In-situ, time resolved monitoring of uranium in BFS:OPC grout. Part 2: Corrosion in water.

To reflect potential conditions in a geological disposal facility, uranium was encapsulated in grout and submersed in de-ionised water for time periods between 2-47 weeks. Synchrotron X-ray Powder Diffraction and X-ray Tomography were used to identify the dominant corrosion products and measure their dimensions. Uranium dioxide was observed as the dominant corrosion product and time dependent thickness measurements were used to calculate oxidation rates. The effectiveness of physical and chemical grout properties to uranium corrosion and mobilisation is discussed and Inductively Coupled Plasma Mass Spectrometry was used to measure 238U(aq) content in the residual water of several samples.

In-situ, time resolved monitoring of uranium in BFS:OPC grout. Part 1: Corrosion in water vapour.

Uranium encapsulated in grout was exposed to water vapour for extended periods of time. Through synchrotron x-ray powder diffraction and tomography measurements, uranium dioxide was determined the dominant corrosion product over a 50-week time period. The oxide growth rate initiated rapidly, with rates comparable to the U + H2O reaction. Over time, the reaction rate decreased and eventually plateaued to a rate similar to the U + H2O + O2 reaction. This behaviour was not attributed to oxygen ingress, but instead the decreasing permeability of the grout, limiting oxidising species access to the metal surface.

Novel approaches for the promotion of physical activity and exercise for prevention and management of type 2 diabetes.

Despite increased evidence for the importance of lifestyle modification, physical activity and diet in diabetes prevention and management, habitual physical activity levels have declined in recent decades in China and India. Further, other risk factors for type 2 diabetes, including overweight, obesity and physical inactivity, have also worsened. Here we present evidence for the importance of physical activity and exercise in the amelioration of type 2 diabetes and propose a novel approach to address the challenge of improving lifestyle behaviors in China and India-Movement is Medicine and a P4 (predictive, preventive, personalized and participatory) approach.

Prion protein genotype survey confirms low frequency of scrapie-resistant K222 allele in British goat herds.

Scrapie in goats is a transmissible, fatal prion disease, which is endemic in the British goat population. The recent success in defining caprine PRNP gene variants that provide resistance to experimental and natural classical scrapie has prompted the authors to conduct a survey of PRNP genotypes in 10 goat breeds and 52 herds to find goats with the resistant K222 allele. They report here the frequencies in 1236 tested animals of the resistance-associated K222 and several other alleles by breed and herd. Eight animals were found to be heterozygous QK222 goats (0.64 per cent genotype frequency, 95 per cent CI 0.28 to 1.27 per cent) but no homozygous KK222 goats were detected. The K222 allele was found in Saanen, Toggenburg and Anglo-Nubian goats. The fact that only a few goats with the K222 allele have been identified does not preclude the possibility to design and implement successful breeding programmes at national level.

Windows of opportunity for physical activity in the prevention of obesity.

Tackling increasing rates of obesity is likely to be a defining feature of health care over the next several decades. Adult obesity is a persistent and treatment-resistant problem. Consequently, an emerging theme in the literature is to commence prevention efforts earlier in the developmental time course. This view is based primarily on epidemiological data demonstrating a link between traits manifesting early during development and increased obesity risk in adulthood. Physical activity is a perennial factor in discussions of obesity prevention. However, the optimal timing and type of physical activity interventions to commence remains unclear. Critical developmental windows of plasticity may afford time-limited opportunities to shape body composition across the life course; however, physical activity has not been explicitly considered in these discussions. Although animal models suggest that physical activity commenced earlier in development has differential effects on obesity onset compared to physical activity commenced in adulthood, human research is lacking. In this conceptual review, we consider physical activity during critical developmental periods as a way to mitigate obesity risk later in life.

Experimental evidence for the co-evolution of hominin tool-making teaching and language.

Hominin reliance on Oldowan stone tools-which appear from 2.5 mya and are believed to have been socially transmitted-has been hypothesized to have led to the evolution of teaching and language. Here we present an experiment investigating the efficacy of transmission of Oldowan tool-making skills along chains of adult human participants (N=184) using five different transmission mechanisms. Across six measures, transmission improves with teaching, and particularly with language, but not with imitation or emulation. Our results support the hypothesis that hominin reliance on stone tool-making generated selection for teaching and language, and imply that (i) low-fidelity social transmission, such as imitation/emulation, may have contributed to the ~700,000 year stasis of the Oldowan technocomplex, and (ii) teaching or proto-language may have been pre-requisites for the appearance of Acheulean technology. This work supports a gradual evolution of language, with simple symbolic communication preceding behavioural modernity by hundreds of thousands of years.

Getting Australia more active: challenges and opportunities for health promotion.

A growing body of evidence demonstrates that regular physical activity promotes health and assists in the prevention of non-communicable diseases but this is presently curtailed by low and unhealthy participation rates in Australia and comparable industrialised countries. Compounding the problem is knowledge that physical inactivity is independently associated with poor health outcomes. Despite physical activity being described as public health's 'best bet' or 'best buy', motivating individuals and groups to adopt and maintain physical activity continues to be a major challenge for health professionals. Global advocacy for prevention efforts must be operationalised through national to local strategies to promote and support physical activity in multiple settings including the home, schools and workplace. The Australian health promotion community has and continues to play a leadership role in physical activity promotion. However, there is an urgent need to continue to promote the importance of physical activity, along with its pivotal role in the prevention of non-communicable diseases, alongside related agendas including healthy diets, tobacco control and environmental sustainability. This commentary overviews the contemporary status of physical activity promotion in Australia and identifies key challenges and opportunities moving forward.

Genetic load is associated with hypothalamic-pituitary-adrenal axis dysregulation in macaques.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis pathway is associated with several neuropsychiatric disorders, including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), schizophrenia and alcohol abuse. Studies have demonstrated an association between HPA axis dysfunction and gene variants within the cortisol, serotonin and opioid signaling pathways. We characterized polymorphisms in genes linked to these three neurotransmitter pathways and tested their potential interactions with HPA axis activity, as measured by dexamethasone (DEX) suppression response. We determined the percent DEX suppression of adrenocorticotropic hormone (ACTH) and cortisol in 62 unrelated, male rhesus macaques. While DEX suppression of cortisol was robust amongst 87% of the subjects, ACTH suppression levels were broadly distributed from -21% to 66%. Thirty-seven monkeys from the high and low ends of the ACTH suppression distribution (18 'high' and 19 'low' animals) were genotyped at selected polymorphisms in five unlinked genes (rhCRH, rhTPH2, rhMAOA, rhSLC6A4 and rhOPRM). Associations were identified between three variants (rhCRH-2610C>T, rhTPH2 2051A>C and rh5-HTTLPR) and level of DEX suppression of ACTH. In addition, a significant additive effect of the 'risk' genotypes from these three loci was detected, with an increasing number of 'risk' genotypes associated with a blunted ACTH response (P = 0.0009). These findings suggest that assessment of multiple risk alleles in serotonin and cortisol signaling pathway genes may better predict risk for HPA axis dysregulation and associated psychiatric disorders than the evaluation of single gene variants alone.

Spontaneous intracranial hypotension presenting to the ENT surgeon: case report.

OBJECTIVE: To highlight a case of spontaneous intracranial hypotension presenting to the ENT surgeon. METHOD: We present a case report and a review of the literature concerning spontaneous intracranial hypotension. RESULTS: Spontaneous intracranial hypotension is a rare diagnosis, particularly to the ENT surgeon. We report a patient with tinnitus, hearing loss and headache, symptoms suggestive of an ENT diagnosis such as Ménière's disease or vestibular schwannoma. However, magnetic resonance imaging revealed the characteristic findings of spontaneous intracranial hypotension. The patient's symptoms resolved, except for a mild residual tinnitus, with conservative management alone. CONCLUSION: This case highlights the importance of considering spontaneous intracranial hypotension as a differential diagnosis of certain ENT symptoms.

A comparison of chronic multi-channel cortical implantation techniques: manual versus mechanical insertion.

High-density multi-channel intra-cortical electrode arrays allow researchers to record simultaneously from populations of neurons for the purpose of understanding neural coding and plasticity. These devices have tens to hundreds of electrodes spaced within a few square millimeters. During insertion, the high-density probes can compress the cortex several millimeters prior to breaking through the pia. Compression of cortical tissue has been demonstrated to result in traumatic brain injury (TBI) which may be a major contributor to low electrode yield and decreased recording longevity. Two insertion techniques for chronically implanting multi-wire electrode arrays in layer IV of primary auditory cortex were compared. A mechanical insertion device, capable of rapidly inserting the electrode array without visible compression of the brain, was constructed. The neural responses to broadband clicks and pure tones recorded from the arrays inserted with the mechanical device were compared to the results from a manual insertion method using a micromanipulator. Both techniques result in a similar number of active channels directly following surgery with a mean signal-to-noise ratio of approximately 4.5. Over 60% of the animals implanted with the mechanical insertion device had driven activity at week 6 whereas none of the animals with manually inserted arrays exhibited functional responses after 3 weeks. This report provides initial evidence that mechanical insertion devices, which prevent cortical compression, increase electrode recording longevity.

An economical multi-channel cortical electrode array for extended periods of recording during behavior.

We report the development of a low-cost chronic multi-channel microwire electrode array for recording multi-unit cortical responses in behaving rodents. The design was motivated by three issues. First, standard connector systems tended to disconnect from the head-stage during extended periods of behavior. Disconnections resulted in a loss of data and an interruption of the animals' behavior. Second, the use of low insertion force connectors with locking mechanisms was cost prohibitive. Finally, connecting the head-stage to a skull-mounted connector on an unrestrained animal was highly stressful for both the researcher and animal. The design developed uses a high insertion force DIP socket separated from the skullcap that prevents inadvertent disconnects, is inexpensive, and simplifies connecting unrestrained rodents. Electrodes were implanted in layer IV of primary auditory cortex in 11 Sprague-Dawley rats. Performance of the electrodes was monitored for 6 weeks. None of the behaving animals became disconnected from the recording system during recording sessions lasting 6 h. The mean signal-to-noise ratio on all channels (154) following surgery was 3.9+/-0.2. Of the 154 channels implanted, 130 exhibited driven activity following surgery. Forty percent of the arrays continued to exhibit driven neural activity at 6 weeks.

Spectroscopic analysis of the tribological behavior of a model boundary layer lubricant.

Highly ordered alkanethiol self-assembled monolayers (SAMs) on gold substrates are suitable models of boundary layer lubricants and may be used in actual nanoscale device applications. Here, such monolayers were studied by spectroscopic methods as a function of tribological wear (rubbing) using a pin-on-disk microtribometer. The coefficient of friction (COF) (ratio of the frictional force to the load) was measured with the tribometer, and reflectance infrared spectra and X-ray photoelectron spectra were obtained as the monolayer film failed and the COF changed. The results show that it is possible to correlate disorder in the monolayer film with tribological failure of the film, and that continued rubbing produces a chemical change in the monolayer film. Disorder in the monolayer is distinct from the influence of wear in the underlying gold substrate. Aged SAMs, having sulfonate rather than thiol headgroups and initially less well ordered, behave differently to the well-ordered freshly prepared SAMs. Interestingly, they show a lower COF over many more cycles of exposure to the rubbing pin. The impact of the mechanism of film failure in boundary layer lubrication is discussed.

Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member ectodysplasin-A.

Mutations in the epithelial morphogen ectodysplasin-A (EDA), a member of the tumor necrosis factor (TNF) family, are responsible for the human disorder X-linked hypohidrotic ectodermal dysplasia (XLHED) characterized by impaired development of hair, eccrine sweat glands, and teeth. EDA-A1 and EDA-A2 are two splice variants of EDA, which bind distinct EDA-A1 and X-linked EDA-A2 receptors. We identified a series of novel EDA mutations in families with XLHED, allowing the identification of the following three functionally important regions in EDA: a C-terminal TNF homology domain, a collagen domain, and a furin protease recognition sequence. Mutations in the TNF homology domain impair binding of both splice variants to their receptors. Mutations in the collagen domain can inhibit multimerization of the TNF homology region, whereas those in the consensus furin recognition sequence prevent proteolytic cleavage of EDA. Finally, a mutation affecting an intron splice donor site is predicted to eliminate specifically the EDA-A1 but not the EDA-A2 splice variant. Thus a proteolytically processed, oligomeric form of EDA-A1 is required in vivo for proper morphogenesis.

Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis.

Perforin (pfp) and interferon-gamma (IFN-gamma) together in C57BL/6 (B6) and BALB/c mouse strains provided optimal protection in 3 separate tumor models controlled by innate immunity. Using experimental (B6, RM-1 prostate carcinoma) and spontaneous (BALB/c, DA3 mammary carcinoma) models of metastatic cancer, mice deficient in both pfp and IFN-gamma were significantly less proficient than pfp- or IFN-gamma-deficient mice in preventing metastasis of tumor cells to the lung. Pfp and IFN-gamma-deficient mice were as susceptible as mice depleted of natural killer (NK) cells in both tumor metastasis models, and IFN-gamma appeared to play an early role in protection from metastasis. Previous experiments in a model of fibrosarcoma induced by the chemical carcinogen methylcholanthrene indicated an important role for NK1.1(+) T cells. Herein, both pfp and IFN-gamma played critical and independent roles in providing the host with protection equivalent to that mediated by NK1.1(+) T cells. Further analysis demonstrated that IFN-gamma, but not pfp, controlled the growth rate of sarcomas arising in these mice. Thus, this is the first study to demonstrate that host IFN-gamma and direct cytotoxicity mediated by cytotoxic lymphocytes expressing pfp independently contribute antitumor effector functions that together control the initiation, growth, and spread of tumors in mice.

Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma.

Immune surveillance by cytotoxic lymphocytes against cancer has been postulated for decades, but direct evidence for the role of cytotoxic lymphocytes in protecting against spontaneous malignancy has been lacking. As the rejection of many experimental cancers by cytotoxic T lymphocytes and natural killer cells is dependent on the pore-forming protein perforin (pfp), we examined pfp-deficient mice for increased cancer susceptibility. Here we show that pfp-deficient mice have a high incidence of malignancy in distinct lymphoid cell lineages (T, B, NKT), indicating a specific requirement for pfp in protection against lymphomagenesis. The susceptibility to lymphoma was accentuated by simultaneous lack of expression of the p53 gene, mutations in which also commonly predispose to human malignancies, including lymphoma. In contrast, the incidence and age of onset of sarcoma was unaffected in p53-deficient mice. Pfp-deficient mice were at least 1,000-fold more susceptible to these lymphomas when transplanted, compared with immunocompetent mice in which tumor rejection was controlled by CD8(+) T lymphocytes. This study is the first that implicates direct cytotoxicity by lymphocytes in regulating lymphomagenesis.

The anti-tumor activity of IL-12: mechanisms of innate immunity that are model and dose dependent.

IL-12 has been demonstrated to have potent anti-tumor activities in a variety of mouse tumor models, but the relative roles of NK, NKT, and T cells and their effector mechanisms in these responses have not been fully addressed. Using a spectrum of gene-targeted or Ab-treated mice we have shown that for any particular tumor model the effector mechanisms downstream of IL-12 often mimic the natural immune response to that tumor. For example, metastasis of the MHC class I-deficient lymphoma, EL4-S3, was strictly controlled by NK cells using perforin either naturally or following therapy with high-dose IL-12. Intriguingly, in B16F10 and RM-1 tumor models both NK and NKT cells contribute to natural protection from tumor metastasis. In these models, a lower dose of IL-12 or delayed administration of IL-12 dictated a greater relative role of NKT cells in immune protection from tumor metastasis. Overall, both NK and NKT cells can contribute to natural and IL-12-induced immunity against tumors, and the relative role of each population is tumor and therapy dependent.

Differential tumor surveillance by natural killer (NK) and NKT cells.

Natural tumor surveillance capabilities of the host were investigated in six different mouse tumor models where endogenous interleukin (IL)-12 does or does not dictate the efficiency of the innate immune response. Gene-targeted and lymphocyte subset-depleted mice were used to establish the relative importance of natural killer (NK) and NK1.1(+) T (NKT) cells in protection from tumor initiation and metastasis. In the models examined, CD3(-) NK cells were responsible for tumor rejection and protection from metastasis in models where control of major histocompatibility complex class I-deficient tumors was independent of IL-12. A protective role for NKT cells was only observed when tumor rejection required endogenous IL-12 activity. In particular, T cell receptor Jalpha281 gene-targeted mice confirmed a critical function for NKT cells in protection from spontaneous tumors initiated by the chemical carcinogen, methylcholanthrene. This is the first description of an antitumor function for NKT cells in the absence of exogenously administered potent stimulators such as IL-12 or alpha-galactosylceramide.