Publications by authors named "Xi Jiang"

523 Publications

Joint Analysis of Functional and Structural Connectomes Between Preterm and Term Infant Brains via Canonical Correlation Analysis With Locality Preserving Projection.

Front Neurosci 2021 6;15:724391. Epub 2021 Oct 6.

School of Automation, Northwestern Polytechnical University, Xi'an, China.

Preterm is a worldwide problem that affects infants' lives significantly. Moreover, the early impairment is more than limited to isolated brain regions but also to global and profound negative outcomes later, such as cognitive disorder. Therefore, seeking the differences of brain connectome between preterm and term infant brains is a vital step for understanding the developmental impairment caused by preterm. Existing studies revealed that studying the relationship between brain function and structure, and further investigating their differentiable connectomes between preterm and term infant brains is a way to comprehend and unveil the differences that occur in the preterm infant brains. Therefore, in this article, we proposed a novel canonical correlation analysis (CCA) with locality preserving projection (LPP) approach to investigate the relationship between brain functional and structural connectomes and how such a relationship differs between preterm and term infant brains. CCA is proposed to study the relationship between functional and structural connections, while LPP is adopted to identify the distinguishing features from the connections which can differentiate the preterm and term brains. After investigating the whole brain connections on a fine-scale connectome approach, we successfully identified 89 functional and 97 structural connections, which mostly contributed to differentiate preterm and term infant brains from the functional MRI (fMRI) and diffusion MRI (dMRI) of the public developing Human Connectome Project (dHCP) dataset. By further exploring those identified connections, the results innovatively revealed that the identified functional connections are short-range and within the functional network. On the contrary, the identified structural connections are usually remote connections across different functional networks. In addition, these connectome-level results show the new insights that longitudinal functional changes could deviate from longitudinal structural changes in the preterm infant brains, which help us better understand the brain-behavior changes in preterm infant brains.
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http://dx.doi.org/10.3389/fnins.2021.724391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526737PMC
October 2021

Silencing long noncoding RNA LINC01138 inhibits aerobic glycolysis to reduce glioma cell proliferation by regulating the microRNA‑375/SP1 axis.

Mol Med Rep 2021 Dec 13;24(6). Epub 2021 Oct 13.

Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.

Glioma is a primary cerebral neoplasm that originates from glial tissue and spreads to the central nervous system. Long noncoding RNAs are known to play a role in glioma cells by regulating cell proliferation, migration and invasion. The aim of the present study was to investigate the mechanism by which long intergenic non‑protein coding RNA (LINC) 01138 affects glycolysis and proliferation in glioma cells via the microRNA (miR)‑375/specificity protein 1 (SP1) axis. LINC01138 expression was assessed in glioma tissues and cells using reverse transcription‑quantitative PCR and the association between LINC01138 and patient clinicopathological features was analyzed. Glucose uptake, lactic acid secretion, cell proliferation, and glycolysis‑related enzyme levels were detected following LINC01138 silencing using CCK‑8, EDU assay and western blot analysis. miR‑375 and SP1 expression levels were also assessed, and the distribution of LINC01138 in the nucleus and cytoplasm was investigated using subcellular fractionation localization. Furthermore, the binding relationships between LINC01138 and miR‑375, and between miR‑375 and SP1 were assessed via dual‑luciferase experiment, RIP and RNA pull‑down assays. Finally, xenograft transplantation models were used to verify the results. LINC01138 was highly expressed in glioma, which was independent of patient sex or age but was significantly related to tumor diameter, the World Health Organization tumor grade and lymph node metastasis. Silencing LINC01138 significantly reduced glioma glycolysis and cell proliferation. Moreover, LINC01138 acted as a competing endogenous RNA to sponge miR‑375 and promote SP1 expression. miR‑375 inhibition significantly reversed the effect of LINC01138 silencing. In addition, silencing LINC01138 significantly reduced tumor growth . The present study demonstrated that silencing LINC01138 inhibited aerobic glycolysis and thus reduced glioma cell proliferation, potentially by modulating the miR‑375/SP1 axis.
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http://dx.doi.org/10.3892/mmr.2021.12486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524433PMC
December 2021

A broad and potent IgM antibody against tetra-EV-As induced by EVA71 and CVA16 co-immunization.

Vaccine 2021 10 29;39(44):6510-6519. Epub 2021 Sep 29.

Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China. Electronic address:

Objective: To determine the potent and broad neutralizing monoclonal antibody (mAb) against enterovirus A (EV-A) in vitro and in vivo induced by enterovirus A71(EVA71) and coxsackievirus 16 (CVA16) co-immunization.

Methods: The mAb was Generated by co-immunization with EVA71 and CVA16 through hybridomas technology. The characteristics and neutralizing ability of mAb were analysed in vitro and in mice.

Results: We screened three mAb, the IgM antibody M20 and IgG antibody B1 and C31. All three antibodies showed cross-reactivity against tetra-EV-As. However, M20 showed potent and broad neutralizing ability against tetra-EV-As than B1 and C31. Meanwhile, M20 provided cross-antiviral efficacy in tetra-EV-As orally infected mice. Moreover, M20 binds to a conserved neutralizing epitope within the GH loop of tetra-EV-As VP1.

Conclusions: M20 and its property exhibited potent and broad antiviral activity against tetra-EV-As, and that is expected to be a potential preventive and therapeutic candidate against EV-As.
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http://dx.doi.org/10.1016/j.vaccine.2021.09.056DOI Listing
October 2021

Dental Pulp Mesenchymal Stem Cells Attenuate Limb Ischemia via Promoting Capillary Proliferation and Collateral Development in a Preclinical Model.

Stem Cells Int 2021 31;2021:5585255. Epub 2021 Aug 31.

Beijing SH Biotechnology Co. Ltd., Beijing 100070, China.

Critical limb ischemia (CLI), an end-stage manifestation of peripheral artery disease (PAD), still lacks effective therapeutic strategies. Recently, dental pulp-derived mesenchymal stem cells (DP-MSCs) have been attracting more and more attentions in therapeutic applications due to their high proliferation ability, powerful osteogenic differentiation potential, and effective anti-inflammatory effects. In this study, we compared the therapeutic effects of MSCs derived from different sources in a femoral artery-ligated preclinical ischemic model. We found that treatments with MSCs, including bone marrow- (BM-), adipose- (AD-), dental pulp- (DP-), and umbilical cord- (UC-) derived MSCs, improved limb functions, reduced inflammatory responses, increased angiogenesis, and promoted regeneration of muscle fiber. Among them, DP-MSCs and BM-MSCs produced much more impressive effects in restoring limb functions and promoting angiogenesis. The flow velocity restored to nearly 20% of the normal level at 3 weeks after treatments with DP-MSCs and BM-MSCs, and obvious capillary proliferation and collateral development could be observed. Although neovascularization was induced in the ischemic limb after ligation, MSCs, especially DP-MSCs, significantly enhanced the angiogenesis. experiments showed that serum deprivation improved the expression of angiogenic factors, growth factors, and chemokines in DP-MSCs and UC-MSCs, but not in BM-MSCs and AD-MSCs. However, DP-MSCs produced stronger therapeutic responses than UC-MSCs, which might be due to the higher expression of hepatocyte growth factor (HGF) and hypoxia-inducible factor-1 (HIF-1). We speculated that DP-MSCs might stimulate angiogenesis and promote tissue repair via expressing and secreting angiogenic factors, growth factors, and chemokines, especially HGF and HIF-1. In conclusion, DP-MSCs might be a promising approach for treating CLI.
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http://dx.doi.org/10.1155/2021/5585255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427677PMC
August 2021

Ferulic acid improves motor function induced by spinal cord injury in rats via inhibiting neuroinflammation and apoptosis.

Acta Cir Bras 2021 3;36(7):e360705. Epub 2021 Sep 3.

MM. Department of Pharmacy - Zhejiang Pharmaceutical College - Ningbo, China.

Purpose: To investigate the effect of ferulic acid (FA) on spinal cord injury (SCI)-induced motor dysfunction and to explore the possible pharmacological mechanisms.

Methods: Adult male Wistar rats were used in our study. SCI was achieved by clipping the spinal cord T9 of the rat by a vascular clip for 2 minutes. The motor function of the rat was evaluated by Basso, Beattie, and Bresnahan scoring method (BBB) and inclined plane test. Hematoxylin and eosin (HE) staining, NISSL staining, and transmission electron microscopic examination were used to evaluate alterations at the histological level. Polymerase chain reaction (PCR), Western blots, and enzyme-linked immunosorbent assays (ELISA) were employed in biochemical analysis.

Results: The BBB score and inclined plane test score significantly decreased after SCI surgery, whereas chronic FA treatment (dose of 90 mg/kg, i.g.) for 28 days improved SCI-induced motor dysfunction. HE staining showed that SCI surgery induced internal spinal cord edema, but the structural changes of the spinal cord could be reversed by FA treatment. NISSL staining and transmission electron microscopic examination confirmed the improvement of the effect of FA on the injury site. In the biochemical analysis, it could be found that FA inhibitedSCI-induced mRNA and protein overexpression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), as well as iNOS and COX-2 via the modulation of NF-κB level in the spinal cord of SCI rat. Moreover, the SCI-induced decrease of Bcl-2/Bax ratio was also reversed by FA treatment. However, the effect of FA on the expression of Beclin-1 was not statistically significant.

Conclusions: FA showed a therapeutic effect on SCI, which may be associated with the regulation of neuroinflammation and apoptosis.
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http://dx.doi.org/10.1590/ACB360705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428671PMC
September 2021

Understanding the Role of Endothelial Glycocalyx in Mechanotransduction via Computational Simulation: A Mini Review.

Front Cell Dev Biol 2021 17;9:732815. Epub 2021 Aug 17.

Department of Mechanical Engineering, University College London, London, United Kingdom.

Endothelial glycocalyx (EG) is a forest-like structure, covering the lumen side of blood vessel walls. EG is exposed to the mechanical forces of blood flow, mainly shear, and closely associated with vascular regulation, health, diseases, and therapies. One hallmark function of the EG is mechanotransduction, which means the EG senses the mechanical signals from the blood flow and then transmits the signals into the cells. Using numerical modelling methods or experiments to investigate EG-related topics has gained increasing momentum in recent years, thanks to tremendous progress in supercomputing. Numerical modelling and simulation allows certain very specific or even extreme conditions to be fulfilled, which provides new insights and complements experimental observations. This mini review examines the application of numerical methods in EG-related studies, focusing on how computer simulation contributes to the understanding of EG as a mechanotransducer. The numerical methods covered in this review include macroscopic (i.e., continuum-based), mesoscopic [e.g., lattice Boltzmann method (LBM) and dissipative particle dynamics (DPD)] and microscopic [e.g., molecular dynamics (MD) and Monte Carlo (MC) methods]. Accounting for the emerging trends in artificial intelligence and the advent of exascale computing, the future of numerical simulation for EG-related problems is also contemplated.
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http://dx.doi.org/10.3389/fcell.2021.732815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415899PMC
August 2021

Structural basis of P[II] rotavirus evolution and host ranges under selection of histo-blood group antigens.

Proc Natl Acad Sci U S A 2021 Sep;118(36)

Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056;

Group A rotaviruses cause severe gastroenteritis in infants and young children worldwide, with P[II] genogroup rotaviruses (RVs) responsible for >90% of global cases. RVs have diverse host ranges in different human and animal populations determined by host histo-blood group antigen (HBGA) receptor polymorphism, but details governing diversity, host ranges, and species barriers remain elusive. In this study, crystal structures of complexes of the major P[II] genogroup P[4] and P[8] genotype RV VP8* receptor-binding domains together with Lewis epitope-containing LNDFH I glycans in combination with VP8* receptor-glycan ligand affinity measurements based on NMR titration experiments revealed the structural basis for RV genotype-specific switching between ββ and βα HBGA receptor-binding sites that determine RV host ranges. The data support the hypothesis that P[II] RV evolution progressed from animals to humans under the selection of type 1 HBGAs guided by stepwise host synthesis of type 1 ABH and Lewis HBGAs. The results help explain disease burden, species barriers, epidemiology, and limited efficacy of current RV vaccines in developing countries. The structural data has the potential to impact the design of future vaccine strategies against RV gastroenteritis.
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http://dx.doi.org/10.1073/pnas.2107963118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433580PMC
September 2021

Macrophage-derived extracellular vesicles regulates USP5-mediated HDAC2/NRF2 axis to ameliorate inflammatory pain.

FASEB J 2021 09;35(9):e21332

Department of Rheumatology, The First Hospital of Jilin University, Changchun, P.R. China.

Emerging research has highlighted the capacity of microRNA-23a-3p (miR-23a-3p) to alleviate inflammatory pain. However, the molecular mechanism by which miR-23a-3p attenuates inflammatory pain is yet to be fully understood. Hence, the current study aimed to elucidate the mechanism by which miR-23a-3p influences inflammatory pain. Bioinformatics was initially performed to predict the inflammatory pain related downstream targets of miR-23a-3p in macrophage-derived extracellular vesicles (EVs). An animal inflammatory pain model was established using Complete Freund's Adjuvant (CFA). The miR-23a-3p expression was downregulated in the microglia of CFA-induced mice, after which the inflammatory factors were determined by ELISA. FISH and immunofluorescence were performed to analyze the co-localization of miR-23a-3p and microglia. Interestingly, miR-23a-3p was transported to the microglia via M2 macrophage-EVs, which elevated the mechanical allodynia and the thermal hyperalgesia thresholds in mice model. The miR-23a-3p downstream target, USP5, was found to stabilize HDAC2 via deubiquitination to promote its expression while inhibiting the expression of NRF2. Taken together, the key findings of the current study demonstrate that macrophage-derived EVs containing miR-23a-3p regulates the HDAC2/NRF2 axis by decreasing USP5 expression to alleviate inflammatory pain, which may provide novel therapeutic targets for the treatment of inflammatory pain.
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http://dx.doi.org/10.1096/fj.202001185RRDOI Listing
September 2021

Double-bowl state in photonic Dirac nodal line semimetal.

Light Sci Appl 2021 Aug 20;10(1):170. Epub 2021 Aug 20.

National Laboratory of Solid State Microstructures, School of Physics, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, 210093, Nanjing, China.

The past decade has seen a proliferation of topological materials for both insulators and semimetals in electronic systems and classical waves. Topological semimetals exhibit topologically protected band degeneracies, such as nodal points and nodal lines. Dirac nodal line semimetals (DNLS), which own four-fold line degeneracy, have drawn particular attention. DNLSs have been studied in electronic systems but there is no photonic DNLS. Here in this work, we provide a new mechanism, which is unique for photonic systems to investigate a stringent photonic DNLS. When truncated, the photonic DNLS exhibits double-bowl states (DBS), which comprise two sets of perpendicularly polarized surface states. In sharp contrast to nondegenerate surface states in other photonic systems, here the two sets of surface states are almost degenerate over the whole-spectrum range. The DBS and the bulk Dirac nodal ring (DNR) dispersion along the relevant directions, are experimentally resolved.
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http://dx.doi.org/10.1038/s41377-021-00614-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379272PMC
August 2021

PASSer: Prediction of Allosteric Sites Server.

Mach Learn Sci Technol 2021 Sep 13;2(3). Epub 2021 May 13.

Department of Chemistry, Center for Research Computing, Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, Texas, United States of America.

Allostery is considered important in regulating protein's activity. Drug development depends on the understanding of allosteric mechanisms, especially the identification of allosteric sites, which is a prerequisite in drug discovery and design. Many computational methods have been developed for allosteric site prediction using pocket features and protein dynamics. Here, we present an ensemble learning method, consisting of eXtreme gradient boosting (XGBoost) and graph convolutional neural network (GCNN), to predict allosteric sites. Our model can learn physical properties and topology without any information, and shows good performance under multiple indicators. Prediction results showed that 84.9% of allosteric pockets in the test set appeared in the top 3 positions. The PASSer: Protein Allosteric Sites Server (https://passer.smu.edu), along with a command line interface (CLI, https://github.com/smutaogroup/passerCLI) provide insights for further analysis in drug discovery.
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http://dx.doi.org/10.1088/2632-2153/abe6d6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360383PMC
September 2021

Characterization of Functional Components in Bovine Colostrum That Inhibit Norovirus Capsid Protruding Domains Interacting with HBGA Ligands.

Pathogens 2021 Jul 7;10(7). Epub 2021 Jul 7.

State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.

Human noroviruses (huNoVs) cause epidemic acute gastroenteritis with significant mortality and morbidity worldwide. However, there are no commercial vaccines or antivirals against these important pathogens so far. In this study, we found that bovine colostrum (bCM) inhibited huNoV VLPs and their capsid-protruding (P) domains binding to histo-blood group antigens (HBGAs) that are huNoV receptor or attachment factors for infection, suggesting that bCM may function as a natural antiviral against huNoVs. We then characterized the bCM for the functional inhibition components by sequentially separating bCM into multiple fractions through various chromatography approaches, followed by determining their inhibitory abilities against huNoV receptor-binding P protein interacting with HBGAs. The protein components of bCM functional fractions were examined by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). Our data suggested that some milk proteins, likely in the form of glycoproteins, contribute to the observed blocking effects of bCM. Our findings lay an important foundation to further develop bCM into a potential natural antiviral against huNoVs.
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http://dx.doi.org/10.3390/pathogens10070857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308730PMC
July 2021

Simvastatin Reduces Protection and Intestinal T Cell Responses Induced by a Norovirus P Particle Vaccine in Gnotobiotic Pigs.

Pathogens 2021 Jul 1;10(7). Epub 2021 Jul 1.

Center for Emerging, Zoonotic, and Arthropod-Borne Pathogens, Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.

Noroviruses (NoVs) are a leading cause of acute gastroenteritis worldwide. P particles are a potential vaccine candidate against NoV. Simvastatin is a cholesterol-reducing drug that is known to increase NoV infectivity. In this study, we examined simvastatin's effects on P particle-induced protective efficacy and T-cell immunogenicity using the gnotobiotic pig model of human NoV infection and diarrhea. Pigs were intranasally inoculated with three doses (100 µg/dose) of GII.4/VA387-derived P particles together with monophosphoryl lipid A and chitosan adjuvants. Simvastatin-fed pigs received 8 mg/day orally for 11 days prior to challenge. A subset of pigs was orally challenged with 10 ID of a NoV GII.4/2006b variant at post-inoculation day (PID) 28 and monitored for 7 days post-challenge. Intestinal and systemic T cell responses were determined pre- and postchallenge. Simvastatin abolished the P particle's protection and significantly increased diarrhea severity after NoV infection. Simvastatin decreased proliferation of virus-specific and non-specific CD8 T cells in duodenum and virus-specific CD4 and CD8 T cells in spleen and significantly reduced numbers of intestinal mononuclear cells in vaccinated pigs. Furthermore, simvastatin significantly decreased numbers of duodenal CD4+IFN-γ+, CD8+IFN-γ+ and regulatory T cells and total duodenal activated CD4+ and CD8+ T cells in vaccinated pigs pre-challenge at PID 28. Following challenge, simvastatin prevented the IFN-γ+ T cell response in spleen of vaccinated pigs. These results indicate that simvastatin abolished P particle vaccine-induced partial protection through, at least in part, impairing T cell immunity. The findings have specific implications for the development of preventive and therapeutic strategies against NoV gastroenteritis, especially for the elderly population who takes statin-type drugs.
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http://dx.doi.org/10.3390/pathogens10070829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308729PMC
July 2021

Detachable string magnetically controlled capsule endoscopy for detecting high-risk varices in compensated advanced chronic liver disease (CHESS1801): A prospective multicenter study.

Lancet Reg Health West Pac 2021 Jan 11;6:100072. Epub 2020 Dec 11.

Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.

Background: Gastroesophageal varices is a serious complication of compensated advanced chronic liver disease (cACLD). Primary prophylaxis to reduce the risk of variceal hemorrhage is recommended if high-risk varices (HRV) are detected. We performed this study to compare the accuracy, patients' satisfaction and safety of detection of HRV by detachable string magnetically controlled capsule endoscopy (DS-MCCE) with esophagogastroduodenoscopy (EGD) as the reference.

Methods: We prospectively recruited participants with cACLD from 12 university hospitals (11 in China and one in the United Kingdom) between November 2018 and December 2019 (ClinicalTrials.gov, NCT03749954). All participants underwent DS-MCCE, followed by EGD within a week in a blinded fashion. Following endoscopy, and on the same day, participants were asked to fill in a satisfaction questionnaire regarding their experience.

Findings: A total of 105 eligible participants were enrolled. With EGD as the reference standard, the concordance index, sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of DS-MCCE in diagnosis of HRV were 0•90 (95% confidence interval [CI]: 0•83-0•95), 92% (95% CI: 78-98%), 88% (95% CI: 78-95%), 80% (95% CI: 70-92%), 95% (95% CI: 90-100%), 7•91 (95% CI: 4•10-15•30), and 0•09 (95% CI: 0•03-0•30), respectively. The kappa score of 0•78 (95% CI: 0•65-0•90) suggested substantial agreement between DS-MCCE and EGD. Moreover, in participants undergoing EGD without sedation, the satisfaction of DS-MCCE was significantly better than that of EGD ( < 0•0001,  = 1•15 [95%CI: 0•88-1•42]). All participants confirmed the excretion of the capsule, and no adverse events occurred.

Interpretation: DS-MCCE is an accurate alternative to EGD for detecting HRV in cACLD, which is safe and associated with better satisfaction.

Funding: A full list of funding can be found in the Funding Support section.
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http://dx.doi.org/10.1016/j.lanwpc.2020.100072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315440PMC
January 2021

Intrinsic and growth-mediated cell and matrix specialization during murine meniscus tissue assembly.

FASEB J 2021 08;35(8):e21779

McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

The incredible mechanical strength and durability of mature fibrous tissues and their extremely limited turnover and regenerative capacity underscores the importance of proper matrix assembly during early postnatal growth. In tissues with composite extracellular matrix (ECM) structures, such as the adult knee meniscus, fibrous (Collagen-I rich), and cartilaginous (Collagen-II, proteoglycan-rich) matrix components are regionally segregated to the outer and inner portions of the tissue, respectively. While this spatial variation in composition is appreciated to be functionally important for resisting complex mechanical loads associated with gait, the establishment of these specialized zones is poorly understood. To address this issue, the following study tracked the growth of the murine meniscus from its embryonic formation through its first month of growth, encompassing the critical time-window during which animals begin to ambulate and weight bear. Using histological analysis, region specific high-throughput qPCR, and Col-1, and Col-2 fluorescent reporter mice, we found that matrix and cellular features defining specific tissue zones were already present at birth, before continuous weight-bearing had occurred. These differences in meniscus zones were further refined with postnatal growth and maturation, resulting in specialization of mature tissue regions. Taken together, this work establishes a detailed timeline of the concurrent spatiotemporal changes that occur at both the cellular and matrix level throughout meniscus maturation. The findings of this study provide a framework for investigating the reciprocal feedback between cells and their evolving microenvironments during assembly of a mechanically robust fibrocartilage tissue, thus providing insight into mechanisms of tissue degeneration and effective regenerative strategies.
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http://dx.doi.org/10.1096/fj.202100499RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323983PMC
August 2021

Hemoglobin Fukuoka caused unexpected hemoglobin A results: A case report.

World J Clin Cases 2021 Jul;9(20):5568-5574

Department of Clinical Medical Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China.

Background: Glycated hemoglobin (Hb) (HbA) is an indicator that is used to diagnose and monitor the treatment of diabetes. Many factors can affect the detection of HbA. One of the most important of these factors is the Hb variant. Here, we report a rare Hb variant and evaluate its effect on HbA.

Case Summary: A 35-year-old man was suspected of harboring an Hb variant following the measurement of HbA with the Variant II Turbo 2.0 Hb detection system during a routine examination. Subsequently, we used the Arkray HA-8160 and ARCHITECT c4000 system to reanalyze HbA. Finally, the Hb variant was detected with a Capillary2FP analyzer that operates on the principle of capillary electrophoresis. We also used gene sequencing to investigate the mutation site. The value of HbA detected with the Variant II Turbo 2.0 system was 52.7%. However, the Arkray HA-8160 system did not display a result while the ARCHITECT c16000 system showed a result of 5.4%. The Capillary2FP analyzer did not reveal any abnormal Hb zones. However, gene sequencing identified the presence of a mutation in the Hb β2 chain [CD2(CAC>TAC), His>Tyr, : c.7C>T]; the genotype was Hb Fukuoka.

Conclusion: Hb variants could cause abnormal HbA results. For patients with Hb variants, different methods should be used to detect HbA.
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http://dx.doi.org/10.12998/wjcc.v9.i20.5568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281434PMC
July 2021

Activation, development, and attenuation of modeling- and remodeling-based bone formation in adult rats.

Biomaterials 2021 09 9;276:121015. Epub 2021 Jul 9.

McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

Activation of modeling-based bone formation (MBF - bone formation without prior activation of bone resorption), has been identified as an important mechanism by which anabolic agents, such as intermittent parathyroid hormone (PTH), rapidly elicit new bone formation. Using a novel cryohistology imaging platform, coupled with sequential multicolor fluorochrome injections, we demonstrated that MBF and remodeling-based bone formation (RBF) in the adult rat tibia model have similar contributions to trabecular bone homeostasis. PTH treatment resulted in a 2.4-4.9 fold greater bone formation rate over bone surface (BFR/BS) by RBF and a 4.3-8.5 fold greater BFR/BS by MBF in male, intact female, and ovariectomized female rats. Moreover, regardless of bone formation type, once a formation site is activated by PTH, mineral deposition continues throughout the entire treatment duration. Furthermore, by tracking the sequence of multicolor fluorochrome labels, we discovered that MBF, a highly efficient but often overlooked regenerative mechanism, is activated more rapidly but attenuated faster than RBF in response to PTH. This suggests that MBF and RBF contribute differently to PTH's anabolic effect in rats: MBF has a greater contribution to the acute elevation in bone mass at the early stage of treatment while RBF contributes to the sustained treatment effect.
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http://dx.doi.org/10.1016/j.biomaterials.2021.121015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523222PMC
September 2021

The complete chloroplast genome of Shap. (Leguminosae).

Mitochondrial DNA B Resour 2021 30;6(8):2128-2130. Epub 2021 Jun 30.

Xinjiang Production and Construction Corps Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin, College of Life Science, Tarim University, Alar, China.

Shap. is a perennial herbaceous plant belonging to the genus , Leguminosae. This species is of high nutritional, medicinal and ecological values. The complete chloroplast genome was 128,418 bp and lost an IR (inverted repeat) region. Further annotation revealed the chloroplast genome contains 108 genes, including 75 protein coding genes, 29 tRNA genes, and 4 rRNA genes. A total of 103 simple sequence repeats (SSRs) were identified in the chloroplast genome. This chloroplast genome resource will be useful for study on the evolution and genetic diversity of in the future.
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http://dx.doi.org/10.1080/23802359.2021.1944366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253187PMC
June 2021

Cross talk between endothelial and red blood cell glycocalyces via near-field flow.

Biophys J 2021 08 29;120(15):3180-3191. Epub 2021 Jun 29.

Department of Mechanical Engineering, University College London, London, United Kingdom. Electronic address:

Vascular endothelial cells and circulating red blood cell (RBC) surfaces are both covered by a layer of bushy glycocalyx. The interplay between these glycocalyx layers is hardly measurable and insufficiently understood. This study aims to investigate and qualify the possible interactions between the glycocalyces of RBCs and endothelial cells using mathematical modeling and numerical simulation. Dissipative particle dynamics (DPD) simulations are conducted to investigate the response of the endothelial glycocalyx (EG) to varying ambient conditions. A two-compartment model including EG and flow and a three-compartment model comprising EG, RBC glycocalyx, and flow are established. The two-compartment analysis shows that a relatively fast flow is associated with a predominantly bending motion of the EG, whereas oscillatory motions are predominant in a relatively slow flow. Results show that circulating RBCs cause the contactless deformation of EG. Its deformation is dependent on the chain layout, chain length, bending stiffness, RBC-to-EG distance, and RBC velocities. Specifically, shorter EG chains or RBC-to-EG distance leads to greater relative deflections of EG. Deformation of EG is enhanced when the EG chains are rarefied or RBCs move faster. The bending stiffness maintains stretching conformation of EG. Moreover, a compact EG chain layout and shedding EG chains disturb the neighboring flow field, causing disordered flow velocity distributions. In contrast, the movement of EG chains on RBC surfaces exerts a marginal driving force on RBCs. The DPD method is used for the first time, to our knowledge, in the three-compartment system to explore the cross talk between EG and RBC glycocalyx. This study suggests that RBCs drive the EG deformation via the near-field flow, whereas marginal propulsion of RBCs by the EG is observed. These new, to our knowledge, findings provide a new angle to understand the roles of glycocalyx in mechanotransduction and microvascular permeability and their perturbations under idealized pathophysiologic conditions associated with EG degradation.
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http://dx.doi.org/10.1016/j.bpj.2021.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392098PMC
August 2021

The impact of autologous concentrated growth factors on the alveolar ridge preservation after posterior tooth extraction: A prospective, randomized controlled clinical trial.

Clin Implant Dent Relat Res 2021 Aug 23;23(4):579-592. Epub 2021 Jun 23.

First Clinical Division, Peking University School and Hospital of Stomatology, National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China.

Background: Alveolar ridge preservation can effectively decrease alveolar ridge resorption following tooth extraction, but it can be limited by reducing new bone formation and residual bone graft material. Efforts to develop more efficacious approaches are thus an area of active research.

Purpose: To assess the impact of autologous concentrated growth factors (CGF) on alveolar ridge absorption and osteogenesis following posterior tooth extraction.

Materials And Methods: Fifty patients were randomly assigned to have extraction sockets treated with CGF or no treatment. At 10 days, 1 month, and 3 months postextraction, soft tissue color and texture were examined and evaluated with healing score. Cone-beam computed tomography (CBCT) scans were performed before and 3 months after extraction, while radiographic analyses were used to assess vertical and horizontal bone changes. Bone samples were collected from the extraction sockets during implant placement, and micro-computed tomography (micro-CT) scans and histological analysis were performed to evaluate new bone formation. t-Test or Mann-Whitney U test was used to compare data and the level of statistical significance was set at 0.05 for all analyses.

Results: Forty-six patients completed the trial. Sockets in the experimental group exhibited significantly better healing score on Day 10 postextraction relative to the control group, whereas comparable healing was observed in both groups at 1 and 3 months postextraction. Experimental group exhibited reduced vertical bone changes relative to the control (p < 0.05). Significant reductions were observed in ridge width changes at 1 and 2 mm apical to the crest (p < 0.05), although differences at 3 and 5 mm apical to the crest were not significant. Significant differences of bone mineral density (BMD) and microarchitecture of trabecular bone were observed via micro-CT analyses, and the experimental group had better results.

Conclusion: CGF application following posterior tooth extraction may reduce vertical and horizontal bone resorption and promote new bone formation.
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http://dx.doi.org/10.1111/cid.13026DOI Listing
August 2021

Anti-Tumor Effects of in Acute Myeloid Leukemia.

Front Oncol 2021 4;11:694594. Epub 2021 Jun 4.

Department of Pharmacology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Dysregulation of ketone metabolism has been reported in various types of cancer. In order to find out its role in acute myeloid leukemia (AML) pathogenesis, we first analyzed the expression levels of 10 key genes involved in ketone metabolism in AML blasts and CD34 hematopoietic stem cells (HSCs) from healthy donors. We found that the expression level of was significantly lower in AML than in normal HSCs. The downregulation of gene expression in AML cell lines as compared with normal HSCs was further confirmed with real-time RT-PCR. Analysis of TCGA and other database revealed that the downregulation of was associated with worse prognosis in AML patients. In addition, we showed that overexpression of inhibited the viability and proliferation of AML cells. In contrast, knock-down promoted AML cell growth. Collectively, our results suggest the previously unappreciated anti-tumor role of in AML, and low expression predicts poor survival.
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http://dx.doi.org/10.3389/fonc.2021.694594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213090PMC
June 2021

Lipopolysaccharide-induced depression is associated with estrogen receptor-α/SIRT1/NF-κB signaling pathway in old female mice.

Neurochem Int 2021 09 11;148:105097. Epub 2021 Jun 11.

Department of Pharmacy, Zhejiang Pharmaceutical College, Ningbo, 315000, China.

The present study aims to investigate the influence of sex/age on depressive-like behaviors in lipopolysaccharide (LPS)-challenged mice model, and explore the underlying mechanisms. Tail suspension test and forced swimming test were used to evaluate the depressive-like behaviors. SIRT1 mRNA expression was assessed by PCR. Levels of 17β-estradiol (E2), SIRT1, NF-κB, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6) were detected by enzyme linked immunosorbent assay (ELISA). In the behavior tests, under the same LPS stimulation, significant depressive-like behavior was observed in young male mice but not in young female mice, however, female mice were more likely to be depressed than male mice in the old age. Moreover, we found age-related depression difference existed only in female mice. In the experiments of mechanism exploration in old female mice, E2 improved LPS-induced depressive-like behavior, and simultaneously elevated SIRT1 levels and downregulated expressions of NF-κB and inflammatory cytokines in the hippocampus and frontal cortex. Interestingly, ERα inhibition, not ERβ inhibition, abolished E2's function. Additionally, SIRT1 antagonist also reversed E2's effects on depressive-like behavior and the expressions of NF-κB and inflammatory cytokines. These results suggested that E2 could protect the old female mice from depression via E2/ERα/SIRT1/NF-κB signaling pathway. In other words, LPS-induced depression was associated with ER-α/SIRT1/NF-κB signaling pathway in old female mice. By comparing the results of mechanism exploration in old male mice and old female mice and the different expression levels of E2, SIRT1, NF-κB and inflammatory cytokines in young female mice and old female mice, we speculate that the age or gender-related depression difference may be associated with the different activation levels of the ERα/SIRT1/NF-κB signaling pathway.
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http://dx.doi.org/10.1016/j.neuint.2021.105097DOI Listing
September 2021

Minimizing Crinkling of Soft Specimens Using Holey Gold Films on Molybdenum Grids for Cryogenic Electron Microscopy.

Microsc Microanal 2021 Aug;27(4):767-775

Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA94720, USA.

We introduce a novel composite holey gold support that prevents cryo-crinkling and reduces beam-induced motion of soft specimens, building on the previously introduced all-gold support. The composite holey gold support for high-resolution cryogenic electron microscopy of soft crystalline membranes was fabricated in two steps. In the first step, a holey gold film was transferred on top of a molybdenum grid. In the second step, a continuous thin carbon film was transferred onto the holey gold film. This support (Au/Mo grid) was used to image crystalline synthetic polymer membranes. The low thermal expansion of Mo is not only expected to avoid cryo-crinkling of the membrane when the grids are cooled to cryogenic temperatures, but it may also act to reduce whatever crinkling existed even before cooling. The Au/Mo grid exhibits excellent performance with specimens tilted to 45°. This is demonstrated by quantifying beam-induced motion and differences in local defocus values. In addition, images of specimens on the Au/Mo grids that are tilted at 45° show high-resolution information of the crystalline membranes that, after lattice-unbending, extends beyond 1.5 Å in the direction perpendicular to the tilt axis.
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http://dx.doi.org/10.1017/S1431927621000520DOI Listing
August 2021

Structure-based virtual screening of highly potent inhibitors of the nematode chitinase Cht1.

J Enzyme Inhib Med Chem 2021 Dec;36(1):1198-1204

State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China.

Nematode chitinases play vital roles in various physiological processes, including egg hatching, larva moulting, and reproduction. Small-molecule inhibitors of nematode chitinases have potential applications for controlling nematode pests. On the basis of the crystal structure of Cht1, a representative chitinase indispensable to the eggshell chitin degradation of the model nematode , we have discovered a series of novel inhibitors bearing a ()-3,4-diphenyl-4,5-dihydropyrrolo[3,4-]pyrazol-6(2)-one scaffold by hierarchical virtual screening. The crystal structures of Cht1 complexed with two of these inhibitors clearly elucidated their interactions with the enzyme active site. Based on the inhibitory mechanism, several analogues with improved inhibitory activities were identified, among which the compound exhibited the most potent activity with a value of 0.18 μM. This work provides the structural basis for the development of novel nematode chitinase inhibitors.
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http://dx.doi.org/10.1080/14756366.2021.1931862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174485PMC
December 2021

Intra-species sialic acid polymorphism in humans: a common niche for influenza and coronavirus pandemics?

Emerg Microbes Infect 2021 Dec;10(1):1191-1199

Department of Chemistry and Biochemistry, Miami University, Oxford, OH, USA.

The ongoing COVID-19 pandemic has led to more than 159 million confirmed cases with over 3.3 million deaths worldwide, but it remains mystery why most infected individuals (∼98%) were asymptomatic or only experienced mild illness. The same mystery applies to the deadly 1918 H1N1 influenza pandemic, which has puzzled the field for a century. Here we discuss dual potential properties of the 1918 H1N1 pandemic viruses that led to the high fatality rate in the small portion of severe cases, while about 98% infected persons in the United States were self-limited with mild symptoms, or even asymptomatic. These variations now have been postulated to be impacted by polymorphisms of the sialic acid receptors in the general population. Since coronaviruses (CoVs) also recognize sialic acid receptors and cause severe acute respiratory syndrome epidemics and pandemics, similar principles of influenza virus evolution and pandemicity may also apply to CoVs. A potential common principle of pathogen/host co-evolution of influenza and CoVs under selection of host sialic acids in parallel with different epidemic and pandemic influenza and coronaviruses is discussed.
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http://dx.doi.org/10.1080/22221751.2021.1935329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208123PMC
December 2021

Global sensitivity analysis of VISSIM parameters for project-level traffic emissions: a case study at a signalized intersection.

Environ Technol 2021 Sep 9:1-20. Epub 2021 Sep 9.

State Key Laboratory of Rail Traffic Control and Safety, Beijing Jiaotong University, Beijing, People's Republic of China.

Combining traffic micro-simulation models and emission models is a primary method to estimate traffic emissions. However, there has been limited research on the impact of traffic micro-simulation model parameters on simulator outputs, which are critical to emissions calculations. Based on combining VISSIM and MOVES, this study uses the Morris and Sobol methods to explore the impact of parameters in VISSIM on operating mode distribution and travel time distribution. Taking an urban signal control intersection with three traffic scenarios in Chengdu, China as an example, this study verifies the methods' feasibility. Apart from these parameters, which have been proved to be necessary calibration parameters, including the desired speed distribution, the desired acceleration function, and the desired deceleration function, an additional 24 parameters related to simulation setting and driving behaviour models are selected as the initial parameters. The number of interaction objects, maximum look-ahead distance, average standstill distance, additive part of safety distance, and safety distance reduction factor close to a stop line, are considered to be the important parameters for this case study. The impact of these five parameters on the bins of operating mode distribution and travel time distribution are further analyzed with One-at-a-time, and these parameters are compared with those reported in previous studies. It is concluded that the important parameters selected in this study are reasonable and can support the calibration of VISSIM parameters for this case's traffic emissions.
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http://dx.doi.org/10.1080/09593330.2021.1934737DOI Listing
September 2021

Decreased homotopic interhemispheric functional connectivity in children with autism spectrum disorder.

Autism Res 2021 08 28;14(8):1609-1620. Epub 2021 Apr 28.

The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for NeuroInformation, Center for Information in Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.

While several functional and structural changes occur in large-scale brain networks in autism spectrum disorder (ASD), reduced interhemispheric resting-state functional connectivity (rsFC) between homotopic regions may be of particular importance as a biomarker. ASD is an early-onset developmental disorder and neural alterations are often age-dependent. Although there is some evidence for homotopic interhemispheric rsFC alterations in language processing regions in ASD children, wider analyses using large data sets have not been performed. The present study, therefore, conducted a voxel-based homotopic interhemispheric rsFC analysis in 146 ASD and 175 typically developing children under-age 10 and examined associations with symptom severity in the autism brain imaging data exchange data sets. Given the role of corpus callosum (CC) in interhemispheric connectivity and reported CC volume changes in ASD we additionally examined whether there were parallel volumetric changes. Results demonstrated decreased homotopic rsFC in ASD children in the posterior cingulate cortex (PCC) and precuneus of the default mode network, the precentral gyrus of the mirror neuron system, and the caudate of the reward system. Homotopic rsFC of the PCC was associated with symptom severity. Furthermore, although no significant CC volume changes were found in ASD children, there was a significant negative correlation between the anterior CC volumes and homotopic rsFC strengths in the caudate. The present study shows that a reduced pattern of homotopic interhemispheric rsFC in ASD adults/adolescents is already present in children of 5-10 years old and further supports their potential use as a general ASD biomarker. LAY SUMMARY: Homotopic interhemispheric functional connectivity plays an important role in synchronizing activity between the two hemispheres and is altered in adults and adolescents with autism spectrum disorder (ASD). In the present study focused on children with ASD, we have observed a similar pattern of decreased homotopic connectivity, suggesting that alterations in homotopic interhemispheric connectivity may occur early in ASD and be a useful general biomarker across ages.
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http://dx.doi.org/10.1002/aur.2523DOI Listing
August 2021

Discovery of Kasugamycin as a Potent Inhibitor of Glycoside Hydrolase Family 18 Chitinases.

Front Mol Biosci 2021 7;8:640356. Epub 2021 Apr 7.

School of Bioengineering, Dalian University of Technology, Dalian, China.

Kasugamycin, a well-known aminoglycoside antibiotic, has been used widely in agriculture and medicine to combat microbial pathogens by binding the ribosome to inhibit translation. Here, kasugamycin was discovered to be a competitive inhibitor of glycoside hydrolase family 18 (GH18) chitinases from three different organisms (bacterium, insect and human). Results from tryptophan fluorescence spectroscopy and molecular docking revealed that kasugamycin binds to the substrate-binding clefts in a similar mode as the substrate. An electrostatic interaction between the amino group of kasugamycin and the carboxyl group of a conserved aspartate in GH18 chitinase (one of the catalytic triad residues) was found to be vital for the inhibitory activity. This paper not only reports new molecular targets of kasugamycin, but also expands our thinking about GH inhibitor design by using a scaffold unrelated to the substrate.
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http://dx.doi.org/10.3389/fmolb.2021.640356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058351PMC
April 2021

Variation of microRNA expression in the human placenta driven by population identity and sex of the newborn.

BMC Genomics 2021 Apr 20;22(1):286. Epub 2021 Apr 20.

Skolkovo Institute of Science and Technology, 121205, Moscow, Russia.

Background: Analysis of lymphocyte cell lines revealed substantial differences in the expression of mRNA and microRNA (miRNA) among human populations. The extent of such population-associated differences in actual human tissues remains largely unexplored. The placenta is one of the few solid human tissues that can be collected in substantial numbers in a controlled manner, enabling quantitative analysis of transient biomolecules such as RNA transcripts. Here, we analyzed microRNA (miRNA) expression in human placental samples derived from 36 individuals representing four genetically distinct human populations: African Americans, European Americans, South Asians, and East Asians. All samples were collected at the same hospital following a unified protocol, thus minimizing potential biases that might influence the results.

Results: Sequence analysis of the miRNA fraction yielded 938 annotated and 70 novel miRNA transcripts expressed in the placenta. Of them, 82 (9%) of annotated and 11 (16%) of novel miRNAs displayed quantitative expression differences among populations, generally reflecting reported genetic and mRNA-expression-based distances. Several co-expressed miRNA clusters stood out from the rest of the population-associated differences in terms of miRNA evolutionary age, tissue-specificity, and disease-association characteristics. Among three non-environmental influenced demographic parameters, the second largest contributor to miRNA expression variation after population was the sex of the newborn, with 32 miRNAs (3% of detected) exhibiting significant expression differences depending on whether the newborn was male or female. Male-associated miRNAs were evolutionarily younger and correlated inversely with the expression of target mRNA involved in neuron-related functions. In contrast, both male and female-associated miRNAs appeared to mediate different types of hormonal responses. Demographic factors further affected reported imprinted expression of 66 placental miRNAs: the imprinting strength correlated with the mother's weight, but not height.

Conclusions: Our results showed that among 12 assessed demographic variables, population affiliation and fetal sex had a substantial influence on miRNA expression variation among human placental samples. The effect of newborn-sex-associated miRNA differences further led to expression inhibition of the target genes clustering in specific functional pathways. By contrast, population-driven miRNA differences might mainly represent neutral changes with minimal functional impacts.
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http://dx.doi.org/10.1186/s12864-021-07542-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059241PMC
April 2021

Retraction notice to "Immunogenicity of newcastle disease virus vectors expressing norwalk virus capsid protein in the presence or absence of VP2 protein" [Virology (484) (October 2015) 163-169].

Virology 2021 Jun 11;558:152. Epub 2021 Mar 11.

Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, MD, USA.

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http://dx.doi.org/10.1016/j.virol.2021.03.001DOI Listing
June 2021

Crystal Structure and Structure-Based Discovery of Inhibitors of the Nematode Chitinase Cht1.

J Agric Food Chem 2021 Mar 10;69(11):3519-3526. Epub 2021 Mar 10.

State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China.

Nematode chitinases play crucial roles in various processes of the nematode lifecycle, including hatching, molting, and reproduction. Small-molecule inhibitors of nematode chitinases have shown promise for controlling nematode pests. However, the lack of structural information makes it a challenge to develop nematicides targeting nematode chitinases. Here, we report the first crystal structure of a representative nematode chitinase, that of Cht1 from the model nematode , to a 1.7 Å resolution. Cht1 is a highly conserved chitinase among nematodes, and structural comparison with other chitinases revealed that Cht1 has a classical TIM-barrel fold with some subtle structural differences in the substrate-binding cleft. Benefiting from the obtained crystal structure, we identified a series of novel inhibitors by hierarchical virtual screening. Analysis of the structure-activity relationships of these compounds provided insight into their interactions with the enzyme active site, which may inform future work in improving the potencies of their inhibitory activities. This work gives an insight into the structural features of nematode chitinases and provides a solid basis for the development of inhibitors.
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http://dx.doi.org/10.1021/acs.jafc.1c00162DOI Listing
March 2021
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