SUMMARY The transcriptional co-activators YAP and TAZ are key regulators of organ size and tissue homeostasis, and their dysregulation contributes to human cancer. Here we discover YAP/TAZ as bona fide downstream effectors of the alternative Wnt signaling pathway. Wnt5a/b and Wnt3a induce YAP/TAZ activation independent of canonical Wnt/β-catenin signaling. Mechanistically, we delineate the ‘alternative Wnt-YAP/TAZ signaling axis’ that consists of Wnt - FZD/ROR - Gα12/13 - Rho GTPases -Lats1/2 to promote YAP/TAZ activation and TEAD-mediated transcription. YAP/TAZ mediate the biological functions of alternative Wnt signaling including gene expression, osteogenic differentiation, cell migration, and antagonism of Wnt/β-catenin signaling. Together, our work establishes YAP/TAZ as critical mediators of alternative Wnt signaling.

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19In many experiments, neuroscientists tightly control behavior, record many trials, and obtain trial-averaged 20 firing rates from hundreds of neurons in circuits containing billions of behaviorally relevant neurons. Di-21 mensionality reduction methods reveal a striking simplicity underlying such multi-neuronal data: they can 22 be reduced to a low-dimensional space, and the resulting neural trajectories in this space yield a remarkably questions, and test it using physiological recordings from reaching monkeys. This theory reveals conceptual 28 insights into how task complexity governs both neural dimensionality and accurate recovery of dynamic 29 portraits, thereby providing quantitative guidelines for future large-scale experimental design.

Chitinases are important enzymes required for chitin degradation and reconstruction in insects. Based on a bioinformatics investigation, we identified 12 genes encoding putative chitinase-like proteins, including 10 chitinases (Cht), one imaginal disc growth factor (IDGF) and one endo-β-N-acetylglucosaminidase (ENGase) in the genome of the brown planthopper, Nilaparvata lugens (Hemiptera: Delphacidae). These 12 genes were clustered into nine different groups, with 11 in glycoside hydrolase family 18 groups (groups I-VIII) and one in the ENGase group. Developmental and tissue-specific expression pattern analysis revealed that the transcript levels of eight genes peaked periodically during moulting and were mainly expressed in the integument, except NlCht2, NlCht4, NlIDGF and NlENGase. NlCht2, NlIDGF and NlENGase were expressed at all stages with slight periodical changes and mainly expressed in the female reproductive organs in adults, whereas NlCht4 was highly expressed only at the adult stage in the male reproductive organs. Lethal phenotypes were observed in insects challenged by double-stranded RNAs for NlCht1, NlCht5, NlCht7, NlCht9 and NlCht10 during moulting, suggesting their significant roles in old cuticle degradation. NlCht1 was the most sensitive gene, inducing 50% mortality even at 0.01 ng per insect. Our results illustrate the structural and functional differences of chitinase-like family genes and provide potential targets for RNA interference-based rice planthopper management.

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Aging-related bone loss and osteoporosis affect millions of patients worldwide. Chronic inflammation associated with aging and arthritis promotes bone resorption and impairs bone formation. Here we show that Wnt4 attenuated bone loss in osteoporosis and skeletal aging by inhibiting nuclear factor-kappa B (NF-κB) via non-canonical Wnt signaling. Transgenic mice expressing Wnt4 from osteoblasts were significantly protected from bone loss and chronic inflammation induced by ovariectomy, tumor necrosis factor or natural aging. In addition to promoting bone formation, Wnt4 could inhibit osteoclast formation and bone resorption. Mechanistically, Wnt4 inhibited transforming growth factor beta-activated kinase 1-mediated NF-κB activation in macrophages and osteoclast precursors independent of β-catenin. Moreover, recombinant Wnt4 proteins were able to alleviate osteoporotic bone loss and inflammation by inhibiting NF-κB in vivo. Taken together, our results suggest that Wnt4 might be used as a therapeutic agent for treating osteoporosis by attenuating NF-κB.

Abstract. Glioblastoma multiforme (GBM) is one of the most common encephalic malignant tumors. Due to a high recurrence rate and a lack of effective treatments, the average survival rate remains low. Temozolomide (TMZ), a class of alkylating agent, is widely used as a first-line therapeutic drug during the adjuvant treatment for GBM patients. However, most patients exhibit a palpable resistance to TMZ treatment. Additionally, the underlying mechanism remains to be clarified. In this study, glutathione (GSH) and reactive oxygen species (ROS) levels were found to be closely associated with the sensitivity of GBM cells to TMZ. We also found that TMZ markedly induced xCT, the subunit of glutamate/cystine transporter system x c -expression, which together with the GSH synthesis was increased while the TMZ-inducible ROS level was decreased in GBM cells. In addition, the cystathionine γ-lyase (CTH) acivity, a key enzyme in the transsulfuration pathway was enhanced by TMZ, which insured a cysteine supply and GSH synthesis in a compensatory manner when xCT was blocked. Thus, the individual inhibition of xCT by siRNA and a pharmacological inhibitor (sulfasalazine) only partially inhibited GSH synthesis and moderately enhanced the GBM cell sensitivity to TMZ. However, the TMZ-induced cytotoxicity was markedly increased along with a marked decrease in GSH levels as result of co-treatment with erastin, which inhibited cysteine uptake from xCT transporter and suppressed CTH activity, leading to impaired transformation from methionine to cysteine. In conclusion, to GBM therapy with a drug combination of TMZ and erastin may be beneficial.

Aberrant lineage specification of skeletal stem cells (SSCs) contributes to reduced bone mass and increased marrow adipose tissue (MAT) in osteoporosis and skeletal aging. Although master regulators of osteoblastic and adipogenic lineages have been identified, little is known about factors that are associated with MAT accumulation and osteoporotic bone loss. Here, we identify peroxisome-proliferator-activated receptor γ coactivator 1-α (PGC-1α) as a critical switch of cell fate decisions whose expression decreases with aging in human and mouse SSCs. Loss of PGC-1α promoted adipogenic differentiation of murine SSCs at the expense of osteoblastic differentiation. Deletion of PGC-1α in SSCs impaired bone formation and indirectly promoted bone resorption while enhancing MAT accumulation. Conversely, induction of PGC-1α attenuated osteoporotic bone loss and MAT accumulation. Mechanistically, PGC-1α maintains bone and fat balance by inducing TAZ. Our results suggest that PGC-1α is a potentially important therapeutic target in the treatment of osteoporosis and skeletal aging.