Publications by authors named "Haili Zhang"

108 Publications

Development of selective bispecific Wnt mimetics for bone loss and repair.

Nat Commun 2021 05 31;12(1):3247. Epub 2021 May 31.

Surrozen, Inc., South San Francisco, CA, USA.

The Wnt signaling pathway is intricately connected with bone mass regulation in humans and rodent models. We designed an antibody-based platform that generates potent and selective Wnt mimetics. Using this platform, we engineer bi-specific Wnt mimetics that target Frizzled and low-density lipoprotein receptor-related proteins and evaluate their effects on bone accrual in murine models. These synthetic Wnt agonists induce rapid and robust bone building effects, and correct bone mass deficiency and bone defects in various disease models, including osteoporosis, aging, and long bone fracture. Furthermore, when these Wnt agonists are combined with antiresorptive bisphosphonates or anti-sclerostin antibody therapies, additional bone accrual/maintenance effects are observed compared to monotherapy, which could benefit individuals with severe and/or acute bone-building deficiencies. Our data support the continued development of Wnt mimetics for the treatment of diseases of low bone mineral density, including osteoporosis.
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http://dx.doi.org/10.1038/s41467-021-23374-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167098PMC
May 2021

Laparoscopic liver resection for hepatocellular carcinoma presents less respiratory complications compared with open procedure: A propensity score analysis in the elderly.

Eur J Surg Oncol 2021 Apr 30. Epub 2021 Apr 30.

Department of Biliary Surgery, West China Hospital of Sichuan University, No. 37 Guo Xue Xiang, 610041, Chengdu, Sichuan Province, PR China. Electronic address:

Background: Resection is still the most efficacious treatment to hepatocellular carcinoma (HCC), among which laparoscopic liver resection (LLR) have controversial effects against conventional open procedure (OLR). With a predictable aging tendency of population worldwide, conventional surgical procedures need to be modified to better accommodate elderly patients. Here, we designed a retrospective study based on propensity score analysis, aiming to compare the efficacy of OLR and LLR in patients over 65 years.

Methods: We retrospectively analyzed patients with an age over 65 who underwent liver resection between January 2015 and September 2018. Patients were divided into the LLR group and OLR group. Short-term and long-term outcomes were compared before and after 1:1 propensity score matching.

Results: Among 240 enrolled patients, 142 were matched with comparable baseline (71 each group). In the matched cohort, LLR group presented with shorter postoperative hospital stay (median 7 vs 6 days, p = 0.003) and fewer respiratory complications (19.7% vs. 7.0%, p = 0.049), especially pleural effusion (15.5% vs. 2.8%, p = 0.020). Meanwhile, LLR had comparable overall hospital cost (6142 vs. 6243 USD, p = 0.977) compared with OLR. The overall survival (OS) and disease-free survival (DFS) did not differ in the two groups.

Conclusions: Our study showed that laparoscopic liver resection for HCC in the older age groups is associated with shorter postoperative hospital stay and comparable hospital cost compared with open procedure, which could be attributable to less respiratory complications. We recommend that laparoscopy be taken as a priority option for elderly patients with resectable HCC.
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http://dx.doi.org/10.1016/j.ejso.2021.04.032DOI Listing
April 2021

PAL-mediated SA biosynthesis pathway contributes to nematode resistance in wheat.

Plant J 2021 May 11. Epub 2021 May 11.

Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China.

The pathogen cereal cyst nematode (CCN) is deleterious to Triticeae crops and is a threat to the global crop yield. Accession no. 1 of Aegilops variabilis, a relative of Triticum aestivum (bread wheat), is highly resistant to CCN. Our previous study demonstrated that the expression of the phenylalanine ammonia lyase (PAL) gene AevPAL1 in Ae. variabilis is strongly induced by CCN. PAL, the first enzyme of phenylpropanoid metabolism, is involved in abiotic and biotic stress responses. However, its role in plant-CCN interaction remains unknown. In the present study, we proved that AevPAL1 helps to confer CCN resistance through affecting the synthesis of salicylic acid (SA) and downstream secondary metabolites. The silencing of AevPAL1 increased the incidence of CCN infection in roots and decreased the accumulation of SA and phenylalanine (Phe)-derived specialized metabolites. The exogenous pre-application of SA also improved CCN resistance. Additionally, the functions of PAL in phenylpropanoid metabolism correlated with tryptophan decarboxylase (TDC) functioning in tryptophan metabolism pathways. The silencing of either AevPAL1 or AevTDC1 exhibited a concomitant reduction in the expression of both genes and the contents of metabolites downstream of PAL and TDC. These results suggested that AevPAL1, possibly in coordination with AevTDC1, positively contributes to CCN resistance by altering the downstream secondary metabolites and SA content in Ae. variabilis. Moreover, AevPAL1 overexpression significantly enhanced CCN resistance in bread wheat and did not exhibit significant negative effects on yield-related traits, suggesting that AevPAL1 is valuable for the genetic improvement of CCN resistance in bread wheat.
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http://dx.doi.org/10.1111/tpj.15316DOI Listing
May 2021

Identification and candidate gene mining of HvSS1, a novel qualitative locus on chromosome 6H, regulating the uppermost internode elongation in barley (Hordeum vulgare L.).

Theor Appl Genet 2021 May 3. Epub 2021 May 3.

Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, Sichuan, People's Republic of China.

Key Message: A novel qualitative locus regulating the uppermost internode elongation of barley was identified and mapped on 6H, and the candidate gene mining was performed by employing various barley genomic resources. The stem of grass crops, such as barley and wheat, is composed of several interconnected internodes. The extent of elongation of these internodes determines stem height, and hence lodging, canopy architecture, and grain yield. The uppermost internode (UI) is the last internode to elongate. Its elongation contributes largely to stem height and facilitates spike exsertion, which is crucial for final grain yield. Despite the molecular mechanism underlying regulation of UI elongation was extensively investigated in rice, little is known in barley. In this study, we characterized a barley spontaneous mutant, Sheathed Spike 1 (SS1), showing significantly shortened UI and sheathed spike (SS). The extension of UI parenchyma cell in SS1 was significantly suppressed. Exogenous hormone treatments and RNA-seq analysis indicated that the suppression of UI elongation is possibly related to insufficient content of endogenous bioactive gibberellin. Genetic analysis showed that SS1 is possibly controlled by a qualitative dominant nuclear factor. Bulked segregant analysis and further molecular marker mapping identified a novel major locus, HvSS1, in a recombination cold spot expanding 173.44-396.33 Mb on chromosome 6H. The candidate gene mining was further conducted by analyzing sequence differences, spatiotemporal expression patterns, and variant distributions of genes in the candidate interval by employing various barley genomic resources of worldwide collections of barley accessions. This study made insight into genetic control of UI elongation in barley and laid a solid foundation for further gene cloning and functional characterization. The results obtained here also provided valuable information for similar research in wheat.
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http://dx.doi.org/10.1007/s00122-021-03837-8DOI Listing
May 2021

Identification and Validation of a Novel Locus Controlling Spikelet Number in Bread Wheat ( L.).

Front Plant Sci 2021 26;12:611106. Epub 2021 Feb 26.

Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.

Spikelet number is an important target trait for wheat yield improvement. Thus, the identification and verification of novel quantitative trait locus (QTL)/genes controlling spikelet number are essential for dissecting the underlying molecular mechanisms and hence for improving grain yield. In the present study, we constructed a high-density genetic map for the Kechengmai1/Chuanmai42 doubled haploid (DH) population using 13,068 single-nucleotide polymorphism (SNP) markers from the Wheat 55K SNP array. A comparison between the genetic and physical maps indicated high consistence of the marker orders. Based on this genetic map, a total of 27 QTLs associated with total spikelet number per spike (TSN) and fertile spikelet number per spike (FSN) were detected on chromosomes 1B, 1D, 2B, 2D, 3D, 4A, 4D, 5A, 5B, 5D, 6A, 6B, and 7D in five environments. Among them, five QTLs on chromosome 2D, 3D, 5A, and 7D were detected in multiple environments and combined QTL analysis, explaining the phenotypic variance ranging from 3.64% to 23.28%. Particularly, for TSN and FSN [phenotypic variation explained (PVE) = 5.97-23.28%, limit of detection (LOD) = 3.73-18.51] is probably a novel locus and located in a 4.5-cM interval on chromosome arm 3DL flanking by the markers and This QTL was further validated in other two populations with different genetic backgrounds using the closely linked Kompetitive Allele-Specific PCR (KASP) marker . The results indicated that significantly increased the TSN (5.56-7.96%) and FSN (5.13-9.35%), which were significantly correlated with grain number per spike (GNS). We also preliminary analyzed the candidate genes within this locus by sequence similarity, spatial expression patterns, and collinearity analysis. These results provide solid foundation for future fine mapping and cloning of . The developed and validated KASP markers could be utilized in molecular breeding aiming to increase the grain yield in wheat.
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http://dx.doi.org/10.3389/fpls.2021.611106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952655PMC
February 2021

Patterns, timing, and predictors of recurrence after laparoscopic liver resection for hepatocellular carcinoma: results from a high-volume HPB center.

Surg Endosc 2021 Feb 23. Epub 2021 Feb 23.

Department of Liver Surgery & Liver Transplantation Center, West China Hospital of Sichuan University, 37 Guo Xue Road, Wuhou District, Chengdu, 610041, China.

Background: Although long-term outcomes may be comparable between laparoscopic liver resection (LLR) and open liver resection (OLR) for hepatocellular carcinoma (HCC), there has been little discussion regarding the patterns of recurrence after LLR.

Methods: Patients with HCC who underwent hepatectomy between April 2015 and November 2018 were included in this study. The recurrence patterns were analyzed in detail. The recurrence outcomes following laparoscopic versus OLR for HCC were compared after 1:2 propensity score matching. Potential risk factors for recurrence were also assessed with Cox proportional risk models.

Results: Among 425 patients after LLR, 144 (33.8%) experienced recurrence at the last follow-up, with a median recurrence-free survival (RFS) of 10.0 months (range 1-58 months). The most frequent recurrence site was the liver (n = 99, 68.8%), followed by the surgical margin (n = 15, 10.4%) and distant metastases (n = 12, 8.3%). Liver recurrence with distant metastasis (n = 10, 6.9%) tended to occur early (median 8.0 months), while peritoneal recurrence (n = 8, 5.6%) occurred later (median 14.0 months). A total of 120 (83.3%) patients had recurrence within 2 years after LLR. No trocar site recurrence was observed in this study. The recurrence patterns, timing, and treatment did not show significant differences between the LLR and OLR. The independent risk factors for recurrence included ALBI grade, postoperative α-fetoprotein > 8 ng/ml, tumor size > 5 cm, surgical margin ≤ 1 cm, and multiple tumors. Patients with recurrence had 1- and 5-year overall survival rates of 81.1% and 60.7%, respectively, compared with rates of 95.8% and 92.9% for patients without recurrence (P < 0.000).

Conclusion: This study suggested that intrahepatic recurrence was still the most common recurrence pattern for HCC after LLR and that LLR did not increase the risk of trocar hole recurrence or implantation. Most cases of recurrence occurred within 2 years after LLR, suggesting that surveillance should be targeted to early recurrence.
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http://dx.doi.org/10.1007/s00464-021-08390-5DOI Listing
February 2021

Genetically Engineered Methanotroph as a Platform for Bioaugmentation of Chemical Pesticide Contaminated Soil.

ACS Synth Biol 2021 03 22;10(3):487-494. Epub 2021 Feb 22.

Institute of Organic Contaminant Control and Soil Remediation, College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, 210095, P. R. China.

Bioaugmentation is a promising alternative in soil remediation. One challenge of bioaugmentation is that exogenous pollutant-degrading microbes added to soil cannot establish enough biomass to eliminate pollutants. Considering that methanotrophs have a growth advantage in the presence of methane, we hypothesize that genetically engineered methanotrophs could degrade contaminants efficiently in soil with methane. Here, methanotroph sp. LW13, herbicide bensulfuron-methyl (BSM), and two kinds of soil were chosen to confirm this hypothesis. The unmarked gene knock-in method was first developed for strain LW13. Then, BSM hydrolase encoding gene E was inserted into the chromosome of strain LW13, conferring it BSM-degrading ability. After inoculation, the cell amount of strain LW13-E in soil raised considerably (over 100 fold in 9 days) with methane provision; meanwhile, >90% of BSM in soil was degraded. This study provides a proof of the concept that genetically engineered methanotroph is a potential platform for soil remediation.
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http://dx.doi.org/10.1021/acssynbio.0c00532DOI Listing
March 2021

Diabetes mellitus affects long-term survival in hepatitis B virus-related hepatocellular carcinoma patients: A propensity score-matched analysis.

Medicine (Baltimore) 2021 Jan;100(4):e24354

Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu.

Abstract: Diabetes mellitus (DM) increases the risk of developing hepatocellular carcinoma (HCC), and how DM affects the prognosis of HCC have not been elucidated. The aim of this study was to compare clinicopathological characteristics and survival between hepatitis B virus (HBV)-related HCC patients with and without DM and to determine risk factors for overall survival after hepatectomy.Among 474 patients with HBV-related HCC, 119 patients had DM. Patients were divided into the diabetic group and nondiabetic group. The short-term and long-term outcomes were evaluated by using propensity score matching analysis.After 1:2 propensity score matching, there were 107 patients in diabetic group, 214 patients in nondiabetic group. The proportion of vessels invasion were higher in diabetic group. The overall survival rate in the diabetic group was 44.7% at 3 years, which was lower than that in the nondiabetic group (56.1%, P = .025). The multivariate analysis indicated that fasting blood glucose >7.0, capsular invasion, microvascular invasion and satellite were independent risk factor of poor prognosis in HCC.DM dose affect the recurrence-free survival and overall survival in HBV-related HCC patients after hepatectomy. One of the more significant findings to emerge from this study is that DM induced higher proportion of major vessel invasion in HCC patients implied unfavorable prognosis.
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http://dx.doi.org/10.1097/MD.0000000000024354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850751PMC
January 2021

Quantitative Trait Locus (QTLs) Mapping for Quality Traits of Wheat Based on High Density Genetic Map Combined With Bulked Segregant Analysis RNA-seq (BSR-Seq) Indicates That the Gene Is Related to Falling Number.

Front Plant Sci 2020 10;11:600788. Epub 2020 Dec 10.

Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.

Numerous quantitative trait loci (QTLs) have been identified for wheat quality; however, most are confined to low-density genetic maps. In this study, based on specific-locus amplified fragment sequencing (SLAF-seq), a high-density genetic map was constructed with 193 recombinant inbred lines derived from Chuanmai 42 and Chuanmai 39. In total, 30 QTLs with phenotypic variance explained (PVE) up to 47.99% were identified for falling number (FN), grain protein content (GPC), grain hardness (GH), and starch pasting properties across three environments. Five genes closely adjacent to probably have effects on GPC. was the only one detected for GH with high PVE of 33.31-47.99% across the three environments and was assumed to be related to the nearest and genes. Three QTLs were identified for FN in at least two environments, of which had relatively higher PVE of 16.58-25.74%. The positive effect of for high FN was verified in a double-haploid population derived from Chuanmai 42 Kechengmai 4. The combination of these QTLs has a considerable effect on increasing FN. The transcript levels of and in were significantly different between low FN and high FN bulks, as observed through bulk segregant RNA-seq (BSR). These QTLs and candidate genes based on the high-density genetic map would be beneficial for further understanding of the genetic mechanism of quality traits and molecular breeding of wheat.
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http://dx.doi.org/10.3389/fpls.2020.600788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793810PMC
December 2020

Fitness maps to a large-effect locus in introduced stickleback populations.

Proc Natl Acad Sci U S A 2021 01;118(3)

Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305;

Mutations of small effect underlie most adaptation to new environments, but beneficial variants with large fitness effects are expected to contribute under certain conditions. Genes and genomic regions having large effects on phenotypic differences between populations are known from numerous taxa, but fitness effect sizes have rarely been estimated. We mapped fitness over a generation in an F2 intercross between a marine and a lake stickleback population introduced to a freshwater pond. A quantitative trait locus map of the number of surviving offspring per F2 female detected a single, large-effect locus near (), a gene having an ancient freshwater allele causing reduced bony armor and other changes. F2 females homozygous for the freshwater allele had twice the number of surviving offspring as homozygotes for the marine allele, producing a large selection coefficient, = 0.50 ± 0.09 SE. Correspondingly, the frequency of the freshwater allele increased from 0.50 in F2 mothers to 0.58 in surviving offspring. We compare these results to allele frequency changes at the gene in an Alaskan lake population colonized by marine stickleback in the 1980s. The frequency of the freshwater allele rose steadily over multiple generations and reached 95% within 20 y, yielding a similar estimate of selection, = 0.49 ± 0.05, but a different degree of dominance. These findings are consistent with other studies suggesting strong selection on this gene (and/or linked genes) in fresh water. Selection on ancient genetic variants carried by colonizing ancestors is likely to increase the prevalence of large-effect fitness variants in adaptive evolution.
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http://dx.doi.org/10.1073/pnas.1914889118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826376PMC
January 2021

Inhibition of Intermedin (Adrenomedullin 2) Suppresses the Growth of Glioblastoma and Increases the Antitumor Activity of Temozolomide.

Mol Cancer Ther 2021 02 9;20(2):284-295. Epub 2020 Dec 9.

Department of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan, China.

Glioblastoma multiforme (GBM; grade IV glioma) is the most malignant type of primary brain tumor and is characterized by rapid proliferation and invasive growth. Intermedin (IMD) is an endogenous peptide belonging to the calcitonin gene-related peptide family and has been reported to play an important role in cell survival and invasiveness in several types of cancers. In this study, we found that the expression level of IMD was positively related to the malignancy grade of gliomas. The highest expression of IMD was found in GBM, indicating that IMD may play an important role in glioma malignancy. IMD increased the invasive ability of glioma cells by promoting filopodia formation, which is dependent on ERK1/2 activation. IMD-induced ERK1/2 phosphorylation also promoted GBM cell proliferation. In addition, IMD enhanced mitochondrial function and hypoxia-induced responses in GBM cells. Treatment with anti-IMD monoclonal antibodies not only inhibited tumor growth in both ectopic and orthotopic models of GBM but also significantly enhanced the antitumor activity of temozolomide. Our study may provide novel insights into the mechanism of GBM cell invasion and proliferation and provide an effective strategy to improve the therapeutic effect of GBM treatments.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0619DOI Listing
February 2021

Chemical and Genetic Studies on the Formation of Pyrrolones During the Biosynthesis of Cytochalasans.

Chemistry 2021 Feb 14;27(9):3106-3113. Epub 2021 Jan 14.

Institute for Organic Chemistry, Leibniz Universität Hannover, Schneiderberg 1B, 30167, Hannover, Germany.

A key step during the biosynthesis of cytochalasans is a proposed Knoevenagel condensation to form the pyrrolone core, enabling the subsequent 4+2 cycloaddition reaction that results in the characteristic octahydroisoindolone motif of all cytochalasans. In this work, we investigate the role of the highly conserved α,β-hydrolase enzymes PyiE and ORFZ during the biosynthesis of pyrichalasin H and the ACE1 metabolite, respectively, using gene knockout and complementation techniques. Using synthetic aldehyde models we demonstrate that the Knoevenagel condensation proceeds spontaneously but results in the 1,3-dihydro-2H-pyrrol-2-one tautomer, rather than the required 1,5-dihydro-2H-pyrrol-2-one tautomer. Taken together our results suggest that the α,β-hydrolase enzymes are essential for first ring cyclisation, but the precise nature of the intermediates remains to be determined.
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http://dx.doi.org/10.1002/chem.202004444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898483PMC
February 2021

Selective usage of ANP32 proteins by influenza B virus polymerase: Implications in determination of host range.

PLoS Pathog 2020 10 12;16(10):e1008989. Epub 2020 Oct 12.

State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin, P. R. China.

The influenza B virus (IBV) causes seasonal influenza and has accounted for an increasing proportion of influenza outbreaks. IBV mainly causes human infections and has not been found to spread in poultry. The replication mechanism and the determinants of interspecies transmission of IBV are largely unknown. In this study, we found that the host ANP32 proteins are required for the function of the IBV polymerase. Human ANP32A/B strongly supports IBV replication, while ANP32E has a limited role. Unlike human ANP32A/B, chicken ANP32A has low support activity to IBV polymerase because of a unique 33-amino-acid insert, which, in contrast, exhibits species specific support to avian influenza A virus (IAV) replication. Chicken ANP32B and ANP32E have even lower activity compared with human ANP32B/E due to specific amino acid substitutions at sites 129-130. We further revealed that the sites 129-130 affect the binding ability of ANP32B/E to IBV polymerase, while the 33-amino-acid insert of chicken ANP32A reduces its binding stability and affinity. Taken together, the features of avian ANP32 proteins limited their abilities to support IBV polymerase, which could prevent efficient replication of IBV in chicken cells. Our results illustrate roles of ANP32 proteins in supporting IBV replication and may help to understand the ineffective replication of IBV in birds.
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http://dx.doi.org/10.1371/journal.ppat.1008989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580981PMC
October 2020

Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence.

Breast Cancer Res 2020 09 29;22(1):103. Epub 2020 Sep 29.

Department of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, No. 1, Ke Yuan 4th Road, Gao Peng Street, Chengdu, 610041, Sichuan, People's Republic of China.

Background: Sunitinib, a receptor tyrosine kinase (RTK) inhibitor that targets multiple receptors such as vascular endothelial growth factor receptors (VEGFRs), was approved for cancer treatment in 2006. However, it was unsuccessful in treating certain cancers, particularly metastatic breast cancer (MBC), and the mechanism underlying this "sunitinib resistance" remains unclear. Herein, we investigated whether the sunitinib-associated inferior survival benefit in MBC was due to sunitinib-induced endothelial cell (EC) injury or EC senescence.

Methods: 4T1 murine breast cancer cells were used as the main breast tumor model for it produces a highly metastatic solid tumor that can spontaneously metastasize to the lung, which closely mimics highly metastatic human breast cancer. Senescence-associated β-galactosidase (SA-β-Gal, immunohistochemistry [IHC]-staining), P16, P53, and P57 (immunoblotting) were used as markers of cell senescence. A protein array containing 25 senescence-associated chemokines and the transwell chemotaxis assay were used to examine whether sunitinib increases inflammatory chemokine secretion which attracts tumor cells via chemokinesis. Flow cytometry and IHC were used to detect whether the sunitinib-induced senescent ECs recruit cancer-associated inflammatory myeloid cells. Finally, the spontaneous metastatic model was used to monitor whether sunitinib causes the formation of "pre-metastatic niche" which promotes MBC to metastasize to the lungs.

Results: We demonstrated that sunitinib induced a senescence-like endothelial cell (EC) phenotype. Inflammatory chemokine secretion and VCAM1 expression were significantly increased in senescent ECs, resulting in tumor cell (TC) chemotaxis and TC/EC interactions. Meanwhile, EC senescence caused loosening of EC junctions, facilitating TC transmigration through the endothelial barrier. Sunitinib-induced senescent ECs also recruited cancer-associated myeloid cells to form a "pre-metastatic niche"-like microenvironment. Alterations at the molecular level and in the tissue environment ultimately led to an increase in distant metastasis.

Conclusion: Although sunitinib was designed to target the EC directly, the increase in tumor metastasis may ironically be due to sunitinib "correctly" playing its role. Our findings suggest that we should carefully weigh the pros and cons before using sunitinib and other antiangiogenic drugs that directly target the ECs.
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http://dx.doi.org/10.1186/s13058-020-01346-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526390PMC
September 2020

Development of the embryonic liver and pancreas of the Chinese softshell turtle .

J Histotechnol 2021 03 10;44(1):2-11. Epub 2020 Sep 10.

College of Agriculture and Bioengineering, Heze University, Heze, China.

The research on hatching ecology of the Chinese softshell turtle has essential guiding roles to clarify the physiological and ecological mechanism of reptile evolution. The aim of this study is to describe the histological changes, differentiation, and maturation of some functional cells during the genesis and development of the liver and pancreas of the Chinese softshell turtle . Softshell turtle eggs were incubated under artificial conditions and hatched within 41-45 days. Hematoxylin and eosin-stained embryonic pancreas and liver were examined at various time points from 2 to 31 days and compared with that of other reptiles, amphibians, fishes, and birds in the literature. Immunohistochemical assay for glucagon and insulin was performed on paraformaldehyde-fixed embryos to identify functional cells in the pancreas. Pancreatic endocrine cells of have secretory ability at day 26 of embryonic development, and the dispersed pancreatic endocrine cells may be the result of the incomplete pancreatic development.
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http://dx.doi.org/10.1080/01478885.2020.1775013DOI Listing
March 2021

[New progress of IGF-1 and allosteroid injection in the treatment of sudden deafness complicated with type 2 diabetes].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2020 Jun;34(6):569-572

Glucocorticoids are a recognized treatment for sudden deafness, and there has always been a contradiction between the control of blood glucose levels and the use of glucocorticoids. The systemic use of hormones may lead to a series of adverse events, which are dose-dependent. High doses can induce an increase in blood sugar, especially for patients with type 2 diabetes, which can aggravate their condition or cause complications. The systemic application of glucocorticoids has been largely replaced by local glucocorticoids treatment. Topical insulin-like growth factor (IGF-1) is used without increasing blood sugar, thus avoiding the possible complications. The author intends to compare the local IGF-1 treatment and local glucocorticoid treatment to systemic therapy. The efficacy of local IGF-1 therapy in treating corticosteroid-refractory sudden sensorineural hearing loss combined with type 2 diabetes is reviewed.
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http://dx.doi.org/10.13201/j.issn.2096-7993.2020.06.021DOI Listing
June 2020

Tissue-targeted R-spondin mimetics for liver regeneration.

Sci Rep 2020 08 18;10(1):13951. Epub 2020 Aug 18.

Surrozen Inc., 171 Oyster Point Blvd, Suite 400, South San Francisco, CA, 94080, USA.

R-spondin (RSPO) proteins amplify Wnt signaling and stimulate regeneration in a variety of tissues. To repair tissue in a tissue-specific manner, tissue-targeted RSPO mimetic molecules are desired. Here, we mutated RSPO (RSPO2 F105R/F109A) to eliminate LGR binding while preserving ZNRF3/RNF43 binding and targeted the mutated RSPO to a liver specific receptor, ASGR1. The resulting bi-specific molecule (αASGR1-RSPO2-RA) enhanced Wnt signaling effectively in vitro, and its activity was limited to ASGR1 expressing cells. Systemic administration of αASGR1-RSPO2-RA in mice specifically upregulated Wnt target genes and stimulated cell proliferation in liver but not intestine (which is more responsive to non-targeted RSPO2) in healthy mice, and improved liver function in diseased mice. These results not only suggest that a tissue-specific RSPO mimetic protein can stimulate regeneration in a cell-specific manner, but also provide a blueprint of how a tissue-specific molecule might be constructed for applications in a broader context.
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http://dx.doi.org/10.1038/s41598-020-70912-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435267PMC
August 2020

Novel Antiparasitic Activity of the Antifungal Lead Occidiofungin.

Antimicrob Agents Chemother 2020 07 22;64(8). Epub 2020 Jul 22.

Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas, USA

Novel antiparasitic activity was observed for the antifungal occidiofungin. It efficaciously and irreversibly inhibited the zoonotic enteric parasite with limited cytotoxicity (50% effective concentration [EC] = 120 nM versus 50% cytotoxic concentration [TC] = 988 nM), and its application disrupted the parasite morphology. This study expands the spectrum of activity of a glycolipopeptide named occidiofungin. Occidiofungin has poor gastrointestinal tract absorption properties, supporting future investigations into its potential activities on other enteric parasites.
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http://dx.doi.org/10.1128/AAC.00244-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526809PMC
July 2020

Berberine suppresses influenza virus-triggered NLRP3 inflammasome activation in macrophages by inducing mitophagy and decreasing mitochondrial ROS.

J Leukoc Biol 2020 07 9;108(1):253-266. Epub 2020 Apr 9.

Department of Immunology and Microbiology, School of Life Science, Beijing University of Chinese Medicine, Beijing, China.

Berberine (BBR) is an isoquinoline alkaloid extracted from several commonly used Chinese herbs. Our previous studies demonstrated BBR-mediated alleviation of lung injury due to inflammation and decrease in the mortality of mice with influenza viral pneumonia. The recent argument of autophagy against inflammatory responses has aroused wide concerns. This study focuses on the reactive oxygen species-Nod-like receptor protein 3 (ROS-NLRP3) pathway to investigate whether BBR inhibits NLRP3 inflammasome activation by inducing mitophagy. Our results demonstrate that BBR and mitochondrion-targeted superoxide dismutase mimetic (Mito-TEMPO; a specific mitochondrial ROS scavenger) significantly restricted NLRP3 inflammasome activation, increased mitochondrial membrane potential (MMP), and decreased mitochondrial ROS (mtROS) generation in J774A.1 macrophages infected with PR8 influenza virus. These observations suggest that the inhibitory effects of BBR on NLRP3 inflammasome activation were associated with the amelioration of mtROS generation. BBR treatment induced regular mitophagy, as evident from the increase in microtubule-associated protein 1 light chain 3 II, decrease in p62, colocalization of LC3 and mitochondria, and formation of autophagosomes. However, 3-methyladenine, an autophagy inhibitor, reversed the inhibitory effects of BBR on mitochondrial damage and NLRP3 inflammasome activation in influenza virus-infected macrophages, indicating the involvement of mitophagy in mediating the inhibitory effects of BBR on NLRP3 inflammasome activation. Furthermore, the knockdown of Bcl-2/adenovirus E18-19-kDa interacting protein 3 (BNIP3) expression attenuated the effects of BBR on mitophagy induction to some extent, suggesting that the BBR-induced mitophagy may be, at least in part, mediated in a BNIP3-dependent manner. Similar results were obtained in vivo using a mouse model of influenza viral pneumonia that was administered with BBR. Taken together, these findings suggest that restricting NLRP3 inflammasome activation by decreasing ROS generation through mitophagy induction may be crucial for the BBR-mediated alleviation of influenza virus-induced inflammatory lesions.
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http://dx.doi.org/10.1002/JLB.3MA0320-358RRDOI Listing
July 2020

Development of Potent, Selective Surrogate WNT Molecules and Their Application in Defining Frizzled Requirements.

Cell Chem Biol 2020 05 26;27(5):598-609.e4. Epub 2020 Mar 26.

Surrozen Inc., 171 Oyster Point Boulevard, Suite 400, South San Francisco, CA 94080, USA. Electronic address:

WNTs regulate myriad biological processes during embryonic development and are key regulators of stem cell function, tissue homeostasis, and injury repair in adults. The creation of WNT-based therapies has been hampered by challenges in developing soluble, potent, and selective WNT molecules. Soluble WNT surrogates have been reported, but they demonstrate relatively weak WNT signaling activity. Here, we describe a platform for potent, selective WNT surrogate generation. We identify multivalent binding to Frizzleds (FZDs) and low-density lipoprotein receptor-related proteins (LRPs) to be a requirement for maximal WNT/β-catenin activation. Furthermore, we show that recruitment of two different FZDs together with LRP causes efficient signaling. Surrogate WNT targeting either FZD or FZD induces expansive growth of intestinal organoids. This flexible WNT surrogate platform yields potent agonists with any desired receptor specificity and will be useful for research and therapeutic applications for tissue regeneration.
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http://dx.doi.org/10.1016/j.chembiol.2020.02.009DOI Listing
May 2020

A unique feature of swine ANP32A provides susceptibility to avian influenza virus infection in pigs.

PLoS Pathog 2020 02 21;16(2):e1008330. Epub 2020 Feb 21.

State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, The Chinese Academy of Agricultural Sciences, Harbin, China.

Both the replication and transcription of the influenza virus are catalyzed by the viral polymerase complex. The polymerases of most avian influenza A viruses have poor performance in mammalian cells, which is considered to be one of the important species barriers. Pigs have been long considered as important intermediate hosts for interspecies transmission of the avian influenza virus, because of their susceptibility to infection with both avian and mammalian influenza viruses. However, the molecular basis of influenza polymerase adaptation in pigs remains largely unknown. ANP32A and ANP32B proteins have been identified as playing fundamental roles in influenza virus replication and host range determination. In this study, we found that swine ANP32A (swANP32A), unlike swine ANP32B or other mammalian ANP32A or B, shows stronger supporting activity to avian viral polymerase. Knockout of ANP32A in pig cells PK15 dramatically reduced avian influenza polymerase activity and viral infectivity, suggesting a unique feature of swANP32A in supporting avian influenza viral polymerase. This species-specific activity is mapped to two key sites, 106V and 156S, in swANP32A. Interestingly, the amino acid 106V is unique to pigs among all the vertebrate species studied, and when combined with 156S, exhibits positive epistasis in pigs. Mutation of 106V and 156S to the signature found in ANP32As from other mammalian species weakened the interaction between swANP32A and chicken viral polymerase, and reduced polymerase activity. Understanding the molecular basis of ANP32 proteins may help to discover new antiviral targets and design avian influenza resistant genome edited pigs.
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http://dx.doi.org/10.1371/journal.ppat.1008330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055917PMC
February 2020

The N-glycosylation of Equine Tetherin Affects Antiviral Activity by Regulating Its Subcellular Localization.

Viruses 2020 02 16;12(2). Epub 2020 Feb 16.

State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China.

Tetherin is an interferon-inducible type II transmembrane glycoprotein which inhibits the release of viruses, including retroviruses, through a "physical tethering" model. However, the role that the glycosylation of tetherin plays in its antiviral activity remains controversial. In this study, we found that mutation of N-glycosylation sites resulted in an attenuation of the antiviral activity of equine tetherin (eqTHN), as well as a reduction in the expression of eqTHN at the plasma membrane (PM). In addition, eqTHN N-glycosylation mutants colocalize obviously with ER, CD63, LAMP1 and endosomes, while WT eqTHN do not. Furthermore, we also found that N-glycosylation impacts the transport of eqTHN in the cell not by affecting the endocytosis, but rather by influencing the anterograde trafficking of the protein. These results suggest that the N-glycosylation of eqTHN is important for the antiviral activity of the protein through regulating its normal subcellular localization. This finding will enhance our understanding of the function of this important restriction factor.
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http://dx.doi.org/10.3390/v12020220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077275PMC
February 2020

Emergency medicine in China: A review of the history of progress and current and future challenges after 40 years of reform.

Am J Emerg Med 2020 03 10;38(3):662-669. Epub 2019 Dec 10.

Division of Emergency Critical Care Medicine, Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.

The year 2018 marks the 40th anniversary of China's reform, tremendous change had taken place in Chinese society. Looking back 40 years from 1978 to 2018, China's medical reform had made remarkable achievements, but still faces many challenges. These papers review the historical progress of emergency medicine, the current and the future challenges in China's medical reform process.
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http://dx.doi.org/10.1016/j.ajem.2019.11.008DOI Listing
March 2020

Equine Mx1 Restricts Influenza A Virus Replication by Targeting at Distinct Site of its Nucleoprotein.

Viruses 2019 12 2;11(12). Epub 2019 Dec 2.

State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China.

Interferon-mediated host factors myxovirus (Mx) proteins are key features in regulating influenza A virus (IAV) infections. Viral polymerases are essential for viral replication. The Mx1 protein has been known to interact with viral nucleoprotein (NP) and PB2, resulting in the influence of polymerase activity and providing interspecies restriction. The equine influenza virus has evolved as an independent lineage to influenza viruses from other species. We estimated the differences in antiviral activities between human MxA (huMxA) and equine Mx1 (eqMx1) against a broad range of IAV strains. We found that huMxA has antiviral potential against IAV strains from non-human species, whereas eqMx1 could only inhibit the polymerase activity of non-equine species. Here, we demonstrated that NP is the main target of eqMx1. Subsequently, we found adaptive mutations in the NP of strains A/equine/Jilin/1/1989 (H3N8) and A/chicken/Zhejiang/DTID-ZJU01/2013 (H7N9) that confer eqMx1 resistance and sensitivity respectively. A substantial reduction in Mx1 resistance was observed for the two mutations G34S and H52N in H3N8 NP. Thus, eqMx1 is an important dynamic force in IAV nucleoprotein evolution. We, therefore, suggest that the amino acids responsible for Mx1 resistance should be regarded as a robust indicator for the pandemic potential of lately evolving IAVs.
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http://dx.doi.org/10.3390/v11121114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950424PMC
December 2019

Immunohistochemical distribution of glucagon-like peptide 1 in the digestive system of different aquatic vertebrates.

Anat Histol Embryol 2020 Jan 1;49(1):31-37. Epub 2019 Oct 1.

College of Agriculture and Bioengineering, Heze University, Heze, China.

The distribution of glucagon-like peptide 1 (GLP-1)-positive cells in digestive tracts and pancreases of aquatic vertebrates was investigated by immunohistochemical staining method. The results suggested that GLP-1-positive cells were distributed in the columnar mucous epithelium and tubular glands of lamina propria in the digestive system. However, GLP-1-positive cells were also found in subepithelial lamina propria of the mucosae and muscularis in each segment of the digestive tract of Rana nigromaculata. The distribution densities of these cells reached peaks in the stomachs, and the middle or end segments of small intestines of Chinese softshell turtle, Bufo gargarizans, R. nigromaculata and catfish, and there was the third distribution density peak in the rectum of catfish. The total amount or overall density of GLP-1-positive cells varied a lot in the digestive tracts of different animal species. The distribution density was relatively low in the digestive tract of chub and reached the maximum in the digestive tracts of snakehead and catfish, but no GLP-1-positive cells were found in the digestive tract of bighead carp. GLP-1-positive cells were densely distributed in the pancreases of Chinese softshell turtle, B. gargarizans and R. nigromaculata. These cells spread over the superficial layers of islets or scattered in exocrine pancreas in the pancreas of B. gargarizans, spread in the endocrine cells or scattered in the pancreas of Chinese softshell turtle, scattered in the pancreas of R. nigromaculata and distributed in the superficial layers of islets in the pancreas of catfish.
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http://dx.doi.org/10.1111/ahe.12479DOI Listing
January 2020

Discovery of Novel Anti-cryptosporidial Activities From Natural Products by High-Throughput Phenotypic Screening.

Front Microbiol 2019 29;10:1999. Epub 2019 Aug 29.

Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, United States.

is a globally distributed zoonotic protozoan parasite of both medical and veterinary importance. Nitazoxanide is the only FDA-approved drug to treat cryptosporidiosis in immunocompetent people, but it is not fully effective. There is no drug approved by FDA for use in immunocompromised patients or in animals. In the present study, we conducted phenotypic screening of 800 nature products with defined chemical structures for potential novel activity against the growth of . We identified a large number of compounds showing low to sub-micromolar anti-cryptosporidial activity, and fully characterized 16 top hits for anti-parasitic efficacies [EC values from 0.122 to 3.940 μM, cytotoxicity (TC) values from 6.31 to >100 μm] and their safety margins. Among them, 11 compounds were derived from plants with EC values from 0.267 to 3.940 μM [i.e., cedrelone, deoxysappanone B 7,4'-dimethyl ether (Deox B 7,4), tanshinone IIA, baicalein, deoxysappanone B 7,3'-dimethyl ether acetate, daunorubicin, dihydrogambogic acid, deacetylgedunin, deacetoxy-7-oxogedunin, dihydrotanshinone I, 2,3,4'-trihydroxy-4-methoxybenzophenone, and 3-deoxo-3beta-hydroxy-mexicanolide 16-enol ether]. Three compounds with sub-micromolar EC values (i.e., cedrelone, Deox B 7,4, and baicalein) were further investigated for their effectiveness on various parasite developmental stages . Cedrelone and baicalein were more effective than Dexo B 7,4 when treating parasite for shorter periods of time, but all three compounds could kill the parasite irreversibly. These findings provide us a large selection of new structures derived from natural products to be explored for developing anti-cryptosporidial therapeutics.
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http://dx.doi.org/10.3389/fmicb.2019.01999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736568PMC
August 2019

High-Throughput Screening of Drugs Against the Growth of Cryptosporidium parvum In Vitro by qRT-PCR.

Methods Mol Biol 2020 ;2052:319-334

Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA.

An effective method to quantify the parasite loads is the key to the evaluation of anti-cryptosporidial drug efficacy in vitro. However, high-throughput screening (HTS) of drugs against Cryptosporidium parvum in vitro was impractical by the labor-intensive traditional assays. Here we describe a simplified quantitative RT-PCR assay suitable for HTS of compounds and for evaluating drug efficacy against the growth of C. parvum in vitro.
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http://dx.doi.org/10.1007/978-1-4939-9748-0_18DOI Listing
November 2020

ANP32A and ANP32B are key factors in the Rev-dependent CRM1 pathway for nuclear export of HIV-1 unspliced mRNA.

J Biol Chem 2019 10 23;294(42):15346-15357. Epub 2019 Aug 23.

State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China

The nuclear export receptor CRM1 is an important regulator involved in the shuttling of various cellular and viral RNAs between the nucleus and the cytoplasm. HIV-1 Rev interacts with CRM1 in the late phase of HIV-1 replication to promote nuclear export of unspliced and single spliced HIV-1 transcripts. However, other cellular factors involved in the CRM1-dependent viral RNA nuclear export remain largely unknown. Here, we demonstrate that ANP32A and ANP32B mediate the export of unspliced or partially spliced viral mRNA via interactions with Rev and CRM1. We found that a double, but not single, knockout of ANP32A and ANP32B significantly decreased the expression of gag protein. Reconstitution of either ANP32A or ANP32B restored the viral production equally. Disruption of both ANP32A and ANP32B expression led to a dramatic accumulation of unspliced viral mRNA in the nucleus. We further identified that ANP32A and ANP32B interact with both Rev and CRM1 to promote RNA transport. Our data strongly suggest that ANP32A and ANP32B play an important role in the Rev-CRM1 pathway, which is essential for HIV-1 replication, and our findings provide a candidate therapeutic target for host defense against retroviral infection.
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http://dx.doi.org/10.1074/jbc.RA119.008450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802516PMC
October 2019

Molecular and Biochemical Characterization of a Type II Thioesterase From the Zoonotic Protozoan Parasite .

Front Cell Infect Microbiol 2019 7;9:199. Epub 2019 Jun 7.

Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, United States.

is a globally important zoonotic parasite capable of causing severe to deadly diarrhea in humans and animals. Its small genome (~9.1 Mb) encodes not only a highly streamlined metabolism, but also a 25-kb, 3-module fatty acid synthase (CpFAS1) and a 40-kb, 7-module polyketide synthase (CpPKS1). The two megasynthases contain a C-terminal reductase domain to release the final products with predicted chain lengths of ≥C22 for CpFAS1 or C28 to C38 for CpPKS1.The parasite genome also encodes a discrete thioesterase ortholog, suggesting its role to be an alternative tool in releasing the final products from CpFAS1 and/or CpPKS1, or as an editor to remove non-reactive residues or aberrant intermediates, or to control starter units as seen in other parasites. In this study, we have confirmed that this thioesterase is a type II thioesterase (thus named as CpTEII). CpTEII contains motifs and a catalytic triad characteristic to the type II thioesterase family. CpTEII is expressed during the entire parasite life cycle stages with the highest levels of expression in the later developmental stages. CpTEII showed the highest hydrolytic activity toward C10:0 decanoyl-CoA, so we speculated that CpTEII may mainly act as an editor to remove non-reactive residues and/or aberrant medium acyl chain from CpFAS1 and/or CpPKS1. However, we cannot rule out the possibility that CpTEII may also participate in the release of final products from CpFAS1 because of its moderate activity on C20:0, C:22:0 and C24:0 acyl-CoA thioesters (i.e., ~20-30% activity vs. decanoyl-CoA).
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http://dx.doi.org/10.3389/fcimb.2019.00199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6568194PMC
February 2020