The Hedgehog (HH) signaling pathway was discovered originally as a key pathway in embryonic patterning and development. Since its discovery, it has become increasingly clear that the HH pathway also plays important roles in a multitude of cancers. Therefore, HH signaling has emerged as a therapeutic target of interest for cancer therapy. In this review, we provide a brief overview of HH signaling and the key molecular players involved and offer an up-to-date summary of our current knowledge of endogenous and exogenous small molecules that modulate HH signaling. We discuss experiences and lessons learned from the decades-long efforts toward the development of cancer therapies targeting the HH pathway. Challenges to develop next-generation cancer therapies are highlighted.

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Human heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) serves as a key regulating protein in RNA metabolism. Malfunction of hnRNPA1 in nucleo-cytoplasmic transport or dynamic phase separation leads to abnormal amyloid aggregation and neurodegeneration. The low complexity (LC) domain of hnRNPA1 drives both dynamic phase separation and amyloid aggregation. Here, we use cryo-electron microscopy to determine the amyloid fibril structure formed by hnRNPA1 LC domain. Remarkably, the structure reveals that the nuclear localization sequence of hnRNPA1 (termed PY-NLS), which is initially known to mediate the nucleo-cytoplamic transport of hnRNPA1 through binding with karyopherin-β2 (Kapβ2), represents the major component of the fibril core. The residues that contribute to the binding of PY-NLS with Kapβ2 also exert key molecular interactions to stabilize the fibril structure. Notably, hnRNPA1 mutations found in familial amyotrophic lateral sclerosis (ALS) and multisystem proteinopathoy (MSP) are all involved in the fibril core and contribute to fibril stability. Our work illuminates structural understandings of the pathological amyloid aggregation of hnRNPA1 and the amyloid disaggregase activity of Kapβ2, and highlights the multiple roles of PY-NLS in hnRNPA1 homeostasis.

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Abstract. We prove Kudla-Rallis's conjecture on first occurrences of orthogonalsymplectic dual pair correspondence, for a local field of characteristic zero.

We report the crystal structure and magnetic properties of the Zn1−xMnxO compounds synthesized by a combustion method. The Zn1−xMnxO compounds with x=0–0.1 crystallize in the wurtzite ZnO structure. The lattice parameters a and c of Zn1−xMnxO increase linearly with the Mn content, indicating that Mn2+ ions substitute for Zn2+ ions. Scanning electron microscopy shows that the average particle radius of Zn0.95Mn0.05O is about 40 nm. From the Curie–Weiss behavior of susceptibility at high temperature, it was found that the Mn–Mn interaction is dominated by antiferromagnetic coupling with effective nearest-neighbor exchange constant J about −32 K and the large negative value of the Curie–Weiss temperature.