Mathematical modelling of nanoparticle delivery to vascular tumours

This paper was presented at the 2nd Micro and Nano Flows Conference (MNF2009), which was held at Brunel University, West London, UK. The conference was organised by Brunel University and supported by the Institution of Mechanical Engineers, IPEM, the Italian Union of Thermofluid dynamics, the Process Intensification Network, HEXAG - the Heat Exchange Action Group and the Institute of Mathematics and its Applications.The goal of any cancer therapy is to achieve efficient, tissue-specific targeting of drugs to cancer cells. However, most anticancer agents act on healthy and malignant tissue alike, potentially resulting in side effects to healthy tissue. This has motivated the development of treatment strategies that are cancer-cell specific; one approach uses biomimetic polymer vesicles (BPV) to deliver chemotherapeutic drugs into cells before releasing them. BPVs are synthetic membrane enclosed, nanometre-sized structures, and provide ideal drug delivery vectors because specific targeting to cancer cells can be achieved by coating with tumourspecific molecules. We present several mathematical models covering a wide range of length-scales pertinent to BPV-mediated delivery protocols and focus on capturing the in vivo environment by evaluating the impact of the underlying vascular structure upon the governing transport mechanisms. Firstly, we present models of specific binding of BPVs to cancer cells. Subsequently we examine the implications of these model outputs in the contexts of both discrete capillary architectures and higher level homogenized-models that track blood and BPV transport at the tissue scale (both intra- and extra-tumorally). Numerical solutions are discussed, and recommendations are presented on that optimal integration of the models to generate quantitative predictions associated with BPV treatment efficacy

A novel high-resolution optical instrument for imaging oceanic bubbles

The formation of bubbles from breaking waves has a significant effect on air-sea gas transfer and aerosol production. Detailed data in situ about the bubble populations are required to understand these processes. However, these data are difficult to acquire because bubble populations are complex, spatially inhomogeneous, and short lived. This paper describes the design and development of a novel high-resolution underwater optical instrument for imaging oceanic bubbles at the sea. The instrument was successfully deployed in 2013 as part of the HiWINGS campaign in the North Atlantic Ocean. It contains a high-resolution machine vision camera, strobe flash unit to create a light sheet, and single board computer to control system operation. The instrument is shown to successfully detect bubbles of radii in the range 20-10 000 μm

Sexual behaviour, sexually transmitted infections and attitudes to chlamydia testing among a unique national sample of young Australians: Baseline data from a randomised controlled trial

Background: Chlamydia infection is the most common notifiable sexually transmitted infection (STI) in Australia and mostly affects young people (15 - 25 years). This paper presents baseline data from a randomised controlled trial that aimed to increase chlamydia testing among sexually active young people. The objectives were to identify associations between sexual behaviour, substance use and STI history and explore attitudes to chlamydia testing. Methods: This study was conducted in cyberspace. Study recruitment, allocation, delivery of interventions and baseline and follow up data collection all took place online. Participants were 16 - 25 years old and resided in Australia. Substance use correlates of sexual activity; predictors of history of STIs; barriers to and facilitators of chlamydia testing were analysed. Results: Of 856 participants (79.1% female), 704 had experienced penetrative intercourse. Sexually active participants were more likely to smoke regularly or daily, to drink alcohol, or to have binge drunk or used marijuana or other illicit substances recently. Risk factors for having a history of any STI were 3 or more sexual partners ever, 6 or more partners in the past 12 months, condom non-use and being 20 years or older. Almost all sexually active participants said that they would have a chlamydia test if their doctor recommended it. Conclusions: Sexually active young people are at risk of STIs and may engage in substance use risk behaviours. Where one health risk behaviour is identified, it is important to seek information about others. Chlamydia testing can be facilitated by doctors and nurses recommending it. Primary care providers have a useful role in chlamydia control. © 2014 Kang et al.; licensee BioMed Central Ltd

PHOTOELECTRON-SPECTRA OF AMORPHOUS SIXHY ALLOY-FILMS - THE EFFECT OF MICROSTRUCTURE ON THE SI-2P LEVEL SHIFT

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Large emissions from floodplain trees close the Amazon methane budget

Wetlands are the largest global source of atmospheric methane (CH4), a potent greenhouse gas. However, methane emission inventories from the Amazon floodplain, the largest natural geographic source of CH4 in the tropics, consistently underestimate the atmospheric burden of CH4 determined via remote sensing and inversion modelling, pointing to a major gap in our understanding of the contribution of these ecosystems to CH4 emissions. Here we report CH4 fluxes from the stems of 2,357 individual Amazonian floodplain trees from 13 locations across the central Amazon basin. We find that escape of soil gas through wetland trees is the dominant source of regional CH4 emissions. Methane fluxes from Amazon tree stems were up to 200 times larger than emissions reported for temperate wet forests6 and tropical peat swamp forests, representing the largest non-ebullitive wetland fluxes observed. Emissions from trees had an average stable carbon isotope value (δ13C) of −66.2 ± 6.4 per mil, consistent with a soil biogenic origin. We estimate that floodplain trees emit 15.1 ± 1.8 to 21.2 ± 2.5 teragrams of CH4 a year, in addition to the 20.5 ± 5.3 teragrams a year emitted regionally from other sources. Furthermore, we provide a ‘top-down’ regional estimate of CH4 emissions of 42.7 ± 5.6 teragrams of CH4 a year for the Amazon basin, based on regular vertical lower-troposphere CH4 profiles covering the period 2010–2013. We find close agreement between our ‘top-down’ and combined ‘bottom-up’ estimates, indicating that large CH4 emissions from trees adapted to permanent or seasonal inundation can account for the emission source that is required to close the Amazon CH4 budget. Our findings demonstrate the importance of tree stem surfaces in mediating approximately half of all wetland CH4 emissions in the Amazon floodplain, a region that represents up to one-third of the global wetland CH4 source when trees are combined with other emission sources

What is macroecology?

The symposium 'What is Macroecology?' was held in London on 20 June 2012. The event was the inaugural meeting of the Macroecology Special Interest Group of the British Ecological Society and was attended by nearly 100 scientists from 11 countries. The meeting reviewed the recent development of the macroecological agenda. The key themes that emerged were a shift towards more explicit modelling of ecological processes, a growing synthesis across systems and scales, and new opportunities to apply macroecological concepts in other research fields

Engineering key components in a synthetic eukaryotic signal transduction pathway

Signal transduction underlies how living organisms detect and respond to stimuli. A goal of synthetic biology is to rewire natural signal transduction systems. Bacteria, yeast, and plants sense environmental aspects through conserved histidine kinase (HK) signal transduction systems. HK protein components are typically comprised of multiple, relatively modular, and conserved domains. Phosphate transfer between these components may exhibit considerable cross talk between the otherwise apparently linear pathways, thereby establishing networks that integrate multiple signals. We show that sequence conservation and cross talk can extend across kingdoms and can be exploited to produce a synthetic plant signal transduction system. In response to HK cross talk, heterologously expressed bacterial response regulators, PhoB and OmpR, translocate to the nucleus on HK activation. Using this discovery, combined with modification of PhoB (PhoB-VP64), we produced a key component of a eukaryotic synthetic signal transduction pathway. In response to exogenous cytokinin, PhoB-VP64 translocates to the nucleus, binds a synthetic PlantPho promoter, and activates gene expression. These results show that conserved-signaling components can be used across kingdoms and adapted to produce synthetic eukaryotic signal transduction pathways

A primary care, multi-disciplinary disease management program for opioid-treated patients with chronic non-cancer pain and a high burden of psychiatric comorbidity

BACKGROUND: Chronic non-cancer pain is a common problem that is often accompanied by psychiatric comorbidity and disability. The effectiveness of a multi-disciplinary pain management program was tested in a 3 month before and after trial. METHODS: Providers in an academic general medicine clinic referred patients with chronic non-cancer pain for participation in a program that combined the skills of internists, clinical pharmacists, and a psychiatrist. Patients were either receiving opioids or being considered for opioid therapy. The intervention consisted of structured clinical assessments, monthly follow-up, pain contracts, medication titration, and psychiatric consultation. Pain, mood, and function were assessed at baseline and 3 months using the Brief Pain Inventory (BPI), the Center for Epidemiological Studies-Depression Scale scale (CESD) and the Pain Disability Index (PDI). Patients were monitored for substance misuse. RESULTS: Eighty-five patients were enrolled. Mean age was 51 years, 60% were male, 78% were Caucasian, and 93% were receiving opioids. Baseline average pain was 6.5 on an 11 point scale. The average CESD score was 24.0, and the mean PDI score was 47.0. Sixty-three patients (73%) completed 3 month follow-up. Fifteen withdrew from the program after identification of substance misuse. Among those completing 3 month follow-up, the average pain score improved to 5.5 (p = 0.003). The mean PDI score improved to 39.3 (p < 0.001). Mean CESD score was reduced to 18.0 (p < 0.001), and the proportion of depressed patients fell from 79% to 54% (p = 0.003). Substance misuse was identified in 27 patients (32%). CONCLUSIONS: A primary care disease management program improved pain, depression, and disability scores over three months in a cohort of opioid-treated patients with chronic non-cancer pain. Substance misuse and depression were common, and many patients who had substance misuse identified left the program when they were no longer prescribed opioids. Effective care of patients with chronic pain should include rigorous assessment and treatment of these comorbid disorders and intensive efforts to insure follow up

RNA polymerase II stalling promotes nucleosome occlusion and pTEFb recruitment to drive immortalization by Epstein-Barr virus

Epstein-Barr virus (EBV) immortalizes resting B-cells and is a key etiologic agent in the development of numerous cancers. The essential EBV-encoded protein EBNA 2 activates the viral C promoter (Cp) producing a message of ~120 kb that is differentially spliced to encode all EBNAs required for immortalization. We have previously shown that EBNA 2-activated transcription is dependent on the activity of the RNA polymerase II (pol II) C-terminal domain (CTD) kinase pTEFb (CDK9/cyclin T1). We now demonstrate that Cp, in contrast to two shorter EBNA 2-activated viral genes (LMP 1 and 2A), displays high levels of promoter-proximally stalled pol II despite being constitutively active. Consistent with pol II stalling, we detect considerable pausing complex (NELF/DSIF) association with Cp. Significantly, we observe substantial Cp-specific pTEFb recruitment that stimulates high-level pol II CTD serine 2 phosphorylation at distal regions (up to +75 kb), promoting elongation. We reveal that Cp-specific pol II accumulation is directed by DNA sequences unfavourable for nucleosome assembly that increase TBP access and pol II recruitment. Stalled pol II then maintains Cp nucleosome depletion. Our data indicate that pTEFb is recruited to Cp by the bromodomain protein Brd4, with polymerase stalling facilitating stable association of pTEFb. The Brd4 inhibitor JQ1 and the pTEFb inhibitors DRB and Flavopiridol significantly reduce Cp, but not LMP1 transcript production indicating that Brd4 and pTEFb are required for Cp transcription. Taken together our data indicate that pol II stalling at Cp promotes transcription of essential immortalizing genes during EBV infection by (i) preventing promoter-proximal nucleosome assembly and ii) necessitating the recruitment of pTEFb thereby maintaining serine 2 CTD phosphorylation at distal regions