Publications by authors named "Qiming Sun"

85 Publications

Redox-sensitive CDC-42 clustering promotes wound closure in C. elegans.

Cell Rep 2021 Nov;37(8):110040

Center for Stem Cell and Regenerative Medicine and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Zhejiang University-University of Edinburgh Institute, Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address:

Tissue damage induces immediate-early signals, activating Rho small GTPases to trigger actin polymerization essential for later wound repair. However, how tissue damage is sensed to activate Rho small GTPases locally remains elusive. Here, we found that wounding the C. elegans epidermis induces rapid relocalization of CDC-42 into plasma membrane-associated clusters, which subsequently recruits WASP/WSP-1 to trigger actin polymerization to close the wound. In addition, wounding induces a local transient increase and subsequent reduction of HO, which negatively regulates the clustering of CDC-42 and wound closure. CDC-42 CAAX motif-mediated prenylation and polybasic region-mediated cation-phospholipid interaction are both required for its clustering. Cysteine residues participate in intermolecular disulfide bonds to reduce membrane association and are required for negative regulation of CDC-42 clustering by HO. Collectively, our findings suggest that HO-regulated fine-tuning of CDC-42 localization can create a distinct biomolecular cluster that facilitates rapid epithelial wound repair after injury.
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http://dx.doi.org/10.1016/j.celrep.2021.110040DOI Listing
November 2021

Correction to: Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model.

Protein Cell 2021 Nov 1. Epub 2021 Nov 1.

Department of Biochemistry & Research Center of Clinical Pharmacy of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.

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http://dx.doi.org/10.1007/s13238-021-00873-4DOI Listing
November 2021

Advances in Catalytic Applications of Zeolite-Supported Metal Catalysts.

Adv Mater 2021 Oct 5:e2104442. Epub 2021 Oct 5.

Innovation Center for Chemical Sciences|College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, P. R. China.

Zeolites possessing large specific surface areas, ordered micropores, and adjustable acidity/basicity have emerged as ideal supports to immobilize metal species with small sizes and high dispersities. In recent years, the zeolite-supported metal catalysts have been widely used in diverse catalytic processes, showing excellent activity, superior thermal/hydrothermal stability, and unique shape-selectivity. In this review, a comprehensive summary of the state-of-the-art achievements in catalytic applications of zeolite-supported metal catalysts are presented for important heterogeneous catalytic processes in the last five years, mainly including 1) the hydrogenation reactions (e.g., CO/CO hydrogenation, hydrogenation of unsaturated compounds, and hydrogenation of nitrogenous compounds); 2) dehydrogenation reactions (e.g., alkane dehydrogenation and dehydrogenation of chemical hydrogen storage materials); 3) oxidation reactions (e.g., CO oxidation, methane oxidation, and alkene epoxidation); and 4) other reactions (e.g., hydroisomerization reaction and selective catalytic reduction of NO with ammonia reaction). Finally, some current limitations and future perspectives on the challenge and opportunity for this subject are pointed out. It is believed that this review will inspire more innovative research on the synthesis and catalysis of zeolite-supported metal catalysts and promote their future developments to meet the emerging demands for practical applications.
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http://dx.doi.org/10.1002/adma.202104442DOI Listing
October 2021

Author Correction: Mechanical activation of spike fosters SARS-CoV-2 infection.

Cell Res 2021 Nov;31(11):1223

Department of Cardiology of the Second Affiliated Hospital and Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

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http://dx.doi.org/10.1038/s41422-021-00576-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480123PMC
November 2021

Characterization of the molecular mechanisms underlying azithromycin-induced cardiotoxicity using human-induced pluripotent stem cell-derived cardiomyocytes.

Clin Transl Med 2021 09;11(9):e549

Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.

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http://dx.doi.org/10.1002/ctm2.549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444559PMC
September 2021

Aberrant Stress Granule Dynamics and Aggrephagy in ALS Pathogenesis.

Cells 2021 08 30;10(9). Epub 2021 Aug 30.

Department of Biochemistry, and Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.

Stress granules are conserved cytosolic ribonucleoprotein (RNP) compartments that undergo dynamic assembly and disassembly by phase separation in response to stressful conditions. Gene mutations may lead to aberrant phase separation of stress granules eliciting irreversible protein aggregations. A selective autophagy pathway called aggrephagy may partially alleviate the cytotoxicity mediated by these protein aggregates. Cells must perceive when and where the stress granules are transformed into toxic protein aggregates to initiate autophagosomal engulfment for subsequent autolysosomal degradation, therefore, maintaining cellular homeostasis. Indeed, defective aggrephagy has been causally linked to various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In this review, we discuss stress granules at the intersection of autophagy and ALS pathogenesis.
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http://dx.doi.org/10.3390/cells10092247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468025PMC
August 2021

A new type of ERGIC-ERES membrane contact mediated by TMED9 and SEC12 is required for autophagosome biogenesis.

Cell Res 2021 Sep 24. Epub 2021 Sep 24.

State Key Laboratory of Membrane Biology, Beijing, China.

Under stress, the endomembrane system undergoes reorganization to support autophagosome biogenesis, which is a central step in autophagy. How the endomembrane system remodels has been poorly understood. Here we identify a new type of membrane contact formed between the ER-Golgi intermediate compartment (ERGIC) and the ER-exit site (ERES) in the ER-Golgi system, which is essential for promoting autophagosome biogenesis induced by different stress stimuli. The ERGIC-ERES contact is established by the interaction between TMED9 and SEC12 which generates a short distance opposition (as close as 2-5 nm) between the two compartments. The tight membrane contact allows the ERES-located SEC12 to transactivate COPII assembly on the ERGIC. In addition, a portion of SEC12 also relocates to the ERGIC. Through both mechanisms, the ERGIC-ERES contact promotes formation of the ERGIC-derived COPII vesicle, a membrane precursor of the autophagosome. The ERGIC-ERES contact is physically and functionally different from the TFG-mediated ERGIC-ERES adjunction involved in secretory protein transport, and therefore defines a unique endomembrane structure generated upon stress conditions for autophagic membrane formation.
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http://dx.doi.org/10.1038/s41422-021-00563-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461442PMC
September 2021

Mechanical activation of spike fosters SARS-CoV-2 viral infection.

Cell Res 2021 10 31;31(10):1047-1060. Epub 2021 Aug 31.

Department of Cardiology of the Second Affiliated Hospital and Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

The outbreak of SARS-CoV-2 (SARS2) has caused a global COVID-19 pandemic. The spike protein of SARS2 (SARS2-S) recognizes host receptors, including ACE2, to initiate viral entry in a complex biomechanical environment. Here, we reveal that tensile force, generated by bending of the host cell membrane, strengthens spike recognition of ACE2 and accelerates the detachment of spike's S1 subunit from the S2 subunit to rapidly prime the viral fusion machinery. Mechanistically, such mechano-activation is fulfilled by force-induced opening and rotation of spike's receptor-binding domain to prolong the bond lifetime of spike/ACE2 binding, up to 4 times longer than that of SARS-S binding with ACE2 under 10 pN force application, and subsequently by force-accelerated S1/S2 detachment which is up to ~10 times faster than that in the no-force condition. Interestingly, the SARS2-S D614G mutant, a more infectious variant, shows 3-time stronger force-dependent ACE2 binding and 35-time faster force-induced S1/S2 detachment. We also reveal that an anti-S1/S2 non-RBD-blocking antibody that was derived from convalescent COVID-19 patients with potent neutralizing capability can reduce S1/S2 detachment by 3 × 10 times under force. Our study sheds light on the mechano-chemistry of spike activation and on developing a non-RBD-blocking but S1/S2-locking therapeutic strategy to prevent SARS2 invasion.
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http://dx.doi.org/10.1038/s41422-021-00558-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406658PMC
October 2021

LIN28 coordinately promotes nucleolar/ribosomal functions and represses the 2C-like transcriptional program in pluripotent stem cells.

Protein Cell 2021 Jul 31. Epub 2021 Jul 31.

Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences and the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.

LIN28 is an RNA binding protein with important roles in early embryo development, stem cell differentiation/reprogramming, tumorigenesis and metabolism. Previous studies have focused mainly on its role in the cytosol where it interacts with Let-7 microRNA precursors or mRNAs, and few have addressed LIN28's role within the nucleus. Here, we show that LIN28 displays dynamic temporal and spatial expression during murine embryo development. Maternal LIN28 expression drops upon exit from the 2-cell stage, and zygotic LIN28 protein is induced at the forming nucleolus during 4-cell to blastocyst stage development, to become dominantly expressed in the cytosol after implantation. In cultured pluripotent stem cells (PSCs), loss of LIN28 led to nucleolar stress and activation of a 2-cell/4-cell-like transcriptional program characterized by the expression of endogenous retrovirus genes. Mechanistically, LIN28 binds to small nucleolar RNAs and rRNA to maintain nucleolar integrity, and its loss leads to nucleolar phase separation defects, ribosomal stress and activation of P53 which in turn binds to and activates 2C transcription factor Dux. LIN28 also resides in a complex containing the nucleolar factor Nucleolin (NCL) and the transcriptional repressor TRIM28, and LIN28 loss leads to reduced occupancy of the NCL/TRIM28 complex on the Dux and rDNA loci, and thus de-repressed Dux and reduced rRNA expression. Lin28 knockout cells with nucleolar stress are more likely to assume a slowly cycling, translationally inert and anabolically inactive state, which is a part of previously unappreciated 2C-like transcriptional program. These findings elucidate novel roles for nucleolar LIN28 in PSCs, and a new mechanism linking 2C program and nucleolar functions in PSCs and early embryo development.
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http://dx.doi.org/10.1007/s13238-021-00864-5DOI Listing
July 2021

Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model.

Protein Cell 2021 10 21;12(10):769-787. Epub 2021 Jul 21.

Department of Biochemistry & Research Center of Clinical Pharmacy of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.

Chaperone-mediated autophagy (CMA) is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases. However, the mechanisms that regulate CMA are not fully understood. Here, using unbiased drug screening approaches, we discover Metformin, a drug that is commonly the first medication prescribed for type 2 diabetes, can induce CMA. We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA, Hsc70, and its activation. Notably, we find that amyloid-beta precursor protein (APP) is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner. The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity. Importantly, we find that in the APP/PS1 mouse model of Alzheimer's disease (AD), activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβ plaque levels and reverses the molecular and behavioral AD phenotypes. Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases, such as AD, where such therapeutic intervention could be beneficial.
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http://dx.doi.org/10.1007/s13238-021-00858-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464644PMC
October 2021

Post-translational regulation of autophagy is involved in intra-microbiome suppression of fungal pathogens.

Microbiome 2021 06 6;9(1):131. Epub 2021 Jun 6.

State Key Laboratory of Rice Biology, and Key Laboratory of Molecular Biology of Crop Pathogens and Insects, Institute of Biotechnology, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China.

Background: Microbiome interactions are important determinants for ecosystem functioning, stability, and health. In previous studies, it was often observed that bacteria suppress potentially pathogenic fungal species that are part of the same plant microbiota; however, the underlying microbe-microbe interplay remains mostly elusive. Here, we explored antagonistic interactions of the fungus Fusarium graminearum and bacterium Streptomyces hygroscopicus at the molecular level. Both are ubiquitous members of the healthy wheat microbiota; under dysbiosis, the fungus causes devastating diseases.

Results: In co-cultures, we found that Streptomyces alters the fungal acetylome leading to substantial induction of fungal autophagy. The bacterium secrets rapamycin to inactivate the target of rapamycin (TOR), which subsequently promotes the degradation of the fungal histone acetyltransferase Gcn5 through the 26S proteasome. Gcn5 negatively regulates fungal autophagy by acetylating the autophagy-related protein Atg8 at the lysine site K13 and blocking cellular relocalization of Atg8. Thus, degradation of Gcn5 triggered by rapamycin was found to reduce Atg8 acetylation, resulting in autophagy induction in F. graminearum.

Conclusions: Autophagy homeostasis plays an essential role in fungal growth and competition, as well as for virulence. Our work reveals a novel post-translational regulation of autophagy initiated by a bacterial antibiotic. Rapamycin was shown to be a powerful modulator of bacteria-fungi interactions with potential importance in explaining microbial homeostasis in healthy plant microbiomes. The autophagic process provides novel possibilities and targets to biologically control pathogens. Video abstract.
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http://dx.doi.org/10.1186/s40168-021-01077-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182927PMC
June 2021

Efficient Four-Component Dirac-Coulomb-Gaunt Hartree-Fock in the Pauli Spinor Representation.

J Chem Theory Comput 2021 Jun 24;17(6):3388-3402. Epub 2021 May 24.

Department of Chemistry, University of Washington, Seattle, Washington 98195, United States.

Four-component Dirac-Hartree-Fock is an accurate mean-field method for treating molecular systems where relativistic effects are important. However, the computational cost and complexity of the two-electron interaction make this method less common, even though we can consider the Dirac-Hartree-Fock Hamiltonian the "ground truth" of the electronic structure, barring explicit quantum electrodynamical effects. Being able to calculate these effects is then vital to the design of lower scaling methods for accurate predictions in computational spectroscopy and properties of heavy element complexes that must include relativistic effects for even qualitative accuracy. In this work, we present a Pauli quaternion formalism of maximal component and spin separation for computing the Dirac-Coulomb-Gaunt Hartree-Fock ground state, with a minimal floating point operation count algorithm. This approach also allows one to explicitly separate different spin physics from the two-body interactions, such as spin-free, spin-orbit, and spin-spin contributions. Additionally, we use this formalism to examine relativistic trends in the periodic table and analyze the basis set dependence of atomic gold and gold dimer systems.
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http://dx.doi.org/10.1021/acs.jctc.1c00137DOI Listing
June 2021

PHC1 maintains pluripotency by organizing genome-wide chromatin interactions of the Nanog locus.

Nat Commun 2021 05 14;12(1):2829. Epub 2021 May 14.

Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.

Polycomb group (PcG) proteins maintain cell identity by repressing gene expression during development. Surprisingly, emerging studies have recently reported that a number of PcG proteins directly activate gene expression during cell fate determination process. However, the mechanisms by which they direct gene activation in pluripotency remain poorly understood. Here, we show that Phc1, a subunit of canonical polycomb repressive complex 1 (cPRC1), can exert its function in pluripotency maintenance via a PRC1-independent activation of Nanog. Ablation of Phc1 reduces the expression of Nanog and overexpression of Nanog partially rescues impaired pluripotency caused by Phc1 depletion. We find that Phc1 interacts with Nanog and activates Nanog transcription by stabilizing the genome-wide chromatin interactions of the Nanog locus. This adds to the already known canonical function of PRC1 in pluripotency maintenance via a PRC1-dependent repression of differentiation genes. Overall, our study reveals a function of Phc1 to activate Nanog transcription through regulating chromatin architecture and proposes a paradigm for PcG proteins to maintain pluripotency.
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http://dx.doi.org/10.1038/s41467-021-22871-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121881PMC
May 2021

Impregnating Subnanometer Metallic Nanocatalysts into Self-Pillared Zeolite Nanosheets.

J Am Chem Soc 2021 May 4;143(18):6905-6914. Epub 2021 Mar 4.

State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, People's Republic of China.

Impregnation is the most commonly used approach to prepare supported metal catalysts in industry. However, this method suffers from the formation of large metal particles with uneven dispersion, poor thermal stability, and thus unsatisfied catalytic performance. Here, we demonstrate that the self-pillared zeolite (silicalite-1 and ZSM-5) nanosheets with larger surface area and abundant Si-OH groups are ideal supports to immobilize ultrasmall monometallic (e.g., Rh and Ru) and various bimetallic clusters via simple incipient wetness impregnation method. The loaded subnanometric metal clusters are uniformly dispersed within sinusoidal five-membered rings of and remain stable at high temperatures. The Rh/SP-S-1 is highly efficient in ammonia borane (AB) hydrolysis, showing a TOF value of 430 mol mol min at 298 K, which is more than 6-fold improvement over that of nanosized zeolite-supported Rh catalyst and even comparable with that of zeolite-supported Rh single-atom catalyst. Because of the synergistic effect between bimetallic Rh-Ru clusters and zeolite acidity, the H generation rate from AB hydrolysis over RhRu/SP-ZSM-5-100 reaches up to 1006 mol mol min at 298 K, and also shows record activities in cascade hydrogenation of various nitroarenes by coupling with the hydrolysis of AB. This work demonstrates that zeolite nanosheets are excellent supports to anchor diverse ultrasmall metallic species via the simple impregnation method, and the obtained nanocatalysts can be applied in various industrially important catalytic reactions.
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http://dx.doi.org/10.1021/jacs.1c00578DOI Listing
May 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Transfer learning with graph neural networks for optoelectronic properties of conjugated oligomers.

J Chem Phys 2021 Jan;154(2):024906

Chemistry and Chemical Biology, University of California, Merced, California 95343, USA.

Despite the remarkable progress of machine learning (ML) techniques in chemistry, modeling the optoelectronic properties of long conjugated oligomers and polymers with ML remains challenging due to the difficulty in obtaining sufficient training data. Here, we use transfer learning to address the data scarcity issue by pre-training graph neural networks using data from short oligomers. With only a few hundred training data, we are able to achieve an average error of about 0.1 eV for the excited-state energy of oligothiophenes against time-dependent density functional theory (TDDFT) calculations. We show that the success of our transfer learning approach relies on the relative locality of low-lying electronic excitations in long conjugated oligomers. Finally, we demonstrate the transferability of our approach by modeling the lowest-lying excited-state energies of poly(3-hexylthiophene) in its single-crystal and solution phases using the transfer learning models trained with the data of gas-phase oligothiophenes. The transfer learning predicted excited-state energy distributions agree quantitatively with TDDFT calculations and capture some important qualitative features observed in experimental absorption spectra.
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http://dx.doi.org/10.1063/5.0037863DOI Listing
January 2021

CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1.

Signal Transduct Target Ther 2020 12 26;5(1):298. Epub 2020 Dec 26.

Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, 310016, Hangzhou, China.

Sorafenib is the first-line chemotherapeutic therapy for advanced hepatocellular carcinoma (HCC). However, sorafenib resistance significantly limits its therapeutic efficacy, and the mechanisms underlying resistance have not been fully clarified. Here we report that a circular RNA, circRNA-SORE (a circular RNA upregulated in sorafenib-resistant HCC cells), plays a significant role in sorafenib resistance in HCC. We found that circRNA-SORE is upregulated in sorafenib-resistant HCC cells and depletion of circRNA-SORE substantially increases the cell-killing ability of sorafenib. Further studies revealed that circRNA-SORE binds the master oncogenic protein YBX1 in the cytoplasm, which prevents YBX1 nuclear interaction with the E3 ubiquitin ligase PRP19 and thus blocks PRP19-mediated YBX1 degradation. Moreover, our in vitro and in vivo results suggest that circRNA-SORE is transported by exosomes to spread sorafenib resistance among HCC cells. Using different HCC mouse models, we demonstrated that silencing circRNA-SORE by injection of siRNA could substantially overcome sorafenib resistance. Our study provides a proof-of-concept demonstration for a potential strategy to overcome sorafenib resistance in HCC patients by targeting circRNA-SORE or YBX1.
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http://dx.doi.org/10.1038/s41392-020-00375-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762756PMC
December 2020

Mesenteric Neural Crest Cells Are the Embryological Basis of Skip Segment Hirschsprung's Disease.

Cell Mol Gastroenterol Hepatol 2021 16;12(1):1-24. Epub 2020 Dec 16.

Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China. Electronic address:

Background & Aims: Defective rostrocaudal colonization of the gut by vagal neural crest cells (vNCCs) results in Hirschsprung's disease (HSCR), which is characterized by aganglionosis in variable lengths of the distal bowel. Skip segment Hirschsprung's disease (SSHD), referring to a ganglionated segment within an otherwise aganglionic intestine, contradicts HSCR pathogenesis and underscores a significant gap in our understanding of the development of the enteric nervous system. Here, we aimed to identify the embryonic origin of the ganglionic segments in SSHD.

Methods: Intestinal biopsy specimens from HSCR patients were prepared via the Swiss-roll technique to search for SSHD cases. NCC migration from the neural tube to the gut was spatiotemporally traced using targeted cell lineages and gene manipulation in mice.

Results: After invading the mesentery surrounding the foregut, vNCCs separated into 2 populations: mesenteric NCCs (mNCCs) proceeded to migrate along the mesentery, whereas enteric NCCs invaded the foregut to migrate along the gut. mNCCs not only produced neurons and glia within the gut mesentery, but also continuously complemented the enteric NCC pool. Two new cases of SSHD were identified from 183 HSCR patients, and Ednrb-mutant mice, but not Ret mice, showed a high incidence rate of SSHD-like phenotypes.

Conclusions: mNCCs, a subset of vNCCs that migrate into the gut via the gut mesentery to give rise to enteric neurons, could provide an embryologic explanation for SSHD. These findings lead to novel insights into the development of the enteric nervous system and the etiology of HSCR.
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http://dx.doi.org/10.1016/j.jcmgh.2020.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082118PMC
December 2020

Pharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer's disease mouse model.

Nat Commun 2020 11 12;11(1):5731. Epub 2020 Nov 12.

Department of Biochemistry & Molecular Medical Center, Zhejiang University School of Medicine, Hangzhou, 310058, China.

There is increasing evidence that inducing neuronal mitophagy can be used as a therapeutic intervention for Alzheimer's disease. Here, we screen a library of 2024 FDA-approved drugs or drug candidates, revealing UMI-77 as an unexpected mitophagy activator. UMI-77 is an established BH3-mimetic for MCL-1 and was developed to induce apoptosis in cancer cells. We found that at sub-lethal doses, UMI-77 potently induces mitophagy, independent of apoptosis. Our mechanistic studies discovered that MCL-1 is a mitophagy receptor and directly binds to LC3A. Finally, we found that UMI-77 can induce mitophagy in vivo and that it effectively reverses molecular and behavioral phenotypes in the APP/PS1 mouse model of Alzheimer's disease. Our findings shed light on the mechanisms of mitophagy, reveal that MCL-1 is a mitophagy receptor that can be targeted to induce mitophagy, and identify MCL-1 as a drug target for therapeutic intervention in Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-020-19547-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665171PMC
November 2020

Machine learning Frenkel Hamiltonian parameters to accelerate simulations of exciton dynamics.

J Chem Phys 2020 Aug;153(7):074111

Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

In this manuscript, we develop multiple machine learning (ML) models to accelerate a scheme for parameterizing site-based models of exciton dynamics from all-atom configurations of condensed phase sexithiophene systems. This scheme encodes the details of a system's specific molecular morphology in the correlated distributions of model parameters through the analysis of many single-molecule excited-state electronic-structure calculations. These calculations yield excitation energies for each molecule in the system and the network of pair-wise intermolecular electronic couplings. Here, we demonstrate that the excitation energies can be accurately predicted using a kernel ridge regression (KRR) model with Coulomb matrix featurization. We present two ML models for predicting intermolecular couplings. The first one utilizes a deep neural network and bi-molecular featurization to predict the coupling directly, which we find to perform poorly. The second one utilizes a KRR model to predict unimolecular transition densities, which can subsequently be analyzed to compute the coupling. We find that the latter approach performs excellently, indicating that an effective, generalizable strategy for predicting simple bimolecular properties is through the indirect application of ML to predict higher-order unimolecular properties. Such an approach necessitates a much smaller feature space and can incorporate the insight of well-established molecular physics.
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http://dx.doi.org/10.1063/5.0016009DOI Listing
August 2020

Zeolite-Encaged Pd-Mn Nanocatalysts for CO Hydrogenation and Formic Acid Dehydrogenation.

Angew Chem Int Ed Engl 2020 Nov 15;59(45):20183-20191. Epub 2020 Sep 15.

Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, 117585, Singapore, Singapore.

A CO -mediated hydrogen storage energy cycle is a promising way to implement a hydrogen economy, but the exploration of efficient catalysts to achieve this process remains challenging. Herein, sub-nanometer Pd-Mn clusters were encaged within silicalite-1 (S-1) zeolites by a ligand-protected method under direct hydrothermal conditions. The obtained zeolite-encaged metallic nanocatalysts exhibited extraordinary catalytic activity and durability in both CO hydrogenation into formate and formic acid (FA) dehydrogenation back to CO and hydrogen. Thanks to the formation of ultrasmall metal clusters and the synergic effect of bimetallic components, the PdMn @S-1 catalyst afforded a formate generation rate of 2151 mol  mol  h at 353 K, and an initial turnover frequency of 6860 mol  mol  h for CO-free FA decomposition at 333 K without any additive. Both values represent the top levels among state-of-the-art heterogeneous catalysts under similar conditions. This work demonstrates that zeolite-encaged metallic catalysts hold great promise to realize CO -mediated hydrogen energy cycles in the future that feature fast charge and release kinetics.
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http://dx.doi.org/10.1002/anie.202008962DOI Listing
November 2020

Bromo- and extraterminal domain protein inhibition improves immunotherapy efficacy in hepatocellular carcinoma.

Cancer Sci 2020 Oct 17;111(10):3503-3515. Epub 2020 Aug 17.

Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China.

Hepatocellular carcinoma (HCC) represents the majority of liver cancer and is the fourth most common cause of cancer-related death. Although advances in molecular targeted therapy have shown promise, none of these agents has yet demonstrated significant clinical benefit. Bromo- and extraterminal domain (BET) protein inhibitors have been considered potential therapeutic drugs for HCC but the biological activity remains unclear. This study found that BET protein inhibition did not effectively suppress the progression of HCC, using a transgenic HCC mouse model. Mechanistically, the BET protein inhibitor JQ1 upregulated the expression of programmed cell death-ligand 1 (PD-L1) on the plasma membrane in vivo and in vitro. Moreover, JQ1 enhanced the expression of Rab8A, which upregulated the expression of PD-L1 on the plasma membrane. This study also showed that JQ1 combined with anti-PD-L1 Ab effectively suppressed HCC progression, and this benefit was obtained by enhancing the activation and cytotoxic capabilities of CD8 T cells. These results revealed the crucial role and regulation of BET protein inhibition on the expression of PD-L1 in HCC. Thus, combining BET protein inhibition with immune checkpoint blockade offers an efficient therapeutic approach for HCC.
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http://dx.doi.org/10.1111/cas.14588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540980PMC
October 2020

Integrating Biomass into the Organonitrogen Chemical Supply Chain: Production of Pyrrole and d-Proline from Furfural.

Angew Chem Int Ed Engl 2020 11 31;59(45):19846-19850. Epub 2020 Aug 31.

Department of Chemical & Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore, 117585, Singapore.

Production of renewable, high-value N-containing chemicals from lignocellulose will expand product diversity and increase the economic competitiveness of the biorefinery. Herein, we report a single-step conversion of furfural to pyrrole in 75 % yield as a key N-containing building block, achieved via tandem decarbonylation-amination reactions over tailor-designed [email protected] and H-beta zeolite catalytic system. Pyrrole was further transformed into dl-proline in two steps following carboxylation with CO and hydrogenation over Rh/C catalyst. After treating with Escherichia coli, valuable d-proline was obtained in theoretically maximum yield (50 %) bearing 99 % ee. The report here establishes a route bridging commercial commodity feedstock from biomass with high-value organonitrogen chemicals through pyrrole as a hub molecule.
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http://dx.doi.org/10.1002/anie.202006315DOI Listing
November 2020

Recent developments in the PySCF program package.

J Chem Phys 2020 Jul;153(2):024109

Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520, USA.

PySCF is a Python-based general-purpose electronic structure platform that supports first-principles simulations of molecules and solids as well as accelerates the development of new methodology and complex computational workflows. This paper explains the design and philosophy behind PySCF that enables it to meet these twin objectives. With several case studies, we show how users can easily implement their own methods using PySCF as a development environment. We then summarize the capabilities of PySCF for molecular and solid-state simulations. Finally, we describe the growing ecosystem of projects that use PySCF across the domains of quantum chemistry, materials science, machine learning, and quantum information science.
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http://dx.doi.org/10.1063/5.0006074DOI Listing
July 2020

Nanopore-Supported Metal Nanocatalysts for Efficient Hydrogen Generation from Liquid-Phase Chemical Hydrogen Storage Materials.

Adv Mater 2020 Nov 8;32(44):e2001818. Epub 2020 Jul 8.

State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, Jilin University, Changchun, 130012, P. R. China.

Hydrogen has emerged as an environmentally attractive fuel and a promising energy carrier for future applications to meet the ever-increasing energy challenges. The safe and efficient storage and release of hydrogen remain a bottleneck for realizing the upcoming hydrogen economy. Hydrogen storage based on liquid-phase chemical hydrogen storage materials is one of the most promising hydrogen storage techniques, which offers considerable potential for large-scale practical applications for its excellent safety, great convenience, and high efficiency. Recently, nanopore-supported metal nanocatalysts have stood out remarkably in boosting the field of liquid-phase chemical hydrogen storage. Herein, the latest research progress in catalytic hydrogen production is summarized, from liquid-phase chemical hydrogen storage materials, such as formic acid, ammonia borane, hydrous hydrazine, and sodium borohydride, by using metal nanocatalysts confined within diverse nanoporous materials, such as metal-organic frameworks, porous carbons, zeolites, mesoporous silica, and porous organic polymers. The state-of-the-art synthetic strategies and advanced characterizations for these nanocatalysts, as well as their catalytic performances in hydrogen generation, are presented. The limitation of each hydrogen storage system and future challenges and opportunities on this subject are also discussed. References in related fields are provided, and more developments and applications to achieve hydrogen energy will be inspired.
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http://dx.doi.org/10.1002/adma.202001818DOI Listing
November 2020

BET Protein Inhibition Prolongs Cardiac Transplant Survival via Enhanced Myocardial Autophagy.

Transplantation 2020 11;104(11):2317-2326

Department of General Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou City, China.

Background: Graft rejection continues to be a major barrier to long-term engraftment after transplantation. Autophagy plays an important role in cardiac injury pathogenesis. The bromodomain and extraterminal protein inhibitor (S)-tert-butyl2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (JQ1) inhibits inflammatory responses. However, the beneficial effect of JQ1 on transplant and the potential role of autophagy in the protective effect of graft survival are yet to be investigated.

Methods: Syngeneic or allogeneic heterotopic heart transplantation was performed using C57BL/6 or BALB/c donors for C57BL/6 recipients through different treatments. Some mice were used to observe the survival of the grafts. The other mice were euthanized on the third, fifth, and seventh days after surgery. The graft samples were taken for cytokines and autophagy pathway analyses.

Results: Our study revealed that JQ1 treatment prolonged cardiac allograft survival. JQ1 increased the expression levels of liver kinase beta 1, autophagy-specific gene 5, and microtubule-associated protein light chain3-II (LC3-II) and potentiated the phosphorylation of AMP-activated protein kinase, unc-51-like kinase 1 (ULK1), and autophagy-specific gene 14 in allografts. A conditional autophagy-specific gene 5 deletion donor was utilized to abrogate the effect induced by JQ1. The combined use of JQ1 with bafilomycin A1 partially reversed the effect of JQ1, suggesting that autophagy is involved in the signaling pathway in graft survival. JQ1 downregulated the expression of inflammatory cytokines, such as interleukin-6, interleukin-1β, tumor necrosis factor-α, and interferon-γ, which was abrogated when autophagy was inhibited.

Conclusions: JQ1 prolonged cardiac allograft survival by potentiating myocardial autophagy through the liver kinase beta 1-AMP-activated protein kinase-ULK1 signaling pathway and inhibiting the subsequent release of inflammatory cytokines. This result might provide novel insights for extending transplant survival.
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http://dx.doi.org/10.1097/TP.0000000000003319DOI Listing
November 2020

Acetylation of STX17 (syntaxin 17) controls autophagosome maturation.

Autophagy 2021 05 15;17(5):1157-1169. Epub 2020 Apr 15.

Department of Biochemistry and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

The fusion of autophagosomes and endosomes/lysosomes, also called autophagosome maturation, ensures the degradation of autophagic cargoes. It is an important regulatory step of the macroautophagy/autophagy process. STX17 is the key autophagosomal SNARE protein that mediates autophagosome maturation. Here, we report that the acetylation of STX17 regulates its SNARE activity and autophagic degradation. The histone acetyltransferase CREBBP/CBP and the deacetylase HDAC2 specifically regulate the acetylation of STX17. In response to cell starvation and MTORC1 inhibition, the inactivation of CREBBP leads to the deacetylation of STX17 at its SNARE domain. This deacetylation promotes the interaction between STX17 and SNAP29 and the formation of the STX17-SNAP29-VAMP8 SNARE complex with no effect on the recruitment of STX17 to autophagosomal membranes. Deacetylation of STX17 also enhances the interaction between STX17 and the tethering complex HOPS, thereby further promoting autophagosome-lysosome fusion. Our study suggests a mechanism by which acetylation regulates the late-stage of autophagy, and possibly other STX17-related intracellular membrane fusion events. ACTB: actin beta; CREBBP/CBP: CREB binding protein; Ctrl: control; GFP: green fluorescent protein; GST: glutathione S-transferase; HDAC: histone deacetylase; HOPS: homotypic fusion and protein sorting complex; KO: knockout; LAMP1/2: lysosomal associated membrane protein 1/2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEFs: mouse embryonic fibroblasts; MS: mass spectrometry; MTORC1: mechanistic target of rapamycin kinase complex 1; NAM: nicotinamide; PtdIns3K: phosphatidylinositol 3-kinase; RFP: red fluorescent protein; SNAP29: synaptosome associated protein 29; SNARE: soluble N-ethylamide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TSA: trichostatin A; TSC1/2: TSC complex subunit 1/2; VAMP8: vesicle associated membrane protein 8; WT: wild type.
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http://dx.doi.org/10.1080/15548627.2020.1752471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143222PMC
May 2021

Subnanometer Bimetallic Platinum-Zinc Clusters in Zeolites for Propane Dehydrogenation.

Angew Chem Int Ed Engl 2020 Oct 11;59(44):19450-19459. Epub 2020 May 11.

State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, Jilin University, Changchun, 130012, P. R. China.

Propane dehydrogenation (PDH) has great potential to meet the increasing global demand for propylene, but the widely used Pt-based catalysts usually suffer from short-term stability and unsatisfactory propylene selectivity. Herein, we develop a ligand-protected direct hydrogen reduction method for encapsulating subnanometer bimetallic Pt-Zn clusters inside silicalite-1 (S-1) zeolite. The introduction of Zn species significantly improved the stability of the Pt clusters and gave a superhigh propylene selectivity of 99.3 % with a weight hourly space velocity (WHSV) of 3.6-54 h and specific activity of propylene formation of 65.5 mol  g  h (WHSV=108 h ) at 550 °C. Moreover, no obvious deactivation was observed over [email protected] catalyst even after 13000 min on stream (WHSV=3.6 h ), affording an extremely low deactivation constant of 0.001 h , which is 200 times lower than that of the PtZn4/Al O counterpart under the same conditions. We also show that the introduction of Cs ions into the zeolite can improve the regeneration stability of catalysts, and the catalytic activity kept unchanged after four continuous cycles.
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http://dx.doi.org/10.1002/anie.202003349DOI Listing
October 2020

BDF: A relativistic electronic structure program package.

J Chem Phys 2020 Feb;152(6):064113

Qingdao Institute for Theoretical and Computational Sciences, Shandong University, Qingdao, Shandong 266237, People's Republic of China.

The BDF (Beijing Density Functional) program package is in the first place a platform for theoretical and methodological developments, standing out particularly in relativistic quantum chemical methods for chemistry and physics of atoms, molecules, and periodic solids containing heavy elements. These include the whole spectrum of relativistic Hamiltonians and their combinations with density functional theory for the electronic structure of ground states as well as time-dependent and static density functional linear response theories for electronically excited states and electric/magnetic properties. However, not to be confused by its name, BDF nowadays comprises also of standard and novel wave function-based correlation methods for the ground and excited states of strongly correlated systems of electrons [e.g., multireference configuration interaction, static-dynamic-static configuration interaction, static-dynamic-static second-order perturbation theory, n-electron valence second-order perturbation theory, iterative configuration interaction (iCI), iCI with selection plus PT2, and equation-of-motion coupled-cluster]. Additional features of BDF include a maximum occupation method for finding excited states of Hartree-Fock/Kohn-Sham (HF/KS) equations, a very efficient localization of HF/KS and complete active space self-consistent field orbitals, and a unique solver for exterior and interior roots of large matrix eigenvalue problems.
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http://dx.doi.org/10.1063/1.5143173DOI Listing
February 2020

FAM134B oligomerization drives endoplasmic reticulum membrane scission for ER-phagy.

EMBO J 2020 03 13;39(5):e102608. Epub 2020 Jan 13.

Department of Biochemistry, Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Degradation of endoplasmic reticulum (ER) by selective autophagy (ER-phagy) is crucial for ER homeostasis. However, it remains unclear how ER scission is regulated for subsequent autophagosomal sequestration and lysosomal degradation. Here, we show that oligomerization of ER-phagy receptor FAM134B (also referred to as reticulophagy regulator 1 or RETREG1) through its reticulon-homology domain is required for membrane fragmentation in vitro and ER-phagy in vivo. Under ER-stress conditions, activated CAMK2B phosphorylates the reticulon-homology domain of FAM134B, which enhances FAM134B oligomerization and activity in membrane fragmentation to accommodate high demand for ER-phagy. Unexpectedly, FAM134B G216R, a variant derived from a type II hereditary sensory and autonomic neuropathy (HSAN) patient, exhibits gain-of-function defects, such as hyperactive self-association and membrane scission, which results in excessive ER-phagy and sensory neuron death. Therefore, this study reveals a mechanism of ER membrane fragmentation in ER-phagy, along with a signaling pathway in regulating ER turnover, and suggests a potential implication of excessive selective autophagy in human diseases.
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http://dx.doi.org/10.15252/embj.2019102608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049798PMC
March 2020
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