Decreased soluble guanylate cyclase contributes to cardiac dysfunction induced by chronic doxorubicin treatment in mice

Aims: The use of doxorubicin, a potent chemotherapeutic agent, is limited by cardiotoxicity. We tested the hypothesis that decreased soluble guanylate cyclase (sGC) enzyme activity contributes to the development of doxorubicin-induced cardiotoxicity. Results: Doxorubicin administration (20 mg/kg, intraperitoneally [IP]) reduced cardiac sGC activity in wild-type (WT) mice. To investigate whether decreased sGC activity contributes to doxorubicin-induced cardiotoxicity, we studied mice with cardiomyocyte-specific deficiency of the sGC alpha 1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGC alpha 1 allele [sGC alpha 1(-/-CM)]). After 12 weeks of doxorubicin administration (2 mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGC alpha 1(-/-CM) than WT mice. To further assess whether reduced sGC activity plays a pathogenic role in doxorubicin-induced cardiotoxicity, we studied a mouse model in which decreased cardiac sGC activity was induced by cardiomyocyte-specific expression of a dominant negative sGC alpha 1 mutant (DNsGC alpha 1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGC alpha 1(tg/+), but not WT, mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGC alpha 1(tg/+) and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGC alpha 1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species generation was higher in sGC alpha 1-deficient than WT hearts. Innovation and Conclusion: These data demonstrate that a reduction in cardiac sGC activity worsens doxorubicin-induced cardiotoxicity in mice and identify sGC as a potential therapeutic target. Various pharmacological sGC agonists are in clinical development or use and may represent a promising approach to limit doxorubicin-associated cardiotoxicity

Observational evidence for the convective transport of dust over the central United States

Bulk aerosol composition and aerosol size distributions measured aboard the DC-8 aircraft during the Deep Convective Clouds and Chemistry Experiment mission in May/June 2012 were used to investigate the transport of mineral dust through nine storms encountered over Colorado and Oklahoma. Measurements made at low altitudes (\u3c5 km mean sea level (MSL)) in the storm inflow region were compared to those made in cirrus anvils (altitude \u3e 9 km MSL). Storm mean outflow Ca2+ mass concentrations and total coarse (1 µm \u3c diameter \u3c 5 µm) aerosol volume (Vc) were comparable to mean inflow values as demonstrated by average outflow/inflow ratios greater than 0.5. A positive relationship between Ca2+, Vc, ice water content, and large (diameter \u3e 50 µm) ice particle number concentrations was not evident; thus, the influence of ice shatter on these measurements was assumed small. Mean inflow aerosol number concentrations calculated over a diameter range (0.5 µm \u3c diameter \u3c 5.0 µm) relevant for proxy ice nuclei (NPIN) were ~15–300 times higher than ice particle concentrations for all storms. Ratios of predicted interstitial NPIN (calculated as the difference between inflow NPIN and ice particle concentrations) and inflow NPIN were consistent with those calculated for Ca2+ and Vc and indicated that on average less than 10% of the ingested NPIN were activated as ice nuclei during anvil formation. Deep convection may therefore represent an efficient transport mechanism for dust to the upper troposphere where these particles can function as ice nuclei cirrus forming in situ

Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder

Background Recurrent microdeletions and microduplications of w555 kb at 16p11.2 confer susceptibility to autism spectrum disorder (ASD) in up to 1% of ASD patients. No physical or behavioural features have been identified that distinguish these individuals as having a distinct ASD subtype, but clinical data are limited. Methods We report five autistic probands identified by microarray analysis with copy number variation (CNV) of 16p11.2 (three deletions, two duplications). Each patient was assessed for ASD and dysmorphic features. We also describe a deletion positive 26-month-old female who has developmental delay (DD) and autistic features. Results Proband 1 (female with ASD, de novo deletion) is not dysmorphic. Proband 2 (male with autism, de novo deletion) and proband 3 and his brother (males with autism, inherited deletions) are dysmorphic, but the two probands do not resemble one another. The mother of proband 3 has mild mental retardation (MR), minor dysmorphism and meets the criteria for ASD. Proband 4 (dysmorphic autistic male, de novo duplication) had a congenital diaphragmatic hernia. Proband 5 (nondysmorphic ASD female with a duplication) has two apparently healthy duplication positive relatives. Probands 1 and 2 have deletion negative siblings with ASD and Asperger syndrome, respectively. Proband 6 (a female with DD and an inherited duplication) is dysmorphic, but has oligohydramnios sequence. Conclusions The phenotypic spectrum associated with CNV at 16p11.2 includes ASD, MR/DD and/or possibly other primary psychiatric disorders. Compared with the microduplications, the reciprocal microdeletions are more likely to be penetrant and to be associated with nonspecific major or minor dysmorphism. There are deletion positive ASD probands with a less severe phenotype than deletion negative ASD siblings underscoring the significant phenotypic heterogeneity.published_or_final_versio

Magnetic core-shell nanoparticles for drug delivery by nebulization

BACKGROUND: Aerosolized therapeutics hold great potential for effective treatment of various diseases including lung cancer. In this context, there is an urgent need to develop novel nanocarriers suitable for drug delivery by nebulization. To address this need, we synthesized and characterized a biocompatible drug delivery vehicle following surface coating of Fe(3)O(4) magnetic nanoparticles (MNPs) with a polymer poly(lactic-co-glycolic acid) (PLGA). The polymeric shell of these engineered nanoparticles was loaded with a potential anti-cancer drug quercetin and their suitability for targeting lung cancer cells via nebulization was evaluated. RESULTS: Average particle size of the developed MNPs and PLGA-MNPs as measured by electron microscopy was 9.6 and 53.2 nm, whereas their hydrodynamic swelling as determined using dynamic light scattering was 54.3 nm and 293.4 nm respectively. Utilizing a series of standardized biological tests incorporating a cell-based automated image acquisition and analysis procedure in combination with real-time impedance sensing, we confirmed that the developed MNP-based nanocarrier system was biocompatible, as no cytotoxicity was observed when up to 100 μg/ml PLGA-MNP was applied to the cultured human lung epithelial cells. Moreover, the PLGA-MNP preparation was well-tolerated in vivo in mice when applied intranasally as measured by glutathione and IL-6 secretion assays after 1, 4, or 7 days post-treatment. To imitate aerosol formation for drug delivery to the lungs, we applied quercitin loaded PLGA-MNPs to the human lung carcinoma cell line A549 following a single round of nebulization. The drug-loaded PLGA-MNPs significantly reduced the number of viable A549 cells, which was comparable when applied either by nebulization or by direct pipetting. CONCLUSION: We have developed a magnetic core-shell nanoparticle-based nanocarrier system and evaluated the feasibility of its drug delivery capability via aerosol administration. This study has implications for targeted delivery of therapeutics and poorly soluble medicinal compounds via inhalation route

Energy Dependence of Nuclear Transparency in C(p,2p) Scattering

The transparency of carbon for (p,2p) quasi-elastic events was measured at beam energies ranging from 6 to 14.5 GeV at 90 degrees c.m. The four momentum transfer squared q*q ranged from 4.8 to 16.9 (GeV/c)**2. We present the observed energy dependence of the ratio of the carbon to hydrogen cross sections. We also apply a model for the nuclear momentum distribution of carbon to normalize this transparency ratio. We find a sharp rise in transparency as the beam energy is increased to 9 GeV and a reduction to approximately the Glauber level at higher energies.Comment: 4 pages, 2figures, submitted to PR

Increasing protein content of wheat by breeding

The most efficient means of increasing protein content of WesternAustralian wheat is by breeding new varieties with higher inherent protein in their grain. But is this possible without sacrificing yeild or other desirable characteristics

Variation in wheat protein content : the effect of environment

Over the past 20 years, the average protein content of WesternAustralian wheat has ranged from 9.3 to 12.0 per cent, with a mean level of 10.4 per cent. At most grain receival points, in any one season, individual loads can often vary in protein content by as much as 5 per cent protein or more. Rainfall and soil fertility account for much of this variation