Computational Modeling of Interactions between Multiple Myeloma and the Bone Microenvironment

Multiple Myeloma (MM) is a B-cell malignancy that is characterized by osteolytic bone lesions. It has been postulated that positive feedback loops in the interactions between MM cells and the bone microenvironment form reinforcing ‘vicious cycles’, resulting in more bone resorption and MM cell population growth in the bone microenvironment. Despite many identified MM-bone interactions, the combined effect of these interactions and their relative importance are unknown. In this paper, we develop a computational model of MM-bone interactions and clarify whether the intercellular signaling mechanisms implemented in this model appropriately drive MM disease progression. This new computational model is based on the previous bone remodeling model of Pivonka et al. [1], and explicitly considers IL-6 and MM-BMSC (bone marrow stromal cell) adhesion related pathways, leading to formation of two positive feedback cycles in this model. The progression of MM disease is simulated numerically, from normal bone physiology to a well established MM disease state. Our simulations are consistent with known behaviors and data reported for both normal bone physiology and for MM disease. The model results suggest that the two positive feedback cycles identified for this model are sufficient to jointly drive the MM disease progression. Furthermore, quantitative analysis performed on the two positive feedback cycles clarifies the relative importance of the two positive feedback cycles, and identifies the dominant processes that govern the behavior of the two positive feedback cycles. Using our proposed quantitative criteria, we identify which of the positive feedback cycles in this model may be considered to be ‘vicious cycles’. Finally, key points at which to block the positive feedback cycles in MM-bone interactions are identified, suggesting potential drug targets

Enhancement of Multiwalled Carbon Nanotubes’ Electrical Conductivity Using Metal Nanoscale Copper Contacts and Its Implications for Carbon Nanotube-Enhanced Copper Conductivity

Herein, we present an experimental/computational approach for probing the interaction between metal contacts and carbon nanotubes (CNTs) with regard to creating the most efficient, low resistance junction. Tungsten probes have been coated with copper or chromium and the efficiency of nanocontact transport into multiwalled carbon nanotubes (MWCNTs) has been investigated experimentally, using scanning tunneling spectroscopy and nanoscale two-point probe I-V measurements, and in silico, employing DFT calculations. Experimental I-V measurements suggest the relative conductivity of the metal-CNT interaction to be Cu > W > Cr. It has been found that copper when in contact with MWCNTs results in a high density of states at the Fermi level, which contributes states to the conduction band. It was observed that the density of states also increased when chromium and tungsten probes were in contact with CNTs; however, in these cases the density of states increase would only occur under high voltage/high temperature situations. This is demonstrated by an increase in the experimental electrical resistance when compared to the copper probe. These results suggest that in future copper tips should be used when carrying out all intrinsic conduction measurements on CNTs, and they also provide a rationale for the ultraconductivity of Cu-CNT and Cu-graphene composites

Serum 25-Hydroxyvitamin D, Calcium Intake, and Risk of Type 2 Diabetes After 5 Years: Results from a national, population-based prospective study (the Australian Diabetes, Obesity and Lifestyle study)

OBJECTIVE To examine whether serum 25-hydroxyvitamin D (25OHD) and dietary calcium predict incident type 2 diabetes and insulin sensitivity.RESEARCH DESIGN AND METHODS A total of 6,537 of the 11,247 adults evaluated in 1999&ndash;2000 in the Australian Diabetes, Obesity and Lifestyle (AusDiab) study, returned for oral glucose tolerance test (OGTT) in 2004&ndash;2005. We studied those without diabetes who had complete data at baseline (n = 5,200; mean age 51 years; 55% were women; 92% were Europids). Serum 25OHD and energy-adjusted calcium intake (food frequency questionnaire) were assessed at baseline. Logistic regression was used to evaluate associations between serum 25OHD and dietary calcium on 5-year incidence of diabetes (diagnosed by OGTT) and insulin sensitivity (homeostasis model assessment of insulin sensitivity [HOMA-S]), adjusted for multiple potential confounders, including fasting plasma glucose (FPG).RESULTS During the 5-year follow-up, 199 incident cases of diabetes were diagnosed. Those who developed diabetes had lower serum 25OHD (mean 58 vs. 65 nmol/L; P &lt; 0.001) and calcium intake (mean 881 vs. 923 mg/day; P = 0.03) compared with those who remained free of diabetes. Each 25 nmol/L increment in serum 25OHD was associated with a 24% reduced risk of diabetes (odds ratio 0.76 [95% CI 0.63&ndash;0.92]) after adjusting for age, waist circumference, ethnicity, season, latitude, smoking, physical activity, family history of diabetes, dietary magnesium, hypertension, serum triglycerides, and FPG. Dietary calcium intake was not associated with reduced diabetes risk. Only serum 25OHD was positively and independently associated with HOMA-S at 5 years.CONCLUSIONS Higher serum 25OHD levels, but not higher dietary calcium, were associated with a significantly reduced risk of diabetes in Australian adult men and women.<br /

Farming fit? Dispelling the Australian agrarian myth

Background: Rural Australians face a higher mental health and lifestyle disease burden (obesity, diabetes andcardiovascular disease) than their urban counterparts. Our ongoing research reveals that the Australian farmingcommunity has even poorer physical and mental health outcomes than rural averages. In particular, farm men andwomen have high rates of overweightness, obesity, abdominal adiposity, high blood pressure and psychologicaldistress when compared against Australian averages. Within our farming cohort we observed a significantassociation between psychological distress and obesity, abdominal adiposity and body fat percentage in thefarming population.Presentation of hypothesis: This paper presents a hypothesis based on preliminary data obtained from anongoing study that could potentially explain the complex correlation between obesity, psychological distress andphysical activity among a farming population. We posit that spasmodic physical activity, changing farm practicesand climate variability induce prolonged stress in farmers. This increases systemic cortisol that, in turn, promotesabdominal adiposity and weight gain.Testing the hypothesis: The hypothesis will be tested by anthropometric, biochemical and psychological analysismatched against systemic cortisol levels and the physical activity of the subjects.Implications of the hypothesis tested: Previous studies indicate that farming populations have elevated rates ofpsychological distress and high rates of suicide. Australian farmers have recently experienced challenging climaticconditions including prolonged drought, floods and cyclones. Through our interactions and through the media it isnot uncommon for farmers to describe the effect of this long-term stress with feelings of &lsquo;defeat&rsquo;. By gaining agreater understanding of the role cortisol and physical activity have on mental and physical health we maypositively impact the current rates of psychological distress in farmers.<br /

Acute cardiometabolic effects of brief active breaks in sitting for patients with rheumatoid arthritis

Exercise is a treatment in rheumatoid arthritis, but participation in moderate-to-vigorous exercise is challenging for some patients. Light-intensity breaks in sitting could be a promising alternative. We compared the acute effects of active breaks in sitting with those of moderate-to-vigorous exercise on cardiometabolic risk markers in patients with rheumatoid arthritis. In a crossover fashion, 15 women with rheumatoid arthritis underwent three 8-h experimental conditions: prolonged sitting (SIT), 30-min bout of moderate-to-vigorous exercise followed by prolonged sitting (EX), and 3-min bouts of light-intensity walking every 30 min of sitting (BR). Postprandial glucose, insulin, c-peptide, triglycerides, cytokines, lipid classes/subclasses (lipidomics), and blood pressure responses were assessed. Muscle biopsies were collected following each session to assess targeted proteins/genes. Glucose [−28% in area under the curve (AUC), P = 0.036], insulin (−28% in AUC, P = 0.016), and c-peptide (−27% in AUC, P = 0.006) postprandial responses were attenuated in BR versus SIT, whereas only c-peptide was lower in EX versus SIT (−20% in AUC, P = 0.002). IL-1β decreased during BR, but increased during EX and SIT (P = 0.027 and P = 0.085, respectively). IL-1ra was increased during EX versus BR (P = 0.002). TNF-α concentrations decreased during BR versus EX (P = 0.022). EX, but not BR, reduced systolic blood pressure (P = 0.013). Lipidomic analysis showed that 7 of 36 lipid classes/subclasses were significantly different between conditions, with greater changes being observed in EX. No differences were observed for protein/gene expression. Brief active breaks in sitting can offset markers of cardiometabolic disturbance, which may be particularly useful for patients who may find it difficult to adhere to exercise. NEW & NOTEWORTHY Exercise is a treatment in rheumatoid arthritis but is challenging for some patients. Light-intensity breaks in sitting could be a promising alternative. Our findings show beneficial, but differential, cardiometabolic effects of active breaks in sitting and exercise in patients with rheumatoid arthritis. Breaks in sitting mainly improved glycemic and inflammatory markers, whereas exercise improved lipidomic and hypotensive responses. Breaks in sitting show promise in offsetting aspects of cardiometabolic disturbance associated with prolonged sitting in rheumatoid arthritis

Long-Chain Omega-3 Polyunsaturated Fatty Acids May Be Beneficial for Reducing Obesity—A Review

Current recommendations for counteracting obesity advocate the consumption of a healthy diet and participation in regular physical activity, but many individuals have difficulty complying with these recommendations. Studies in rodents and humans have indicated that long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) potentially elicit a number of effects which might be useful for reducing obesity, including suppression of appetite, improvements in circulation which might facilitate nutrient delivery to skeletal muscle and changes in gene expression which shift metabolism toward increased accretion of lean tissue, enhanced fat oxidation and energy expenditure and reduced fat deposition. While LC n-3 PUFA supplementation has been shown to reduce obesity in rodents, evidence in humans is limited. Epidemiological associations between LC n-3 PUFA intakes and obesity are inconclusive but small cross-sectional studies have demonstrated inverse relationships between markers of LC n-3 PUFA status and markers of obesity. Human intervention trials indicate potential benefits of LC n-3 PUFA supplementation, especially when combined with energy-restricted diets or exercise, but more well-controlled and long-term trials are needed to confirm these effects and identify mechanisms of action

Quantum Dots for Multiplexed Detection and Characterisation of Prostate Cancer Cells Using a Scanning Near-Field Optical Microscope

In this study scanning near-field optical microscopy (SNOM) has been utilised in conjunction with quantum dot labelling to interrogate the biomolecular composition of cell membranes. The technique overcomes the limits of optical diffraction found in standard fluorescence microscopy and also yields vital topographic information. The technique has been applied to investigate cell-cell adhesion in human epithelial cells. This has been realised through immunofluorescence labelling of the cell-cell adhesion protein E-cadherin. Moreover, a dual labelling protocol has been optimised to facilitate a comparative study of the adhesion mechanisms and the effect of aberrant adhesion protein expression in both healthy and cancerous epithelial cells. This study reports clear differences in the morphology and phenotype of healthy and cancerous cells. In healthy prostate epithelial cells (PNT2), E-cadherin was predominantly located around the cell periphery and within filopodial extensions. The presence of E-cadherin appeared to be enhanced when cell-cell contact was established. In contrast, examination of metastatic prostate adenocarcinoma cells (PC-3) revealed no E-cadherin labelling around the periphery of the cells. This lack of functional E-cadherin in PC-3 cells coincided with a markedly different morphology and PC-3 cells were not found to form close cell-cell associations with their neighbours. We have demonstrated that with a fully optimised sample preparation methodology, multiplexed quantum dot labelling in conjunction with SNOM imaging can be successfully applied to interrogate biomolecular localisation within delicate cellular membranes

25-Hydroxyvitamin D levels and chronic kidney disease in the AusDiab (Australian Diabetes, Obesity and Lifestyle) study

<p>Abstract</p> <p>Background</p> <p>Low 25-hydroxy vitamin D (25(OH)D) levels have been associated with an increased risk of albuminuria, however an association with glomerular filtration rate (GFR) is not clear. We explored the relationship between 25(OH)D levels and prevalent chronic kidney disease (CKD), albuminuria and impaired GFR, in a national, population-based cohort of Australian adults (AusDiab Study).</p> <p>Methods</p> <p>10,732 adults ≥25 years of age participating in the baseline survey of the AusDiab study (1999–2000) were included. The GFR was estimated using an enzymatic creatinine assay and the CKD-EPI equation, with CKD defined as eGFR <60 ml/min/1.73 m². Albuminuria was defined as a spot urine albumin to creatinine ratio (ACR) of ≥2.5 mg/mmol for men and ≥3.5 for women. Serum 25(OH)D levels of <50 nmol/L were considered vitamin D deficient. The associations between 25(OH)D level, albuminuria and impaired eGFR were estimated using multivariate regression models.</p> <p>Results</p> <p>30.7% of the study population had a 25(OH)D level <50 nmol/L (95% CI 25.6-35.8). 25(OH)D deficiency was significantly associated with an impaired eGFR in the univariate model (OR 1.52, 95% CI 1.07-2.17), but not in the multivariate model (OR 0.95, 95% CI 0.67-1.35). 25(OH)D deficiency was significantly associated with albuminuria in the univariate (OR 2.05, 95% CI 1.58-2.67) and multivariate models (OR 1.54, 95% CI 1.14-2.07).</p> <p>Conclusions</p> <p>Vitamin D deficiency is common in this population, and 25(OH)D levels of <50 nmol/L were independently associated with albuminuria, but not with impaired eGFR. These associations warrant further exploration in prospective and interventional studies.</p

An argument against the focus on Community Resilience in Public Health

Background - It has been suggested that Public Health professionals focus on community resilience in tackling chronic problems, such as poverty and deprivation; is this approach useful? Discussion - Resilience is always i) of something ii) to something iii) to an endpoint, as in i) a rubber ball, ii) to a blunt force, iii) to its original shape. “Community resilience” might be: of a neighbourhood, to a flu pandemic, with the endpoint, to return to normality. In these two examples, the endpoint is as-you-were. This is unsuitable for some examples of resilience. A child that is resilient to an abusive upbringing has an endpoint of living a happy life despite that upbringing: this is an as-you-should-be endpoint. Similarly, a chronically deprived community cannot have the endpoint of returning to chronic deprivation: so what is its endpoint? Roughly, it is an as-you-should-be endpoint: to provide an environment for inhabitants to live well. Thus resilient communities will be those that do this in the face of challenges. How can they be identified? One method uses statistical outliers, neighbourhoods that do better than would be expected on a range of outcomes given a range of stressors. This method tells us that a neighbourhood is resilient but not why it is. In response, a number of researchers have attributed characteristics to resilient communities; however, these generally fail to distinguish characteristics of a good community from those of a resilient one. Making this distinction is difficult and we have not seen it successfully done; more importantly, it is arguably unnecessary. There already exist approaches in Public Health to assessing and developing communities faced with chronic problems, typically tied to notions such as Social Capital. Communityresilience to chronic problems, if it makes sense at all, is likely to be a property that emerges from the various assets in a community such as human capital, built capital and natural capital. Summary - Public Health professionals working with deprived neighbourhoods would be better to focus on what neighbourhoods have or could develop as social capital for living well, rather than on the vague and tangential notion of community resilience.</p

Investigation into the effects of surface stripping ZnO nanosheets

ZnO nanosheets are polycrystalline nanostructures that are used in devices including solar cells and gas sensors. However, for efficient and reproducible device operation and contact behaviour the conductivity characteristics must be controlled and surface contaminants removed. Here we use low doses of argon bombardment to remove surface contamination and make reproducible lower resistance contacts. Higher doses strip the surface of the nanosheets altering the contact type from near-ohmic to rectifying by removing the donor-type defects, which photoluminescence shows to be concentrated in the near-surface. Controlled doses of argon treatments allow nanosheets to be customised for device formation