An unprecedented rhodium(III)‐catalyzed hydroarylation of α,α‐difluoromethylene alkynes with N‐pivaloxyl aroylamides through sequential C−H activation and aryl migration is detailed herein. A large ...array of α,α‐difluoromethylene alkynes and N‐pivaloxyl aryl amides were amenable to this transformation, thus providing a novel synthetic protocol for the construction of difluorinated 2‐alkenyl aniline derivatives in high yields and with excellent regioselectivity. Notably, unique fluorine effects were found to underlie the thus unconventional reaction manifold.
Exploring new avenues: Rhodium(III)‐catalyzed hydroarylation of α,α‐difluoromethylene alkynes with N‐pivaloyloxy aryl amides enabled the efficient regiospecific synthesis of difluorinated 2‐alkenyl aniline derivatives (see scheme). The fluorine substituents in the alkyne substrates diverted the course of the reaction from the conventional annulation pathway to promote the hydroarylation process involving Lossen rearrangement.
Abiotic stresses, such as low or high temperature, deficient or excessive water, high salinity, heavy metals, and ultraviolet radiation, are hostile to plant growth and development, leading to great ...crop yield penalty worldwide. It is getting imperative to equip crops with multistress tolerance to relieve the pressure of environmental changes and to meet the demand of population growth, as different abiotic stresses usually arise together in the field. The feasibility is raised as land plants actually have established more generalized defenses against abiotic stresses, including the cuticle outside plants, together with unsaturated fatty acids, reactive species scavengers, molecular chaperones, and compatible solutes inside cells. In stress response, they are orchestrated by a complex regulatory network involving upstream signaling molecules including stress hormones, reactive oxygen species, gasotransmitters, polyamines, phytochromes, and calcium, as well as downstream gene regulation factors, particularly transcription factors. In this review, we aimed at presenting an overview of these defensive systems and the regulatory network, with an eye to their practical potential via genetic engineering and/or exogenous application.
Lipid nanoparticles (LNPs) are a clinically mature technology for the delivery of genetic medicines but have limited therapeutic applications due to liver accumulation. Recently, our laboratory ...developed selective organ targeting (SORT) nanoparticles that expand the therapeutic applications of genetic medicines by enabling delivery of messenger RNA (mRNA) and gene editing systems to non-liver tissues. SORT nanoparticles include a supplemental SORT molecule whose chemical structure determines the LNP's tissue-specific activity. To understand how SORT nanoparticles surpass the delivery barrier of liver hepatocyte accumulation, we studied the mechanistic factors which define their organ-targeting properties. We discovered that the chemical nature of the added SORT molecule controlled biodistribution, global/apparent pK
, and serum protein interactions of SORT nanoparticles. Additionally, we provide evidence for an endogenous targeting mechanism whereby organ targeting occurs via 1) desorption of poly(ethylene glycol) lipids from the LNP surface, 2) binding of distinct proteins to the nanoparticle surface because of recognition of exposed SORT molecules, and 3) subsequent interactions between surface-bound proteins and cognate receptors highly expressed in specific tissues. These findings establish a crucial link between the molecular composition of SORT nanoparticles and their unique and precise organ-targeting properties and suggest that the recruitment of specific proteins to a nanoparticle's surface can enable drug delivery beyond the liver.
We examine whether internal governance affects the extent of real earnings management in U.S. corporations. Internal governance refers to the process through which key subordinate executives provide ...checks and balances in the organization and affect corporate decisions. Using the number of years to retirement to capture key subordinate executives' horizon incentives and using their compensation relative to CEO compensation to capture their influence within the firm, we find that the extent of real earnings management decreases with key subordinate executives' horizon and influence. The results are robust to alternative measures of internal governance and to various approaches used to address potential endogeneity, including a difference-in-differences approach. In cross-sectional analyses, we find that the effect of internal governance is stronger for firms with more complex operations where key subordinate executives' contribution is higher, is enhanced when CEOs are less powerful, is weaker when the capital markets benefit of meeting or beating earnings benchmarks is higher, and is stronger in the post-SOX period. This paper contributes to the literature by examining how internal governance affects the extent of real earnings management and by shedding light on how the members of the management team work together in shaping financial reporting quality.
Family firm research——A review Cheng, Qiang
China journal of accounting research,
09/2014, Volume:
7, Issue:
3
Journal Article
Peer reviewed
Open access
This article reviews family firm studies in the finance and accounting literature,primarily those conducted using data from the United States and China. Family owners have unique features such as ...concentrated ownership, long investment horizon, and reputation concerns. Given the distinguishing features of family ownership and control, family firms face unique agency conflicts. We discuss the agency problems in family firms and review the findings of recent family firm studies. We call for more research to understand the unique family effects and encourage more research on Chinese family firms.Part I of the article discusses the fundaments of family firms: the prevalence of and the agency conflicts within family firms. Part II summarizes the findings of recent U.S. family firm studies. It reviews the evidence on the family firm premium(how, which, and when family firms are associated with a valuation premium), the manifestation of the agency conflict between majority and minority shareholders in family firms, earnings quality and corporate disclosure, and the determinants of family ownership and control. Part III discusses the prevalence and characteristics of Chinese family firms and reviews the findings of related studies. The article concludes with some suggestions for future research.
For viral diseases, vaccination with live attenuated vaccine (LAV) is one of the most effective means for fighting the diseases. However, LAV occasionally overflows from vaccinated individuals ...circulate in the population with unforeseen consequences. Currently, SARS-CoV-2 LAVs are undergoing clinical trials. In this study, we found that the viruses isolated from Indian SARS CoV-2 infected persons may be candidate LAV-derived strains, indicating the risk of SARS-CoV-2 LAV spillover from vaccinated persons, increasing the complexity of SARS-CoV-2 detection. In addition, the property of frequent recombination of SARS-CoV-2 increases the chance of LAV virulence reversion. Therefore, how to distinguish the LAV viruses from the wild strain and how to avoid the recombination of the circulating vaccine strain and the wild strain are the challenges currently faced by SARS CoV-2 LAV development.
CRISPR-Cas9 has emerged as a powerful technology that relies on Cas9/sgRNA ribonucleoprotein complexes (RNPs) to target and edit DNA. However, many therapeutic targets cannot currently be accessed ...due to the lack of carriers that can deliver RNPs systemically. Here, we report a generalizable methodology that allows engineering of modified lipid nanoparticles to efficiently deliver RNPs into cells and edit tissues including muscle, brain, liver, and lungs. Intravenous injection facilitated tissue-specific, multiplexed editing of six genes in mouse lungs. High carrier potency was leveraged to create organ-specific cancer models in livers and lungs of mice though facile knockout of multiple genes. The developed carriers were also able to deliver RNPs to restore dystrophin expression in DMD mice and significantly decrease serum PCSK9 level in C57BL/6 mice. Application of this generalizable strategy will facilitate broad nanoparticle development for a variety of disease targets amenable to protein delivery and precise gene correction approaches.
CRISPR-Cas gene editing and messenger RNA-based protein replacement therapy hold tremendous potential to effectively treat disease-causing mutations with diverse cellular origin. However, it is ...currently impossible to rationally design nanoparticles that selectively target specific tissues. Here, we report a strategy termed selective organ targeting (SORT) wherein multiple classes of lipid nanoparticles are systematically engineered to exclusively edit extrahepatic tissues via addition of a supplemental SORT molecule. Lung-, spleen- and liver-targeted SORT lipid nanoparticles were designed to selectively edit therapeutically relevant cell types including epithelial cells, endothelial cells, B cells, T cells and hepatocytes. SORT is compatible with multiple gene editing techniques, including mRNA, Cas9 mRNA/single guide RNA and Cas9 ribonucleoprotein complexes, and is envisioned to aid the development of protein replacement and gene correction therapeutics in targeted tissues.
•A graph learning framework, which captures both the global and local structure in data, is proposed.•Theoretical analysis builds the connections of our model to k-means, spectral clustering, and ...kernel k-means.•Extensions to semi-supervised classification and multiple kernel learning are presented.
Graphs have become increasingly popular in modeling structures and interactions in a wide variety of problems during the last decade. Graph-based clustering and semi-supervised classification techniques have shown impressive performance. This paper proposes a graph learning framework to preserve both the local and global structure of data. Specifically, our method uses the self-expressiveness of samples to capture the global structure and adaptive neighbor approach to respect the local structure. Furthermore, most existing graph-based methods conduct clustering and semi-supervised classification on the graph learned from the original data matrix, which doesn’t have explicit cluster structure, thus they might not achieve the optimal performance. By considering rank constraint, the achieved graph will have exactly c connected components if there are c clusters or classes. As a byproduct of this, graph learning and label inference are jointly and iteratively implemented in a principled way. Theoretically, we show that our model is equivalent to a combination of kernel k-means and k-means methods under certain condition. Extensive experiments on clustering and semi-supervised classification demonstrate that the proposed method outperforms other state-of-the-art methods.
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