Properties of small molecular drug loading and diffusion in a fluorinated PEG hydrogel studied by ^1H molecular diffusion NMR and ^(19)F spin diffusion NMR

R_f-PEG (fluoroalkyl double-ended poly(ethylene glycol)) hydrogel is potentially useful as a drug delivery depot due to its advanced properties of sol–gel two-phase coexistence and low surface erosion. In this study, ^1H molecular diffusion nuclear magnetic resonance (NMR) and ^(19)F spin diffusion NMR were used to probe the drug loading and diffusion properties of the R_f-PEG hydrogel for small anticancer drugs, 5-fluorouracil (FU) and its hydrophobic analog, 1,3-dimethyl-5-fluorouracil (DMFU). It was found that FU has a larger apparent diffusion coefficient than that of DMFU, and the diffusion of the latter was more hindered. The result of ^(19)F spin diffusion NMR for the corresponding freeze-dried samples indicates that a larger portion of DMFU resided in the R_f core/IPDU intermediate-layer region (where IPDU refers to isophorone diurethane, as a linker to interconnect the R_f group and the PEG chain) than that of FU while the opposite is true in the PEG–water phase. To understand the experimental data, a diffusion model was proposed to include: (1) hindered diffusion of the drug molecules in the R_f core/IPDU-intermediate-layer region; (2) relatively free diffusion of the drug molecules in the PEG-water phase (or region); and (3) diffusive exchange of the probe molecules between the above two regions. This study also shows that molecular diffusion NMR combined with spin diffusion NMR is useful in studying the drug loading and diffusion properties in hydrogels for the purpose of drug delivery applications

Estimation of changes in the force of infection for intestinal and urogenital schistosomiasis in countries with Schistosomiasis Control Initiative-assisted programmes

The last decade has seen an expansion of national schistosomiasis control programmes in Africa based on large-scale preventative chemotherapy. In many areas this has resulted in considerable reductions in infection and morbidity levels in treated individuals. In this paper, we quantify changes in the force of infection (FOI), defined here as the per (human) host parasite establishment rate, to ascertain the impact on transmission of some of these programmes under the umbrella of the Schistosomiasis Control Initiative (SCI)

Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study.

PurposeOsteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI.MethodsUsing data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves.ResultsIn children, the median z-scores for height in OI types I, III, and IV were -0.66, -6.91, and -2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was -4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P < 0.001), age, bisphosphonate use, and rodding (P < 0.05).ConclusionFrom the largest cohort of individuals with OI, we provide median values for height, weight, and BMI z-scores that can aid the evaluation of overall growth in the clinic setting. This study is an important first step in the generation of OI-specific growth curves

The role of multiple marks in epigenetic silencing and the emergence of a stable bivalent chromatin state

We introduce and analyze a minimal model of epigenetic silencing in budding yeast, built upon known biomolecular interactions in the system. Doing so, we identify the epigenetic marks essential for the bistability of epigenetic states. The model explicitly incorporates two key chromatin marks, namely H4K16 acetylation and H3K79 methylation, and explores whether the presence of multiple marks lead to a qualitatively different systems behavior. We find that having both modifications is important for the robustness of epigenetic silencing. Besides the silenced and transcriptionally active fate of chromatin, our model leads to a novel state with bivalent (i.e., both active and silencing) marks under certain perturbations (knock-out mutations, inhibition or enhancement of enzymatic activity). The bivalent state appears under several perturbations and is shown to result in patchy silencing. We also show that the titration effect, owing to a limited supply of silencing proteins, can result in counter-intuitive responses. The design principles of the silencing system is systematically investigated and disparate experimental observations are assessed within a single theoretical framework. Specifically, we discuss the behavior of Sir protein recruitment, spreading and stability of silenced regions in commonly-studied mutants (e.g., sas2, dot1) illuminating the controversial role of Dot1 in the systems biology of yeast silencing.Comment: Supplementary Material, 14 page

Tracking of fatness during childhood, adolescence and young adulthood: a 7-year follow-up study in Madeira Island, Portugal

Aims: Investigating tracking of fatness from childhood to adolescence, early adolescence to young adulthood and late adolescence to young adulthood. Subjects and methods: Participants from the Madeira Growth Study were followed during an average period of 7.2 years. Height, body mass, skin-folds and circumferences were measured, nine health- and performance-related tests were administered and the Baecke questionnaire was used to assess physical activity. Skeletal maturity was estimated using the TW3 method. Results: The prevalence of overweight plus obesity ranged from 8.2–20.0% at baseline and from 20.4–40.0% at followup, in boys. Corresponding percentages for girls were 10.6– 12.0% and 13.2–18.0%. Inter-age correlations for fatness indicators ranged from 0.43–0.77. BMI, waist circumference and sum of skin-folds at 8, 12 and 16-years old were the main predictors of these variables at 15, 19 and 23-years old, respectively. Strength, muscular endurance and aerobic fitness were negatively related to body fatness. Physical activity and maturation were independently associated with adolescent (15 years) and young adult (19 years) fatness. Conclusions: Over 7.2 years, tracking was moderate-to-high for fatness. Variance was explained by fatness indicators and to a small extent by physical fitness, physical activity and maturation

Body mass index, adiposity rebound and early feeding in a longitudinal cohort (Raine study)

Objective: This study examined the influence of type and duration of infant feeding on adiposity rebound and the tracking of body mass index (BMI) from birth to 14 years. Methods: A sample of 1330 individuals over eight follows-ups was drawn from the Western Australian Pregnancy Cohort (Raine) Study. Trajectories of BMI from birth to adolescence using linear mixed model (LMM) analysis investigated the influence of age breastfeeding stopped and age other milk introduced (binomial 4-month cut-point). A sub-sample of LMM predicted BMI was used to determine BMI and age at nadir for early infant feeding groups. Results: Chi square analysis between early feeding and weight status (normal weight, overweight and obese) groups found a significant difference between age breastfeeding stopped (p Conclusions: Early infant feeding was important in the timing and BMI at adiposity rebound. The relationship between infant feeding and BMI remained up to age 14 years. Although confounding factors cannot be excluded, these findings support the importance of exclusive breastfeeding for longer than four months as a protective behaviour against the development of adolescent obesity

Exploring synergies and trade-offs among the sustainable development goals: collective action and adaptive capacity in marginal mountainous areas of India

Global environmental change (GEC) threatens to undermine the sustainable development goals (SDGs). Smallholders in marginal mountainous areas (MMA) are particularly vulnerable due to precarious livelihoods in challenging environments. Acting collectively can enable and constrain the ability of smallholders to adapt to GEC. The objectives of this paper are: (i) identify collective actions in four MMA of the central Indian Himalaya Region, each with differing institutional contexts; (ii) assess the adaptive capacity of each village by measuring livelihood capital assets, diversity, and sustainable land management practices. Engaging with adaptive capacity and collective action literatures, we identify three broad approaches to adaptive capacity relating to the SDGs: natural hazard mitigation (SDG 13), social vulnerability (SDG 1, 2 and 5), and social–ecological resilience (SDG 15). We then develop a conceptual framework to understand the institutional context and identify SDG synergies and trade-offs. Adopting a mixed method approach, we analyse the relationships between collective action and the adaptive capacity of each village, the sites where apparent trade-offs and synergies among SDGs occur. Results illustrate each village has unique socio-environmental characteristics, implying distinct development challenges, vulnerabilities and adaptive capacities exist. Subsequently, specific SDG synergies and trade-offs occur even within MMA, and it is therefore crucial that institutions facilitate locally appropriate collective actions in order to achieve the SDGs. We suggest that co-production in the identification, prioritisation and potential solutions to the distinct challenges facing MMA can increase understandings of the specific dynamics and feedbacks necessary to achieve the SDGs in the context of GEC

Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2-extracellular domain in human cancer cells

Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic efficacy against HER2-positive breast and gastric cancers; however, acquired resistance presents a formidable obstacle to long-term tumor responses in the majority of patients. Here, we show the mechanism of resistance to trastuzumab in HER2-positive human cancer cells and explore the molecular sensitization by exogenous expression of HER2-extracellular domain (ECD) in HER2-negative or trastuzumab-resistant human cancer cells. We found that long-term exposure to trastuzumab induced resistance in HER2-positive cancer cells; HER2 expression was downregulated, and antibody-dependent cellular cytotoxicity (ADCC) activity was impaired. We next examined the hypothesis that trastuzumab-resistant cells could be re-sensitized by the transfer of non-functional HER2-ECD. Exogenous HER2-ECD expression induced by the stable transfection of a plasmid vector or infection with a replication-deficient adenovirus vector had no apparent effect on the signaling pathway, but strongly enhanced ADCC activity in low HER2-expressing or trastuzumab-resistant human cancer cells. Our data indicate that restoration of HER2-ECD expression sensitizes HER2-negative or HER2-downregulated human cancer cells to trastuzumab-mediated ADCC, an outcome that has important implications for the treatment of human cancers