Predator control promotes invasive dominated ecological states

Invasive species are regarded as one of the top five drivers of the global extinction crisis. In response, extreme measures have been applied in an attempt to control or eradicate invasives, with little success overall. We tested the idea that state shifts to invasive dominance are symptomatic of losses in ecosystem resilience, due to the suppression of apex predators. This concept was investigated in Australia where the high rate of mammalian extinctions is largely attributed to the destructive influence of invasive species. Intensive pest control is widely applied across the continent, simultaneously eliminating Australia’s apex predator, the dingo (Canis lupus dingo). We show that predator management accounts for shifts between two main ecosystem states. Lethal control fractures dingo social structure and leads to bottom-up driven increases in invasive mesopredators and herbivores. Where control is relaxed, dingoes re-establish top–down regulation of ecosystems, allowing for the recovery of biodiversity and productivity.

Protected species use of a coastal marine migratory corridor connecting marine protected areas

The establishment of protected corridors linking the breeding and foraging grounds of many migratory species remains deficient, particularly in the world's oceans. For example, Australia has recently established a network of Commonwealth Marine Reserves, supplementing existing State reserves, to protect a wide range of resident and migratory marine species; however, the routes used by mobile species to access these sites are often unknown. The flatback marine turtle (Natator depressus) is endemic to the continental shelf of Australia, yet information is not available about how this species uses the marine area. We used a geospatial approach to delineate a coastal corridor from 73 adult female flatback postnesting migratory tracks from four rookeries along the north-west coast of Australia. A core corridor of 1,150 km length and 30,800 km2 area was defined, of which 52 % fell within 11 reserves, leaving 48 % (of equivalent size to several Commonwealth Reserves) of the corridor outside of the reserve network. Despite limited data being available for other marine wildlife in this region, humpback whale migratory tracks overlapped with 96 % of the core corridor, while the tracks of three other species overlapped by 5-10 % (blue whales, olive ridley turtles, whale sharks). The overlap in the distribution ranges of at least 20 other marine vertebrates (dugong, cetaceans, marine turtles, sea snakes, crocodiles, sharks) with the corridor also imply potential use. In conclusion, this study provides valuable information towards proposing new locations requiring protection, as well as identifying high-priority network linkages between existing marine protected areas. © 2014 Springer-Verlag Berlin Heidelberg.

Renal bioenergetics during early gram-negative mammalian sepsis and angiotensin II infusion

Purpose: To measure renal adenosine triphosphate (ATP) (bioenergetics) during hypotensive sepsis with or without angiotensin II (Ang II) infusion. Methods: In anaesthetised sheep implanted with a renal artery flow probe and a magnetic resonance coil around one kidney, we induced hypotensive sepsis with intravenous Escherichia coli injection. We measured mean arterial pressure (MAP), heart rate, renal blood flow RBF and renal ATP levels using magnetic resonance spectroscopy. After 2 h of sepsis, we randomly assigned sheep to receive an infusion of Ang II or vehicle intravenously and studied the effect of treatment on the same variables. Results: After E. coli administration, the experimental animals developed hypotensive sepsis (MAP from 92 ± 9 at baseline to 58 ± 4 mmHg at 4 h). Initially, RBF increased, then, after 4 h, it decreased below control levels (from 175 ± 28 at baseline to 138 ± 27 mL/min). Despite decreased RBF and hypotension, renal ATP was unchanged (total ATP to inorganic phosphate ratio from 0.69 ± 0.02 to 0.70 ± 0.02). Ang II infusion restored MAP but caused significant renal vasoconstriction. However, it induced no changes in renal ATP (total ATP to inorganic phosphate ratio from 0.79 ± 0.03 to 0.80 ± 0.02). Conclusions:During early hypotensive experimental Gram-negative sepsis, there was no evidence of renal bioenergetic failure despite decreased RBF. In this setting, the addition of a powerful renal vasoconstrictor does not lead to deterioration in renal bioenergetics.

A fission yeast homolog of Int-6, the mammalian oncoprotein and eIF3 subunit, induces drug resistance when overexpressed

Through a screen to identify genes that induce multi-drug resistance when overexpressed, we have identified a fission yeast homolog of Int-6, a component of the human translation initiation factor eIF3. Disruption of the murine Int-6 gene by mouse mammary tumor virus (MMTV) has been implicated previously in tumorigenesis, although the underlying mechanism is not yet understood. Fission yeast Int6 was shown to interact with other presumptive components of eIF3 in vivo, and was present in size fractions consistent with its incorporation into a 43S translation preinitiation complex. Drug resistance induced by Int6 overexpression was dependent on the AP-1 transcription factor Pap1, and was associated with increased abundance of Pap1-responsive mRNAs, but not with Pap1 relocalization. Fission yeast cells lacking the int6 gene grew slowly. This growth retardation could be corrected by the expression of full length Int6 of fission yeast or human origin, or by a C-terminal fragment of the fission yeast protein that also conferred drug resistance, but not by truncated human Int-6 proteins corresponding to the predicted products of MMTV-disrupted murine alleles. Studies in fission yeast may therefore help to explain the ways in which Int-6 function can be perturbed during MMTV-induced mammary tumorigenesis.

Subcellular localization of proteasomes and their regulatory complexes in mammalian cells

Proteasomes can exist in several different molecular forms in mammalian cells. The core 20S proteasome, containing the proteolytic sites, binds regulatory complexes at the ends of its cylindrical structure. Together with two 19S ATPase regulatory complexes it forms the 26S proteasome, which is involved in ubiquitin-dependent proteolysis. The 20S proteasome can also bind 11S regulatory complexes (REG, PA28) which play a role in antigen processing, as do the three variable c-interferoninducible catalytic b-subunits (e.g. LMP7). In the present study, we have investigated the subcellular distribution of the different forms of proteasomes using subunit speci®c antibodies. Both 20S proteasomes and their 19S regulatory complexes are found in nuclear, cytosolic and microsomal preparations isolated from rat liver. LMP7 was enriched approximately two-fold compared with core a-type proteasome subunits in the microsomal preparations. 20S proteasomes were more abundant than 26S proteasomes, both in liver and cultured cell lines. Interestingly, some signi®cant differences were observed in the distribution of different subunits of the 19S regulatory complexes. S12, and to a lesser extent p45, were found to be relatively enriched in nuclear fractions from rat liver, and immuno¯uorescent labelling of cultured cells with anti-p45 antibodies showed stronger labelling in the nucleus than in the cytoplasm. The REG was found to be localized predominantly in the cytoplasm. Three- to six-fold increases in the level of REG were observed following cinterferon treatment of cultured cells but c-interferon had no obvious effect on its subcellular distribution. These results demonstrate that different regulatory complexes and subpopulations of proteasomes have different distributions within mammalian cells and, therefore, that the distribution is more complex than has been reported for yeast proteasomes.

Mammalian phylogeny

Living mammals can be divided into three subclasses (monotremes, marsupials and placentals) and within these, about 27 orders. Final resolution of the relationships between the orders is only now being achieved with the increased availability of deoxyribonucleic acid (DNA) sequences. Highlights include the deep division of placental mammals into African (Afrotheria), South American (Xenarthra) and northern hemisphere (Boreoeutheria) super-orders, and the finding that the once considered primitive ‘Insectivora’ and ‘Edentata’ clades, in fact, have members distributed widely among these super-orders. Another surprise finding from DNA studies has been that whale origins lie among the even-toed ungulates (Artiodactyla). Our order, Primates is most closely related to the flying lemurs and next, the tree shrews. With the mammal phylogeny becoming well resolved, it is increasingly being used as a framework for inferring evolutionary and ecological processes, such as adaptive radiation.

'Nothing exists for one cause' : putting biology back into evolution

The opening phrase of the title is from Charles Darwin’s notebooks (Schweber 1977). It is a double reminder, firstly that mainstream evolutionary theory is not just about describing nature but is particularly looking for mechanisms or ‘causes’, and secondly, that there will usually be several causes affecting any particular outcome. The second part of the title is our concern at the almost universal rejection of the idea that biological mechanisms are sufficient for macroevolutionary changes, thus rejecting a cornerstone of Darwinian evolutionary theory. Our primary aim here is to consider ways of making it easier to develop and to test hypotheses about evolution. Formalizing hypotheses can help generate tests. In an absolute sense, some of the discussion by scientists about evolution is little better than the lack of reasoning used by those advocating intelligent design. Our discussion here is in a Popperian framework where science is defined by that area of study where it is possible, in principle, to find evidence against hypotheses – they are in principle falsifiable. However, with time, the boundaries of science keep expanding. In the past, some aspects of evolution were outside the current boundaries of falsifiable science, but increasingly new techniques and ideas are expanding the boundaries of science and it is appropriate to re-examine some topics. It often appears that over the last few decades there has been an increasingly strong assumption to look first (and only) for a physical cause. This decision is virtually never formally discussed, just an assumption is made that some physical factor ‘drives’ evolution. It is necessary to examine our assumptions much more carefully. What is meant by physical factors ‘driving’ evolution, or what is an ‘explosive radiation’. Our discussion focuses on two of the six mass extinctions, the fifth being events in the Late Cretaceous, and the sixth starting at least 50,000 years ago (and is ongoing). Cretaceous/Tertiary boundary; the rise of birds and mammals. We have had a long-term interest (Cooper and Penny 1997) in designing tests to help evaluate whether the processes of microevolution are sufficient to explain macroevolution. The real challenge is to formulate hypotheses in a testable way. For example the numbers of lineages of birds and mammals that survive from the Cretaceous to the present is one test. Our first estimate was 22 for birds, and current work is tending to increase this value. This still does not consider lineages that survived into the Tertiary, and then went extinct later. Our initial suggestion was probably too narrow in that it lumped four models from Penny and Phillips (2004) into one model. This reduction is too simplistic in that we need to know about survival and ecological and morphological divergences during the Late Cretaceous, and whether Crown groups of avian or mammalian orders may have existed back into the Cretaceous. More recently (Penny and Phillips 2004) we have formalized hypotheses about dinosaurs and pterosaurs, with the prediction that interactions between mammals (and groundfeeding birds) and dinosaurs would be most likely to affect the smallest dinosaurs, and similarly interactions between birds and pterosaurs would particularly affect the smaller pterosaurs. There is now evidence for both classes of interactions, with the smallest dinosaurs and pterosaurs declining first, as predicted. Thus, testable models are now possible. Mass extinction number six: human impacts. On a broad scale, there is a good correlation between time of human arrival, and increased extinctions (Hurles et al. 2003; Martin 2005; Figure 1). However, it is necessary to distinguish different time scales (Penny 2005) and on a finer scale there are still large numbers of possibilities. In Hurles et al. (2003) we mentioned habitat modification (including the use of Geogenes III July 2006 31 fire), introduced plants and animals (including kiore) in addition to direct predation (the ‘overkill’ hypothesis). We need also to consider prey switching that occurs in early human societies, as evidenced by the results of Wragg (1995) on the middens of different ages on Henderson Island in the Pitcairn group. In addition, the presence of human-wary or humanadapted animals will affect the distribution in the subfossil record. A better understanding of human impacts world-wide, in conjunction with pre-scientific knowledge will make it easier to discuss the issues by removing ‘blame’. While continued spontaneous generation was accepted universally, there was the expectation that animals continued to reappear. New Zealand is one of the very best locations in the world to study many of these issues. Apart from the marine fossil record, some human impact events are extremely recent and the remains less disrupted by time.

Localization of Mineralocorticoid Receptors at Mammalian Synapses

In the brain, membrane associated nongenomic steroid receptors can induce fast-acting responses to ion conductance and second messenger systems of neurons. Emerging data suggest that membrane associated glucocorticoid and mineralocorticoid receptors may directly regulate synaptic excitability during times of stress when adrenal hormones are elevated. As the key neuron signaling interface, the synapse is involved in learning and memory, including traumatic memories during times of stress. The lateral amygdala is a key site for synaptic plasticity underlying conditioned fear, which can both trigger and be coincident with the stress response. A large body of electrophysiological data shows rapid regulation of neuronal excitability by steroid hormone receptors. Despite the importance of these receptors, to date, only the glucocorticoid receptor has been anatomically localized to the membrane. We investigated the subcellular sites of mineralocorticoid receptors in the lateral amygdala of the Sprague-Dawley rat. Immunoblot analysis revealed the presence of mineralocorticoid receptors in the amygdala. Using electron microscopy, we found mineralocorticoid receptors expressed at both nuclear including: glutamatergic and GABAergic neurons and extra nuclear sites including: presynaptic terminals, neuronal dendrites, and dendritic spines. Importantly we also observed mineralocorticoid receptors at postsynaptic membrane densities of excitatory synapses. These data provide direct anatomical evidence supporting the concept that, at some synapses, synaptic transmission is regulated by mineralocorticoid receptors. Thus part of the stress signaling response in the brain is a direct modulation of the synapse itself by adrenal steroids.

Overexpression of the mammalian target of rapamycin (mTOR) and angioinvasion are poor prognostic factors in early stage NSCLC: A verification study

Background: A recent study by Dhillon et al. [12], identified both angioinvasion and mTOR as prognostic biomarkers for poor survival in early stage NSCLC. The aim of this study was to verify the above study by examining the angioinvasion and mTOR expression profile in a cohort of early stage NSCLC patients and correlate the results to patient clinico-pathological data and survival. Methods: Angioinvasion was routinely recorded by the pathologist at the initial assessment of the tumor following resection. mTOR was evaluated in 141 early stage (IA-IIB) NSCLC patients (67 - squamous; 60 - adenocarcinoma; 14 - others) using immunohistochemistry (IHC) analysis with an immunohistochemical score (IHS) calculated (% positive cells × staining intensity). Intensity was scored as follows: 0 (negative); 1+ (weak); 2+ (moderate); 3+ (strong). The range of scores was 0-300. Based on the previous study a cut-off score of 30 was used to define positive versus negative patients. The impact of angioinvasion and mTOR expression on prognosis was then evaluated. Results: 101 of the 141 tumors studied expressed mTOR. There was no difference in mTOR expression between squamous cell carcinoma and adenocarcinoma. Angioinvasion (p= 0.024) and mTOR staining (p= 0.048) were significant univariate predictors of poor survival. Both remained significant after multivariate analysis (p= 0.037 and p= 0.020, respectively). Conclusions: Our findings verify angioinvasion and mTOR expression as new biomarkers for poor outcome in patients with early stage NSCLC. mTOR expressing patients may benefit from novel therapies targeting the mTOR survival pathway. © 2011 Elsevier Ireland Ltd.

Structures of μOconotoxins from Conusmarmoreus. Inhibitors of tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels in mammalian sensory neurons

The μO-conotoxins are an intriguing class of conotoxins targeting various voltage-dependent sodium channels and molluscan calcium channels. In the current study, we have shown MrVIA and MrVIB to be the first known peptidic inhibitors of the transient tetrodotoxin-resistant (TTX-R) Na+ current in rat dorsal root ganglion neurons, in addition to inhibiting tetrodotoxin-sensitive Na+ currents. Human TTX-R sodium channels are a therapeutic target for indications such as pain, highlighting the importance of the μO-conotoxins as potential leads for drug development. Furthermore, we have used NMR spectroscopy to provide the first structural information on this class of conotoxins. MrVIA and MrVIB are hydrophobic peptides that aggregate in aqueous solution but were solubilized in 50% acetonitrile/water. The three-dimensional structure of MrVIB consists of a small β-sheet and a cystine knot arrangement of the three-disulfide bonds. It contains four backbone “loops” between successive cysteine residues that are exposed to the solvent to varying degrees. The largest of these, loop 2, is the most disordered part of the molecule, most likely due to flexibility in solution. This disorder is the most striking difference between the structures of MrVIB and the known δ- and ω-conotoxins, which along with the μO-conotoxins are members of the O superfamily. Loop 2 of ω-conotoxins has previously been shown to contain residues critical for binding to voltage-gated calcium channels, and it is interesting to speculate that the flexibility observed in MrVIB may accommodate binding to both sodium and molluscan calcium channels.