Photochemical internalisation of a macromolecular protein toxin using a cell penetrating peptide-photosensitiser conjugate.

Photochemical internalisation (PCI) is a site-specific technique for improving cellular delivery of macromolecular drugs. In this study, a cell penetrating peptide, containing the core HIV-1 Tat 48-57 sequence, conjugated with a porphyrin photosensitiser has been shown to be effective for PCI. Herein we report an investigation of the photophysical and photobiological properties of a water soluble bioconjugate of the cationic Tat peptide with a hydrophobic tetraphenylporphyrin derivative. The cellular uptake and localisation of the amphiphilic bioconjugate was examined in the HN5 human head and neck squamous cell carcinoma cell line. Efficient cellular uptake and localisation in endo/lysosomal vesicles was found using fluorescence detection, and light-induced, rupture of the vesicles resulting in a more diffuse intracellular fluorescence distribution was observed. Conjugation of the Tat sequence with a hydrophobic porphyrin thus enables cellular delivery of an amphiphilic photosensitiser which can then localise in endo/lysosomal membranes, as required for effective PCI treatment. PCI efficacy was tested in combination with a protein toxin, saporin, and a significant reduction in cell viability was measured versus saporin or photosensitiser treatment alone. This study demonstrates that the cell penetrating peptide-photosensitiser bioconjugation strategy is a promising and versatile approach for enhancing the therapeutic potential of bioactive agents through photochemical internalisation

Hydro-economic modeling with aquifer-river interactions to guide sustainable basin management

Policymakers in arid and semiarid basins face hard choices on water policies needed for adaptation to climate change. Hydro-economic modeling is a state-of-the art approach that can be used to guide the design and implementation of these policies in basins. A major gap in developments of hydro-economic modeling to date has been the weak integration of physically-based representations of water sources and uses such as the interaction between ground and surface water resources, to inform complex basin scale policy choices. This paper presents an integrated hydro-economic modeling framework to address this gap with application to an important and complex river basin in Spain, the Jucar basin, for the assessment of a range of climate change scenarios and policy choices. Results indicate that in absence of adequate policies protecting water resources and natural ecosystems, water users will strategically deplete reservoirs, aquifers and river flows for short-term adaptation to climate change, disregarding the impacts on the environment and future human activities. These impacts can be addressed by implementing sustainable management policies. However, these policies could have disproportionate costs for some stakeholders groups, and their opposition may undermine attempts at sustainable policy. These tradeoffs among water policy choices are important guides to the design of policies aimed at basin-wide adaptation to climate change

Flexible synthesis of cationic peptide-porphyrin derivatives for light-triggered drug delivery and photodynamic therapy

Efficient syntheses of cell-penetrating peptide-porphyrin conjugates are described using a variety of bioconjugation chemistries. This provides a flexible means to convert essentially hydrophobic tetrapyrolle photosensitisers into amphiphilic derivatives which are well-suited for use in light-triggered drug delivery by photochemical internalisation (PCI) and targeted photodynamic therapy (PDT)

Impact of Emerging Health Insurance Arrangements on Diabetes Outcomes and Disparities: Rationale and Study Design

Consumer-directed health plans combine lower premiums with high annual deductibles, Internet-based quality-of-care information, and health savings mechanisms. These plans may encourage members to seek better value for health expenditures but may also decrease essential care. The expansion of high-deductible health plans (HDHPs) represents a natural experiment of tremendous proportion. We designed a pre–post, longitudinal, quasi-experimental study to determine the effect of HDHPs on diabetes quality of care, outcomes, and disparities. We will use a 13-year rolling sample (2001–2013) of members of an HDHP and members of a control group. To reduce selection bias, we will limit participants to those whose employers mandate a single health insurance type. The study will measure rates of monthly hemoglobin A1c, lipid, and albuminuria testing; availability of blood glucose test strips; and rates of retinal examinations, high-severity emergency department visits, and preventable hospitalizations. Results could be used to design health plan features that promote high-quality care and better outcomes among people who have diabetes

Advancing national greenhouse gas inventories for agriculture in developing countries : improving activity data, emission factors and software technology

Peer reviewedPublisher PD

What’s Sex (Composition) Got to Do with It? The Importance of Sex Composition of Gangs for Female and Male Members’ Offending and Victimization

Sex composition of groups has been theorized in organizational sociology and found in prior work to structure female and male members’ behaviors and experiences. Peer group and gang literature similarly finds that the sex gap in offending varies across groups of differing sex ratios. Drawing on this and other research linking gang membership, offending, and victimization, we examine whether sex composition of gangs is linked to sex differences in offending in this sample, further assess whether sex composition similarly structures females’ and males’ victimization experiences, and if so, why. Self-report data from gang members in a multi-site, longitudinal study of 3,820 youths are employed. Results support previous findings about variations in member delinquency by both sex and sex composition of the gang and also indicate parallel variations in members’ victimization. These results are further considered within the context of facilitating effects such as gender dynamics, gang characteristics, and normative orientation