Bone metastases occur in 50-70% of patients with late-stage breast cancers and effective therapies are needed. The expression of enhancer of zeste homolog 2 (EZH2) is correlated with breast cancer ...metastasis, but its function in bone metastasis hasn't been well-explored. Here we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGFβ) signaling. EZH2 induces cancer cell proliferation and osteoclast maturation, whereas EZH2 knockdown decreases bone metastasis incidence and outgrowth in vivo. Mechanistically, EZH2 transcriptionally increases ITGB1, which encodes for integrin β1. Integrin β1 activates focal adhesion kinase (FAK), which phosphorylates TGFβ receptor type I (TGFβRI) at tyrosine 182 to enhance its binding to TGFβ receptor type II (TGFβRII), thereby activating TGFβ signaling. Clinically applicable FAK inhibitors but not EZH2 methyltransferase inhibitors effectively inhibit breast cancer bone metastasis in vivo. Overall, we find that the EZH2-integrin β1-FAK axis cooperates with the TGFβ signaling pathway to promote bone metastasis of breast cancer.
Block Partitioning Structure in the VVC Standard Huang, Yu-Wen; An, Jicheng; Huang, Han ...
IEEE transactions on circuits and systems for video technology,
10/2021, Letnik:
31, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Versatile Video Coding (VVC) is the latest video coding standard jointly developed by ITU-T VCEG and ISO/IEC MPEG. In this paper, technical details and experimental results for the VVC block ...partitioning structure are provided. Among all the new technical aspects of VVC, the block partitioning structure is identified as one of the most substantial changes relative to the previous video coding standards and provides the most significant coding gains. The new partitioning structure is designed using a more flexible scheme. Each coding tree unit (CTU) is either treated as one coding unit or split into multiple coding units by one or more recursive quaternary tree partitions followed by one or more recursive multi-type tree splits. The latter can be horizontal binary tree split, vertical binary tree split, horizontal ternary tree split, or vertical ternary tree split. A CTU dual tree for intra-coded slices is described on top of the new block partitioning structure, allowing separate coding trees for luma and chroma. Also, a new way of handling picture boundaries is presented. Additionally, to reduce hardware decoder complexity, virtual pipeline data unit constraints are introduced, which forbid certain multi-type tree splits. Finally, a local dual tree is described, which reduces the number of small chroma intra blocks.
Carbene insertion reactions initiated with diazo compounds have been widely used to develop unnatural enzymatic reactions. However, alternative functionalization of diazo compounds in enzymatic ...processes has been unexploited. Herein, we describe a photoenzymatic strategy for radical‐mediated stereoselective hydroalkylation with diazo compounds. This method generates carbon‐centered radicals through an ene reductase catalyzed photoinduced electron transfer process from diazo compounds, enabling the synthesis of γ‐stereogenic carbonyl compounds in good yields and stereoselectivities. This study further expands the possible reaction patterns in photo‐biocatalysis and offers a new approach to solving the selectivity challenges of radical‐mediated reactions.
A photoenzymatic strategy for radical‐mediated stereoselective hydroalkylation with diazo compounds has been developed. By this method, a series of γ‐chiral carbonyl compounds were synthesized in high yields and stereoselectivities.
Control of translation is a fundamental source of regulation in gene expression. The induction of protein synthesis by brain-derived neurotrophic factor (BDNF) critically contributes to enduring ...modifications of synaptic function, but how BDNF selectively affects only a minority of expressed mRNAs is poorly understood. We report that BDNF rapidly elevates Dicer, increasing mature miRNA levels and inducing RNA processing bodies in neurons. BDNF also rapidly induces Lin28, causing selective loss of Lin28-regulated miRNAs and a corresponding upregulation in translation of their target mRNAs. Binding sites for Lin28-regulated miRNAs are necessary and sufficient to confer BDNF responsiveness to a transcript. Lin28 deficiency, or expression of a Lin28-resistant Let-7 precursor miRNA, inhibits BDNF translation specificity and BDNF-dependent dendrite arborization. Our data establish that specificity in BDNF-regulated translation depends upon a two-part posttranscriptional control of miRNA biogenesis that generally enhances mRNA repression in association with GW182 while selectively derepressing and increasing translation of specific mRNAs.
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► Brain-derived neurotrophic factor (BDNF) increases levels of Dicer and mature miRNAs ► BDNF also induces Lin28 and selective miRNA loss in terminally differentiated neurons ► BDNF-induced dendrite growth requires Lin28-mediated degradation of pre-Let-7 miRNAs ► Regulation of miRNA biogenesis underlies BDNF's target selection in protein synthesis
Brain-derived neurotrophic factor selectively increases the translation of a subset of expressed mRNAs by regulating levels of both Dicer and Lin28 and, in this way, dictating the profile of neuronal miRNAs.
Total Synthesis of (+)‐ and (±)‐Hosieine A Huang, Yu‐Wen; Kong, Ke; Wood, John L.
Angewandte Chemie International Edition,
June 25, 2018, Letnik:
57, Številka:
26
Journal Article
Recenzirano
Described herein is a concise total synthesis of the highly potent nicotinic acetylcholine receptor ligand hosieine A in racemic and enantioenriched forms. The synthesis requires only seven steps and ...features a telescoped reaction sequence initiated by a gold‐catalyzed Rautenstrauch reaction.
A concise total synthesis of the highly potent nicotinic acetylcholine receptor ligand hosieine A in racemic and enantioenriched forms is described. The synthesis requires only seven steps and features a telescoped reaction sequence initiated by a gold‐catalyzed Rautenstrauch reaction.
Previously, the double-diffusive convection (or the DDC) generated through the interaction between horizontal temperature and concentration gradients had been investigated by both experimental and ...computational studies. In the present study, we employ a theoretical approach by performing linear stability analysis to examine the stability characteristics of the DDC under a wide range of physical parameters. Results show that, under the competition between the two gradients, the stability can be discerned into thermal, salt-finger, and diffusive types, where all are influenced by both the Prandtl number Pr and Lewis number Le. The onset of instability can be the stationary shear mode (or the SSM) or the oscillatory buoyant mode (or the OBM), depending on both Pr and Le. Specifically, for the solute Grashof number Gs < 10, the onset of instability changes from SSM to OBM at the transition boundary Pr = 12.5; for the thermal Grashof number Gt < 10, the transition boundary is governed by the relation Pr = 12.5Le−1.11 + 0.46. We compare the present results with those of previous studies to justify the linear stability analysis’s correctness and infer that the DDCs observed by previous experiments and nonlinear computations are nonlinear salt-finger convection.
A carboxylate‐directed palladium‐catalyzed Mizoroki–Heck alkenylation of γ,δ‐unsaturated carboxylic acids with alkenyl bromides is reported. This carboxylate group is effective for chelation to a Pd ...center, enabling the distal alkenylation of electronically unbiased internal alkenes in the formation of conjugated 1,3‐dienes with high stereoselectivity. In addition, the conjugated 1,3‐diene products can be used for synthetic applications through reduction, epoxidation, methylation, amidation, and cycloaddition.
This paper provides an overview of the coding algorithms of the Joint Exploration Model (JEM) for video compression with capability beyond HEVC, which was developed by the Joint Video Exploration ...Team (JVET) of the ITU-T Video Coding Experts Group (VCEG) and the ISO/IEC Moving Picture Experts Group (MPEG). The goal of the JEM development and experimentation was to provide evidence that sufficient coding efficiency improvement over the High Efficiency Video Coding (HEVC) standard can be achieved, which would justify the need for a new video coding standard with a compression capability significantly exceeding that of HEVC. The development of the JEM provided an ability to conduct studies toward that goal in a verifiable and collaborative manner and led to the launching of the project to develop the new Versatile Video Coding (VVC) standard. Objective metric gains exceeding 30% were measured for most of the tested high-resolution video content that represents current demanding new applications, and subjective testing using human observers showed even more benefit.
Chitinase‐3‐like protein 1 (CHI3L1/YKL‐40) has long been known as a biomarker for early detection of neuroinflammation and disease diagnosis of Alzheimer's disease (AD). In the brain, CHI3L1 is ...primarily provided by astrocytes and heralds the reactive, neurotoxic state triggered by inflammation and other stress signals. However, how CHI3L1 acts in neuroinflammation or how it contributes to AD and relevant neurodegenerative conditions remains unknown. In peripheral tissues, our group and others have uncovered that CHI3L1 is a master regulator for a wide range of injury and repair events, including the innate immunity pathway that resembles the neuroinflammation process governed by microglia and astrocytes. Based on assessment of current knowledge regarding CHI3L1 biology, we hypothesize that CHI3L1 functions as a signaling molecule mediating distinct neuroinflammatory responses in brain cells and misfunctions to precipitate neurodegeneration. We also recommend future research directions to validate such assertions for better understanding of disease mechanisms.
In blood, apolipoprotein E (ApoE) is a component of circulating lipoproteins and mediates the clearance of these lipoproteins from blood by binding to ApoE receptors. Humans express three genetic ...ApoE variants, ApoE2, ApoE3, and ApoE4, which exhibit distinct ApoE receptor-binding properties and differentially affect Alzheimer's disease (AD), such that ApoE2 protects against, and ApoE4 predisposes to AD. In brain, ApoE-containing lipoproteins are secreted by activated astrocytes and microglia, but their functions and role in AD pathogenesis are largely unknown. Ample evidence suggests that ApoE4 induces microglial dysregulation and impedes Aβ clearance in AD, but the direct neuronal effects of ApoE variants are poorly studied. Extending previous studies, we here demonstrate that the three ApoE variants differentially activate multiple neuronal signaling pathways and regulate synaptogenesis. Specifically, using human neurons (male embryonic stem cell-derived) cultured in the absence of glia to exclude indirect glial mechanisms, we show that ApoE broadly stimulates signal transduction cascades. Among others, such stimulation enhances APP synthesis and synapse formation with an ApoE4>ApoE3>ApoE2 potency rank order, paralleling the relative risk for AD conferred by these ApoE variants. Unlike the previously described induction of
transcription, however, ApoE-induced synaptogenesis involves CREB activation rather than cFos activation. We thus propose that in brain, ApoE acts as a glia-secreted signal that activates neuronal signaling pathways. The parallel potency rank order of ApoE4>ApoE3>ApoE2 in AD risk and neuronal signaling suggests that ApoE4 may in an apparent paradox promote AD pathogenesis by causing a chronic increase in signaling, possibly via enhancing APP expression.
Humans express three genetic variants of apolipoprotein E (ApoE), ApoE2, ApoE3, and ApoE4. ApoE4 constitutes the most important genetic risk factor for Alzheimer's disease (AD), whereas ApoE2 protects against AD. Significant evidence suggests that ApoE4 impairs microglial function and impedes astrocytic Aβ clearance in brain, but the direct neuronal effects of ApoE are poorly understood, and the differences between ApoE variants in these effects are unclear. Here, we report that ApoE acts on neurons as a glia-secreted signaling molecule that, among others, enhances synapse formation. In activating neuronal signaling, the three ApoE variants exhibit a differential potency of ApoE4>ApoE3>ApoE2, which mirrors their relative effects on AD risk, suggesting that differential signaling by ApoE variants may contribute to AD pathogenesis.
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