Publications by authors named "Haitao Yang"

308 Publications

Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332.

Protein Cell 2021 Oct 22. Epub 2021 Oct 22.

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13238-021-00883-2DOI Listing
October 2021

Prevalence of Varied Coat Coloration in a Yellow-Throated Marten () Population.

Animals (Basel) 2021 Sep 29;11(10). Epub 2021 Sep 29.

Ministry of Education Key Laboratory for Biodiversity Science and Engineering, National Forestry and Grassland Administration Key Laboratory for Conservation Ecology of Northeast Tiger and Leopard National Park, Northeast Tiger and Leopard Biodiversity National Observation and Research Station, National Forestry and Grassland Administration Amur Tiger and Amur Leopard Monitoring and Research Center, College of Life Sciences, Beijing Normal University, Beijing 100875, China.

Mammalian coat color is determined by heritable variations such as disease, nutrition, and hormone levels. Variation in animal coat color is also considered an environmental indicator and provides clues for the study of population genetics and biogeography. Records of abnormal coloration in the wild are rare, not only because it is often selected against, but also because of the difficulties in detection of the phenomenon. We used long-term camera-trapping data to first report abnormal coat coloration in yellow-throated marten () in China. Six types of abnormal coloration were found only in the Northeast Tiger and Leopard National Park, Northeast China, which were not reported in other regions in China. A total of 268 videos of contained normal coloration, 455 videos of individuals of the species contained abnormal coloration, 437 contained the 'gloving' type (martens with de-pigmented front toes, paws or lower forelimbs), while the remaining other 18 videos contained five types (different degrees of white-spotting and dilution). The higher relative abundance index (0.428, 'gloving' to 0.329, normal) and wide distribution area of the 'gloving' type indicated that this abnormal coat coloration type is usual in Northeast China, which may reflect genetic variability in the local population. These records will contribute to further research on animal coat color and its corresponding adaptive strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ani11102838DOI Listing
September 2021

Structural and mechanistic insights into the complexes formed by cytoplasmic incompatibility factors.

Proc Natl Acad Sci U S A 2021 Oct;118(41)

School of Life Sciences, Tianjin University, Tianjin, 300072, China;

bacteria, inherited through the female germ line, infect a large fraction of arthropod species. Many strains manipulate host reproduction, most commonly through cytoplasmic incompatibility (CI). CI, a conditional male sterility, results when -infected male insects mate with uninfected females; viability is restored if the female is similarly infected (called "rescue"). CI is used to help control mosquito-borne viruses such as dengue and Zika, but its mechanisms remain unknown. The coexpressed CI factors CifA and CifB form stable complexes in vitro, but the timing and function of this interaction in the insect are unresolved. CifA expression in the female germ line is sufficient for rescue. We report high-resolution structures of a CI-factor complex, CinA-CinB, which utilizes a unique binding mode between the CinA rescue factor and the CinB nuclease; the structures were validated by biochemical and yeast growth analyses. Importantly, transgenic expression in of a nonbinding CinA mutant, designed based on the CinA-CinB structure, suggests CinA expressed in females must bind CinB imported by sperm in order to rescue embryonic viability. Binding between cognate factors is conserved in an enzymatically distinct CI system, CidA-CidB, suggesting universal features in CI induction and rescue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2107699118DOI Listing
October 2021

Activation of TLR2 heterodimers-mediated NF-κB, MAPK, AKT signaling pathways is responsible for Vibrio alginolyticus triggered inflammatory response in vitro.

Microb Pathog 2021 Sep 30:105219. Epub 2021 Sep 30.

Jiangsu Key Laboratory of Marine Biological Resources and Environment, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Ocean University, Lianyungang, 222005, China; Key Laboratory of Zoonosis Research, College of Veterinary Medicine, Jilin University, Changchun, 130062, China. Electronic address:

Vibrio alginolyticus is an important zoonotic marine pathogenic bacterium. Previous studies on the mechanism of innate immune against V. alginolyticus infection have been limited to aquatic animals, however, how V. alginolyticus activates mammalian immune cells has not been fully clarified. Here, ELISA combined RT-qPCR assays were used to detect the secretion and transcription level of pro-inflammatory cytokines and TLRs during V. alginolyticus infection of mice peritoneal macrophages (PMϕs). Western blotting was used to explore the phosphorylation levels of p38, JNK, ERK, AKT and NF-κB protein. Immunofluorescence assay was used to determine the location of NF-κB protein. Inhibition assay was used to study the role of up-regulated TLR in activated signaling pathways and the role of these pathways in the release of pro-inflammatory cytokines. Our data showed that V. alginolyticus can up-regulate the expression levels of IL-1β, IL-6, IL-12 and TNF-α in PMϕs. In addition, V. alginolyticus stimulation activated the phosphorylation of p38, JNK and ERK were TLR2 heterodimers-dependent, whereas inhibitors of SB203580 (p38), SCH772984 (ERK) and SP600125 (JNK) significantly reduced IL-1β, IL-6, IL-12 and TNF-α production. We further revealed that V. alginolyticus activated the signaling pathways of AKT via TLR2 heterodimers. The inhibitor of MK-2206 2HCl (AKT) negatively regulated the IL-1β, IL-6 and TNF-α release levels. Moreover, V. alginolyticus infection of PMϕs resulted in TLR2 heterodimers-mediated activation of NF-κB and induced translocation of phosphorylated NF-κB protein from the cytoplasm into the nucleus via IκBα degradation. V. alginolyticus induced IL-1β, IL-6, IL-12 and TNF-α release were blocked by the specific NF-κB inhibitor, BAY 11-7082. Taken together, our results suggested that activation of the TLR2 heterodimers-mediated downstream signaling pathways NF-κB, MAPK and AKT is responsible for inflammatory response during Vibrio alginolyticus infection in vitro.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.micpath.2021.105219DOI Listing
September 2021

A Rapid and Sensitive Detection Method for Using Visualized Recombinase Polymerase Amplification and Lateral Flow Strip Technology.

Front Cell Infect Microbiol 2021 14;11:698929. Epub 2021 Sep 14.

Laboratory Department of Ningbo First Hospital, Ningbo Hospital of Zhejiang University, Ningbo, China.

is a common opportunistic pathogen that causes acute nosocomial necrotizing pneumonia and is the predominant source of chronic lung infections in patients with the genetic disorder cystic fibrosis. Early diagnosis in infected patients and monitoring contamination is therefore of great importance in controlling disease spread and development with timely drugs intervention treatment and cut off infection source. Traditional culture-biochemical methods are time consuming and highly dependent on technicians and expensive instruments. To address these challenges, the present study aimed to develop a rapid, sensitive, and specific, on-site detection method for based on recombinase polymerase amplification (RPA) combined with lateral flow strip (LFS) technology. The experimental process included screening and modification of primer and probe sets targeting the unique virulence gene (); specificity detection in 29 strains of and 23 closely-related pathogenic bacteria; sensitivity measurements with gradient-diluted genomic DNA and probit regression analysis; and clinical application evaluation using 574 patients samples and calculating coincidence rate and kappa index value in comparison with the culture-biochemical method. The RPA-LFS assay could complete the amplification process at 37°C constant temperature within 30 min and results could be visualized by the naked eye within 10 min on LFS. The assay displayed high sensitivity with a limit of detection of 3.05 CFU/reaction. It also demonstrated high specificity by showing no cross reaction with other pathogenic bacteria, and rapidness by being completed in less than an hour. Furthermore, when used with clinical samples, the assay had a coincidence rate of 98.26% with the culture-biochemical method and a kappa index value of 0.9433. These data indicate that the RPA-LFS assay represents a major improvement for detection, especially in resource-limited areas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcimb.2021.698929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478171PMC
October 2021

Roton pair density wave in a strong-coupling kagome superconductor.

Nature 2021 Sep 29. Epub 2021 Sep 29.

Beijing National Center for Condensed Matter Physics and Institute of Physics, Chinese Academy of Sciences, Beijing, 100190, PR China.

The transition-metal kagome lattice materials host frustrated, correlated, and topological quantum states of matter. Recently, a new family of vanadium-based kagome metals AVSb (A=K, Rb, and Cs) with topological band structures has been discovered. These layered compounds are nonmagnetic and undergo charge density wave transitions before developing superconductivity at low temperatures. Here we report the observation of unconventional superconductivity and pair density wave (PDW) in CsVSb using scanning tunneling microscope/spectroscopy (STM/STS) and Josephson STS. We find that CsVSb exhibits a V-shaped pairing gap Δ~0.5 meV and is a strong-coupling superconductor (2∆/kT~5) that coexists with 4a unidirectional and 2a×2a charge order. Remarkably, we discover a 3Q PDW accompanied by bidirectional 4a/3 spatial modulations of the superconducting gap, coherence peak and gap-depth in the tunneling conductance. We term this novel quantum state a roton-PDW associated with an underlying vortex-antivortex lattice that can account for the observed conductance modulations. Probing the electronic states in the vortex halo in an applied magnetic field, in strong-field that suppresses superconductivity, and in zero-field above T reveals that the PDW is a primary state responsible for an emergent pseudogap and intertwined electronic order. Our findings show striking analogies and distinctions to the phenomenology of high-T cuprate superconductors, and provide groundwork for understanding the microscopic origin of correlated electronic states and superconductivity in vanadium-based kagome metals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03983-5DOI Listing
September 2021

circRNA-binding protein site prediction based on multi-view deep learning, subspace learning and multi-view classifier.

Brief Bioinform 2021 Sep 24. Epub 2021 Sep 24.

School of Biotechnology and Key Laboratory of Industrial Biotechnology Ministry in Jiangnan University, Wuxi, Jiangsu 214012, China.

Circular RNAs (circRNAs) generally bind to RNA-binding proteins (RBPs) to play an important role in the regulation of autoimmune diseases. Thus, it is crucial to study the binding sites of RBPs on circRNAs. Although many methods, including traditional machine learning and deep learning, have been developed to predict the interactions between RNAs and RBPs, and most of them are focused on linear RNAs. At present, few studies have been done on the binding relationships between circRNAs and RBPs. Thus, in-depth research is urgently needed. In the existing circRNA-RBP binding site prediction methods, circRNA sequences are the main research subjects, but the relevant characteristics of circRNAs have not been fully exploited, such as the structure and composition information of circRNA sequences. Some methods have extracted different views to construct recognition models, but how to efficiently use the multi-view data to construct recognition models is still not well studied. Considering the above problems, this paper proposes a multi-view classification method called DMSK based on multi-view deep learning, subspace learning and multi-view classifier for the identification of circRNA-RBP interaction sites. In the DMSK method, first, we converted circRNA sequences into pseudo-amino acid sequences and pseudo-dipeptide components for extracting high-dimensional sequence features and component features of circRNAs, respectively. Then, the structure prediction method RNAfold was used to predict the secondary structure of the RNA sequences, and the sequence embedding model was used to extract the context-dependent features. Next, we fed the above four views' raw features to a hybrid network, which is composed of a convolutional neural network and a long short-term memory network, to obtain the deep features of circRNAs. Furthermore, we used view-weighted generalized canonical correlation analysis to extract four views' common features by subspace learning. Finally, the learned subspace common features and multi-view deep features were fed to train the downstream multi-view TSK fuzzy system to construct a fuzzy rule and fuzzy inference-based multi-view classifier. The trained classifier was used to predict the specific positions of the RBP binding sites on the circRNAs. The experiments show that the prediction performance of the proposed method DMSK has been improved compared with the existing methods. The code and dataset of this study are available at https://github.com/Rebecca3150/DMSK.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bib/bbab394DOI Listing
September 2021

Structural biology of SARS-CoV-2 and implications for therapeutic development.

Nat Rev Microbiol 2021 11 17;19(11):685-700. Epub 2021 Sep 17.

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an unprecedented global health crisis. However, therapeutic options for treatment are still very limited. The development of drugs that target vital proteins in the viral life cycle is a feasible approach for treating COVID-19. Belonging to the subfamily Orthocoronavirinae with the largest RNA genome, SARS-CoV-2 encodes a total of 29 proteins. These non-structural, structural and accessory proteins participate in entry into host cells, genome replication and transcription, and viral assembly and release. SARS-CoV-2 proteins can individually perform essential physiological roles, be components of the viral replication machinery or interact with numerous host cellular factors. In this Review, we delineate the structural features of SARS-CoV-2 from the whole viral particle to the individual viral proteins and discuss their functions as well as their potential as targets for therapeutic interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41579-021-00630-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447893PMC
November 2021

Dosing Regimen Prediction and Confirmation with Rivaroxaban for Thromboprophylaxis in Children after the Fontan Procedure: Insights from the Phase III UNIVERSE Study.

J Clin Pharmacol 2021 Sep 15. Epub 2021 Sep 15.

Janssen Research & Development, LLC, Raritan, NJ, USA.

Thrombosis remains an important complication for children with single ventricle physiology post-Fontan procedure and effective thromboprophylaxis is an important unmet medical need. To obviate conventional dose-finding studies and expedite clinical development, a rivaroxaban dose regimen for this indication was determined utilizing a model-informed drug development approach. A physiologically based pharmacokinetic (PBPK) rivaroxaban model was used to predict a pediatric dosing regimen that would produce drug exposures similar to that of 10 mg once daily in adults. This regimen was used in an open-label, multicenter Phase 3 study, which investigated the use of rivaroxaban for thromboprophylaxis in post-Fontan patients 2 to 8 years of age. The pharmacokinetics (PK) of rivaroxaban was assessed in Part A (n = 12) and in Part B (n = 64) of UNIVERSE. The safety and efficacy in the rivaroxaban group were compared to those in the acetylsalicylic acid group for 12 months. Pharmacodynamic endpoints were assessed in both parts of the study. Rivaroxaban exposures achieved in Part A and B were similar to the adult reference exposures. Prothrombin time also showed similarity to the adult reference. Exposure-response analysis did not identify a quantitative relationship between rivaroxaban exposures and efficacy/safety outcomes within the observed exposure ranges. A body-weight based dose regimen selected by PBPK modeling was shown in the UNIVERSE study to be appropriate for thromboprophylaxis in the post-Fontan pediatric population. Model-based dose selection can support pediatric drug development and bridge adult dose data to pediatrics, thereby obviating the need for dose-finding studies in pediatric programs. This article is protected by copyright. All rights reserved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcph.1966DOI Listing
September 2021

regulates proinflammatory immune response in mouse macrophages via activating the MAPK, AKT, and NF-κB pathways.

J Zhejiang Univ Sci B 2021 Sept 15;22(9):782-790

Key Jiangsu Institute of Marine Resources Development, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang 222005, China.

Aeromonas sobria, a Gram-negative bacterium that can colonize both humans and animals, is found in a variety of environments, including water, seafood, meat, and vegetables (Cahill, 1990; Galindo et al., 2004; Song et al., 2019). Aeromonas spp. are conditionally pathogenic bacteria in aquaculture, which can rapidly proliferate, causing disease and even death in fish, especially when the environment is degraded (Neamat-Allah et al., 2020, 2021a, 2021b). In developing countries, Aeromonas spp. have been associated with a wide spectrum of infections in humans, including gastroenteritis, wound infections, septicemia, and lung infections (San Joaquin and Pickett, 1988; Wang et al., 2009; Su et al., 2013). Infections caused by Aeromonas spp. are usually more severe in immunocompromised individuals (Miyamoto et al., 2017). The presence of a plasmid encoding a β‍-lactamase in A. sobria that confers resistance to β-lactam antibiotics poses a huge challenge to the treatment of diseases caused by this microorganism (Lim and Hong, 2020). Consequently, an in-depth understanding of the interaction between A. sobria and its hosts is urgently required to enable the development of effective strategies for the treatment of A. sobria infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1631/jzus.B2100456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435340PMC
September 2021

Induces Proinflammatory Cytokines Production in Mouse Macrophages Activating NLRP3 Inflammasome Signaling Pathways.

Front Cell Infect Microbiol 2021 26;11:691445. Epub 2021 Aug 26.

Key Jiangsu Institute of Marine Resources Development, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, China.

, a common conditional pathogenic bacteria, is widely distributed in the environment and causes gastroenteritis in humans or septicemia in fish. Of all species, is the most frequently isolated from human infections especially in immunocompromised subjects. Innate immunity is the first protection system of organism to resist non-specific pathogens invasion; however, the immune response process of hosts against infection re\mains unexplored. The present study established an infection model using primary mouse peritoneal macrophages (PMφs). The adherence and cytotoxicity of on PMφs were determined by May-Grünwald Giemsa staining and LDH release measurement. Pro-inflammatory cytokine expression levels were measured using qPCR, western blotting, and ELISA methods. We also investigated the levels of ASC oligomerization and determined the roles of active caspase-1 in IL-1β secretion through inhibition assays and explored the activated pattern recognition receptors through immunofluorescence. We further elucidated the roles of activated inflammasome in regulating the host's inflammatory response through inhibition combined with ELISA assays. Our results showed that induced lytic cell death and LDH release, whereas it had no adhesive properties on PMφs. triggered various proinflammatory cytokine transcription level upregulation, and IL-1β occupied the highest levels. The pro-IL-1β protein expression levels increased in a dose-dependent manner with MOI ranging from 1 to 100. This process was regulated by ASC-dependent inflammasome, which cleavage pro-IL-1β into active IL-1β p17 with activated caspase-1 p20. Meanwhile, the expression levels of NLRP3 receptor significantly increased, location analysis revealed puncta-like surrounding nuclear, and inhibition of NLRP3 inflammasome downregulated caspase-1 activation and IL-1β secretion. Blocking of NLRP3 inflammasome activation through K efflux and cathepsin B or caspase approaches downregulated -induced proinflammatory cytokine production. Overall, these data indicated that induced proinflammatory cytokine production in PMφs through activating NLRP3 inflammasome signaling pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcimb.2021.691445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428973PMC
October 2021

Inhibition of hypoxia-inducible factor-1 by Salidroside in an in vitro model of choroidal neovascularization.

Cutan Ocul Toxicol 2021 Aug 24:1-17. Epub 2021 Aug 24.

Department of Neurosurgery, The second Fuzhou Hospital Affiliated to Xiamen University, Fuzhou 350007, People's Republic of China.

Purpose: As a characteristic of age-related macular degeneration (AMD), choroidal neovascularization (CNV) causes severe vision loss. The current treatment has limited efficacy. This study was to investigate effects of Salidroside against CNV and explore its underlying mechanisms.

Methods: RF/6A cells were treated with 200 mM cobalt chloride (CoCl) for 6 hr to mimic hypoxic condition. Cells were then treated with Salidroside at 10, 30 and 100 µM for 24 hr. Cells treated with DMSO were used as negative control. The cell proliferation was assessed using 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium-bromid assay. The tube formation was investigated on Matrigel. The cell migration was measured by a Transwell assay. RT-qPCR was used to detect the gene expression. Immuohistochemistry and western blot were used to detect the expression of proteins.

Results: Salidroside significantly inhibited the cell migration and tube formation activity of RF/6A cells under hypoxia. Moreover, Salidroside reduced the expression levels of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF-1) in RF/6A cells.

Conclusions: Our data suggested that Salidroside could be a potential novel therapeutic agent against CNV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15569527.2021.1973023DOI Listing
August 2021

IGHG1 upregulation promoted gastric cancer malignancy via AKT/GSK-3β/β-Catenin pathway.

Cancer Cell Int 2021 Jul 27;21(1):397. Epub 2021 Jul 27.

Department of Gastrointestinal Surgery, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou City, 362002, Fujian Province, China.

Background: Despite current advances in gastric cancer treatment, disease metastasis and chemo-resistance remain as major hurdles against better overall prognosis. Previous studies indicated that IGHG1 as well as -Catenin serve as important regulators of tumor cellular malignancy. Therefore, understanding detailed molecular mechanism and identifying druggable target will be of great potentials in future therapeutic development.

Methods: Surgical tissues and gastric cancer cell lines were retrieved to evaluate IGHG1 expression for patients with or without lymph node/distal organ metastasis. Functional assays including CCK8 assay, Edu assay, sphere formation assay and transwell assay, wound healing assay, etc. were subsequently performed to evaluate the impact of IGHG1/-catenin axis on tumor cell proliferation, migration and chemo-resistance.

Results: Gastric cancer tissues and tumor cell lines demonstrated significantly higher level of IGHG1. Functional study further demonstrated that IGHG1 promoted proliferative and migration as well as chemo-resistance of gastric cancer tumor cells. Further experiments indicated that IGHG1 activated AKT/GSK-3/-Catenin axis, which played crucial role in regulation of proliferative and chemo-resistance of gastric cancer cells.

Conclusion: This study provided novel evidences that IGHG1 acted as oncogene by promotion of gastric cancer cellular proliferation, migration and chemo-resistance. Our research further suggested that IGHG1/AKT/GSK-3β/β-Catenin axis acted as novel pathway which regulated gastric cancer cellular malignant behavior. Our research might inspire future therapy development to promote overall prognosis of gastric cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12935-021-02098-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314571PMC
July 2021

Cation-Induced Assembly of Conductive MXene Fibers for Wearable Heater, Wireless Communication, and Stem Cell Differentiation.

ACS Biomater Sci Eng 2021 Jul 23. Epub 2021 Jul 23.

Department of Chemical and Biomolecular Engineering, University of Maryland, College Park, Maryland 20742, United States.

Emerging wearable electronics, wireless communication, and tissue engineering require the development of conductive fiber-shaped electrodes and biointerfaces. TiCT MXene nanosheets serve as promising building block units for the construction of highly conductive fibers with integrated functionalities, yet a facile and scalable fabrication scheme is highly required. Herein, a cation-induced assembly process is developed for the scalable fabrication of conductive fibers with MXene sheaths and alginate cores (abbreviated as [email protected]). The fabrication scheme of [email protected] fibers includes the fast extrusion of alginate fibers followed by electrostatic assembly of MXene nanosheets, enabling high-speed fiber production. When multiple fabrication parameters are optimized, the [email protected] fibers exhibit a superior electrical conductivity of 1083 S cm, which can be integrated as Joule heaters into textiles for wearable thermal management. By triggering reversible de/hydration of alginate cores upon heating, the [email protected] fibers can be repeatedly contracted and generate large contraction stress that is >40 times higher than the ones of mammalian skeletal muscle. Furthermore, the [email protected] springs demonstrate large contraction strains up to 65.5% and are then fabricated into a reconfigurable dipole antenna to wirelessly monitor the surrounding heat sources. In the end, with the biocompatibility of MXene nanosheets, the [email protected] fibers enable the guidance of neural stem/progenitor cells differentiation and the promotion of neurite outgrowth. With a cation-induced assembly process, our multifunctional [email protected] fibers exhibit high scalability for future manufacturing and hold the prospect to inspire other applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsbiomaterials.1c00591DOI Listing
July 2021

Population pharmacokinetic analysis of rivaroxaban in children and comparison to prospective physiologically-based pharmacokinetic predictions.

CPT Pharmacometrics Syst Pharmacol 2021 Oct 23;10(10):1195-1207. Epub 2021 Aug 23.

Research and Development, Pharmaceuticals, Bayer AG, Wuppertal/Leverkusen, Germany.

Rivaroxaban has been investigated in the EINSTEIN-Jr program for the treatment of acute venous thromboembolism (VTE) in children aged 0 to 18 years and in the UNIVERSE program for thromboprophylaxis in children aged 2 to 8 years with congenital heart disease after Fontan-procedure. Physiologically-based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) modeling were used throughout the pediatric development of rivaroxaban according to the learn-and-confirm paradigm. The development strategy was to match pediatric drug exposures to adult exposure proven to be safe and efficacious. In this analysis, a refined pediatric PopPK model for rivaroxaban based on integrated EINSTEIN-Jr data and interim PK data from part A of the UNIVERSE phase III study was developed and the influence of potential covariates and intrinsic factors on rivaroxaban exposure was assessed. The model adequately described the observed pediatric PK data. PK parameters and exposure metrics estimated by the PopPK model were compared to the predictions from a previously published pediatric PBPK model for rivaroxaban. Ninety-one percent of the individual post hoc clearance estimates were found within the 5th to 95th percentile of the PBPK model predictions. In patients below 2 years of age, however, clearance was underpredicted by the PBPK model. The iterative and integrative use of PBPK and PopPK modeling and simulation played a major role in the establishment of the bodyweight-adjusted rivaroxaban dosing regimen that was ultimately confirmed to be a safe and efficacious dosing regimen for children aged 0 to 18 years with acute VTE in the EINSTEIN-Jr phase III study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/psp4.12688DOI Listing
October 2021

Mechanisms of non-contact anterior cruciate ligament injury as determined by bone contusion location and severity.

Quant Imaging Med Surg 2021 Jul;11(7):3263-3273

Department of Radiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Background: The location and severity of tibiofemoral bone contusions in magnetic resonance imaging scans in patients with acute non-contact anterior cruciate ligament injuries can reflect the primary mechanisms of anterior cruciate ligament injuries. There has been limited investigation to subdividing the bone contusion model in the medial and lateral directions of the tibial plateau and the femoral condyle.

Methods: A retrospective review of 93 consecutive magnetic resonance imaging examinations of patients with acute non-contact anterior cruciate ligament injuries was conducted to identify bone contusions of the knee. The locations and the severity of the bone contusions were determined using magnetic resonance imaging scans for each anatomic site, including the lateral femoral condyle, the lateral tibial plateau, the medial femoral condyle, and the medial tibial plateau. The bone contusions in the lateral-medial and anterior-posterior directions of four anatomical sites were subdivided into six compartments. The severity of the bone contusions was graded on a scale of 1-4. The location and the severity of bone contusions were accessed in the sagittal and coronal planes on the femoral and tibial sides of the knee using the radiology information system.

Results: The prevalence of bone contusions on the magnetic resonance imaging scans was as follows: 78.49% on the lateral femoral condyle, 88.17% on the lateral tibial plateau, 49.46% on the medial femoral condyle, and 69.89% on the medial tibial plateau. The most common and severe compartments of the lateral femoral condyle, the lateral tibial plateau, the medial femoral condyle, and the medial tibial plateau were the central-lateral (CL), the posterior-medial (PM), the CL, and the posterior-lateral (PL) compartments, respectively.

Conclusions: The location patterns and severity of bone contusions in patients indicated that internal tibial rotation, valgus, and the anterior and lateral translation of the tibia were the primary mechanisms of non-contact anterior cruciate ligament injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/qims-20-1212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249998PMC
July 2021

A quantitative MRI investigation of the association between iliotibial band syndrome and patellofemoral malalignment.

Quant Imaging Med Surg 2021 Jul;11(7):3209-3218

Department of Radiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Background: The iliotibial band (ITB) has a wide patellar insertion that provides lateral restraint to the patella and maintains the patellofemoral joint's stability. There has been limited investigation into the relationship between patellofemoral malalignment and iliotibial band syndrome (ITBS).

Methods: We retrospectively analyzed 47 knees with ITBS by retrieving magnetic resonance imaging (MRI) data collected over an approximately 6-year period from our database. The Insall-Salvati ratio, lateral patellofemoral angle (LPA), lateral patellar tilt (LPT), lateral trochlear length (LTL), angle of the non-weight-bearing facet of the lateral femoral condyle (nwb-LFCA), and the ITB-lateral femoral condyle (IT-LFC) distance were measured on MR images. The knees of 47 age- and gender-matched subjects were enrolled as the normal group.

Results: In the ITBS group, over one third (34%, 16/47) of knees had abnormal patellofemoral measurements, including 8 (17%, 8/47) knees with patellar alta, 11 (23.4%, 11/47) knees with an abnormally decreased LPA, and 5 (10.6%, 5/47) knees with an abnormally increased LPT indicating lateral patellar tilt. Moreover, 8 knees had simultaneous combinations of two or three abnormality parameters, and 8 (17%, 8/47) knees presented with superolateral Hoffa's fat pad edema. The Insall-Salvati ratio, LPT, and nwb-LFCA in the ITBS group were significantly higher than those in the normal group (P=0.001, P<0.001, and P<0.001, respectively); the LPA and IT-LFC distances in the ITBS group were significantly lower (P=0.003, P<0.001, respectively) than those in the normal group. There were mild to moderate correlations between the MRI parameters and ITBS (P=0.006, P<0.001, respectively).

Conclusions: This study confirmed that a higher position or lateral tilt of the patella and a steeper morphology of the anterior part of the lateral femoral condyle were associated with the development of ITBS, which is helpful in understanding and further exploring the mechanism of ITBS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/qims-20-1101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250009PMC
July 2021

An ultra-red fluorescent biosensor for highly sensitive and rapid detection of biliverdin.

Anal Chim Acta 2021 Aug 31;1174:338709. Epub 2021 May 31.

School of Life Sciences, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, College of Precision Instrument and Opto-electronics Engineering, Tianjin University, Tianjin, 300072, China; Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin, 300457, China. Electronic address:

The important role of BV in clinical diagnostics of liver-related diseases has been established in veterinary medicine. However, the sensitivity and selectivity of the current BV assays remain relatively low compromising its wider application in clinical diagnosis. Herein, we developed a rapid and sensitive BV-detecting biosensor based on a novel far-red fluorescent protein smURFP, which produced fluorescence only through specific interaction with its cofactor BV. In our study, the binding of BV to smURFP was then systematically optimized based on the structures of the smURFP + BV complex to increase the sensitivity of our biosensor. A wide linear range from 0 μM to 25 μM was obtained in both chicken and human serum. The limit of detection (LOD) and limit of quantification (LOQ) for BV was as low as 0.4 nM and 1.5 nM in human serum, and 0.4 nM and 1.2 nM in chicken serum. To our knowledge, this is the lowest LOD that has ever been reported for a BV biosensor. Our study sheds light on the biological and clinical analysis of BV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.aca.2021.338709DOI Listing
August 2021

Machine Vision Automated Chiral Molecule Detection and Classification in Molecular Imaging.

J Am Chem Soc 2021 Jul 6;143(27):10177-10188. Epub 2021 Jul 6.

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

Scanning probe microscopy (SPM) is recognized as an essential characterization tool in a broad range of applications, allowing for real-space atomic imaging of solid surfaces, nanomaterials, and molecular systems. Recently, the imaging of chiral molecular nanostructures via SPM has become a matter of increased scientific and technological interest due to their imminent use as functional platforms in a wide scope of applications, including nonlinear chiroptics, enantioselective catalysis, and enantiospecific sensing. Due to the time-consuming and error-prone image analysis process, a highly efficient analytic framework capable of identifying complex chiral patterns in SPM images is needed. Here, we adopted a state-of-the-art machine vision algorithm to develop a one-image-one-system deep learning framework for the analysis of SPM images. To demonstrate its accuracy and versatility, we employed it to determine the chirality of the molecules comprising two supramolecular self-assemblies with two distinct chiral organization patterns. Our framework accurately detected the position and labeled the chirality of each molecule. This framework underpins the tremendous potential of machine learning algorithms for the automated recognition of complex SPM image patterns in a wide range of research disciplines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jacs.1c03091DOI Listing
July 2021

CT-scan based anatomical study as a guidance for infra-acetabular screw placement.

BMC Musculoskelet Disord 2021 Jun 24;22(1):576. Epub 2021 Jun 24.

Department of Radiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.

Background: The infra-acetabular corridor is quite narrow, which makes a challenge for the orthopedists to insert the screw. This study aimed to explore the relationship between the infra-acetabular corridor diameter (IACD) and the minimum thickness of medial acetabular wall (MTMAW), and to clarify the way of screw placement.

Methods: The Computed tomography (CT) data of 100 normal adult pelvises (50 males and 50 females respectively) were collected and pelvis three-dimensional (3D) reconstruction was performed by using Mimics software and the 3D model was imported into Geomagic Studio software. The perspective of acetabulum was carried out orienting from iliopubic eminence to ischial tuberosity and the IACD was measured by placing virtual screws which was vertical to the corridor transverse section of "teardrop". The relationship between IACD and MTMAW was analyzed. When IACD was ≥5 mm, 3.5 mm all-in screws were placed. When IACD was < 5 mm, 3.5 mm in-out-in screws were placed.

Results: The IACD of males and females were (6.15 ± 1.24) mm and (5.42 ± 1.01) mm and the MTMAW in males and females were (4.40 ± 1.23) mm and (3.60 ± 0.81) mm respectively. The IACD and MTMAW in males were significantly wider than those of females (P < 0.05), and IACD was positively correlated with MTMAW (r = 0.859), the regression equation was IACD = 2.111 + 0.917 MTMAW. In the all-in screw group, 38 cases (76%) were males and 33 cases (66%) were females respectively. The entry point was located at posteromedial of the apex of iliopubic eminence, and the posterior distance and medial distance were (8.03 ± 2.01) mm and (8.49 ± 2.68) mm respectively in males. As for females, those were (8.68 ± 2.35) mm and (8.87 ± 2.79) mm respectively. In the in-out-in screw group, 12 cases (24%) were males and 17 cases (34%) were females, respectively. The posterior distance and medial distance between the entry point and the apex of iliopubic eminence were (10.49 ± 2.58) mm and (6.17 ± 1.84) mm respectively in males. As for females, those were (10.10 ± 2.63) mm and (6.63 ± 1.49) mm respectively. The angle between the infra-acetabular screw and the sagittal plane was medial inclination (0.42 ± 6.49) °in males, lateral inclination (8.09 ± 6.33) °in females, and the angle between the infra-acetabular screw and the coronal plane was posterior inclination (54.06 ± 7.37) °.

Conclusions: The placement mode of the infra-acetabular screw (IAS) can be determined preoperatively by measuring the MTMAW in the CT axial layers. Compared with all-in screw, the in-out-in screw entry point was around 2 mm outwards and backwards, and closer to true pelvic rim.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12891-021-04419-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223348PMC
June 2021

Monolayer Iridium Sulfide Halides with High Mobility Transport Anisotropy and Highly Efficient Light Harvesting.

J Phys Chem Lett 2021 Jul 24;12(25):6007-6013. Epub 2021 Jun 24.

Institute of Physics & University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100190, China.

The discovery and design of two-dimensional semiconductors with high carrier mobilities is of vital importance for high-speed electronic and optoelectronic devices. Herein, based on high-throughput computations, we identify a group of semiconductors, iridium sulfide halides IrSX' (X' = F, Cl, Br, I), with high carrier mobilities (∼10 cm V s) and highly efficient light harvesting (∼34%). Moreover, these materials exhibit anisotropic in-plane transport behavior, which is switchable via ferroelastic switching, providing the monolayer (ML) IrSX's great potential for applications in direction-controlled high-speed electronic and optoelectronic devices. The high carrier mobility and anisotropic transport are stemming from the anisotropic distribution of 3d orbitals of Ir atoms at the conduction band minimum (CBM) and valence band maximum (VBM) in the rectangular lattices. The ML IrSX's (X' = F, Cl, Br) show good dynamical and thermal stabilities and are thermodynamically stable based on phase diagram calculations, thus meriting experimental realization in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jpclett.1c01086DOI Listing
July 2021

Spin pinning effect to reconstructed oxyhydroxide layer on ferromagnetic oxides for enhanced water oxidation.

Nat Commun 2021 Jun 15;12(1):3634. Epub 2021 Jun 15.

School of Materials Science and Engineering, Nanyang Technological University, Singapore, Singapore.

Producing hydrogen by water electrolysis suffers from the kinetic barriers in the oxygen evolution reaction (OER) that limits the overall efficiency. With spin-dependent kinetics in OER, to manipulate the spin ordering of ferromagnetic OER catalysts (e.g., by magnetization) can reduce the kinetic barrier. However, most active OER catalysts are not ferromagnetic, which makes the spin manipulation challenging. In this work, we report a strategy with spin pinning effect to make the spins in paramagnetic oxyhydroxides more aligned for higher intrinsic OER activity. The spin pinning effect is established in oxide/oxyhydroxide interface which is realized by a controlled surface reconstruction of ferromagnetic oxides. Under spin pinning, simple magnetization further increases the spin alignment and thus the OER activity, which validates the spin effect in rate-limiting OER step. The spin polarization in OER highly relies on oxyl radicals (O∙) created by 1 dehydrogenation to reduce the barrier for subsequent O-O coupling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23896-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206068PMC
June 2021

Janus Photothermal Membrane as an Energy Generator and a Mass-Transfer Accelerator for High-Efficiency Solar-Driven Membrane Distillation.

ACS Appl Mater Interfaces 2021 Jun 3;13(23):26861-26869. Epub 2021 Jun 3.

Shenzhen Key Laboratory of Special Functional Materials, Shenzhen Engineering Laboratory for Advanced Technology of Ceramics, Guangdong Research Center for Interfacial Engineering of Functional Materials, College of Materials Science and Engineering, Shenzhen University, Shenzhen 518060, P. R. China.

Membrane distillation (MD) is an emerging membrane-based evaporation technology with great promise for the desalination and separation industries. However, its widespread application still depends on substantial development to increase the distillation flux, reduce the energy consumption, and extend the lifespan of the membrane. Herein, we report for the first time the integration of multiple functions, that is, energy-saving, flux-enhancing, and anti-fouling properties, into a single membrane. Such a membrane was fabricated by coating the top surface of a poly(vinylidene fluoride)-co-hexafluoropropylene (PVDF-HFP) nanofibrous mat with photothermal and hydrophobic graphitic carbon spheres and subsequently coating the bottom surface with a hydrophilic polydopamine layer, yielding a novel Janus photothermal membrane (JPTM). Owing to the high photothermal efficiency and accelerated mass transport across the membrane, the JPTM demonstrated an excellent desalination performance when assembled into a solar-driven MD system, with a distillation flux of 1.29 kg m h, which is 10 times higher than that of the conventional un-modified PVDF-HFP membrane, requiring only 1 kW m solar illumination as the energy input.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.1c01072DOI Listing
June 2021

Identification of proteasome and caspase inhibitors targeting SARS-CoV-2 M.

Signal Transduct Target Ther 2021 06 1;6(1):214. Epub 2021 Jun 1.

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41392-021-00639-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166895PMC
June 2021

Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives.

Nat Commun 2021 05 24;12(1):3061. Epub 2021 May 24.

Molecular Biophysics Group, Department of Biochemistry and System Biology, Institute of System, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, L69 7ZB, UK.

The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (M), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent M inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in M via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger M inhibition than ebselen and potent ability to rescue infected cells were observed for a number of derivatives. A free selenium atom bound with cysteine of catalytic dyad has been revealed in crystallographic structures of M with ebselen and MR6-31-2 suggesting hydrolysis of the enzyme bound organoselenium covalent adduct and formation of a phenolic by-product, confirmed by mass spectrometry. The target engagement with selenation mechanism of inhibition suggests wider therapeutic applications of these compounds against SARS-CoV-2 and other zoonotic beta-corona viruses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23313-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144557PMC
May 2021

Spin-polarized oxygen evolution reaction under magnetic field.

Nat Commun 2021 May 10;12(1):2608. Epub 2021 May 10.

School of Material Science and Engineering, Nanyang Technological University, Singapore, Singapore.

The oxygen evolution reaction (OER) is the bottleneck that limits the energy efficiency of water-splitting. The process involves four electrons' transfer and the generation of triplet state O from singlet state species (OH or HO). Recently, explicit spin selection was described as a possible way to promote OER in alkaline conditions, but the specific spin-polarized kinetics remains unclear. Here, we report that by using ferromagnetic ordered catalysts as the spin polarizer for spin selection under a constant magnetic field, the OER can be enhanced. However, it does not applicable to non-ferromagnetic catalysts. We found that the spin polarization occurs at the first electron transfer step in OER, where coherent spin exchange happens between the ferromagnetic catalyst and the adsorbed oxygen species with fast kinetics, under the principle of spin angular momentum conservation. In the next three electron transfer steps, as the adsorbed O species adopt fixed spin direction, the OER electrons need to follow the Hund rule and Pauling exclusion principle, thus to carry out spin polarization spontaneously and finally lead to the generation of triplet state O. Here, we showcase spin-polarized kinetics of oxygen evolution reaction, which gives references in the understanding and design of spin-dependent catalysts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-22865-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110536PMC
May 2021

Influence of Patellar Morphology Classified by Wiberg Classification on Knee Joint Function and Patellofemoral Tracking After Total Knee Arthroplasty Without Patellar Resurfacing.

J Arthroplasty 2021 09 18;36(9):3148-3153. Epub 2021 Apr 18.

Department of Orthopaedics, Fuyang Hospital of Anhui Medical University, Fuyang, Anhui Province, China.

Background: To evaluate the influence of patellar morphology on knee joint function and patellofemoral tracking in patients with primary osteoarthritis after total knee arthroplasty (TKA) without patellar resurfacing.

Methods: We performed a retrospective study of 156 patients with primary osteoarthritis who underwent TKA without patellar resurfacing from April 2018 to July 2019. As per Wiberg classification, patients were divided into Wiberg type I (group A, n = 38), II (group B, n = 88), and III (group C, n = 30) groups. The clinical data, postoperative follow-up data, and radiological data between three groups were compared.

Results: There was no statistically significant difference in the HSS score and Feller score between the three groups before surgery and at each follow-up point after surgery (P > .05). At the last follow-up, there were no significant differences in the height and relative thickness of the patella between the three groups (P > .05). However, the incidence of anterior knee pain was significantly higher in group C than in the group B (P < .05). The patellar tilt angle was significantly larger in group C than in the groups A and B (both P < .05). The patellar facet angle was significantly larger in group A than in group B and C, which was also significantly larger in group B than in group C (both P < .05).

Conclusion: Patients with three different morphologic types of the patella both exhibited improved knee joint function after TKA, however, patients with Wiberg type Ⅲ patella were more prone to have poor patellofemoral tracking and anterior knee pain after surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.arth.2021.04.009DOI Listing
September 2021

Traditional Chinese Medicine Brucea Javanica Oil Enhances the Efficacy of Anlotinib in a Mouse Model of Liver-Metastasis of Small-cell Lung Cancer.

In Vivo 2021 May-Jun;35(3):1437-1441

AntiCancer Inc., San Diego, CA, U.S.A.

Background/aim: Small-cell lung cancer (SCLC) is a recalcitrant disease with liver and other metastasis. The present study evaluated the efficacy of the traditional Chinese medicine Brucea javanica oil (BJO) combined with anlotinib, a multi-tyrosine kinase inhibitor with anti-angiogenic activity, on a nude-mouse model of SCLC liver metastasis.

Materials And Methods: The mouse model was established by injecting NCI-H446 cells (1×10) in Matrigel (20 μl) into the upper liver lobe. All animals were randomized and assigned to three groups: Control (n=8); anlotinib alone (n=8; 3 mg/kg, qd×14+7-day interval with two cycles, oral); anlotinib plus BJO (n=8; 3 mg/kg anlotinib qd×14+7-day interval with two cycles, orally; BJO: 1 g/kg, qd×6 weeks, orally). Body weight was determined every week. Six weeks after initial treatment, tumors were collected for analysis of angiogenesis using immunohistochemistry.

Results: The combination of anlotinib and BJO significantly inhibited growth of SCLC liver metastases and angiogenesis more than anlotinib monotherapy (p=0.043). In addition, BJO alleviated body-weight loss associated with anlotinib therapy, including general mouse condition.

Conclusion: The results of the present study indicate that the combination of anlotinib with BJO is promisingly active against liver metastases of SCLC, and has clinical potential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/invivo.12395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193324PMC
June 2021

Structural basis for GTP-induced dimerization and antiviral function of guanylate-binding proteins.

Proc Natl Acad Sci U S A 2021 Apr;118(15)

School of Life Sciences, Tianjin University, Tianjin, 300072, China;

Guanylate-binding proteins (GBPs) form a family of dynamin-related large GTPases which mediate important innate immune functions. They were proposed to form oligomers upon GTP binding/hydrolysis, but the molecular mechanisms remain elusive. Here, we present crystal structures of C-terminally truncated human GBP5 (hGBP5), comprising the large GTPase (LG) and middle (MD) domains, in both its nucleotide-free monomeric and nucleotide-bound dimeric states, together with nucleotide-free full-length human GBP2. Upon GTP-loading, hGBP5 forms a closed face-to-face dimer. The MD of hGBP5 undergoes a drastic movement relative to its LG domain and forms extensive interactions with the LG domain and MD of the pairing molecule. Disrupting the MD interface (for hGBP5) or mutating the hinge region (for hGBP2/5) impairs their ability to inhibit HIV-1. Our results point to a GTP-induced dimerization mode that is likely conserved among all GBP members and provide insights into the molecular determinants of their antiviral function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2022269118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054025PMC
April 2021

High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors.

Protein Cell 2021 Apr 17. Epub 2021 Apr 17.

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (M), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC values ranging from 1.39 to 5.63 μmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three "hot" spots on PLpro, including the substrate-binding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13238-021-00836-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052528PMC
April 2021
-->