Publications by authors named "Jianjun Chen"

573 Publications

Efficient Synthesis and Bioevaluation of Novel Dual Tubulin/Histone Deacetylase 3 Inhibitors as Potential Anticancer Agents.

J Med Chem 2021 Jun 7. Epub 2021 Jun 7.

School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.

Novel dual HDAC3/tubulin inhibitors were designed and efficiently synthesized by combining the pharmacophores of SMART (tubulin inhibitor) and MS-275 (HDAC inhibitor), among which compound was found to be the most potent and balanced HDAC3/tubulin dual inhibitor with high HDAC3 activity (IC = 30 nM) and selectivity (SI > 1000) as well as excellent antiproliferative potency against various cancer cell lines, including an HDAC-resistant gastric cancer cell line (YCC3/7) with IC values in the range of 30-144 nM. Compound inhibited B16-F10 cancer cell migration and colony formation. In addition, demonstrated significant antitumor efficacy in a B16-F10 melanoma tumor model with a better TGI (70.00%, 10 mg/kg) than that of the combination of MS-275 and SMART. Finally, presented a safe cardiotoxicity profile and did not cause nephro-/hepatotoxicity. Collectively, this work shows that compound represents a novel tubulin/HDAC3 dual-targeting agent deserving further investigation as a potential anticancer agent.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00413DOI Listing
June 2021

Floating chitosan-alginate microspheres loaded with chlorantraniliprole effectively control Chilo suppressalis (Walker) and Sesamia inferens (Walker) in rice fields.

Sci Total Environ 2021 Aug 14;783:147088. Epub 2021 Apr 14.

Key Laboratory of Natural Pesticide & Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou 510642, China. Electronic address:

Striped rice stem borer, Chilo suppressalis (Walker) and pink stem borer, Sesamia inferens (Walker) are two important pests, causing substantial yield loss in rice production. Application of conventional synthetic pesticides, such as suspension concentrates and water-dispersible granules, is a primary method for control of the two pests. Due to the flow of water in rice field, spray drift, and soil adsorption, applied such pesticides are often out of the target, resulting in low control efficacy, potential contamination of soil or surface water, and also threat to human health. Thus, there is an urgent need for developing environmentally friendly and highly targeted pesticide formulations to meet the challenges. The present study synthesized chlorantraniliprole loaded chitosan-alginate floating hydrogel microspheres (CCAM) through physical embedding, ionic crosslinking, and incorporation of citronellol as an oil phase. The morphology, particle size, entrapment efficiency, loading capacity, in vitro slow-release kinetics, and floating ability of the CCAM were tested in laboratory conditions. The CCAM and two commercial formulations (suspended and granulated) of chlorantraniliprole were respectively evaluated in two rice fields located in two provinces of China. The CCAM was able to float on the surface of rice field, gather around rice stems, and slowly release chlorantraniliprole, which resulted in significantly higher concentrations of chlorantraniliprole in rice stems and leaves for a prolonged time than suspended and granulated controls. The application of CCAM provided an on-target control of both striped stem borer and pink stem borer. Furthermore, CCAM application had very low residue of chlorantraniliprole in soils. As far as is known, this is the first report of chlorantraniliprole loaded on chitosan-alginate floating hydrogel microspheres for rice stem borer control. Our results indicate that the synthesized CCAM could potentially be used as a controlled-release product for effective control of the two rice pests, while reducing the residual chlorantraniliprole in the soil and avoiding pesticide drift.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147088DOI Listing
August 2021

Application of Trehalose and Salicylic Acid Mitigates Drought Stress in Sweet Basil and Improves Plant Growth.

Plants (Basel) 2021 May 27;10(6). Epub 2021 May 27.

Laboratory of Extremophile Plants, Centre of Biotechnology of Borj-Cedria, P.O. Box 901, Hammam-Lif 2050, Tunisia.

Trehalose (Tre) and salicylic acid (SA) are increasingly used to mitigate drought stress in crop plants. In this study, a pot experiment was performed to study the influence of Tre and SA applied individually or in combination on the growth, photosynthesis, and antioxidant responses of sweet basil ( L.) exposed to drought stress. Basil plants were watered to 60% or 100% field capacity with or without treatment with 30 mM Tre and/or 1 mM SA. Drought negatively affected growth, physiological parameters, and antioxidant responses. Application of Tre and/or SA resulted in growth recovery, increased photosynthesis, and reduced oxidative stress. Application of Tre mitigated the detrimental effects of drought more than SA. Furthermore, co-application of Tre and SA largely eliminated the negative impact of drought by reducing oxidative stress through increased activities of antioxidant enzymes superoxide dismutase, peroxidase, and catalase, as well as the accumulation of the protective osmolytes proline and glycine betaine. Combined Tre and SA application improved water use efficiency and reduced the amount of malondialdehyde in drought-stressed plants. Our results suggested that combined application of Tre and SA may trigger defense mechanisms of sweet basil to better mitigate oxidative stress induced by drought stress, thereby improving plant growth.
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http://dx.doi.org/10.3390/plants10061078DOI Listing
May 2021

A Novel BLOC1S5-Related HPS-11 Patient and Zebrafish with bloc1s5 Disruption.

Pigment Cell Melanoma Res 2021 May 31. Epub 2021 May 31.

Translation research institute of brain and brain-like intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.

HPS (Hermansky-Pudlak Syndrome) cases present with a variable degree of OCA and bleeding tendency. HPS is categorized into eleven types based on eleven causative genes and disease severity varies among different types. By whole exome sequencing performed on a family trio and Sanger sequencing of candidate variants, we identified a novel homozygous variant (NM_201280.3: c.181delC, p.Val61*) in BLOC1S5 in the patient who presents OCA and mild bleeding diathesis, and his healthy parents are heterozygous carriers. The variant can be considered pathogenic based on the guideline American College of Medical Genetics and Genomics and the patient is proposed to be affected with HPS-11. In this study, we also explored bloc1s5 in zebrafish. bloc1s5 mRNA can be detected during early development of zebrafish. bloc1s5 knockdown zebrafish present with retinal hypopigmentation, thrombocytes loss and pericardial oedema, and dll4/notch1 signaling and vascular integrity signaling are downregulated at mRNA level in bloc1s5 morphants. The data from the first HPS-11 patient in Chinese population expands phenotypic and genotypic spectrum of HPS-11. Disruption of bloc1s5 in zebrafish recapitulates HPS-11-like phenotypes and the potential signaling pathways associated with bloc1s5 are proposed. Altogether, this study may facilitate genetic counseling of HPS and investigation about BLOC1S5.
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http://dx.doi.org/10.1111/pcmr.12995DOI Listing
May 2021

Transformation of Long-Lived Albino 'Golden Pothos' and Restoring Chloroplast Development.

Front Plant Sci 2021 12;12:647507. Epub 2021 May 12.

Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC, United States.

Chloroplasts are organelles responsible for chlorophyll biosynthesis, photosynthesis, and biosynthesis of many metabolites, which are one of key targets for crop improvement. Elucidating and engineering genes involved in chloroplast development are important approaches for studying chloroplast functions as well as developing new crops. In this study, we report a long-lived albino mutant derived from a popular ornamental plant 'Golden Pothos' which could be used as a model for analyzing the function of genes involved in chloroplast development and generating colorful plants. Albino mutant plants were isolated from regenerated populations of variegated 'Golden Pothos' whose albino phenotype was previously found to be due to impaired expression of , encoding Mg-protoporphyrin IX monomethyl ester cyclase. Using petioles of the mutant plants as explants with a traceable gene, an efficient transformation system was developed. Expressing Arabidopsis (a homolog of ) but not in albino plants restored green color and chloroplast development. Interestingly, in addition to the occurrence of plants with solid green color, plants with variegated leaves and pale-yellow leaves were also obtained in the regenerated populations. Nevertheless, our study shows that these long-lived albino plants along with the established efficient transformation system could be used for creating colorful ornamental plants. This system could also potentially be used for investigating physiological processes associated with chlorophyll levels and chloroplast development as well as certain biological activities, which are difficult to achieve using green plants.
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http://dx.doi.org/10.3389/fpls.2021.647507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149757PMC
May 2021

Role of P2X7R in eosinophilic and non‑eosinophilic chronic rhinosinusitis with nasal polyps.

Mol Med Rep 2021 Jul 26;24(1). Epub 2021 May 26.

Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammation‑mediated disease of the nasal mucosa. P2X7R has been reported to be a potential biomarker for inflammation. The aim of the present study was to explore the role of P2X7R in CRSwNP, and the interaction between P2X7R and the NLRP3 inflammasome in the development of CRSwNP. Firstly, the expression profiles of P2X7R in nasal mucosa were investigated using western blotting (WB), polymerase chain reaction (PCR) and immunofluorescence (IF) staining. Next, the effect of inflammatory stimulation with lipopolysaccharides (LPS) combined with 2'(3')‑O‑(4‑benzoylbenzoyl) adenosine 5'‑triphosphate triethylammonium salt (BzATP) on primary human nasal epithelial cells (HNECs) was determined. Then, the therapeutic effect of the selective P2X7R antagonist, A740003, on P3X7R, NOD‑like receptor pyrin domain containing 3 (NLRP3) inflammasome and IL‑1β alterations in HNECs was explored using enzyme‑linked immunosorbent assay, WB and PCR. It was found that P2X7R was overexpressed in CRSwNP, especially in eosinophilic CRSwNP, the expression of P2X7R, NLRP3 and IL‑1β were upregulated in HNECs after induction by LPS combined with BzATP; but the expression of NLRP3 and IL‑1β were downregulated after stimulation with A740003. The aforementioned results indicate that P2X7R‑mediated NLRP3 inflammasome activation may have a role in the pathogenesis of CRSwNP.
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http://dx.doi.org/10.3892/mmr.2021.12160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160476PMC
July 2021

Transcriptome Analyses Implicate Endogenous Retroviruses Involved in the Host Antiviral Immune System through the Interferon Pathway.

Virol Sin 2021 May 19. Epub 2021 May 19.

CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.

Human endogenous retroviruses (HERVs) are the remains of ancient retroviruses that invaded our ancestors' germline cell and were integrated into the genome. The expression of HERVs has always been a cause for concern because of its association with various cancers and diseases. However, few previous studies have focused on specific activation of HERVs by viral infections. Our previous study has shown that dengue virus type 2 (DENV-2) infection induces the transcription of a large number of abnormal HERVs loci; therefore, the purpose of this study was to explore the relationship between exogenous viral infection and HERV activation further. In this study, we retrieved and reanalyzed published data on 21 transcriptomes of human cells infected with various viruses. We found that infection with different viruses could induce transcriptional activation of HERV loci. Through the comparative analysis of all viral datasets, we identified 43 key HERV loci that were up-regulated by DENV-2, influenza A virus, influenza B virus, Zika virus, measles virus, and West Nile virus infections. Furthermore, the neighboring genes of these HERVs were simultaneously up-regulated, and almost all such neighboring genes were interferon-stimulated genes (ISGs), which are enriched in the host's antiviral immune response pathways. Our data supported the hypothesis that activation of HERVs, probably via an interferon-mediated mechanism, plays an important role in innate immunity against viral infections.
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http://dx.doi.org/10.1007/s12250-021-00370-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131884PMC
May 2021

Nano-assembly of ursolic acid with platinum prodrug overcomes multiple deactivation pathways in platinum-resistant ovarian cancer.

Biomater Sci 2021 Jun;9(11):4110-4119

Department of Pharmacy, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan 528300, P. R. China. and A School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, P. R. China.

As the most common cause of gynecological cancer-related deaths worldwide, ovarian cancer requires novel therapy strategies. Pt(ii)-Based antitumor drugs (e.g. cisplatin) are one of the most successful and frequently used drugs in ovarian cancer chemotherapy at present. However, drug resistance and severe side effects are the major problems in cancer treatment. Herein, the design of a reduction responsive platinum(iv) (Pt(iv))/ursolic acid (UA)/polyethylene glycol (PEG) dual prodrug amphiphile (Pt(iv)-UA-PEG) to treat cisplatin-resistant ovarian cancer is reported for the first time. Pt(iv)-UA-PEG could self-assemble into nanoparticles (Pt(iv)-UA NPs) with a fixed and precise Pt/UA ratio, and a constantly high content of drugs. Pt(iv)-UA NPs could be efficiently taken up by cisplatin-resistant ovarian cancer cells and release the drug in intracellular reductive and acidic environments. In vitro studies show that the released UA and cisplatin have different anticancer mechanisms, and their synergistic effects overcome the detoxification and anti-apoptotic mechanisms of cancer cells. Furthermore, the in vivo results indicate that Pt(iv)-UA NPs have a prolonged blood circulation time, enhanced tumor accumulation, and significantly improved antitumor efficacy in A2780/DDP tumor-bearing mice, without causing any side effects. In summary, our results demonstrate that the development of the stimuli-responsive dual prodrug amphiphile nano-assembly provides a new strategy to overcome drug resistance.
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http://dx.doi.org/10.1039/d1bm00087jDOI Listing
June 2021

Discovery of novel 3-hydroxyandrosta-5,7-Diene-17-Carboxylic acid derivatives as anti-inflammatory bowel diseases (IBD) agents.

Eur J Med Chem 2021 Aug 24;220:113468. Epub 2021 Apr 24.

School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China. Electronic address:

A series of steroidal compounds based on 3-hydroxyandrosta-5,7-diene-17-carboxylic acid core structure were designed, synthesized and bio-evaluated for their anti-inflammatory potency. Among them, compound 5c, 6f, and 6q effectively inhibited the production of nitric oxide (NO) in lipopolysaccharide (LPS) stimulated RAW 264.7 macrophages. They inhibited the expression of inducible NO synthase (iNOS) and prostaglandin synthase-2 (COX-2) at mRNA level. Compound 6q displayed inhibitory effects on both iNOS and COX-2 expression in a concentration-dependent manner. Furthermore, 6q was found to effectively decrease the mRNA and protein levels of interleukin 6 (IL-6). Mechanically, 6q could potently downregulate NF-κB signaling via suppression of the Akt/PI3K pathway. Moreover, 6q demonstrated high in vivo anti-inflammatory activities in a mouse colitis model induced by dextran sulfate sodium (DSS). Taken together, these data indicate that 6q represents a novel and promising anti-inflammatory bowel diseases (IBD) agent worthy of further investigation.
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http://dx.doi.org/10.1016/j.ejmech.2021.113468DOI Listing
August 2021

Ten-eleven translocation protein 1 modulates medulloblastoma progression.

Genome Biol 2021 Apr 29;22(1):125. Epub 2021 Apr 29.

Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA.

Background: Medulloblastoma (MB) is the most common malignant pediatric brain tumor that originates in the cerebellum and brainstem. Frequent somatic mutations and deregulated expression of epigenetic regulators in MB highlight the substantial role of epigenetic alterations. 5-hydroxymethylcytosine (5hmC) is a highly abundant cytosine modification in the developing cerebellum and is regulated by ten-eleven translocation (TET) enzymes.

Results: We investigate the alterations of 5hmC and TET enzymes in MB and their significance to cerebellar cancer formation. We show total abundance of 5hmC is reduced in MB, but identify significant enrichment of MB-specific 5hmC marks at regulatory regions of genes implicated in stem-like properties and Nanog-binding motifs. While TET1 and TET2 levels are high in MBs, only knockout of Tet1 in the smoothened (SmoA1) mouse model attenuates uncontrolled proliferation, leading to a favorable prognosis. The pharmacological Tet1 inhibition reduces cell viability and platelet-derived growth factor signaling pathway-associated genes.

Conclusions: These results together suggest a potential key role of 5hmC and indicate an oncogenic nature for TET1 in MB tumorigenesis, suggesting it as a potential therapeutic target for MBs.
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http://dx.doi.org/10.1186/s13059-021-02352-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082834PMC
April 2021

Photosynthetic Responses of × 'Red' under Different Light Conditions.

Plants (Basel) 2021 Apr 23;10(5). Epub 2021 Apr 23.

Mid-Florida Research Education Center and Environmental Horticulture Department, Institute of Food and Agricultural Sciences, University of Florida, Apopka, FL 32703, USA.

Light is an essential energy source for plant photosynthesis, although it can also be a stress-causing element. Therefore, the current research was aimed to compare photosynthetic responses of × 'Red' leaves at different positions (bottom old leaf, 1; center mature leaf, 2; top expanded leaf, 3) established under three photosynthetic photon flux densities (PPFDs): 550 μmol·m·s as high (H), 350 μmol·m·s as medium (M), and 255 μmol·m·s as low (L). After six months, all the replicates were relocated to interior rooms with a PPFD of 30 μmol·m·s. There were no significant differences in chlorophyll concentration of the old leaf among treatments, before (Day 0) and after shifting the plants to interior rooms (Day 30). The total chlorophyll concentrations of the mature and top leaves increased significantly. In greenhouse conditions, H and M treatments did not show any significant change for net photosynthetic rate (n) at various leaf positions. However, M2 exhibited an improved n in the interior conditions. Plants grown under M treatment were greener and had bigger leaves compared to other treatments. Our study reveals that × 'Red' photosynthesis responses to different light conditions varied distinctly. However, M treatment can keep the plants looking green by accumulating enough energy for indoor conditions, and middle and lower leaves may be triggered to restore photosynthetic activity under low light or indoor conditions.
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http://dx.doi.org/10.3390/plants10050857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145403PMC
April 2021

Avian influenza A (H7N9) virus: from low pathogenic to highly pathogenic.

Front Med 2021 Apr 16. Epub 2021 Apr 16.

Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen, 518114, China.

The avian influenza A (H7N9) virus is a zoonotic virus that is closely associated with live poultry markets. It has caused infections in humans in China since 2013. Five waves of the H7N9 influenza epidemic occurred in China between March 2013 and September 2017. H7N9 with low-pathogenicity dominated in the first four waves, whereas highly pathogenic H7N9 influenza emerged in poultry and spread to humans during the fifth wave, causing wide concern. Specialists and officials from China and other countries responded quickly, controlled the epidemic well thus far, and characterized the virus by using new technologies and surveillance tools that were made possible by their preparedness efforts. Here, we review the characteristics of the H7N9 viruses that were identified while controlling the spread of the disease. It was summarized and discussed from the perspectives of molecular epidemiology, clinical features, virulence and pathogenesis, receptor binding, T-cell responses, monoclonal antibody development, vaccine development, and disease burden. These data provide tools for minimizing the future threat of H7N9 and other emerging and re-emerging viruses, such as SARS-CoV-2.
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http://dx.doi.org/10.1007/s11684-020-0814-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190734PMC
April 2021

Rapid Acquisition of High-Quality SARS-CoV-2 Genome via Amplicon-Oxford Nanopore Sequencing.

Virol Sin 2021 Apr 13. Epub 2021 Apr 13.

CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.

Genome sequencing has shown strong capabilities in the initial stages of the COVID-19 pandemic such as pathogen identification and virus preliminary tracing. While the rapid acquisition of SARS-CoV-2 genome from clinical specimens is limited by their low nucleic acid load and the complexity of the nucleic acid background. To address this issue, we modified and evaluated an approach by utilizing SARS-CoV-2-specific amplicon amplification and Oxford Nanopore PromethION platform. This workflow started with the throat swab of the COVID-19 patient, combined reverse transcript PCR, and multi-amplification in one-step to shorten the experiment time, then can quickly and steadily obtain high-quality SARS-CoV-2 genome within 24 h. A comprehensive evaluation of the method was conducted in 42 samples: the sequencing quality of the method was correlated well with the viral load of the samples; high-quality SARS-CoV-2 genome could be obtained stably in the samples with Ct value up to 39.14; data yielding for different Ct values were assessed and the recommended sequencing time was 8 h for samples with Ct value of less than 20; variation analysis indicated that the method can detect the existing and emerging genomic mutations as well; Illumina sequencing verified that ultra-deep sequencing can greatly improve the single read error rate of Nanopore sequencing, making it as low as 0.4/10,000 bp. In summary, high-quality SARS-CoV-2 genome can be acquired by utilizing the amplicon amplification and it is an effective method in accelerating the acquisition of genetic resources and tracking the genome diversity of SARS-CoV-2.
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http://dx.doi.org/10.1007/s12250-021-00378-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043101PMC
April 2021

AIM2 Inhibits BRAF-Mutant Colorectal Cancer Growth in a Caspase-1-Dependent Manner.

Front Cell Dev Biol 2021 25;9:588278. Epub 2021 Mar 25.

Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Absent in melanoma 2 (AIM2), a DNA sensor that plays an important role in natural immunity system, has been reported to participate in colorectal cancer (CRC) development. However, the functional role of AIM2 in BRAF-mutant CRC remains unclear. In this study, we first investigated AIM2 expression level in BRAF-mutant CRC tumor tissues. Overexpression of AIM2 in CRC cells was performed to investigate the effect of AIM2 on CRC cell viability, and cell death detection and caspase activity assay were performed to explore the mechanism that AIM2 impacts the growth of BRAF-mutant CRC cells. Moreover, we confirmed the antitumor effect of AIM2 in BRAF-mutant CRC cell-derived tumor xenograft (CDX) models as well as patient-derived organoids (PDOs). Herein, we reported that AIM2 expression was lower in BRAF-mutant than that in BRAF wild-type CRC tumor tissues. Restoring the expression of AIM2 in BRAF-mutant CRC cells greatly inhibits the tumor cell growth by inducing necrotic cell death. Mechanism studies revealed that AIM2-induced cell death is in a caspase-1-dependent manner. Additionally, overexpression of AIM2 significantly inhibits tumor growth and metastasis in BRAF-mutant CRC , which was further confirmed in BRAF-mutant CRC PDOs. Taken together, our data suggested that AIM2 inhibits BRAF-mutant colon cancer growth in a caspase-1-dependent manner, which may provide evidence to understand the pathogenesis of CRC with BRAF-mutant, as well as new strategies for manipulation of CRC.
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http://dx.doi.org/10.3389/fcell.2021.588278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027362PMC
March 2021

Diffuser screen with flat-top angular distribution of scattered light realized by a dual-beam holographic speckle.

Opt Express 2021 Mar;29(6):8523-8530

Holographic speckle screens with the Gaussian type distribution of scattered light, which are used to increase the viewing angle of the image in projection display systems, result in nonuniform image brightness in different observing positions. In this study, based on Helmholtz-Kirchhoff theory, a dual-beam scattering theory of rough surface is derived. By analyzing the spatial frequency spectrum of the scattered light, it is found that when two laser beams irradiated the ground glass at a certain angle, the resulting speckles recorded on the photoresist can generate a flat-top angular distribution of the scattered light. Speckle screens are fabricated by two light beams at different angles, and the angular intensity distribution of scattered light is measured. The results are in good agreement with the theory. Compared with the Gaussian type diffuser, the energy efficiency of the speckle screen proposed has a 46% increase when the angular luminance uniformity is set to be 80%, which effectively improves the brightness when used in a head up display system.
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http://dx.doi.org/10.1364/OE.420910DOI Listing
March 2021

Effects of Maternal Environment on Seed Germination and Seedling Vigor of × under Different Abiotic Stresses.

Plants (Basel) 2021 Mar 19;10(3). Epub 2021 Mar 19.

Mid-Florida Research Center, IFAS-University of Florida, Apopka, FL 32703, USA.

Seed germination and seedling vigor can be affected by environmental cues experienced by the mother plant. However, information about how the maternal environment affects seed quality is scarce in ornamental plants. This study aimed to investigate the effects of two different maternal environments on the seed germination and seedling vigor of a × under a variety of abiotic stresses. Petunia mother plants were grown in either a greenhouse during the summer months or an indoor controlled-temperature-and-light environment. Collected seeds were subjected to external stressors, including polyethylene glycol (PEG), sodium chloride (NaCl), high temperature, and abscisic acid (ABA), to determine seed germination percentage and seedling vigor. Results indicated that seeds harvested from the mother plants grown in a controlled environment germinated better than seeds harvested from the mother plants grown in the greenhouse when suboptimal germination conditions were applied. Additionally, the seedlings from the controlled maternal environment performed better in both ABA and salinity stress tests than the greenhouse seedlings. Interestingly, the greenhouse seedlings displayed less reactive oxygen species (ROS) damage and lower electrolyte leakage than the controlled environment seedlings under dehydration stress. The difference in germination and seedling vigor of seeds from the two different maternal environments might be due to the epigenetic memory inherited from the mother plants. This study highlighted the strong impact of the maternal environment on seed germination and seedling vigor in Petunia and may assist in high-quality seed production in ornamental plants.
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http://dx.doi.org/10.3390/plants10030581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003445PMC
March 2021

Intratumoral Virotherapy with Wild-Type Newcastle Disease Virus in Carcinoma Krebs-2 Cancer Model.

Viruses 2021 03 25;13(4). Epub 2021 Mar 25.

FRC of Fundamental and Translational Medicine, Eurasian Institute of Zoonotic Infections, Timakova Street 2, 630117 Novosibirsk, Russia.

The results of experimental and clinical trials of the agents based on oncolytic Newcastle disease virus (NDV) strains provided hope for the development of virotherapy as a promising method for treating human tumors. However, the mechanism of the antitumor effect of NDV and realization of its cytotoxic potential in a cancer cell remains to be elucidated. In the current work, we have studied the antitumor effect of NDV in a syngeneic model of mouse Krebs-2 carcinoma treated with intratumoral injections of a wild-type strain NDV/Altai/pigeon/770/2011. Virological methods were used for preparation of a virus-containing sample. Colorimetric MTS assay was used to assess the viability of Krebs-2 tumor cells infected with a viral strain in vitro. In vivo virotherapy was performed in eight-week-old male BALB/c mice treated with serial intratumoral injections of NDV in an experimental model of Krebs-2 solid carcinoma. Changes in the tumor nodes of Krebs-2 carcinoma after virotherapy were visualized by MRI and immunohistological staining. Light microscopy examination, immunohistochemical and morphometric analyses have shown that intratumoral viral injections contribute to the inhibition of tumor growth, appearance of necrosis-like changes in the tumor tissue and the antiangiogenic effect of the virus. It has been established that a course of intratumoral virotherapy with NDV/Altai/pigeon/770/2011 strain in a mouse Krebs-2 carcinoma resulted in increased destructive changes in the tumor tissue, in the volume density of necrotic foci and numerical density of endothelial cells expressing CD34 and VEGFR. These results indicate that intratumoral NDV injection reduces tumor progression of an aggressive tumor.
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http://dx.doi.org/10.3390/v13040552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067130PMC
March 2021

Targeting differentiation blockade in AML: New hope from cell-surface-based CRISPR screens.

Cell Stem Cell 2021 04;28(4):585-587

Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA; Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA. Electronic address:

Accumulation of undifferentiated myeloid progenitors is a hallmark of AML, and targeting differentiation blockade represents a promising therapeutic strategy for AML. In this issue of Cell Stem Cell, Wang et al. (2021) conducted surface antigen-guided CRISPR screening and identified ZFP36L2 as a myeloid leukemia differentiation regulator and new therapeutic target.
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http://dx.doi.org/10.1016/j.stem.2021.03.006DOI Listing
April 2021

[A preliminary study on the biomarkers of local inflammation in allergic rhinitis].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2021 Apr;35(4):306-311;315

Department of Otolaryngology Head and Neck Surgery,Union Hospital of Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430022,China.

This study aimed to explore the biomarkers in nasal secretion that can assist in the diagnosis of allergic rhinitis(AR) and can be used to evaluate the therapeutic effect of AR. Thirty-three patients with AR and 21 healthy controls were included. The nasal secretion of healthy controls and patients with AR(before and after treatment) were collected. The cytology, the concentrations of cytokines(IL-5, IL-6, IL-8, IL-33, IFN-γ) and inflammatory mediators(ECP, MPO) were detected. Then, we compared the differences of various biomarkers between healthy controls and AR patients(before and after treatment group). And analyzed the correlation between each biomarkers/biomarkers difference value/the percentage of biomarkers difference value and clinical symptom score/ score difference value / the percentage of score difference value. Compared with normal controls, the levels of ECP, IL-5, IL-6, IL-8, IL-33 and IFN-γ in nasal secretion of AR patients were significantly higher than those of normal controls(<0.05). There was no significant difference in MPO. After treatment, ECP decreased significantly(<0.01), inflammatory cell grade and eosinophil percentage are also decreased(<0.01). However, MPO, IL-5, IL-6, IL-8, IL-33 and IFN-γ did not change significantly. The difference value of ECP before and after treatment was correlated with the difference value of VAS score(=0.348, =0.047). The difference value of IL-5 was correlated with the difference value of VAS score and rhinorrhea, the correlation coefficients were 0.406(=0.019) and 0.429(=0.013), respectively. The difference value of eosinophil percentage in nasal secretion before and after treatment was correlated with nasal congestion, and the correlation coefficient was 0.383. The difference value of eosinophil percentage multiplied by inflammatory cell grade before and after treatment was correlated with VAS score(=0.417, =0.016) and nasal congestion difference value(=0.519, =0.002). The percentage of difference value of IFN-γ before and after treatment was correlated with the percentage of difference value of VAS score / rhinorrhea / sneeze / total nasal symptom score. ECP, IL-6, IL-8 and IL-33 in nasal secretion are expected to be objective biomarkers for auxiliary diagnosis of AR. And ECP, IL-5, IFN-γ, eosinophil percentage multiplied by grade is expected to be an objective index to judge the improvement of patients' symptoms after treatment.
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http://dx.doi.org/10.13201/j.issn.2096-7993.2021.04.005DOI Listing
April 2021

Discovery of Novel Benzimidazole and Indazole Analogues as Tubulin Polymerization Inhibitors with Potent Anticancer Activities.

J Med Chem 2021 04 31;64(8):4498-4515. Epub 2021 Mar 31.

School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.

Novel indazole and benzimidazole analogues were designed and synthesized as tubulin inhibitors with potent antiproliferative activities. Among them, compound exhibited the strongest inhibitory effects on the growth of cancer cells with an average IC value of 50 nM, slightly better than colchicine. exhibited nearly equal potency against both, a paclitaxel-resistant cancer cell line (A2780/T, IC = 9.7 nM) and the corresponding parental cell line (A2780S, IC = 6.2 nM), thus effectively overcoming paclitaxel resistance . The crystal structure of in complex with tubulin was solved to 2.45 Å resolution by X-ray crystallography, and its direct binding was confirmed to the colchicine site. Furthermore, displayed significant antitumor efficacy in a melanoma tumor model with tumor growth inhibition rates of 78.70% (15 mg/kg) and 84.32% (30 mg/kg). Collectively, this work shows that is a promising lead compound deserving further investigation as a potential anticancer agent.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01837DOI Listing
April 2021

Integrated characterization of SARS-CoV-2 genome, microbiome, antibiotic resistance and host response from single throat swabs.

Cell Discov 2021 Mar 30;7(1):19. Epub 2021 Mar 30.

State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, 100871, China.

The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, poses a severe threat to humanity. Rapid and comprehensive analysis of both pathogen and host sequencing data is critical to track infection and inform therapies. In this study, we performed unbiased metatranscriptomic analysis of clinical samples from COVID-19 patients using a recently developed RNA-seq library construction method (TRACE-seq), which utilizes tagmentation activity of Tn5 on RNA/DNA hybrids. This approach avoids the laborious and time-consuming steps in traditional RNA-seq procedure, and hence is fast, sensitive, and convenient. We demonstrated that TRACE-seq allowed integrated characterization of full genome information of SARS-CoV-2, putative pathogens causing coinfection, antibiotic resistance, and host response from single throat swabs. We believe that the integrated information will deepen our understanding of pathogenesis and improve diagnostic accuracy for infectious diseases.
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http://dx.doi.org/10.1038/s41421-021-00248-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008776PMC
March 2021

Discovery of novel quinazoline-based covalent inhibitors of KRAS G12C with various cysteine-targeting warheads as potential anticancer agents.

Bioorg Chem 2021 May 13;110:104825. Epub 2021 Mar 13.

School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China. Electronic address:

A series of novel quinazoline analogs with a variety of cysteine-targeting warheads (electrophiles) were designed and synthesized based on ARS-1620 as covalent KRAS G12C inhibitors. Among them, compounds LLK10 and LLK14 exhibited similar or better antiproliferative activity than ARS-1620. LLK10 was used for subsequent biological studies due to the higher selectivity towards KRAS G12C-mutated cells than LLK14. LLK10 maintained the mechanism of action by forming a covalent bond with KRAS G12C protein, thus decreasing the level of phosphorylated Mek and Erk, and leading to tumor cell apoptosis. In addition, LLK10 was able to suppress the formation of H358 tumor colonies. Molecular modeling study indicated that LLK10 binds with high affinity to the SWII binding site in KRAS G12C and overlaps well with ARS-1620. The high binding affinity of LLK10 was further confirmed by the isothermal titration calorimetry (ITC) assay in which LLK10 exhibited a K of 115 nM for binding to KRAS G12C. These results suggest that the novel covalent inhibitors of KRAS G12C with different warheads deserve further investigation as potential anticancer agents.
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http://dx.doi.org/10.1016/j.bioorg.2021.104825DOI Listing
May 2021

YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner.

Blood 2021 Mar 24. Epub 2021 Mar 24.

Wuhan University, Wuhan, China.

RNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Although RBPs are increasingly appreciated as being important for normal hematopoiesis and for hematological malignancies as oncogenes or tumor suppressors, essential RBPs for leukemia maintenance and survival remain elusive. Here we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival in an m6A-dependent manner. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 dramatically induces apoptosis, promotes differentiation, coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia (AML) cells in vitro and in vivo. Loss of YBX1 does not obviously affect normal hematopoiesis. Mechanistically, YBX1 interacts with IGF2BPs and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency dysregulates the expression of apoptosis-related genes, and promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival due to YBX1 deletion. Thus, our findings uncover a selective and critical role of YBX1 in maintaining myeloid leukemia survival that might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.
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http://dx.doi.org/10.1182/blood.2020009676DOI Listing
March 2021

Synthesis and pharmacological evaluation of novel resorcinol biphenyl ether analogs as small molecule inhibitors of PD-1/PD-L1 with benign toxicity profiles for cancer treatment.

Biochem Pharmacol 2021 Jun 17;188:114522. Epub 2021 Mar 17.

School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China. Electronic address:

Programmed death protein 1 (PD-1)/programmed death protein ligand 1 (PD-L1) pathway is one of the most actively pursued targets in cancer immunotherapy. In a continuation of our research interest in this pathway, we synthesized and evaluated the pharmacological activities of a series of resorcinol biphenyl ether analogs as small molecule PD-1/PD-L1 inhibitors for cancer treatment. Among the 27 newly synthesized compounds, CH1 was found to have the highest inhibitory effect against PD-1/PDL-1 with an IC value of 56.58 nM in the HTRF (homogenous time-resolved fluorescence) assay. In addition, CH1 dose-dependently promoted HepG2 cell death in a co-culture model of HepG2/hPD-L1 and Jurkat T cells. Furthermore, molecular modeling study indicated that CH1 binds with high affinity to the binding interface of PD-L1. Moreover, CH1 effectively inhibited tumor growth (TGI of 76.4% at 90 mg/kg) in an immune checkpoint humanized mouse model with no obvious toxicity. Finally, CH1 did not cause in vivo cardiotoxicity and bone marrow suppression (myelosuppression) to BALB/c mice. Taken together, these results suggest that CH1 deserves further investigation as a potent and safe PD-1/PDL-1 inhibitor for cancer treatment.
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http://dx.doi.org/10.1016/j.bcp.2021.114522DOI Listing
June 2021

Balance of activation and ring-breaking for toluene oxidation over CuO-MnO bimetallic oxides.

J Hazard Mater 2021 Aug 13;415:125637. Epub 2021 Mar 13.

State Key Joint Laboratory of Environment Simulation and Pollution Control, National Engineering Laboratory for Multi Flue Gas Pollution Control Technology and Equipment, School of Environment, Tsinghua University, Beijing 100084, PR China.

CuMn oxides have been studied for many years to catalytic degradation of toluene, but there are still many divergences on the essence of their great catalytic activity and reaction mechanism. A series of CuMn bimetallic oxides were synthesized for the catalytic oxidation of toluene in this study. CuMn exhibited the highest toluene oxidation rate per specific surface area, which was approximately 4 times that of monometallic CuO and MnO. Benzoic acid was the only intermediates which could be observed during toluene oxidation. Between monometallic CuO and MnO, toluene was more difficult to be activated by MnO to generate benzoic acid (toluene activation), whereas benzoic acid was oxidized (ring-breaking) by CuO with more difficulty. As for CuMn, the superior reducibility combined with the balance between ring-breaking of benzoic acid and activation of toluene-to-benzoic acid determined the high toluene oxidation rate. DFT simulations exhibited that in O-Cu-O-Mn-O structure, the Mn-O site was a more effective activation site for toluene-to-benzoic acid oxidation, whereas Cu-O mainly performed as an adsorption site for toluene. This work identifies the different roles of Cu and Mn entities in toluene oxidation and provides the novel design strategy for toluene removal catalysts.
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http://dx.doi.org/10.1016/j.jhazmat.2021.125637DOI Listing
August 2021

The investigation of surface composition of nitrogen-doped niobium for superconducting RF cavities.

Nanotechnology 2021 Mar 3. Epub 2021 Mar 3.

Sichuan University, Chengdu, Sichuan, CHINA.

Systematic analysis of the surface morphology, crystalline phase, chemical composition and elemental distribution along depth for nitrogen-doped niobium was carried out through different ways of characterization, including SEM, AFM, GIXRD, RBS and layer-by-layer XPS analysis. The results showed that, after nitrogen doping, the surface was covered by densely distributed trigonal precipitates with average crystallite size of 32 ± 8 nm, in line with the calculation result (29.9 nm) of nitrogen-enriched β-Nb2N from GIXRD, demonstrating the phase composion of trigonal precipitates. The depth analysis through RBS and XPS indicated that β-Nb2N was dominant in the topmost 9.7 nm and extended to depth of 575 nm with gradually decreased content. In addition, the successive change of naturally oxidized states of niobium after nitrogen doping along depth was revealed along depth. It was interesting to find that oxygen diffusion depth could be moderately enhanced by nitridation process. These results established the near-surface phase composition of nitrided niobium, which was of great significance for evaluating the effect of nitrogen doping and further understanding the Q improvement of the SRF cavities.
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http://dx.doi.org/10.1088/1361-6528/abeb99DOI Listing
March 2021

Design, synthesis and biological evaluation of benz-fused five-membered heterocyclic compounds as tubulin polymerization inhibitors with anticancer activities.

Chem Biol Drug Des 2021 May 11;97(5):1109-1116. Epub 2021 Mar 11.

School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, China.

A series of benz-fused five-membered heterocyclic compounds were designed and synthesized as novel tubulin inhibitors targeting the colchicine binding site. Among them, compound 4d displayed the highest antiproliferative activity against four cancer cell lines with an IC value of 4.9 μM in B16-F10 cells. Compound 4d effectively inhibited tubulin polymerization in vitro (IC of 13.1 μM). Further, 4d induced cell cycle arrest in G2/M phase. Finally, 4d inhibited the migration of cancer cells in a dose-dependent manner. In summary, these results suggest that compound 4d represents a new class of tubulin inhibitors deserving further investigation.
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http://dx.doi.org/10.1111/cbdd.13832DOI Listing
May 2021

N(6)-methyladenosine-binding protein YTHDF1 suppresses EBV replication and promotes EBV RNA decay.

EMBO Rep 2021 04 19;22(4):e50128. Epub 2021 Feb 19.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.

N -methyladenosine (m A) modification of mRNA mediates diverse cellular and viral functions. Infection with Epstein-Barr virus (EBV) is causally associated with nasopharyngeal carcinoma (NPC), 10% of gastric carcinoma, and various B-cell lymphomas, in which the viral latent and lytic phases both play vital roles. Here, we show that EBV transcripts exhibit differential m A modification in human NPC biopsies, patient-derived xenograft tissues, and cells at different EBV infection stages. m A-modified EBV transcripts are recognized and destabilized by the YTHDF1 protein, which leads to the m A-dependent suppression of EBV infection and replication. Mechanistically, YTHDF1 hastens viral RNA decapping and mediates RNA decay by recruiting RNA degradation complexes, including ZAP, DDX17, and DCP2, thereby post-transcriptionally downregulating the expression of EBV genes. Taken together, our results reveal the critical roles of m A modifications and their reader YTHDF1 in EBV replication. These findings contribute novel targets for the treatment of EBV-associated cancers.
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http://dx.doi.org/10.15252/embr.202050128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025027PMC
April 2021

Cytoplasmic DROSHA and non-canonical mechanisms of MiR-155 biogenesis in FLT3-ITD acute myeloid leukemia.

Leukemia 2021 Feb 15. Epub 2021 Feb 15.

Gehr Family Center for Leukemia Research, Hematology Malignancies and Stem Cell Transplantation Institute, City of Hope Medical Center, Duarte, CA, USA.

We report here on a novel pro-leukemogenic role of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) that interferes with microRNAs (miRNAs) biogenesis in acute myeloid leukemia (AML) blasts. We showed that FLT3-ITD interferes with the canonical biogenesis of intron-hosted miRNAs such as miR-126, by phosphorylating SPRED1 protein and inhibiting the "gatekeeper" Exportin 5 (XPO5)/RAN-GTP complex that regulates the nucleus-to-cytoplasm transport of pre-miRNAs for completion of maturation into mature miRNAs. Of note, despite the blockage of "canonical" miRNA biogenesis, miR-155 remains upregulated in FLT3-ITD+ AML blasts, suggesting activation of alternative mechanisms of miRNA biogenesis that circumvent the XPO5/RAN-GTP blockage. MiR-155, a BIC-155 long noncoding (lnc) RNA-hosted oncogenic miRNA, has previously been implicated in FLT3-ITD+ AML blast hyperproliferation. We showed that FLT3-ITD upregulates miR-155 by inhibiting DDX3X, a protein implicated in the splicing of lncRNAs, via p-AKT. Inhibition of DDX3X increases unspliced BIC-155 that is then shuttled by NXF1 from the nucleus to the cytoplasm, where it is processed into mature miR-155 by cytoplasmic DROSHA, thereby bypassing the XPO5/RAN-GTP blockage via "non-canonical" mechanisms of miRNA biogenesis.
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http://dx.doi.org/10.1038/s41375-021-01166-9DOI Listing
February 2021