A central function for perlecan in skeletal muscle and cardiovascular development

Perlecan's developmental functions are difficult to dissect in placental animals because perlecan disruption is embryonic lethal. In contrast to mammals, cardiovascular function is not essential for early zebrafish development because the embryos obtain adequate oxygen by diffusion. In this study, we use targeted protein depletion coupled with protein-based rescue experiments to investigate the involvement of perlecan and its C-terminal domain V/endorepellin in zebrafish development. The perlecan morphants show a severe myopathy characterized by abnormal actin filament orientation and disorganized sarcomeres, suggesting an involvement of perlecan in myopathies. In the perlecan morphants, primary intersegmental vessel sprouts, which develop through angiogenesis, fail to extend and show reduced protrusive activity. Live videomicroscopy confirms the abnormal swimming pattern caused by the myopathy and anomalous head and trunk vessel circulation. The phenotype is partially rescued by microinjection of human perlecan or endorepellin. These findings indicate that perlecan is essential for the integrity of somitic muscle and developmental angiogenesis and that endorepellin mediates most of these biological activities

Relationship Between Grit with Academic Performance and Attainment of Postgraduate Training in Pharmacy Students

Objective. To determine if Grit-S scores correlate with academic success in a doctor of pharmacy (PharmD) program, as well as the pursuit and attainment of pharmacy postgraduate (residency or fellowship) training. Methods. A 28-item survey was administered to third- and fourth-year (P3 and P4) pharmacy students. Variables queried included Grit-S score, demographics, pharmacy experience prior to the PharmD program, and factors that may affect academic performance during didactic coursework. Didactic coursework GPA was used as a surrogate for academic success. Information about pursuit and attainment of a postgraduate training position was also documented and used in the analyses. Results. There was no significant correlation between Grit-S scores and variables related to academic success. However, students were more likely to pursue postgraduate training with higher academic success and higher Grit-S. Lastly, students with higher Grit-S were also more likely to obtain a postgraduate training position. Conclusion. Grit-S scores correlated with the pursuit and successful attainment of postgraduate training, but not with academic success during the didactic years of a PharmD program

Zebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation.

Anesthetics are generally associated with sedation, but some anesthetics can also increase brain and motor activity-a phenomenon known as paradoxical excitation. Previous studies have identified GABAA receptors as the primary targets of most anesthetic drugs, but how these compounds produce paradoxical excitation is poorly understood. To identify and understand such compounds, we applied a behavior-based drug profiling approach. Here, we show that a subset of central nervous system depressants cause paradoxical excitation in zebrafish. Using this behavior as a readout, we screened thousands of compounds and identified dozens of hits that caused paradoxical excitation. Many hit compounds modulated human GABAA receptors, while others appeared to modulate different neuronal targets, including the human serotonin-6 receptor. Ligands at these receptors generally decreased neuronal activity, but paradoxically increased activity in the caudal hindbrain. Together, these studies identify ligands, targets, and neurons affecting sedation and paradoxical excitation in vivo in zebrafish

Demand-Driven Scheduling of Movies in a Multiplex

This paper describes a model that generates weekly movie schedules in a multiplex movie theater. A movie schedule specifies within each day of the week, on which screen(s) different movies will be played, and at which time(s). The model consists of two parts: (i) conditional forecasts of the number of visitors per show for any possible starting time; and (ii) an optimization procedure that quickly finds an almost optimal schedule (which can be demonstrated to be close to the optimal schedule). To generate this schedule we formulate the so-called movie scheduling problem as a generalized set partitioning problem. The latter is solved with an algorithm based on column generation techniques. We have applied this combined demand forecasting /schedule optimization procedure to a multiplex in Amsterdam where we supported the scheduling of fourteen movie weeks. The proposed model not 2 only makes movie scheduling easier and less time consuming, but also generates schedules that would attract more visitors than the current ‘intuition-based’ schedules

A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis

BACKGROUND: The cause of neuronal death in amyotrophic lateral sclerosis (ALS) is uncertain but mitochondrial dysfunction may play an important role. Ketones promote mitochondrial energy production and membrane stabilization. RESULTS: SOD1-G93A transgenic ALS mice were fed a ketogenic diet (KD) based on known formulations for humans. Motor performance, longevity, and motor neuron counts were measured in treated and disease controls. Because mitochondrial dysfunction plays a central role in neuronal cell death in ALS, we also studied the effect that the principal ketone body, D-β-3 hydroxybutyrate (DBH), has on mitochondrial ATP generation and neuroprotection. Blood ketones were > 3.5 times higher in KD fed animals compared to controls. KD fed mice lost 50% of baseline motor performance 25 days later than disease controls. KD animals weighed 4.6 g more than disease control animals at study endpoint; the interaction between diet and change in weight was significant (p = 0.047). In spinal cord sections obtained at the study endpoint, there were more motor neurons in KD fed animals (p = 0.030). DBH prevented rotenone mediated inhibition of mitochondrial complex I but not malonate inhibition of complex II. Rotenone neurotoxicity in SMI-32 immunopositive motor neurons was also inhibited by DBH. CONCLUSION: This is the first study showing that diet, specifically a KD, alters the progression of the clinical and biological manifestations of the G93A SOD1 transgenic mouse model of ALS. These effects may be due to the ability of ketone bodies to promote ATP synthesis and bypass inhibition of complex I in the mitochondrial respiratory chain

The slope of the black-hole mass versus velocity dispersion correlation

Observations of nearby galaxies reveal a strong correlation between the mass of the central dark object M and the velocity dispersion sigma of the host galaxy, of the form log(M/M_sun) = a + b*log(sigma/sigma_0); however, published estimates of the slope b span a wide range (3.75 to 5.3). Merritt & Ferrarese have argued that low slopes (<4) arise because of neglect of random measurement errors in the dispersions and an incorrect choice for the dispersion of the Milky Way Galaxy. We show that these explanations account for at most a small part of the slope range. Instead, the range of slopes arises mostly because of systematic differences in the velocity dispersions used by different groups for the same galaxies. The origin of these differences remains unclear, but we suggest that one significant component of the difference results from Ferrarese & Merritt's extrapolation of central velocity dispersions to r_e/8 (r_e is the effective radius) using an empirical formula. Another component may arise from dispersion-dependent systematic errors in the measurements. A new determination of the slope using 31 galaxies yields b=4.02 +/- 0.32, a=8.13 +/- 0.06, for sigma_0=200 km/s. The M-sigma relation has an intrinsic dispersion in log M that is no larger than 0.3 dex. In an Appendix, we present a simple model for the velocity-dispersion profile of the Galactic bulge.Comment: 37 pages, 9 figure

Thermochemistry of Alane Complexes for Hydrogen Storage: A Theoretical and Experimental Comparison

Knowledge of the relative stabilities of alane (AlH3) complexes with electron donors is essential for identifying hydrogen storage materials for vehicular applications that can be regenerated by off-board methods; however, almost no thermodynamic data are available to make this assessment. To fill this gap, we employed the G4(MP2) method to determine heats of formation, entropies, and Gibbs free energies of formation for thirty-eight alane complexes with NH3-nRn (R = Me, Et; n = 0-3), pyridine, pyrazine, triethylenediamine (TEDA), quinuclidine, OH2-nRn (R = Me, Et; n = 0-2), dioxane, and tetrahydrofuran (THF). Monomer, bis, and selected dimer complex geometries were considered. Using these data, we computed the thermodynamics of the key formation and dehydrogenation reactions that would occur during hydrogen delivery and alane regeneration, from which trends in complex stability were identified. These predictions were tested by synthesizing six amine-alane complexes involving trimethylamine, triethylamine, dimethylethylamine, TEDA, quinuclidine, and hexamine, and obtaining upper limits of delta G for their formation from metallic aluminum. Combining these computational and experimental results, we establish a criterion for complex stability relevant to hydrogen storage that can be used to assess potential ligands prior to attempting synthesis of the alane complex. Based on this, we conclude that only a subset of the tertiary amine complexes considered and none of the ether complexes can be successfully formed by direct reaction with aluminum and regenerated in an alane-based hydrogen storage system.Comment: Accepted by the Journal of Physical Chemistry

Mechanical design and development of TES bolometer detector arrays for the Advanced ACTPol experiment

The next generation Advanced ACTPol (AdvACT) experiment is currently underway and will consist of four Transition Edge Sensor (TES) bolometer arrays, with three operating together, totaling ~5800 detectors on the sky. Building on experience gained with the ACTPol detector arrays, AdvACT will utilize various new technologies, including 150mm detector wafers equipped with multichroic pixels, allowing for a more densely packed focal plane. Each set of detectors includes a feedhorn array of stacked silicon wafers which form a spline profile leading to each pixel. This is then followed by a waveguide interface plate, detector wafer, back short cavity plate, and backshort cap. Each array is housed in a custom designed structure manufactured from high purity copper and then gold plated. In addition to the detector array assembly, the array package also encloses cryogenic readout electronics. We present the full mechanical design of the AdvACT high frequency (HF) detector array package along with a detailed look at the detector array stack assemblies. This experiment will also make use of extensive hardware and software previously developed for ACT, which will be modified to incorporate the new AdvACT instruments. Therefore, we discuss the integration of all AdvACT arrays with pre-existing ACTPol infrastructure.Comment: 9 pages, 5 figures, SPIE Astronomical Telescopes and Instrumentation conference proceeding