Autosomal-dominant (AD) polycystic kidney disease (PKD) is a leading cause of renal failure in the United States, and currently lacks available treatment options to slow disease progression. Mutations in the gene coding for polycystin-1 (PC1) underlie the majority of cases but the function of PC1 has remained poorly understood. We have previously shown that PC1 regulates the transcriptional activity of signal transducer and activator of transcription-6 (STAT6). Here we show that STAT6 is aberrantly activated in cyst-lining cells in PKD mouse models. Activation of the STAT6 pathway leads to a positive feedback loop involving auto/ paracrine signaling by IL13 and the IL4/13 receptor. The presence of IL13 in cyst fluid and the overexpression of IL4/13 receptor chains suggests a mechanism of sustained STAT6 activation in cysts. Genetic inactivation of STAT6 in a PKD mouse model leads to significant inhibition of proliferation and cyst growth and preservation of renal function. We show that the active metabolite of leflunomide, a drug approved for treatment of arthritis, inhibits STAT6 in renal epithelial cells. Treatment of PKD mice with this drug leads to amelioration of the renal cystic disease similar to genetic STAT6 inactivation. These results suggest STAT6 as a promising drug target for treatment of ADPKD.signal transduction | cytokines | preclinical

In this paper we will prove that for a threefold of general type and large volume the second plurigenera is positive and the fifth canonical map is birational. * The author would like to thank Professor Christopher Hacon for suggesting the problem and many useful conversations and suggestions.

We prove an analogue of Fujino and Mori's "bounding the denominators" [7, Theorem 3.1] in the log canonical bundle formula (see also [19, Theorem 8.1]) for Kawamata log terminal pairs of relative dimension one. As an application we prove that for a klt pair (X, ∆) of Kodaira codimension one and dimension at most three such that the coefficients of ∆ are in a DCC set A, there is a natural number N that depends only on A for which ⌊N (K X + ∆)⌋ induces the Iitaka fibration. We also prove a birational boundedness result for klt surfaces of general type.

We prove the effectiveness of the log Iitaka fibration in Kodaira codimension two for varieties of dimension ≤ 4. In particular, we finish the proof of effective log Iitaka fibration in dimension two. Also, we show that for the log Iitaka fibration, if the fiber is of dimension two, the denominator of the moduli part is bounded.

Abstract. Hurwitz numbers count ramified covers of a Riemann surface with prescribed monodromy. As such, they are purely combinatorial objects. Tautological classes, on the other hand, are distinguished classes in the intersection ring of the moduli spaces of Riemann surfaces of a given genus, and are thus "geometric". Localization computations in Gromov-Witten theory provide non-obvious relations between the two. This paper makes one such computation, and shows how it leads to a "master" relation (Theorem 0.1) that reduces the ratios of certain interesting tautological classes to the pure combinatorics of Hurwitz numbers. As a corollary, we obtain a purely combinatorial proof of a theorem of Bryan and Pandharipande, expressing in generating function form classical computations by Faber/Looijenga (Theorem 0.2).