miR-9 Acts as an OncomiR in Prostate Cancer through Multiple Pathways That Drive Tumour Progression and Metastasis

Identification of dysregulated microRNAs (miRNAs) in prostate cancer is critical not only for diagnosis, but also differentiation between the aggressive and indolent forms of the disease. miR-9 was identified as an oncomiR through both miRNA panel RT-qPCR as well as high-throughput sequencing analysis of the human P69 prostate cell line as compared to its highly tumorigenic and metastatic subline M12, and found to be consistently upregulated in other prostate cell lines including DU-145 and PC3. While miR-9 has been characterized as dysregulated either as an oncomiR or tumour suppressor in a variety of other cancers including breast, ovarian, and nasopharyngeal carcinomas, it has not been previously evaluated and proven as an oncomiR in prostate cancer. miR-9 was confirmed an oncomiR when found to be overexpressed in tumour tissue as compared to adjacent benign glandular epithelium through laser-capture microdissection of radical prostatectomy biopsies. Inhibition of miR-9 resulted in reduced migratory and invasive potential of the M12 cell line, and reduced tumour growth and metastases in male athymic nude mice. Analysis showed that miR-9 targets e-cadherin and suppressor of cytokine signalling 5 (SOCS5), but not NF-ĸB mRNA. Expression of these proteins was shown to be affected by modulation in expression of miR-9

Interplay of Mre11 Nuclease with Dna2 plus Sgs1 in Rad51-Dependent Recombinational Repair

The Mre11/Rad50/Xrs2 complex initiates IR repair by binding to the end of a double-strand break, resulting in 5′ to 3′ exonuclease degradation creating a single-stranded 3′ overhang competent for strand invasion into the unbroken chromosome. The nuclease(s) involved are not well understood. Mre11 encodes a nuclease, but it has 3′ to 5′, rather than 5′ to 3′ activity. Furthermore, mutations that inactivate only the nuclease activity of Mre11 but not its other repair functions, mre11-D56N and mre11-H125N, are resistant to IR. This suggests that another nuclease can catalyze 5′ to 3′ degradation. One candidate nuclease that has not been tested to date because it is encoded by an essential gene is the Dna2 helicase/nuclease. We recently reported the ability to suppress the lethality of a dna2Δ with a pif1Δ. The dna2Δ pif1Δ mutant is IR-resistant. We have determined that dna2Δ pif1Δ mre11-D56N and dna2Δ pif1Δ mre11-H125N strains are equally as sensitive to IR as mre11Δ strains, suggesting that in the absence of Dna2, Mre11 nuclease carries out repair. The dna2Δ pif1Δ mre11-D56N triple mutant is complemented by plasmids expressing Mre11, Dna2 or dna2K1080E, a mutant with defective helicase and functional nuclease, demonstrating that the nuclease of Dna2 compensates for the absence of Mre11 nuclease in IR repair, presumably in 5′ to 3′ degradation at DSB ends. We further show that sgs1Δ mre11-H125N, but not sgs1Δ, is very sensitive to IR, implicating the Sgs1 helicase in the Dna2-mediated pathway

Molecular evidence for horizontal transmission of chelonid alphaherpesvirus 5 at green turtle (Chelonia mydas) foraging grounds in Queensland, Australia

Fibropapillomatosis (FP) is a marine turtle disease recognised by benign tumours on the skin, eyes, shell, oral cavity and/or viscera. Despite being a globally distributed disease that affects an endangered species, research on FP and its likely causative agent chelonid alphaherpesvirus 5 (ChHV5) in Australia is limited. Here we present improved molecular assays developed for detection of ChHV5, in combination with a robust molecular and phylogenetic analysis of ChHV5 variants. This approach utilised a multi-gene assay to detect ChHV5 in all FP tumors sampled from 62 marine turtles found at six foraging grounds along the Great Barrier Reef. Six distinct variants of ChHV5 were identified and the distribution of these variants was associated with host foraging ground. Conversely, no association between host genetic origin and ChHV5 viral variant was found. Together this evidence supports the hypothesis that marine turtles undergo horizontal transmission of ChHV5 at foraging grounds and are unlikely to be contracting the disease at rookeries, either during mating or vertically from parent to offspring

The Link between General Relativity and Shape Dynamics

We show that one can construct two equivalent gauge theories from a linking theory and give a general construction principle for linking theories which we use to construct a linking theory that proves the equivalence of General Relativity and Shape Dynamics, a theory with fixed foliation but spatial conformal invariance. This streamlines the rather complicated construction of this equivalence performed previously. We use this streamlined argument to extend the result to General Relativity with asymptotically flat boundary conditions. The improved understanding of linking theories naturally leads to the Lagrangian formulation of Shape Dynamics, which allows us to partially relate the degrees of freedom.Comment: 19 pages, LaTeX, no figure

Environmental effects of aircraft operations and airspace charging regimes. Final report

Project aim and outline: There has been anecdotal evidence that differences in airspace charging regimes influence airlines’ preferred routes and flight plans through European airspace. Routing aircraft over longer distances in order to reduce direct operating costs has a range of fuel burn and greenhouse gas emission consequences that have yet to be adequately quantified. The aim of this project is to study the environmental costs of different airspace charging regimes in Europe to ascertain whether the level of route charges that are levied for performing a flight affects the route that is flown between specific origin/destination pairs. Through a strategic assessment of a sample of airline flight plans and discussion with stakeholders, the study investigates the drivers of these apparently inefficient flight plans, quantifies the proportion of European routes that are affected (and the additional distances that are travelled) and identifies the greenhouse gas emission (focussing on carbon dioxide) implications of the observed behaviours

Climate related air traffic management. Final report. Assessing the role of air traffic management in reducing environmental impacts of aviation

Climate related air traffic management. Final report. Assessing the role of air traffic management in reducing environmental impacts of aviatio

Prva analiza izotopov in novi radiokarbonski datumi poljedelcev kulture Tripolje iz jame Verteba, Bilche Zolote, Ukrajina

This paper presents an analysis of human and animal remains from Verteba cave, near Bilche Zolote, western Ukraine. This study was prompted by a paucity of direct dates on this material and the need to contextualise these remains in relation both to the transition from hunting and gathering to farming in Ukraine, and their specific place within the Cucuteni-Trypillia culture sequence. The new absolute dating places the remains studied here in Trypillia stages BII/CI at c. 3900–3500 cal BC, with one individual now redated to the Early Scythian period. As such, these finds are even more exceptional than previously assumed, being some of the earliest discovered for this culture. The isotope analyses indicate that these individuals are local to the region, with the dietary stable isotopes indicating a C3 terrestrial diet for the Trypillia-period humans analysed. The Scythian period individual has δ13C ratios indicative of either c. 50% marine, or alternatively C4 plant inputs into the diet, despite δ18O and 87Sr/86Sr ratios that are comparable to the other individuals studied.V članku predstavljamo analizo človeških in živalskih ostankov iz jame Verteba blizu kra­ja Bilche Zolote v zahodni Ukrajini. Študija je nastala zaradi pomanjkljivega števila datumov iz teh ostankov in iz potrebe po kontekstualiziranju najdb v odnosu tako do prehoda iz lovsko-nabiral­niške družbe v poljedelsko v Ukrajini kot tudi glede na poseben prostor, ki ga imajo te najdbe znotraj kulturne sekvence Cucuteni-Tripolje. Novi absolutni datumi postavljajo ostanke faze BII/CI kulture Tripolje v čas ok. 3900–3500 pr. n. št., medtem ko je eden od pokopov zdaj ponovno datiran v čas zgod­­njega skitskega obdobja, kar pomeni, da gre za ene najstarejših najdb te kulture. Analiza izoto­pov kaže, da so bili pokojni lokalni prebi­val­ci regije, analiza stabilnih izotopov pa kaže na C3 ko­pen­sko prehrano ljudi v času kulture Tri­po­lje. Pokop iz skitskega obdobja kaže glede na δ13C vredno­sti na ok. 50 % morske prehrane, oziroma na C4 rastline, vključene v prehrano, kljub temu da so deleži izotopov δ18O in 87Sr/86Sr primerljivi s preo­sta­limi vzorci ljudi na najdišču

Role of bulk and surface phonons in the decay of metal surface states

We present a comprehensive theoretical investigation of the electron-phonon contribution to the lifetime broadening of the surface states on Cu(111) and Ag(111), in comparison with high-resolution photoemission results. The calculations, including electron and phonon states of the bulk and the surface, resolve the relative importance of the Rayleigh mode, being dominant for the lifetime at small hole binding energies. Including the electron-electron interaction, the theoretical results are in excellent agreement with the measured binding energy and temperature dependent lifetime broadening.Comment: 4 pages, 3 figure

Addressing Profound Disadvantages to Improve Indigenous Health and Reduce Hospitalisation: A Collaborative Community Program in Remote Northern Territory

BACKGROUND: Aboriginal people in rural and remote areas of the Northern Territory of Australia have suffered longstanding issues of homelessness and profound health and social inequities. The town and region of Katherine are particularly impacted by such inequities and have the highest rates of homelessness in Australia, composed almost entirely of Aboriginal people who represent 51% of the total population of 24,000 people. The region is serviced by a 60-bed hospital, and a small cohort of frequent attenders (FAs) represent 11% of the Emergency Department (ED) case load. The vast majority of FAs are Aboriginal and have very high burdens of social inequity and homelessness. FAs are a challenge to efficient and effective use of resources for most hospitals around the world, and investment in programs to address underlying social and chronic health issues contributing to frequent attendance have been demonstrated to be effective. METHODS: These are the interim findings of a prospective cohort study using five sources of linked health and related data to evaluate a community-based case management pilot in a culturally competent framework to support frequent attenders to the Katherine Hospital ED. FAs were defined as people with six or more presentations in 12 preceding months. The intervention composed of a community-based case management program with a multi-agency service delivery addressing underlying vulnerabilities contributing to ED presentations. RESULTS: Among this predominantly Aboriginal cohort (91%), there were high rates of homelessness (64%), food insecurity (60%) and alcohol misuse (64%), limited access to transport, and complex comorbidities (average of 2.8 chronic conditions per client). Following intervention, there was a statistically significant reduction in ED presentations (IRR 0.77, 95% CI 0.69-0.85), increased engagement with primary health care (IRR 1.90, 95% CI 1.78-2.03), and ambulance utilisation (IRR 1.21, 95% CI 1.07-1.38). Reductions in hospital admissions (IRR 0.93, 95% CI 0.77-1.10) and aeromedical retrievals (IRR 0.67, 95% CI 0.35-1.20) were not statistically significant. CONCLUSIONS: This study demonstrates the short-term impacts of community-led case management extending beyond the hospital setting, to address causes of recurrent ED presentations among people with complex social and medical backgrounds. Improving engagement with primary care is a particularly important outcome given the national impetus to reduce preventable hospital admissions