Potential Effects of Landscape Change on Water Supplies in the Presence of Reservoir Storage

This work presents a set of methods to evaluate the potential effects of landscape changes on water supplies. Potential impacts are a function of the seasonality of precipitation, losses of water to evapotranspiration and deep recharge, the flow-regulating ability of watersheds, and the availability of reservoir storage. For a given reservoir capacity, simple reservoir simulations with daily precipitation and streamflow enable the determination of the maximum steady supply of water for both the existing watershed and a hypothetical counter-factual that has neither flow-regulating benefits nor any losses. These two supply values, representing land use end-members, create an envelope that defines the water-supply service and bounds the effect of landscape change on water supply. These bounds can be used to discriminate between water supplies that may be vulnerable to landscape change and those that are unlikely to be affected. Two indices of the water-supply service exhibit substantial variability across 593 watersheds in the continental United States. Rcross, the reservoir capacity at which landscape change is unlikely to have any detrimental effect on water supply has an interquartile range of 0.14–4% of mean-annual-streamflow. Steep, forested watersheds with seasonal climates tend to have greater service values, and the indices of water-supply service are positively correlated with runoff ratios during the months with lowest flows

Potential Effects of Landscape Change on Water Supplies in the Presence of Reservoir Storage

This work presents a set of methods to evaluate the potential effects of landscape changes on water supplies. Potential impacts are a function of the seasonality of precipitation, losses of water to evapotranspiration and deep recharge, the flow-regulating ability of watersheds, and the availability of reservoir storage. For a given reservoir capacity, simple reservoir simulations with daily precipitation and streamflow enable the determination of the maximum steady supply of water for both the existing watershed and a hypothetical counter-factual that has neither flow-regulating benefits nor any losses. These two supply values, representing land use end-members, create an envelope that defines the water-supply service and bounds the effect of landscape change on water supply. These bounds can be used to discriminate between water supplies that may be vulnerable to landscape change and those that are unlikely to be affected. Two indices of the water-supply service exhibit substantial variability across 593 watersheds in the continental United States. Rcross, the reservoir capacity at which landscape change is unlikely to have any detrimental effect on water supply has an interquartile range of 0.14–4% of mean-annual-streamflow. Steep, forested watersheds with seasonal climates tend to have greater service values, and the indices of water-supply service are positively correlated with runoff ratios during the months with lowest flows

Low-degree convection with melting and application to the Martian northern hemisphere

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Earth, Atmospheric, and Planetary Sciences, 2006.Includes bibliographical references (leaves 57-64).I investigate the hypothesis that the young and smooth surface of the Martian northern hemisphere is due to volcanic resurfacing driven by degree-one convection. I implement a batch melting process in a finite element convection model and run numerical experiments to quantify the melt fraction, timing of melting, and timing of the onset of degree-one convection. All models include a stratified viscosity to induce degree-one flow. To assure that the model's result is robust I vary the model's initial conditions, core-mantle boundary temperature and radius, and the thickness of the lithospheric lid. Long-wavelength convection is a consistent result of the viscosity stratification, and degree-one occurs in one third of the numerical experiments. I compare the melt fraction and onset of degree-one convection to the geological evidence from Martian orbiters, rovers, and meteorites. Good agreement is found between the numerical models and geological evidence, so this model suggests that volcanism driven by degree-one convection may play a significant role in the young age of the northern hemisphere of Mars.by P. James Dennedy-Frank.S.M

Mitotane Targets Lipid Droplets to Induce Lipolysis in Adrenocortical Carcinoma

INTRODUCTION Adrenocortical carcinoma (ACC) is a rare aggressive cancer with low overall survival. Adjuvant mitotane improves survival but is limited by poor response rates and resistance. Mitotane's efficacy is attributed to the accumulation of toxic free cholesterol, predominantly through cholesterol storage inhibition. However, targeting this pathway has proven unsuccessful. We hypothesize that mitotane-induced free-cholesterol accumulation is also mediated through enhanced breakdown of lipid droplets. METHODOLOGY ATCC-H295R (mitotane-sensitive) and MUC-1 (mitotane-resistant) ACC cells were evaluated for lipid content using specific BODIPY dyes. Protein expression was evaluated by immunoblotting and flow cytometry. Cell viability was measured by quantifying propidium iodide-positive cells following mitotane treatment and pharmacological inhibitors of lipolysis. RESULTS H295R and MUC-1 cells demonstrated similar neutral lipid droplet numbers at baseline. However, evaluation of lipid machinery demonstrated distinct profiles in each model. Analysis of intracellular lipid droplet content showed H295R cells preferentially store cholesteryl esters, whereas MUC-1 cells store triacylglycerol. Decreased lipid droplets were associated with increased lipolysis in H295R and in MUC-1 at toxic mitotane concentrations. Pharmacological inhibition of lipolysis attenuated mitotane-induced toxicity in both models. CONCLUSION We highlight that lipid droplet breakdown and activation of lipolysis represent a putative additional mechanism for mitotane-induced cytotoxicity in ACC. Further understanding of cholesterol and lipids in ACC offers potential novel therapeutic exploitation, especially in mitotane-resistant disease

Liver X receptor inhibition potentiates mitotane induced adrenotoxicity in ACC

Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with a poor outcome largely due to limited treatment options. Here, we propose a novel therapeutic approach through modulating intracellular free cholesterol via the liver X receptor alpha (LXRα) in combination with current first line pharmacotherapy, mitotane. H295R and MUC-1 ACC cell lines were pretreated with LXRα inhibitors in combination with mitotane. In H295R, mitotane (20, 40, 50µM) induced dose-dependent cell death, however, in MUC-1 this only occurred at a supratherapeutic concentration (200µM). LXRα inhibition potentiated mitotane-induced cytotoxicity in both cell lines. This was confirmed through use of the CompuSyn model which showed moderate pharmacological synergism and was indicative of apoptotic cell death via an increase in annexinV and cleaved-caspase 3 expression. Inhibition of LXRα was confirmed through downregulation of cholesterol efflux pumps ABCA1 and ABCG1, however, combination treatment with mitotane attenuated this effect. Intracellular free cholesterol levels were associated with increased cytotoxicity in H295R (r2=0.5210) and MUC-1 (r2=0.9299) cells. While both cell lines exhibited similar levels of free cholesterol at baseline, H295R were cholesterol ester rich whereas MUC-1 were cholesterol ester poor. We highlight the importance of LXRα mediated cholesterol metabolism in the management of ACC, drawing attention to its role in the therapeutics of mitotane sensitive tumours. We also demonstrate significant differences in cholesterol storage between mitotane sensitive and resistant disease.</jats:p

Low DHEAS: A Sensitive and Specific Test for the Detection of Subclinical Hypercortisolism in Adrenal Incidentalomas.

CONTEXT: Subclinical hypercortisolism (SH) occurs in 5% to 30% of adrenal incidentalomas (AIs). Common screening tests for adrenocorticotropin-independent hypercortisolism have substantial false-positive rates, mandating further time and resource-intensive investigations. OBJECTIVE: To determine whether low basal dehydroepiandrosterone sulfate (DHEAS) is a sensitive and specific screening test for SH in AI. SETTING AND PATIENTS: In total, 185 patients with AI were screened for adrenal medullary (plasma metanephrines) and cortical [1 mg overnight dexamethasone suppression test (ONDST), 24-hour urinary free cortisol (UFC), serum DHEAS, plasma renin, and aldosterone] hyperfunction. Positive ONDST [≥1.8 mcg/dL (≥50 nmol/L)] and/or UFC (more than the upper limit of reference range) results were further investigated. We diagnosed SH when at least 2 of the following were met: raised UFC, raised midnight serum cortisol, 48-hour dexamethasone suppression test (DST) cortisol ≥1.8 mcg/dL (≥50 nmol/L). RESULTS: 29 patients (16%) were diagnosed with SH. Adrenocorticotropin was 99%) and specific (91.9%) for the diagnosis of SH. Cortisol following 1 mg ONDST of 1.9 mcg/dL (53 nmol/L) was a sensitive (>99%) screening test for SH but had lower specificity (82.9%). The 24-hour UFC lacked sensitivity (69%) and specificity (72%). CONCLUSION: A single basal measurement of DHEAS offers comparable sensitivity and greater specificity to the existing gold-standard 1 mg DST for the detection of SH in patients with AIs