Transdermal delivery of scopolamine by natural submicron injectors: in-vivo study in pig

Transdermal drug delivery has made a notable contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. While transdermal delivery systems would appear to provide an attractive solution for local and systemic drug delivery, only a limited number of drugs can be delivered through the outer layer of the skin. The most difficult to deliver in this way are hydrophilic drugs. The aquatic phylum Cnidaria, which includes sea anemones, corals, jellyfish and hydra, is one of the most ancient multicellular phyla that possess stinging cells containing organelles (cnidocysts), comprising a sophisticated injection system. The apparatus is folded within collagenous microcapsules and upon activation injects a thin tubule that immediately penetrates the prey and delivers its contents. Here we show that this natural microscopic injection system can be adapted for systemic transdermal drug delivery once it is isolated from the cells and uploaded with the drug. Using a topically applied gel containing isolated natural sea anemone injectors and the muscarinic receptor antagonist scopolamine, we found that the formulated injectors could penetrate porcine skin and immediately deliver this hydrophilic drug. An in-vivo study in pigs demonstrated, for the first time, rapid systemic delivery of scopolamine, with T(max) of 30 minutes and C(max) 5 times higher than in controls treated topically with a scopolamine-containing gel without cnidocysts. The ability of the formulated natural injection system to penetrate a barrier as thick as the skin and systemically deliver an exogenous compound presents an intriguing and attractive alternative for hydrophilic transdermal drug delivery.     

The Bcl6-SMRT/NCoR cistrome represses inflammation to attenuate atherosclerosis

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Highlights? Bcl6 is a critical antiatherogenic regulator ? Inhibition of Bcl6-SMRT/NCoR interactions induces atherogenic gene expression ? SMRT and NCoR cistromes each exceed 30,000 sites, with a nearly 50% overlap ? Bcl6 recruits SMRT and NCoR to NF-κB-driven inflammatory and tissue remodeling genes     

White Blood Cell Count and the Risk for Coronary Artery Disease in Young Adults

Background

The association between white blood cell (WBC) count and coronary artery disease (CAD) is unknown in young adults. Our objective was to assess the association between WBC count and its changes over time with CAD incidence in the Metabolic, Life-style and Nutrition Assessment in Young adults (MELANY) study, a cohort of Israeli army personnel.

Methods and Findings

29,120 apparently healthy young men (mean age; 31.2±5.5 years) with a normal baseline WBC count (3,000–12,000 cells/mm³) were followed during a mean follow up of 7.5±3.8 years for incidence of CAD. Participants were screened every 3–5 years using a stress test, and CAD was confirmed by coronary angiography. In a multivariate model adjusted for age, body mass index (BMI), LDL- and HDL-cholesterol, blood pressure, family history of CAD, physical activity, diabetes, triglycerides and smoking status, WBC levels (divided to quintiles) above 6,900 cells/mm³ (quintile 4) were associated with a 2.17-fold increase (95%CI = 1.18–3.97) in the risk for CAD as compared with men in quintile 1 (WBC≤5,400 cells/mm³). When modeled as a continuous variable, a WBC increment of 1000 cells/mm³ was associated with a 17.4% increase in CAD risk (HR 1.174; 95%CI = 1.067–1.290, p = 0.001). A decrease in the WBC level (within the normal range) during the follow-up period was associated with increased physical activity and decreased triglyceride levels as well as with reduced incidence of CAD.

Conclusions

WBC count is an independent risk factor for CAD in young adults at values well within the normal range. WBC count may assist in detecting subgroups of young men at either low or high risk for progression to CAD.     

The effects of climate change on harp seals (Pagophilus groenlandicus)

Harp seals (Pagophilus groenlandicus) have evolved life history strategies to exploit seasonal sea ice as a breeding platform. As such, individuals are prepared to deal with fluctuations in the quantity and quality of ice in their breeding areas. It remains unclear, however, how shifts in climate may affect seal populations. The present study assesses the effects of climate change on harp seals through three linked analyses. First, we tested the effects of short-term climate variability on young-of-the year harp seal mortality using a linear regression of sea ice cover in the Gulf of St. Lawrence against stranding rates of dead harp seals in the region during 1992 to 2010. A similar regression of stranding rates and North Atlantic Oscillation (NAO) index values was also conducted. These analyses revealed negative correlations between both ice cover and NAO conditions and seal mortality, indicating that lighter ice cover and lower NAO values result in higher mortality. A retrospective cross-correlation analysis of NAO conditions and sea ice cover from 1978 to 2011 revealed that NAO-related changes in sea ice may have contributed to the depletion of seals on the east coast of Canada during 1950 to 1972, and to their recovery during 1973 to 2000. This historical retrospective also reveals opposite links between neonatal mortality in harp seals in the Northeast Atlantic and NAO phase. Finally, an assessment of the long-term trends in sea ice cover in the breeding regions of harp seals across the entire North Atlantic during 1979 through 2011 using multiple linear regression models and mixed effects linear regression models revealed that sea ice cover in all harp seal breeding regions has been declining by as much as 6 percent per decade over the time series of available satellite data.     

Unique Prokaryotic Consortia in Geochemically Distinct Sediments from Red Sea Atlantis II and Discovery Deep Brine Pools

The seafloor is a unique environment, which allows insights into how geochemical processes affect the diversity of biological life. Among its diverse ecosystems are deep-sea brine pools - water bodies characterized by a unique combination of extreme conditions. The 'polyextremophiles' that constitute the microbial assemblage of these deep hot brines have not been comprehensively studied. We report a comparative taxonomic analysis of the prokaryotic communities of the sediments directly below the Red Sea brine pools, namely, Atlantis II, Discovery, Chain Deep, and an adjacent brine-influenced site. Analyses of sediment samples and high-throughput pyrosequencing of PCR-amplified environmental 16S ribosomal RNA genes (16S rDNA) revealed that one sulfur (S)-rich Atlantis II and one nitrogen (N)-rich Discovery Deep section contained distinct microbial populations that differed from those found in the other sediment samples examined. Proteobacteria, Actinobacteria, Cyanobacteria, Deferribacteres, and Euryarchaeota were the most abundant bacterial and archaeal phyla in both the S- and N-rich sections. Relative abundance-based hierarchical clustering of the 16S rDNA pyrotags assigned to major taxonomic groups allowed us to categorize the archaeal and bacterial communities into three major and distinct groups; group I was unique to the S-rich Atlantis II section (ATII-1), group II was characteristic for the N-rich Discovery sample (DD-1), and group III reflected the composition of the remaining sediments. Many of the groups detected in the S-rich Atlantis II section are likely to play a dominant role in the cycling of methane and sulfur due to their phylogenetic affiliations with bacteria and archaea involved in anaerobic methane oxidation and sulfate reduction.     

Prevalence and Predictors of Sub-Acute Phase Disability after Injury among Hospitalised and Non-Hospitalised Groups: A Longitudinal Cohort Study

Introduction

To reduce the burden on injury survivors and their supporters, factors associated with poor outcomes need to be identified so that timely post-injury interventions can be implemented. To date, few studies have investigated outcomes for both those who were hospitalised and those who were not.

Aim

To describe the prevalence and to identify pre-injury and injury-related predictors of disability among hospitalised and non-hospitalised people, three months after injury.

Methods

Participants in the Prospective Outcomes of Injury Study were aged 18–64 years and on an injury entitlement claims register with New Zealand''s no-fault injury compensation insurer, following referral by healthcare professionals. A wide range of pre-injury demographic, health and injury-related characteristics were collected at interview. Participants were categorised as ‘hospitalised’ if they were placed on New Zealand''s National Minimum Data Set within seven days of the injury event. Injury severity scores (NISS) and 12 injury categories were derived from ICD-10 codes. WHODAS assessed disability. Multivariable analyses examined relationships between explanatory variables and disability.

Results

Of 2856 participants, 2752 (96%) had WHODAS scores available for multivariable analysis; 673 were hospitalised; 2079 were not. Disability was highly prevalent among hospitalised (53.6%) and non-hospitalised (39.4%) participants, three-months after injury. In both groups, pre-injury disability, obesity and higher injury severity were associated with increased odds of post-injury disability. A range of other factors were associated with disability in only one group: e.g. female, ≥2 chronic conditions and leg fracture among hospitalised; aged 35–54 years, trouble accessing healthcare, spine or lower extremity sprains/dislocations and assault among non-hospitalised.

Significance

Disability was highly prevalent among both groups yet, with a few exceptions, factors associated with disability were not common to both groups. Where possible, including a range of injured people in studies, hospitalised and not, will increase understanding of the burden of disability in the sub-acute phase.     

Gulping rather than sipping: macropinocytosis as a way of virus entry

Macropinocytosis has emerged as a major endocytic mechanism in the cell entry of animal viruses. The process differs fundamentally from other endocytic mechanisms involved in virus internalization. By activating growth factor receptors or other signaling molecules, plasma membrane-bound viruses trigger the activation of a signaling pathway. When amplified, this causes a transient, global change in cell behavior. The consequences of this change include the actin-dependent formation of membrane protrusions, the elevation of non-specific uptake of fluid, and the internalization of membrane together with surface-bound ligands and particles including viruses. Recent studies show that this strategy is used by a variety of enveloped and non-enveloped viruses.     

A catalogue of putative HIV-1 protease host cell substrates

Abstract Processing of human immunodeficiency virus (HIV) proteins by the HIV-1 protease is essential for HIV infectivity. In addition, several studies have revealed cleavage of human proteins by this viral protease during infection; however, no large-scale HIV-1 protease degradomics study has yet been performed. To identify putative host substrates in an unbiased manner and on a proteome-wide scale, we used positional proteomics to identify peptides reporting protein processing by the HIV-1 protease, and a catalogue of over 120 cellular HIV-1 protease substrates processed in vitro was generated. This catalogue includes previously reported substrates as well as recently described interaction partners of HIV-1 proteins. Cleavage site alignments revealed a specificity profile in good correlation with previous studies, even though the ELLE consensus motif was not cleaved efficiently when incorporated into peptide substrates due to subsite cooperativity. Our results are further discussed in the context of HIV-1 infection and the complex substrate recognition by the viral protease.