Decorin-evoked paternally expressed gene 3 (PEG3) is an upstream regulator of the transcription factor EB (TFEB) in endothelial cell autophagy.

Macroautophagy is a fundamental and evolutionarily conserved catabolic process that eradicates damaged and aging macromolecules and organelles in eukaryotic cells. Decorin, an archetypical small leucine-rich proteoglycan, initiates a protracted autophagic program downstream of VEGF receptor 2 (VEGFR2) signaling that requires paternally expressed gene 3 (PEG3). We have discovered that PEG3 is an upstream transcriptional regulator of transcription factor EB (TFEB), a master transcription factor of lysosomal biogenesis, for decorin-evoked endothelial cell autophagy. We found a functional requirement of PEG3 for TFEB transcriptional induction and nuclear translocation in human umbilical vein endothelial and PAER2 cells. Mechanistically, inhibiting VEGFR2 or AMP-activated protein kinase (AMPK), a major decorin-activated energy sensor kinase, prevented decorin-evoked TFEB induction and nuclear localization. In conclusion, our findings indicate a non-canonical (nutrient- and energy-independent) mechanism underlying the pro-autophagic bioactivity of decorin via PEG3 and TFEB

Functionalized Polycarbonate Commercial Filters for Water Purification

Can commerercially available filtration membranes be easily functionalized in such a way to enhence the removal the charged contaminants in the water treatment process? The literature demonstrates there have been two pioneering works that demonstrated that Ultrathin Self-Assembled Nanoparticle (USANP) membranes (composed of ~5 nm diameter metallic gold nanoparticles surrounded by organic ligands) when applied to commercial membranes displayed charge sensitive rejection to molecular dyes and also have the ability to charge modify the openings in commercial filters. The rejection mechanisms in these works are proposed to be either size dependent or charged based. Recent experimental results have demonstrated that the supporting filter for these USANP membranes can be functionalized solely with highly charged molecular dye Direct Red 80 using no USANP membranes. After functionalization with direct red 80 alone, average rejection for tested molecular dyes at a concentration of 145 µM increased from 31.8 % to 85.6 % even without the addition of a USANP layer. This indicates that dyes themselves are capable of functionalizing the commercial membranes providing an additional method to enhanced rejection of charged contaminants. This poster highlights the efforts made by a Preservice and Early Career Research for Teachers (PERT) team and an Undergraduate student who was awarded an Summer Undergraduate Research Experience Award to measure the rejection results of these two different functionalization methods. Knowledge gained from these experiments may allow for enhanced rejection of charged based contaminants in polluted waters

Partners in Water Quality Monitoring at Mammoth Cave National Park, Kentucky

Water resources are essential to landscape development and maintenance of the extraordinary ecosystem at Mammoth Cave National Park, Kentucky. The National Park Service has implemented many policies and management practices in an effort to maintain and improve the water quality in the park. As part of their resources management, the Park evaluates current hydrologic conditions, as well as, anticipates and responds to emerging issues. With regards to that goal, Mammoth Cave National Park Service partnered with Tennessee State University, the Mammoth Cave International Center for Science and Learning, and the U.S. Geological Survey on a series of water-related projects from 2007-2013. The objective of this paper is to highlight some of the findings and lessons learned from the past 6 years. Many of the results presented in this paper have been presented at other conferences or published in other reports. Collaborative projects included storm-water runoff from parking lots and roads, evaluating storm-water filters, and transport of chemicals in the caves. These projects purposefully engaged students to provide professional experience and educational outreach opportunities. Over 50 student presentations related to these monitoring activities have been made at regional and national conferences in the past 6 years, resulting in numerous awards and publications. Major funding or in-kind services were provided by the partnering agencies and institutions. Additional funding for supplies and student support was provided by the National Science Foundation (Opportunity for Enhancing Diversity in Geoscience, 2007-8; Undergraduate Research and Mentoring, 2009-13), and, the Department of Energy (Massey Chair – NNSA, 2007-13). The following summaries are excerpts from previously published student papers (West et al., 2010; Diehl et al., 2012, Embry, et al., 2012, West et al., 2012)

Climate: Past, present, and future

Climatology and meteorology studies in the Yucca Mountain area have resulted in the following key observations and conclusions: • The present-day arid climate of the Yucca Mountain area can be understood in terms of global-scale atmospheric circulation and regional to-local physiographic features. In general terms, the area is under the influence of mid-latitude westerly winds and associated storm systems during the cool part of the year and and is under the influence of moist air advected from the eastern tropical Pacific Ocean and Gulf of California during the summer. Temperature and precipitation data from Nevada regions 3 and 4 (southern Nevada) between 1895 and 1998 suggest a mean annual temperature of 13.4 °C and a mean annual precipitation of 125 mm at 1524 m (5,000 feet) elevation (Thompson et al. 1999 [109470], Figures 13, 14, pp. 27-28). • Climate change over the past several hundred thousand years can be partially understood in terms of changes in these atmospheric circulation patterns, physiographic features, and predictable variations in the earth\u27s orbital characteristics. • Past climate change can be timed using the Earth\u27s orbital parameters: eccentricity and precession. This implies some past climate or aspects of past climate will recur in the future because future eccentricity and precession can be calculated. • Regional and local evidence indicates that the Yucca Mountain site has experienced, over the past several hundred thousand years, many different climate states, ranging from glacial to interglacial periods. Glacial and intermediate climate periods were periods of sustained greater effective moisture (commonly defined as precipitation minus evaporation, thus temperature is important) with greater infiltration and recharge than the present interglacial period. Although Yucca Mountain experienced glacial climates, it did not experience glaciation. • For the purposes of this report, long-term past climate proxy data were simplified into four climate states (interglacial, monsoon, intermediate, glacial), each with a different level of effective moisture. Climate states typical of the past 500,000 years are thought likely to reoccur in the next 500,000 years. These climate states, their duration, and magnitude are based on the assumptions and methods used and discussed herein. • Six glacial stages are predicted to occur over the next 500,000 years. They may range between 8,000 and 38,000 years in duration and encompass about 19% (95,000 years) of the next 500,000 years. These glacials will vary in magnitude, ranging from relatively warm and wet to cold and dry. • Future glacial period upper bound (most conservative) estimates for mean annual temperature and mean annual precipitation in the Yucca Mountain area are 0°C and 513 mm, respectively. Glacial period lower bound estimates for mean annual temperature and mean annual precipitation in the Yucca Mountain area are approximately 9°C and 430 mm, respectively. Other published estimates of past temperature and precipitation for the Yucca Mountain area and western Great Basin during glacial periods range from 5-15° C colder than today and precipitation from 1.4 to 2.6 times modern. • The intermediate and intermediate/monsoon climate states are estimated to encompass over 68% of the next 500,000 years (\u3e340,000 years). Intermediate climate state bounds range from approximately 9 to 10°C and 430 to 200 mm per year. • Monsoon climate states, which tend to occur between interglacial and intermediate climate states, are estimated to occur 3% of the time over the next 500,000 years during the intermediate/monsoon climate state. Monsoon climate state bounds range from about 13 to 17°C and 125 to 400 mm per year. • Interglacial (e.g. modern) climate is the warmest and driest of all climate states. This climate state has been dominant in the Yucca Mountain area, with some variation, for only the last 7 to 8 ka. The interglacial climate state is estimated to occur about 13% (65,000 years) of the time during the next 500,000 years. Mean annual temperature and precipitation are estimated to be about 13°C and 125 mm per year. • Present-day meteorological stations were selected to represent the four past climate state

Three Examples of Chemical Transport in Storm Runoff at Mammoth Cave National Park, Kentucky

The karst landscape at Mammoth Cave National Park, Kentucky, was formed by water through the dissolution of soluble rocks forming sinkholes, disappearing streams, emerging springs, closed depressions, and a combination of wet and dry caves. The Park’s cave streams and pools provide a home to unique organisms. Surface waters in the Park tend to rapidly drain into subsurface geologic features and caves. This rapid infiltration makes the subsurface vulnerable to contamination. The objective of this investigation was to characterize chemical transport from the surface into the cave. The preliminary results were achieved by tracer studies and monitoring water chemistry along known flowpaths. The results presented in this paper are the outcome of several studies occurring between 2009-2012 in a partnership between Mammoth Cave National Park, Tennessee State University, Mammoth Cave International Center for Science and Learning, and U.S. Geological Survey. Processes that influenced chemical transport included storm intensity, time between storms, epikarst saturation, dispersion, dilution, and complex fl ow paths in the geology

Combining High-Throughput Synthesis and High-Throughput Protein Crystallography for Accelerated Hit Identification

Protein crystallography (PX) is widely used to drive advanced stages of drug optimization or to discover medicinal chemistry starting points by fragment soaking. However, recent progress in PX could allow for a more integrated role into early drug discovery. Here, we demonstrate for the first time the interplay of high throughput synthesis and high throughput PX. We describe a practical multicomponent reaction approach to acrylamides and ‐esters from diverse building blocks suitable for mmol scale synthesis on 96‐well format and on a high‐throughput nanoscale format in a highly automated fashion. High‐throughput PX of our libraries efficiently yielded potent covalent inhibitors of the main protease of the COVID‐19 causing agent, SARS‐CoV‐2. Our results demonstrate, that the marriage of in situ HT synthesis of (covalent) libraires and HT PX has the potential to accelerate hit finding and to provide meaningful strategies for medicinal chemistry projects

The Newcomer Health Clinic in Nova Scotia: A Beacon Clinic to Support the Health Needs of the Refugee Population

Abstract Refugees tend to have greater vulnerability compared to the general population reporting greater need for physical, emotional, or dental problems compared to the general population. Despite the importance of creating strong primary care supports for these patients, it has been demonstrated that there is a significant gap in accessing primary care providers who are willing to accept the refugee population. These have resulted in bottlenecks in the transition or bridge clinics and have left patients orphaned without a primary care provider. This in turn results in higher use of emergency service and other unnecessary costs to the healthcare system. Currently there are few studies that have explored these challenges from primary care provider perspectives and very few to none from patient perspectives. A novel collaborative implementation initiative in primary healthcare (PHC) is seeking to improve primary medical care for the refugee population by creating a globally recommended transition or beacon clinic to support care needs of new arrivals and transitions to primary care providers. We discuss the innovative elements of the clinic model in this paper

Bactericidal Activity of the Human Skin Fatty Acid cis-6-Hexadecanoic Acid on Staphylococcus aureus

Human skin fatty acids are a potent aspect of our innate defenses, giving surface protection against potentially invasive organisms. They provide an important parameter in determining the ecology of the skin microflora, and alterations can lead to increased colonization by pathogens such as Staphylococcus aureus. Harnessing skin fatty acids may also give a new avenue of exploration in the generation of control measures against drug-resistant organisms. Despite their importance, the mechanism(s) whereby skin fatty acids kill bacteria has remained largely elusive. Here, we describe an analysis of the bactericidal effects of the major human skin fatty acid cis-6-hexadecenoic acid (C6H) on the human commensal and pathogen S. aureus. Several C6H concentration-dependent mechanisms were found. At high concentrations, C6H swiftly kills cells associated with a general loss of membrane integrity. However, C6H still kills at lower concentrations, acting through disruption of the proton motive force, an increase in membrane fluidity, and its effects on electron transfer. The design of analogues with altered bactericidal effects has begun to determine the structural constraints on activity and paves the way for the rational design of new antistaphylococcal agents

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead