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1.
Stem Cell Res Ther ; 12(1): 534, 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34627378

RESUMO

BACKGROUND: Mesenchymal stromal cells (MSCs) transplantation showed promising therapeutic results in liver fibrosis. However, efficient cell delivery method is urgently needed and the therapeutic mechanism remains unclear. This study focused on developing a minimally invasive open-flow microperfusion (OFM) technique, which combined orthotopic transplantation of human umbilical cord-derived (hUC)-MSCs to liver and in vivo monitoring of liver microenvironment in mice with CCl4-induced liver fibrosis. METHODS: The therapeutic potential of OFM route was evaluated by comparing OFM with intravenous (IV) injection route in terms of hUC-MSCs engraftment at the fibrosis liver, liver histopathological features, liver function and fibrotic markers expression after hUC-MSCs administration. OFM was also applied to sample liver interstitial fluid in vivo, and subsequent metabolomic analysis was performed to investigate metabolic changes in liver microenvironment. RESULTS: Compared with IV route, OFM route caused more hUC-MSCs accumulation in the liver and was more effective in improving the remodeling of liver structure and reducing collagen deposition in fibrotic liver. OFM transplantation of hUC-MSCs reduced blood ALT, AST, ALP and TBIL levels and increased ALB levels, to a greater extent than IV route. And OFM route appeared to have a more pronounced effect on ameliorating the CCl4-induced up-regulation of the fibrotic markers, such as α-SMA, collagen I and TGF-ß. In vivo monitoring of liver microenvironment demonstrated the metabolic perturbations induced by pathological condition and treatment intervention. Two metabolites and eight metabolic pathways, which were most likely to be associated with the liver fibrosis progression, were regulated by hUC-MSCs administration. CONCLUSION: The results demonstrated that the novel OFM technique would be useful for hUC-MSCs transplantation in liver fibrosis treatment and for monitoring of the liver metabolic microenvironment to explore the underlying therapeutic mechanisms.

2.
Proc Natl Acad Sci U S A ; 118(41)2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34607953

RESUMO

Chemokine production by epithelial cells is important for neutrophil recruitment during viral infection, the appropriate regulation of which is critical for restraining inflammation and attenuating subsequent tissue damage. Epithelial cell expression of long noncoding RNAs (lncRNAs), RNA-binding proteins, and their functional interactions during viral infection and inflammation remain to be fully understood. Here, we identified an inducible lncRNA in the Cxcl2 gene locus, lnc-Cxcl2, which could selectively inhibit Cxcl2 expression in mouse lung epithelial cells but not in macrophages. lnc-Cxcl2-deficient mice exhibited increased Cxcl2 expression, enhanced neutrophils recruitment, and more severe inflammation in the lung after influenza virus infection. Mechanistically, nucleus-localized lnc-Cxcl2 bound to Cxcl2 promoter, recruited a ribonucleoprotein La, which inhibited the chromatin accessibility of chemokine promoters, and consequently inhibited Cxcl2 transcription in cis However, unlike mouse lnc-Cxcl2, human lnc-CXCL2-4-1 inhibited multiple immune cytokine expressions including chemokines in human lung epithelial cells. Together, our results demonstrate a self-protecting mechanism within epithelial cells to restrain chemokine and neutrophil-mediated inflammation, providing clues for better understanding chemokine regulation and epithelial cell function in lung viral infection.

3.
Nanoscale ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34613321

RESUMO

Coupled with renewable electricity, electrochemical reduction of CO2 (CO2RR) is one of the sustainable strategies for the production of value-added carbon-containing chemicals. Cu-based catalysts are by far the most widely studied electrocatalytic materials for CO2RR, although they exhibit poor performance in CO selectivity. In this work, we have designed a Cu1.96S/Cu tandem structure via a combined electrospinning and calcination method. The catalyst enables CO2 reduction to CO with high selectivity >80% with a production rate of 34.6 µmol h-1 cm-2 at -0.68 V vs. RHE, which is superior to most of the Cu-based catalysts under the same operation conditions. Theoretical simulations show that the improved CO2RR performance stems from the Cu1.96S/Cu tandem structure in which Cu acts as a *CO-producing site and the neighboring Cu1.96S facilitates the following *CO desorption step. This work opens new possibilities for exploiting tandem catalysis mechanisms.

4.
New Phytol ; 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34665465

RESUMO

ALUMINUM-ACTIVATED MALATE TRANSPORTER1 (ALMT1)-mediated malate exudation from roots is critical for aluminum (Al) resistance in Arabidopsis. Its upstream molecular signaling regulation is not yet well understood. The role of CALMODULIN-LIKE24 (CML24) in Al-inhibited root growth and downstream molecular regulation of ALMT1-meditaed Al resistance was investigated. CML24 confers Al resistance demonstrated by an increased root growth inhibition of the cml24 loss-of-function mutant under Al stress. This occurs mainly through the regulation of the ALMT1-mediated malate exudation from roots. The mutation and overexpression of CML24 leads to an elevated and reduced Al accumulation in the cell-wall of roots, respectively. Al stress induced both transcript and protein abundance of CML24 in root tips, especially in the TZ. CML24 interacts with CALMODULIN BINDING TRANSCRIPTION ACTIVATOR2 (CAMTA2) and promotes its transcriptional activity in the regulation of ALMT1 expression. This results in an enhanced malate exudation from roots and less root-growth inhibition under Al stress. Both CML24 and CAMTA2 interacted with WRKY46 suppressing the transcriptional repression of ALMT1 by WRKY46. The study provides novel insights into understanding of the upstream molecular signaling of the ALMT1-depdendent Al resistance.

5.
Commun Biol ; 4(1): 1196, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645933

RESUMO

Emerging mutations in SARS-CoV-2 cause several waves of COVID-19 pandemic. Here we investigate the infectivity and antigenicity of ten emerging SARS-CoV-2 variants-B.1.1.298, B.1.1.7(Alpha), B.1.351(Beta), P.1(Gamma), P.2(Zeta), B.1.429(Epsilon), B.1.525(Eta), B.1.526-1(Iota), B.1.526-2(Iota), B.1.1.318-and seven corresponding single amino acid mutations in the receptor-binding domain using SARS-CoV-2 pseudovirus. The results indicate that the pseudovirus of most of the SARS-CoV-2 variants (except B.1.1.298) display slightly increased infectivity in human and monkey cell lines, especially B.1.351, B.1.525 and B.1.526 in Calu-3 cells. The K417N/T, N501Y, or E484K-carrying variants exhibit significantly increased abilities to infect mouse ACE2-overexpressing cells. The activities of furin, TMPRSS2, and cathepsin L are increased against most of the variants. RBD amino acid mutations comprising K417T/N, L452R, Y453F, S477N, E484K, and N501Y cause significant immune escape from 11 of 13 monoclonal antibodies. However, the resistance to neutralization by convalescent serum or vaccines elicited serum is mainly caused by the E484K mutation. The convalescent serum from B.1.1.7- and B.1.351-infected patients neutralized the variants themselves better than other SARS-CoV-2 variants. Our study provides insights regarding therapeutic antibodies and vaccines, and highlights the importance of E484K mutation.

6.
J Am Heart Assoc ; 10(20): e021436, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34612059

RESUMO

Background We examined the association of long-term exposure to air pollution and road traffic noise with incident heart failure (HF). Methods And Results Using data on female nurses from the Danish Nurse Cohort (aged >44 years), we investigated associations between 3-year mean exposures to air pollution and road traffic noise and incident HF using Cox regression models, adjusting for relevant confounders. Incidence of HF was defined as the first hospital contact (inpatient, outpatient, or emergency) between cohort baseline (1993 or 1999) and December 31, 2014, based on the Danish National Patient Register. Annual mean levels of particulate matter with a diameter <2.5 µm since 1990 and NO2 and road traffic noise since 1970 were estimated at participants' residences. Of the 22 189 nurses, 484 developed HF. We detected associations with all 3 pollutants, with hazard ratios (HRs) of 1.17 (95% CI, 1.01-1.36), 1.10 (95% CI, 0.99-1.22), and 1.12 (95% CI, 0.99-1.26) per increase of 5.1 µg/m3 in particulate matter with a diameter <2.5 µm, 8.6 µg/m3 in NO2, and 9.3 dB in road traffic noise, respectively. We observed an enhanced risk of HF incidence for those exposed to high levels of the 3 pollutants; however, the effect modification of coexposure was not statistically significant. Former smokers and nurses with hypertension showed the strongest associations with particulate matter with a diameter <2.5 µm (Peffect modification<0.05). Conclusions We found that long-term exposures to air pollution and road traffic noise were independently associated with HF.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34499729

RESUMO

BACKGROUND: The increasing use of colistin causes a serious breach in our last line of defence against MDR Gram-negative pathogens. Our previous study showed that CpxR overexpression increases the susceptibility of acrB and cpxR double-deleted Salmonella enterica serovar Typhimurium to colistin. OBJECTIVES: To identify the mechanism of CpxAR and efflux pumps that synergistically enhance the susceptibility of S. Typhimurium to colistin. METHODS: A series of cpxR- and tolC-deleted mutants and a cpxR-complemented strain from a multidrug-susceptible standard strain of S. Typhimurium (JS) were generated in our previous study. Herein, we investigated the susceptibility of these strains to colistin through the broth microdilution method, time-kill curves and survival assays. Growth curves were measured by OD600 in LB broth, tryptone-soy broth (TSB) and M9-glucose (0.2%) minimal media. Finally, molecular mechanisms underlying the mode of action were elucidated by transcriptomic analysis. RESULTS: We found that in contrast to JS (0.8 mg/L), the MIC of colistin for JSΔtolC::kan showed a 16-fold decrease (0.05 mg/L). Notably, JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR were associated with a 256-fold decrease (0.0031 mg/L) compared with JS. Growth curves identified that JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR displayed a markedly lower growth rate and poorer adaptability. In addition, time-kill curves and survival assays showed that JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR were more susceptible to colistin. Lastly, double deletion of cpxR and tolC enhanced oxidative damage through promoting oxidative phosphorylation, the tricarboxylic acid (TCA) cycle and trimethylamine N-oxide (TMAO) respiration. CONCLUSIONS: Our findings revealed that double deletion of cpxR and tolC significantly increases the susceptibility of S. Typhimurium to colistin.

8.
Am J Addict ; 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34532935

RESUMO

BACKGROUND AND OBJECTIVES: The prevalence of problematic Internet use (PIU) in the post-COVID-19 pandemic era is not known. This cross-sectional study aimed to determine the prevalence of PIU among baccalaureate nursing students (hereafter: nursing students) in the post-COVID-19 era. METHODS: A total of 1070 nursing students were consecutively invited to participate in this study from the nursing schools of five universities. PIU and quality of life (QOL) were assessed using the Internet Addiction Test (IAT) and the World Health Organization Quality of Life Scale Brief Version (WHOQOL-BREF), respectively. t Tests, χ2 , tests, and Kruskal-Wallis tests were used to compare basic demographic and clinical characteristics between participants with and without PIU. Binary logistic regression analysis was used to examine independent correlates. RESULTS: The prevalence of PIU was 23.3% (95% confidence interval [CI]: 20.7%-25.8%). Multiple logistic regression analysis revealed that second- (p = .024) and third-year (p = .012) students were more likely to suffer from PIU compared with first year students. Students with more severe depressive (p = .014) and anxiety symptoms (p = .011) were independently and significantly associated with more severe PIU. After controlling for covariates, nursing students with PIU had a lower overall QOL score (p = .002). CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Problematic Internet use (PIU) was common among nursing students in the post-COVID-19 era. Considering the negative impact of PIU on QOL and academic performance, regular screening should be conducted and effective interventions implemented for nursing students with PIU. This was the first study on the prevalence of PIU among nursing students in the post-COVID-19 era. The findings of this study could help health professionals and education authorities to understand the patterns of PIU and its influence on QOL among nursing students and to allocate health resources and develop effective measures to reduce the risk of PIU in this population.

9.
Inorg Chem ; 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34523919

RESUMO

The construction of a porous carbon structure with a high specific surface area is conducive to enhanced electrocatalytic activity due to the accessibility of active sites and improvement of the mass transfer. Herein, we explored the possibility of using micelles of mesoporous silica (MCM-48) as the carbon source to generate porous carbon under the confinement of MCM-48 channels. The complexes formed by Co2+ and 4,4'-bipyridine were in situ incorporated into the micelles to derive Co-related active sites (Co-Nx, Co, and Co3O4) for catalyzing the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). After pyrolysis in the N2 atmosphere and subsequent removal of the MCM-48 skeleton, the target porous carbon electrocatalyst was obtained, which exhibited promising performance for both ORR and OER and has great potential as the cathode material for Zn-air battery application. This work not only confirms the effectiveness of using the micelles of MCM-48 as the carbon source for preparing the porous carbon materials, but also provides a new platform for design and synthesis of structurally controllable materials for energy-related electrocatalytic applications.

10.
BMJ ; 374: n1904, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34470785

RESUMO

OBJECTIVE: To investigate the associations between air pollution and mortality, focusing on associations below current European Union, United States, and World Health Organization standards and guidelines. DESIGN: Pooled analysis of eight cohorts. SETTING: Multicentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) in six European countries. PARTICIPANTS: 325 367 adults from the general population recruited mostly in the 1990s or 2000s with detailed lifestyle data. Stratified Cox proportional hazard models were used to analyse the associations between air pollution and mortality. Western Europe-wide land use regression models were used to characterise residential air pollution concentrations of ambient fine particulate matter (PM2.5), nitrogen dioxide, ozone, and black carbon. MAIN OUTCOME MEASURES: Deaths due to natural causes and cause specific mortality. RESULTS: Of 325 367 adults followed-up for an average of 19.5 years, 47 131 deaths were observed. Higher exposure to PM2.5, nitrogen dioxide, and black carbon was associated with significantly increased risk of almost all outcomes. An increase of 5 µg/m3 in PM2.5 was associated with 13% (95% confidence interval 10.6% to 15.5%) increase in natural deaths; the corresponding figure for a 10 µg/m3 increase in nitrogen dioxide was 8.6% (7% to 10.2%). Associations with PM2.5, nitrogen dioxide, and black carbon remained significant at low concentrations. For participants with exposures below the US standard of 12 µg/m3 an increase of 5 µg/m3 in PM2.5 was associated with 29.6% (14% to 47.4%) increase in natural deaths. CONCLUSIONS: Our study contributes to the evidence that outdoor air pollution is associated with mortality even at low pollution levels below the current European and North American standards and WHO guideline values. These findings are therefore an important contribution to the debate about revision of air quality limits, guidelines, and standards, and future assessments by the Global Burden of Disease.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Doenças Cardiovasculares/mortalidade , Exposição Ambiental/efeitos adversos , Doenças não Transmissíveis/mortalidade , Europa (Continente) , Humanos
11.
Lancet Planet Health ; 5(9): e620-e632, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34508683

RESUMO

BACKGROUND: Long-term exposure to outdoor air pollution increases the risk of cardiovascular disease, but evidence is unclear on the health effects of exposure to pollutant concentrations lower than current EU and US standards and WHO guideline limits. Within the multicentre study Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), we investigated the associations of long-term exposures to fine particulate matter (PM2·5), nitrogen dioxide (NO2), black carbon, and warm-season ozone (O3) with the incidence of stroke and acute coronary heart disease. METHODS: We did a pooled analysis of individual data from six population-based cohort studies within ELAPSE, from Sweden, Denmark, the Netherlands, and Germany (recruited 1992-2004), and harmonised individual and area-level variables between cohorts. Participants (all adults) were followed up until migration from the study area, death, or incident stroke or coronary heart disease, or end of follow-up (2011-15). Mean 2010 air pollution concentrations from centrally developed European-wide land use regression models were assigned to participants' baseline residential addresses. We used Cox proportional hazards models with increasing levels of covariate adjustment to investigate the association of air pollution exposure with incidence of stroke and coronary heart disease. We assessed the shape of the concentration-response function and did subset analyses of participants living at pollutant concentrations lower than predefined values. FINDINGS: From the pooled ELAPSE cohorts, data on 137 148 participants were analysed in our fully adjusted model. During a median follow-up of 17·2 years (IQR 13·8-19·5), we observed 6950 incident events of stroke and 10 071 incident events of coronary heart disease. Incidence of stroke was associated with PM2·5 (hazard ratio 1·10 [95% CI 1·01-1·21] per 5 µg/m3 increase), NO2 (1·08 [1·04-1·12] per 10 µg/m3 increase), and black carbon (1·06 [1·02-1·10] per 0·5 10-5/m increase), whereas coronary heart disease incidence was only associated with NO2 (1·04 [1·01-1·07]). Warm-season O3 was not associated with an increase in either outcome. Concentration-response curves indicated no evidence of a threshold below which air pollutant concentrations are not harmful for cardiovascular health. Effect estimates for PM2·5 and NO2 remained elevated even when restricting analyses to participants exposed to pollutant concentrations lower than the EU limit values of 25 µg/m3 for PM2·5 and 40 µg/m3 for NO2. INTERPRETATION: Long-term air pollution exposure was associated with incidence of stroke and coronary heart disease, even at pollutant concentrations lower than current limit values. FUNDING: Health Effects Institute.

12.
Spectrochim Acta A Mol Biomol Spectrosc ; 265: 120365, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34509893

RESUMO

Sulfur quantum dots (S-dots) show great potential for applications in various field, due to their favorable biocompatibility, high stability, and antibacterial properties. However, the use of S-dots in chemical sensing is limited by the lack of functional groups on the surface. In this work, a fluorescence glutathione (GSH) assay is developed based on the GSH modulated quenching effect of Cu2O nanoparticles (NP) on S-dots. The fluorescence of S-dots is effectively quenched after forming complex with Cu2O NP through a static quenching effect (SQE). Introducing of GSH can trigger the decomposition of Cu2O NP into GSH-Cu(I) complex, which leads to the weaken of SQE and the partial recover of the fluorescence. The intensity of recovered fluorescence shows a positive correlation with the concentration of GSH in the concentration range of 20 to 500 µM. The fluorescence GSH assay shows excellent selectivity and robustness towards various interferences and high concentration salt, which endow the successful detection of GSH in human blood sample. The presented results provide a new door for the design of fluorescence assays, which also provides a platform for the applications in nanomedicine and environmental science.

13.
Vaccine ; 39(41): 6050-6056, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34521552

RESUMO

The development of an effective vaccine to control the global coronavirus disease-2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2) is of utmost importance. In this study, a synthetic DNA-based vaccine candidate, known as pSV10-SARS-CoV-2, expressing the SARS-CoV-2 spike protein was designed and tested in 39 BALB/c mice with BC01, an adjuvant derived from unmethylated CpG motif-containing DNA fragments from the Bacillus Calmette-Guerin genome. Mice vaccinated with pSV10-SARS-CoV-2 with BC01 produced early neutralizing antibodies and developed stronger humoral and cellular immune responses compared to mice that received the DNA vaccine only. Moreover, sera from mice vaccinated with pSV10-SARS-CoV-2 with BC01 can neutralize certain variants, including 614G, 614G + 472 V, 452R, 483A, 501Y.V2, and B.1.1.7. The results of this study demonstrate that the addition of BC01 to a DNA-vaccine for COVID-19 could elicit more effective neutralizing antibody titers for disease prevention.


Assuntos
COVID-19 , Vacinas de DNA , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Vacina BCG , Vacinas contra COVID-19 , DNA , Genômica , Humanos , Imunidade Celular , Camundongos , Camundongos Endogâmicos BALB C , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética
14.
J Endourol ; 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34549603

RESUMO

BACKGROUND: The mean length of stay (LOS) following minimally invasive radical prostatectomy (MI-RP) is less than 2 days. Our main objective was to utilize the National Surgical Quality Improvement Program Database (NSQIP) to evaluate preoperative factors that may contribute to prolonged hospital stay and readmission. MATERIALS AND METHODS: Utilizing the NSQIP database, records for surgery with the Current Procedural Terminology (CPT) code 55866 (prostatectomy) between 2007 and 2017 were evaluated. Chi-square and t-tests were used to assess the effects of preoperative factors on prolonged LOS and rates of hospital readmission within 30 days. Odds ratios, p-values, and confidence intervals were determined using multivariable logistic regression. RESULTS: 40,764 patients underwent MI-RP between 2007 and 2017. Of these, 11.7% reported a LOS of more than 2 days, while 3.9% of patients were readmitted to the hospital within 30 days. Preoperative congestive heart failure within 30 days of surgery was shown to be strongly associated with both prolonged LOS (OR = 6.16) and readmission (OR = 3.28). Bleeding requiring transfusion was demonstrated to be the most significant postoperative factor for prolonged LOS (OR= 23.9), while unplanned intubation was shown to be the most significant postoperative factor for readmission (OR=57.1). BMI over 30 was associated with both prolonged LOS and increase in readmission. CONCLUSIONS: Upon NSQIP database analysis, cardiopulmonary factors and BMI were demonstrated to have negative impacts on postoperative quality indicators. Patients with comorbidities should be counselled preoperatively concerning their individual risk factors. Mitigation of these factors is important in ensuring optimal outcomes.

15.
BMC Oral Health ; 21(1): 463, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556116

RESUMO

BACKGROUND: To research the first-order features of apparent diffusion coefficient (ADC) values on diffusion-weighted magnetic resonance imaging (DWI) in maxillofacial malignant mesenchymal tumours. METHODS: The clinical data of 12 patients with rare malignant mesenchymal tumours of the maxillofacial region (6 cases of sarcoma and 6 cases of lymphoma) treated in the hospital from May 2018 to June 2020 and were confirmed by postoperative pathology were retrospectively analyzed. The patients were all examined by 1.5T magnetic resonance imaging. PyRadiomics were used to extract radiomics imaging first-order features. Group differences in quantitative variables were examined using independent-samples t-tests. RESULTS: The voxels number of ADCmean and ADCmedian of sarcoma tissues were 44.9124 and 44.2064, respectively, significantly higher than those in lymphoma tissues (ADCmean (- 68.8379) and ADCmedian (- 74.0045)), the difference considered statistically significant, so do the ADCkurt and ADCskew. CONCLUSIONS: The statistical difference of ADCmean and ADCmedian is significant, it is consistent with the outcome of the manual measurement of the ADC mean value of the most significant cross-section of twelve cases of lymphoma. Development of tumour volume based on the ADC parameter map of DWI demonstrates that the first-order ADC radiomics features analysis can provide new imaging markers for the differentiation of maxillofacial sarcoma and lymphoma. Therefore, first-order ADC features of ADCkurt combined ADCskew may improve the diagnosis level.


Assuntos
Linfoma , Sarcoma , Imagem de Difusão por Ressonância Magnética , Humanos , Linfoma/diagnóstico por imagem , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Sarcoma/diagnóstico por imagem
16.
Drug Deliv ; 28(1): 2011-2023, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34569888

RESUMO

In the present study, we describe the development of betaxolol hydrochloride and montmorillonite with ion exchange in a single formulation to create a novel micro-interactive dual-functioning sustained-release delivery system (MIDFDS) for the treatment of glaucoma. Betaxolol hydrochloride molecule was loaded onto the montmorillonite by ion exchange and MIDFDS formation was confirmed by XPS data. MIDFDS showed similar physicochemical properties to those of Betoptic, such as particle size, pH, osmotic pressure, and rheological properties. Nevertheless, the microdialysis and intraocular pressure test revealed better in vivo performance of MIDFDS, such as pharmacokinetics and pharmacodynamics. With regards to wettability, MIDFDS had a larger contact angle (54.66 ± 5.35°) than Betoptic (36.68 ± 1.77°), enabling the MIDFDS (2.93 s) to spread slower on the cornea than Betoptic (2.50 s). Moderate spreading behavior and oppositely charged electrostatic micro-interactions had a comprehensive influence on micro-interactions with the tear film residue, resulting in a longer precorneal retention time. Furthermore, MIDFDS had a significant sustained-release effect, with complete release near the cornea. The dual-functioning sustained-release carrier together with prolonged pre-corneal retention time (80 min) provided sufficiently high drug concentrations in the aqueous humor to achieve a more stable and long-term IOP reduction for 10 h. In addition, cytotoxicity and hemolysis tests showed that MIDFDS had better biocompatibility than Betoptic. The dual-functioning microspheres presented in this study provide the possibility for improved compliance due to low cytotoxicity and hemolysis, which suggests promising clinical implications.

17.
BMC Biotechnol ; 21(1): 54, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34544395

RESUMO

BACKGROUND: With the emergence of CRISPR/Cas9 technology, multiple gene editing procedures became available for the silkworm. Although binary transgene-based methods have been widely used to generate mutants, delivery of the CRISPR/Cas9 system via DNA-free ribonucleoproteins offers several advantages. However, the T7 promoter that is widely used in the ribonucleoprotein-based method for production of sgRNAs in vitro requires a 5' GG motif for efficient initiation. The resulting transcripts bear a 5' GG motif, which significantly constrains the number of targetable sites in the silkworm genome. RESULTS: In this study, we used the T7 promoter to add two supernumerary G residues to the 5' end of conventional (perfectly matched) 20-nucleotide sgRNA targeting sequences. We then asked if sgRNAs with this structure can generate mutations even if the genomic target does not contain corresponding GG residues. As expected, 5' GG mismatches depress the mutagenic activity of sgRNAs, and a single 5' G mismatch has a relatively minor effect. However, tests involving six sgRNAs targeting two genes show that the mismatches do not eliminate mutagenesis in vivo, and the efficiencies remain at useable levels. One sgRNA with a 5' GG mismatch at its target performed mutagenesis more efficiently than a conventional sgRNA with 5' matched GG residues at a second target within the same gene. Mutations generated by sgRNAs with 5' GG mismatches are also heritable. We successfully obtained null mutants with detectable phenotypes from sib-mated mosaics after one generation. CONCLUSIONS: In summary, our method improves the utility and flexibility of the ribonucleoprotein-based CRISPR/Cas9 system in silkworm.

18.
Virus Res ; 306: 198566, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34582833

RESUMO

Coronavirus disease 2019 (COVID-19), caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first reported in Wuhan, China, and rapidly spread throughout the world. This newly emerging pathogen is highly transmittable and can cause fatal disease. More than 35 million cases have been confirmed, with a fatality rate of about 2.9% to October 9, 2020. However, the original and intermediate hosts of SARS-CoV-2 remain unknown. Here, 3160 poultry samples collected from 14 provinces of China between September and December 2019 were tested for SARS-CoV-2 infection. All the samples were SARS-CoV-2 negative, but 593 avian coronaviruses were detected, including 485 avian infectious bronchitis viruses, 72 duck coronaviruses, and 36 pigeon coronaviruses, with positivity rates of 15.35%, 2.28%, and 1.14%, respectively. Our surveillance demonstrates the diversity of avian coronaviruses in China, with higher prevalence rates in some regions. Furthermore, the possibility that SARS-CoV-2 originated from a known avian-origin coronavirus can be preliminarily ruled out. More surveillance of and research into avian coronaviruses are required to better understand the diversity, distribution, cross-species transmission, and clinical significance of these viruses.

19.
Animals (Basel) ; 11(7)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34359193

RESUMO

The circadian rhythm of gut microbiota is an important biological rhythm that plays a crucial role in host health. However, few studies have determined the associations between the circadian rhythm and gut microbiota in laying hens. The present experiment investigated the circadian rhythm of fecal microbiota in laying hens. Feces samples were collected from 10 laying hens at nine different time points (06:00-12:00-18:00-00:00-06:00-12:00-18:00-00:00-06:00) to demonstrate the circadian rhythm of fecal microbiota. The results showed that the α and ß diversity of the fecal microbiota fluctuated significantly at different time points. Beta nearest taxon index analysis suggested that assembly strategies of the abundant and rare amplicon sequence variant (ASV) sub-communities were different. Abundant ASVs preferred dispersal limitation (weak selection), and rare ASVs were randomly formed due to the "non-dominant" fractions. Highly robust fluctuations of fecal microbiota at the phylum level were found. For example, Firmicutes and Proteobacteria fluctuated inversely to each other, but the total ratio remained in a dynamic balance over 48 h. We identified that temporal dynamic changes had a significant effect on the relative abundance of the important bacteria in the feces microbial community using the random forest algorithm. Eight bacteria, Ruminococcus gnavus, Faecalibacterium, Ruminococcaceae, Enterococcus cecorum, Lachnospiraceae, Clostridium, Clostridiales, and Megamonas, showed significant changes over time. One unexpected finding was the fact that these eight bacteria belong to Firmicutes. The pathways showed significant fluctuation, including xenobiotic biodegradation and metabolism, carbohydrate metabolism, and amino acid metabolism, which were consistent with the metabolic functions of amino acids and carbohydrates from the feed. This study showed that the defecation time may be an important factor in the diversity, proportion, and functions of the feces microbial community. However, there was no circadian rhythm of microbial community assembly confirmed by JTK_Cycle analysis. These results might suggest there was no obvious circadian rhythm of fecal microbiota in laying hens under common light.

20.
J Cell Physiol ; 2021 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-34459512

RESUMO

Acetaminophen (APAP)-induced acute liver injury (AILI) is the most frequent cause of acute liver failure in developed countries. Trimethylamine N-oxide (TMAO) is a metabolite derived from the gut microbiota and is relatively high in the circulation of the elderly, individuals with diabetes, and heart disease. Herein, we showed that TMAO exacerbates APAP hepatotoxicity. It is possible that delayed liver repair and regeneration that resulted from reduced macrophage accumulation was responsible for this combined hepatotoxicity. Moreover, matrix metalloproteinase 12 (Mmp12), expressed predominantly by macrophages, were reduced by TMAO in vitro and in vivo. This led to the inhibition of macrophage migration and a subsequent decrease in the recruitment of proresolving macrophages to the necrosis area. Furthermore, the administration of recombinant Mmp12 mitigated the enhanced hepatotoxicity in mice cotreated with TMAO and APAP. Overall, this study indicates that TMAO exacerbates APAP-induced hepatotoxicity by hindering macrophage-mediated liver repair, which might stem from the inhibition of Mmp12. These findings imply that liver damage in patients with high levels of circulating TMAO may be more severe in AILI and should exercise caution when treating with NAC.

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