Otx but Not Mitf Transcription Factors Are Required for Zebrafish Retinal Pigment Epithelium Development

Otx and Mitf transcription factors have been implicated in the development of the retinal pigmented epithelium (RPE), but the relationship between these factors and their specific roles in the development of the RPE have not been fully defined. The role of the three Otx transcription factors (Otx1a, Otx1b, and Otx2) and two Mitf transcription factors (Mitfa and Mitfb) in the development of the zebrafish RPE was explored in these experiments. The loss of Otx activity through morpholino knockdown produced variable eye defects, ranging from delayed RPE pigmentation to severe coloboma, depending on the combination of Otx factors that were targeted. Expression analysis through in situ hybridization demonstrates that otxtranscription factors are necessary for the proper expression of mitfa and mitfb while Mitf transcription factors are not required for the expression of otx genes. Surprisingly, the loss of Mitf activity in mitfa, mitfb, or double mitf mutant zebrafish had no effect on RPE pigmentation or development. Moreover, histological analysis revealed that retinal lamination is unaffected inmitf mutants, as well as in otx morphants, even in regions lacking RPE. Otx and Mitf combined loss of function experiments suggest that mitfa and mitfb may still influence zebrafish RPE development. This is further supported by the ability of mitfa to induce pigmentation in the zebrafish retina when misexpressed. These findings suggest that one or more Otx targets in addition to mitfa and mitfb, possibly another mitf family member, are necessary for development of the RPE in zebrafish

Steroid-sensitive nephrotic syndrome candidate gene CLVS1 regulates podocyte oxidative stress and endocytosis

We performed next-generation sequencing in patients with familial steroid-sensitive nephrotic syndrome (SSNS) and identified a homozygous segregating variant (p.H310Y) in the gene encoding clavesin-1 (CLVS1) in a consanguineous family with 3 affected individuals. Knockdown of the clavesin gene in zebrafish (clvs2) produced edema phenotypes due to disruption of podocyte structure and loss of glomerular filtration barrier integrity that could be rescued by WT CLVS1 but not the p.H310Y variant. Analysis of cultured human podocytes with CRISPR/Cas9-mediated CLVS1 knockout or homozygous H310Y knockin revealed deficits in clathrin-mediated endocytosis and increased susceptibility to apoptosis that could be rescued with corticosteroid treatment, mimicking the steroid responsiveness observed in patients with SSNS. The p.H310Y variant also disrupted binding of clavesin-1 to α-tocopherol transfer protein, resulting in increased reactive oxygen species (ROS) accumulation in CLVS1-deficient podocytes. Treatment of CLVS1-knockout or homozygous H310Y-knockin podocytes with pharmacological ROS inhibitors restored viability to control levels. Taken together, these data identify CLVS1 as a candidate gene for SSNS, provide insight into therapeutic effects of corticosteroids on podocyte cellular dynamics, and add to the growing evidence of the importance of endocytosis and oxidative stress regulation to podocyte function

Carotenoids are the likely precursor of a significant fraction of marine dissolved organic matter.

The ocean's biota sequester atmospheric carbon dioxide (CO2) in part by producing dissolved organic matter (DOM) that persists in the ocean for millennia. This long-term accumulation of carbon may be facilitated by abiotic and biotic production of chemical structures that resist degradation, consequently contributing disproportionately to refractory DOM. Compounds that are selectively preserved in seawater were identified in solid-phase extracted DOM (PPL-DOM) using comprehensive gas chromatography (GC) coupled to mass spectrometry (MS). These molecules contained cyclic head groups that were linked to isoprenoid tails, and their overall structures closely resembled carotenoid degradation products (CDP). The origin of these compounds in PPL-DOM was further confirmed with an in vitro β-carotene photooxidation experiment that generated water-soluble CDP with similar structural characteristics. The molecular-level identification linked at least 10% of PPL-DOM carbon, and thus 4% of total DOM carbon, to CDP. Nuclear magnetic resonance spectra of experimental CDP and environmental PPL-DOM overlapped considerably, which indicated that even a greater proportion of PPL-DOM was likely composed of CDP. The CDP-rich DOM fraction was depleted in radiocarbon (14C age > 1500 years), a finding that supports the possible long-term accumulation of CDP in seawater. By linking a specific class of widespread biochemicals to refractory DOM, this work provides a foundation for future studies that aim to examine how persistent DOM forms in the ocean

Tropical cyclone wind speed constraints from resultant storm surge deposition : a 2500 year reconstruction of hurricane activity from St. Marks, FL

Author Posting. © American Geophysical Union, 2013. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry, Geophysics, Geosystems 14 (2013): 2993–3008, doi:10.1002/ggge.20217.Recent work suggests that the patterns of intense (≥category 3 on the Saffir-Simpson scale) hurricane strikes over the last few millennia might differ from that of overall hurricane activity during this period. Prior studies typically rely on assigning a threshold storm intensity required to produce a sedimentological overwash signal at a particular coastal site based on historical analogs. Here, we improve on this approach by presenting a new inverse-model technique that constrains the most likely wind speeds required to transport the maximum grain size within resultant storm deposits. As a case study, the technique is applied to event layers observed in sediments collected from a coastal sinkhole in northwestern Florida. We find that (1) simulated wind speeds for modern deposits are consistent with the intensities for historical hurricanes affecting the site, (2) all deposits throughout the ∼2500 year record are capable of being produced by hurricanes, and (3) a period of increased intense hurricane frequency is observed between ∼1700 and ∼600 years B.P. and decreased intense storm frequency is observed from ∼2500 to ∼1700 and ∼600 years B.P. to the present. This is consistent with prior reconstructions from nearby sites. Changes in the frequency of intense hurricane strikes may be related to the degree of penetration of the Loop Current in the Gulf of Mexico.This work was supported by the National Science Foundation.2014-02-2

Genetics of Childhood Steroid Sensitive Nephrotic Syndrome: An Update

Advances in genome science in the last 20 years have led to the discovery of over 50 single gene causes and genetic risk loci for steroid resistant nephrotic syndrome (SRNS). Despite these advances, the genetic architecture of childhood steroid sensitive nephrotic syndrome (SSNS) remains poorly understood due in large part to the varying clinical course of SSNS over time. Recent exome and genome wide association studies from well-defined cohorts of children with SSNS identified variants in multiple MHC class II molecules such as HLA-DQA1 and HLA-DQB1 as risk factors for SSNS, thus stressing the central role of adaptive immunity in the pathogenesis of SSNS. However, evidence suggests that unknown second hit risk loci outside of the MHC locus and environmental factors also make significant contributions to disease. In this review, we examine what is currently known about the genetics of SSNS, the implications of recent findings on our understanding of pathogenesis of SSNS, and how we can utilize these results and findings from future studies to improve the management of children with nephrotic syndrome

Numerical Evaluation of Advanced Laser Control Strategies Influence on Residual Stresses for Laser Powder Bed Fusion Systems

AbstractProcess-dependent residual stresses are one of the main burdens to a widespread adoption of laser powder bed fusion technology in industry. Residual stresses are directly influenced by process parameters, such as laser path, laser power, and speed. In this work, the influence of various scan speed and laser power control strategies on residual stresses is investigated. A set of nine different laser scan patterns is printed by means of a selective laser melting process on a bare plate of nickel superalloy 625 (IN625). A finite element model is experimentally validated comparing the simulated melt pool areas with high-speed thermal camera in situ measurements. Finite element analysis is then used to evaluate residual stresses for the nine different laser scan control strategies, in order to identify the strategy which minimizes the residual stress magnitude. Numerical results show that a constant power density scan strategy appears the most effective to reduce residual stresses in the considered domain

The Grizzly, March 22, 2007

Speaker on Ethics in the Pharmaceutical Industry • New Plans for the Field House • Potential Carcinogen Found Abundant in Collegeville • WeCAN Button and T-Shirt Campaign Successful • Scientific Sexual Healing • Nutrition Tips: Atkins in the News • Brief History of St. Patrick\u27s Day • Spotlight on Professor Laurian Bowles • Opinions: Obama-mania! • Bears Hungry for CC Crown • Longball Key to Bears Victoryhttps://digitalcommons.ursinus.edu/grizzlynews/1734/thumbnail.jp

The Grizzly, February 22, 2007

Students Join with Local Labor Leaders to Confront Jones Apparel Group • Francophone Film Marathon • Gardasil • WeCAN Strike • New Group Fighting Cancer • The How Article • Spotlight on Dr. Ross Doughty • Nutrition Tips: Stretch it Out! • An Afternoon with Billy Bob Thornton • Opinions: Fixing the Primaries • UC Wrestling Wins Fifth Running CC Championship • Ursinus Senior Flying Through Final Semester with Wngshttps://digitalcommons.ursinus.edu/grizzlynews/1732/thumbnail.jp

The Grizzly, March 29, 2007

Re-opening of Bomberger Hall • Incite AAAS Program Debut Newsletter • Young Girl\u27s Death Sparks Ethics Debate • Professor Vosburgh Awaits Trial • The Burning Question • Beat It! • Ursinus Theater Hosting Musical Farce • Mr. Ursinus Crowned • Nutrition Tips: Alcohol\u27s Caloric Content • Opinions: Injustice in Justice • Rangers Upset Ursinus with Last Second Goalhttps://digitalcommons.ursinus.edu/grizzlynews/1735/thumbnail.jp