. Our data suggest that stimulation with TGF-β in vitro is not sufficient for imprinting T cells with stable expression of Foxp3. Administration of IL-2 in vivo results in stabilization of Foxp3 expression and may prove to be a valuable adjunct for the use of iTreg for the treatment of autoimmune diseases.     

Adoptive T-cell therapy for malignant melanoma patients with TILs obtained by ultrasound-guided needle biopsy

Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) can mediate objective responses in up to 50% of malignant melanoma patients with a good performance status refractory to standard treatments. Current protocols for generation of TILs rely on open surgery for access to tumor tissue. We obtained tumor material by ultrasound-guided core needle biopsy or surgery from melanoma patients with progressive disease and were able to isolate >5 × 10⁶ TILs from 23 of 24 patients who were subsequently treated with these cells. One-third of the individual TIL-positive cultures displayed interferon gamma activity after stimulation with relevant melanoma cell lines. When expanded TILs were used for treatment in combination with daily low dose s.c. IL-2 after prior lymphodepleting chemotherapy, we observed objective clinical responses in one patient treated with TILs obtained from surgery and 4 patients treated with TILs from core biopsies. The results of this study demonstrate for the first time the potential of core biopsies for generation of relevant numbers of TILs that can mediate objective responses in patients with metastatic malignant melanoma. Ultrasound-guided core needle biopsy is a robust, safe and inexpensive approach to obtain tumor tissue for TIL generation, and is especially valuable in instances where surgery is contraindicated.     

More than Mere Numbers: The Impact of Lethal Control on the Social Stability of a Top-Order Predator

Population control of socially complex species may have profound ecological implications that remain largely invisible if only their abundance is considered. Here we discuss the effects of control on a socially complex top-order predator, the dingo (Canis lupus dingo). Since European occupation of Australia, dingoes have been controlled over much of the continent. Our aim was to investigate the effects of control on their abundance and social stability. We hypothesized that dingo abundance and social stability are not linearly related, and proposed a theoretical model in which dingo populations may fluctuate between three main states: (A) below carrying capacity and socially fractured, (B) above carrying capacity and socially fractured, or (C) at carrying capacity and socially stable. We predicted that lethal control would drive dingoes into the unstable states A or B, and that relaxation of control would allow recovery towards C. We tested our predictions by surveying relative abundance (track density) and indicators of social stability (scent-marking and howling) at seven sites in the arid zone subject to differing degrees of control. We also monitored changes in dingo abundance and social stability following relaxation and intensification of control. Sites where dingoes had been controlled within the previous two years were characterized by low scent-marking activity, but abundance was similar at sites with and without control. Signs of social stability steadily increased the longer an area was allowed to recover from control, but change in abundance did not follow a consistent path. Comparison of abundance and stability among all sites and years demonstrated that control severely fractures social groups, but that the effect of control on abundance was neither consistent nor predictable. Management decisions involving large social predators must therefore consider social stability to ensure their conservation and ecological functioning.