Programmable disorder in random DNA tilings

Scaling up the complexity and diversity of synthetic molecular structures will require strategies that exploit the inherent stochasticity of molecular systems in a controlled fashion. Here we demonstrate a framework for programming random DNA tilings and show how to control the properties of global patterns through simple, local rules. We constructed three general forms of planar network—random loops, mazes and trees—on the surface of self-assembled DNA origami arrays on the micrometre scale with nanometre resolution. Using simple molecular building blocks and robust experimental conditions, we demonstrate control of a wide range of properties of the random networks, including the branching rules, the growth directions, the proximity between adjacent networks and the size distribution. Much as combinatorial approaches for generating random one-dimensional chains of polymers have been used to revolutionize chemical synthesis and the selection of functional nucleic acids, our strategy extends these principles to random two-dimensional networks of molecules and creates new opportunities for fabricating more complex molecular devices that are organized by DNA nanostructures

Typology of Environment-Related Provisions in Regional Trade Agreements

The last 25 years have witnessed a rapid increase in regional trade agreements (RTAs). Although RTAs generally aim at lowering tariff and non-tariff trade barriers, an increasing number of trade agreements extend their scope to cover specific policy areas such as environmental protection and sustainable development. This paper establishes a comprehensive typology and quantitative analysis of environment-related provisions included in RTAs. The analysis covers all the RTAs currently into force that have been notified to the WTO between 1957 and May 2016, namely 270 trade agreements. While environmental exceptions, along with environmental cooperation continue to be the most common types of environment-related provisions, many other different types of provisions are incorporated in an increasing number of RTAs. The common feature of all environment-related provisions, including environmental exceptions, is their heterogeneity in terms of structure, language and scope

A Small Mammal Community in a Forest Fragment, Vegetation Corridor and Coffee Matrix System in the Brazilian Atlantic Forest

The objective of our work was to verify the value of the vegetation corridor in the conservation of small mammals in fragmented tropical landscapes, using a model system in the southeastern Minas Gerais. We evaluated and compared the composition and structure of small mammals in a vegetation corridor, forest fragments and a coffee matrix. A total of 15 species were recorded, and the highest species richness was observed in the vegetation corridor (13 species), followed by the forest fragments (10) and the coffee matrix (6). The absolute abundance was similar between the vegetation corridor and fragments (F = 22.94; p = 0.064), and the greatest differences occurred between the vegetation corridor and the matrix (F = 22.94; p = 0.001) and the forest fragments and the matrix (F = 22.94; p = 0.007). Six species showed significant habitat preference possibly related to the sensitivity of the species to the forest disturbance. Marmosops incanus was the species most sensitive to disturbance; Akodon montensis, Cerradomys subflavus, Gracilinanus microtarsus and Rhipidomys sp. displayed little sensitivity to disturbance, with a high relative abundance in the vegetation corridor. Calomys sp. was the species least affected by habitat disturbance, displaying a high relative abundance in the coffee matrix. Although the vegetation corridors are narrow (4 m width), our results support the hypothesis in which they work as a forest extension, share most species with the forest fragment and support species richness and abundance closer to forest fragments than to the coffee matrix. Our work highlights the importance and cost-effectiveness of these corridors to biodiversity management in the fragmented Atlantic Forest landscapes and at the regional level

The Role of Magnetic Resonance Imaging in Diagnosis and Management of Breast Cancer

A review of the literature on the current applications of breast magnetic resonance imaging (MRI) indications, their rationale and their place in diagnosis and management of breast cancer was given. Contrast-enhanced breast MRI is developing as a valuable adjunct to mammography and sonography. Its high sensitivity for invasive breast cancer establishes its superiority in evaluation of multifocality/multicentricity, tumor response to neoadjuvant chemotherapy, detection of recurrence, and staging. Emerging applications include spectroscopy, usage of new contrast agents, and MRI-guided interventions, including noninvasive treatment of breast cancer. Its potential benefit in screening high-risk women has yet to be established with prospective studies, particularly with regard to false positive results

The influence of P-glycoprotein expression and its inhibitors on the distribution of doxorubicin in breast tumors

Abstract Background Anti-cancer drugs access solid tumors via blood vessels, and must penetrate tumor tissue to reach all cancer cells. Previous studies have demonstrated steep gradients of decreasing doxorubicin fluorescence with increasing distance from blood vessels, such that many tumor cells are not exposed to drug. Studies using multilayered cell cultures show that increased P-glycoprotein (PgP) is associated with better penetration of doxorubicin, while PgP inhibitors decrease drug penetration in tumor tissue. Here we evaluate the effect of PgP expression on doxorubicin distribution in vivo. Methods Mice bearing tumor sublines with either high or low expression of PgP were treated with doxorubicin, with or without pre-treatment with the PgP inhibitors verapamil or PSC 833. The distribution of doxorubicin in relation to tumor blood vessels was quantified using immunofluorescence. Results Our results indicate greater uptake of doxorubicin by cells near blood vessels in wild type as compared to PgP-overexpressing tumors, and pre-treatment with verapamil or PSC 833 increased uptake in PgP-overexpressing tumors. However, there were steeper gradients of decreasing doxorubicin fluorescence in wild-type tumors compared to PgP overexpressing tumors, and treatment of PgP overexpressing tumors with PgP inhibitors led to steeper gradients and greater heterogeneity in the distribution of doxorubicin. Conclusion PgP inhibitors increase uptake of doxorubicin in cells close to blood vessels, have little effect on drug uptake into cells at intermediate distances, and might have a paradoxical effect to decrease doxorubicin uptake into distal cells. This effect probably contributes to the limited success of PgP inhibitors in clinical trials

Hyperoxia increases the uptake of 5-fluorouracil in mammary tumors independently of changes in interstitial fluid pressure and tumor stroma

<p>Abstract</p> <p>Background</p> <p>Hypoxia is associated with increased resistance to chemo- and radiation-therapy. Hyperoxic treatment (hyperbaric oxygen) has previously been shown to potentiate the effect of some forms of chemotherapy, and this has been ascribed to enhanced cytotoxicity or neovascularisation. The aim of this study was to elucidate whether hyperoxia also enhances any actual uptake of 5FU (5-fluorouracil) into the tumor tissue and if this can be explained by changes in the interstitium and extracellular matrix.</p> <p>Methods</p> <p>One group of tumor bearing rats was exposed to repeated hyperbaric oxygen (HBO) treatment (2 bar, pO₂= 2 bar, 4 exposures à 90 min), whereas one group was exposed to one single identical HBO treatment. Animals housed under normal atmosphere (1 bar, pO₂= 0.2 bar) served as controls. Three doses of 5FU were tested for dose response. Uptake of [³H]-5FU in the tumor was assessed, with special reference to factors that might have contributed, such as interstitial fluid pressure (P_if), collagen content, oxygen stress (measured as malondialdehyd levels), lymphatics and transcapillary transport in the tumors.</p> <p>Results</p> <p>The uptake of the cytostatic agent increases immediately after a single HBO treatment (more than 50%), but not 24 hours after the last repeated HBO treatment. Thus, the uptake is most likely related to the transient increase in oxygenation in the tumor tissue. Factors like tumor P_ifand collagen content, which decreased significantly in the tumor interstitium after repeated HBO treatment, was without effect on the drug uptake.</p> <p>Conclusion</p> <p>We showed that hyperoxia increases the uptake of [³H]-5FU in DMBA-induced mammary tumors <it>per se</it>, independently of changes in P_if, oxygen stress, collagen fibril density, or transendothelial transport alone. The mechanism by which such an uptake occur is still not elucidated, but it is clearly stimulated by elevated pO₂.</p

Charting Disaster Recovery via Google Street View: A Social Science Perspective on Challenges Raised by the Fukushima Nuclear Disaster

There is increasing interest in using Google Street View (GSV) for research purposes, particularly with regard to “virtually auditing” the built environment to assess environmental quality. Research in this field to date generally suggests GSV is a reliable means of understanding the “real world” environment. But limitations around the dates and resolution of images have been identified. An emerging strand within this literature is also concerned with the potential of GSV to understand recovery post-disaster. Using the GSV data set for the evacuated area around the Fukushima Dai’ichi nuclear power plant as a case study, this article evaluates GSV as a means of assessing disaster recovery in a dynamic situation with remaining uncertainty and a significant value and emotive dimension. The article suggests that GSV does have value in giving a high-level overview of the post-disaster situation and has potential to track recovery and resettlement over time. Drawing on social science literature relating to Fukushima, and disasters more widely, the article also argues it is imperative for researchers using GSV to reflect carefully on the wider socio-cultural contexts that are often not represented in the photo montage

A tumor cord model for Doxorubicin delivery and dose optimization in solid tumors

<p>Abstract</p> <p>Background</p> <p>Doxorubicin is a common anticancer agent used in the treatment of a number of neoplasms, with the lifetime dose limited due to the potential for cardiotoxocity. This has motivated efforts to develop optimal dosage regimes that maximize anti-tumor activity while minimizing cardiac toxicity, which is correlated with peak plasma concentration. Doxorubicin is characterized by poor penetration from tumoral vessels into the tumor mass, due to the highly irregular tumor vasculature. I model the delivery of a soluble drug from the vasculature to a solid tumor using a tumor cord model and examine the penetration of doxorubicin under different dosage regimes and tumor microenvironments.</p> <p>Methods</p> <p>A coupled ODE-PDE model is employed where drug is transported from the vasculature into a tumor cord domain according to the principle of solute transport. Within the tumor cord, extracellular drug diffuses and saturable pharmacokinetics govern uptake and efflux by cancer cells. Cancer cell death is also determined as a function of peak intracellular drug concentration.</p> <p>Results</p> <p>The model predicts that transport to the tumor cord from the vasculature is dominated by diffusive transport of free drug during the initial plasma drug distribution phase. I characterize the effect of all parameters describing the tumor microenvironment on drug delivery, and large intercapillary distance is predicted to be a major barrier to drug delivery. Comparing continuous drug infusion with bolus injection shows that the optimum infusion time depends upon the drug dose, with bolus injection best for low-dose therapy but short infusions better for high doses. Simulations of multiple treatments suggest that additional treatments have similar efficacy in terms of cell mortality, but drug penetration is limited. Moreover, fractionating a single large dose into several smaller doses slightly improves anti-tumor efficacy.</p> <p>Conclusion</p> <p>Drug infusion time has a significant effect on the spatial profile of cell mortality within tumor cord systems. Therefore, extending infusion times (up to 2 hours) and fractionating large doses are two strategies that may preserve or increase anti-tumor activity and reduce cardiotoxicity by decreasing peak plasma concentration. However, even under optimal conditions, doxorubicin may have limited delivery into advanced solid tumors.</p