Proteolysis-targeting chimera (PROTAC) is a heterobifunctional molecule. Typically, PROTAC consists of two terminals which are the ligand of the protein of interest (POI) and the specific ligand of ...E3 ubiquitin ligase, respectively, via a suitable linker. PROTAC degradation of the target protein is performed through the ubiquitin–proteasome system (UPS). The general process is that PROTAC binds to the target protein and E3 ligase to form a ternary complex and label the target protein with ubiquitination. The ubiquitinated protein is recognized and degraded by the proteasome in the cell. At present, PROTAC, as a new type of drug, has been developed to degrade a variety of cancer target proteins and other disease target proteins, and has shown good curative effects on a variety of diseases. For example, PROTACs targeting AR, BR, BTK, Tau, IRAK4, and other proteins have shown unprecedented clinical efficacy in cancers, neurodegenerative diseases, inflammations, and other fields. Recently, PROTAC has entered a phase of rapid development, opening a new field for biomedical research and development. This paper reviews the various fields of targeted protein degradation by PROTAC in recent years and summarizes and prospects the hot targets and indications of PROTAC.
Polycomb group (PcG) proteins repress master regulators of development and differentiation through organization of chromatin structure. Mutation and dysregulation of PcG genes cause developmental ...defects and cancer. PcG proteins form condensates in the cell nucleus, and these condensates are the physical sites of PcG-targeted gene silencing via formation of facultative heterochromatin. However, the physiochemical principles underlying the formation of PcG condensates remain unknown, and their determination could shed light on how these condensates compact chromatin. Using fluorescence live-cell imaging, we observed that the Polycomb repressive complex 1 (PRC1) protein chromobox 2 (CBX2), a member of the CBX protein family, undergoes phase separation to form condensates and that the CBX2 condensates exhibit liquid-like properties. Using site-directed mutagenesis, we demonstrated that the conserved residues of CBX2 within the intrinsically disordered region (IDR), which is the region for compaction of chromatin in vitro, promote the condensate formation both in vitro and in vivo. We showed that the CBX2 condensates concentrate DNA and nucleosomes. Using genetic engineering, we report that trimethylation of Lys-27 at histone H3 (H3K27me3), a marker of heterochromatin formation produced by PRC2, had minimal effects on the CBX2 condensate formation. We further demonstrated that the CBX2 condensate formation does not require CBX2–PRC1 subunits; however, the condensate formation of CBX2–PRC1 subunits depends on CBX2, suggesting a mechanism underlying the assembly of CBX2–PRC1 condensates. In summary, our results reveal that PcG condensates assemble through liquid–liquid phase separation (LLPS) and suggest that phase-separated condensates can organize PcG-bound chromatin.
MicroRNA 21 (miR-21) has been implicated in various aspects of carcinogenesis. However, its function and molecular mechanism in cervical squamous carcinoma have not been studied. Using TaqMan ...quantitative real-time PCR and Northern blot, we confirmed that miR-21 is significantly overexpressed in human cervical squamous cancer tissues and cell lines. Remarkably, we showed that the level of miR-21 correlates with the tumor differentiation and nodal status by ISH. Furthermore, we demonstrated that miR-21 regulates proliferation, apoptosis, and migration of HPV16-positive cervical squamous cells. In order to identify candidate target genes for miR-21, we used gene expression profiling. By luciferase reporter assays, we confirmed that CCL20 is one of its target genes, which is related to the HPV16 E6 and E7 oncogenes. Our results suggest that miR-21 may be involved in cervical squamous cell tumorigenesis.
► We confirmed the overexpression of miR-21 in human cervical squamous cancer and the level of miR-21 correlating with the nodal status and differentiation. ► We demonstrated that miR-21 may involve in cervical squamous cells proliferation, apoptosis, and migration with HPV16. ► By bioinformatic analysis and luciferase activity assays, we proved that CCL20 contains putative miR-21 binding sites.
Due to the lack of effective treatment, metastasis is the main cause of cancer related deaths. TGF-β pathway has been reported related to cervical cancer metastasis. However, mechanism is still ...unclear.
After agonist of TGF-β treatment, RNA sequencing revealed the expression profiles of circRNA in cervical cancer. In situ hybridization was used to analysis relationship between CDR1as and prognosis. Real-time PCR, Western blot, RNA interference, Transwell assay, Wound healing assay, RNA pulldown assay and RIP assays were performed in vitro. And in vivo cervical cancer model (including foot pad model and subcutaneous tumor formation) was also performed.
CDR1as was found upregulated obviously following TGF-β activation. In situ hybridization showed CDR1as was positively correlated with lymph node metastasis and shortened survival length. Simultaneously, overexpression of CDR1as promoted cervical cancer metastasis in vitro and in vivo. It was also found that CDR1as could facilitate the orchestration of IGF2BP1 on the mRNA of SLUG and stabilize it from degradation. Silencing IGF2BP1 hampers CDR1as related metastasis in cervical cancer. Additionally, effective CDR1as has been proven to activate TGF-β signaling factors known to promote EMT, including P-Smad2 and P-Smad3.
Our study proved TGF-β signaling may promote cervical cancer metastasis via CDR1as.
Abstract
Background
Endometriosis is a common and challenging disease in women of childbearing age with high personal and social costs. Many molecular differences between ectopic and eutopic ...endometrium present difficulties in the development of new drug therapies and therapies. Autophagy is a response to stress and has recently been studied in human cancers. Two important autophagy genes, Beclin-1 and LC3, have been reported in several human cancers. However, the reports of Beclin-1 and LC3 in endometriosis are limited and controversial.
Methods
In this study, we investigated the expression of Beclin-1 and LC3 by Immunohistochemistry.
Results
We found their downregulation in endometriosis. We also found these two autophagy gene expression are negatively correlated with the stage of endometriosis.
Conclusions
Decreased expression of Beclin-1 and LC3 may be related to the occurrence and development of endometriosis.
In this article, a method for design automation high-efficiency power amplifiers (PAs) based on an optimization-oriented is proposed. The advantages of using particle swarm optimization to design PAs ...in electronic design automatic tools are analyzed, and then, simulated annealing is combined to form simulated annealing particle swarm optimization (SA-PSO). In this article, the perfectly inelastic collision used in conventional PSO is replaced by the perfectly elastic collision to improve the searching ability through reducing kinetic energy consumption. A stepped fitness function is defined to avoid the performance pit at a single-frequency point, and the concept "missing and returning" is introduced to solve the nonconvergence problem in simulation. Based on the improved SA-PSO algorithm, a broadband 10 W and a triband 6-W PA are designed. The broadband 10-W PA achieves an average drain efficiency (DE) of 62.5% and an output power of 41.2 dBm in the 0.8-3-GHz frequency band, respectively; the triband 6-W PA achieves an average of 57.4%/47.9%/47.3% DE and 37.7-/38.3-/37.4 dBm output power in 3.35-3.55-/5.75-5.95-/7.65-7.95-GHz frequency bands, respectively, while the gains of most stopbands reach less than 0 dB. With digital predistortion technology, the adjacent channel power ratio (ACPR) can reach less than −45 dBc.
The photoanodes with heterojunction behavior could enable the development of solar energy conversion, but their performance largely suffers from the poor charge separation and transport process ...through the multiple interfacial energy levels involved. The question is how to efficiently manipulate these energy levels. Taking the n-Si Schottky photoanode as a prototype, the undesired donor-like interfacial defects and its adverse effects on charge transfer in n-Si/ITO photoanode are well recognized and diminished through the treatment on electronic energy level. The obtained n-Si/TiO x /ITO Schottky junction exhibits a highly efficient charge transport and a barrier height of 0.95 eV, which is close to the theoretical optimum for n-Si/ITO Schottky contact. Then, the holes extraction can be further facilitated through the variation of surface energy level, with the NiOOH coated ITO layer. This is confirmed by a 115% increase in surface photovoltage of the photoanodes. Eventually, an unprecedentedly low onset potential of 0.9 V (vs RHE) is realized for water oxidation among n-Si photoanodes. For the water oxidation reaction, the n-Si/TiO x /ITO/NiOOH photoanode presents a charge separation efficiency up to 100% and an injection efficiency greater than 90% at a wide voltage range. This work identifies the important role of interfacial energetics played in photoelectrochemical conversion.
Despite significant advances in biological and analytical approaches, a comprehensive portrait of the proteome and its dynamic interactions and modifications remains a challenging goal. Chemical ...proteomics is a growing area of chemical biology that seeks to design small molecule probes to elucidate protein composition, distribution, and relevant physiological and pharmacological functions. Click chemistry focuses on the development of new combinatorial chemical methods for carbon heteroatom bond (C-X-C) synthesis, which have been utilized extensively in the field of chemical proteomics. Click reactions have various advantages including high yield, harmless by-products, and simple reaction conditions, upon which the molecular diversity can be easily and effectively obtained. This paper reviews the application of click chemistry in proteomics from four aspects: (1) activity-based protein profiling, (2) enzyme-inhibitors screening, (3) protein labeling and modifications, and (4) hybrid monolithic column in proteomic analysis.
Solar rechargeable flow cells (SRFCs) provide an attractive approach for in situ capture and storage of intermittent solar energy via photoelectrochemical regeneration of discharged redox species for ...electricity generation. However, overall SFRC performance is restricted by inefficient photoelectrochemical reactions. Here we report an efficient SRFC based on a dual-silicon photoelectrochemical cell and a quinone/bromine redox flow battery for in situ solar energy conversion and storage. Using narrow bandgap silicon for efficient photon collection and fast redox couples for rapid interface charge injection, our device shows an optimal solar-to-chemical conversion efficiency of ∼5.9% and an overall photon-chemical-electricity energy conversion efficiency of ∼3.2%, which, to our knowledge, outperforms previously reported SRFCs. The proposed SRFC can be self-photocharged to 0.8 V and delivers a discharge capacity of 730 mAh l(-1). Our work may guide future designs for highly efficient solar rechargeable devices.
Acting as a cornerstone in conserving biodiversity, protected areas (PAs) have played important roles in protecting the unique flora and fauna in China, yet a variety of issues have arisen, such as ...fragmented management, dispersed spatial pattern, and conflicts with socioeconomic development. To grapple with the problems associated with the current PA system, China is implementing nationwide institutional reforms by proposing a new coherent PA system with national parks as the main body. The reforms provide unprecedented opportunities to integrate the existing disjointed PAs into a unified and efficient system, and to meet international commitments. However, no previous experience is available for how to construct China’s new national park system. We decipher how the institutional reforms would change China’s PA system, and what the reforms can provide for China’s PAs and biodiversity, as well as potential challenges. Importantly, China’s PAs are stepping into a new era for nature conservation, with a strong hope to provide a quality environmental space for the rich and unique biodiversity.
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