Objectives/Goals: The study’s goal is to investigate the role of PPAR-α on regulating blood pressure, glomerular filtration rate (GFR), renal inflammation, and renal sodium reabsorption in mice on a 4% high-salt diet. Methods/Study Population: GFR, systolic blood pressure (SBP), inflammatory biomarkers (KIM-1, TIMP2, NGAL, MCP-1, TNF-α, IL-6, IL-10, and IL-17), and renal sodium transporter expression (NKA, NHE3, NKCC2, NCC, ENaC, Aqp-2, and NHERF1) were measured in PPAR-α KO mice and wild-type controls treated with a 4% high-salt (HS) diet. Male C57BL6, B129S1, and PPAR-α KO mice (12 weeks old) will be treated with 4% HS diet for 28 days. Systolic blood pressure is measured by tail cuff. GFR is measured by transdermal FITC-Inulin radioactive fluorescence. Inflammatory biomarkers will be measured by cytokine array and western blot. Sodium transporter expression will be measured by western blot. Results/Anticipated Results: Baseline SBP was 146 ± 31 mmHg (C57), 140 ± 24 mmHg (B129), and 153 ± 23 mmHg (KO). After 21 days of normal (control diet) or treatment (HS diet), control systolic pressures were 139 ± 18 mmHg (C57), 107 ± 23 mmHg (B129) and 147 ± 34 mmHg (KO), while HS systolic pressures were 166 ± 23 mmHg (C57) and 119 ± 34 mmHg (B129). We are collecting blood pressure for the KO HS group. Baseline GFR was 1194 ± 140 µL/min/g (C57), 1167 ± 279 µL/min/g (B129), and 1191 ± 157 µL/min/g (KO). Discussion/Significance of Impact: We hypothesize significantly higher SBP, inflammatory marker expression, and renal sodium transporter expression in KO and B129 mice on a HS diet. We predict that PPAR-α expression in the kidney will be higher in C57 compared to B129. We predict that PPAR-α activity plays a vital role in reducing high-salt-induced hypertension and inflammatory markers.

This paper presents an algorithm for simulating multiple equilibria in otherwise-linear dynamic models with occasionally-binding constraints. Our algorithm extends the guess-and-verify approach of Guerrieri and Iacoviello (2015) to detect and simulate multiple perfect foresight equilibria, and allows arbitrary “news shocks” up to a finite horizon. When there are multiple equilibria, we show how to compute expected paths using a “prior probabilities” approach and we provide an approach for running stochastic simulations with switching between equilibria on the simulated path. A policy application studies a New Keynesian model with a zero lower bound on nominal interest rates and multiple equilibria, including a “bad” solution based on self-fulfilling pessimistic expectations. A price-level targeting rule does not always eliminate the bad solution, but it shrinks the indeterminacy region substantially and improves stabilization and welfare relative to more conventional interest rate rules or forward guidance.

This article seeks to provide a constitutional law perspective on the contribution of the Lords Spiritual to the scrutiny of legislation in the House of Lords. It examines the legal basis of the bishops’ role in the Upper House and how this has evolved. It considers how far the bishops currently meet expectations about their role against the background of calls for reform of the House of Lords and changes in religious affiliation in the United Kingdom. The paper draws, amongst other things, on the experience of a group of current and former Lords Spiritual who shared their views with the author in the course of some informal semi-structured conversations. It also examines the relationship between the Lords Spiritual and the Church of England's national institutions. It concludes that the Lords Spiritual make a distinctive contribution to the legislature which should be maintained, with some modifications to meet the needs of the time.

OBJECTIVES/GOALS: We are investigating the role of IL-6 in regulating renal function by measuring mean arterial pressure (MAP), renal plasma flow (RPF) and glomerular filtration rate (GFR) in wild type (WT) and IL-6-knockout (KO) mice in established mouse models of angiotensin II (AII)-dependent- hypertension and -salt-sensitive hypertension. METHODS/STUDY POPULATION: Twelve-week-old male WT and KO mice on the C57BL6 background strain were infused with vehicle (V; saline) or angiotensin II (AII; 200 ng/kg/min) for 12-14 days. Half of the AII-treatment groups were maintained on a high salt (HS; 6% NaCl) diet for the duration of the experiment, while the other half of the AII treatment groups and both vehicle groups were fed normal rat chow. MAP was continuously measured by a fluid filled catheter in conscious mice for the duration of the experiment. RPF and GFR were measured on days 12-14 in anesthetized mice by the para-aminohippurate, and fluorescein isothiocynate-Inulin techniques, respectively. All data were analyzed by 2-way ANOVA; *p<0.05 vs. WT, same treatment; #p<0.05 vs.V, same genotype; ^p<0.05, AII vs. AII+HS, same genotype. RESULTS/ANTICIPATED RESULTS: MAP was 31% lower in KO vs WT mice. AII increased MAP (1.2-fold) in WT but not KO mice. HS diet magnified AII-induced increases in MAP in WT and moderately increased MAP in AII-KO mice: [MAP (mmHg): WT+V, 130±7.0; KO+V, 91.0+4.0*; WT+AII, 153±5.0#; KO+AII, 83.0±4.0*; WT+AII+HS, 150±11#; KO+AII+HS, 93.0±4.0#]. AII infusion reduced RPF in the KO but not WT mice. Addition of HS reduced RPF in WT and exacerbated AII-induced reductions in RPF in KO mice [RPF (ml/min/g): WT+V, 1.82±0.23; KO+V, 1.91+0.40; WT+AII, 3.16±0.75#; KO+AII, 1.65±0.42*; WT+AII+HS, 1.10±0.31#^; KO+AII+HS, 1.13±0.XX#^]. The HS diet reduced GFR in AII-infused KO but not WT mice [GFR (µl/min/g): WT+V, 756±XX; KO+V, 788±XX; WT+AII, 1010±63*#; KO+AII, 756±23*; WT+AII+HS, 1100±150#; KO+AII+HS: 540±210*#^]. DISCUSSION/SIGNIFICANCE: The absence of IL-6 in male mice attenuated AII- and/or AII+HS-induced increases in MAP; however, it exacerbated HS-induced reductions in RPF and GFR. These findings suggest inhibiting IL-6 has therapeutic potential as an antihypertensive but not as a renal protective agent in hypertension and salt-sensitive hypertension disease states.

Short-selling constraints are common in financial markets, while physical assets such as housing often lack markets for short-selling altogether. As a result, investment decisions are often restricted by such constraints. This paper studies asset prices in behavioral heterogeneous-belief models with short-selling constraints and arbitrarily many belief types. We provide conditions on beliefs such that short-selling constraints bind for different types, along with analytic expressions for price and demands that allow us to construct fast solution algorithms relevant for a wide range of models. An application studies how an alternative uptick rule, as in the United States, affects price dynamics and wealth distribution in a market with many belief types in evolutionary competition. In a numerical example, we highlight a scenario in which a modified version of the alternative uptick rule, triggered by smaller percentage falls in price, reduces both asset mispricing and wealth inequality relative to the current regulation. As extensions, we show how our method applies to multiple asset markets with short-selling constraints, additional heterogeneities, and price setting by a market maker.

OBJECTIVES/GOALS: Approximately 37 million people in the U.S. have chronic kidney disease, which is a major risk factor for cardiovascular and end stage renal diseases. PPAR-αknockout (KO) mice exhibit increased renal inflammation and blood pressure. In this study, we investigated the role of PPAR-αin renal function in a mouse model of hypertension. METHODS/STUDY POPULATION: Male 4-month-old wild type (WT) and PPAR-αKO mice were instrumented with radio transmitters by artery canulation (Data Science Intl). This method minimizes stress and artifacts by avoiding the use of tethering, restraining, or anesthetizing the mice during data sampling. After recovery from surgery, we continuously measured mean arterial pressure (MAP) via radio telemetry in conscious ambulatory mice. After baseline MAP was established, vehicle (Veh; saline) or angiotensin II (Ang II) were infused using an osmotic minipump at a slow pressor dose (400 ng/kg/min) for 12 days. On day 12, we injected an intravenous bolus of fluorescin-sinistrin (3.74µl/g body weight) and collected 8 blood samples (20µl/sample) over 75 minutes to enable calculation of the glomerular filtration rate (GFR) using [GFR = I/(A/α+ B/ß)]. RESULTS/ANTICIPATED RESULTS: Similar to our prior observations, no significant (ns) differences in baseline MAP were observed between WT and PPAR-αKO mice [(mmHg): WT (n=6), 111 ± 20 vs. PPAR-αKO (n=6), 113 ± 10; ns] whereas after 12 days of the slow pressor effect of Ang II, MAP was increased in both strains [(mmHg): WT (n=8), 138 ± 11# vs. PPAR-αKO (n=8) , 156 ± 16#; #p DISCUSSION/SIGNIFICANCE: PPAR-αprotects mice from worsening hypertension and is critical to preserving GFR during normotensive conditions. Ongoing studies are further investigating how PPAR-αregulates renal function. These finding suggest therapeutics designed to increase PPAR-αactivity could have clinical benefit in chronic kidney disease.

1 Th. 5:17 tells us to pray without ceasing. Many have worried that praying without ceasing seems impossible. Most address the problem by giving an account of the true nature of prayer. Unexplored are strategies for dealing with the problem that are neutral on the nature of prayer, strategies consistent, for example, with the view that only petition is prayer. In this article, after clarifying the nature of the problem for praying without ceasing, I identify and explore the prospects of five different strategies that are neutral in this sense. I also raise problems for each strategy.

We derive and analyse an energy to model lipid raft formation on biological membranes involving a coupling between the local mean curvature and the local composition. We apply a perturbation method recently introduced by Fritz, Hobbs and the first author to describe the geometry of the surface as a graph over an undeformed Helfrich energy minimising surface. The result is a surface Cahn–Hilliard functional coupled with a small deformation energy. We show that suitable minimisers of this energy exist and consider a gradient flow with conserved Allen–Cahn dynamics, for which existence and uniqueness results are proven. Finally, numerical simulations show that for the long-time behaviour raft-like structures can emerge and stabilise, and their parameter dependence is further explored.