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TFEB is a master regulator of autophagy, lysosome biogenesis and mitochondrial metabolism that works, and immunity, primarily through transcription controlled by cytosol-to-nuclear translocation. Emerging data indicate additional regulatory interactions at the surface of organelles such as lysosomes. Here we show that TFEB has a non-transcriptional role in mitochondria, regulating the electron transport chain complex I to down-modulate inflammation. Proteomic analysis revealed extensive TFEB co-precipitation with several mitochondrial proteins, whose interactions are disrupted upon infection withS.Typhimurium. Localization of TFEB in the mitochondrial matrix was confirmed by high resolution confocal microscopy and biochemistry with translocation dependent on a conserved N-terminal TOMM20-binding motif enhanced by mTOR inhibition. Within the mitochondria, TFEB and protease LONP1 antagonistically co-regulate complex I, reactive oxygen species and the inflammatory response. Consequently, during infection, lack of TFEB specifically in the mitochondria exacerbates the expression of pro-inflammatory cytokines, contributing to innate immune pathogenesis.

The mitochondrial rhomboid protease PARL regulates mitophagy by balancing intramembrane proteolysis of PINK1 and PGAM5. It has been implicated in the pathogenesis of Parkinson's disease, but its investigation as a possible therapeutic target is challenging in this context because genetic deficiency of PARL may result in compensatory mechanisms. To address this problem, we undertook a hitherto unavailable chemical biology strategy. We developed potent PARL-targeting ketoamide inhibitors and investigated the effects of acute PARL suppression on the processing status of PINK1 intermediates and on Parkin activation. This approach revealed that PARL inhibition leads to a robust activation of the PINK1/Parkin pathway without major secondary effects on mitochondrial properties, which demonstrates that the pharmacological blockage of PARL to boost PINK1/Parkin-dependent mitophagy is a feasible approach to examine novel therapeutic strategies for Parkinson's disease. More generally, this study showcases the power of ketoamide inhibitors for cell biological studies of rhomboid proteases.

Modulation of protein-RNA interaction (PRI) using small molecules is a promising strategy to develop therapeutics. LIN28 is an RNA-binding protein that blocks the maturation of the tumor suppressor let-7 microRNAs. Herein, we performed a fluorescence polarization-based screening and identified trisubstituted pyrrolinones as small-molecule inhibitors disrupting the LIN28-let-7 interaction. The most potent compound C902 showed dose-dependent inhibition in an EMSA validation assay, enhanced thermal stability of the cold shock domain of LIN28, and increased mature let-7 levels in JAR cells. The structure-activity relationship study revealed key structural features contributing to either PRI inhibition or stabilization of protein-protein interaction (PPI). The pyrrolinones identified in this study not only represent a new class of LIN28-binding molecules that diversify the limited available LIN28 inhibitors but also represent the first examples of small molecules that showed substituent-dependent PRI inhibitory and PPI activating activities.

We introduce an expansion formula for elements in quantum cluster algebras associated to type A and Kronecker quivers with principal quantization. Our formula is parametrized by perfect matchings of snake graphs as in the classical case. In the Kronecker case, the coefficients are q-powers whose exponents are given by a weight function induced by the lattice of perfect matchings. As an application, we prove that a reflectional symmetry on the set of perfect matchings satisfies Stembridge's q=-1 phenomenon with respect to the weight function., 22 pages

The immunoregulatory enzyme indoleamine‐2,3‐dioxygenase (IDO1) strengthens cancer immune escape, and inhibition of IDO1 by means of new chemotypes and mechanisms of action is considered a promising opportunity for IDO1 inhibitor discovery. IDO1 is a cofactor‐binding, redox‐sensitive protein, which calls for monitoring of IDO1 activity in its native cellular environment. We developed a new, robust fluorescence‐based assay amenable to high throughput, which detects kynurenine in cells. Screening of a ca. 150 000‐member compound library discovered unprecedented, potent IDO1 modulators with different mechanisms of action, including direct IDO1 inhibitors, regulators of IDO1 expression, and inhibitors of heme synthesis. Three IDO1‐modulator chemotypes were identified that bind to apo‐IDO1 and compete with the heme cofactor. Our new cell‐based technology opens up novel opportunities for medicinal chemistry programs in immuno‐oncology., Heme‐competitive indoleamine‐2,3‐dioxygenase (IDO1) small‐molecule modulators are under‐represented as heme displacement is delayed in in vitro assays. This limitation can be overcome by cell‐based screening as employed in this study, which revealed novel chemotypes that potently inhibit IDO1 activity and kynurenine production by competing with heme.

Aminothiophene is a scaffold that is widely present in drugs and biologically active small molecules as chemical probes. In this study, 43 compounds sharing a 2-aminothiophenone-3-carboxylate (ATPC) scaffold, known to activate the ribonuclease L (RNase L), were synthesized and selected ATPCs showed enhancement of thermal stability of RNase L upon binding. Screening of antiproliferation activities against human cancer cell lines revealed that ATPCs represented by compounds 4l and 50 showed potent single-digit micromolar antiproliferation activity against human cancer cell lines. Compounds 4l and 50 exhibited time- and dose-dependent proliferation inhibition, induced cellular apoptosis measured by cleaved PARP and via flow cytometry, inhibited cell migration, and inhibited cell colony formation. Combining the results reported in this work, ATPCs were evaluated as potential anticancer agents mediated by RNase L-binding and apoptosis induction. The work contributes to the study on the polypharmacological properties of aminothiophene-containing small molecules.

Modulation of protein–RNA interaction (PRI) using small molecules is a promising strategy to develop therapeutics. LIN28 is an RNA-binding protein that blocks the maturation of the tumor suppressor let-7 microRNAs. Herein, we performed a fluorescence polarization-based screening and identified trisubstituted pyrrolinones as small-molecule inhibitors disrupting the LIN28–let-7 interaction. The most potent compound C902 showed dose-dependent inhibition in an EMSA validation assay, enhanced thermal stability of the cold shock domain of LIN28, and increased mature let-7 levels in JAR cells. The structure–activity relationship study revealed key structural features contributing to either PRI inhibition or stabilization of protein–protein interaction (PPI). The pyrrolinones identified in this study not only represent a new class of LIN28-binding molecules that diversify the limited available LIN28 inhibitors but also represent the first examples of small molecules that showed substituent-dependent PRI inhibitory and PPI activating activities.

Cluster algebras are a class of commutative algebras whose generators are defined by a recursive process called mutation. We give a brief introduction to cluster algebras, and explain how discrete integrable systems can appear in the context of cluster mutation. In particular, we give examples of birational maps that are integrable in the Liouville sense and arise from cluster algebras with periodicity, as well as examples of discrete Painleve equations that are derived from Y-systems.

We study Fomin-Zelevinsky's mutation rule in the context of non-crystallographic root systems. In particular, we construct approximately periodic sequences of real numbers for the non-crystallographic root systems of rank 2 by adjusting the exchange relation for cluster algebras. Moreover, we describe matrix mutation classes for types H-3 and H-4.

Locally acyclic cluster algebras are Krull domains. Hence their factorization theory is determined by their (divisor) class group and the set of classes containing height-1 prime ideals. Motivated by this, we investigate class groups of cluster algebras. We show that any cluster algebra that is a Krull domain has a finitely generated free abelian class group, and that every class contains infinitely many height-$1$ prime ideals. For a cluster algebra associated to an acyclic seed, we give an explicit description of the class group in terms of the initial exchange matrix. As a corollary, we reprove and extend a classification of factoriality for cluster algebras of Dynkin type. In the acyclic case, we prove the sufficiency of necessary conditions for factoriality given by Geiss--Leclerc--Schr\"oer., Comment: 35 pages; significant revision (numbering of main theorems has changed; added section 7)

Motivated by Fomin and Zelevinsky's theory of cluster algebras we introduce a variant of the Markov equation; we show that all natural solutions of the equation arise from an initial solution by cluster transformations., Comment: 11 pages, 7 figures

The article concerns the existence and uniqueness of quantisations of cluster algebras. We prove that cluster algebras with an initial exchange matrix of full rank admit a quantisation in the sense of Berenstein-Zelevinsky and give an explicit generating set to construct all quantisations.

The article concerns the subalgebra U_v^+(w) of the quantized universal enveloping algebra of the complex Lie algebra sl_{n+1} associated with a particular Weyl group element of length 2n. We verify that U_v^+(w) can be endowed with the structure of a quantum cluster algebra of type A_n. The quantum cluster algebra is a deformation of the ordinary cluster algebra Geiss-Leclerc-Schroeer attached to w using the representation theory of the preprojective algebra. Furthermore, we prove that the quantum cluster variables are, up to a power of v, elements in the dual of Lusztig's canonical basis under Kashiwara's bilinear form., 48 pages

The article concerns the dual of Lusztig's canonical basis of a subalgebra of the positive part U_q(n) of the universal enveloping algebra of a Kac-Moody Lie algebra of type A_1^{(1)}. The examined subalgebra is associated with a terminal module M over the path algebra of the Kronecker quiver via an Weyl group element w of length four. Geiss-Leclerc-Schroeer attached to M a category C_M of nilpotent modules over the preprojective algebra of the Kronecker quiver together with an acyclic cluster algebra A(C_M). The dual semicanonical basis contains all cluster monomials. By construction, the cluster algebra A(C_M) is a subalgebra of the graded dual of the (non-quantized) universal enveloping algebra U(n). We transfer to the quantized setup. Following Lusztig we attach to w a subalgebra U_q^+(w) of U_q(n). The subalgebra is generated by four elements that satisfy straightening relations; it degenerates to a commutative algebra in the classical limit q=1. The algebra U_q^+(w) possesses four bases, a PBW basis, a canonical basis, and their duals. We prove recursions for dual canonical basis elements. The recursions imply that every cluster variable in A(C_M) is the specialization of the dual of an appropriate canonical basis element. Therefore, U_q^+(w) is a quantum cluster algebra in the sense of Berenstein-Zelevinsky. Furthermore, we give explicit formulae for the quantized cluster variables and for expansions of products of dual canonical basis elements., 32 pages

Solution by Philipp Lampe, Bonn, Germany. Let T be a triangular cell in A. The center M of the circle O is the circumcenter of T. According to Euler's formula, the distance d from M to the incenter of T is given by d2 = R2 ? 2Rr, where R denotes the circumradius of T (which is equal to the radius of O) and r denotes the inradius of T. Let x, y, and z be the signed distances from M to the sides of T, where the sign of the distance is positive if and only if M lies on the same half-plane as the triangle T. Carnot's theorem states that R + r=x + y + z. It follows that