Leisure Preference and Corporate Tax Planning

Using a novel cross-country measure of leisure preference to quantify managerial effort aversion, we examine its relation to corporate tax avoidance, and document a negative association between the two. The result is stronger for firms located in countries with a more complex tax system, and for firms with less access to tax consulting services — situations in which corporate tax planning can be especially onerous. Finally, tax planning appears to be one mechanism mediating the negative relation between leisure preference and firm value, implying that effort aversion is a source of agency costs that impedes value-enhancing tax planning activities

Impact of histone H4 lysine 20 methylation on 53BP1 responses to chromosomal double strand breaks.

Recruitment of 53BP1 to chromatin flanking double strand breaks (DSBs) requires γH2AX/MDC1/RNF8-dependent ubiquitination of chromatin and interaction of 53BP1 with histone H4 methylated on lysine 20 (H4K20me). Several histone methyltransferases have been implicated in 53BP1 recruitment, but their quantitative contributions to the 53BP1 response are unclear. We have developed a multi-photon laser (MPL) system to target DSBs to subfemtoliter nuclear volumes and used this to mathematically model DSB response kinetics of MDC1 and of 53BP1. In contrast to MDC1, which revealed first order kinetics, the 53BP1 MPL-DSB response is best fitted by a Gompertz growth function. The 53BP1 MPL response shows the expected dependency on MDC1 and RNF8. We determined the impact of altered H4K20 methylation on 53BP1 MPL response kinetics in mouse embryonic fibroblasts (MEFs) lacking key H4K20 histone methyltransferases. This revealed no major requirement for the known H4K20 dimethylases Suv4-20h1 and Suv4-20h2 in 53BP1 recruitment or DSB repair function, but a key role for the H4K20 monomethylase, PR-SET7. The histone methyltransferase MMSET/WHSC1 has recently been implicated in 53BP1 DSB recruitment. We found that WHSC1 homozygous mutant MEFs reveal an alteration in balance of H4K20 methylation patterns; however, 53BP1 DSB responses in these cells appear normal

Prion-like proteins sequester and suppress the toxicity of huntingtin exon 1

Expansions of preexisting polyglutamine (polyQ) tracts in at least nine different proteins cause devastating neurodegenerative diseases. There are many unique features to these pathologies, but there must also be unifying mechanisms underlying polyQ toxicity. Using a polyQ-expanded fragment of huntingtin exon-1 (Htt103Q), the causal protein in Huntington disease, we and others have created tractable models for investigating polyQ toxicity in yeast cells. These models recapitulate key pathological features of human diseases and provide access to an unrivalled genetic toolbox. To identify toxicity modifiers, we performed an unbiased overexpression screen of virtually every protein encoded by the yeast genome. Surprisingly, there was no overlap between our modifiers and those from a conceptually identical screen reported recently, a discrepancy we attribute to an artifact of their overexpression plasmid. The suppressors of Htt103Q toxicity recovered in our screen were strongly enriched for glutamine- and asparagine-rich prion-like proteins. Separated from the rest of the protein, the prion-like sequences of these proteins were themselves potent suppressors of polyQ-expanded huntingtin exon-1 toxicity, in both yeast and human cells. Replacing the glutamines in these sequences with asparagines abolished suppression and converted them to enhancers of toxicity. Replacing asparagines with glutamines created stronger suppressors. The suppressors (but not the enhancers) coaggregated with Htt103Q, forming large foci at the insoluble protein deposit in which proteins were highly immobile. Cells possessing foci had fewer (if any) small diffusible oligomers of Htt103Q. Until such foci were lost, cells were protected from death. We discuss the therapeutic implications of these findings.Howard Hughes Medical InstituteNational Institutes of Health (U.S.) (Grant GM25874)National Science Foundation (U.S.). Graduate Research Fellowship Program (Grant 1122374)G. Harold and Leila Y. Mathers FoundationBeckman Laser Institute FoundationEleanor Schwartz Charitable FoundationWhitehead Institute for Biomedical Researc

High-Affinity Accumulation of a Maytansinoid in Cells via Weak Tubulin Interaction

The microtubule-targeting maytansinoids accumulate in cells and induce mitotic arrest at 250- to 1000-fold lower concentrations than those required for their association with tubulin or microtubules. To identify the mechanisms of this intracellular accumulation and exceptional cytotoxicity of maytansinoids we studied interaction of a highly cytotoxic maytansinoid, S-methyl DM1 and several other maytansinoids with cells. S-methyl DM1 accumulated inside the cells with a markedly higher apparent affinity than to tubulin or microtubules. The apparent affinities of maytansinoids correlated with their cytotoxicities. The number of intracellular binding sites for S-methyl DM1 in MCF7 cells was comparable to the number of tubulin molecules per cell (~ 4–6 × 107 copies). Efflux of 3 [H]-S-methyl DM1 from cells was enhanced in the presence of an excess of non-labeled S-methyl DM1, indicating that re-binding of 3 [H]-S-methyl DM1 to intracellular binding sites contributed to its intracellular retention. Liposomes loaded with non-polymerized tubulin recapitulated the apparent high-affinity association of S-methyl DM1 to cells. We propose a model for the intracellular accumulation of maytansinoids in which molecules of the compounds diffuse into a cell and associate with tubulin. Affinities of maytansinoids for individual tubulin molecules are weak, but the high intracellular concentration of tubulin favors, after dissociation of a compound-tubulin complex, their re-binding to a tubulin molecule, or to a tip of a microtubule in the same cell, over their efflux. As a result, a significant fraction of microtubule tips is occupied with a maytansinoid when added to cells at sub-nanomolar concentrations, inducing mitotic arrest and cell death

Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma.

Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively

LRF maintains genome integrity by regulating the non-homologous end joining pathway of DNA repair

Leukemia/lymphoma-related factor (LRF) is a POZ/BTB and Krüppel (POK) transcriptional repressor characterized by context-dependent key roles in cell fate decision and tumorigenesis. Here we demonstrate an unexpected transcription-independent function for LRF in the classical non-homologous end joining (cNHEJ) pathway of double-strand break (DSB) repair. We find that LRF loss in cell lines and mouse tissues results in defective cNHEJ, genomic instability and hypersensitivity to ionizing radiation. Mechanistically, we show that LRF binds and stabilizes DNA-PKcs on DSBs, in turn favouring DNA-PK activity. Importantly, LRF loss restores ionizing radiation sensitivity to p53 null cells, making LRF an attractive biomarker to direct p53-null LRF-deficient tumours towards therapeutic treatments based on genotoxic agents or PARP inhibitors following a synthetic lethal strategy

Supporting Speaking Practice by Social Network-Based Interaction in Artificial Intelligence (AI)-Assisted Language Learning

In recent decades, the rapid development of artificial intelligence (AI) technology has led to the increasing use of AI speaking apps in foreign language learning. This research investigates the impact of social network-based interaction on students’ English speaking practice with the assistance of AI speaking apps in China. During the summer vacation, 70 students from different Chinese universities and majors were recruited for the experiment. They were required to practice speaking skills with AI apps for five weeks and were divided into two groups. Participants in the experimental group were encouraged to engage in various interactive activities when practicing speaking with AI apps, while those in the control group were asked to use AI speaking apps without interaction. Data were collected through questionnaires and semi-structured interviews as well as pre-and post-tests. The results indicated that students generally held positive attitudes towards interactive activities when using AI apps to practice their spoken English. The finding also showed that social network-based interaction can effectively improve learners’ speaking skills in the AI context. This study contributes to the research on the implementation and promotion of AI speaking apps with social networking and extends the previous studies on network-based interaction to the AI-assisted learning environment. An investigation of interactions based on Chinese social network-based platforms such as WeChat can be further applied to other social networking platforms such as Facebook or WhatsApp in different cultural contexts for AI-assisted speaking practice

Supporting Speaking Practice by Social Network-Based Interaction in Artificial Intelligence (AI)-Assisted Language Learning

In recent decades, the rapid development of artificial intelligence (AI) technology has led to the increasing use of AI speaking apps in foreign language learning. This research investigates the impact of social network-based interaction on students’ English speaking practice with the assistance of AI speaking apps in China. During the summer vacation, 70 students from different Chinese universities and majors were recruited for the experiment. They were required to practice speaking skills with AI apps for five weeks and were divided into two groups. Participants in the experimental group were encouraged to engage in various interactive activities when practicing speaking with AI apps, while those in the control group were asked to use AI speaking apps without interaction. Data were collected through questionnaires and semi-structured interviews as well as pre-and post-tests. The results indicated that students generally held positive attitudes towards interactive activities when using AI apps to practice their spoken English. The finding also showed that social network-based interaction can effectively improve learners’ speaking skills in the AI context. This study contributes to the research on the implementation and promotion of AI speaking apps with social networking and extends the previous studies on network-based interaction to the AI-assisted learning environment. An investigation of interactions based on Chinese social network-based platforms such as WeChat can be further applied to other social networking platforms such as Facebook or WhatsApp in different cultural contexts for AI-assisted speaking practice

Superoxide Dismutase, BDNF, and Cognitive Improvement in Drug-Naive First-Episode Patients With Schizophrenia: A 12-Week Longitudinal Study

Objective Cognitive improvement after antipsychotic agents in patients with schizophrenia (SCZ) appears to involve redox regulation through neurotrophins such as brain derived neurotropic factor (BDNF). This study examined whether cognitive improvement was associated with the increase in superoxide dismutase (SOD) and whether higher levels of BDNF could have a permissive role in allowing SOD to improve cognition. Methods We examined this hypothesis in 183 drug-naive first-episode SCZ patients taking risperidone monotherapy for 12 weeks. We measured total copper-zinc SOD (CuZn-SOD), manganese SOD (Mn-SOD), and SOD activities and BDNF levels in these patients and compared their levels with 152 healthy controls. We assessed cognitive functioning and clinical symptoms at baseline and 12-week follow-up. Results After treatment with risperidone, CuZn-SOD activity was significantly increased, and BDNF levels were slightly increased. Increased CuZn-SOD activity was associated with the cognitive effectiveness of risperidone monotherapy. The BDNF levels and SOD activities were correlated at baseline but not after 12-week treatment. Furthermore, baseline CuZn-SOD activity positively correlated with improvement on the delayed memory subscale of the Repeatable Battery for the Assessment of Neuropsychological Status only in the high BDNF subgroup. Conclusions Our longitudinal study suggests that risperidone can enhance SOD activity and that, in combination with higher baseline BDNF levels acting in a permissive role, can improve cognitive impairments in SCZ. Greater baseline CuZn-SOD activity also may have predictive value for cognitive improvement of delayed memory in SCZ patients receiving risperidone treatment.</p