Reversing Blood Flows Act through klf2a to Ensure Normal Valvulogenesis in the Developing Heart

Heart valve anomalies are some of the most common congenital heart defects, yet neither the genetic nor the epigenetic forces guiding heart valve development are well understood. When functioning normally, mature heart valves prevent intracardiac retrograde blood flow; before valves develop, there is considerable regurgitation, resulting in reversing (or oscillatory) flows between the atrium and ventricle. As reversing flows are particularly strong stimuli to endothelial cells in culture, an attractive hypothesis is that heart valves form as a developmental response to retrograde blood flows through the maturing heart. Here, we exploit the relationship between oscillatory flow and heart rate to manipulate the amount of retrograde flow in the atrioventricular (AV) canal before and during valvulogenesis, and find that this leads to arrested valve growth. Using this manipulation, we determined that klf2a is normally expressed in the valve precursors in response to reversing flows, and is dramatically reduced by treatments that decrease such flows. Experimentally knocking down the expression of this shear-responsive gene with morpholine antisense oligonucleotides (MOs) results in dysfunctional valves. Thus, klf2a expression appears to be necessary for normal valve formation. This, together with its dependence on intracardiac hemodynamic forces, makes klf2a expression an early and reliable indicator of proper valve development. Together, these results demonstrate a critical role for reversing flows during valvulogenesis and show how relatively subtle perturbations of normal hemodynamic patterns can lead to both major alterations in gene expression and severe valve dysgenesis

Uptake of Multiple Microinsurance Schemes: Evidence from Sri Lanka

Since it is common among households to use more than one form of microinsurance, this paper estimates the uptake of different kinds of microinsurance by the same population. We use a multivariate probit model which examines the participation in the different forms of insurance simultaneously. By doing this, we can establish whether participation patterns in different types of microinsurance options indicate if the participation in specific insurance schemes is complementary or a substitute. We establish that membership of a microfinance institution means that households are more likely to have purchased an insurance policy. Furthermore, the study describes a need for more inclusive and composite packages of microinsurance products for greater financial inclusion of the poor

Synthetic Testing of Load Current Interruption in Medium Voltage Load Break Switches

To conduct the mainly active load current test duty according to IEC 62271-103, a directly powered test circuit and therefore a medium voltage connection or a power generator is needed. A newly developed synthetic test circuit allows to replicate the current as well as the full transient recovery voltage (TRV) and the power frequent recovery voltage (RV) of the direct test circuit up to its crest value. It is dimensioned for voltage classes up to 52 kV and can be adapted to test currents between 630 A and 1250 A. The test circuit allows a detailed investigation of load break switches without costly high power sources and loads. Many parameters, like current and voltage steepness at current zero, as well as different parameters defining the TRV steepness can be varied individually

A comparative analysis of form and function in Centrarchidae hearing ability: Does otolith variation affect auditory responsiveness?

There exists a wealth of knowledge on hearing ability in individual fish species, but the role of interspecific variation, and drivers behind it, remains understudied, making it difficult to understand evolutionary drivers. The current study quantified hearing thresholds for three species of sunfish in the family Centrarchidae [bluegill sunfish (Lepomis macrochirus), pumpkinseed sunfish (Lepomis gibbosus), and rock bass (Ambloplites rupestris)] using auditory evoked potentials and behavioral trials and saccular otolith size and hair cell density. In auditory physiological experiments, 10-ms tone bursts were played and responses monitored to measure hearing. In behavioral experiments, fish were exposed to the same tone bursts for 1 s, and changes in fish behaviors were monitored. Saccular otolith morphology and hair cell densities were also quantified. Physiological thresholds varied between species, but behavioral thresholds did not. Rock bass had larger S:O ratio (percentage of the saccular otolith surface occupied by the sulcus), but no differences in hair cell densities were found. Our study allows for a direct comparison between confamilial species, allowing a deeper understanding of sound detection abilities and possible mechanisms driving differential hearing. Using both approaches also allows future research into how these species may be impacted by increasing levels of anthropogenic noise

Influence of cosine corrector and UAS platform dynamics on airborne spectral irradiance measurements

Measuring solar-induced chlorophyll fluorescence from small-sized Unmanned Aircraft Systems (UAS) can potentially fill the scaling gap between ground-based and airborne/space-borne observations. These measurements require well calibrated' high-spectral resolution spectroradiometers and precise measurements of vegetation radiance and incoming solar irradiance. Here we present a system equipped with a spectroradiometer with a split optical path that measures incoming irradiance through a cosine corrector/diffuser. The objectives of this study are to characterise cosine corrected solar irradiance measurements with regard to sensor homogeneity and possible offset from an ideal cosine response. We further suggest a methodology to calculate a corrected zenith angle that accounts for changing sensor orientation due to pitch, roll and heading of the UAS platform during flight. We found that the cosine corrector is sufficiently homogeneous, thus measurements are independent of UAS heading. The response follows the cosine law for zenith angles, however, the sensor significantly underestimated irradiance for zenith angles > 10°, with overall cosine errors ranging from 0.991 to 1.229. Yet, typical in-flight platform pitch and roll angles produce a zenith angle offset of up to 6° in low wind conditions. Cosine sensor measurements corrected for the zenith angle offset and the cosine error resulted in a 1.7 % change in irradiance

Thermal Infrared Spectrometers for the Polar Radiant Energy in the Far‐Infrared Experiment (PREFIRE)

Plain Language Summary: Earth absorbs energy emitted by the Sun, radiating some of that as heat back into space. The energy exchange between Earth and space drives weather and climate. Scientists measure and track this energy using satellite instruments that can identify which parts of Earth's surface and atmosphere emit specific portions of the overall heat radiated into space. But these instruments are complicated and expensive, and until now, no one has built a sensor that can look at and separate all of Earth's heat emissions in a systematic way. The Polar Radiant Energy in the Far‐InfraRed Experiment (PREFIRE) has developed a novel instrument that combines simple, miniaturized heat sensors with specially shaped optics and microelectronics to provide such measurements to further our understanding of the planet's weather and climate. Furthermore, implementation of the sensors has been done within a cost‐capped mission profile that encourages development of a sustainable sensor system for Earth monitoring. This manuscript describes the instrument design, including its components and their characteristics, the system and its functionality, its trade‐offs, cost limitations, and testing and performance information. PREFIRE began operating two of these instruments in space in 2024, in order to start quantifying the heat exchange processes in Earth's polar regions

Developmental trajectories and cooperating genomic events define molecular subtypes of BCR::ABL1-positive ALL

Distinct diagnostic entities within BCR::ABL1-positive acute lymphoblastic leukemia (ALL) are currently defined by the International Consensus Classification of myeloid neoplasms and acute leukemias (ICC): "lymphoid only", with BCR::ABL1 observed exclusively in lymphatic precursors, vs "multilineage", where BCR::ABL1 is also present in other hematopoietic lineages. Here, we analyzed transcriptomes of 327 BCR::ABL1-positive patients with ALL (age, 2-84 years; median, 46 years) and identified 2 main gene expression clusters reproducible across 4 independent patient cohorts. Fluorescence in situ hybridization analysis of fluorescence-activated cell-sorted hematopoietic compartments showed distinct BCR::ABL1 involvement in myeloid cells for these clusters (n = 18/18 vs n = 3/16 patients; P < .001), indicating that a multilineage or lymphoid BCR::ABL1 subtype can be inferred from gene expression. Further subclusters grouped samples according to cooperating genomic events (multilineage: HBS1L deletion or monosomy 7; lymphoid: IKZF1-/- or CDKN2A/PAX5 deletions/hyperdiploidy). A novel HSB1L transcript was highly specific for BCR::ABL1 multilineage cases independent of HBS1L genomic aberrations. Treatment on current German Multicenter Study Group for Adult ALL (GMALL) protocols resulted in comparable disease-free survival (DFS) for multilineage vs lymphoid cluster patients (3-year DFS: 70% vs 61%; P = .530; n = 91). However, the IKZF1-/- enriched lymphoid subcluster was associated with inferior DFS, whereas hyperdiploid cases showed a superior outcome. Thus, gene expression clusters define underlying developmental trajectories and distinct patterns of cooperating events in BCR::ABL1-positive ALL with prognostic relevance

Chemical Diversity and Complexity of Scotch Whisky as Revealed by High-Resolution Mass Spectrometry

Scotch Whisky is an important product, both culturally and economically. Chemically, Scotch Whisky is a complex mixture, which comprises thousands of compounds, the nature of which are largely unknown. Here, we present a thorough overview of the chemistry of Scotch Whisky as observed by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Eighty-five whiskies, representing the majority of Scotch Whisky produced and sold, were analyzed by untargeted high-resolution mass spectrometry. Thousands of chemical formulae were assigned for each sample based on parts-per-billion mass accuracy of FT-ICR MS spectra. For the first time, isotopic fine structure analysis was used to confirm the assignment of high molecular weight CHOS species in Scotch Whisky. The assigned spectra were compared using a number of visualization techniques, including van Krevelen diagrams, double bond equivalence (DBE) plots, as well as heteroatomic compound class distributions. Additionally, multivariate analysis, including PCA and OPLS-DA, was used to interpret the data, with key compounds identified for discriminating between types of whisky (blend or malt) or maturation wood type. FT-ICR MS analysis of Scotch Whisky was shown to be of significant potential in further understanding of the complexity of mature spirit drinks and as a tool for investigating the chemistry of the maturation processes. [Figure: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13361-016-1513-y) contains supplementary material, which is available to authorized users

ILK Induces Cardiomyogenesis in the Human Heart

Integrin-linked kinase (ILK) is a widely conserved serine/threonine kinase that regulates diverse signal transduction pathways implicated in cardiac hypertrophy and contractility. In this study we explored whether experimental overexpression of ILK would up-regulate morphogenesis in the human fetal heart.Primary cultures of human fetal myocardial cells (19-22 weeks gestation) yielded scattered aggregates of cardioblasts positive for the early cardiac lineage marker nk × 2.5 and containing nascent sarcomeres. Cardiac cells in colonies uniformly expressed the gap junction protein connexin 43 (C × 43) and displayed a spectrum of differentiation with only a subset of cells exhibiting the late cardiomyogenic marker troponin T (cTnT) and evidence of electrical excitability. Adenovirus-mediated overexpression of ILK potently increased the number of new aggregates of primitive cardioblasts (p<0.001). The number of cardioblast colonies was significantly decreased (p<0.05) when ILK expression was knocked down with ILK targeted siRNA. Interestingly, overexpression of the activation resistant ILK mutant (ILK(R211A)) resulted in much greater increase in the number of new cell aggregates as compared to overexpression of wild-type ILK (ILK(WT)). The cardiomyogenic effects of ILK(R211A) and ILK(WT) were accompanied by concurrent activation of β-catenin (p<0.001) and increase expression of progenitor cell marker islet-1, which was also observed in lysates of transgenic mice with cardiac-specific over-expression of ILK(R211A) and ILK(WT). Finally, endogenous ILK expression was shown to increase in concert with those of cardiomyogenic markers during directed cardiomyogenic differentiation in human embryonic stem cells (hESCs).In the human fetal heart ILK activation is instructive to the specification of mesodermal precursor cells towards a cardiomyogenic lineage. Induction of cardiomyogenesis by ILK overexpression bypasses the requirement of proximal PI3K activation for transduction of growth factor- and β1-integrin-mediated differentiation signals. Altogether, our data indicate that ILK represents a novel regulatory checkpoint during human cardiomyogenesis