Cool Sex? Hibernation and Reproduction Overlap in the Echidna

During hibernation there is a slowing of all metabolic processes, and thus it is normally considered to be incompatible with reproduction. In Tasmania the egg-laying mammal, the echidna (Tachyglossus aculeatus) hibernates for several months before mating in mid-winter, and in previous studies we observed males with females that were still hibernating. We monitored the reproductive activity of radio-tracked echidnas by swabbing the reproductive tract for sperm while external temperature loggers provided information on the timing of hibernation. Additional information was provided by camera traps and ultrasound imaging. More than a third of the females found in mating groups were torpid, and the majority of these had mated. Some females re-entered deep torpor for extended periods after mating. Ultrasound examination showed a developing egg in the uterus of a female that had repeatedly re-entered torpor. The presence of fresh sperm in cloacal swabs taken from this female on three occasions after her presumed date of fertilization indicated she mated several times after being fertilized. The mating of males with torpid females is the result of extreme competition between promiscuous males, while re-entry into hibernation by pregnant females could improve the possibility of mating with a better quality male

Integrating public participation, transparency and accountability into governance of marketing authorisation for genome editing products

Public participation, transparency and accountability are three of the pillars of good governance. These pillars become particularly important for innovative, personalised health technologies, because of the tendency of these technologies to raise distinct scientific, ethical, legal and social issues. Genome editing is perhaps the most personal of all innovative health technologies, involving precise modifications to an individual’s genome. This article focuses on the adequacy of current requirements for public participation, transparency and accountability in the governance of the market authorisation for genome edited products. Although clinical trials for genome edited products are only just underway, lessons can be drawn from the marketing approvals pathways for related gene therapy products. This article provides a broad overview of the regulatory pathways that have been adopted by the US Food and Drugs Administration, the European Medicines Authority, and the Australian Therapeutic Goods Administration for reviewing gene therapy products for marketing approval. This analysis focuses on the extent to which public participation processes and transparency and accountability of review pathways are incorporated into marketing approval policy and practice. Following this review, the article proposes the application of Sheila Jasanoff’s “technologies of humility” as a foundation for meaningfully incorporating these pillars of good governance into regulatory processes for the review of products of genome editing. We conclude by articulating clear mechanisms for operationalising technologies of humility in the context of public participation, transparency and accountability, providing a blueprint for future policy development

Beyond the disease: Is Toxoplasma gondii infection causing population declines in the eastern quoll (Dasyurus viverrinus)?

Disease is often considered a key threat to species of conservation significance. For some, it has resulted in localised extinctions and declines in range and abundance. However, for some species, the assertion that a disease poses a significant threat of extinction is based solely on correlative or anecdotal evidence, often inferred from individual clinical case reports. While a species' susceptibility to a disease may be demonstrated in a number of individuals, investigations rarely extend to measuring the impact of disease at the population level and its contribution, if any, to population declines. The eastern quoll (Dasyurus viverrinus) is a medium-sized Australian marsupial carnivore that is undergoing severe and rapid decline in Tasmania, its last refuge. Reasons for the decline are currently not understood. Feral cats (Felis catus) may be undergoing competitive release following the ongoing decline of the Tasmanian devil (Sarcophilus harrisii), with cats suppressing eastern quolls through increased predation, competition, exclusion or exposure to diseases such as toxoplasmosis. To investigate the effects of Toxoplasma gondii infection, eastern quoll populations at four sites were regularly screened for the seroprevalence of T. gondii-specific IgG antibodies. Seroprevalence was approximately five times higher at sites with declining quoll populations, and there was a negative association between seroprevalence and quoll abundance. However, T. gondii infection did not reduce quoll survival or reproduction. Despite a high susceptibility to T. gondii infection, eastern quoll populations do not appear to be limited by the parasite or its resultant disease. Significantly higher seroprevalence is a signal of greater exposure to feral cats at sites where eastern quolls are declining, suggesting that increased predation, competition or exclusion by feral cats may be precipitating population declines

Devil Declines and Catastrophic Cascades: Is Mesopredator Release of Feral Cats Inhibiting Recovery of the Eastern Quoll?

The eastern quoll (Dasyurus viverrinus) is a medium-sized Australian marsupial carnivore that has recently undergone a rapid and severe population decline over the 10 years to 2009, with no sign of recovery. This decline has been linked to a period of unfavourable weather, but subsequent improved weather conditions have not been matched by quoll recovery. A recent study suggested another mechanism: that declines in Tasmanian devil (Sarcophilus harrisii) populations, due to the spread of the fatal Devil Facial Tumour Disease, have released feral cats (Felis catus) from competitive suppression, with eastern quoll declines linked to a subsequent increase in cat sightings. Yet current evidence of intraguild suppression among devils, cats and quolls is scant and equivocal. We therefore assessed the influences of top-down effects on abundance and activity patterns among devils, feral cats and eastern quolls. Between 2011 and 2013, we monitored four carnivore populations using longitudinal trapping and camera surveys, and performed camera surveys at 12 additional sites throughout the eastern quoll's range. We did not find evidence of a negative relationship between devil and cat abundance, nor of higher cat abundance in areas where devil populations had declined the longest. Cats did not appear to avoid devils spatially; however, there was evidence of temporal separation of cat and devil activity, with reduced separation and increasing nocturnal activity observed in areas where devils had declined the longest. Cats and quolls used the same areas, and there was no evidence that cat and quoll abundances were negatively related. Temporal overlap in observed cat and quoll activity was higher in summer than in winter, but this seasonal difference was unrelated to devil declines. We suggest that cats did not cause the recent quoll decline, but that predation of juvenile quolls by cats could be inhibiting low density quoll populations from recovering their former abundance through a 'predator pit' effect following weather-induced decline. Predation intensity could increase further should cats become increasingly nocturnal in response to devil declines

Monotreme lactation protein is highly expressed in monotreme milk and provides antimicrobial protection

Monotremes (platypus and echidna) are the descendants of the oldest ancestor of all extant mammals distinguished from other mammals by mode of reproduction. Monotremes lay eggs following a short gestation period and after an even briefer incubation period, altricial hatchlings are nourished over a long lactation period with milk secreted by nipple-less mammary patches located on the female\u27s abdomen. Milk is the sole source of nutrition and immune protection for the developing young until weaning. Using transcriptome and mass spectrometry analysis of milk cells and milk proteins, respectively, a novel Monotreme Lactation Protein (MLP) was identified as a major secreted protein in milk. We show that platypus and short-beaked echidna MLP genes show significant homology and are unique to monotremes. The MLP transcript was shown to be expressed in a variety of tissues; however, highest expression was observed in milk cells and was expressed constitutively from early to late lactation. Analysis of recombinant MLP showed that it is an N-linked glycosylated protein and biophysical studies predicted that MLP is an amphipathic, α-helical protein, a typical feature of antimicrobial proteins. Functional analysis revealed MLP antibacterial activity against both opportunistic pathogenic Staphylococcus aureus and commensal Enterococcus faecalis bacteria but showed no effect on Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, and Salmonella enterica. Our data suggest that MLP is an evolutionarily ancient component of milk-mediated innate immunity absent in other mammals. We propose that MLP evolved specifically in the monotreme lineage supporting the evolution of lactation in these species to provide bacterial protection, at a time when mammals lacked nipples

Precision scans of the pixel cell response of double sided 3D pixel detectors to pion and x-ray beams

hree-dimensional (3D) silicon sensors offer potential advantages over standard planar sensors for radiation hardness in future high energy physics experiments and reduced charge-sharing for X-ray applications, but may introduce inefficiencies due to the columnar electrodes. These inefficiencies are probed by studying variations in response across a unit pixel cell in a 55μm pitch double-sided 3D pixel sensor bump bonded to TimePix and Medipix2 readout ASICs. Two complementary characterisation techniques are discussed: the first uses a custom built telescope and a 120GeV pion beam from the Super Proton Synchrotron (SPS) at CERN; the second employs a novel technique to illuminate the sensor with a micro-focused synchrotron X-ray beam at the Diamond Light Source, UK. For a pion beam incident perpendicular to the sensor plane an overall pixel efficiency of 93.0±0.5% is measured. After a 10o rotation of the device the effect of the columnar region becomes negligible and the overall efficiency rises to 99.8±0.5%. The double-sided 3D sensor shows significantly reduced charge sharing to neighbouring pixels compared to the planar device. The charge sharing results obtained from the X-ray beam study of the 3D sensor are shown to agree with a simple simulation in which charge diffusion is neglected. The devices tested are found to be compatible with having a region in which no charge is collected centred on the electrode columns and of radius 7.6±0.6μm. Charge collection above and below the columnar electrodes in the double-sided 3D sensor is observed

Biodistribution and inflammatory profiles of novel penton and hexon double-mutant serotype 5 adenoviruses

The use of adenovirus serotype 5 (Ad5) vectors in the clinical setting is severely hampered by the profound liver tropism observed after intravascular delivery coupled with the pronounced inflammatory and innate immune response elicited by these vectors. Liver transduction by circulating Ad5 virions is mediated by a high-affinity interaction between the capsid hexon protein and blood coagulation factor X (FX), whilst penton-α(v)integrin interactions are thought to contribute to the induction of anti-Ad5 inflammatory and innate immune responses. To overcome these limitations, we sought to develop and characterise for the first time novel Ad5 vectors possessing mutations ablating both hexon:FX and penton:integrin interactions. As expected, intravascular administration of the FX binding-ablated Ad5HVR5*HVR7*E451Q vector (AdT*) resulted in significantly reduced liver transduction in vivo compared to Ad5. In macrophage-depleted mice, increased spleen uptake of AdT* was accompanied by an elevation in the levels of several inflammatory mediators. However ablation of the penton RGD motif in the AdT* vector background (AdT*RGE) resulted in a significant 5-fold reduction in spleen uptake and attenuated the antiviral inflammatory response. A reduction in spleen uptake and inflammatory activation was also observed in animals after intravascular administration of Ad5RGE compared to the parental Ad5 vector, with reduced co-localisation of the viral beta-galactosidase transgene with MAdCAM-1+ sinus-lining endothelial cells. Our detailed assessment of these novel adenoviruses indicates that penton base RGE mutation in combination with FX binding-ablation may be a viable strategy to attenuate the undesired liver uptake and pro-inflammatory responses to Ad5 vectors after intravascular deliver

Meta-analysis of the prevalence of renal cancer detected by abdominal ultrasonography

$\textbf{BACKGROUND}$: The potential for an ultrasound-based screening programme for renal cell carcinoma (RCC) to improve survival through early detection has been the subject of much debate. The prevalence of ultrasound-detected asymptomatic RCC is an important first step to establishing whether a screening programme may be feasible. $\textbf{METHODS}$: A systematic search of MEDLINE and Embase was performed up to March 2016 to identify studies reporting the prevalence of renal masses and RCC. Two populations of patients were chosen: asymptomatic individuals undergoing screening ultrasonography and patients undergoing ultrasonography for abdominal symptoms not related to RCC. A random-effects meta-analysis was performed. Study quality was evaluated using a validated eight-point checklist. $\textbf{RESULTS}$: Sixteen studies (413 551 patients) were included in the final analysis. The pooled prevalence of renal mass was 0·36 (95 per cent c.i. 0·23 to 0·52) per cent and the prevalence of histologically proven RCC was 0·10 (0·06 to 0·15) per cent. The prevalence of RCC was more than double in studies from Europe and North America than in those from Asia: 0·17 (0·09 to 0·27) versus 0·06 (0·03 to 0·09) per cent respectively. Data on 205 screen-detected RCCs showed that 84·4 per cent of tumours were stage T1-T2 N0, 13·7 per cent were T3-T4 N0, and only 2·0 per cent had positive nodes or metastases at diagnosis. $\textbf{CONCLUSION}$: At least one RCC would be detected per 1000 individuals screened. The majority of tumours identified are early stage (T1-T2).E.C.F.W. and G.D.S. are joint senior authors of this article. The authors thank J. J. Earnshaw, D. Hanbury and C. Watson for their advice and contribution to the design of the study. The authors acknowledge the Urology Foundation, which provided a travel grant for S.H.R. covering the cost of a course on performing meta-analyses, and the Renal Cancer Research Fund for providing a grant for S.H.R. to attend a health economics course. E.C.F.W. is funded by the NIHR Cambridge Biomedical Research Centre and S.H.R. is funded by an NIHR Academic Clinical Fellowship. There are no other sources of funding