Derivation of cochlear cells from pathological or isogenic human iPSCs for modeling hereditary hearing loss

Alström Syndrome (AS) is a human autosomal recessive genetic disorder characterized by numerous clinical symptoms including deafness. AS is caused by mutations in the ALMS1 gene encoding for ALMS1 protein expressed at the basal body and implicated in ciliogenesis, cell cycle and proliferation (Jagger et al., 2011; Zulato et al., 2011 & Shenje et al., 2014). We are interesting in understanding the unknown mechanisms involving this protein in the genetic deafness of AS patients. To develop a model as closer as possible to the human pathology, we are using human induced pluripotent stem cells (hiPSCs) generated from fibroblasts of healthy and AS patients. Using a stepwise protocol, we demonstrated that healthy hiPSCs (waiting for isogenic hiPSCs) can generate a population of cells with gene and protein expression patterns consistent with the ones of otic progenitor cells (OSCs). At this differentiation stage, we observed some proliferation and apoptotic defects between healthy and AS cells. When human OSCs are co-cultured with mouse feeder cells, they are able to differentiate into hair cells (HCs). We successfully differentiated AS hiPSCs generated from AS patients into HCs. We are currently confirming gene expression pattern and testing HCs functionality.  To exclude patient linked epigenetics and differentiation defects, we are correcting the genomic mutation in the AS hiPSCs to generate isogenic hiPSCs using the CRIPSR/Cas9 system. Thanks to the isogenic hiPSCs we will be able to confirm that these defects are well due to the ALMS1 mutation.Derivation of cochlear cells from pathological or isogenic human iPSCs for modeling hereditary hearing los

PROMIS measures of pain, fatigue, negative affect, physical function, and social function demonstrated clinical validity across a range of chronic conditions

To present an overview of a series of studies in which the clinical validity of the National Institutes of Health’s Patient Reported Outcome Measurement Information System (NIH; PROMIS) measures was evaluated, by domain, across six clinical populations

Unravelling migration connectivity reveals unsustainable hunting of the declining ortolan bunting

In France, illegal hunting of the endangered ortolan bunting Emberiza hortulana has been defended for the sake of tradition and gastronomy. Hunters argued that ortolan buntings trapped in southwest France originate from large and stable populations across the whole of Europe. Yet, the European Commission referred France to the Court of Justice of the European Union (EU) in December 2016 for infringements to legislation (IP/16/4213). To better assess the impact of hunting in France, we combined Pan-European data from archival light loggers, stable isotopes, and genetics to determine the migration strategy of the species across continents. Ortolan buntings migrating through France come from northern and western populations, which are small, fragmented and declining. Population viability modeling further revealed that harvesting in southwest France is far from sustainable and increases extinction risk. These results provide the sufficient scientific evidence for justifying the ban on ortolan harvesting in France.Peer reviewe

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Incorporation of physical hydrology in a land-surface process model for climate modeling.

There is a need to improve hydrology in land-surface process models for weather and climate modeling. In this study, physical runoff processes were added to the Biosphere-Atmosphere Transfer Scheme (BATS). Runoff is important in both global modeling and regional impact analyses. It impacts soil moisture distribution and feeds back to the atmosphere through its influence on the moisture and energy budgets. General circulation models (GCM's) do not incorporate wetlands and small lakes into their radiation and moisture budgets. These ecosystems have been shown to affect the regional precipitation pattern that GCM's try to reproduce. Hortonian overland flow and the "variable contributing area" concept were incorporated into BATS in a model called BATS/HYDRO. Precipitation that reaches the surface is stored in surface detentions (puddles). When the maximum storage is exceeded, sheet flow commences. Water is routed through a hierarchy of channels to the edge of the grid cell where it is considered surface runoff. Overland and return flow are functions of terrain, vegetation type and soil type. The saturated area of the grid cell is calculated by assuming soil moisture is normally distributed. Return flow is calculated to exit the ground in saturated areas, and saturation overland flow is produced when precipitation falls on saturated areas. BATS/HYDRO has been developed further by coupling overland flow horizontally into a three-dimensional land-surface model, BATS3D. The models were tested on the Saline River in Southeast Lower Michigan, a temperate watershed. It contains extensive wetlands and shows the feasibility of using the models on similar watersheds. Daily streamflow observations for the Saline River were compared with runoff from the models. The influence of subgrid-scale heterogeneity and runoff routing on smaller grid size were also investigated to determine the model's accuracy. The physical hydrology in BATS/HYDRO and BATS3D produced more realistic runoff than BATS. This, in turn, increased the soil moisture and latent heat flux eliminating the summer dryness problem inherent in BATS.Ph.D.Atmospheric and Space SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/104609/1/9542822.pdfDescription of 9542822.pdf : Restricted to UM users only

Building for Disaster

In today’s political climate, public mood appears receptive to rolling back various regulations. To inform the public discourse on these matters, however, it is important to consider the costs and benefits of the regulation at stake, that is, to compare the benefits of the regulation against the cost it imposes. The recent catastrophic events of Hurricanes Harvey, Irma, Maria, and Nate bring to the forefront the regulatory debate over building codes. Strong and well-enforced building codes increase the costs of property construction, but they also have the potential to reduce future property damage from hurricanes in vulnerable areas. Twenty-five years ago, Hurricane Andrew devastated south Florida. At that time, Hurricane Andrew was the costliest disaster in U.S. history. Andrew revealed that construction practices and code enforcement in Florida for the 20 years prior had deteriorated, leading to increased damage when the hurricane struck. In response, the state of Florida created the Florida Building Code (FBC), fully enacted in 2001, as the strongest statewide building code in the United States. The FBC was based on national model codes developed by the International Code Council and heavily emphasized wind-engineering principles. Still, amid recent concerns about the increased costs of construction, efforts are underway to weaken the stringency of the FBC, long held as the gold standard. On the other hand, the extensive damage wrought by Hurricane Harvey in Texas has renewed conversations in that state about the need for stronger building codes. Currently, Texas has some of the most lenient building code standards in the country. Because increased costs of construction is often the fundamental argument against more stringent codes, the key question, then, from an economic perspective is: Has the reduction in damage from hurricanes exceeded the increased cost to comply with the strong statewide code? To answer this question, we conducted a study of the difference in damage to homes built before and after enactment of the FBC in 2001 from the windstorms that struck Florida in the 10 years after the FBC was put in place. During the period 2001 to 2010, Florida experienced seven land-falling hurricanes, four of which reached category three or higher on the Saffir-Simpson scale of hurricane strength. In our analysis, we first quantified the reduction of residential property wind damage due to the implementation of the FBC using realized insurance policy, claim, and paid insured loss data across the entire state of Florida spanning the years 2001 to 2010 provided to us by the Insurance Services Office (ISO). We found that homes built to the FBC suffered 53 percent less damage than homes built prior to the implementation of the FBC. In addition, homes built to the FBC were less likely to file a claim than were older homes. Taken together, the full reduction in damage to new versus older homes amounts to 72 percent. Although the reduction in damage from homes built to the FBC is striking, the economic public policy litmus test of the statewide code is how that benefit compares to the cost of complying with the code. Following from our claim-based empirical loss estimations, we further assessed the economic effectiveness of the FBC through a benefit-cost analysis. We have found that for different samples of our loss data, the benefit-cost ratios range from a low of 2.67 to a high of 7.93. In other words, comparing the increased construction cost to the expected reduction in windstorm damage across the life of the home shows anywhere from $2 to$8 in expected damage reduction—the benefit—for every dollar of increased cost. These results easily support the conclusion that the FBC is good public policy from an economic perspective. It is quite possible that other states at risk of events such as hurricanes, tornadoes, and windstorms would be likely to achieve similar benefit-to-cost results were they to emulate Florida and increase their building code standards. For example, the city of Moore, Oklahoma adopted a relatively stringent wind resistant building code after the 2013 tornado there caused $2 billion in damage and killed 24 people, including seven children at Plaza Towers Elementary School. When the Moore code is considered statewide, the benefit-to-cost comparison is$3 in benefits for each $1 in cost. Further, both of these studies have only considered the avoided damages to property. Additional benefits, and, hence, larger benefit-cost ratios would be expected when also considering avoided fatalities and injuries and avoided longer-term indirect damages to a community. The momentum to adopt stronger building codes ebbs as memories fade of what the winds from a major hurricane can do. Our research reminds us that political leaders should strive to look beyond the politics of the moment and make long-term decisions that advance overall net benefits to society

Terrestrial Environmental Variables Derived From EOS Platform Sensors

The three main objectives of the overall project were: 1. Adaptation of environmental constraint methods to take advantage of EOS sensors, specifically, MODIS, ASTER, and Landsat-7, in addition to the PM AVHRR observations 2. Refinement of environmental constraint methods based on fundamental scientific knowledge. 3. Assessment of spatial scaling patterns in environmental constraint measurements to evaluate the potential biases and errors that occur when estimating regional and global-scale NPP patterns with moderate to coarse satellite observations. These goals were modified because, on one hand, MODIS data did not become available until after the first year of the project and because of project staffing issues at the University of Maryland., The OSU portion of the project contained a modest amount of funding and responsibility compared to the University of Maryland and the University of Toledo