Accountability with Large Electorates

We show that ignorant voters can succeed in establishing high levels of electoral accountability. In our model, an incumbent politician is confronted with a large number of voters who receive fuzzy private signals about her performance. A sampling effect enables the incumbent to form a precise estimate of the median voter's signal, and the resulting level of accountability is as if the incumbent faced a perfectly informed social planner. Public information or ideological preferences can impair the beneficial impact of the sampling effect on accountability; overconfidence of voters can restore the full benefit of the sampling effect

Sphingolipid concentration in selected tissues of inducible Sgpl1-deficient mice.

<p>Two weeks after tamoxifen induction, tissues of Sgpl1^Flox/Flox Cre^+/− mice (open bars) and of Sgpl1^Flox/Flox Cre^−/− controls (filled bars) were obtained (n = 5/group). Tissues were extracted and sphingolipids were quantified by LC/MS. <i>A, B,</i> S1P; <i>C, D</i>, Sph; <i>E,</i> C16-ceramide. <i>A, C,</i> and <i>E</i> show absolute concentrations per weight of tissue; <i>B and D</i> show fold increase in inducible KO mice.</p

Foxp3⁺ Treg are overrepresented in LN and spleen of in inducible Sgpl1-deficient mice.

<p>Two weeks after tamoxifen treatment, cells from blood, LN and spleen were stained for T cell markers and Foxp3. <i>A,</i> Mean percentage and <i>B</i>, absolute numbers of Foxp3⁺ cells among CD4⁺ T cells (n = 4/group).</p

An Oral Sphingosine 1‑Phosphate Receptor 1 (S1P₁) Antagonist Prodrug with Efficacy in Vivo: Discovery, Synthesis, and Evaluation

A prodrug approach to optimize the oral exposure of a series of sphingosine 1-phosphate receptor 1 (S1P₁) antagonists for chronic efficacy studies led to the discovery of (<i>S</i>)-2-{[3′-(4-chloro-2,5-dimethylphenylsulfonylamino)-3,5-dimethylbiphenyl-4-carbonyl]­methylamino}-4-dimethylaminobutyric acid methyl ester <b>14</b>. Methyl ester prodrug <b>14</b> is hydrolyzed in vivo to the corresponding carboxylic acid <b>15</b>, a potent and selective S1P₁ antagonist. Oral administration of the prodrug <b>14</b> induces sustained peripheral blood lymphocyte reduction in rats. In a rat cardiac transplantation model coadministration of a nonefficacious dose of prodrug <b>14</b> with a nonefficacious dose of sotrastaurin (<b>19</b>), a protein kinase C inhibitor, or everolimus (<b>20</b>), an mTOR inhibitor, effectively prolonged the survival time of rat cardiac allografts. This demonstrates that clinically useful immunomodulation mediated by the S1P₁ receptor can be achieved with an S1P₁ antagonist generated in vivo after oral administration of its prodrug

Normal T cell development, reduced splenic cellularity, and increased LN cell number in inducible Sgpl1-deficient mice.

<p>B and T cell subpopulations in tamoxifen-treated Sgpl1^Flox/FloxCre^+/− (open bars) and Sgpl1^Flox/Flox Cre^−/− mice (closed bars) (n = 4/group), were enumerated based on total live cell counts and cell proportions as established by flow cytometry. <i>A</i>, Thymus; <i>B, C</i>, spleen; <i>D, E</i> lymph nodes. In <i>C</i> and <i>E</i>, CD8 and CD4 T cells were analysed for co-expression of CD44 and CD62L to define populations of naive and memory T cells; the insert in <i>C</i> provides a gating example for naïve/memory type T cells.</p

Protection of inducible Sgpl1-deficient mice in EAE.

<p>Tamoxifen-induced Sgpl1^Flox/Flox Cre^+/−, Sgpl1^Flox/Flox Cre^−/−, Cre^+/−, and Cre^−/− mice (n = 6–10/group) were immunized with MOG emulsified in Complete Freund’s Adjuvans. Data from one representative experiment out of three independent studies are shown. <i>A</i>, Incidence of mice with a clinical EAE score ≥1; <i>B</i>, clinical score; <i>C</i>, body weight. For histological analysis thoracic sections of spinal cord tissue from Sgpl1^Flox/Flox Cre^+/− and Sgpl1^Flox/Flox Cre^−/− mice undergoing EAE (day 24) were stained (<i>D</i>) with H&E to visualize CNS-invading cells (scale bar is 500 µm, arrows highlight areas of inflammation); <i>E</i>, for CD3⁺ T cells (scale bar is 500 µm, rectangles indicate area of magnification, where scale bar represents 100 µm); and <i>F</i>, with solochrome to assess the integrity of the myelin sheath (scale bar is 500 µm, arrows highlight areas of beginning demyeliniation).</p

Histology of inducible Sgpl1-deficient mice in EAE.

<p>For histological analysis thoracic sections of spinal cord tissue from Sgpl1^Flox/Flox Cre^+/− and Sgpl1^Flox/Flox Cre^−/− mice undergoing EAE (day 24) were stained (<i>A</i>) with H&E to visualize CNS-invading cells (scale bar is 500 µm, arrows highlight areas of inflammation); <i>B</i>, for CD3⁺ T cells (scale bar is 500 µm, rectangles indicate area of magnification, where scale bar represents 100 µm); and <i>C</i>, with solochrome to assess the integrity of the myelin sheath (scale bar is 500 µm, arrows highlight areas of beginning demyeliniation).</p

Pathophysiological Consequences of a Break in S1P1-Dependent Homeostasis of Vascular Permeability Revealed by S1P1 Competitive Antagonism

<div><p>Rational</p><p>Homeostasis of vascular barriers depends upon sphingosine 1-phosphate (S1P) signaling via the S1P1 receptor. Accordingly, S1P1 competitive antagonism is known to reduce vascular barrier integrity with still unclear pathophysiological consequences. This was explored in the present study using NIBR-0213, a potent and selective S1P1 competitive antagonist.</p><p>Results</p><p>NIBR-0213 was tolerated at the efficacious oral dose of 30 mg/kg BID in the rat adjuvant-induced arthritis (AiA) model, with no sign of labored breathing. However, it induced dose-dependent acute vascular pulmonary leakage and pleural effusion that fully resolved within 3–4 days, as evidenced by MRI monitoring. At the supra-maximal oral dose of 300 mg/kg QD, NIBR-0213 impaired lung function (with increased breathing rate and reduced tidal volume) within the first 24 hrs. Two weeks of NIBR-0213 oral dosing at 30, 100 and 300 mg/kg QD induced moderate pulmonary changes, characterized by alveolar wall thickening, macrophage accumulation, fibrosis, micro-hemorrhage, edema and necrosis. In addition to this picture of chronic inflammation, perivascular edema and myofiber degeneration observed in the heart were also indicative of vascular leakage and its consequences.</p><p>Conclusions</p><p>Overall, these observations suggest that, in the rat, the lung is the main target organ for the S1P1 competitive antagonism-induced acute vascular leakage, which appears first as transient and asymptomatic but could lead, upon chronic dosing, to lung remodeling with functional impairments. Hence, this not only raises the question of organ specificity in the homeostasis of vascular barriers, but also provides insight into the pre-clinical evaluation of a potential safety window for S1P1 competitive antagonists as drug candidates.</p></div

NIBR-0213-induced vascular leakage in the lungs evaluated by MRI.

<p><b>(A)</b> Axial MRI sections through the chest of one animal at approximately the same anatomical location acquired before (baseline) and at different time points with respect to beginning of treatment with NIBR-0213 (30 mg/kg BID). The white and red arrows display fluid signals in the lungs and the pleura, respectively, elicited by the compound. <b>(B)</b> Differential MRI signal volumes (mean ± s.e.m; n = 4–8) in the lungs and pleura. For the lungs, differential volumes (<i>i</i>.<i>e</i>. baseline-subtracted) are presented. <b>(C)</b> MRI signals (means ± s.e.m, n = 3) in the lungs and pleura at 24 h and 96 h after beginning of treatment with NIBR-0213 (3, 10 or 30 mg/kg BID) or FTY720 (1 mg/kg QD). For the lungs, differential signal volumes (<i>i</i>.<i>e</i>. baseline-subtracted) are presented. * p<0.05.</p

Chronic microscopic changes provoked by NIBR-0213 in rat lungs.

<p>An overview of chronic changes with alveolar degeneration /regeneration and accumulation of macrophages (<b>A:</b> 10X, H&E.) and of fibrotic foci (<b>B:</b> 12X, H&E.) observed in the lungs of a rat treated orally over 2 weeks with NIBR-0213 at 300 and 100 mg/kg QD, respectively.</p