The transcriptome of utricle hair cell regeneration in the avian inner ear

Sensory hair cell loss is the major cause of hearing and balance disorders. Mammals are incapable of sustained hair cell regeneration, but lower vertebrates can regenerate these mechano-electrical transducers. We present the first comprehensive transcriptome (by mRNA-Seq) of hair cell regeneration in the chick utricle. We provide pathway and pattern annotations and correlate these with the phenotypic events that occur during regeneration. These patterns are surprisingly synchronous and highly punctuated. We show how these patterns are a new resource for identifying components of the hair cell transcriptome and identify 494 new putative hair-cell-specific genes and validate three of these (of three tested) by immunohistochemical staining. We describe many surprising new components and dynamic expression patterns, particularly within NOTCH signaling. For example, we show that HES7 is specifically expressed during utricle hair cell regeneration and closely parallels the expression of HES5. Likewise, the expression of ATOH1 is closely correlated with HEYL and the HLH inhibitory transcription factors ID1, ID2, and ID4. We investigate the correlation between fibroblast growth factor signaling and supporting cell proliferation and show that FGF20 inhibits supporting cell proliferation. We also present an analysis of 212 differentially expressed transcription factor genes in the regenerative time course that fall into nine distinct gene expression patterns, many of which correlate with phenotypic events during regeneration and represent attractive candidates for future analysis and manipulation of the regenerative program in sensory epithelia and other vertebrate neuroepithelia

Providing Reliability Services through Demand Response: A Prelimnary Evaluation of the Demand Response Capabilities of Alcoa Inc.

Demand response is the largest underutilized reliability resource in North America. Historic demand response programs have focused on reducing overall electricity consumption (increasing efficiency) and shaving peaks but have not typically been used for immediate reliability response. Many of these programs have been successful but demand response remains a limited resource. The Federal Energy Regulatory Commission (FERC) report, 'Assessment of Demand Response and Advanced Metering' (FERC 2006) found that only five percent of customers are on some form of demand response program. Collectively they represent an estimated 37,000 MW of response potential. These programs reduce overall energy consumption, lower green house gas emissions by allowing fossil fuel generators to operate at increased efficiency and reduce stress on the power system during periods of peak loading. As the country continues to restructure energy markets with sophisticated marginal cost models that attempt to minimize total energy costs, the ability of demand response to create meaningful shifts in the supply and demand equations is critical to creating a sustainable and balanced economic response to energy issues. Restructured energy market prices are set by the cost of the next incremental unit of energy, so that as additional generation is brought into the market, the cost for the entire market increases. The benefit of demand response is that it reduces overall demand and shifts the entire market to a lower pricing level. This can be very effective in mitigating price volatility or scarcity pricing as the power system responds to changing demand schedules, loss of large generators, or loss of transmission. As a global producer of alumina, primary aluminum, and fabricated aluminum products, Alcoa Inc., has the capability to provide demand response services through its manufacturing facilities and uniquely through its aluminum smelting facilities. For a typical aluminum smelter, electric power accounts for 30% to 40% of the factory cost of producing primary aluminum. In the continental United States, Alcoa Inc. currently owns and/or operates ten aluminum smelters and many associated fabricating facilities with a combined average load of over 2,600 MW. This presents Alcoa Inc. with a significant opportunity to respond in areas where economic opportunities exist to help mitigate rising energy costs by supplying demand response services into the energy system. This report is organized into seven chapters. The first chapter is the introduction and discusses the intention of this report. The second chapter contains the background. In this chapter, topics include: the motivation for Alcoa to provide demand response; ancillary service definitions; the basics behind aluminum smelting; and a discussion of suggested ancillary services that would be particularly useful for Alcoa to supply. Chapter 3 is concerned with the independent system operator, the Midwest ISO. Here the discussion examines the evolving Midwest ISO market structure including specific definitions, requirements, and necessary components to provide ancillary services. This section is followed by information concerning the Midwest ISO's classifications of demand response parties. Chapter 4 investigates the available opportunities at Alcoa's Warrick facility. Chapter 5 involves an in-depth discussion of the regulation service that Alcoa's Warrick facility can provide and the current interactions with Midwest ISO. Chapter 6 reviews future plans and expectations for Alcoa providing ancillary services into the market. Last, chapter 7, details the conclusion and recommendations of this paper

Fine tuning Exo2, a small molecule inhibitor of secretion and retrograde trafficking pathways in mammalian cells

The small molecule 4-hydroxy-3-methoxybenzaldehyde (5,6,7,8-tetrahydro[1]benzothieno[2,3- d]pyrimidin-4-yl)hydrazone (Exo2) stimulates morphological changes at the mammalian Golgi and trans-Golgi network that are virtually indistinguishable from those induced by brefeldin A. Both brefeldin A and Exo2 protect cells from intoxication by Shiga(-like) toxins by acting on other targets that operate at the early endosome, but do so at the cost of high toxicity to target cells. The advantage of Exo2 is that it is much more amenable to chemical modification and here we report a range of Exo2 analogues produced by modifying the tetrahydrobenzothienopyrimidine core, the vanillin moiety and the hydrazone bond that links these two. These compounds were examined for the morphological changes they stimulated at the Golgi stack, the trans Golgi network and the transferrin receptor-positive early endosomes and this activity correlated with their inherent toxicity towards the protein manufacturing ability of the cell and their protective effect against toxin challenge. We have developed derivatives that can separate organelle morphology, target specificity, innate toxicity and toxin protection. Our results provide unique compounds with low toxicity and enhanced specificity to unpick the complexity of membrane trafficking networks

The secretion inhibitor Exo2 perturbs trafficking of Shiga toxin between endosomes and the trans-Golgi network

The small-molecule inhibitor Exo2 {4-hydroxy-3-methoxy-(5,6,7,8-tetrahydrol[1]benzothieno[2,3-d]pyrimidin-4-yl)hydraz-one benzaldehyde} has been reported to disrupt the Golgi apparatus completely and to stimulate Golgi–ER (endoplasmic reticulum) fusion in mammalian cells, akin to the well-characterized fungal toxin BFA (brefeldin A). It has also been reported that Exo2 does not affect the integrity of the TGN (trans-Golgi network), or the direct retrograde trafficking of the glycolipid-binding cholera toxin from the TGN to the ER lumen. We have examined the effects of BFA and Exo2, and found that both compounds are indistinguishable in their inhibition of anterograde transport and that both reagents significantly disrupt the morphology of the TGN in HeLa and in BS-C-1 cells. However, Exo2, unlike BFA, does not induce tubulation and merging of the TGN and endosomal compartments. Furthermore, and in contrast with its effects on cholera toxin, Exo2 significantly perturbs the delivery of Shiga toxin to the ER. Together, these results suggest that the likely target(s) of Exo2 operate at the level of the TGN, the Golgi and a subset of early endosomes, and thus Exo2 provides a more selective tool than BFA for examining membrane trafficking in mammalian cells

Globally Gridded Satellite (GridSat) Observations for Climate Studies

Geostationary satellites have provided routine, high temporal resolution Earth observations since the 1970s. Despite the long period of record, use of these data in climate studies has been limited for numerous reasons, among them: there is no central archive of geostationary data for all international satellites, full temporal and spatial resolution data are voluminous, and diverse calibration and navigation formats encumber the uniform processing needed for multi-satellite climate studies. The International Satellite Cloud Climatology Project set the stage for overcoming these issues by archiving a subset of the full resolution geostationary data at approx.10 km resolution at 3 hourly intervals since 1983. Recent efforts at NOAA s National Climatic Data Center to provide convenient access to these data include remapping the data to a standard map projection, recalibrating the data to optimize temporal homogeneity, extending the record of observations back to 1980, and reformatting the data for broad public distribution. The Gridded Satellite (GridSat) dataset includes observations from the visible, infrared window, and infrared water vapor channels. Data are stored in the netCDF format using standards that permit a wide variety of tools and libraries to quickly and easily process the data. A novel data layering approach, together with appropriate satellite and file metadata, allows users to access GridSat data at varying levels of complexity based on their needs. The result is a climate data record already in use by the meteorological community. Examples include reanalysis of tropical cyclones, studies of global precipitation, and detection and tracking of the intertropical convergence zone

Are different groups of patients with stroke more likely to be excluded from the new UK general medical services contract? A cross-sectional retrospective analysis of a large primary care population

Peer reviewedPublisher PD

Effects of Commercial Harvest on Shovelnose Sturgeon Populations in the Upper Mississippi River

Shovelnose sturgeon Scaphirhynchus platorynchus have become an increasingly important commercial species in the upper Mississippi River (UMR) because of the collapse of foreign sturgeon (family Acipenseridae) populations and bans on imported caviar. In response to concerns about the sustainability of the commercial shovelnose sturgeon fishery in the UMR, we undertook this study to describe the demographics of the shovelnose sturgeon population and evaluate the influence of commercial harvest on shovelnose sturgeon populations in the UMR. A total of 1,682 shovelnose sturgeon were collected from eight study pools in 2006 and 2007 (Pools 4, 7, 9, 11, 13, 14, 16, and 18). Shovelnose sturgeon from upstream pools generally had greater lengths, weights, and ages than those from downstream pools. Additionally, mortality estimates were lower in upstream pools (Pools 4, 7, 9, and 11) than in downstream pools (Pools 13, 14, 16, and 18). Linear regression suggested that the slower growth of shovelnose sturgeon is a consequence of commercial harvest in the UMR. Modeling of potential management scenarios suggested that a 685-mm minimum length limit is necessary to prevent growth and recruitment overfishing of shovelnose sturgeon in the UMR

Changes in body composition and performance with supplemental HMB-FA+ATP (Manuscript Clarification)

Additional co-authors: Matthew D. Vukovich, Colin Wilborn, and Darryn S. Willoughb

Reducing Legionella Colonization of Water Systems with Monochloramine

Monochloramine reduced colonization in building hot water systems