Publications by authors named "Hai Yu"

652 Publications

Engineering Tough Metallosupramolecular Hydrogel Films with Kirigami Structures for Compliant Soft Electronics.

Small 2021 Sep 12:e2103836. Epub 2021 Sep 12.

Ministry of Education Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China.

A simple and effective approach is demonstrated to fabricate tough metallosupramolecular hydrogel films of poly(acrylic acid) by one-pot photopolymerization of the precursor solution in the presence of Zr ions that form coordination complexes with the carboxyl groups and serve as the physical crosslinks of the matrix. Both as-prepared and equilibrated hydrogel films are transparent, tough, and stable over a wide range of temperature, ionic strength, and pH. The thickness of the films can be easily tailored with minimum value of ≈7 μm. Owing to the fast polymerization and gelation process, kirigami structures can be facilely encoded to the gel films by photolithographic polymerization, affording versatile functions such as additional stretchability and better compliance of the planar films to encapsulate objects with sophisticated geometries that are important for the design of soft electronics. By stencil printing of liquid metal on the hydrogel film with a kirigami structure, the integrated soft electronics shows good compliance to cover curved surfaces and high sensitivity to monitor human motions. Furthermore, this strategy is applied to diverse natural and synthetic macromolecules containing carboxyl groups to develop tough hydrogel films, which will open opportunities for the applications of hydrogel films in biomedical and engineering fields.
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http://dx.doi.org/10.1002/smll.202103836DOI Listing
September 2021

Prognostic Value of a New Integrated Parameter-Both Collateral Circulation and Permeability Surface-in Hemorrhagic Transformation of Middle Cerebral Artery Occlusion Acute Ischemic Stroke: Retrospective Cohort Study.

Front Aging Neurosci 2021 25;13:703734. Epub 2021 Aug 25.

Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China.

Background: Multimodal CT, including CT angiography (CTA) and CT perfusion (CTP), was increasingly used in stroke triage. This study was to determine the relationship between a new integrated parameter-both collateral circulation and relative permeability surface (PS)-and the hemorrhagic transformation (HT) in acute ischemic stroke (AIS) with middle cerebral artery occlusion (MCAO).

Methods: We retrospectively reviewed consecutive AIS patients with MCAO who underwent baseline CTA/CTP within 4 h of symptom onset and follow-up susceptibility-weighted imaging (SWI) within 3 weeks. Collateral circulation was assessed on the baseline CTA. Baseline CTP data were postprocessed to generate PS parameter. The patients with poor collateral circulation and at the same time with high relative PS were classified as the group of both poor collateral circulation and high relative PS. HT was defined according to European Cooperative Acute Stroke Study II criteria on follow-up SWI imaging. Multivariate logistic regression analysis was performed using HT as an outcome variable.

Results: The group of patients with both poor collateral circulation and high relative PS was thirteen and thirty-three (52%) developed HT of the final cohort sixty-three AIS patients with MCAO. Multivariate logistic analysis revealed the new integrated parameter-both collateral circulation and relative PS (odds ratio, 16.59; 95% confidence interval, 13.09-19.10; < 0.001) was independent predictor of HT. The area under the curve was 0.85 (95% confidence interval, 0.81-0.89). The sensitivity was 57%, specificity 97% and positive predictive value 92%, negative predictive value 58%.

Conclusions: For AIS patients with MCAO, these with poor collateral circulation on CTA and at the same time with high relative PS on CTP were at high risk for HT.
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http://dx.doi.org/10.3389/fnagi.2021.703734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424095PMC
August 2021

[Clinical and genetic analysis of a case with Thiamine metabolism dysfunction syndrome 5].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2021 Sep;38(9):873-876

Department of Children's Health Care, Women and Children's Hospital of Huli District, Xiamen, Fujian 361009, China.

Objective: To report the clinical manifestation and genetic characteristics of a child with Thiamine metabolism dysfunction syndrome 5.

Methods: Clinical data and genetic results were collected and analyzed. Peripheral blood samples of the child and their parents were collected for whole exome sequencing, and the functional effect of the variants on the TPK1 enzyme activity was verified by an in vitro assay.

Results: A four-year-old boy presented with preschool onset of ataxia were characterized. High-throughput sequencing identified a novel homozygous variant of TPK1 gene c.382G>A (p.Leu128Phe). His father and mother were both found carrying the variant. The variant protein showed a 30.9% reduction in TPK1 enzyme activity compared with the wildtype.

Conclusion: A novel pathogenic variant has been identified in a boy with thiamine metabolic dysfunction syndrome type 5.
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http://dx.doi.org/10.3760/cma.j.cn511374-20200428-00310DOI Listing
September 2021

Superpixels With Content-Adaptive Criteria.

IEEE Trans Image Process 2021 10;30:7702-7716. Epub 2021 Sep 10.

Superpixels are widely used in computer vision applications. Most of the existing superpixel methods use established criteria to indiscriminately process all pixels, resulting in superpixel boundary adherence and regularity being unnecessarily inter-inhibitive. This study builds upon a previous work by proposing a new segmentation strategy that classifies image content into meaningful areas containing object boundaries and meaningless parts that include color-homogeneous and texture-rich regions. Based on this classification, we design two distinct criteria to process the pixels in different environments to achieve highly accurate superpixels in content-meaningful areas and keep the regularity of the superpixels in content-meaningless regions. Additionally, we add a group of weights when adopting the color feature, successfully reducing the undersegmentation error. The superior accuracy and the moderate compactness achieved by the proposed method in comparative experiments with several state-of-the-art methods indicate that the content-adaptive criteria efficiently reduce the compromise between boundary adherence and compactness.
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http://dx.doi.org/10.1109/TIP.2021.3108403DOI Listing
September 2021

Efficacy and safety of modified reduced-dose rituximab in Chinese patients with neuromyelitis optica spectrum disorder: A retrospective cohort study.

J Neurol Sci 2021 Aug 12;429:117616. Epub 2021 Aug 12.

Department of Neurology, First Affiliated Hospital of Soochow University, Suzhou 215006, China; Jiangsu Institute of Clinical Immunology, Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, Suzhou 215006, China; Suzhou Clinical Medical Centre of Neurological Disorders, Suzhou 215004, China. Electronic address:

Objective: To evaluate the long-term efficacy and safety of a modified reduced-dose rituximab (mRTX) regimen compared with azathioprine (AZA) and mycophenolate mofetil (MMF) in Chinese patients with neuromyelitis optica spectrum disorder (NMOSD).

Methods: In this retrospective cohort study, 71 patients with NMOSD were treated with AZA (n = 24), MMF (n = 18), or mRTX (n = 29). The primary outcome was initial relapse after first-line immunosuppressant therapy. The annualized relapse rate (ARR), expanded disability status scale (EDSS) score, activities of daily living (ADL) scale score, and treatment-related adverse events were compared between groups.

Results: Significant ARR reductions were observed in the three groups, with relapse-free rates of 37.5%, 72.2%, and 79.3% in the AZA, MMF, and RTX groups, respectively. Compared with AZA, mRTX and MMF significantly reduced the NMOSD relapse risk. Relapse within 1 year before immunosuppressant therapy or ARR before immunosuppressant therapy increased the NMOSD relapse risk. mRTX and MMF were superior to AZA in reducing the EDSS score and increasing the ADL score, but there was no significant difference between the mRTX and MMF groups. Additionally, mRTX-treated patients were less likely to use steroids concurrently than those treated with AZA and MMF. The adverse event rate in the AZA group was relatively higher than that in the MMF and mRTX groups, though no significant difference was noted among the three groups.

Conclusions: Compared with AZA, mRTX and MMF significantly reduced the NMOSD relapse risk. mRTX-treated patients presented less concomitant steroid use than those treated with AZA and MMF, fewer adverse events, and better tolerance.
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http://dx.doi.org/10.1016/j.jns.2021.117616DOI Listing
August 2021

Immune efficacy of a candidate porcine reproductive and respiratory syndrome vaccine rHN-NP49 administered by a Needle-free intradermal delivery system in comparison with intramuscular injection.

Vaccine 2021 Sep 16;39(39):5557-5562. Epub 2021 Aug 16.

Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, PR China; Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonosis Yangzhou University, Yangzhou 225009, PR China. Electronic address:

Porcine reproductive and respiratory syndrome (PRRS) is one of the major drivers of economic loss in the swine industry worldwide. In commercial pig production, vaccination is the first option in an attempt to control infectious diseases. Pigs are therefore often immunized with different vaccines, and almost all of them are delivered via the intramuscular (IM) route. However, the IM injection may result in physical damage, stress reactions, and is labor demanding. An alternative route is urgently needed to reduce the disadvantages of conventional vaccination. In this study, a needle-free intradermal (ID) delivery system was evaluated for delivering a live PRRS vaccine as compared with the traditional needle-syringe method. Fifty-two 4-week-old piglets were divided into six groups: piglets in groups A-C were immunized using ID delivery system with 10, 10 and 10 TCID of PRRS candidate vaccine strain rHN-NP49, respectively; piglets in group D were immunized IM with 10 TCID of rHN-NP49; and group E and F were used as challenge and control groups, respectively. At 28 days post vaccination, piglets in group A to E were challenged with a lethal dose of highly-pathogenic PRRSV. Similar results were found in viremia and antibody response among the ID and IM groups during the immunization stage. After challenge, similar results were found in average body weight gain, viral shedding, serum viral load, and clinical score among the immunization groups, with a higher protection ratio in the ID group compared with IM group with the same immunization dose. These results demonstrated that the ID delivery system could provide similar or even better protection compared with IM route, and could be an effective route for PRRS vaccination.
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http://dx.doi.org/10.1016/j.vaccine.2021.08.023DOI Listing
September 2021

Targeting Loss in Cancers.

Cancers (Basel) 2021 Jul 25;13(15). Epub 2021 Jul 25.

Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan.

Retinoblastoma protein 1 (RB1) is encoded by a tumor suppressor gene that was discovered more than 30 years ago. Almost all mitogenic signals promote cell cycle progression by braking on the function of RB1 protein through mono- and subsequent hyper-phosphorylation mediated by cyclin-CDK complexes. The loss of RB1 function drives tumorigenesis in limited types of malignancies including retinoblastoma and small cell lung cancer. In a majority of human cancers, RB1 function is suppressed during tumor progression through various mechanisms. The latter gives rise to the acquisition of various phenotypes that confer malignant progression. The RB1-targeted molecules involved in such phenotypic changes are good quarries for cancer therapy. Indeed, a variety of novel therapies have been proposed to target loss. In particular, the inhibition of a number of mitotic kinases appeared to be synthetic lethal with RB1 deficiency. A recent study focusing on a neighboring gene that is often collaterally deleted together with revealed a pharmacologically targetable vulnerability in -deficient cancers. Here we summarize current understanding on possible therapeutic approaches targeting functional or genomic aberration of RB1 in cancers.
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http://dx.doi.org/10.3390/cancers13153737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345210PMC
July 2021

Emergence of novel recombinant type 2 porcine reproductive and respiratory syndrome viruses with high pathogenicity for piglets in China.

J Infect 2021 Jul 28. Epub 2021 Jul 28.

Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, No.518, Ziyue Roa, Minhang District, Shanghai 200241, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal, Infectious Diseases and Zoonoses, Yangzhou 225009, China. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2021.07.033DOI Listing
July 2021

Serum Antibodies to N-Glycolylneuraminic Acid Are Elevated in Duchenne Muscular Dystrophy and Correlate with Increased Disease Pathology in Cmahmdx Mice.

Am J Pathol 2021 08;191(8):1474-1486

Department of Molecular Medicine, University of California, San Diego, California.

Humans cannot synthesize the common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc) because of an inactivating deletion in the cytidine-5'-monophospho-(CMP)-N-acetylneuraminic acid hydroxylase (CMAH) gene responsible for its synthesis. Human Neu5Gc deficiency can lead to development of anti-Neu5Gc serum antibodies, the levels of which can be affected by Neu5Gc-containing diets and by disease. Metabolic incorporation of dietary Neu5Gc into human tissues in the face of circulating antibodies against Neu5Gc-bearing glycans is thought to exacerbate inflammation-driven diseases like cancer and atherosclerosis. Probing of sera with sialoglycan arrays indicated that patients with Duchenne muscular dystrophy (DMD) had a threefold increase in overall anti-Neu5Gc antibody titer compared with age-matched controls. These antibodies recognized a broad spectrum of Neu5Gc-containing glycans. Human-like inactivation of the Cmah gene in mice is known to modulate severity in a variety of mouse models of human disease, including the X chromosome-linked muscular dystrophy (mdx) model for DMD. Cmahmdx mice can be induced to develop anti-Neu5Gc-glycan antibodies as humans do. The presence of anti-Neu5Gc antibodies, in concert with induced Neu5Gc expression, correlated with increased severity of disease pathology in Cmahmdx mice, including increased muscle fibrosis, expression of inflammatory markers in the heart, and decreased survival. These studies suggest that patients with DMD who harbor anti-Neu5Gc serum antibodies might exacerbate disease severity when they ingest Neu5Gc-rich foods, like red meats.
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http://dx.doi.org/10.1016/j.ajpath.2021.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351128PMC
August 2021

EGR1 Suppresses Porcine Epidemic Diarrhea Virus Replication by Regulating IRAV To Degrade Viral Nucleocapsid Protein.

J Virol 2021 09 9;95(19):e0064521. Epub 2021 Sep 9.

Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People's Republic of China.

Porcine epidemic diarrhea virus (PEDV) is a globally distributed alphacoronavirus that has reemerged lately, resulting in large economic losses. During viral infection, type I interferon (IFN-I) plays a vital role in the antiviral innate immunity. However, PEDV has evolved strategies to limit IFN-I production. To suppress virus replication, the host must activate IFN-stimulated genes and some host restriction factors to circumvent viral replication. This study observed that PEDV infection induced early growth response gene 1 (EGR1) expression in PEDV-permissive cells. EGR1 overexpression remarkably suppressed PEDV replication. In contrast, depletion of EGR1 led to a significant increase in viral replication. EGR1 suppressed PEDV replication by directly binding to the IFN-regulated antiviral (IRAV) promoter and upregulating IRAV expression. A detailed analysis revealed that IRAV interacts and colocalizes with the PEDV nucleocapsid (N) protein, inducing N protein degradation via the E3 ubiquitin ligase MARCH8 to catalyze N protein ubiquitination. Knockdown of endogenous MARCH8 significantly reversed IRAV-mediated N protein degradation. The collective findings demonstrate a new mechanism of EGR1-mediated viral restriction, in which EGR1 upregulates the expression of IRAV to degrade PEDV N protein through MARCH8. PEDV is a highly contagious enteric coronavirus that has rapidly emerged worldwide and has caused severe economic losses. No currently available drugs or vaccines can effectively control PEDV. PEDV has evolved many strategies to limit IFN-I production. We identified EGR1 as a novel host restriction factor and demonstrated that EGR1 suppresses PEDV replication by directly binding to the IRAV promoter and upregulating the expression of IRAV, which interacts with and degrades the PEDV N protein via the E3 ubiquitin ligase MARCH8 to catalyze nucleocapsid protein ubiquitination, which adds another layer of complexity to the innate antiviral immunity of this newly identified restriction factor. A better understanding of the innate immune response to PEDV infection will aid the development of novel therapeutic targets and more effective vaccines against virus infection.
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http://dx.doi.org/10.1128/JVI.00645-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428380PMC
September 2021

Sesamol-loaded stearic acid-chitosan nanomicelles mitigate the oxidative stress-stimulated apoptosis and induction of pro-inflammatory cytokines in motor neuronal of the spinal cord through NF-ĸB signaling pathway.

Int J Biol Macromol 2021 Sep 29;186:23-32. Epub 2021 Jun 29.

Department of Neurosurgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. Electronic address:

As natural potential antioxidants suffer from low cellular uptake, the development of drug-loaded nanoplatforms may provide useful information about the treatment of spinal cord injury (SCI). In the present study, sesamol (SM)-loaded stearic acid (SA) -chitosan (CS) nanomicelles were fabricated and well-characterized. Afterwards, the neuroprotective effects of [email protected] nanomicelles against lipopolysaccharide (LPS)-induced oxidative stress in NSC-34 cells was assessed by different cellular and molecular pathways. It was deduced that the size of synthesized [email protected] was in the range of 10-20 nm and the hydrodynamic radii of SA-CA and [email protected] nanomicelles were 53.12 ± 6.21 nm and 59.12 ± 7.31 nm, respectively. Furthermore, [email protected] nanomicelles displayed a sustained drug release at physiological pH, potential dissolution rate and stability even up to 15 days. Cellular assay showed that [email protected] nanomicelles co-incubation with LPS for 24 h in comparison with free drug remarkably regulated cell survival, membrane leakage, generation of ROS, activity of non-enzymatic and enzymatic antioxidant systems, and apoptotic and inflammatory signaling pathway through NF-ĸB signaling pathway. These data indicated that [email protected] nanomicelles can be developed as a promising platform for the mitigation of oxidative stress-mediated apoptosis in neural cells.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.06.171DOI Listing
September 2021

Are sialic acids involved in COVID-19 pathogenesis?

Glycobiology 2021 Sep;31(9):1068-1071

Departments of Medicine and Cellular and Molecular Medicine, UC San Diego, 9500 Gilman Drive, La Jolla, CA, USA.

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http://dx.doi.org/10.1093/glycob/cwab063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344891PMC
September 2021

Genetic characterization and phylogenetic analysis of porcine epidemic diarrhea virus in Guangdong, China, between 2018 and 2019.

PLoS One 2021 24;16(6):e0253622. Epub 2021 Jun 24.

College of Life Science and Engineering, Foshan University, Foshan, Guangdong, China.

Porcine epidemic diarrhea virus (PEDV), a leading cause of piglet diarrhea outbreaks, poses a significant danger to the swine industry. The aim of this study was to investigate the epidemic characteristics of PEDV that was circulating in Guangdong province, one of China's major pig producing provinces. Clinical samples were collected from eight pig farms in Guangdong province between 2018 and 2019 and tested for the major porcine enteric pathogens, including PEDV, transmissible gastroenteritis virus (TGEV), Swine enteric coronavirus (SeCoV), Swine acute diarrhea syndrome coronavirus (SADS-CoV), porcine deltacoronavirus (PDCoV), and porcine rotavirus (RV). As a result, only PEDV and RV were detected at a rate of 47.0% (16/34) and 18.6% (8/34), respectively. Coinfectoin with PEDV and RV occurred at a rate of PEDV 12.5% (2/16). Subsequently, the full-length S gene sequences of 13 PEDV strains were obtained, and phylogenetic analysis suggested the presence of GII-c group PEDV strains in this region (non-S-INDEL). Two novel common amino acid insertions (55T/IG56 and 551L) and one novel glycosylation site (1199G+) were detected when the CV777 and ZJ08 vaccine strains were compared. Furthermore, intragroup recombination events in the S gene regions 51-548 and 2478-4208 were observed in the PEDV strains studied. In summary, the observations provide current information on the incidence of viral agents causing swine diarrhea in southern China and detailed the genetic characteristics and evolutionary history of the dominant PEDV field strains. Our findings will aid in the development of an updated vaccine for the prevention and control of PEDV variant strains.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253622PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224968PMC
July 2021

A GH89 human α-N-acetylglucosaminidase (hNAGLU) homologue from gut microbe Bacteroides thetaiotaomicron capable of hydrolyzing heparosan oligosaccharides.

AMB Express 2021 Jun 24;11(1):94. Epub 2021 Jun 24.

Department of Chemistry, University of California, One Shields Avenue, Davis, CA, 95616, USA.

Carbohydrate-Active enZYme (CAZY) GH89 family enzymes catalyze the cleavage of terminal α-N-acetylglucosamine from glycans and glycoconjugates. Although structurally and mechanistically similar to the human lysosomal α-N-acetylglucosaminidase (hNAGLU) in GH89 which is involved in the degradation of heparan sulfate in the lysosome, the reported bacterial GH89 enzymes characterized so far have no or low activity toward α-N-acetylglucosamine-terminated heparosan oligosaccharides, the preferred substrates of hNAGLU. We cloned and expressed several soluble and active recombinant bacterial GH89 enzymes in Escherichia coli. Among these enzymes, a truncated recombinant α-N-acetylglucosaminidase from gut symbiotic bacterium Bacteroides thetaiotaomicron ∆22Bt3590 was found to catalyze the cleavage of the terminal α1-4-linked N-acetylglucosamine (GlcNAc) from a heparosan disaccharide with high efficiency. Heparosan oligosaccharides with lengths up to decasaccharide were also suitable substrates. This bacterial α-N-acetylglucosaminidase could be a useful catalyst for heparan sulfate analysis.
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http://dx.doi.org/10.1186/s13568-021-01253-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225759PMC
June 2021

A Novel PilR/PilS Two-Component System Regulates Necrotic Enteritis Pilus Production in Clostridium perfringens.

J Bacteriol 2021 Aug 9;203(17):e0009621. Epub 2021 Aug 9.

Guelph Research and Development Centre, Agriculture and Agri-Food Canada, Guelph, Ontario, Canada.

Clostridium perfringens causes necrotic enteritis (NE) in poultry. A chromosomal locus (VR-10B) was previously identified in NE-causing C. perfringens strains that encodes an adhesive pilus (NE pilus), along with a two-component system (TCS) designated here as PilRS. While the NE pilus is important in pathogenesis, the role of PilRS remains to be determined. The current study investigated the function of PilRS, as well as the Agr-like quorum-sensing (QS) system and VirSR TCS in the regulation of pilin production. Isogenic , , and null mutants were generated from the parent strain CP1 by insertional inactivation using the ClosTron system, along with the respective complemented strains. Immunoblotting analyses showed no detectable pilus production in the CP1 mutant, while production in its complement (CP1+) was greater than wild-type levels. In contrast, pilus production in the and mutants was comparable or higher than the wild type but reduced in their respective complemented strains. When examined for collagen-binding activity, the mutant showed significantly lower binding to most collagen types (types I to V) than parental CP1 (0.05), whereas this activity was restored in the complemented strain (0.05). In contrast, binding of and mutants to collagen showed no significant differences in collagen-binding activity compared to CP1 (0.05), whereas the complemented strains exhibited significantly reduced binding (0.05). These data suggest the PilRS TCS positively regulates pilus production in C. perfringens, while the Agr-like QS system may serve as a negative regulator of this operon. Clostridium perfringens type G isolates cause necrotic enteritis (NE) in poultry, presenting a major challenge for poultry production in the postantibiotic era. Multiple factors in C. perfringens, including both virulent and nonvirulent, are involved in the development of the disease. We previously discovered a cluster of C. perfringens genes that encode a pilus involved in adherence and NE development, along with a predicted two-component regulatory system (TCS), designated PilRS. In the present study, we have demonstrated the role of PilRS in regulating pilus production and collagen binding of C. perfringens. In addition, the Agr-like quorum sensing signaling pathway was found to be involved in the regulation. These findings have identified additional targets for developing nonantibiotic strategies to control NE disease.
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http://dx.doi.org/10.1128/JB.00096-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351629PMC
August 2021

Chemoenzymatic Total Synthesis of GM3 Gangliosides Containing Different Sialic Acid Forms and Various Fatty Acyl Chains.

J Org Chem 2021 07 21;86(13):8672-8682. Epub 2021 Jun 21.

Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, United States.

Gangliosides are sialic acid-containing glycosphingolipids that have been found in the cell membranes of all vertebrates. Their important biological functions are contributed by both the glycan and the ceramide lipid components. GM3 is a major ganglioside and a precursor for many other more complex gangliosides. To obtain structurally diverse GM3 gangliosides containing various sialic acid forms and different fatty acyl chains in low cost, an improved process was developed to chemically synthesize lactosyl sphingosine from an inexpensive l-serine derivative. It was then used to obtain GM3 sphingosines from diverse modified sialic acid precursors by an efficient one-pot multienzyme sialylation system containing sialyltransferase 3 (PmST3) with generation of sugar nucleotides. A highly effective chemical acylation and facile C18-cartridge purification process was then used to install fatty acyl chains of varying lengths and different modifications. The chemoenzymatic method represents a powerful total synthetic strategy to access a library of structurally defined GM3 gangliosides to explore their functions.
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http://dx.doi.org/10.1021/acs.joc.1c00450DOI Listing
July 2021

Antioxidant activity of Lactobacillus plantarum NJAU-01 in an animal model of aging.

BMC Microbiol 2021 06 15;21(1):182. Epub 2021 Jun 15.

Key Lab of Meat Processing and Quality Control, Jiangsu Collaborative Innovation Center of Meat Production and Processing, College of Food Science and Technology, Ministry of Education, Nanjing Agricultural University, 210095, Nanjing, Jiangsu, China.

Background: Excessive reactive oxygen species (ROS) can cause serious damage to the human body and may cause various chronic diseases. Studies have found that lactic acid bacteria (LAB) have antioxidant and anti-aging effects, and are important resources for the development of microbial antioxidants. This paper was to explore the potential role of an antioxidant strain, Lactobacillus plantarum NJAU-01 screened from traditional dry-cured meat product Jinhua Ham in regulating D-galactose-induced subacute senescence of mice. A total of 48 specific pathogen free Kun Ming mice (SPF KM mice) were randomly allocated into 6 groups: control group with sterile saline injection, aging group with subcutaneously injection of D-galactose, treatments groups with injection of D-galactose and intragastric administration of 10, 10, and 10 CFU/mL L. plantarum NJAU-01, and positive control group with injection of D-galactose and intragastric administration of 1 mg/mL Vitamin C.

Results: The results showed that the treatment group of L. plantarum NJAU-01 at 10 CFU/mL showed higher total antioxidant capacity (T-AOC) and the antioxidant enzymatic activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) than those of the other groups in serum, heart and liver. In contrast, the content of the oxidative stress marker malondialdehyde (MDA) showed lower levels than the other groups (P < 0.05). The antioxidant capacity was improved with the supplement of the increasing concentration of L. plantarum NJAU-01.

Conclusions: Thus, this study demonstrates that L. plantarum NJAU-01 can alleviate oxidative stress by increasing the activities of enzymes involved in oxidation resistance and decreasing level of lipid oxidation in mice.
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http://dx.doi.org/10.1186/s12866-021-02248-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207596PMC
June 2021

Study on natural convection heat transfer in a closed cavity with hot and cold tubes.

Sci Prog 2021 Apr-Jun;104(2):368504211020965

School of Mechatronic Engineering, Southwest Petroleum University, Chengdu, Sichuan, P.R. China.

Laminar natural convection with a pair of hot and cold tube in a closed cubic cavity is carried out. This configuration can be founded in performance of nuclear power plant containment passive residual heat removal system. The basic government aquations are sloved by means of finite volume method. The effect of number (10-10), shape of tube and spatial position on local and mean heat transfer characteristics is studied. It is found that the number increased when raising number. The number is higher when the shapes are circle and triangle. In adddition, it is founded that the heat transfer has a better effect when the cold tube locates above the hot tube among the five spatial positions. The results provides theoretical basis for performance of nuclear power plant containment passive residual heat removal system.
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http://dx.doi.org/10.1177/00368504211020965DOI Listing
June 2021

Biomolecular Recognition of the Glycan Neoantigen CA19-9 by Distinct Antibodies.

J Mol Biol 2021 07 11;433(15):167099. Epub 2021 Jun 11.

Department of Chemical and Structural Biology, Weizmann Institute of Science, 76100 Rehovot, Israel. Electronic address:

Glycans decorate the cell surface, secreted glycoproteins and glycolipids, and altered glycans are often found in cancers. Despite their high diagnostic and therapeutic potential, however, glycans are polar and flexible molecules that are quite challenging for the development and design of high-affinity binding antibodies. To understand the mechanisms by which glycan neoantigens are specifically recognized by antibodies, we analyze the biomolecular recognition of the tumor-associated carbohydrate antigen CA19-9 by two distinct antibodies using X-ray crystallography. Despite the potential plasticity of glycans and the very different antigen-binding surfaces presented by the antibodies, both structures reveal an essentially identical extended CA19-9 conformer, suggesting that this conformer's stability selects the antibodies. Starting from the bound structure of one of the antibodies, we use the AbLIFT computational algorithm to design a variant with seven core mutations in the variable domain's light-heavy chain interface that exhibits tenfold improved affinity for CA19-9. The results reveal strategies used by antibodies to specifically recognize glycan antigens and show how automated antibody-optimization methods may be used to enhance the clinical potential of existing antibodies.
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http://dx.doi.org/10.1016/j.jmb.2021.167099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611348PMC
July 2021

Marital Status Independently Predicts Glioma Patient Mortality: A Surveillance, Epidemiology, and End Results (SEER) Analysis.

World Neurosurg 2021 Aug 29;152:e302-e312. Epub 2021 May 29.

Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P. R. China. Electronic address:

Objective: To examine the impact of marital status on the mortality of patients with primary malignant brain tumors excluding bias from basic characteristics and treatment.

Methods: We used the Surveillance, Epidemiology, and End Results program to identify 81,277 patients diagnosed from 2000 through 2016 with the most common primary malignant brain tumors, including glioma, ependymoma, and medulloblastoma. To avoid bias, we used the propensity score matching method to match 44,854 patients with complete clinical and follow-up information. Then, we used Cox regression and Kaplan-Meier survival analysis to investigate the impact of marital status on cancer patient mortality.

Results: Married patients were more likely to receive surgery and adjuvant chemo- or radiotherapy than single and divorced, separated, and widowed (DSW) patients (all P < 0.001). Married patients with high grade glioma were more likely to survive longer and less likely to die of their malignance compared with single (adjusted odds ratio [OR] 1.120; 95% confidence interval [CI], 1.069 to 1.174; P < 0.001; OR 1.078; 95% CI, 1.025 to 1.133; P = 0.003; respectively), and DSW patients (OR 1.117; 95% CI, 1.074 to 1.161; P <0.001; OR 1.090; 95% CI, 1.046 to 1.136; P<0.001; respectively) (all adjusted to the married group). Similar results were identified in patients with low-grade glioma but not ependymoma and medulloblastoma.

Conclusions: Even after adjusting for known confounders, married patients with high-grade glioma and low-grade glioma are at higher possibility to have a better outcome. This study highlights the potential significance that intimate support from spouse can improve glioma patient survival.
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http://dx.doi.org/10.1016/j.wneu.2021.05.091DOI Listing
August 2021

Comment on: Efficacy and safety of neoadjuvant immunotherapy in resectable nonsmall cell lung cancer: A meta-analysis.

Lung Cancer 2021 09 3;159:179-180. Epub 2021 May 3.

Department of Oncology, Baotou Fourth Hospital, Baotou, Inner Mongolia Province, 014030, China. Electronic address:

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http://dx.doi.org/10.1016/j.lungcan.2021.04.026DOI Listing
September 2021

Hydroxyethyl starch 130/0.4 for volume replacement therapy in surgical patients: a systematic review and meta-analysis of randomized controlled trials.

Perioper Med (Lond) 2021 May 11;10(1):16. Epub 2021 May 11.

Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.

Background: The safety of perioperative intravenous hydroxyethyl starch (HES) products, specifically HES 130/0.4, continues to be the source of much debate. The aim of this meta-analysis was to update the existing evidence and gain further insight into the clinical effects of HES 130/0.4 on postoperative outcomes for volume replacement therapy in surgical patients.

Methods: MEDLINE, EMBASE, and Cochrane Library databases were searched from inception to March 2020 for relevant randomized controlled trials (RCTs) on perioperative use of HES 130/0.4 in adult surgical patients. The primary outcome was postoperative mortality and secondary outcomes were the incidence of acute kidney injury (AKI) and requirement for renal replacement therapy (RRT). The analysis was performed using the random-effects method and the risk ratio (RR) with a 95% confidence interval (CI). We performed the risk-of-bias assessment of eligible studies and assessed the overall quality of evidence for each outcome.

Results: Twenty-five RCTs with 4111 participants were finally included. There were no statistical differences between HES 130/0.4 and other fluids in mortality at 30 days (RR 1.28, 95% CI 0.88 to 1.86, p = 0.20), the incidence of AKI (RR 1.23, 95% CI 0.99 to 1.53, p = 0.07), or requirement for RRT (RR 0.75, 95% CI 0.37 to 1.53, p = 0.43). Overall, there was a moderate certainty of evidence for all the outcomes. There was no subgroup difference related to the type of surgery (p = 0.17) in the incidence of AKI. As for the type of comparator fluids, however, there was a trend that was not statistically significant (p = 0.06) towards the increased incidence of AKI in the HES 130/0.4 group (RR 1.22, 95% CI 0.97 to 1.54) compared with the crystalloid group (RR 1.21, 95% CI 0.27 to 3.91). Subgroup analyses according to the type of surgery demonstrated consistent findings.

Conclusions: This systematic review and meta-analysis suggests that the use of HES 130/0.4 for volume replacement therapy compared with other fluids resulted in no significant difference in postoperative mortality or kidney dysfunction among surgical patients. Given the absent evidence of confirmed benefit and the potential trend of increased kidney injury, we cannot recommend the routine clinical use of HES 130/0.4 for volume replacement therapy in surgical patients from the perspective of benefit/risk profile. However, the results need to be interpreted with caution due to the limited sample size, and further well-powered RCTs are warranted.

Trial Registration: PROSPERO registry reference: CRD42020173058.
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http://dx.doi.org/10.1186/s13741-021-00182-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111748PMC
May 2021

Therapeutic antibodies, targeting the SARS-CoV-2 spike N-terminal domain, protect lethally infected K18-hACE2 mice.

iScience 2021 May 26;24(5):102479. Epub 2021 Apr 26.

Israel Institute for Biological Research, Ness-Ziona, Israel.

Neutralizing antibodies represent a valuable therapeutic approach to countermeasure the current COVID-19 pandemic. Emergence of SARS-CoV-2 variants emphasizes the notion that antibody treatments need to rely on highly neutralizing monoclonal antibodies (mAbs), targeting several distinct epitopes for circumventing therapy escape mutants. Previously, we reported efficient human therapeutic mAbs recognizing epitopes on the spike receptor-binding domain (RBD) of SARS-CoV-2. Here we report the isolation, characterization, and recombinant production of 12 neutralizing human mAbs, targeting three distinct epitopes on the spike N-terminal domain of the virus. Neutralization mechanism of these antibodies involves receptors other than the canonical hACE2 on target cells, relying both on amino acid and -glycan epitope recognition, suggesting alternative viral cellular portals. Two selected mAbs demonstrated full protection of K18-hACE2 transgenic mice when administered at low doses and late post-exposure, demonstrating the high potential of the mAbs for therapy of SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.isci.2021.102479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074524PMC
May 2021

Neutralizing antibodies against SARS-CoV-2: current understanding, challenge and perspective.

Antib Ther 2020 Dec 28;3(4):285-299. Epub 2020 Dec 28.

State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen 361102, Fujian, China.

The rapid emergence of Coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2) as a pandemic that presents an urgent human health crisis. Many SARS-CoV-2 neutralizing antibodies (NAbs) were developed with efficient therapeutic potential. NAbs-based therapeutics against SARS-CoV-2 are being expedited to preclinical and clinical studies with two antibody drugs, LY3819253 (LY-CoV555) and REGN-COV2 (REGN10933 and REGN10987), approved by the US Food and Drug Administration for emergency use authorization for treating COVID-19. In this review, we provide a systemic overview of SARS-CoV-2 specific or cross-reactive NAbs and discuss their structures, functions and neutralization mechanisms. We provide insight into how these NAbs specific recognize the spike protein of SARS-CoV-2 or cross-react to other CoVs. We also summarize the challenges of NAbs therapeutics such as antibody-dependent enhancement and viral escape mutations. Such evidence is urgently needed to the development of antibody therapeutic interventions that are likely required to reduce the global burden of COVID-19.
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http://dx.doi.org/10.1093/abt/tbaa028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799234PMC
December 2020

A Virulent PEDV Strain FJzz1 with Genomic Mutations and Deletions at the High Passage Level Was Attenuated in Piglets via Serial Passage In Vitro.

Virol Sin 2021 Apr 28. Epub 2021 Apr 28.

Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241, China.

Highly virulent porcine epidemic diarrhea virus (PEDV) strains re-emerged and circulated in China at the end of 2010, causing significant economic losses in the pork industry worldwide. To understand the genetic dynamics of PEDV during its passage in vitro, the PEDV G2 strain FJzz1 was serially propagated in Vero cells for up to 200 passages. The susceptibility and adaptability of the FJzz1 strain increased gradually as it was serially passaged in vitro. Sequence analysis revealed that amino acid (aa) changes were mainly concentrated in the S glycoprotein, which accounted for 72.22%-85.71% of all aa changes. A continuous aa deletion (IGE → KΔΔ) occurred in the N-terminal domain of S1 (S1-NTD). To examine how the aa changes affected its virulence, FJzz1-F20 and FJzz1-F200 were selected to simultaneously evaluate their pathogenicity in suckling piglets. All the piglets in the FJzz1-F20-infected group showed typical diarrhea at 24 h postinfection, and the piglets died successively by 48 h postinfection. However, the clinical signs of the piglets in the FJzz1-F200-infected group were significantly weaker, and no deaths occurred. The FJzz1-F200-infected group also showed a lower level of fecal viral shedding and lower viral loads in the intestinal tissues, and no obvious histopathological lesions. Type I and III interferon were induced in the FJzz1-F200 infection group, together with pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-8. These results indicate that the identified genetic changes may contribute to the attenuation of FJzz1 strain, and the attenuated FJzz1-F200 may have the potential for developing PEDV live-attenuated vaccines.
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http://dx.doi.org/10.1007/s12250-021-00368-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080196PMC
April 2021

TRIM21 inhibits porcine epidemic diarrhea virus proliferation by proteasomal degradation of the nucleocapsid protein.

Arch Virol 2021 Jul 26;166(7):1903-1911. Epub 2021 Apr 26.

Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People's Republic of China.

Tripartite motif protein 21 (TRIM21) is an E3 ubiquitin ligase and cytosolic antibody receptor of the TRIM family. Previous reports have indicated that TRIM21 plays an important role during viral infection. This study aimed at examining the role of TRIM21 in the replication of porcine epidemic diarrhea virus (PEDV) and showed that TRIM21 inhibits PEDV proliferation by targeting and degrading the nucleocapsid (N) protein through the proteasomal pathway. Furthermore, the endogenous expression of TRIM21 was found to be downregulated by PEDV infection in Vero and LLC-PK1 cells. Overexpression of TRIM21 inhibited PEDV replication, whereas knockdown of TRIM21 increased viral titers and N protein levels. TRIM21 was found to interact and colocalize with the N protein, and the TRIM21-mediated antiviral effect was dependent on its ubiquitin ligase activity, which engages in polyubiquitination and degradation of the N protein in a proteasome-dependent manner. Taken together, these findings provide information about the role of TRIM21 in PEDV proliferation and increase our understanding of host-virus interactions.
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http://dx.doi.org/10.1007/s00705-021-05080-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074351PMC
July 2021

Overexpression of FBXO17 Promotes the Proliferation, Migration and Invasion of Glioma Cells Through the Akt/GSK-3β/Snail Pathway.

Cell Transplant 2021 Jan-Dec;30:9636897211007395

Department of Neurosurgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

FBXO17 is a newly studied F-box protein associated with high-grade glioma. However, its exact role in glioma remains unclear. In the present study, we aimed to investigate the role of FBXO17 in glioma both in vitro and in vivo and explore the underlying mechanism. Our results showed that FBXO17 mRNA and protein levels were upregulated in glioma cells including U87, U251, SHG44, and U-118-MG cells as compared to the HA1800 cells. Downregulation of FBXO17 significantly suppressed the cellular behaviors of glioma cells including cell proliferation, migration, and invasion. In addition, FBXO17 knockdown induced E-cadherin expression and inhibited N-cadherin and vimentin expression at mRNA and protein levels in glioma cells. In contrast, overexpression of FBXO17 promoted cell proliferation, migration, invasion and EMT process. Furthermore, FBXO17 regulated the Akt/GSK-3β/snail signaling pathway in glioma cells with significant changes in the expression levels of p-Akt, p-GSK-3β and snail. Additionally, inhibition of Akt by LY294002 reversed the effects of FBXO17 overexpression on cellular behaviors of glioma cells. Finally, in vivo mouse xenograft assay proved that downregulation of FBXO17 suppresses the tumorigenesis of glioma. In conclusion, these findings demonstrated that FBXO17 acted as a promotor of glioma development via modulating Akt/GSK-3β/snail signaling pathway.
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http://dx.doi.org/10.1177/09636897211007395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058804PMC
April 2021

Microbial production of human milk oligosaccharide lactodifucotetraose.

Metab Eng 2021 07 1;66:12-20. Epub 2021 Apr 1.

Department of Chemistry, University of California, Davis, One Shields Ave, Davis, CA, 95616, USA. Electronic address:

Human milk oligosaccharides (HMOs) are potent bioactive compounds that modulate neonatal health and are of interest for development as potential drug treatments for adult diseases. The potential of these molecules, their limited access from natural sources, and difficulty in large-scale isolation of individual HMOs for studies and applications have motivated the development of chemical syntheses and in vitro enzymatic catalysis strategies. Whole cell biocatalysts are emerging as alternative self-regulating production platforms that have the potential to reduce the cost for enzymatic synthesis of HMOs. Whole cell biocatalysts for the production of short-chained, linear and small monofucosylated HMOs have been reported but those for fucosylated structures with higher complexity have not been explored. In this study, we established a strategy for producing a difucosylated HMO, lactodifucotetraose (LDFT), from lactose and L-fucose in Escherichia coli. We used two bacterial fucosyltransferases with narrow acceptor selectivity to drive the sequential fucosylation of lactose and intermediate 2'-fucosyllactose (2'-FL) to produce LDFT. Deletion of substrate degradation pathways that decoupled cellular growth from LDFT production, enhanced expression of native substrate transporters and modular induction of the genes in the LDFT biosynthetic pathway allowed complete conversion of lactose into LDFT and minor quantities of the side product 3-fucosyllactose (3-FL). Overall, 5.1 g/L of LDFT was produced from 3 g/L lactose and 3 g/L L-fucose in 24 h. Our results demonstrate promising applications of engineered microbial biosystems for the production of multi-fucosylated HMOs for biochemical studies.
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http://dx.doi.org/10.1016/j.ymben.2021.03.014DOI Listing
July 2021

Comparative Study on Pale, Soft and Exudative (PSE) and Red, Firm and Non-Exudative (RFN) Pork: Protein Changes during Aging and the Differential Protein Expression of the Myofibrillar Fraction at 1 h Postmortem.

Foods 2021 Mar 30;10(4). Epub 2021 Mar 30.

Jiangsu Key Laboratory of Animal Genetic Breeding and Molecular Design, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China.

In this paper, the protein changes during aging and the differences in the myofibrillar protein fraction at 1 h postmortem of pale, soft and exudative (PSE), and red, firm and non-exudative (RFN) pork (LT) were comparatively studied. The PSE and RFN groups were screened out based on the differences in their pH and lightness () at 1 h, and their purge loss at 24 h postmortem. Based on the measured MFI, desmin degradation, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis, PSE meat presented more significant changes in the myofibrillar protein fraction compared to RFN meat during postmortem aging. Through liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS) analysis, a total of 172 differential proteins were identified, among which 151 were up-regulated and 21 were down-regulated in the PSE group. The differential proteins were muscle contraction, motor proteins, microfilaments, microtubules, glycolysis, glycogen metabolism, energy metabolism, molecular chaperones, transport, and enzyme proteins. The AMP activated protein kinase (AMPK) signaling pathway, HIF-1 signaling pathway, calcium signaling pathway, and PI3K-Akt signaling pathway were identified as the significant pathways related to meat quality. This study suggested that the different changes of the myofibrillar protein fraction were involved in the biochemical metabolism in postmortem muscle, which may contribute to the molecular understanding of PSE meat formation.
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http://dx.doi.org/10.3390/foods10040733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066169PMC
March 2021

Reversible -Acetyl Migration within the Sialic Acid Side Chain and Its Influence on Protein Recognition.

ACS Chem Biol 2021 Mar 26. Epub 2021 Mar 26.

Department of Chemistry, University of California, Davis, California 95616, United States.

-Acetylation is a common naturally occurring modification of carbohydrates and is especially widespread in sialic acids, a family of nine-carbon acidic monosaccharides. -Acetyl migration within the exocyclic glycerol-like side chain of mono--acetylated sialic acid reported previously was from the C7- to C9-hydroxyl group with or without an 8--acetyl intermediate, which resulted in an equilibrium that favors the formation of the 9--acetyl sialic acid. Herein, we provide direct experimental evidence demonstrating that -acetyl migration is bidirectional, and the rate of equilibration is influenced predominantly by the pH of the sample. While the -acetyl group on sialic acids and sialoglycans is stable under mildly acidic conditions (pH < 5, the rate of -acetyl migration is extremely low), reversible -acetyl migration is observed readily at neutral pH and becomes more significant when the pH increases to slightly basic. Sialoglycan microarray studies showed that esterase-inactivated porcine torovirus hemagglutinin-esterase bound strongly to sialoglycans containing a more stable 9--acetylated sialic acid analog, but these compounds were less resistant to periodate oxidation treatment compared to their 9--acetyl counterparts. Together with prior studies, the results support the possible influence of sialic acid -acetylation and -acetyl migration to host-microbe interactions and potential application of the more stable synthetic -acetyl mimics.
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http://dx.doi.org/10.1021/acschembio.0c00998DOI Listing
March 2021
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