Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors

Tolvaptan is a selective vasopressin V2 receptor antagonist, approved in several countries for the treatment of hyponatremia and autosomal dominant polycystic kidney disease (ADPKD). No liver injury has been observed with tolvaptan treatment in healthy subjects and in non-ADPKD indications, but ADPKD clinical trials showed evidence of drug-induced liver injury (DILI). Although all DILI events resolved, additional monitoring in tolvaptan-treated ADPKD patients is required. In vitro assays identified alterations in bile acid disposition and inhibition of mitochondrial respiration as potential mechanisms underlying tolvaptan hepatotoxicity. This report details the application of DILIsym software to determine whether these mechanisms could account for the liver safety profile of tolvaptan observed in ADPKD clinical trials. DILIsym simulations included physiologically based pharmacokinetic estimates of hepatic exposure for tolvaptan and2 metabolites, and their effects on hepatocyte bile acid transporters and mitochondrial respiration. The frequency of predicted alanine aminotransferase (ALT) elevations, following simulated 90/30 mg split daily dosing, was 7.9% compared with clinical observations of 4.4% in ADPKD trials. Toxicity was multifactorial as inhibition of bile acid transporters and mitochondrial respiration contributed to the simulated DILI. Furthermore, simulation analysis identified both pre-treatment risk factors and on-treatment biomarkers predictive of simulated DILI. The simulations demonstrated that in vivo hepatic exposure to tolvaptan and the DM-4103 metabolite, combined with these 2 mechanisms of toxicity, were sufficient to account for the initiation of tolvaptan-mediated DILI. Identification of putative risk-factors and potential novel biomarkers provided insight for the development of mechanism-based tolvaptan risk-mitigation strategies

Cryogenic Optical Performance of a Lightweighted Mirror Assembly for Future Space Astronomical Telescopes: Correlating Optical Test Results and Thermal Optical Model

A 43cm diameter stacked core mirror demonstrator was interferometrically tested at room temperature down to 250 degrees Kelvin for thermal deformation. The 2.5m radius of curvature spherical mirror assembly was constructed by low temperature fusing three abrasive waterjet core sections between two CNC pocket milled face sheets. The 93% lightweighted Corning ULE mirror assembly represents the current state of the art for future UV, optical, near IR space telescopes. During the multiple thermal test cycles, test results of interferometric test, thermal IR images of the front face were recorded in order to validate thermal optical model

Cryogenic Optical Performance of a Light-weight Mirror Assembly for Future Space Astronomical Telescopes: Optical Test Results and Thermal Optical Model

A 40 cm diameter mirror assembly was interferometrically tested at room temperature down to 250 degrees Kelvin for thermal deformation. The 2.5 m radius of curvature spherical mirror assembly was constructed by low temperature fusing three abrasive waterjet core sections between two face sheets. The 93% lightweighted Corning ULE mirror assembly represents the current state of the art for future UV, optical, near IR space telescopes. During the multiple thermal test cycles, test results of interferometric test, thermal IR images of the front face were recorded in order to validate thermal optical model

The First Flight of the Marshall Grazing Incidence X-ray Spectrometer (MaGIXS)

The Marshall Grazing Incidence X-ray Spectrometer (MaGIXS) sounding rocket experiment launched on July 30, 2021 from the White Sands Missile Range in New Mexico. MaGIXS is a unique solar observing telescope developed to capture X-ray spectral images, in the 6 - 24 Angstrom wavelength range, of coronal active regions. Its novel design takes advantage of recent technological advances related to fabricating and optimizing X-ray optical systems as well as breakthroughs in inversion methodologies necessary to create spectrally pure maps from overlapping spectral images. MaGIXS is the first instrument of its kind to provide spatially resolved soft X-ray spectra across a wide field of view. The plasma diagnostics available in this spectral regime make this instrument a powerful tool for probing solar coronal heating. This paper presents details from the first MaGIXS flight, the captured observations, the data processing and inversion techniques, and the first science results.Comment: 20 pages, 18 figure

Optimizing Dietary Restriction for Genetic Epistasis Analysis and Gene Discovery in C. elegans

Dietary restriction (DR) increases mammalian lifespan and decreases susceptibility to many age-related diseases. Lifespan extension due to DR is conserved across a wide range of species. Recent research has focused upon genetically tractable model organisms such as C. elegans to uncover the genetic mechanisms that regulate the response to DR, in the hope that this information will provide insight into the mammalian response and yield potential therapeutic targets. However, no consensus exists as to the best protocol to apply DR to C. elegans and potential key regulators of DR are protocol-specific. Here we define a DR method that better fulfills criteria required for an invertebrate DR protocol to mirror mammalian studies. The food intake that maximizes longevity varies for different genotypes and informative epistasis analysis with another intervention is only achievable at this ‘optimal DR’ level. Importantly therefore, the degree of restriction imposed using our method can easily be adjusted to determine the genotype-specific optimum DR level. We used this protocol to test two previously identified master regulators of DR in the worm. In contrast to previous reports, we find that DR can robustly extend the lifespan of worms lacking the AMP-activated protein kinase catalytic subunit AAK2 or the histone deacetylase SIR-2.1, highlighting the importance of first optimizing DR to identify universal regulators of DR mediated longevity

The First Flight of the Marshall Grazing Incidence X-Ray Spectrometer (MaGIXS)

The Marshall Grazing Incidence X-ray Spectrometer (MaGIXS) sounding rocket experiment launched on 2021 July 30 from the White Sands Missile Range in New Mexico. MaGIXS is a unique solar observing telescope developed to capture X-ray spectral images of coronal active regions in the 6–24 Å wavelength range. Its novel design takes advantage of recent technological advances related to fabricating and optimizing X-ray optical systems, as well as breakthroughs in inversion methodologies necessary to create spectrally pure maps from overlapping spectral images. MaGIXS is the first instrument of its kind to provide spatially resolved soft X-ray spectra across a wide field of view. The plasma diagnostics available in this spectral regime make this instrument a powerful tool for probing solar coronal heating. This paper presents details from the first MaGIXS flight, the captured observations, the data processing and inversion techniques, and the first science results

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016

A mechanical energy analysis of the overarm pitch

Bibliography : pages 93-97.The purpose of this investigation was to apply a method of mechanical energy analysis to the overarm pitching pattern of a major league pitcher. At the time of filming, the subject was a member of the Chicago White Sox starting rotation with a major league lifetime record of 38 wins and 27 losses with an earned run average of 3.29. He was 6 feet, 5 inches tall, and weighed 218 pounds. The filming was performed during an exhibition game during spring training in 1983. The subject was filmed from a side view and from a front view. Two types of pitches were analyzed, fastballs and sliders. Most of the measurements taken from the digitized film were two-dimensional in nature with the exceptions of hip rotation, shoulder rotation, the relative angle formed by the forearm and upperarm of the pitching arm, and the degree of rotation of the humerus of the pitching arm about its long axis. The actions of horizontal flexion and extension at the shoulder were neglected. Only the movements occurring from the completion of the stride to the release of the ball were examined in the final analysis. The results of the mechanical energy analysis supported several conclusions. The sequence of movements from the completion of the stride to the release of the ball was initiated by extension of the knee of the striding leg and extension at the hip of the striding leg. Rotation of the hips and shoulders towards the plate and the extension of the elbow of the pitching arm began simultaneously, and all continued through the point of release. The final actions were medial rotation at the shoulder of the pitching arm followed by wrist extension and, finally, wrist flexion. The largest contributors of mechanical energy appeared to be the actions of shoulder rotation and hip rotation. Other actions in descending order of relative contribution were medial rotation of the humerus, elbow extension, knee extension, and hip extension. The total mechanical energy of the body at the point of release was the highest for fastballs. Finally, there was no significant difference in the knee action of the striding leg between the fastball and the slider.M.S. Ed. (Master of Education