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1.
ISA Trans ; 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35551819

RESUMO

This brief disposes the finite-time anti-unwinding trajectory tracking control problem of the autonomous underwater vehicle (AUV) encountering model uncertainties, ocean disturbances and actuator failures. Primarily, the kinematic model of translational and rotational motions is depicted by unit quaternion in lieu of classical Euler angle such that the AUV's dynamics could be globally and uniquely formulated. Subsequently, two finite-time control strategies are presented here to leave the state variables of AUV can converge to an adjustable region. Additionally, the adaptive laws could be applicable to the existence of actuator faults by utilizing a passive fault-tolerant technology. By integrating the initial value of the scalar quaternion into the sliding mode surface, the proposed controllers are characterized with anti-unwinding property. Then, with the application of hyperbolic tangent function, finite-time stability will be achieved for tracking errors without singularity. Stability of the closed-loop system is verified via the Lyapunov theorem. Finally, numerical simulations are presented to demonstrate the effectiveness of the proposed controllers.

2.
iScience ; : 104431, 2022 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-35607524

RESUMO

The different variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have attracted most public concern because they caused "wave and wave" COVID-19 pandemic. The initial step of viral infection is mediated by the SARS-CoV-2 Spike (S) protein, which mediates the receptor recognition and membrane fusion between virus and host cells. Neutralizing antibodies (nAbs) targeting the S protein of SARS-CoV-2 have become promising candidates for clinical intervention strategy, while multiple studies have shown that different variants have enhanced infectivity and antibody resistance. Here, we explore the structure and function of STS165, a broadly inter-Spike bivalent nAb against SARS-CoV-2 variants and even SARS-CoV, contributing to further understanding of the working mechanism of nAbs.

3.
J Clin Virol ; 150-151: 105162, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35461042

RESUMO

A recently identified SARS-CoV-2 variant, Lambda, has spread to many countries around the world. Here, we measured and evaluated the reduced sensitivity of Lambda variant to the neutralization by plasma polyclonal antibodies elicited by the natural SARS-CoV-2 infection and inactivated vaccine. The combination of two substitutions appearing in the RBD of spike protein (L452Q and F490S) resulted in noticeably reduced neutralization against Lambda variant. F490S contributed more than L452Q in affecting the neutralization. In addition, the neutralization test with 12 published nAbs binding to RBD of SARS-CoV-2 with defined structures suggested that Lambda variant resisted the neutralization by some antibodies from Class 2 and Class 3. Overall, these results suggest that pre-existing antibody neutralization established by natural infection from non-Lambda variants or immunization could be significantly decreased, re-emphasizing the importance of ongoing viral mutation monitoring.

4.
J Med Virol ; 2022 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-35474319

RESUMO

The SARS-CoV-2 vaccines have been widely used to build an immunologic barrier in the population against the COVID-19 pandemic. However, a newly emerging Omicron variant, including BA.1, BA.1.1, BA.2, and BA.3 sublineages, largely escaped the neutralization of existing neutralizing antibodies (nAbs), even those elicited by three doses of vaccines. Here, we used the Omicron BA.1 RBD as a fourth dose of vaccine to induce potent Omicron-specific nAbs and evaluated the broadly neutralizing activities against SARS-CoV-2 variants. The BA.1-based vaccine was indeed prone to induce a strain-specific antibody response substantially cross-reactive with BA.2 sublineage, and yet triggered broad neutralization against SARS-CoV-2 variants when it was used in the sequential immunization with WT and other variant vaccines. These results demonstrated that the booster of Omicron RBD vaccine could be a rational strategy to enhance the broadly nAb response.

5.
Discov Oncol ; 13(1): 15, 2022 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-35306579

RESUMO

Ovarian cancer is the most fatal gynecological cancer worldwide, yet the fundamental mechanism of malignancy acquisition in ovarian cancer remains unknown. miRNA has been implicated to a variety of diseases, including cancer initiation and progression. Cyclin-D2 (CCND2) is ubiquitously implicated in cancer uncontrol cell proliferation. Bioinformatic research revealed that CCND2 is a candidate gene for miR-93-5p with a binding site in its 3'UTR region in the current study. Using our ovarian cancer sample, we verified that miR-93-5p is negatively correlated with CCND2 mRNA and protein levels. Luciferase report assay revealed miR-93-5p inhibits CCND2 production through binding to the 3'UTR region. The expression of miR-93-5p in ovarian cancer patient samples was then determined, and a survival analysis was performed. Our findings showed that miR-93-5p is downregulated in ovarian cancer and is a favorable predictive factor in ovarian cancer patient. CCK8 assay, wound healing assay and flow cytometry-based cell cycle and apoptotic cell analyses were employed here. We found that miR-93-5p suppresses ovarian cancer cell proliferation and migration while enhances cell death. Our research certified that miR-93-5p reduces ovarian cancer malignancy by targeting CCND2.

9.
Virol J ; 19(1): 2, 2022 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-34983583

RESUMO

The current COVID-19 pandemic caused by constantly emerging SARS-CoV-2 variants still poses a threat to public health worldwide. Effective next-generation vaccines and optimized booster vaccination strategies are urgently needed. Here, we sequentially immunized mice with a SARS-CoV-2 wild-type inactivated vaccine and a heterologous mutant RBD vaccine, and then evaluated their neutralizing antibody responses against variants including Beta, Delta, Alpha, Iota, Kappa, and A.23.1. These data showed that a third booster dose of heterologous RBD vaccine especially after two doses of inactivated vaccines significantly enhanced the GMTs of nAbs against all SARS-CoV-2 variants we tested. In addition, the WT and variants all displayed good cross-immunogenicity and might be applied in the design of booster vaccines to induce broadly neutralizing antibodies.


Assuntos
Vacinas contra COVID-19 , COVID-19 , SARS-CoV-2 , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Camundongos , SARS-CoV-2/imunologia
10.
Front Microbiol ; 12: 784856, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34912322

RESUMO

The intestinal pathogen Clostridioides (C.) difficile is a major cause of diarrhea both in hospitals and outpatient in industrialized countries. This bacterium produces two large exotoxins, toxin A (TcdA) and toxin B (TcdB), which are directly responsible for the onset of clinical symptoms of C. difficile-associated diseases (CDADs), such as antibiotics-associated diarrhea and the severe, life-threatening pseudomembranous colitis. Both toxins are multidomain proteins and taken up into host eukaryotic cells via receptor-mediated endocytosis. Within the cell, TcdA and TcdB inactivate Rho and/or Ras protein family members by glucosylation, which eventually results in cell death. The cytotoxic mode of action of the toxins is the main reason for the disease. Thus, compounds capable of inhibiting the cellular uptake and/or mode-of-action of both toxins are of high therapeutic interest. Recently, we found that the sterol regulatory element-binding protein 2 (SREBP-2) pathway, which regulates cholesterol content in membranes, is crucial for the intoxication of cells by TcdA and TcdB. Furthermore, it has been shown that membrane cholesterol is required for TcdA- as well as TcdB-mediated pore formation in endosomal membranes, which is a key step during the translocation of the glucosyltransferase domain of both toxins from endocytic vesicles into the cytosol of host cells. In the current study, we demonstrate that intoxication by TcdA and TcdB is diminished in cultured cells preincubated with the compound U18666A, an established inhibitor of cholesterol biosynthesis and/or intracellular transport. U18666A-pretreated cells were also less sensitive against TcdA and TcdB variants from the epidemic NAP1/027 C. difficile strain. Our study corroborates the crucial role of membrane cholesterol for cell entry of TcdA and TcdB, thus providing a valuable basis for the development of novel antitoxin strategies in the context of CDADs.

12.
Nat Commun ; 12(1): 5652, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34580306

RESUMO

The emergence of numerous variants of SARS-CoV-2, the causative agent of COVID-19, has presented new challenges to the global efforts to control the COVID-19 pandemic. Here, we obtain two cross-neutralizing antibodies (7D6 and 6D6) that target Sarbecoviruses' receptor-binding domain (RBD) with sub-picomolar affinities and potently neutralize authentic SARS-CoV-2. Crystal structures show that both antibodies bind a cryptic site different from that recognized by existing antibodies and highly conserved across Sarbecovirus isolates. Binding of these two antibodies to the RBD clashes with the adjacent N-terminal domain and disrupts the viral spike. Both antibodies confer good resistance to mutations in the currently circulating SARS-CoV-2 variants. Thus, our results have direct relevance to public health as options for passive antibody therapeutics and even active prophylactics. They can also inform the design of pan-sarbecovirus vaccines.


Assuntos
Anticorpos Antivirais/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , COVID-19/terapia , Imunização Passiva/métodos , SARS-CoV-2/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Monoclonais/metabolismo , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/isolamento & purificação , Anticorpos Antivirais/metabolismo , Sítios de Ligação/genética , Sítios de Ligação/imunologia , Anticorpos Amplamente Neutralizantes/administração & dosagem , Anticorpos Amplamente Neutralizantes/isolamento & purificação , Anticorpos Amplamente Neutralizantes/metabolismo , Células CHO , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/virologia , Chlorocebus aethiops , Cricetulus , Epitopos/imunologia , Células HEK293 , Humanos , Camundongos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Testes de Neutralização , Pandemias/prevenção & controle , Multimerização Proteica , Receptores Virais/metabolismo , SARS-CoV-2/genética , Células Sf9 , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero
13.
Org Lett ; 23(17): 6925-6930, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34428067

RESUMO

A mixture of HBPin with KOtBu was found to activate cobalt salt to form a heterotopic cobalt species that is highly active for catalytic intermolecular trimerization of alkynes. This protocol affords 1,2,4-regioisomers in good yields with high regioselectivities under mild conditions. These salient features, together with the operational simplicity and high efficiency, as well as obviating the use of any costly and/or air sensitive ligands, renders the protocol promising for practical applications.

14.
Nat Commun ; 12(1): 4210, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244522

RESUMO

Neutralizing antibodies (nAbs) to SARS-CoV-2 hold powerful potentials for clinical interventions against COVID-19 disease. However, their common genetic and biologic features remain elusive. Here we interrogate a total of 165 antibodies from eight COVID-19 patients, and find that potent nAbs from different patients have disproportionally high representation of IGHV3-53/3-66 usage, and therefore termed as public antibodies. Crystal structural comparison of these antibodies reveals they share similar angle of approach to RBD, overlap in buried surface and binding residues on RBD, and have substantial spatial clash with receptor angiotensin-converting enzyme-2 (ACE2) in binding to RBD. Site-directed mutagenesis confirms these common binding features although some minor differences are found. One representative antibody, P5A-3C8, demonstrates extraordinarily protective efficacy in a golden Syrian hamster model against SARS-CoV-2 infection. However, virus escape analysis identifies a single natural mutation in RBD, namely K417N found in B.1.351 variant from South Africa, abolished the neutralizing activity of these public antibodies. The discovery of public antibodies and shared escape mutation highlight the intricate relationship between antibody response and SARS-CoV-2, and provide critical reference for the development of antibody and vaccine strategies to overcome the antigenic variation of SARS-CoV-2.


Assuntos
Enzima de Conversão de Angiotensina 2/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Receptores Virais/imunologia , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Sítios de Ligação/imunologia , COVID-19/imunologia , Cricetinae , Modelos Animais de Doenças , Epitopos/imunologia , Feminino , Humanos , Masculino , Testes de Neutralização , Receptores de Antígenos de Linfócitos B/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia
15.
J Nutr Biochem ; 96: 108785, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34087411

RESUMO

Recent studies have revealed that calorie restriction is able to modulate immune system and aid in intervention of immune disorders. Inflammatory bowel disease (IBD) is an immune disease in the intestine caused by interplay between genetic susceptibility and environmental factors such as diets. Here we analyzed the therapeutic effect of intermittent calorie restriction with a fasting-mimicking diet (FMD) on dextran sodium sulfate (DSS)-induced chronic IBD model in mice. Two cycles of FMD was administered after IBD symptoms occurred in the mice. FMD administration significantly reduced the score of disease activity index. FMD reversed DSS-mediated shortening of colon length, infiltration of lymphocytes in the crypt of colon, and accumulation of CD4+ cells in the colon and small intestine. The expression of an inflammation marker NLRP3 was also reduced by FMD administration. The percentage of CD4+ T cells in both peripheral blood and spleen was also reduced by FMD. In addition, FMD application reversed DSS-mediated reduction in intestinal stem cell marker Lgr5, while the cell proliferation markers Ki67 and PCNA were increased by FMD. Taken together, these results indicate that in the mouse model of IBD, application of the FMD can effectively ameliorate the symptoms and pathogenesis of IBD through reducing the inflammation of intestine and promoting the regeneration and repair of the damaged intestinal epithelium.


Assuntos
Doenças Inflamatórias Intestinais/dietoterapia , Animais , Colo/patologia , Colo/ultraestrutura , Dieta , Jejum , Feminino , Inflamação/dietoterapia , Inflamação/patologia , Doenças Inflamatórias Intestinais/patologia , Camundongos , Camundongos Endogâmicos C57BL
16.
Nat Commun ; 12(1): 3813, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34155208

RESUMO

Homogeneous earth-abundant metal catalysis based on well-defined molecular complexes has achieved great advance in synthetic methodologies. However, sophisticated ligand, hazardous activator and multistep synthesis starting from base metal salts are generally required for the generation of active molecular catalysts, which may hinder their broad application in large scale organic synthesis. Therefore, the development of metal cluster catalysts formed in situ from simple earth-abundant metal salts is of importance for the practical utilization of base metal resource, yet it is still in its infancy. Herein, a mixture of catalytic amounts of cobalt (II) iodide and potassium tert-butoxide is discovered to be highly active for selective hydroboration of vinylarenes and dihydroboration of nitriles, affording a good yield of diversified hydroboration products that without isolation can readily undergo further one pot transformations. It should be highlighted that the alkoxide-pinacolborane combination acts as an efficient activation strategy to activate cobalt (II) iodide for the generation of metastable heterotopic cobalt catalysts in situ, which is proposed to be catalytically active species.

17.
Virol J ; 18(1): 87, 2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33910569

RESUMO

The emergence and rapid spread of the B.1.1.7 lineage (VOC-202012/01) SARS-CoV-2 variant has aroused global concern. The N501Y substitution is the only mutation in the interface between the RBD of B.1.1.7 and ACE2, raising concerns that its recognition by neutralizing antibodies may be affected. Here, we assessed the neutralizing activity and binding affinity of a panel of 12 monoclonal antibodies against the wild type and N501Y mutant SARS-CoV-2 pseudovirus and RBD protein, respectively. We found that the neutralization activity and binding affinity of most detected antibodies (10 out of 12) were unaffected, although the N501Y substitution decreased the neutralizing and binding activities of CB6 and increased that of BD-23. These findings could be of value in the development of therapeutic antibodies.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Afinidade de Anticorpos , Sítios de Ligação , Epitopos/imunologia , Células HEK293 , Humanos , Mutação , Testes de Neutralização , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética
18.
Clin Lab ; 67(2)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33616334

RESUMO

BACKGROUND: COVID-19 has recently been declared an epidemic by the WHO, and there is an urgent need for affected countries and laboratories to assess and treat people at risk of COVID-19. A heat procedure has been suggested for specimen inactivation. This study was designed to evaluate the effect of serum heating on biochemical indexes, and providing a basis for accurate detection results of the COVID-19 patients. METHODS: We collected 29 normal cases of two tubes of 5 mL whole blood. One tube was analyzed directly, and the other was analyzed after heating at 56°C 30 minutes. RESULTS: A total of 34 serum biochemical index quantitative results were obtained, 28/34 indexes were not significantly affected by the heat inactivation and remained clinically interpretable. As the thermal inactivation for these indexes showed good correlation, ALB (p = 0.04, Pearson R = 0.91, 2.6% mean increase), CysC (p = 0.03, Pearson R = 0.98, 9.9% mean increase), CO2CP (p < 0.001, Pearson R = 0.96, 13% mean decrease), they were still inter-pretable. Four biochemical indexes ALP, CK, CK-MB, and insulin were inactivated and showed significant statistical differences (p < 0.001). CONCLUSIONS: Our study showed CK, CK-MB, ALP, and insulin were sensitive to heat and will be inhibited or degrade after heating, indicating that the rapid decrease of this indexes in the COVID-19 patients may be caused by sample heat inactivation. For safety and diagnostic accuracy, we recommend the use of a point-of-care device for blood gases, electrolytes, troponin, and liver and renal function tests within a ISL 2 or above biosafety cabinet with level 3 or above biosafety laboratory practice.


Assuntos
Análise Química do Sangue , COVID-19 , Erros de Diagnóstico/prevenção & controle , Temperatura Alta/efeitos adversos , SARS-CoV-2 , Inativação de Vírus , Fosfatase Alcalina/sangue , Análise Química do Sangue/métodos , Análise Química do Sangue/normas , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/virologia , Creatina Quinase/sangue , Feminino , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Sistemas Automatizados de Assistência Junto ao Leito , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Sensibilidade e Especificidade
19.
J Virol ; 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33472937

RESUMO

Human papillomavirus type 58 (HPV58) is associated with cervical cancer and poses a significant health burden worldwide. Although the commercial 9-valent HPV vaccine covers HPV58, the structural and molecular-level neutralization sites of the HPV58 complete virion are not fully understood. Here, we report the high-resolution (∼3.5 Å) structure of the complete HPV58 pseudovirus (PsV58) using cryo-electron microscopy (cryo-EM). Three representative neutralizing monoclonal antibodies (nAbs 5G9, 2H3 and A4B4) were selected through clustering from a nAb panel against HPV58. Bypassing the steric hindrance and symmetry-mismatch in the HPV Fab-capsid immune-complex, we present three different neutralizing epitopes in the PsV58, and show that, despite differences in binding, these nAbs share a common neutralization mechanism. These results offer insight into HPV58 genotype specificity and broaden our understanding of HPV58 neutralization sites for antiviral research.IMPORTANCE Cervical cancer primarily results from persistent infection with high-risk types of human papillomavirus (HPV). HPV type 58 (HPV58) is an important causative agent, especially within Asia. Despite this, we still have limited data pertaining to the structural and neutralizing epitopes of HPV58, and this encumbers our in-depth understanding of the virus mode of infection. Here, we show that representative nAbs (5G9, 10B11, 2H3, 5H2 and A4B4) from three different groups share a common neutralization mechanism that appears to prohibit the virus from associating with the extracellular matrix and cell surface. Furthermore, we identify that the nAbs engage via three different binding patterns: top-center binding (5G9 and 10B11), top-fringe binding (2H3 and 5H2), and fringe binding (A4B4). Our work shows that, despite differences in the pattern in binding, nAbs against HPV58 share a common neutralization mechanism. These results provide new insight into the understanding of HPV58 infection.

20.
Nat Commun ; 12(1): 250, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431856

RESUMO

Understanding the mechanism for antibody neutralization of SARS-CoV-2 is critical for the development of effective therapeutics and vaccines. We recently isolated a large number of monoclonal antibodies from SARS-CoV-2 infected individuals. Here we select the top three most potent yet variable neutralizing antibodies for in-depth structural and functional analyses. Crystal structural comparisons reveal differences in the angles of approach to the receptor binding domain (RBD), the size of the buried surface areas, and the key binding residues on the RBD of the viral spike glycoprotein. One antibody, P2C-1F11, most closely mimics binding of receptor ACE2, displays the most potent neutralizing activity in vitro and conferred strong protection against SARS-CoV-2 infection in Ad5-hACE2-sensitized mice. It also occupies the largest binding surface and demonstrates the highest binding affinity to RBD. More interestingly, P2C-1F11 triggers rapid and extensive shedding of S1 from the cell-surface expressed spike glycoprotein, with only minimal such effect by the remaining two antibodies. These results offer a structural and functional basis for potent neutralization via disruption of the very first and critical steps for SARS-CoV-2 cell entry.


Assuntos
Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Monoclonais/química , Anticorpos Neutralizantes/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/imunologia , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/virologia , Modelos Animais de Doenças , Epitopos , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Receptores Virais/imunologia , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus
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