Publications by authors named "Ning Zheng"

195 Publications

Transcriptome analysis reveals changes in silkworm energy metabolism during Nosema bombycis infection.

Pestic Biochem Physiol 2021 May 27;174:104809. Epub 2021 Feb 27.

State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; Key Laboratory of Sericultural Biology and Genetic Breeding, Ministry of Agriculture, Ministry of Agriculture and Rural Affairs, Chongqing 400716, China. Electronic address:

Energy metabolism is important for the proliferation of microsporidia in infected host cells, but there is limited information on the host response. The energy metabolism response of silkworm (Bombyx mori) to microsporidia may help manage Nosema bombycis infections. We analyzed differentially expressed genes in the B.mori midgut transcriptome at two significant time points of microsporidia infection. A total of 1448 genes were up-regulated, while 315 genes were down-regulated. A high proportion of genes were involved in the phosphatidylinositol signaling system, protein processing in the endoplasmic reticulum, and glycerolipid metabolism at 48 h post infection (h p.i.), and a large number of genes were involved in the TCA cycle and protein processing at 120 h p.i. These results showed that the early stages of microsporidia infection affected the basic metabolism and biosynthesis processes of the silkworm. Knockout of Bm_nscaf2860_46 (Bombyx mori isocitrate dehydrogenase, BmIDH) and Bm_nscaf3027_062 (Bombyx mori hexokinase, BmHXK) reduced the production of ATP and inhibited microsporidia proliferation. Host fatty acid degradation, glycerol metabolism, glycolysis pathway, and TCA cycle response to microsporidia infection were also analyzed, and their importance to microsporidia proliferation was verified. These results increase our understanding of the molecular mechanisms involved in N. bombycis infection and provide new insights for research on microsporidia control. IMPORTANCE: Nosema bombycis can be vertically transmitted in silkworm eggs. The traditional prevention and control strategies for microsporidia are difficult and time-consuming, and this is a problem in silkworm culture. Research has mainly focused on host gene functions related to microsporidia infection and host immune responses after microsporidia infection. Little is known about the metabolic changes occurring in the host after infection. Understanding the metabolic changes in the silkworm host could aid in the recognition of host genes important for microsporidia infection and growth. We analyzed host metabolic changes and the main participating pathways at two time points after microsporidia infection and screened the microsporidia-dependent host energy metabolism genes BmIDH and BmHXK. The results revealed genes that are important for the proliferation of Nosema bombycis. These results illustrate how microsporidia hijack the host genome for their growth and reproduction.
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http://dx.doi.org/10.1016/j.pestbp.2021.104809DOI Listing
May 2021

Phylogenetic Distribution of Polysaccharide-Degrading Enzymes in Marine Bacteria.

Front Microbiol 2021 18;12:658620. Epub 2021 Mar 18.

Microbial Technology Institute and State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China.

Deconstruction is an essential step of conversion of polysaccharides, and polysaccharide-degrading enzymes play a key role in this process. Although there is recent progress in the identification of these enzymes, the diversity and phylogenetic distribution of these enzymes in marine microorganisms remain largely unknown, hindering our understanding of the ecological roles of marine microorganisms in the ocean carbon cycle. Here, we studied the phylogenetic distribution of nine types of polysaccharide-degrading enzymes in marine bacterial genomes. First, we manually compiled a reference sequence database containing 961 experimentally verified enzymes. With this reference database, we annotated 9,335 enzyme sequences from 2,182 high-quality marine bacterial genomes, revealing extended distribution for six enzymes at the phylum level and for all nine enzymes at lower taxonomic levels. Next, phylogenetic analyses revealed intra-clade diversity in the encoding potentials and phylogenetic conservation of a few enzymes at the genus level. Lastly, our analyses revealed correlations between enzymes, with alginate lyases demonstrating the most extensive correlations with others. Intriguingly, chitinases showed negative correlations with cellulases, alginate lyases, and agarases in a few genera. This result suggested that intra-genus lifestyle differentiation occurred many times in marine bacteria and that the utilization of polysaccharides may act as an important driver in the recent ecological differentiation of a few lineages. This study expanded our knowledge of the phylogenetic distribution of polysaccharide enzymes and provided insights into the ecological differentiation of marine bacteria.
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http://dx.doi.org/10.3389/fmicb.2021.658620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012555PMC
March 2021

Long-term microstructure and cerebral blood flow changes in patients recovered from COVID-19 without neurological manifestations.

J Clin Invest 2021 04;131(8)

Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

BACKGROUNDThe coronavirus disease 2019 (COVID-19) rapidly progressed to a global pandemic. Although some patients totally recover from COVID-19 pneumonia, the disease's long-term effects on the brain still need to be explored.METHODSWe recruited 51 patients with 2 subtypes of COVID-19 (19 mild and 32 severe) with no specific neurological manifestations at the acute stage and no obvious lesions on the conventional MRI 3 months after discharge. Changes in gray matter morphometry, cerebral blood flow (CBF), and white matter (WM) microstructure were investigated using MRI. The relationship between brain imaging measurements and inflammation markers was further analyzed.RESULTSCompared with healthy controls, the decrease in cortical thickness/CBF and the changes in WM microstructure were more severe in patients with severe disease than in those with mild disease, especially in the frontal and limbic systems. Furthermore, changes in brain microstructure, CBF, and tract parameters were significantly correlated (P < 0.05) with the inflammatory markers C-reactive protein, procalcitonin, and interleukin 6.CONCLUSIONIndirect injury related to inflammatory storm may damage the brain, altering cerebral volume, CBF, and WM tracts. COVID-19-related hypoxemia and dysfunction of vascular endothelium may also contribute to neurological changes. The abnormalities in these brain areas need to be monitored during recovery, which could help clinicians understand the potential neurological sequelae of COVID-19.FUNDINGNatural Science Foundation of China.
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http://dx.doi.org/10.1172/JCI147329DOI Listing
April 2021

Nontrivial Replication of Loci Detected by Multi-Trait Methods.

Front Genet 2021 3;12:627989. Epub 2021 Feb 3.

Biostatistics Group, School of Life Sciences and School of Ecology, Sun Yat-sen University, Guangzhou, China.

The ever-growing genome-wide association studies (GWAS) have revealed widespread pleiotropy. To exploit this, various methods that jointly consider associations of a genetic variant with multiple traits have been developed. Most efforts have been made concerning improving GWAS discovery power. However, how to replicate these discovered pleiotropic loci has yet to be discussed thoroughly. Unlike a single-trait scenario, multi-trait replication is not trivial considering the underlying genotype-multi-phenotype map of the associations. Here, we evaluate four methods for replicating multi-trait associations, corresponding to four levels of replication strength. Weak replication cannot justify pleiotropic genetic effects, whereas strong replication using our developed correlation methods can inform consistent pleiotropic genetic effects across the discovery and replication samples. We provide a protocol for replicating multi-trait genetic associations in practice. The described methods are implemented in the free and open-source R package MultiABEL.
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http://dx.doi.org/10.3389/fgene.2021.627989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886991PMC
February 2021

Regulatory mechanisms and therapeutic targeting of vasculogenic mimicry in hepatocellular carcinoma.

Pharmacol Res 2021 Apr 18;166:105507. Epub 2021 Feb 18.

Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China. Electronic address:

Hepatocellular carcinoma (HCC) is a typical hyper-vascular solid tumor; aberrantly rich in tumor vascular network contributes to its malignancy. Conventional anti-angiogenic therapies seem promising but transitory and incomplete efficacy on HCC. Vasculogenic mimicry (VM) is one of functional microcirculation patterns independent of endothelial vessels which describes the plasticity of highly aggressive tumor cells to form vasculogenic-like networks providing sufficient blood supply for tumor growth and metastasis. As a pivotal alternative mechanism for tumor vascularization when tumor cells undergo lack of oxygen and nutrients, VM has an association with the malignant phenotype and poor clinical outcome for HCC, and may challenge the classic anti-angiogenic treatment of HCC. Current studies have contributed numerous findings illustrating the underlying molecular mechanisms and signaling pathways supporting VM in HCC. In this review, we summarize the correlation between epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and VM, the role of hypoxia and extracellular matrix remodeling in VM, the involvement of adjacent non-cancerous cells, cytokines and growth factors in VM, as well as the regulatory influence of non-coding RNAs on VM in HCC. Moreover, we discuss the clinical significance of VM in practice and the potential therapeutic strategies targeting VM for HCC. A better understanding of the mechanism underlying VM formation in HCC may optimize anti-angiogenic treatment modalities for HCC.
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http://dx.doi.org/10.1016/j.phrs.2021.105507DOI Listing
April 2021

Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential.

Proc Natl Acad Sci U S A 2021 Feb;118(8)

Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574;

Cullin-RING (really intersting new gene) E3 ubiquitin ligases (CRLs) are the largest E3 family and direct numerous protein substrates for proteasomal degradation, thereby impacting a myriad of physiological and pathological processes including cancer. To date, there are no reported small-molecule inhibitors of the catalytic activity of CRLs. Here, we describe high-throughput screening and medicinal chemistry optimization efforts that led to the identification of two compounds, 33-11 and KH-4-43, which inhibit E3 CRL4 and exhibit antitumor potential. These compounds bind to CRL4's core catalytic complex, inhibit CRL4-mediated ubiquitination, and cause stabilization of CRL4's substrate CDT1 in cells. Treatment with 33-11 or KH-4-43 in a panel of 36 tumor cell lines revealed cytotoxicity. The antitumor activity was validated by the ability of the compounds to suppress the growth of human tumor xenografts in mice. Mechanistically, the compounds' cytotoxicity was linked to aberrant accumulation of CDT1 that is known to trigger apoptosis. Moreover, a subset of tumor cells was found to express cullin4 proteins at levels as much as 70-fold lower than those in other tumor lines. The low-cullin4-expressing tumor cells appeared to exhibit increased sensitivity to 33-11/KH-4-43, raising a provocative hypothesis for the role of low E3 abundance as a cancer vulnerability.
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http://dx.doi.org/10.1073/pnas.2007328118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923628PMC
February 2021

Genomic insights into antioxidant activities of Pyruvatibacter mobilis CGMCC 1.15125, a pyruvate-requiring bacterium isolated from the marine microalgae culture.

Mar Genomics 2021 Feb 19;55:100791. Epub 2020 Jun 19.

Microbial Technology Institute and State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China. Electronic address:

Pyruvate is a well-known scavenger of reactive oxygen species (ROS) like hydrogen peroxide and could prevent cells from oxidative damage. A pyruvate-requiring marine bacterium, Pyruvatibacter mobilis CGMCC 1.15125 (=KCTC 42509), was isolated from the culture broth of a photosynthetic marine microalga. Here we report the complete genome sequence of Pyruvatibacter mobilis, which contained a circular chromosome of 3,333,914 bp with a mean G + C content of 63.9%. Through genomic analysis, we revealed that strain CGMCC 1.15125 encodes genes for some antioxidants like superoxide dismutase, glutathione, rubrerythrin and globin to relieve cellular oxidative stress, while pyruvate added to the medium may reduce extracellular ROS. The genome features of P. mobilis provide further insights into the antioxidant activities of bacteria surviving in oxygen-enriched habitats.
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http://dx.doi.org/10.1016/j.margen.2020.100791DOI Listing
February 2021

[Population status and protection evaluation of a species with extremely small population.]

Ying Yong Sheng Tai Xue Bao 2021 Jan;32(1):103-112

Forestry Bureau of Yong'an City, Yong'an 366000, Fujian, China.

is a plant species with extremely small population and endemic to Yun-xiao County, Fujian Province. We examined its population status and conservation evaluation. The results showed that there were 25 individuals of , with only one mother tree. Except for the mother tree and one small tree, the others were all young seedlings, which was rare in abundance and lack of age stage of middle and strong trees. The spatial distribution of young seedlings was not uniform, with most of individuals within the range of 10-25 m from the mother tree. The age class structure of the population was not continuous and the population development was unsustainable. The competition mainly came from other species. accounted for 66.6% of the total competition index, which was much higher than other species. We established a comprehensive evaluation index system for the protection of rare and endangered plants with extremely small populations and evaluated the protection of from three aspects, , endangered degree, protection value, and protection priority. The endangered degree of was level Ⅰ (the endangered degree index was 4.510), belonging to extremely endangered species, the protection value was level Ⅰ (the protection value index was 4.052), which was of great value, and the protection priority was level Ⅰ (the protection priority index was 4.016), which should be listed as the highest priority protection level.
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http://dx.doi.org/10.13287/j.1001-9332.202101.007DOI Listing
January 2021

Genetic bioengineering of overexpressed guanylate binding protein family BmAtlastin-n enhances silkworm resistance to Nosema bombycis.

Int J Biol Macromol 2021 Mar 13;172:223-230. Epub 2021 Jan 13.

State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; Key Laboratory of Sericultural Biology and Genetic Breeding, Ministry of Agriculture, Southwest University, Chongqing 400716, China. Electronic address:

Microsporidia are obligate single-celled eukaryote parasites. Microsporidian infection can cause large economic losses to beneficial insects such as silkworms and honey bees. Identification of resistance biomacromolecules and breeding of transgenic lines resistant to the microsporidian Nosema bombycis are important for disease management. We previously used transcriptome analysis to identify a guanylate binding protein family BmAtlastin-n gene that was significantly upregulated after Nosema bombycis infection, and we determined that the molecule was highly expressed in resistance-related tissues such as the midgut, fat body and the epidermis. The transgenic silkworm line overexpressing BmAtlastin-n biomolecules had economic characters similar to those of non-transgenic lines. The transgenic OE-BmAtlastin-n lines had significantly improved survival after microspore infection. We used RT-PCR and H&E staining to show that the number of spores in the transgenic lines was significantly lower than in the control lines. In this study, we identified a BmAtlastin-n macromolecule with resistance to N. bombycis and developed a transgenic line. The results improved understanding of the GBP protein family and provided biomacromolecule material for the treatment and prevention of microsporidia.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.01.021DOI Listing
March 2021

Regorafenib inhibits migration, invasion, and vasculogenic mimicry of hepatocellular carcinoma via targeting ID1-mediated EMT.

Mol Carcinog 2021 02 11;60(2):151-163. Epub 2021 Jan 11.

Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, China.

Regorafenib is approved for patients with unresectable hepatocellular carcinoma (HCC) following sorafenib. However, the effect of regorafenib on HCC metastasis and its mechanism are poorly understood. Here, our data showed that regorafenib significantly restrained the migration, invasion and vasculogenic mimicry (VM) of HCC cells, and downregulated the expression of epithelial-to-mesenchymal transition (EMT)/VM-related molecules. Using RNA-seq and cellular thermal shift assays, we found that inhibitor of differentiation 1 (ID1) was a key target of regorafenib. In HCC tissues, the protein expression of ID1 was positively correlated with EMT and VM formation (CD34 /PAS ). Functionally, ID1 knockdown inhibited HCC cell migration, invasion, metastasis, and VM formation in vitro and in vivo, with upregulation of E-cadherin and downregulation of Snail and VE-cadherin. Moreover, Snail overexpression promoted the migration, invasion, and VM formation of ID1 knockdown cells. Snail knockdown reduced the migration, invasion, and VM formation of ID1 overexpression cells. Finally, regorafenib suppressed VM formation and decreased the expression of ID1, VE-cadherin and Snail in HCC PDX model. In conclusion, we manifested that regorafenib distinctly inhibited EMT in HCC cells via targeting ID1, leading to the suppression of cell migration, invasion and VM formation. These findings suggest that regorafenib may be developed as a suitable therapeutic agent for HCC metastasis.
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http://dx.doi.org/10.1002/mc.23279DOI Listing
February 2021

Structural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin.

Nat Commun 2021 01 4;12(1):128. Epub 2021 Jan 4.

Department of Pharmacology, University of Washington, Seattle, WA, 98195, USA.

Voltage-gated sodium (Na) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The α-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac Na1.5 channels with IC = 11.4 nM. Here we reveal the structure of LqhIII bound to Na1.5 at 3.3 Å resolution by cryo-EM. LqhIII anchors on top of voltage-sensing domain IV, wedged between the S1-S2 and S3-S4 linkers, which traps the gating charges of the S4 segment in a unique intermediate-activated state stabilized by four ion-pairs. This conformational change is propagated inward to weaken binding of the fast inactivation gate and favor opening the activation gate. However, these changes do not permit Na permeation, revealing why LqhIII slows inactivation of Na channels but does not open them. Our results provide important insights into the structural basis for gating-modifier toxin binding, voltage-sensor trapping, and fast inactivation of Na channels.
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http://dx.doi.org/10.1038/s41467-020-20078-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782738PMC
January 2021

Dynamic Covalent Polymer Networks: A Molecular Platform for Designing Functions beyond Chemical Recycling and Self-Healing.

Chem Rev 2021 Feb 4;121(3):1716-1745. Epub 2021 Jan 4.

State Key Laboratory of Chemical Engineering, College of Chemical and Biological Engineering, Zhejiang University, 38 Zheda Road, Hangzhou, 310027, People's Republic of China.

Dynamic covalent polymer networks (DCPN) have historically attracted attention for their unique roles in chemical recycling and self-healing, which are both relevant for sustainable societal development. Efforts in these directions have intensified in the past decade with notable progress in newly discovered dynamic covalent chemistry, fundamental material concepts, and extension toward emerging applications including energy and electronic devices. Beyond that, the values of DCPN in discovering/designing functional properties not offered by classical thermoplastic and thermoset polymers have recently gained traction. In particular, the dynamic bond exchangeability of DCPN has shown unparalleled design versatility in various areas including shape-shifting materials/devices, artificial muscles, and microfabrication. Going beyond this basic bond exchangeability, various molecular mechanisms to manipulate network topologies (topological transformation) have led to opportunities to program polymers, with notable concepts such as living networks and topological isomerization. In this review, we provide an overview of the above progress with particular focuses on molecular design strategies for the exploitation of functional material properties. Based on this, we point out the remaining issues and offer perspectives on how this class of materials can shape the future in ways that are complementary with classical thermoplastic and thermoset polymers.
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http://dx.doi.org/10.1021/acs.chemrev.0c00938DOI Listing
February 2021

Stretchable, dynamic covalent polymers for soft, long-lived bioresorbable electronic stimulators designed to facilitate neuromuscular regeneration.

Nat Commun 2020 11 25;11(1):5990. Epub 2020 Nov 25.

Center for Bio-Integrated Electronics, Northwestern University, Evanston, IL, 60208, USA.

Bioresorbable electronic stimulators are of rapidly growing interest as unusual therapeutic platforms, i.e., bioelectronic medicines, for treating disease states, accelerating wound healing processes and eliminating infections. Here, we present advanced materials that support operation in these systems over clinically relevant timeframes, ultimately bioresorbing harmlessly to benign products without residues, to eliminate the need for surgical extraction. Our findings overcome key challenges of bioresorbable electronic devices by realizing lifetimes that match clinical needs. The devices exploit a bioresorbable dynamic covalent polymer that facilitates tight bonding to itself and other surfaces, as a soft, elastic substrate and encapsulation coating for wireless electronic components. We describe the underlying features and chemical design considerations for this polymer, and the biocompatibility of its constituent materials. In devices with optimized, wireless designs, these polymers enable stable, long-lived operation as distal stimulators in a rat model of peripheral nerve injuries, thereby demonstrating the potential of programmable long-term electrical stimulation for maintaining muscle receptivity and enhancing functional recovery.
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http://dx.doi.org/10.1038/s41467-020-19660-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688647PMC
November 2020

Image Forgery Detection and Localization via a Reliability Fusion Map.

Sensors (Basel) 2020 Nov 21;20(22). Epub 2020 Nov 21.

School of Cyberspace, Hangzhou Dianzi University, Hangzhou 310018, China.

Moving away from hand-crafted feature extraction, the use of data-driven convolution neural network (CNN)-based algorithms facilitates the realization of end-to-end automated forgery detection in multimedia forensics. On the basis of fingerprints acquired by images from different camera models, the goal of this paper is to design an effective detector capable of completing image forgery detection and localization. Specifically, relying on the designed constant high-pass filter, we first establish a well-performing CNN architecture to adaptively and automatically extract characteristics, and design a reliability fusion map (RFM) to improve localization resolution, and tamper detection accuracy. The extensive results from our empirical experiments demonstrate the effectiveness of our proposed RFM-based detector, and its better performance than other competing approaches.
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http://dx.doi.org/10.3390/s20226668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700526PMC
November 2020

Structural Basis for High-Affinity Trapping of the Na1.7 Channel in Its Resting State by Tarantula Toxin.

Mol Cell 2021 01 23;81(1):38-48.e4. Epub 2020 Nov 23.

Department of Pharmacology, University of Washington, Seattle, WA 98195, USA. Electronic address:

Voltage-gated sodium channels initiate electrical signals and are frequently targeted by deadly gating-modifier neurotoxins, including tarantula toxins, which trap the voltage sensor in its resting state. The structural basis for tarantula-toxin action remains elusive because of the difficulty of capturing the functionally relevant form of the toxin-channel complex. Here, we engineered the model sodium channel NaAb with voltage-shifting mutations and the toxin-binding site of human Na1.7, an attractive pain target. This mutant chimera enabled us to determine the cryoelectron microscopy (cryo-EM) structure of the channel functionally arrested by tarantula toxin. Our structure reveals a high-affinity resting-state-specific toxin-channel interaction between a key lysine residue that serves as a "stinger" and penetrates a triad of carboxyl groups in the S3-S4 linker of the voltage sensor. By unveiling this high-affinity binding mode, our studies establish a high-resolution channel-docking and resting-state locking mechanism for huwentoxin-IV and provide guidance for developing future resting-state-targeted analgesic drugs.
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http://dx.doi.org/10.1016/j.molcel.2020.10.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043720PMC
January 2021

The conformational cycle of a prototypical voltage-gated sodium channel.

Nat Chem Biol 2020 12 16;16(12):1314-1320. Epub 2020 Nov 16.

Department of Pharmacology and Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.

Electrical signaling was a dramatic development in evolution, allowing complex single-cell organisms like Paramecium to coordinate movement and early metazoans like worms and jellyfish to send regulatory signals rapidly over increasing distances. But how are electrical signals generated in biology? In fact, voltage-gated sodium channels conduct sodium currents that initiate electrical signals in all kingdoms of life, from bacteria to man. They are responsible for generating the action potential in vertebrate nerve and muscle, neuroendocrine cells, and other cell types. Because of the high level of conservation of their core structure, it is likely that their fundamental mechanisms of action are conserved as well. Here we describe the complete cycle of conformational changes that a bacterial sodium channel undergoes as it transitions from resting to activated/open and inactivated/closed states, based on high-resolution structural studies of a single sodium channel. We further relate this conformational cycle of the ancestral sodium channel to the function of its vertebrate orthologs. The strong conservation of amino acid sequence and three-dimensional structure suggests that this model, at a fundamental level, is relevant for both prokaryotic and eukaryotic sodium channels, as well as voltage-gated calcium and potassium channels.
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http://dx.doi.org/10.1038/s41589-020-0644-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678813PMC
December 2020

Comparison of the gut microbiota of short-term and long-term medical workers and non-medical controls: a cross-sectional analysis.

Clin Microbiol Infect 2020 Nov 4. Epub 2020 Nov 4.

Department of Microbiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China. Electronic address:

Objectives: The hospital environment has been implicated in the enrichment and exchange of pathogens and antibiotic resistance, but its potential in shaping the symbiotic microbial community of hospital staff is unclear. This study was designed to evaluate the alteration of the gut microbiome in medical workers compared to non-medical controls.

Methods: A prospective cross-sectional cohort study was conducted in the intensive care unit (ICU) and other departments of a centre in north-eastern China. Faecal samples of 175 healthy medical workers-short-term (1-3 months) workers (n = 80) and long-term (>1 year) workers (n = 95)-and 80 healthy non-medical controls were analysed using 16S rRNA amplicon sequencing. The hospital environmental samples (n = 9) were also analysed.

Results: The gut microbiomes of medical workers exhibited marked deviations in diversity and alteration in microbial composition and function. Short-term workers showed significantly higher abundances of taxa such as Lactobacillus, Butyrivibrio, Clostridiaceae, Clostridium, Ruminococcus, Dialister, Bifidobacterium, Odoribacter, and Desulfovibrio and lower abundances of Bacteroides and Blautia than the controls. Long-term workers showed higher abundances of taxa such as Dialister, Veillonella, Clostridiaceae, Clostridium, Bilophila, Desulfovibrio, Pseudomonas, and Akkermansia and lower abundances of Bacteroides and Coprococcus than the controls. The medical workers' department (ICU versus non-ICU) and position (resident doctor versus nursing staff) also impacted their gut microbiome. Compared with the non-ICU workers, workers in the ICU showed a significant increase in the abundances of Dialister, Enterobacteriaceae, Phascolarctobacterium, Pseudomonas, Veillonella, and Streptococcus and a marked depletion of Faecalibacterium, Blautia, and Coprococcus. In contrast with the nursing staff, the resident doctors showed a significant increase in Erysipelotrichaceae and Clostridium and a decrease in Bacteroides, Blautia, and Ruminococcus in the gut microbiome. Moreover, we found that the microbiota of hospital environments potentially correlated with the workers' gut microbiota.

Conclusions: Our findings demonstrated structural changes in the gut microbial community of medical workers.
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http://dx.doi.org/10.1016/j.cmi.2020.10.033DOI Listing
November 2020

On demand shape memory polymer via light regulated topological defects in a dynamic covalent network.

Nat Commun 2020 08 26;11(1):4257. Epub 2020 Aug 26.

State Key Laboratory of Chemical Engineering, College of Chemical and Biological Engineering, Zhejiang University, 310027, Hangzhou, China.

The ability to undergo bond exchange in a dynamic covalent polymer network has brought many benefits not offered by classical thermoplastic and thermoset polymers. Despite the bond exchangeability, the overall network topologies for existing dynamic networks typically cannot be altered, limiting their potential expansion into unexplored territories. By harnessing topological defects inherent in any real polymer network, we show herein a general design that allows a dynamic network to undergo rearrangement to distinctive topologies. The use of a light triggered catalyst further allows spatio-temporal regulation of the network topology, leading to an unusual opportunity to program polymer properties. Applying this strategy to functional shape memory networks yields custom designable multi-shape and reversible shape memory characteristics. This molecular principle expands the design versatility for network polymers, with broad implications in many other areas including soft robotics, flexible electronics, and medical devices.
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http://dx.doi.org/10.1038/s41467-020-18116-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450050PMC
August 2020

Structural basis of salicylic acid perception by Arabidopsis NPR proteins.

Nature 2020 10 12;586(7828):311-316. Epub 2020 Aug 12.

Department of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.

Salicylic acid (SA) is a plant hormone that is critical for resistance to pathogens. The NPR proteins have previously been identified as SA receptors, although how they perceive SA and coordinate hormonal signalling remain unknown. Here we report the mapping of the SA-binding core of Arabidopsis thaliana NPR4 and its ligand-bound crystal structure. The SA-binding core domain of NPR4 refolded with SA adopts an α-helical fold that completely buries SA in its hydrophobic core. The lack of a ligand-entry pathway suggests that SA binding involves a major conformational remodelling of the SA-binding core of NPR4, which we validated using hydrogen-deuterium-exchange mass spectrometry analysis of the full-length protein and through SA-induced disruption of interactions between NPR1 and NPR4. We show that, despite the two proteins sharing nearly identical hormone-binding residues, NPR1 displays minimal SA-binding activity compared to NPR4. We further identify two surface residues of the SA-binding core, the mutation of which can alter the SA-binding ability of NPR4 and its interaction with NPR1. We also demonstrate that expressing a variant of NPR4 that is hypersensitive to SA could enhance SA-mediated basal immunity without compromising effector-triggered immunity, because the ability of this variant to re-associate with NPR1 at high levels of SA remains intact. By revealing the structural mechanisms of SA perception by NPR proteins, our work paves the way for future investigation of the specific roles of these proteins in SA signalling and their potential for engineering plant immunity.
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http://dx.doi.org/10.1038/s41586-020-2596-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554156PMC
October 2020

[Quantitative determination and optimun extraction technique of nine compounds of ].

Zhejiang Da Xue Xue Bao Yi Xue Ban 2020 May;49(3):356-363

Medical College of Jiaxing University, Jiaxing 314001, Zhejiang Province, China.

Objective: To establish the optimum extraction technique and high performance liquid chromatographic (HPLC) method to simultaneously quantify nine compounds of gallic acid, hydroxy-paeoniflorin, catechin, albiflorin, paeoniflorin, pentagalloylglucose, benzoic acid, benzoylpaeoniflorin and paeonol in .

Methods: Linear gradient elution was applied using water containing 0.1%phosphoric acid and acetonitrile as the mobile phase with a flow rate of 0.8 mL/min, column temperature of 30℃ and wavelength of 230 nm. The method of ultrasound extraction was used. Methanol and ethanol were used as extraction solvents, and three factors and three levels of orthogonal experiments was designed using L (3 ) table to investigate the effects of solvent concentration, ratio of liquid to material and extraction time on the total content of nine components of .

Results: HPLC method was verified to have high specificity, sensitivity and accuracy through methodological validation, and it could be used for simultaneous quantitative analysis of nine components of . The results showed that the optimum extraction technology of nine components of was using 70%ethanol as extraction solvent, ratio of liquid to material was 200 mL/g and ultrasound extraction time was 30 min.

Conclusions: HPLC method for the simultaneous determination of nine components of is established, and the optimum extraction technology is confirmed.
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http://dx.doi.org/10.3785/j.issn.1008-9292.2020.05.01DOI Listing
May 2020

Investigation of robust visual reaction and functional connectivity in the rat brain induced by rocuronium bromide with functional MRI.

Am J Transl Res 2020 15;12(6):2396-2408. Epub 2020 Jun 15.

Center of Brain Science, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences Wuhan 430071, Hubei, P. R. China.

Functional magnetic resonance imaging (fMRI) has been used extensively to understand the brain function of a wide range of neurological and psychiatric disorders. When applied to animal studies, anesthesia is always used to reduce the movement of the animal and also reduce the impacts on the results of fMRI. Several awake models have been proposed by applying physical animal movement restrictions. However, restraining devices were designed for individual subject which limits the promotion of fMRI in awake animals. Here, a clinical muscle relaxant rocuronium bromide (RB) was introduced to restrain the animal in fMRI scanning time. The fMRI reactions of the animal induced with RB and the other two commonly used anesthesia protocols were investigated. The results of the fMRI showed that there were increased functional connectivity and well-round visual responses in the RB induced state. Furthermore, significant BOLD signal changes were found in the cortex and thalamus regions when the animal revived from isoflurane, which should be essential to further understand the effects of anesthesia on the brain.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344061PMC
June 2020

High-definition likelihood inference of genetic correlations across human complex traits.

Nat Genet 2020 08 29;52(8):859-864. Epub 2020 Jun 29.

Biostatistics Group, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.

Genetic correlation is a central parameter for understanding shared genetic architecture between complex traits. By using summary statistics from genome-wide association studies (GWAS), linkage disequilibrium score regression (LDSC) was developed for unbiased estimation of genetic correlations. Although easy to use, LDSC only partially utilizes LD information. By fully accounting for LD across the genome, we develop a high-definition likelihood (HDL) method to improve precision in genetic correlation estimation. Compared to LDSC, HDL reduces the variance of genetic correlation estimates by about 60%, equivalent to a 2.5-fold increase in sample size. We apply HDL and LDSC to estimate 435 genetic correlations among 30 behavioral and disease-related phenotypes measured in the UK Biobank (UKBB). In addition to 154 significant genetic correlations observed for both methods, HDL identified another 57 significant genetic correlations, compared to only another 2 significant genetic correlations identified by LDSC. HDL brings more power to genomic analyses and better reveals the underlying connections across human complex traits.
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http://dx.doi.org/10.1038/s41588-020-0653-yDOI Listing
August 2020

Epithelial salivary gland tumors: Utility of radiomics analysis based on diffusion-weighted imaging for differentiation of benign from malignant tumors.

J Xray Sci Technol 2020 ;28(4):799-808

Medical Imaging Research Institute, Binzhou Medical University, Yantai, Shandong, China.

Objective: To evaluate the utility of radiomics analysis for differentiating benign and malignant epithelial salivary gland tumors on diffusion-weighted imaging (DWI).

Methods: A retrospective dataset involving 218 and 51 patients with histology-confirmed benign and malignant epithelial salivary gland tumors was used in this study. A total of 396 radiomic features were extracted from the DW images. Analysis of variance (ANOVA) and least-absolute shrinkage and selection operator regression (LASSO) were used to select optimal radiomic features. The selected features were used to build three classification models namely, logistic regression method (LR), support vector machine (SVM), and K-nearest neighbor (KNN) by using a five-fold cross validation strategy on the training dataset. The diagnostic performance of each classification model was quantified by receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) in the training and validation datasets.

Results: Eight most valuable features were selected by LASSO. LR and SVM models yielded optimally diagnostic performance. In the training dataset, LR and SVM yielded AUC values of 0.886 and 0.893 via five-fold cross validation, respectively, while KNN model showed relatively lower AUC (0.796). In the testing dataset, a similar result was found, where AUC values for LR, SVM, and KNN were 0.876, 0.870, and 0.791, respectively.

Conclusions: Classification models based on optimally selected radiomics features computed from DW images present a promising predictive value in distinguishing benign and malignant epithelial salivary gland tumors and thus have potential to be used for preoperative auxiliary diagnosis.
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http://dx.doi.org/10.3233/XST-190632DOI Listing
January 2020

A novel system to rapidly detect protein-protein interactions (PPIs) based on fluorescence co-localization.

Biotechnol Lett 2020 Nov 13;42(11):2111-2122. Epub 2020 Jun 13.

State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400716, China.

Objective: Rapid and convenient detection of protein-protein interactions (PPIs) is of great significance for understanding function of protein.

Results: For efficiently detecting PPIs, we used the changes of proteins fluorescence localization to design a novel system, fluorescence translocation co-localization (FTCL), based on nuclear localization signal (NLS) in living cells. Depending on the original state of protein localization (both in the cytoplasm, both in the nucleus, one in the nucleus and another in the cytoplasm), two target proteins can be partitioned into the cytoplasm and nucleus by adding a NLS or mutating an existing NLS. Three independent results display that the changes of protein fluorescence co-localization were observed following co-expression of the two target proteins. At the same time, we verified the accuracy of fluorescence co-localization by co-immunoprecipitation.

Conclusions: There FTCL system provided a novel detection method for PPIs, regardless of protein localization in the nucleus or cytoplasm. More importantly, this study provides a new strategy for future protein interaction studies through organelle localization (such as mitochondria, Golgi and cytomembrane, etc.).
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http://dx.doi.org/10.1007/s10529-020-02934-wDOI Listing
November 2020

Oscillating collective motion of active rotors in confinement.

Proc Natl Acad Sci U S A 2020 06 19;117(22):11901-11907. Epub 2020 May 19.

Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China;

Due to its inherent out-of-equilibrium nature, active matter in confinement may exhibit collective behavior absent in unconfined systems. Extensive studies have indicated that hydrodynamic or steric interactions between active particles and boundary play an important role in the emergence of collective behavior. However, besides introducing external couplings at the single-particle level, the confinement also induces an inhomogeneous density distribution due to particle-position correlations, whose effect on collective behavior remains unclear. Here, we investigate this effect in a minimal chiral active matter composed of self-spinning rotors through simulation, experiment, and theory. We find that the density inhomogeneity leads to a position-dependent frictional stress that results from interrotor friction and couples the spin to the translation of the particles, which can then drive a striking spatially oscillating collective motion of the chiral active matter along the confinement boundary. Moreover, depending on the oscillation properties, the collective behavior has three different modes as the packing fraction varies. The structural origins of the transitions between the different modes are well identified by the percolation of solid-like regions or the occurrence of defect-induced particle rearrangement. Our results thus show that the confinement-induced inhomogeneity, dynamic structure, and compressibility have significant influences on collective behavior of active matter and should be properly taken into account.
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http://dx.doi.org/10.1073/pnas.1922633117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275704PMC
June 2020

Association between 5-HT gene polymorphism rs140700 and primary insomnia in Chinese population.

Intern Med J 2020 Mar 9. Epub 2020 Mar 9.

Sleep Medicine Center of Gansu Provincial Hospital, Lanzhou, China.

Background: Primary insomnia is a worldwide problem and it has a considerable negative impact on one's physical and mental health. Studies have shown that non-synonymous SNPs in 5-hydroxytryptamine(serotonin or 5 -HT)are related to primary insomnia. Previous studies have shown that 5 -HT polymorphism (rs140700) is related to depression, and insomnia is often accompanied by depression and anxiety. The relationship between this site and primary insomnia is unknown. We speculated that this site may be related to primary insomnia, so we investigated the relationship between rs140700 and primary insomnia.

Methods: In this study, we included 57 patients with primary insomnia and 54 age- and gender-matched normal controls. The subjects belonged to the Chinese population were subjected to polysomnography for three consecutive nights. Their sleep quality was assessed, and the genotypes of the 5-HT gene polymorphism rs140700 were determined by the Flight Mass Spectrometry.

Results: The genotype distributions of the 5-HTgene polymorphism rs140700 were in Hardy-Weinberg equilibrium in both patients and controls (P > 0.05). The allele and genotype distributions of this variant were comparable between the patients and controls in all subjects and between genders (all P > 0.05). The influence of rs140700 on S1% (P = 0.015) change and arousal index(P = 0.028) of primary insomnia was statistically significant. The logistic multi-factor regression analysis results revealed that 5-HT gene polymorphism rs140700 was not a risk factor for primary insomnia in Chinese population (P = 0.589).

Conclusion: The 5-HT gene polymorphism rs140700 may not be a susceptibility locus for primary insomnia in the Chinese population. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.14813DOI Listing
March 2020

FBXL5 Regulates IRP2 Stability in Iron Homeostasis via an Oxygen-Responsive [2Fe2S] Cluster.

Mol Cell 2020 04 2;78(1):31-41.e5. Epub 2020 Mar 2.

Department of Pharmacology, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address:

Cellular iron homeostasis is dominated by FBXL5-mediated degradation of iron regulatory protein 2 (IRP2), which is dependent on both iron and oxygen. However, how the physical interaction between FBXL5 and IRP2 is regulated remains elusive. Here, we show that the C-terminal substrate-binding domain of FBXL5 harbors a [2Fe2S] cluster in the oxidized state. A cryoelectron microscopy (cryo-EM) structure of the IRP2-FBXL5-SKP1 complex reveals that the cluster organizes the FBXL5 C-terminal loop responsible for recruiting IRP2. Interestingly, IRP2 binding to FBXL5 hinges on the oxidized state of the [2Fe2S] cluster maintained by ambient oxygen, which could explain hypoxia-induced IRP2 stabilization. Steric incompatibility also allows FBXL5 to physically dislodge IRP2 from iron-responsive element RNA to facilitate its turnover. Taken together, our studies have identified an iron-sulfur cluster within FBXL5, which promotes IRP2 polyubiquitination and degradation in response to both iron and oxygen concentrations.
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http://dx.doi.org/10.1016/j.molcel.2020.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159994PMC
April 2020

Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing.

Elife 2020 02 26;9. Epub 2020 Feb 26.

Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, United States.

Mammalian circadian rhythms are generated by a transcription-based feedback loop in which CLOCK:BMAL1 drives transcription of its repressors (PER1/2, CRY1/2), which ultimately interact with CLOCK:BMAL1 to close the feedback loop with ~24 hr periodicity. Here we pinpoint a key difference between CRY1 and CRY2 that underlies their differential strengths as transcriptional repressors. Both cryptochromes bind the BMAL1 transactivation domain similarly to sequester it from coactivators and repress CLOCK:BMAL1 activity. However, we find that CRY1 is recruited with much higher affinity to the PAS domain core of CLOCK:BMAL1, allowing it to serve as a stronger repressor that lengthens circadian period. We discovered a dynamic serine-rich loop adjacent to the secondary pocket in the photolyase homology region (PHR) domain that regulates differential binding of cryptochromes to the PAS domain core of CLOCK:BMAL1. Notably, binding of the co-repressor PER2 remodels the serine loop of CRY2, making it more CRY1-like and enhancing its affinity for CLOCK:BMAL1.
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http://dx.doi.org/10.7554/eLife.55275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064333PMC
February 2020

Structure of an Inner Membrane Protein Required for PhoPQ-Regulated Increases in Outer Membrane Cardiolipin.

mBio 2020 02 11;11(1). Epub 2020 Feb 11.

Department of Microbiology, University of Washington, Seattle, Washington, USA

The subsp. serovar Typhimurium PhoPQ two-component system is activated within the intracellular phagosome environment, where it promotes remodeling of the outer membrane and resistance to innate immune antimicrobial peptides. Maintenance of the PhoPQ-regulated outer membrane barrier requires PbgA, an inner membrane protein with a transmembrane domain essential for growth, and a periplasmic domain required for PhoPQ-activated increases in outer membrane cardiolipin. Here, we report the crystal structure of cardiolipin-bound PbgA, adopting a novel transmembrane fold that features a cardiolipin binding site in close proximity to a long and deep cleft spanning the lipid bilayer. The end of the cleft extends into the periplasmic domain of the protein, which is structurally coupled to the transmembrane domain via a functionally critical C-terminal helix. In conjunction with a conserved putative catalytic dyad situated at the middle of the cleft, our structural and mutational analyses suggest that PbgA is a multifunction membrane protein that mediates cardiolipin transport, a function essential for growth, and perhaps catalysis of an unknown enzymatic reaction. Gram-negative bacteria cause many types of infections and have become increasingly resistant to available antibiotic drugs. The outer membrane serves as an important barrier that protects bacteria against antibiotics and other toxic compounds. This outer membrane barrier function is regulated when bacteria are in host environments, and the protein PbgA contributes significantly to this increased barrier function by transporting cardiolipin to the outer membrane. We determined the crystal structure of PbgA in complex with cardiolipin and propose a model for its function. Knowledge of the mechanisms of outer membrane assembly and integrity can greatly contribute to the development of new and effective antibiotics, and this structural information may be useful in this regard.
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http://dx.doi.org/10.1128/mBio.03277-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018646PMC
February 2020