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1.
Waste Manag ; 139: 290-299, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34995856

RESUMO

Source separation and recycling (SSR) for municipal solid waste is an important strategy for the transition to a circular economy and requires broader resident participation. How can residents' participation in SSR be promoted? Here, we consider 13 cities in Jiangsu as microcosms of China. We quantify residents' intentions to participate in SSR by distributing a validated questionnaire to 2,963 urban residents, analyze the results through structural equation modeling, and propose localized policy recommendations. We find that residents have positive attitudes toward SSR, although 92.6% of residents in southern Jiangsu were more willing to participate than those in northern Jiangsu (84.6%). Additionally, the influencing factors and their degree of influence on resident SSR participation intentions exhibit disparities across cities. "Accessibility of SSR facilities" simultaneously affects the 13 studied cities and is a key factor. "Environmental knowledge" and "environmental attitudes" are important impact factors, with occurrence frequencies of 84.6% and 69.2%, respectively. However, laws and regulations have no significant effect on residents' SSR participation intentions. We recommend that the government create favorable external conditions related to facilities and services, promote extensive publicity and educational activities through various channels, and improve the effectiveness of SSR laws and regulations. Future SSR management strategies should be localized, flexible and comprehensive. This research could help decision makers in China and other countries design policy guides to promote SSR and help link current research areas to social development.

2.
Medicine (Baltimore) ; 100(44): e27700, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34871257

RESUMO

BACKGROUND: Chronic fatigue syndrome (CFS) is a common disease and characterized by fatigue, exhaustion, heavy limbs, and dizziness. Tuina, as a traditional Chinese manual therapy, is usually used for CFS in China. Several studies have reported that Tuina can improve fatigue exhaustion, and dizziness of patients with CFS. However, the effects of Tuina for CFS still remain controversial. Therefore, the current systematic review and meta-analysis will be conducted to investigate the effects of Tuina in the management of CFS. METHODS: The comprehensive electronic search of PubMed, Web of Science, Chinese National Knowledge Infrastructure, Wanfang Database, Embase, Cochrane Library, Chinese Science Citation Database, Technology Periodical Database from their inception to October 2021 will be conducted. Randomized controlled trials of Tuina for CFS will be included in the review. Two independent reviewers will complete the study selection, data extraction, and the risk of bias. The meta-analysis will be conducted using the Review Manager Version 5.3 software. The heterogeneity will be assessed using the I2 statistic and Q statistic. The standardized mean difference and 95% confidence intervals will be calculated based on different heterogeneity. The subgroup analysis will be conducted based on the duration of treatment, age, gender, duration of CFS. Quality of evidence will be assessed using the Grades of Recommendation, Assessment, Development and Evaluation. RESULTS: The current systematic review and meta-analysis will be to investigate the effects of Tuina in the management of CFS. CONCLUSION: The conclusion of this study will provide the evidence for the treatment of CFS in the future. It is expected that the conclusions drawn from this review will benefit patients, clinical practitioners and policy makers.

3.
Lancet Infect Dis ; 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34890537

RESUMO

BACKGROUND: Large-scale vaccination against COVID-19 is being implemented in many countries with CoronaVac, an inactivated vaccine. We aimed to assess the immune persistence of a two-dose schedule of CoronaVac, and the immunogenicity and safety of a third dose of CoronaVac, in healthy adults aged 18 years and older. METHODS: In the first of two single-centre, double-blind, randomised, placebo-controlled phase 2 clinical trials, adults aged 18-59 years in Jiangsu, China, were initially allocated (1:1) into two vaccination schedule cohorts: a day 0 and day 14 vaccination cohort (cohort 1) and a day 0 and day 28 vaccination cohort (cohort 2); each cohort was randomly assigned (2:2:1) to either a 3 µg dose or 6 µg dose of CoronaVac or a placebo group. Following a protocol amendment on Dec 25, 2020, half of the participants in each cohort were allocated to receive an additional dose 28 days (window period 30 days) after the second dose, and the other half were allocated to receive a third dose 6 months (window period 60 days) after the second dose. In the other phase 2 trial, in Hebei, China, participants aged 60 years and older were assigned sequentially to receive three injections of either 1·5 µg, 3 µg, or 6 µg of vaccine or placebo, administered 28 days apart for the first two doses and 6 months (window period 90 days) apart for doses two and three. The main outcomes of the study were geometric mean titres (GMTs), geometric mean increases (GMIs), and seropositivity of neutralising antibody to SARS-CoV-2 (virus strain SARS-CoV-2/human/CHN/CN1/2020, GenBank accession number MT407649.1), as analysed in the per-protocol population (all participants who completed their assigned third dose). Our reporting is focused on the 3 µg groups, since 3 µg is the licensed formulation. The trials are registered with ClinicalTrials.gov, NCT04352608 and NCT04383574. FINDINGS: 540 (90%) of 600 participants aged 18-59 years were eligible to receive a third dose, of whom 269 (50%) received the primary third dose 2 months after the second dose (cohorts 1a-14d-2m and 2a-28d-2m) and 271 (50%) received a booster dose 8 months after the second dose (cohorts 1b-14d-8m and 2b-28d-8m). In the 3 µg group, neutralising antibody titres induced by the first two doses declined after 6 months to near or below the seropositive cutoff (GMT of 8) for cohort 1b-14d-8m (n=53; GMT 3·9 [95% CI 3·1-5·0]) and for cohort 2b-28d-8m (n=49; 6·8 [5·2-8·8]). When a booster dose was given 8 months after a second dose, GMTs assessed 14 days later increased to 137·9 (95% CI 99·9-190·4) for cohort 1b-14d-8m and 143·1 (110·8-184·7) 28 days later for cohort 2b-28d-8m. GMTs moderately increased following a primary third dose, from 21·8 (95% CI 17·3-27·6) on day 28 after the second dose to 45·8 (35·7-58·9) on day 28 after the third dose in cohort 1a-14d-2m (n=54), and from 38·1 (28·4-51·1) to 49·7 (39·9-61·9) in cohort 2a-28d-2m (n=53). GMTs had decayed to near the positive threshold by 6 months after the third dose: GMT 9·2 (95% CI 7·1-12·0) in cohort 1a-14d-2m and 10·0 (7·3-13·7) in cohort 2a-28d-2m. Similarly, in adults aged 60 years and older who received booster doses (303 [87%] of 350 participants were eligible to receive a third dose), neutralising antibody titres had declined to near or below the seropositive threshold by 6 months after the primary two-dose series. A third dose given 8 months after the second dose significantly increased neutralising antibody concentrations: GMTs increased from 42·9 (95% CI 31·0-59·4) on day 28 after the second dose to 158·5 (96·6-259·2) on day 28 following the third dose (n=29). All adverse reactions reported within 28 days after a third dose were of grade 1 or 2 severity in all vaccination cohorts. There were three serious adverse events (2%) reported by the 150 participants in cohort 1a-14d-2m, four (3%) by 150 participants from cohort 1b-14d-8m, one (1%) by 150 participants in each of cohorts 2a-28d-2m and 2b-28d-8m, and 24 (7%) by 349 participants from cohort 3-28d-8m. INTERPRETATION: A third dose of CoronaVac in adults administered 8 months after a second dose effectively recalled specific immune responses to SARS-CoV-2, which had declined substantially 6 months after two doses of CoronaVac, resulting in a remarkable increase in the concentration of antibodies and indicating that a two-dose schedule generates good immune memory, and a primary third dose given 2 months after the second dose induced slightly higher antibody titres than the primary two doses. FUNDING: National Key Research and Development Program, Beijing Science and Technology Program, and Key Program of the National Natural Science Foundation of China. TRANSLATION: For the Mandarin translation of the abstract see Supplementary Materials section.

4.
Aging Cell ; : e13526, 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34874096

RESUMO

DNA methylation alterations play mechanistic roles in aging; however, the epigenetic regulators/mediators causally involved in renal aging remain elusive. Here, we report that natural and D-galactose (D-gal)-induced aging kidneys display marked suppression of antiaging factor NRF2 (nuclear factor erythroid-derived 2-like 2) and KLOTHO, accompanied by upregulations of DNA methyltransferase (DNMT) 1/3a/3b and NRF2/KLOTHO gene promoter hypermethylations. Administration of a DNMT inhibitor SGI-1072 effectively hypomethylated the promoters, derepressed NRF2/KLOTHO, and mitigated the structural and functional alterations of renal aging in D-gal mice. Moreover, oleuropein (OLP), an olive-derived polyphenol, also displayed similar epigenetic modulation and antiaging effects. OLP inhibited the epigenetic NRF2/KLOTHO suppressions in a gain of DNMT-sensitive manner in cultured renal cells, demonstrating a strong DNA-demethylating capacity. In NRF2 knockout and KLOTHO knockdown D-gal mice, OLP exhibited reduced antiaging effects with KLOTHO displaying a prominent gene effect and effect size; consistently in KLOTHO knockdown mice, the antiaging effects of SGI-1027 were largely abrogated. Therefore, the KLOTHO recovery is critical for the antiaging effects of DNA demethylation. Collectively, our data indicate that aberrant DNMT1/3a/3b elevations and the resultant suppression of antiaging factors contribute significantly to epigenetic renal aging, which might be targeted for epigenetic intervention by synthetic or natural DNA-demethylating agents.

5.
Molecules ; 26(24)2021 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-34946607

RESUMO

ADAMTS13 (A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats, member 13) cleaves von Willebrand Factor (VWF) multimers to limit the prothrombotic function of VWF. The deficiency of ADAMTS13 causes a lethal thrombotic microvascular disease, thrombotic thrombocytopenic purpura (TTP). ADAMTS13 circulates in a "closed" conformation with the distal domain associating the Spacer domain to avoid off-target proteolysis or recognition by auto-antibodies. However, the interactions of the distal TSP8 domain and the Spacer domain remain elusive. Here, we constructed the TSP8-Spacer complex by a combination of homology modelling and flexible docking. Molecular dynamics simulation was applied to map the binding sites on the TSP8 or Spacer domain. The results predicted that R1075, D1090, R1095, and C1130 on the TSP8 domain were key residues that interacted with the Spacer domain. R1075 and R1095 bound exosite-4 tightly, D1090 formed multiple hydrogen bonds and salt bridges with exosite-3, and C1130 interacted with both exosite-3 and exosite-4. Specific mutations of exosite-3 (R568K/F592Y/R660K/Y661F/Y665F) or the four key residues (R1075A/D1090A/R1095A/C1130A) impaired the binding of the TSP8 domain to the Spacer domain. These results shed new light on the understanding of the auto-inhibition of ADAMTS13.

6.
Insect Mol Biol ; 2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34897868

RESUMO

Many endoparasitoids adopt several parasitic factors, such as venom, polydnavirus and teratocytes, to suppress the immune response of their associated hosts including melanization for successful parasitism. A teratocyte-specific expressed serpin gene, designated as CvT-serpin6, was identified from the parasitoid Cotesia vestalis. The immunoblot result suggested that CvT-serpin6 was secreted into extracellular space. qPCR results showed that CvT-serpin6 was mainly transcribed at later stages of parasitism, and the transcriptional abundance of CvT-serpin6 in teratocytes was significantly increased in response to the challenge of bacteria. Inhibitory assay indicated that recombinant CvT-serpin6 (rCvT-serpin6) could inhibit the activation of Plutella xylostella prophenoloxidase and ultimately resulted in the inhibition of melanization in P. xylostella haemolymph. Furthermore, we confirmed that rCvT-serpin6 could form SDS-stable complexes with activated PxPAP1 and PxPAP3 in a dose-dependent manner. Altogether, our results further shed insight into the molecular mechanisms that teratocytes involved in controlling host immune response.

7.
Front Cell Infect Microbiol ; 11: 789723, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34751243

RESUMO

[This corrects the article DOI: 10.3389/fcimb.2021.725392.].

8.
Microbiol Spectr ; : e0064621, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34730435

RESUMO

Herpes simplex virus 1 (HSV-1) infects eye corneal tissues leading to herpetic stromal keratitis (HSK), which is one of the leading causes of blindness. Here in our study, we found that 6-thioguanine (6-TG), a once clinically approved medication for child acute myelogenous leukemia, inhibited multiple strains of HSV-1 infection in vitro and in vivo. 6-TG is more potent than acyclovir (ACV) and ganciclovir (GCV), with the 50% inhibitory concentration (IC50) of 6-TG at 0.104 µM with high stimulation index (SI) (SI = 6,475.48) compared to the IC50 of ACV at 1.253 µM and the IC50 of GCV at 1.257 µM. In addition, 6-TG at 500 µM topically applied to the eyes with HSV-1 infection significantly inhibits HSV-1 replication, alleviates virus-induced HSK pathogenesis, and improves eye conditions. More importantly, 6-TG is effective against ACV-resistant HSV-1 strains, including HSV-1/153 and HSV-1/blue. Knockdown of Rac1 with small interfering RNA (siRNA) negatively affected HSV-1 replication, suggesting that Rac1 facilitated HSV-1 replication. Following HSV-1 infection of human corneal epithelial cells (HCECs), endogenous Rac1 activity was upregulated by glutathione S-transferase (GST) pulldown assay. We further found that Rac1 was highly expressed in the corneal tissue of HSK patients compared to normal individuals. Mechanistic study showed that 6-TG inhibited HSV-1 replication by targeting Rac1 activity in HSV-1 infected cells, and the Rac1 is critical in the pathogenesis of HSK. Our results indicated that 6-TG is a promising therapeutic molecule for the treatment of HSK. IMPORTANCE We reported the discovery of 6-TG inhibition of HSV-1 infection and its inhibitory roles in HSK both in vitro and in vivo. 6-TG was shown to possess at least 10× more potent inhibitory activity against HSV-1 than ACV and GCV and, more importantly, inhibit ACV/GCV-resistant mutant viruses. Animal model studies showed that gel-formulated 6-TG topically applied to eyes locally infected with HSV-1 could significantly inhibit HSV-1 replication, alleviate virus-induced HSK pathogenesis, and improve eye conditions. Further study showed that HSV-1 infection upregulated Rac1 expression, and knockdown of Rac1 using siRNA markedly restricted HSV-1 replication, suggesting that Rac1 is required for HSV-1 replication. In addition, we also documented that Rac1 is highly expressed in corneal tissues from HSK patients, indicating that Rac1 is associated with HSK pathogenesis. In view of the high potency of 6-TG, low cytotoxicity, targeting a distinct therapeutic target, we suggest that 6-TG is a potential candidate for development as a therapeutic agent for HSK therapy.

9.
Mol Ther ; 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34762817

RESUMO

Zika virus (ZIKV), a flavivirus associated with neurological disorders, constitutes a global health threat. During pregnancy, ZIKV traverses the placenta and causes congenital disease such as microcephaly and Guillain-Barré syndrome in newborns. To develop a specific antiviral therapy against ZIKV-induced microcephaly that could cross placental and blood-brain barriers, we designed targeted small extracellular vesicles (sEVs) encapsulating antiviral siRNA (small interfering RNA) to inhibit ZIKV. The neuro-specific targeting was achieved by engineering EVs membrane protein lamp2b fused with a neuron-specific rabies virus glycoprotein derived peptide (RVG). Intravenous administration of the RVG-engineered sEVs loaded with siRNA (ZIKV-specific siRNA) protected pregnant AG6 mice against vertical transmission of ZIKV. Particularly, sEVsRVG-siRNA traversed placental and blood-brain barriers and suppressed ZIKV infection in fetal brains. Moreover, sEVsRVG-siRNA alleviated the neuroinflammation and neurological damage caused by ZIKV in the fetal mouse model. In general, we developed a sEVs-based targeted system of antiviral therapy for brain and fetal brain infections.

10.
Genome Biol Evol ; 13(11)2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34791222

RESUMO

Transposable elements (TEs) comprise a large proportion of the eukaryote genomes. Yet it remains poorly understood how TEs influence the fitness of the hosts carrying them. Here, we empirically test the impact of TEs on the host fitness in the fission yeast Schizosaccharomyces pombe. We find that two families of TEs (Tf1 and Tf2 elements), both of which belong to long terminal repeat retrotransposons, are highly polymorphic among individual S. pombe strains. Only 13 complete Tf2 elements are identified in S. pombe laboratory strain 972. These 13 Tf2 elements integrated into host genomes in very recent time and are segregating within the S. pombe population. Through knocking out each of the 13 Tf2 elements in S. pombe strain 972, we find Tf2 knockout does not affect the host fitness, and Tf2 elements do not alter the expression of nearby genes. Challenged by diverse forms of stress, the Tf2 knockout strains do not exhibit different growth rates from wild-type strain. Together, we conclude that segregating complete Tf2 elements insertions are largely neutral to host fitness in the fission yeast. Our study provides genome-wide empirical support for the selfish nature of TEs in fission yeast.

11.
Artigo em Inglês | MEDLINE | ID: mdl-34622272

RESUMO

OBJECTIVE: Cognitive improvement after antipsychotic agents in patients with schizophrenia (SCZ) appears to involve redox regulation through neurotrophins such as brain derived neurotropic factor (BDNF). This study examined whether cognitive improvement was associated with the increase in superoxide dismutase (SOD), and whether higher levels of BDNF could have a permissive role in allowing SOD to improve cognition. METHODS: We examined this hypothesis in 183 drug-naïve first episode (DNFE) SCZ patients taking risperidone monotherapy for 12 weeks. We measured total copper-zinc superoxide dismutase (CuZn-SOD), manganese superoxide dismutase (Mn-SOD) and SOD activities and BDNF levels in these patients and compared their levels to 152 healthy controls. We assessed cognitive functioning and clinical symptoms at baseline and 12-week follow-up. RESULTS: After treatment with risperidone, CuZn-SOD activity was significantly increased, and BDNF levels were slightly increased. Increased CuZn-SOD activity was associated with the cognitive effectiveness of risperidone monotherapy. The BDNF levels and SOD activities were correlated at baseline, but not correlated after 12-week treatment. Furthermore, baseline CuZn-SOD activity positively correlated with improvement on the delayed memory subscale of the RBANS only in high BDNF subgroup. CONCLUSIONS: Our longitudinal study suggests that risperidone can enhance SOD activity and that in combination with higher baseline BDNF levels acting in a permissive role can improve cognitive impairments in SCZ. Greater baseline CuZn-SOD activity also may have predictive value for cognitive improvement of delayed memory in SCZ patients getting risperidone treatment.

12.
Cell Rep ; 37(3): 109869, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34644535

RESUMO

The dramatically expanding coronavirus disease 2019 (COVID-19) needs multiple effective countermeasures. Neutralizing nanobodies (Nbs) are a potential therapeutic strategy for treating COVID-19. Here, we characterize several receptor binding domain (RBD)-specific Nbs isolated from an Nb library derived from an alpaca immunized with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (S); among them, three Nbs exhibit picomolar potency against SARS-CoV-2 live virus, pseudotyped viruses, and circulating SARS-CoV-2 variants. To improve their efficacy, various configurations of Nbs are engineered. Nb15-NbH-Nb15, a trimer constituted of three Nbs, is constructed to be bispecific for human serum albumin (HSA) and RBD of SARS-CoV-2. Nb15-NbH-Nb15 exhibits single-digit ng/ml neutralization potency against the wild-type and Delta variants of SARS-CoV-2 with a long half-life in vivo. In addition, we show that intranasal administration of Nb15-NbH-Nb15 provides effective protection for both prophylactic and therapeutic purposes against SARS-CoV-2 infection in transgenic hACE2 mice. Nb15-NbH-Nb15 is a potential candidate for both the prevention and treatment of SARS-CoV-2 through respiratory administration.


Assuntos
Administração Intranasal , Enzima de Conversão de Angiotensina 2/imunologia , Anticorpos Biespecíficos/imunologia , COVID-19/imunologia , SARS-CoV-2 , Animais , Anticorpos Monoclonais/química , Anticorpos Neutralizantes , Anticorpos Antivirais/imunologia , Camelídeos Americanos , Epitopos/química , Feminino , Humanos , Cinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Testes de Neutralização , Ligação Proteica , Domínios Proteicos , Engenharia de Proteínas/métodos , Albumina Sérica Humana/química , Anticorpos de Domínio Único , Glicoproteína da Espícula de Coronavírus/imunologia
13.
Materials (Basel) ; 14(17)2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34500994

RESUMO

Conically corrugated tube is a new type of high-efficiency heat exchange tube. In this paper, the mechanical and heat transfer properties of conically corrugated tubes formed by the cold rolling of smooth tubes are studied through experimental measurement and numerical simulation to lay the foundations for applying the tubes in heat exchangers. The results show that while conically corrugated tube has a lower axial elastic stiffness compared with smooth tube, conically corrugated tube has a higher yield strength and ultimate strength. Unlike smooth tubes, conically corrugated tubes develop three-dimensional stresses when an axial tensile load is applied to them. In addition, the heat transfer coefficient of conically corrugated tube is 15%, 17%, and 115% higher than that of spiral grooved tube, convergent divergent tube, and smooth tube, respectively. Finally, the correlation equations of the axial stress concentration factor, stiffness equivalent coefficient, Nusselt number, and flow resistance coefficient of conically corrugated tubes are obtained for engineering application.

14.
J Mol Graph Model ; 109: 108029, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34517169

RESUMO

Metalloprotease ADAMTS13 specifically cleaves VWF (von Willebrand Factor) to prevent excessive platelet aggregation and thrombus formation at the sites of vascular injury. To avoid non-specific cleavage, ADAMTS13 has the auto-inhibition effect in which the Spacer domain in N-terminal interacts with the CUB1 domain in C-terminal, resulting in decreased proteolytic activity. Previous studies reported that exosite-3 in the Spacer domain was a key binding site in the Spacer-CUB1 interaction. When exosite-3 was mutated (R660K/F592Y/R568K/Y661F/Y665F, GOF), the auto-inhibition of ADAMTS13 was disrupted and the enzymatic activity was markedly increased. However, the characteristics of the Spacer-CUB1 interaction is not fully understood. Here, we constructed the model of Spacer-CUB1 complex by homologous modeling and molecular docking to characterize the Spacer-CUB1 binding and predict key amino acid residues via molecular dynamics simulation. Our data showed that G607-S610 was a non-reported potential binding site in the Spacer domain; GOF mutation attenuated the formation of hydrogen bond between exosite-3 and the CUB1 domain; Residues E1231, R1251, L1258, D1259 and T1261 in the CUB1 domain might play an important role in the Spacer-CUB1 interaction. Our study advances the understanding of the structural basis of the auto-inhibition of ADAMTS13 and provides information about the key residues in the binding interface.


Assuntos
Simulação de Dinâmica Molecular , Fator de von Willebrand , Sítios de Ligação , Simulação de Acoplamento Molecular , Proteólise , Fator de von Willebrand/metabolismo
15.
Front Microbiol ; 12: 722748, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531841

RESUMO

Herpes simplex virus type 1 (HSV-1) infection induces various clinical disorders, such as herpes simplex encephalitis (HSE), herpes simplex keratitis (HSK), and genital herpes. In clinical intervention, acyclovir (ACV) is the major therapeutic drug used to suppress HSV-1; however, ACV-resistant strains have gradually increased. In the present study, harringtonine (HT) significantly inhibited infection of HSV-1 as well as two ACV-resistant strains, including HSV-1 blue and HSV-1 153. Time-of-drug addition assay further revealed that HT mainly reduced the early stage of HSV-1 infection. We also demonstrated that HT mainly affected herpes virus entry mediator (HVEM) expression as shown by qPCR, Western Blot, and Immunofluorescence. Collectively, HT showed antiviral activity against HSV-1 and ACV-resistant strains by targeting HVEM and could be a promising therapeutic candidate for mitigating HSV-1-induced-pathogenesis.

16.
Front Cell Infect Microbiol ; 11: 725392, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34485180

RESUMO

Previous studies have shown that DEAD (Glu-Asp-Ala-Glu)-box RNA helicases play important roles in viral infection, either as cytosolic sensors of pathogenic molecules or as essential host factors against viral infection. In the current study, we found that DDX6, an RNA helicase belonging to the DEAD-box family of helicase, exhibited anti-Enterovirus 71 activity through augmenting RIG-I-mediated type-I IFN response. Moreover, DDX6 binds viral RNA to form an RNA-protein complex to positively regulate the RIG-I-mediated interferon response; however, EV71 has evolved a strategy to antagonize the antiviral effect of DDX6 by proteolytic degradation of the molecule through its non-structural protein 2A, a virus-encoded protease.


Assuntos
RNA Helicases DEAD-box , Infecções por Enterovirus/imunologia , Interferon Tipo I , Proteínas Proto-Oncogênicas , Proteína DEAD-box 58 , Enterovirus Humano A , Humanos , Interferon Tipo I/imunologia , Helicase IFIH1 Induzida por Interferon , RNA Viral , Receptores Imunológicos
17.
PLoS One ; 16(8): e0255473, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34343193

RESUMO

BACKGROUND: Applicability of totally implantable venous access port (TIVAP) and peripherally inserted central venous catheter (PICC) in non-hematological malignancies patients remains controversial. METHODS: A systematic studies search in the public databases PubMed, EMBASE, Wan Fang, CNKI (China National Knowledge Infrastructure), the Cochrane Library and Google Scholar (updated to May 1, 2020) was performed to identify eligible researches. All statistical tests in this meta-analysis were performed using Stata 12.0 software (Stata Corp, College Station, TX). A P value less than 0.05 was considered statistically significant. RESULTS: Thirteen studies were included in this final meta-analysis. The pooled data showed that compared with PICC, TIVAP was associated with a higher first-puncture success rate (OR:2.028, 95%CI:1.25-3.289, P<0.05), a lower accidental removal rate (OR:0.447, 95%CI:0.225-0.889, P<0.05) and lower complication rates, including infection (OR:0.570, 95%CI: 0.383-0.850, P<0.05), occlusion (OR:0.172, 95%CI:0.092-0.324, P<0.05), malposition (OR:0.279, 95%CI:0.128-0.608, P<0.05), thrombosis (OR:0.191, 95%CI, 0.111-0.329, P<0.05), phlebitis (OR:0.102, 95%CI, 0.038-0.273, P<0.05), allergy (OR:0.155, 95%CI:0.035-0.696, P<0.05). However, no difference was found in catheter life span (P>0.05) and extravasation (P>0.05). Moreover, TIVAP is more expensive compared with PICC in six-month use (weighted mean difference:3.132, 95%CI:2.434-3.83, P<0.05), but is much similar in 12 months use (P>0.05). CONCLUSION: For the patients with non-hematological malignancies, TIVAP was superior to PICC in the data related to placement and the incidence of complications. Meanwhile, TIVAP is more expensive compared with PICC in six-month use, but it is much similar in twelve-month use.


Assuntos
Cateterismo Venoso Central/efeitos adversos , Cateterismo Periférico/efeitos adversos , Neoplasias/terapia , Infecções Relacionadas a Cateter/epidemiologia , Cateterismo Venoso Central/economia , Cateterismo Periférico/economia , Humanos , Incidência , Flebite/epidemiologia , Flebite/etiologia , Trombose Venosa/epidemiologia , Trombose Venosa/etiologia
18.
Nat Methods ; 18(9): 1013-1026, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34446922

RESUMO

Extracellular vesicles (EVs) are nano-sized lipid bilayer vesicles released by virtually every cell type. EVs have diverse biological activities, ranging from roles in development and homeostasis to cancer progression, which has spurred the development of EVs as disease biomarkers and drug nanovehicles. Owing to the small size of EVs, however, most studies have relied on isolation and biochemical analysis of bulk EVs separated from biofluids. Although informative, these approaches do not capture the dynamics of EV release, biodistribution, and other contributions to pathophysiology. Recent advances in live and high-resolution microscopy techniques, combined with innovative EV labeling strategies and reporter systems, provide new tools to study EVs in vivo in their physiological environment and at the single-vesicle level. Here we critically review the latest advances and challenges in EV imaging, and identify urgent, outstanding questions in our quest to unravel EV biology and therapeutic applications.


Assuntos
Vesículas Extracelulares , Microscopia/métodos , Animais , Corantes/química , Epitopos , Vesículas Extracelulares/química , Vesículas Extracelulares/patologia , Vesículas Extracelulares/fisiologia , Corantes Fluorescentes/química , Humanos
19.
J Immunol ; 207(2): 590-601, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34244294

RESUMO

The nonstructural protein (NSs) of severe fever with thrombocytopenia syndrome virus (SFTSV) plays multiple functions in the virus life cycle. Proteomic screening for host proteins interacting with NSs identified the cellular protein LSm14A. LSm14A, a member of the LSm family involved in RNA processing in the processing bodies, binds to viral RNA or synthetic homolog and mediates IFN regulatory factor 3 activation and IFN-ß induction. NSs interacted with and colocalized with LSm14A, and this interaction effectively inhibited downstream phosphorylation and dimerization of IFN regulatory factor 3, resulting in the suppression of antiviral signaling and IFN induction in several cell types of human origin. Knockdown of NSs resulted in the suppression of SFTSV replication in host cells. Viral RNA bound to LSm14A-NSs protein complex during the interaction. A newly discovered LRRD motif of NSs functioned to interact with LSm14A. Altogether, our data demonstrated a mechanism used by SFTSV to inhibit host innate immune response.


Assuntos
Antivirais/metabolismo , Phlebovirus/metabolismo , Ribonucleoproteínas/metabolismo , Febre Grave com Síndrome de Trombocitopenia/metabolismo , Proteínas não Estruturais Virais/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Células HEK293 , Células HeLa , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Imunidade Inata/fisiologia , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/fisiologia , Proteômica/métodos , Transdução de Sinais/fisiologia
20.
Front Immunol ; 12: 678318, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248960

RESUMO

Cervical cancer caused by human papillomavirus (HPV) infections is the fourth most common cancer in women worldwide. Current prophylactic HPV vaccines have achieved promising success in preventing HPV infection. However, still 570,000 new cases were reported in 2018. The current primary treatment for the patient with cervical cancer is either surgery or chemoradiotherapy. Cervical cancer still lacks standard medical therapy. HPV18 induced cervical cancer has the worst prognosis and high mortality compared to other HPV infections. The development of HPV18 related with cervical malignancy requires the persistent infection of cervical-vaginal epithelium by HPV18 subtype, which can take years to transform the epithelium. This period of repeated infection provides a window for therapeutic intervention. Neutralizing antibodies formulated as topical agents that inhibit HPV18 infection should reduce the chance of cervical malignancy. We previously demonstrated that potent neutralizing anti-sera against HPV18 infection were induced by HPV18 viral like particle (VLP) generated in mammalian cells. We, therefore, isolated two potent neutralizing antibodies, 2A12 and 8H4, from over 3,810 hybridomas prepared from mice immunized with HPV18 VLP. 2A12 and 8H4 exhibited excellent potency, with 50% virus-inhibitory concentrations (IC50) of 0.4 and 0.9 ng/ml, respectively. Furthermore, 2A12 and 8H4 recognized distinct and non-overlapping quaternary epitopes and bound specifically with HPV18. Humanized 2A12 (Hu2A12) retained comparable neutralizing activity against HPV18 infection in various acidic pH settings and in hydrogel formulation with IC50 values of 0.04 to 0.77 ng/ml, indicating that Hu2A12 will be a promising candidate for clinical development as a topical vaginal biopharmaceutical agent against HPV18 infection.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Papillomavirus Humano 18 , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/imunologia , Neoplasias do Colo do Útero/etiologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Gerenciamento Clínico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Relação Dose-Resposta a Droga , Relação Dose-Resposta Imunológica , Feminino , Papillomavirus Humano 18/fisiologia , Humanos , Imunização , Camundongos , Terapia de Alvo Molecular , Testes de Neutralização , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/imunologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Vacinas de Partículas Semelhantes a Vírus/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
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