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1.
Autophagy ; : 1-20, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35506243

RESUMO

Mutations in DNAJC5/CSPα are associated with adult neuronal ceroid lipofuscinosis (ANCL), a dominant-inherited neurodegenerative disease featuring lysosome-derived autofluorescent storage materials (AFSMs) termed lipofuscin. Functionally, DNAJC5 has been implicated in chaperoning synaptic proteins and in misfolding-associated protein secretion (MAPS), but how DNAJC5 dysfunction causes lipofuscinosis and neurodegeneration is unclear. Here we report two functionally distinct but coupled chaperoning activities of DNAJC5, which jointly regulate lysosomal homeostasis: While endolysosome-associated DNAJC5 promotes ESCRT-dependent microautophagy, a fraction of perinuclear and non-lysosomal DNAJC5 mediates MAPS. Functional proteomics identifies a previously unknown DNAJC5 interactor SLC3A2/CD98hc that is essential for the perinuclear DNAJC5 localization and MAPS but dispensable for microautophagy. Importantly, uncoupling these two processes, as seen in cells lacking SLC3A2 or expressing ANCL-associated DNAJC5 mutants, generates DNAJC5-containing AFSMs resembling NCL patient-derived lipofuscin and induces neurodegeneration in a Drosophila ANCL model. These findings suggest that MAPS safeguards microautophagy to avoid DNAJC5-associated lipofuscinosis and neurodegeneration.Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; AFSM: autofluorescent storage materials; ANCL: adult neuronal ceroid lipofuscinosis; Baf. A1: bafilomycin A1; CLN: ceroid lipofuscinosis neuronal; CLU: clusterin; CS: cysteine string domain of DNAJC5/CSPα; CUPS: compartment for unconventional protein secretion; DN: dominant negative; DNAJC5/CSPα: DnaJ heat shock protein family (Hsp40) member C5; eMI: endosomal microautophagy; ESCRT: endosomal sorting complex required for transport; GFP: green fluorescent protein; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; INCL: infant neuronal ceroid lipofuscinosis; JNCL: juvenile neuronal ceroid lipofuscinosis; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAPTM4B: lysosomal protein transmembrane 4 beta; LN: linker domain of DNAJC5/CSPα; MAPS: misfolding-associated protein secretion; mCh/Ch: mCherry; mCi/Ci: mCitrine; MTOR: mechanistic target of rapamycin kinase; NCL: neuronal ceroid lipofuscinosis; PPT1: palmitoyl-protein thioesterase 1; PQC: protein quality control; SBP: streptavidin binding protein; SGT: small glutamine-rich tetratricopeptide repeat; shRNA: short hairpin RNA; SLC3A2/CD98hc: solute carrier family 3 member 2; SNCA/α-synuclein: synuclein alpha; TMED10: transmembrane p24 trafficking protein 10; UV: ultraviolet; VPS4: vacuolar protein sorting 4 homolog; WT: wild type.

2.
Front Immunol ; 13: 814365, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35572565

RESUMO

To effectively control and prevent the pandemic of coronavirus disease 2019 (COVID-19), suitable vaccines have been researched and developed rapidly. Currently, 31 COVID-19 vaccines have been approved for emergency use or authorized for conditional marketing, with more than 9.3 billion doses of vaccines being administered globally. However, the continuous emergence of variants with high transmissibility and an ability to escape the immune responses elicited by vaccines poses severe challenges to the effectiveness of approved vaccines. Hundreds of new COVID-19 vaccines based on different technology platforms are in need of a quick evaluation for their efficiencies. Selection and enrollment of a suitable sample of population for conducting these clinical trials is often challenging because the pandemic so widespread and also due to large scale vaccination. To overcome these hurdles, methods of evaluation of vaccine efficiency based on establishment of surrogate endpoints could expedite the further research and development of vaccines. In this review, we have summarized the studies on neutralizing antibody responses and effectiveness of the various COVID-19 vaccines. Using this data we have analyzed the feasibility of establishing surrogate endpoints for evaluating the efficacy of vaccines based on neutralizing antibody titers. The considerations discussed here open up new avenues for devising novel approaches and strategies for the research and develop as well as application of COVID-19 vaccines.

3.
Diabetes Metab Syndr Obes ; 15: 1357-1364, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35535215

RESUMO

Aim: The study aimed to investigate the association between the nocturnal sleep duration and five obesity indicators, namely, visceral fat area (VFA), subcutaneous fat area (SFA), bodyweight, body mass index (BMI) and waist circumference (WC), among people with type 2 diabetes mellitus (T2DM) in Ningbo, China. Methods: A cross-sectional study was conducted using the National Metabolic Management Centre (MMC) - Ningbo First Hospital data from 1st March 2018 to 28th February 2021. Adults with T2DM were included in the study. Simple and multiple (adjusted for sociodemographic and lifestyle factors and health conditions) linear regression analyses were performed to identify the associations. Results: In terms of VFA, SFA, bodyweight, BMI and WC, the eligibility criteria were satisfied by 2771, 2771, 2863, 2863 and 2862 patients, respectively. In the unadjusted model, the shorter nocturnal sleep duration was associated with higher VFA, SFA, bodyweight, BMI and WC. In other words, an hour increase in the nocturnal sleep duration was associated with a decrease of 2.07 cm2 in VFA (regression coefficient = -2.07; 95% CI = -3.25 to -0.88), 2.67 cm2 in SFA (-2.67; -4.55 to -0.78); 0.82 kg in bodyweight (-0.82; -1.2 to -0.43), 0.2 kg/m2 in BMI (-0.2; -0.31 to -0.09) and 0.46 cm in WC (-0.46; -0.76 to -0.16). In the adjusted models, the shorter nocturnal sleep duration was still found to be associated with higher VFA, SFA, bodyweight, BMI and WC (except SFA and WC in models where we further adjusted for health conditions). Conclusion: The nocturnal sleep duration among people with T2DM in Ningbo, China is negatively associated with visceral and general obesity indicators (VFA, bodyweight and BMI). Thus, there is a need for appropriate interventions to address the issue of sleep deprivation.

4.
Pain ; 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35543644

RESUMO

ABSTRACT: Bone cancer pain (BCP) is a pervasive clinical symptom which impairs the quality life. Long non-coding RNAs (lncRNAs) are enriched in the central nervous system (CNS) and play indispensable roles in numerous biological processes, while its regulatory function in nociceptive information processing remains elusive. Here, we reported that functional modulatory role of ENSRNOT00000071132 (lncRNA71132) in the BCP process and sponging with miR-143 and its downstream GPR85-dependent signaling cascade. Spinal lncRNA71132 was remarkably increased in the rat model of bone cancer pain. The knockdown of spinal lncRNA71132 reverted BCP behaviors and spinal c-Fos neuronal sensitization. Over-expression of spinal lncRNA71132 in naive rat generated pain behaviors, which were accompanied by increased spinal c-Fos neuronal sensitization. Furthermore, it was found that lncRNA71132 participates in the modulation of BCP by inversely regulating the processing of miR-143-5p. In addition, an increase in expression of spinal lncRNA71132 resulted in the decrease in expression of miR-143 under BCP state. Finally, it was found that miR-143-5p regulates pain behaviors by targeting GPR85. Over-expression of miR-143-5p in the spinal cord reverted the nociceptive behaviors triggered by BCP, accompanied by a decrease in expression of spinal GPR85 protein, but no influence on expression of gpr85 mRNA. The findings of the present study indicate that lncRNA71132 works as a miRNA sponge in miR-143-5p mediated post-transcriptional modulation of GPR85 expression in BCP. Therefore, epigenetic interventions against lncRNA71132 may potentially work as novel treatment avenues in treating nociceptive hypersensitivity triggered by bone cancer.

5.
Oncogene ; 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35468939

RESUMO

Kelch superfamily involves a variety of proteins containing multiple kelch motif and is well characterized as substrate adaptors for CUL3 E3 ligases, which play critical roles in carcinogenesis. However, the role of kelch proteins in lung cancer remains largely unknown. In this study, the non-small cell lung cancer (NSCLC) patients with higher expression of a kelch protein, kelch domain containing 3 (KLHDC3), showed worse overall survival. KLHDC3 deficiency affected NSCLC cell lines proliferation in vitro and in vivo. Further study indicated that KLHDC3 mediated CUL2 E3 ligase and tumor suppressor p14ARF interaction, facilitating the N-terminal ubiquitylation and subsequent degradation of p14ARF. Interestingly, Gefitinib-resistant NSCLC cell lines displayed higher KLHDC3 protein levels. Gefitinib and Osimertinib medications were capable of upregulating KLHDC3 expression to promote p14ARF degradation in the NSCLC cell lines. KLHDC3 shortage significantly increased the sensitivity of lung cancer cells to epidermal growth factor receptor (EGFR)-targeted drugs, providing an alternative explanation for the development of Gefitinib and Osimertinib resistance in NSCLC therapy. Our works suggest that CRL2KLHDC3 could be a valuable target to regulate the abundance of p14ARF and postpone the occurrence of EGFR-targeted drugs resistance.

6.
Hum Vaccin Immunother ; : 1-12, 2022 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-35438600

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to circulate worldwide and a variety of variants have emerged. Variants of concern (VOC) designated by the World Health Organization (WHO) have triggered epidemic waves due to their strong infectivity or pathogenicity and potential immune escape, among other reasons. Although large-scale vaccination campaigns undertaken globally have contributed to the improved control of SARS-CoV-2, the efficacies of current vaccines against VOCs have declined to various degrees. In particular, the highly infectious Delta and Omicron variants have caused recent epidemics and prompted concerns about control measures. This review summarizes current VOCs, the protective efficacy of vaccines against VOCs, and the shortcomings in methods for evaluating vaccine efficacy. In addition, strategies for responding to variants are proposed for future epidemic prevention and control as well as for vaccine research and development.

7.
Appl Opt ; 61(11): 2937-2942, 2022 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-35471268

RESUMO

Although many studies on cholesteric liquid crystal (CLC) microdroplet single-mode lasers are available, it has been shown that the stability and tunability of such microdroplets are difficult to achieve simultaneously. In this paper, a new, to the best of our knowledge, method is proposed for the mass and rapid preparation of stable and tunable monodisperse CLC microdroplet single-mode lasers. This is based on the formation of polymer networks on the surface of the microdroplet via interfacial polymerization and a disruption of the orderliness of the polymer networks by increasing the temperature during polymerization, which results in a single pitch inside the microdroplets. This approach enables CLC microdroplet single-mode lasers to achieve improved environmental robustness, while maintaining the same temperature tunability as the unpolymerized sample. Our method has promising future applications in integrated optics, flexible devices, and sensors.

8.
Appl Opt ; 61(10): 2721-2726, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35471343

RESUMO

A liquid crystal microlens array (LCMLA) with positive and negative focal lengths based on a ring-array patterned electrodes is demonstrated. By carefully designing patterned electrodes with a circular electrode array area and outer ring electrode region area, the switching of the positive and negative lens effect can be easily achieved in a single cell. A positive lens effect appeared when the voltage was applied to the outer ring electrode region and the top substrate. The focal length changed from infinity to 1 mm as the voltage varied from 0 to 3Vrms. A negative lens effect occurred when the voltage was applied to the circular electrode array and the top substrate. The focal length varied from infinity to -1mm when the voltage changed from 0 to 2Vrms. The imaging properties of the LCMLA at different voltages are evaluated. Our LCMLA, with simple structure, low driving voltage, and good stability, has potential applications in optical communication, imaging processing, and displays.

9.
Sci Rep ; 12(1): 6294, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35440680

RESUMO

Spike-mediated entry of SARS-CoV-2 into human airway epithelial cells is an attractive therapeutic target for COVID-19. In addition to protein receptors, the SARS-CoV-2 spike (S) protein also interacts with heparan sulfate, a negatively charged glycosaminoglycan (GAG) attached to certain membrane proteins on the cell surface. This interaction facilitates the engagement of spike with a downstream receptor to promote viral entry. Here, we show that Mitoxantrone, an FDA-approved topoisomerase inhibitor, targets a heparan sulfate-spike complex to compromise the fusogenic function of spike in viral entry. As a single agent, Mitoxantrone inhibits the infection of an authentic SARS-CoV-2 strain in a cell-based model and in human lung EpiAirway 3D tissues. Gene expression profiling supports the plasma membrane as a major target of Mitoxantrone but also underscores an undesired activity targeting nucleosome dynamics. We propose that Mitoxantrone analogs bearing similar heparan sulfate-binding activities but with reduced affinity for DNA topoisomerases may offer an alternative therapy to overcome breakthrough infections in the post-vaccine era.


Assuntos
COVID-19 , Glicoproteína da Espícula de Coronavírus , COVID-19/tratamento farmacológico , Heparina/metabolismo , Heparitina Sulfato/metabolismo , Humanos , Mitoxantrona/farmacologia , Ligação Proteica , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismo
10.
Sensors (Basel) ; 22(7)2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35408330

RESUMO

Superresolution (SR) imaging technology based on compression coding has always been considered as the key to break through the geometric resolution of the detector. In addition to factors such as the reconstruction algorithm and mounting platform vibrations, the impact of inherent errors in the optical system itself on the reconstruction results of SR imaging is also obvious. To address this issue, a study on the design of the SR optical system and the influence of optical alignment errors on SR imaging was conducted. The design of the SR optical system based on digital micro-mirror device (DMD) for long-wave infrared wavelength was completed, and an athermal analysis of the system was carried out. The design results showed that the SR optical system has good imaging quality in the operating temperature range. The imaging model of the DMD SR imaging optical system is established according to the designed SR optical system. We investigated the influence of various alignment errors, including decenter, tilt, lens interval error and defocus, on the imaging properties of the SR optical system. Various random combinations of alignment errors were introduced into the optical system, respectively, and the SR reconstructed image quality of the imaging system was analyzed using the inverse sensitivity method to obtain the tolerance limits when the system was assembled. Finally, the effectiveness of the method to obtain the alignment tolerance limit of the compression coding SR imaging optical system was verified through a desktop demonstration experiment.

11.
Nat Commun ; 13(1): 1966, 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35414057

RESUMO

Polygenic risk scores (PRS) have the potential to identify individuals at risk of diseases, optimizing treatment, and predicting survival outcomes. Here, we construct and validate a genome-wide association study (GWAS) derived PRS for nasopharyngeal carcinoma (NPC), using a multi-center study of six populations (6 059 NPC cases and 7 582 controls), and evaluate its utility in a nested case-control study. We show that the PRS enables effective identification of NPC high-risk individuals (AUC = 0.65) and improves the risk prediction with the PRS incremental deciles in each population (Ptrend ranging from 2.79 × 10-7 to 4.79 × 10-44). By incorporating the PRS into EBV-serology-based NPC screening, the test's positive predictive value (PPV) is increased from an average of 4.84% to 8.38% and 11.91% in the top 10% and 5% PRS, respectively. In summary, the GWAS-derived PRS, together with the EBV test, significantly improves NPC risk stratification and informs personalized screening.


Assuntos
Estudo de Associação Genômica Ampla , Neoplasias Nasofaríngeas , Estudos de Casos e Controles , Humanos , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/genética , Medição de Risco , Fatores de Risco
12.
J Chem Inf Model ; 62(8): 1988-1997, 2022 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-35404596

RESUMO

The cell entry of SARS-CoV-2 has emerged as an attractive drug development target. We previously reported that the entry of SARS-CoV-2 depends on the cell surface heparan sulfate proteoglycan (HSPG) and the cortex actin, which can be targeted by therapeutic agents identified by conventional drug repurposing screens. However, this drug identification strategy requires laborious library screening, which is time consuming, and often limited number of compounds can be screened. As an alternative approach, we developed and trained a graph convolutional network (GCN)-based classification model using information extracted from experimentally identified HSPG and actin inhibitors. This method allowed us to virtually screen 170,000 compounds, resulting in ∼2000 potential hits. A hit confirmation assay with the uptake of a fluorescently labeled HSPG cargo further shortlisted 256 active compounds. Among them, 16 compounds had modest to strong inhibitory activities against the entry of SARS-CoV-2 pseudotyped particles into Vero E6 cells. These results establish a GCN-based virtual screen workflow for rapid identification of new small molecule inhibitors against validated drug targets.


Assuntos
Antivirais , SARS-CoV-2 , Internalização do Vírus , Actinas , Antivirais/química , COVID-19/tratamento farmacológico , Proteoglicanas de Heparan Sulfato , Humanos , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
13.
Front Microbiol ; 13: 845500, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35401491

RESUMO

Bacteriophage-encoded depolymerases are responsible for degrading capsular polysaccharides (CPS), lipopolysaccharides (LPS), and exopolysaccharides (EPS) of the host bacteria during phage invasion. They have been considered as promising antivirulence agents in controlling bacterial infections, including those caused by multidrug-resistant (MDR) bacteria. This feature inspires hope of utilizing these enzymes to disarm the polysaccharide capsules of the bacterial cells, which then strengthens the action of antibiotics. Here we have identified, cloned, and expressed a depolymerase Dpo71 from a bacteriophage specific for the gram-negative bacterium Acinetobacter baumannii in a heterologous host Escherichia coli. Dpo71 sensitizes the MDR A. baumannii to the host immune attack, and also acts as an adjuvant to assist or boost the action of antibiotics, for example colistin. Specifically, Dpo71 at 10 µg/ml enables a complete bacterial eradication by human serum at 50% volume ratio. A mechanistic study shows that the enhanced bactericidal effect of colistin is attributed to the improved outer membrane destabilization capacity and binding rate to bacteria after stripping off the bacterial capsule by Dpo71. Dpo71 inhibits biofilm formation and disrupts the pre-formed biofilm. Combination of Dpo71 could significantly enhance the antibiofilm activity of colistin and improve the survival rate of A. baumannii infected Galleria mellonella. Dpo71 retains the strain-specificity of the parent phage from which Dpo71 is derived: the phage-sensitive A. baumannii strains respond to Dpo71 treatment, whereas the phage-insensitive strains do not. In summary, our work demonstrates the feasibility of using recombinant depolymerases as an antibiotic adjuvant to supplement the development of new antibacterials and to battle against MDR pathogens.

14.
Front Cell Infect Microbiol ; 12: 831409, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35392614

RESUMO

Background: The human microbiome has been reported to mediate the response to anticancer therapies. However, research about the influence of the oral microbiome on nasopharyngeal carcinoma (NPC) survival is lacking. We aimed to explore the effect of oral microbiota on NPC prognosis. Methods: Four hundred eighty-two population-based NPC cases in southern China between 2010 and 2013 were followed for survival, and their saliva samples were profiled using 16s rRNA sequencing. We analyzed associations of the oral microbiome diversity with mortality from all causes and NPC. Results: Within- and between-community diversities of saliva were associated with mortality with an average of 5.29 years follow-up. Lower Faith's phylogenetic diversity was related to higher all-cause mortality [adjusted hazard ratio (aHR), 1.52 (95% confidence interval (CI), 1.06-2.17)] and NPC-specific mortality [aHR, 1.57 (95% CI, 1.07-2.29)], compared with medium diversity, but higher phylogenetic diversity was not protective. The third principal coordinate (PC3) identified from principal coordinates analysis (PCoA) on Bray-Curtis distance was marginally associated with reduced all-cause mortality [aHR, 0.85 (95% CI, 0.73-1.00)], as was the first principal coordinate (PC1) from PCoA on weighted UniFrac [aHR, 0.86 (95% CI, 0.74-1.00)], but neither was associated with NPC-specific mortality. PC3 from robust principal components analysis was associated with lower all-cause and NPC-specific mortalities, with HRs of 0.72 (95% CI, 0.61-0.85) and 0.71 (95% CI, 0.60-0.85), respectively. Conclusions: Oral microbiome may be an explanatory factor for NPC prognosis. Lower within-community diversity was associated with higher mortality, and certain measures of between-community diversity were related to mortality. Specifically, candidate bacteria were not related to mortality, suggesting that observed associations may be due to global patterns rather than particular pathogens.


Assuntos
Neoplasias Nasofaríngeas , Saliva , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/microbiologia , Filogenia , RNA Ribossômico 16S/genética , Saliva/microbiologia
15.
Proc Natl Acad Sci U S A ; 119(18): e2201433119, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35476528

RESUMO

SignificanceDue to their small size, nanobodies can recognize protein cavities that are not accessible to conventional antibodies. In this report, we built dromedary camel (Camelus dromedarius) VHH phage libraries for the isolation of high-affinity nanobodies that broadly neutralize SARS-CoV-2 variants. Cryo-EM complex structures reveal that one dromedary camel VHH nanobody (8A2) binds the S1 subunit of the viral spike protein, and the other (7A3) targets a deeply buried region that uniquely extends to the S2 subunit beyond the S1 subunit. These nanobodies can protect mice from the lethal challenge of variants B.1.351 or B.1.617.2, suggesting the therapeutic potential of these nanobodies against COVID-19. The dromedary camel VHH libraries could be helpful to isolate neutralizing nanobodies against future emerging viruses quickly.


Assuntos
COVID-19 , Anticorpos de Domínio Único , Animais , Camelus , Humanos , Camundongos , SARS-CoV-2/genética , Anticorpos de Domínio Único/genética
16.
Vaccine ; 40(14): 2233-2239, 2022 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-35227521

RESUMO

A reference standard is needed for quality control of protein subunit SARS-CoV-2 vaccines to meet urgent domestic needs. The Chinese National Institutes for Food and Drug Control (NIFDC) launched a project to establish the first reference material for the protein subunit SARS-CoV-2 vaccine to be used for calibration of antigen testing. The potency and stability of the national candidate standard (CS) were determined by collaborative calibration, and accelerated and freeze-thaw degradation studies. Moreover, a suitability study of the CS was performed. Eight laboratories in mainland China were asked to detect antigen content of CS using a common validated enzyme-linked immunosorbent assay (ELISA) kit established by NIFDC and in-house kits in the collaborative study. Six laboratories returned valid results, which established that the antigen content of the CS was 876,938 YU/mL, with good agreement across laboratories. In the suitability study, the CS exhibited excellent parallelism and a linear relationship with four samples produced by different expression systems and target proteins. In addition, good stability in the accelerated and freeze-thaw degradation study was observed. In conclusion, the CS was approved by the Biological Product Reference Standards Sub-Committee of the National Drug Reference Standards Committee as the first Chinese national standard for determining antigen content of protein subunit SARS-CoV-2 vaccines, with an assigned antigen content of 877,000 U/mL (Lot. 300050-202101). This standard will contribute to a standardized assessment of protein subunit SARS-CoV-2 vaccine in China and may provide experience for developing reference materials for antigen content detection of SARS-CoV-2 vaccine in other countries.


Assuntos
Vacinas contra COVID-19 , COVID-19 , COVID-19/prevenção & controle , Humanos , Subunidades Proteicas , Padrões de Referência , SARS-CoV-2
17.
Emerg Microbes Infect ; 11(1): 1145-1153, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35343384

RESUMO

Analysis of large-scale gene expression post vaccination can provide an overview of immune responses. We used transcriptional approaches to comprehensively analyze the innate immune response signatures elicited by protein subunit (PS) vaccine ZF2001 and an mRNA vaccine named RRV. A fine-grained time-dependent dissection of large-scale gene expression post immunization revealed that ZF001 induced MHC class II-related genes, including cd74 and H2-Aa, more expeditiously than the RRV. Notably, the RRV induced MHC class I-related genes such as Tap1/2, B2m, and H2-D1/K1. At day 21 post immunization, the titres of binding and neutralization antibody (NAb) induced by both vaccines were comparable, which were accordant with the expression level of genes essential to BCR/TCR signalling transduction and B/T cells activation at day 7. However, compared to ZF2001, the early responses of RRV were more robust, including the activation of pattern recognition receptors (PRRs), expression of genes involved in RNA degradation, and transcription inhibition, which are directly related to anti-viral signals. This pattern also coincided with the induction of cytokines by the RRV. Generally, the transcriptomic patterns of two very different vaccines mapped here provide a framework for establishing correlates between the induction of genes and protection, which can be tailored for evoking specific and potent immune responses against SARS-CoV-2.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , Humanos , Imunidade Inata , Subunidades Proteicas/genética , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus , Transcriptoma , Vacinação , Vacinas de Subunidades , Vacinas Sintéticas
18.
Br J Haematol ; 197(3): 367-372, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35288929

RESUMO

Primary immune thrombocytopenia (ITP) is an autoimmune haemorrhagic disease that could manifest with comorbid type 2 diabetes mellitus (T2DM). However, the exact impact of T2DM in patients with ITP remains uncertain. In this study, we performed a retrospective cohort study of 458 participants with ITP. The prevalence of T2DM was 7.6% in this population (35 patients), which was slightly lower than the Chinese nationwide prevalence of T2DM, calculated to be approximately 10.9%. The participants with pre-existing T2DM displayed a significantly higher response to therapy than those without T2DM (71% vs. 53%). Furthermore, in the T2DM cohort, the response rate reached 88% when metformin was included in the treatment regimen. This clinical evidence suggests that metformin therapy might improve the clinical outcomes of ITP.


Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Adulto , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
19.
J Virol ; 96(8): e0007522, 2022 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-35348362

RESUMO

Epstein-Barr virus (EBV) is an oncogenic herpesvirus that is associated with 200,000 new cases of cancer and 140,000 deaths annually. To date, there are no available vaccines or therapeutics for clinical usage. Recently, the viral heterodimer glycoprotein gH/gL has become a promising target for the development of prophylactic vaccines against EBV. Here, we developed the anti-gH antibody 6H2 and its chimeric version C6H2, which had full neutralizing activity in epithelial cells and partial neutralizing activity in B cells. C6H2 exhibited potent protection against lethal EBV challenge in a humanized mouse model. The cryo-electron microscopy (cryo-EM) structure further revealed that 6H2 recognized a previously unidentified epitope on gH/gL D-IV that is critical for viral attachment and subsequent membrane fusion with epithelial cells. Our results suggest that C6H2 is a promising candidate in the prevention of EBV-induced lymphoproliferative diseases (LPDs) and may inform the design of an EBV vaccine. IMPORTANCE Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that establishes lifelong persistence and is related to multiple diseases, including cancers. Neutralizing antibodies (NAbs) have proven to be highly effective in preventing EBV infection and subsequent diseases. Here, we developed an anti-EBV-gH NAb, 6H2, which blocked EBV infection in vitro and in vivo. This 6H2 neutralizing epitope should be helpful to understand EBV infection mechanisms and guide the development of vaccines and therapeutics against EBV infection.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Proteínas do Envelope Viral , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Microscopia Crioeletrônica , Epitopos/química , Infecções por Vírus Epstein-Barr/prevenção & controle , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/metabolismo , Camundongos , Vacinas , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/imunologia
20.
Infect Drug Resist ; 15: 1225-1234, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35355619

RESUMO

Purpose: Polymorphisms in MBL2 may contribute to the susceptibility to tuberculosis. The aim of the present study was to determine the associations of the polymorphisms of five loci (rs1800450, rs1800451, rs7096206, rs7095891, and rs11003125) in the MBL2 gene with susceptibility to tuberculosis and specific lineages of Mycobacterium tuberculosis causing tuberculosis in the Uyghur population of Xinjiang, China. Methods: From January 2019 to January 2020, we enrolled 170 Uyghur tuberculosis patients as the case group and 147 Uyghur staff with no clinical symptoms as the control group from four designated tuberculosis hospitals in southern Xinjiang, China. The polymorphisms of five loci in MBL2 of human were detected by sequencing. Whole-genome sequencing was applied in 68 M. tuberculosis isolates from the case group and the data were used to perform genealogy analysis. Results: The distributions of allele and genotype frequencies of five loci in MBL2 varied little between the case and control groups and varied little among the groups, including those infected with different lineages of M. tuberculosis and the control (except those of rs11003125), the P values were all >0.05. The distribution of alleles of rs11003125 was statistically different between patients infected with lineages 3 and 4 M. tuberculosis (χ 2=7.037, P=0.008). The C allele and CC genotype of rs11003125 were found to be protective factors against lineage 4 infection when compared to lineage 3 (ORs were 0.190 and 0.158, respectively; 95% confidence intervals were 0.053~0.690 and 0.025~0.999, respectively). Conclusion: Our results suggested that human's susceptibility to tuberculosis is affected both by the host genetic polymorphisms and the lineage of the M. tuberculosis that people were exposed to. However, due to the limitation of the sample size in the present study, larger sample size and more rigorous design should be guaranteed in future studies.

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