Regulation of the cardiomyocyte transcriptome vs translatome by endothelin-1 and insulin: translational regulation of 5' terminal oligopyrimidine tract (TOP) mRNAs by insulin

Background: Changes in cellular phenotype result from underlying changes in mRNA transcription and translation. Endothelin-1 stimulates cardiomyocyte hypertrophy with associated changes in mRNA/protein expression and an increase in the rate of protein synthesis. Insulin also increases the rate of translation but does not promote overt cardiomyocyte hypertrophy. One mechanism of translational regulation is through 5' terminal oligopyrimidine tracts (TOPs) that, in response to growth stimuli, promote mRNA recruitment to polysomes for increased translation. TOP mRNAs include those encoding ribosomal proteins, but the full panoply remains to be established. Here, we used microarrays to compare the effects of endothelin-1 and insulin on the global transcriptome of neonatal rat cardiomyocytes, and on mRNA recruitment to polysomes (i.e. the translatome). Results: Globally, endothelin-1 and insulin (1 h) promoted >1.5-fold significant (false discovery rate 1.25-fold significant changes in expression in total and/or polysomal RNA induced by endothelin-1 or insulin, respectively, of which ~35% of endothelin-1-responsive and ~56% of insulin-responsive transcripts were translationally regulated. Of mRNAs for established proteins recruited to polysomes in response to insulin, 49 were known TOP mRNAs with a further 15 probable/possible TOP mRNAs, but 49 had no identifiable TOP sequences or other consistent features in the 5' untranslated region. Conclusions: Endothelin-1, rather than insulin, substantially affects global transcript expression to promote cardiomyocyte hypertrophy. Effects on RNA recruitment to polysomes are subtle, with differential effects of endothelin-1 and insulin on specific transcripts. Furthermore, although insulin promotes recruitment of TOP mRNAs to cardiomyocyte polysomes, not all recruited mRNAs are TOP mRNAs

The crystal structure of Pneumolysin at 2.0 Å resolution reveals the molecular packing of the pre-pore complex

Pneumolysin is a cholesterol-dependent cytolysin (CDC) and virulence factor of Streptococcus pneumoniae. It kills cells by forming pores assembled from oligomeric rings in cholesterol-containing membranes. Cryo-EM has revealed the structures of the membrane-surface bound pre-pore and inserted-pore oligomers, however the molecular contacts that mediate these oligomers are unknown because high-resolution information is not available. Here we have determined the crystal structure of full-length pneumolysin at 1.98 Å resolution. In the structure, crystal contacts demonstrate the likely interactions that enable polymerisation on the cell membrane and the molecular packing of the pre-pore complex. The hemolytic activity is abrogated in mutants that disrupt these intermolecular contacts, highlighting their importance during pore formation. An additional crystal structure of the membrane-binding domain alone suggests that changes in the conformation of a tryptophan rich-loop at the base of the toxin promote monomer-monomer interactions upon membrane binding by creating new contacts. Notably, residues at the interface are conserved in other members of the CDC family, suggesting a common mechanism for pore and pre-pore assembly

CIRCUITS BASED ON MAGNETOELECTRIC TRANSISTOR DEVICES

Logic circuits constructed with magnetoelectric (ME) transistors are described herein. A ME logic gate device can include at least one conducting device, for example, at least one MOS transistor; and at least one ME transistor coupled to the at least one conducting device. The ME transistor can be a ME field effect transistor (ME-FET), which can be can be an anti-ferromagnetic spin-orbit read (AFSOR) device or a non - AFSOR device. The gates and logic circuits described herein can be included as standard cells in a design library. Cells of the cell library can include standard cells for a ME verter device, a ME minority gate device, a ME majority gate device, a ME full adder, a ME XNOR device, a ME XOR device, or a combination thereof

The use of hydrazine-based derivatization reagents for improved sensitivity and detection of carbonyl containing compounds using MALDI-MSI

Hydrazine-based derivatization reagents have been used to detect the presence of the carbonyl containing glucocorticoid fluticasone proprionate in rat lung tissue by MALDI-MSI. Such reagents also act as a matrix for analysis by MALDI-MS and have been termed “reactive matrices”. Cryosections of rat lung tissue (12 μm), spotted with a range of concentrations of fluticasone proprionate, were derivatized in situ with 2,4-dinitrophenylhydrazine (DNPH) and 4-dimethylamino-6-(4-methoxy-1-naphthyl)-1,3,5-triazine-2-hydrazine (DMNTH) by the use of an acoustic reagent spotter. It has been demonstrated that DMNTH gave superior results compared to DNPH and that analysis of samples immediately after application of DMNTH resulted in the detection of the protonated hydrazone derivative ([MD + H]+) of fluticasone propionate at a concentration of 500 ng/μL. It has been further shown that a prolonged reaction time (~48 h) improves the detection limit of the protonated hydrazone derivative to 50 ng/μL and that improvements in sensitivity and limits of detection are obtained when a conventional MALDI matrix CHCA is employed in conjunction with the DNPH/DMNTH reactive matrix

Impact of a passive social marketing intervention in community pharmacies on oral contraceptive and condom sales: a quasi-experimental study

Abstract Background Almost 50% of pregnancies in the United States are unwanted or mistimed. Notably, just over one-half of unintended pregnancies occurred when birth control was being used, suggesting inappropriate or poor use or contraceptive failure. About two-thirds of all women who are of reproductive age use contraceptives, and oral hormonal contraceptives remain the most common contraceptive method. Often, contraceptive products are obtained in community pharmacies. The purpose of this study was to determine whether a pharmacy-based intervention would impact sales of contraceptive products in pharmacies. Methods This study was conducted in Iowa and used a quasi-experimental design including 55 community pharmacies (independent and grocery) in 12 counties as the intervention and 32 grocery pharmacies in 10 counties as a comparison group. The passive intervention was focused towards 18–30 year old women who visited community pharmacies and prompted those of childbearing age to “plan your pregnancy” and “consider using birth control”. The intervention was delivered via educational tri-fold brochures, posters and ‘shelf talkers.’ Data sources for evaluation were contraceptive sales from intervention and comparison pharmacies, and a mixed negative binomial regression was used with study group*time interactions to examine the impact of the intervention on oral contraceptive and condom sales. Data from 2009 were considered baseline sales. Results From 2009 to 2011, condom sales decreased over time and oral contraceptives sales showed no change. Overall, the units sold were significantly higher in grocery pharmacies than in independent pharmacies for both contraceptive types. In the negative binomial regression for condoms, there was an overall significant interaction between the study group and time variables (p = 0.003), indicating an effect of the intervention, and there was a significant slowing in the drop of sales at time 3 in comparison with time 1 (p < 0.001). There was a statistically significant association between pharmacy type and study group, where the independent intervention pharmacies had a higher proportion of stores with increases in condom sales compared to grocery pharmacies in the intervention or comparison group. Conclusions A passive community pharmacy-based public health intervention appeared to reduce the decrease in condom sales from baseline, particularly in independent pharmacies, but it did not impact oral contraceptive sales.http://deepblue.lib.umich.edu/bitstream/2027.42/110681/1/12889_2015_Article_1495.pd

Autonomous FMCW Radar Survey of Antarctic Shear Zone

Radar survey of the Antarctic shear zone was conducted using an ultra-wideband (2-10 GHz) frequency modulated continuous wave (FMCW) radar. The radar was mounted on a sled and pulled by a robot that was specifically designed to operate in a harsh polar environment. Our FMCW radar had good penetration through Antarctic snow and we observed snow stratigraphy to a depth of 20 m. The radar images also revealed multiple crevasses in the shear zone. Our results demonstrate that autonomous survey using high frequency radar is feasible and safe approach for detecting hidden crevasses

Timing of Intervention Affects Brain Electrical Activity in Children Exposed to Severe Psychosocial Neglect

Background: Early psychosocial deprivation has profound effects on brain activity in the young child. Previous reports have shown increased power in slow frequencies of the electroencephalogram (EEG), primarily in the theta band, and decreased power in higher alpha and beta band frequencies in infants and children who have experienced institutional care. Methodology/Principal Findings: We assessed the consequences of removing infants from institutions and placing them into a foster care intervention on brain electrical activity when children were 8 years of age. We found the intervention was successful for increasing high frequency EEG alpha power, with effects being most pronounced for children placed into foster care before 24 months of age. Conclusions/Significance: The dependence on age of placement for the effects observed on high frequency EEG alpha power suggests a sensitive period after which brain activity in the face of severe psychosocial deprivation is less amenable to recover

Performance of PCA3 and TMPRSS2:ERG urinary biomarkers in prediction of biopsy outcome in the Canary Prostate Active Surveillance Study (PASS).

BackgroundFor men on active surveillance for prostate cancer, biomarkers may improve prediction of reclassification to higher grade or volume cancer. This study examined the association of urinary PCA3 and TMPRSS2:ERG (T2:ERG) with biopsy-based reclassification.MethodsUrine was collected at baseline, 6, 12, and 24 months in the multi-institutional Canary Prostate Active Surveillance Study (PASS), and PCA3 and T2:ERG levels were quantitated. Reclassification was an increase in Gleason score or ratio of biopsy cores with cancer to ≥34%. The association of biomarker scores, adjusted for common clinical variables, with short- and long-term reclassification was evaluated. Discriminatory capacity of models with clinical variables alone or with biomarkers was assessed using receiver operating characteristic (ROC) curves and decision curve analysis (DCA).ResultsSeven hundred and eighty-two men contributed 2069 urine specimens. After adjusting for PSA, prostate size, and ratio of biopsy cores with cancer, PCA3 but not T2:ERG was associated with short-term reclassification at the first surveillance biopsy (OR = 1.3; 95% CI 1.0-1.7, p = 0.02). The addition of PCA3 to a model with clinical variables improved area under the curve from 0.743 to 0.753 and increased net benefit minimally. After adjusting for clinical variables, neither marker nor marker kinetics was associated with time to reclassification in subsequent biopsies.ConclusionsPCA3 but not T2:ERG was associated with cancer reclassification in the first surveillance biopsy but has negligible improvement over clinical variables alone in ROC or DCA analyses. Neither marker was associated with reclassification in subsequent biopsies

Interpreting Sentinel-1 SAR Backscatter Signals of Snowpack Surface Melt/Freeze, Warming, and Ripening, Through Field Measurements and Physically-Based SnowModel

The transition of a cold winter snowpack to one that is ripe and contributing to runoff is crucial to gauge for water resource management, but is highly variable in space and time. Snow surface melt/freeze cycles, associated with diurnal fluctuations in radiative inputs, are hallmarks of this transition. C-band synthetic aperture radar (SAR) reliably detects meltwater in the snowpack. Sentinel-1 (S1) C-band SAR offers consistent acquisition patterns that allow for diurnal investigations of melting snow. We used over 50 snow pit observations from 2020 in Grand Mesa, Colorado, USA, to track temperature and wetness in the snowpack as a function of depth and time during snowpack phases of warming, ripening, and runoff. We also ran the physically-based SnowModel, which provided a spatially and temporally continuous independent indication of snowpack conditions. Snowpack phases were identified and corroborated by comparing field measurements with SnowModel outputs. Knowledge of snowpack warming, ripening, and runoff phases was used to interpret diurnal changes in S1 backscatter values. Both field measurements and SnowModel simulations suggested that S1 SAR was not sensitive to the initial snowpack warming phase on Grand Mesa. In the ripening and runoff phases, the diurnal cycle in S1 SAR co-polarized backscatter was affected by both surface melt/freeze as well as the conditions of the snowpack underneath (ripening or ripe). The ripening phase was associated with significant increases in morning backscatter values, likely due to volume scattering from surface melt/freeze crusts, as well as significant decreases in evening backscatter values associated with snowmelt. During the runoff phase, both morning and evening backscatter decreased compared to reference values. These unique S1 diurnal signatures, and their interpretations using field measurements and SnowModel outputs, highlight the capacities and limitations of S1 SAR to understand snow surface states and bulk phases, which may offer runoff forecasting or energy balance model validation or parameterization, especially useful in remote or sparsely-gauged alpine basins