Characteristics and causal factors of claims in michigan highway construction projects

The US highway system is the largest road network system in the world. MDOT administers about 9,722 route-miles, (28,000 lane-miles) of roadway networks in Michigan. Every year, hundreds of projects worth millions of dollars are let by the State Transportation Agency (STA). Majority of these projects are successfully completed within the original scope of work, budget, schedule, and without litigation. However; some projects end up in litigation and disputes costing tax payers a great amount of money and the STA a great amount of resources. The number and cost of these construction claims has been substantially increasing in recent years. Research on this topic has been limited to-date. Therefore, a research on this subject is needed to investigate all of the factors affecting highway construction claims to improve efficiency and effectiveness of highway project delivery. The data available at the STA provide a rich source of information that can be utilized to study the characteristics and causal factors of claims in highway construction projects at the STA. However, until this point, these separate data sets were not integrated and much of it was not utilized for this type of research or analytical purposes. A research of all of the projects that experienced claims was initiated that was followed by research and collection of all of the projects that were categorized as successful projects at the STA. All of the projects were organized and analyzed using logistic regression modeling. LIMDEP software was utilized to determine the factors that are more likely to affect the filling of construction claims and their likely payouts. The results were tabulated for all of the significant factors based on the values of their Estimated Coefficient, Standard Error, T-Statistic, P-Value, and Logit Relative Elasticity Calculations. The analysis showed that certain projects factors are more likely to affect the filling of a claim, and that certain factors are more likely to affect the payout on the claims. The results also indicated that certain project factors do not seem to have any significant affect on the likelihood of filing of a claim or the payouts of these claims. This research is the first of its kind as it categorizes the projects specific factors according to their likely affect on the filing of construction claims and the payout of these filed claims based on Michigan data. This methodology can be tested and applied in other state transportation agencies to mitigate the risks of construction claims on highway transportation projects

The role of mammalian target of rapamycin complex 1 in hepatic physiology and disease

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2010.Cataloged from PDF version of thesis.Includes bibliographical references.The multi-component kinase mTOR complex 1 (mTORC 1) coordinates nutrient and growth factor inputs with numerous downstream processes including protein translation, autophagy, metabolism and cell growth. We have found that inhibition of mTORC 1 with rapamycin treatment suppressed whole-body postnatal growth similar to reduced caloric intake. We found that while feeding activated mTORC 1 in almost every tissue, there was variability in the upstream activating stimuli. The role of mTORCl in organ growth was further elucidated by studies we performed using liver-specific mTORC1 gain and loss of function mutants. Confirming our studies with rapamycin, genetic activation or suppression of mTORC 1 increased and decreased liver size respectively, and rendered the liver insensitive to nutrients. Rendering the liver insensitive to nutrients also had functional consequences. In response to starvation, the liver shifts to fatty acid catabolism and generates ketone bodies to supplement lowered glucose levels. We find that constitutive activation of mTORC1 prevents the liver from initiating fatty-acid oxidation and ketone production in response to fasting. Many aspects of the hepatic fasting response malfunction in old age including fatty acid catabolism and ketogenesis. We find this aging-dependent process is mediated by mTORC 1, and thus loss of mTORC 1 function throughout the adult life of the animal prevents the aging induced decrease in hepatic ketogenesis. As such, pharmaceutical inhibition of mTORC 1 may be beneficial in battling metabolic disorders due to aging.(cont.) Pharmaceutical inhibition of mTORC is a potential treatment for patients suffering from tuberous sclerosis complex (TSC). The disease TSC in humans is initiated by loss of TSC1 or TSC2, which results in hyperactive mTORC 1 activity. The disease can involve development of multiple lesions including brain harmatomas, angiomyolipomas (AMLs), and lymphangioleiomyomatosis (LAM). We have engineered transgenic mice that express Rheb2, an mTORC 1 activator, in a doxycycline-inducible manner. Overexpression of Rheb2 led to cystic growths with characteristics of both LAM and AML. We hope this mouse model will be helpful in furthering our understanding of the pathology behind these lesions, and provide a mouse model for therapeutic intervention for TSC.by Shomit Sengupta.Ph.D

Toward a Mechanistic Understanding of Hepatic Insulin Action and Resistance

The development of insulin resistance (IR) in the liver is one of the key pathophysiologic events in the development of type 2 diabetes mellitus, but most patients do not become uniformly resistant to the hepatic actions of insulin. Although insulin loses its ability to blunt glucose production, it largely retains its capacity to drive lipogenesis. This "selective IR" results in the characteristic hyperglycemia and dyslipidemia of type 2 diabetes. In this thesis, we take two approaches to better understand the mechanisms underlying selective IR. First, the compensatory chronic hyperinsulinemia (CHI) of insulin resistance downregulates levels of the insulin receptor (InsR). We have therefore modeled CHI in primary hepatocytes to demonstrate that the reduction in InsR number results in insufficient signaling capacity to halt glucose production while still leaving enough residual signaling capacity to promote lipogenesis. That is, the two processes are inherently differentially sensitive to insulin. Second, we hypothesize that FoxO1, a key insulin-inhibited transcription factor, coordinately regulates both hepatic glucose and lipid homeostasis. We have developed a transgenic mouse model heterozygous for a knocked-in allele of DNA binding-deficient FoxO1 and have proceeded to dissect the mechanisms by which FoxO1 differentially regulates glucose and lipid handling. We found that while the former requires FoxO1 to bind to its consensus sequences in target-gene promoters, the latter proceeds via a co-regulatory action of FoxO1. Taken together, these findings reveal novel connections between the glucose and lipid "arms" of the insulin-signaling pathway and how they may go awry in the run-up to diabetes